Enzymatic dihydroxylation of aromatics in enantioselective synthesis: Expanding asymmetric methodology

Abstract

Cited By (since 1996): 212

Full text

Volume 32, Number 2, 1999
Enzymatic Dihydroxylation of Aromatics in Enantioselective
Synthesis: Expanding Asymmetric Methodology
®ALDRICH®
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Both the solution- and solid-phase
synthesis of guanidines have been
accomplished with this reagent.1-3
(1) Wu, Y. et al. Synth. Commun. 1993, 23, 3055.
(2) An, H. et al. Tetrahedron 1998, 54, 3999.
(3) Robinson, S.; Roskamp, E.J. ibid. 1997, 53, 6697.
43,416-7 N,N´-Bis(tert-butoxycarbonyl)-1H-pyrazole-1-carbox-
amidine, 98%
A variety of highly functional bipyridines,
useful as organometallic ligands, have been
prepared from these compounds. The methyl
groups can be easily oxidized to the acid1or
converted to the bromomethyl derivatives.2,3
A number of alkenyl-substituted bipyridines
have been prepared from the dicarboxalde-
hyde.4,5
(1) Odobel, F. et al. Tetrahedron Lett. 1998, 39, 3689.
(2) Schubert, U.S. et al. ibid. 1998, 39, 8643. (3) Ebmeyer,
F.; Voegtle, F Chem. Ber. 1989, 122, 1725. (4) Kocian, O.
et al. Tetrahedron Lett. 1990, 31, 5069. (5) Della, C. et al.
J. Heterocycl. Chem. 1990, 27, 163.
51,304-0 5,5´-Dimethyl-2,2´-dipyridyl, 98%
49,636-7 6,6´-Dimethyl-2,2´-dipyridyl, 98%
47,466-5 2,2´-Bipyridine-4,4´-dicarboxaldehyde, 95%
This peptide coupling agent is a stable
crystalline solid, and is suitable for both
solution- and solid-phase synthesis. No
additives are needed to prevent racemiza-
tion when using this reagent.
Fan, C-X. et al. Synth. Commun. 1996, 26, 1455.
49,596-4 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-
one, 98%
This diene has been reported to be significantly
more reactive than Danishefsky's diene
(1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene).
Kozmin, S.A.; Rawal, V.H. J. Org. Chem. 1997, 62, 5252.
49,595-6 trans-3-(tert-Butyldimethylsilyloxy)-N,N-dimethyl-1,3-
butadien-1-amine, 90%
A variety of 2,2':6',2''-terpyridines can be
prepared from this reagent.
Jameson, D. L.; Guise, L. E. Tetrahedron Lett. 1991, 32,
1999.
51,167-6 3-(Dimethylamino)-1-(2-pyridyl)-2-propen-1-
one, 95%
Glycosyl fluorides are
widely utilized inter-
mediates for C-, O-, N-,
or S-glycosylations.1,2
(1) Drew, K. N.; Gross, P. H.
J. Org. Chem. 1991, 56, 509.
(2) Jegou, A. et al. Tetrahedron 1998, 54, 14779.
51,054-8 β-D-Glucopyranosyl fluoride tetraacetate, 97%
51,172-2 2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl fluoride,
97%, predominantly α
Monomers for the synthesis of azo-aromatic
photoconductive polymers have been prepared
from this compound.1-3
(1) Ho, M.S. et al. Macromolecules 1996, 29, 4613.
(2) Toru, Y.; Tokuji, M. J. Phys. Chem. 1995, 99, 16047.
(3) Zhao, C. et al. Chem. Mater. 1995, 7, 1237.
47,974-8 9H-Carbazole-9-ethanol, 97%
This carbonate resin is used to bind amines or amino acids as ure-
thanes. Dipeptides and hydantoins have been prepared from these
polymer-bound urethanes.1-3
(1) Dixit, D.M.; Leznoff, C.C. J.
Chem. Soc., Chem. Commun. 1977,
798. (2) Dressman, B.A. et al.
Tetrahedron Lett. 1996, 37, 937.
(3) Gouilleux, L. et al. ibid. 1996,
37, 7031.
49,483-6 4-Nitrophenyl carbonate, polymer-bound
Solid-phase synthesis of peptides and
peptidomimetics has been accom-
plished using polymer-bound
carbonylimidazole. Carbamates are
formed by reaction with unprotected
amines. The carbamates are cleaved using trifluoroacetic acid.1,2
(1) Hauske, J.R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589. (2) Rotella, D.P. J. Am. Chem.
Soc. 1996, 118, 12246.
49,823-8 Carbonylimidazole, polymer-bound
Solid-phase synthesis of β-peptoids
using the Wang acrylate resin has
been accomplished through Michael
addition of amines. The peptoids are
formed by further reaction of the
resulting β-amine with acryloyl chloride followed by Michael
addition of another amine. The peptoid is cleaved from the resin with
trifluoroacetic acid.
Hamper, B.C. et al. J. Org. Chem. 1998, 63, 708.
51,017-3 Wang acrylate resin
ONN
H
ON
N
O
O
NN
NN
NN
CHO CHO
51,304-0
49,636-7
47,466-5
NN
N
O
OP
O
(OEt)2
TBSO
NMe2
N
O
NMe2
AcO O
H
H
AcO
H
H
OAc
HF
OAc
BnO O
H
H
BnO
H
F
OBn
HH
OBn
N
OH
OO NO
2
O
ON
O
N
O
O
O
51,054-8 51,172-2
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bis(phenylazo)stilbene. This compound
functions as an azolium 1,3-dipole and is
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azines.
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Ph NN
NNPhPh
Ph
Solid
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-N Ph
Ph
Solution
51,578-7 α,β-Bis(phenylazo)stilbene,
mixture of isomers
Vol. 32, No. 2, 1999 33
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Reagents in the
Laboratory
A
dvances in organometallic chemistry in the
last few decades have brought pyrophoric
and moisture-sensitive reagents, especially
those of organolithium and aluminum, into com-
mon usage in organic chemistry laboratories.
The commercial availability and high selectivity
of these reagents have made them indispens-
able in the modern chemistry laboratory, despite
their highly reactive nature and the risks
associated with their handling. In laboratory
settings, these reagents are most conveniently
transferred from commercial containers to reac-
tion vessels by using either a syringe–needle
combination or cannulation techniques,1,2 without
resorting to the use of a glove box or the Schlenk
line of dedicated glassware.3,4
However, it is almost inevitable that small
amounts of the pyrophoric liquid being trans-
ferred, e.g.,
t
-BuLi solutions and Me3Al, are
exposed to the atmosphere on the tip of the
needle or cannula, often causing sparks or small
fires. While in most cases the fire is localized
and burns out quickly, it always makes one
apprehensive, considering the possibility that the
sparks or fire may spread to other flammable
materials abundant in organic chemistry labora-
tories. A simple device and a procedure to
minimize such risks are described here.
A piece of glass tubing of approximately 6
mm ID and 4 cm in length is capped with rubber
septa at both ends and the septa secured with
copper wires. This tube is purged with inert gas
and serves to protect the needle tip from being
exposed to air. When withdrawing air-sensitive
reagents, the needle is allowed to protrude
through both septa and into the reservoir
(
Figure 1
). Once the desired amount of reagent
is removed, the tip of the needle or cannula is
withdrawn from the reservoir and slid into the
glass tubing filled with inert atmosphere, while
the lower septum is kept in close contact with the
cap of the reservoir to minimize exposure by
the needle tip to the air during the process.
The syringe or cannula is then safely
transported (
Figure 2
) to the reaction flask and
the sequence reversed to dispense the reagent
(
Figure 3
). After the transfer is finished, the
same procedure is followed to withdraw inert
solvent to rinse the residual reagent from the
syringe needle or cannula or to effect final
quenching and cleaning. This simple device has
virtually eliminated sparks associated with the
transfer of pyrophoric reagents in the author's
laboratory.
References:
(1) Kramer, G. W.; Levy, A. B.; Midland, M. M. In
Organic Syntheses via Boranes
; Brown, H.C., Ed.;
Wiley–Interscience: New York, NY, 1975. (2) Lane, C. F.; Kramer,
G. W.
Aldrichimica Acta
1977
,
10
, 11. (3) Capka, M.
Chem. Listy
1973
,
67
, 1104. (4) Shriver, D. F.
The Manipulation of Air-
Sensitive Compounds
; McGraw–Hill: New York, NY, 1969.
Tony Y. Zhang
, Ph.D.
Research Scientist
Lilly Research Laboratories
Lilly Corporate Center
Indianapolis, IN 46285-4813
E-mail: zhang@lilly.com
Maintaining a Constant
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n our laboratories, we are required, for safety
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). This greatly reduces the evap-
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For example, we have heated in this way a 12-L
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34 Vol. 32, No. 2, 1999

1. Introduction
Studies of the microbial oxidation of
aromatic hydrocarbons by soil bacteria led, in
1968, to the isolation of the first stable
cis-cyclohexadienediol, 2(eq 1).1Twenty-
seven years later, Motherwell and Williams2
reported the chemical equivalent of this
reaction in their synthesis of racemic
conduritol E (4) (eq 2).
Prior to 1983, the cis-cyclohexadienediols
produced by bacteria elicited little interest
from synthetic chemists in industry and
academia. In that year, however, chemists
from Imperial Chemical Industries in England
reported the use of the biocatalytically
generated meso-cis-diol 5—derived from
benzene—as a monomer for the synthesis
of polyphenylene (6) on an industrial scale
(eq 3).3,4
In the late eighties, an expansion of the use
of these diols in synthetic ventures took place,
and the meso-cis-diol 5served as the starting
material for many of the early syntheses. The
first academic disclosure was Ley´s synthesis
of racemic pinitol (7) in 1987 (eq 4),5and this
milestone was followed by many applications
reported by several groups worldwide.6
The synthetic achievements in this area
have been reviewed previously on several
occasions.7-18 This review will focus on select-
ed synthetic applications and the categories of
reactions that can be used to exploit the array
of functionalities available in the general struc-
ture 8. The drawing represents the three major
classes of aromatics: single-ring, fused, and
biphenyls. For all such substrates, there have
evolved the corresponding enzymes of slightly
different topologies: toluene, naphthalene, and
biphenyl dioxygenases. A recently published
review18 lists most of the diols for which
accurate characterization data ([α]D, ee) are
available. In this review, Boyd advances the
idea of directing effects for the oxidation, as
depicted in 9, to explain the remarkable regio-
and enantioselectivity of the dioxygenases.
eq 1
eq 2
Enzymatic Dihydroxylation of Aromatics in
Enantioselective Synthesis: Expanding
Asymmetric Methodology†
Tomas Hudlicky,#,* David Gonzalez,#and David T. Gibson†
#Department of Chemistry, University of Florida,
Gainesville, FL 32611-7200, USA
†Department of Microbiology and Center for Biocatalysis and Bioprocessing,
University of Iowa, Iowa City, IA 52242, USA
E-mail: hudlicky@chem.ufl.edu
Vol. 32, No. 2, 1999 35

Some of the reactive modes that are
possible with these diols have already been
reduced to practice, some are self-evident
from the analysis of the reactive manifolds,
and some undoubtedly await discovery.
Most of the synthetic accomplishments
originate in the use of only a few of the
hundreds of diol metabolites isolated to
date, and we include, at the end of
this review, the full listing of diol
metabolites known as of this writing
(see Tables 1-5).
Such a list of actual structures before
the eyes of a synthetic chemist should
stimulate new thinking and the development
of more complex strategies for advanced
synthetic applications. Thus, this particular
treatise contains, in addition to a historical
overview, three areas of focus: production of
metabolites, rationale for synthetic design,
and applications according to the reaction
type. The authors hope that this area will
continue to expand, and that new and
imaginative synthetic ventures from
existing, as well as newly discovered,
metabolites will be forthcoming.
2. Historical Perspective
In 1968, a strain of Pseudomonas putida
(now designated as strain Fl), which grew with
ethylbenzene as the sole source of carbon and
energy, was isolated.19 The organism also
grew on benzene and toluene, and
initial oxidation studies were conducted with
toluene-grown cells. Oxygen uptake experi-
ments showed that P. putida Fl rapidly oxi-
dized benzene (3), cis-l,2-dihydroxycyclo-
hexa-3,5-diene (cis-dihydrobenzenediol) (5),
and catechol (10).19 trans-Dihydrobenzene-
diol, the product of oxidative metabolism in
mammalian systems,20 was not oxidized.
Toluene-grown cells did not accumulate
detectable amounts of cis-dihydrobenzene-
diol, and evidence for its formation from
benzene was provided by isotope experiments
with cell extracts. The same cell extracts
oxidized synthetic cis-dihydrobenzenediol to
catechol (10) when NAD+was provided as an
electron acceptor (eq 5).
The oxidation of fluorobenzene,
chlorobenzene, bromobenzene, and iodo-
benzene by toluene-grown cells led to the
formation of their respective 3-halogenated
catechols which were resistant to further
oxidation. The major product formed from
p-chlorotoluene (1) was identified as
4-chloro-2,3-dihydroxy-l-methylbenzene
(11), and extraction of 25 liters of a culture
filtrate yielded 38 mg of (+)-cis-4-chloro-2,3-
dihydroxy-1-methylcyclohexa-4,6-diene (2),
the first stable cis-cyclohexadienediol.1A
cis-diol dehydrogenase in the cell extracts
oxidized 2to 11 (eq 6).1
Subsequent studies led to the isolation of a
mutant strain of P. putida Fl (strain 39/D, now
designated F39/D) that was devoid of cis-diol
dehydrogenase activity. Benzene-induced
cells of strain F39/D oxidized benzene to
cis-dihydrobenzenediol. Experiments with
18O2showed that both oxygen atoms in the
dihydrodiol were derived from dioxygen,21
stimulating initial thoughts that the intermedi-
ate in the transformation might be a dioxetane.
Such an intermediate is unlikely to be formed
from triplet oxygen species, however.
P. putida F39/D oxidized toluene (12) to
enantiomerically pure cis-(1S,2R)-dihydroxy-
3-methylcyclohexa-3,5-diene (13) (eq 7).22,23
Other substrates oxidized to cis-dihydrodiols
by strain F39/D were ethylbenzene,24,25 p-fluoro-
toluene,25 p-chlorotoluene,25 p-bromotoluene,25
chlorobenzene,25 p-xylene,26 and 3-methyl-
cyclohexene.27
The identification of cis-dihydrodiols as
intermediates in the degradation of benzene,
toluene, and ethylbenzene led to studies of the
reactions used by bacteria to initiate the degra-
dation of aromatic hydrocarbons containing
fused aromatic rings. Prior to 1971, it was
generally believed that bacteria oxidize
eq 3 & 4
eq 5
eq 6
eq 7
eq 8
eq 9
36 Vol. 32, No. 2, 1999

naphthalene to trans-1,2-dihydroxy-1,2-dihy-
dronaphthalene (trans-dihydronaphthalene-
diol).28 However, the techniques used at that
time did not differentiate between cis and trans
isomers and a mutant strain of Pseudomonas
putida (strain 119) was isolated that oxidized
naphthalene (14) to cis-(1R,2S)-dihydroxy-1,2-
dihydronaphthalene (15) (cis-dihydronaph-
thalenediol) (eq 8).29,30 Both oxygen atoms in
the cis-dihydrodiol were derived from a single
molecule of dioxygen.30
Interest in the biodegradation of poly-
chlorinated biphenyls led to the isolation of a
Beijerinckia species strain B131 (now named
Sphingomonas yanoikuyae strain B1)32 that
would grow with biphenyl (16) as the sole
source of carbon. A mutant strain of this organ-
ism (strain B8/36) oxidized biphenyl to
cis-(1S,2R)-dihydroxy-3-phenylcyclohexa-
3,5-diene (17) (cis-dihydrobiphenyldiol)
(eq 9).31 Strain B8/36 oxidized anthracene and
phenanthrene to cis-(1R,2S)-dihydroxy-1,2-
dihydroanthracene and cis-(3S,4R)-dihydroxy-
3,4-dihydrophenanthrene, respectively.33,34 The
major products formed from benzo[a]pyrene
[BP] and benzo[a]anthracene [BA] were cis-
9,10-dihydroxy-9,10-dihydro-BP and cis-1,2-
dihydroxy-1,2-dihydro-BA, respectively.35 In
subsequent experiments, it was shown that S.
yanoikuyae B8/36 oxidizes BA to cis-1,2-, cis-
5,6-, cis-8,9-, and cis-10,11-dihydrodiols.
With the exception of the 5,6-dihydrodiol,
which was formed in trace quantities, the cis-
dihydrodiols have an Rabsolute configuration
at the hydroxylated benzylic centers. More
recently, S. yanoikuyae B8/36 has been report-
ed to oxidize chrysene to cis-(3S,4R)-dihy-
droxy-3,4-dihydrochrysene.36
Although cis-cyclohexadienediols are
common intermediates in the bacterial oxida-
tion of aromatic hydrocarbons, they are not
formed exclusively from this class of
compounds. In 1971, Reiner and Hegeman
isolated a mutant strain of Alcaligenes
eutrophus (strain B9) that oxidized benzoic
acid (18) to (–)-cis-cyclohexadiene-l,2-diol-1-
carboxylic acid (19) (eq 10).37
Subsequent studies by Reineke and
colleagues showed that A. eutrophus strain B9
and Pseudomonas sp. strain B13 oxidize a
variety of halogenated and methyl-substituted
benzoic acids to cis-diol carboxylic acids.38,39 In
contrast to "ipso" dioxygenation, other
Pseudomonas strains oxidize substituted
benzoates to dihydrodiols, as Ribbons has
shown in the case of the oxidation of cumic
acid (20) to 2,3-dihydroxy-4-isopropylcyclo-
hexa-4,6-dienoic acid (21) (eq 11).40,41 (Note
that the stereochemistry of the diol is the
opposite of that in 2with respect to the alkyl
substituent.) Recently, the absolute stereo-
chemistry and the reactive tendencies of the
cis-diol 21 have been reported.42
It is evident from the tables at the end of
this review that some element of predictability
exists with respect to the regio- and stereo-
chemical outcome of the enzymatic dioxy-
genation of aromatic compounds. It should be
noted that the trends in oxidation patterns
(specificities) are unique and sometimes
complementary for individual oxygenases.43
These aspects, combined with the description
of experimental needs in the next section,
allow the nonspecialist access to this technol-
ogy in order to enhance the art of asymmetric
synthesis.
3. Whole-Cell Oxidation of
Aromatics—Diol Formation
Several reviews are available in the area of
microbial degradation of aromatic com-
pounds44-46 and these should be consulted
by the nonspecialist before he/she begins
preparative biotransformations.
Most of our current knowledge of the
products formed by toluene (TDO), naphtha-
lene (NDO), and biphenyl (BPDO) dioxy-
genases has been obtained with mutants that
do not express their respective cis-dihydrodiol
dehydrogenases. A laboratory procedure for
the oxidation of chlorobenzene to 1-chloro-
(2S,3S)-dihydroxycyclohexa-4,6-diene by
P. putida F39/D has been described.47 In
practice, this procedure can be used for other
volatile substrates. Solid substrates such as
naphthalene and biphenyl can be added direct-
ly to the culture flask. Under these conditions,
the aromatic hydrocarbons induce the synthe-
sis of their respective dioxygenases. The
induced cells can be harvested, resuspended in
a mineral salts medium or buffer, and exam-
ined for their ability to oxidize different
substrates. In such cases, pyruvate is usually
added to provide the NADH necessary for the
dioxygenase reaction. Constitutive mutants,
such as P. putida UV4,3do not require an
inducer, since the dioxygenase is present
under all growth conditions.
Inducers are not always the substrates used
for the isolation of the wild type strains. For
example, salicylate and anthranilate induce
the synthesis of NDO in Pseudomonas sp.
NCIB 9816,48 and m-xylene induces BPDO in
Sphingomonas yanoikuyae B8/36.49 Care
must be taken in the interpretation of results
provided by blocked mutants, since other
enzymes may be present that can affect the
final distribution and stereochemistry of the
isolated products.50,51 In addition, it is advis-
able to examine each mutant for reversion to
the wild type strain. For example, P. putida
119, the strain first used to isolate cis-dihy-
dronaphthalenediol,29 produced revertants
when the cells reached the stationary growth
phase. This was accompanied by the rapid
disappearance of cis-dihydronaphthalenediol
from the culture medium.52 The subsequent
use of the stable dihydrodiol dehydrogenase
mutant Pseudomonas sp. 9816/11 alleviated
this problem.53
The genes encoding TDO,54 NDO,55 and
BPDO56 have been cloned and expressed in
Escherichia coli. There are several advantages
to using recombinant strains for the produc-
tion of cis-dihydrodiols. These include the
control of dioxygenase synthesis by the iso-
propyl-β-D-thiogalactoside (IPTG)-inducible
promoters, the use of multicopy plasmids for
the synthesis of increased amounts of enzyme,
and the use of vector controls to identify host
background activity. A major drawback often
encountered in the synthesis of large amounts
of proteins by recombinant strains is the pro-
duction of the desired enzyme in the form of
inactive inclusion bodies. One way to mini-
mize the formation of inclusion bodies is to
lower the temperature of the culture at the start
of dioxygenase synthesis.
TDO, NDO, and BPDO are related multi-
component enzyme systems with overlapping
substrate specificities. Each system uses a short
electron transport chain to transfer electrons
from NAD(P)H to their oxygenase components
that consist of dissimilar (αβ) subunits.57 The
dioxygenation reaction is believed to occur at a
mononuclear iron site in the αsubunit. This is
supported by recent X-ray structural data on the
NDO oxygenase component;58 however, the
precise mechanism of dioxygenation, which
involves the highly endothermic disruption of
aromaticity, is unknown. The components of
the TDO, NDO, and BPDO oxygenase systems
have been purified and used in substrate speci-
ficity studies. Although such experiments are
time-consuming and labor-intensive, they pro-
vide unequivocal evidence for the identification
of the initial oxidation products formed from
specific substrates. They have been particularly
useful in demonstrating that NDO can catalyze
monohydroxylation, desaturation (dehy-
drogenation), O- and N-dealkylation, and
sulfoxidation reactions.43
eq 10 & 11
Vol. 32, No. 2, 1999 37

The discovery of the enzymatic
asymmetric dihydroxylation of aromatic
compounds by toluene, naphthalene, and
biphenyl dioxygenases, and the availability of
mutant and recombinant bacterial strains that
express these enzymes, provided the commu-
nity of organic chemists with the opportunity
to use these biocatalysts in the preparation of
useful synthetic intermediates. The following
discussion aids the chemist not yet acquainted
with these powerful tools.
There are generally two types of bacteria
that are used to oxidize aromatic compounds
to cis-cyclohexadienediols. From the point of
view of a nonspecialist, the following
narrative reiterates the principles mentioned
above and should serve as a guide to those
wishing to learn the technique. The organisms
most commonly used are mutants of the wild
type strain that have lost the ability to dehy-
drogenate cis-diols and recombinant strains of
Escherichia coli that contain the cloned dioxy-
genase genes. Consequently, there are two
procedures to be followed in terms of utilizing
these organisms to produce cis-cyclohexadi-
enediols. Both procedures can be easily
performed with minimal skills in microbiology.
The first procedure involves the use of
blocked mutants in which the enzyme synthe-
sis must be induced by a known aromatic
inducer (for P. putida F39/D this might be
toluene, chlorobenzene, bromobenzene, or
several other monocyclic aromatic
compounds). If the inducer is also the
substrate to be converted to a cis-cyclohexadi-
enediol, the procedure is simple. The mutant
is grown in a mineral salts medium, which
provides the requisite inorganic elements
(N, P, Mg, Fe, etc.), and an organic substrate
that does not repress the synthesis of the
dioxygenase (usually pyruvate or glucose).
The aromatic compound can usually be added
at the start of the growth. The accumulation of
cis-cyclohexadienediol is monitored spectro-
photometrically until the biotransformation
ceases. Variations of this procedure are used
when the substrate does not induce dioxyge-
nase synthesis. The mutant is grown in a
mineral salts medium with pyruvate or
glucose in the presence of an inducing
substrate as described above. Following the
induction period, a new substrate is added,
which, if recognized by the enzyme, is
oxidized to the corresponding diol. The final
fermentation broth contains the metabolites
derived from the inducer and the substrate;
thus, such a process necessitates a separation.
Alternatively, the cells may be separated from
the broth after induction and resuspended in a
fresh medium before addition of the second
substrate. The bacterial cells are then removed
and the clear supernatant extracted with
acid-free ethyl acetate.
22 23
n ee (%)202
1 20 – 28
2 >98
3 >98
n ee (%)
65
1 85
2 >98
3 >98
OH
OH
(CH2)n(CH2)n
OH
OH
(CH2)n
24
NDO TDO
n = 1, 2, 3
Figure 1. Antipodal specificity of toluene and naphthalene dioxygenases.
Figure 2. Local bond-forming sites in the cis-dienediols.
25 directing, hindering,
or tethering groups
polarized diene or electronically differentiated olefins
element of
polarization
and asymmetry
for 1,3-diene
six options for oxidative cleavage, a-f
(-) - space
(+) - space
proenantiotopic
plane of symmetry
OH
OH
X
a
b
c
d
e
f
Figure 3. Global elements for stereomanipulation and enantiodivergence in the
cis-dienediols [(+) and (–) space are assigned arbitrarily].
eq 12
eq 13
38 Vol. 32, No. 2, 1999

The second procedure is slightly more
complex to execute, but leads to potentially
higher cell and product yields, and is ideal for
testing new compounds as substrates for
oxidation. It relies on the use of a recom-
binant organism in which transcription of the
genes encoding the dioxygenase is initiated by
exposure to a known nonaromatic inducer, in
most cases isopropyl-β-D-thiogalactoside
(IPTG). The cells are allowed to grow and
synthesize the dioxygenase before the intro-
duction of the substrate to be oxidized.
Separation problems are avoided, but the
procedure requires the use of a fermentor with
carefully regulated oxygen levels, tempera-
ture, pH, CO2release, and nutrient/substrate
feeds. Quite recently, an attempt has been
made to transfer the genes encoding TDO
from E. coli JM109 (pDTG601) to yeast cells59
by a procedure successfully implemented by
Stewart for cyclohexanone monooxygenase
from Acinetobacter.60 This particular enzyme
has been successfully used in both isolated
and whole-cell fermentations, with applica-
tions in organic synthesis by Furstoss,61
Taschner,62 and Stewart.60 If the genetic infor-
mation for the biosynthesis of the more
complex dioxygenase enzyme systems can be
transferred to yeast also, it will no doubt
greatly enhance the attractiveness of this
methodology to the traditionally trained
synthetic practitioner.
The diols produced from aromatic
substrates vary in stability and are usually
isolated by extraction. They are then crystal-
lized and stored at low temperature. They are
more stable as free diols than in the protected
forms (see section on cycloadditions). For
shipping or long-term storage, it is best to
store them as frozen suspensions in pH 8.5
phosphate buffer. So far, with very few excep-
tions, they are produced with the absolute
stereochemistry as shown, and, in most cases,
absolute enantiomeric purity— except for the
diol derived from fluorobenzene,63 the meso-
diols originating from symmetrical substrates,
and diols from several more highly substituted
aromatic rings. As noted earlier, the
enantiomeric specificities of individual dioxy-
genases are often unique and in some cases
complementary; thus, both enantiomers of
certain oxidation products can be accessed
through the use of different oxygenase
systems.43 For example, naphthalene dioxy-
genase and toluene dioxygenase oxidize some
hydrocarbons related to indene to the antipo-
dal cis-diols, albeit in diverse enantiopurities
(Figure 1). However, recent studies have
identified organisms capable of generating
several enantiopure cis-diols of opposite
chirality to that of previously identified
metabolites. It has been shown that a
carbazole-utilizing strain oxidizes biphenyl,
biphenylene, and 9-fluorenone to previously
unobserved cis-diol enantiomers.64 Thus, both
enantiomers of several cis-diols can be gener-
ated through either subsequent chemical
conversion of the diols,65 enantioselective
enzymatic resolution,66 symmetry-driven
design,67,68 or the use of strains expressing
dioxygenases with different specificities as
mentioned above.
4. Synthetic Design Rationale
cis-Dihydroarenediols of the general
structure 25, and their acetonides 26 contain
an amazing combination of mutually
intertwined functionalities and, therefore,
many possibilities for further use. The intel-
lectual analysis of these possibilities can be
summarized in two separate ways: f irst, vari-
ous "local" bond-forming reactions as divided
by class and shown in Figure 2; second, the
"global" implications that address the
enantio-, stereo-, and regioselectivities that
can be expected from the manipulation of
these compounds (Figure 3).
The issues of enantioselectivity are
addressed by manipulating the order of reac-
tions to a given target in such a manner as to
elaborate specifically only one terminus (or
apex) of the cyclohexadienediol, with the
crucial enantiodifferentiation step performed
in either "D" or "L" space in relation to the
final absolute stereochemistry of the target
(note: +/- and D/L are arbitrarily assigned).
The appropriate "switch" is made following
the removal of the differentiating group X.
These strategies have already been elucidated
and described in several disclosures and need
not be discussed here.10,11,13-17,67,68
Another means by which enantiodiver-
gence is achieved was reported by Boyd.65 It
relies first on the directing effect of the larger
C-1 substituent in the enzymatic oxidation
step of 27, and, then, on the greater reactivity
of the iodine in the Pd/C hydrogenolysis of 28
as shown in eq 12. In this way, the enan-
tiomeric pair of diols 29 is obtained (eq 13).
The efficiency of this method relies on the
ability of the enzyme to completely
differentiate between the iodine and
bromine atoms in the aromatic substrate.
Unfortunately, 28 is obtained in very low opti-
cal purity, and this is translated into optically
impure 29. Boyd overcame this problem by
exposing the scalemic mixture of 29 to a
second fermentation step using a nonblocked
strain of Pseudomonas, which is able to
completely metabolize the undesired enan-
tiomer (in this case the (2S,3S)-(+)-enantiomer)
Figure 4. Enantiodivergence by lipase resolution.
Figure 5. Two approaches to the “diastereomeric switch”of diols.
Vol. 32, No. 2, 1999 39

leaving (–)-29 to accumulate. This approach
has the obvious disadvantage that a consider-
able amount of valuable (+)-29 has to be
created and then destroyed to attain the target.
A completely different approach to
enantiodifferentiation of the dienediol residue
was developed by Johnson.66 The meso-diol 5
was functionalized to the conduritol derivative
31, which was enzymatically resolved into
either of the enantiomers 32 or 33, as shown in
Figure 4, to allow for the enantio-
differentiation of the projected targets.
The issue of enantiodivergence is crucial to
the credibility of chemoenzymatic synthesis:
too frequently the traditionalists in the
synthetic organic community criticize the
use of enzymatic reactions, and justify the
rather inefficient chiral-auxiliary approach to
asymmetric synthesis by pointing out that ent-
enzymes are unavailable. The above result and
the symmetry-based approach13,14,67 clearly
rebuff such criticism.
Boyd69 has also addressed the "diastereo-
meric switch" between the cis diols and their
trans isomers. Boyd’s method for the
conversion of cis diols to the trans isomers is
accomplished as shown in Figure 5. In this
process, the reactive diene needs to be reduced
to the alkene to avoid aromatization during the
Mitsunobu inversion of the proximal hydroxyl
group. The diene is restored later by a bro-
mination–elimination process to furnish 35.
Independently, an alternative procedure for the
preparation of trans diols was reported (also
shown in Figure 5).70 In this case, the diene
system was "protected" by a reversible
Diels–Alder reaction with the active
dienophile, 4-phenyl-1,2,4-triazoline-3,5-
dione, and the inversion performed with 36 to
ultimately yield 37. Interestingly, these two
approaches become complementary, since
they do not involve the inversion of the same
stereocenter.
In addition, Boyd’s method has also been
successfully applied to the synthesis of 3,4-
diols such as 40 from o-iodobromobenzene
(eq 14). All combinations of enantio- and
diastereomeric ventures are now possible from
diol pairs 25/41 and 42/43 (Figure 6). The
latter pair corresponds to diols that would be
formed by the hydrolytic opening of arene
oxides of type 44, which are produced by the
action of more highly evolved eukaryotic
enzymes on aromatics.20,33 Thus, the issues
concerning the availability of metabolites in
both enantiomeric constitutions and the
approach to targets in both absolute
configurations are addressed.
The summary of all design principles
based on symmetry11,13,14,67,68 is offered by the
drawing in Figure 7. Diastereoselectivity
issues are controlled by either directing or
hindering effects of the biochemically
installed diol, whereas the regioselectivity of
the first functionalization is controlled by the
polarization of the diene system. This regio-
selectivity also determines the commitment to
a specific enantiomeric space, here arbitrarily
assigned as "+" for the "upper domain" and
"–" for the "lower domain". There are four
possibilities for the configuration of the next
chiral center to be constructed: syn or anti to
the diol in either "+" or "–" space as con-
figured in the enantiomer of the f inal product
(see projection in Figure 7). These operations
are relatively easy to control and lead to a fully
exhaustive design of a particular class of
compounds.11,13,14,67,68
There are a number of bond-forming reac-
tions possible from the multiple functionalities
of these types of compounds. The diene
undergoes a variety of regioselective [4+2]
cycloadditions, including its intramolecular
variants. Separate cycloaddition chemistry
can be initiated singly at the disubstituted
olefin. The presence of a polarized diene unit
allows for controlled interaction with
electrophilic reagents. The allylic alcohol
functionalities are amenable for use in
Claisen-type rearrangements, as was proposed
in the very first publication from our labora-
tory in 198871 and reduced to practice in
1997.72 Since every carbon atom in these mole-
cules is either unsaturated or oxygenated, the
preparation of polyoxygenated compounds,
such as cyclitols and carbohydrates, starting
from cis-dihydroarenediols, is convenient.
The logic of this design flows from these con-
siderations and is discussed in the following
sections. The oxidation of the periphery of the
dienediol and subsequent cleavage of any one
eq 14
Figure 6. Enantio- and diastereodifferentiation strategy.
OH
OH
OH
X
OH
prodiastereotopic plane
proenantiotopic plane
anti syn
syn
anti
Figure 7. The four complementary spaces for incipient transformations
present in diol topology.
40 Vol. 32, No. 2, 1999

of the six bonds provide access to acyclic
chains with defined stereochemistry, as in the
case of carbohydrates. Their carbon content is
addressed by the controlled oxidative loss of
either 0, 1, or 2 carbon atoms from the diene-
diol unit. The following section briefly out-
lines the diversity of chemical operations pos-
sible with cis-dihydroarenediols, and provides
examples of specific synthetic applications.
5. Applications to Synthesis
Peripheral oxidative functionalization of
dienediols yields the first level of synthons with
increased complexity, here shown as "primary
synthons" in Figure 8. The materials are then
further functionalized to "secondary synthons"
(Figure 9) before a decision is made with
regard to the cleavage of the cyclohexane ring.
The oxidative functionalization of acetonides
26, derived from 25, yields anti-epoxides 45,
diols 46, or aziridines 47. The unusual produc-
tion of chloroepoxide 48 seems to be the
consequence of 1,4-addition of KMnO4across
the polarized diene. Singlet oxygen and acyl-
nitroso compounds yield cyclic peroxides 49
and oxazines 50, the latter regiospecifically,
and both with the expected anti stereochem-
istry. Boronate esters73 and acetals derived from
benzaldehyde74 and other aldehydes75 have been
reported as protecting and directing groups,
although the most common protective group
remains the acetonide. The functionalization of
free diols has been limited to monoprotection
as in 51. In most instances (except for epoxi-
dation in the case of 52), the stereoselectivity in
the transformations of free diols is poor.
The details of these reactions can be found in
several reviews.7-11
These primary synthons can be manipulated
further into the secondary synthons shown in
Figure 9. The most common transformations
involve the removal of the halogen that directed
the primary functionalization to the more
electron-rich olefin and functioned to preserve
the asymmetry. Both primary and secondary
synthons (some of which are now commercial-
ly available) have been used primarily in cycli-
tol and sugar syntheses (see the corresponding
sections for examples).
The reactivity of the dienediols (free or pro-
tected) has been exploited in cycloadditions,
leading to C–C, C–O, or C–N bond
formation; peripheral oxidation; and further
functionalization, as well as partial or full
oxidative cleavage. The latter two aspects find
use in the general design of carbohydrates.
Interesting applications emerged from
Stephenson’s group.76,77 A derivative of the iron
complex 55 (Figure 9) undergoes nucleophilic
addition with sodium malonate, leading to
stereospecific C–C bond formation.77 The
epoxyaziridine 64 results from a rearrangement
of oxazines of type 50.78
5.1. Cycloadditions
cis-Cyclohexadienediols derived from mono-
cyclic aromatics are reactive towards cycload-
ditions; the halodienes (X= Cl, Br,I, F), where the
diene functionality is quite polarized, are espe-
cially reactive. In fact, acetonides 26 dimerize
readily, even at (or below) room temperature,79-81
although the free diols are reasonably stable in
the crystalline state. The acetonide of dihy-
drostyrenediol, 66, dimerizes to three different
Diels–Alder products82 with spectacular regio-
and stereoselectivity, as shown in Figure 10.
Figure 8. Examples of primary synthons.
Figure 9. Examples of secondary synthons.
Vol. 32, No. 2, 1999 41

The electronic parameters of cis-cyclo-
hexadienediols have been investigated both
experimentally79-87 and by calculations.83,87
Complete regioselectivity is expected for
cycloadditions with polarized dienophiles,
such as acylnitroso compounds. Other types
of cycloadditions also exhibit preference for
the more electron-rich olefin. These parame-
ters have been exploited in many cycloaddi-
tions, as indicated in Figure 11. The selectivi-
ty of cycloadditions of dienediols and their
derivatives, where X is not a halogen, is, as
expected, much lower. Cyclopropanation;88-92
ketene addition;93 benzyne cycloaddition;84-85
benzo- and naphthoquinone additions ([4+2]
and photo [2+2]);85 a variety of acrylate,87 pro-
piolate,87 and maleic anhydride85 Diels–Alder
additions; singlet-oxygen,68,71,83,94 and acylni-
troso cycloadditions68,78,83,87,95,96 have all been
exploited. The cis-diol derived from benzene
undergoes a photosensitized [2+2] cycloaddi-
tion to produce dimer 78 (Figure 11).97
The singlet-oxygen and acylnitroso cycloaddi-
tions have found applications in the synthesis
of conduritols and conduramines (see exam-
ples in the next section and in recent
reviews).8,10,11,13,18,98,99
Advanced intermediates with applications
in natural product synthesis have been
obtained by means of simple cycloaddition
processes. For example, the lower portion of
morphine, with all five contiguous stereogenic
centers, has been synthesized by the intra-
molecular Diels–Alder reaction from dihydro-
toluene- and β-azidoethyldihydrobenzenediols,
respectively. In the first model study, the
diene was partially reduced; this allowed the
remaining olefin to function as a dienophile
and lead to 82 (Figure 12). The more
advanced intermediate, 85, was similarly
synthesized from 83. With diene 86, the initial
cycloaddition produced 87, which underwent
a Cope rearrangement to furnish 88, possess-
ing the same skeleton as 82, albeit with a
different stereochemistry.100 Adduct 82 was
originally reported with the wrong stereochem-
istry;100 the correct stereochemical assignment101
was made in 1998 by X-ray analysis when dis-
crepancies were noted in the spectra of 82 and
85. The stereochemistry of 88 was obtained as
shown by a Diels–Alder/Cope sequence, but
the correlation of the two routes was not chem-
ically confirmed.100 Banwell has also applied
the tandem Diels–Alder/Cope sequence to the
synthesis of octalins 91,86 and later to interme-
diates such as 92, that are used in taxane
synthesis.74
5.2. Cyclitols, Conduritols,
Conduramines, Inositols, and
Derivatives
Conduritols A–F, as well as some of the
inositols—all shown in Figure 13—have been
synthesized from either epoxide 45 or 52,102
diol 46, or the singlet-oxygen adduct 49.
Because the details of their syntheses have
been reviewed in several instances,11,15,98,99 only
the generalized approaches are shown here.
The cis-dihydroarenediols, as well as the
primary synthons shown in Figure 8, are ide-
ally suited for the synthesis of this simple class
of cyclitols (Figure 14).68,103 Conduramines
become available by cleaving the nitrosyl
Diels–Alder adducts 50 to ketoamines 58 and
hydroxyamines 59, or by opening epoxides
with nitrogen nucleophiles to 54. Lipase
desymmetrization of meso conduramines has
been used by Johnson in enantiodivergent syn-
theses of conduramine A-1.104 All of the
sequences leading to cyclitols begin with the
protected cis diol 26 (X = Cl, Br), except the
conduritol C synthesis by Carless, which
employed the syn epoxide 52.102 Inositol
synthesis becomes possible by careful
peripheral oxidation of the dienediols.
Figure 10. Diels–Alder adducts of some dienediol acetonides.
Figure 11. Cycloadditions of some dienediols and their acetonides.
42 Vol. 32, No. 2, 1999

Following Ley’s pioneering preparation of
racemic 7,5a resolution using (–)-menthoxy-
acetyl chloride105 produced both enantiomers,
as shown in Figure 15. Hudlicky’s group
accomplished the enantiodivergent prepara-
tion of both pinitols (Figure 15) by employing
the symmetry principles discussed in the
previous section.67,68
In 1990, we reported two enantiodivergent
syntheses of (+)- and (–)-pinitol from optically
pure, protected diol 26 (Figure 15). The
concept of "proenantiotopic symmetry" was
first reported in connection with this
synthesis, whereby identical sets of reagents
were used in a different order to attain
enantiodivergence.67,68
Of the nine isomeric inositols portrayed in
Figure 13, D-chiro-, L-chiro-, allo-, neo-, and
muco-inositols have been synthesized from
bromobenzene. D-chiro- and allo-inositols
have also been prepared from the unique
chloroepoxide 48.106,107 Recently, the prepara-
tion of some of these inositols has been
optimized to medium scale.108,109 A recently
published handbook compiles structures and
includes references to the synthesis of major
cyclitols and derivatives.110
Amino inositols, fluorodeoxyinositols, and
fluorodeoxyamino inositols have also been
synthesized, as shown in Figure 16. In all of
these preparations, careful planning with
respect to the placement of the electrophilic
epoxides (the recipients of F–, N3–, NHR,
OH, etc.) is the key to efficient synthesis.
Recently, 3-deoxy-3-fluoro-L-chiro-inositol
(117) has been made, via fluorohydrin
116, by the selective opening of
vinyloxirane 45 with fluoride.111 Fortamine
(118) was prepared by Vandewalle from the
meso diol derived from benzene.112 The
fluoroamino inositol 119, along with its
enantiomer, were synthesized recently in our
laboratories because of its structural
resemblance to the antibiotic L-myo
inosamine.113 Conduritol analogs such as
120114 and 121115 led to investigations of
"unnatural" derivatives that contain the
cyclitol or conduramine motifs.
Figure 12. Examples of cycloadditions and sigmatropic processes aimed at natural product synthesis.
Vol. 32, No. 2, 1999 43

As the field of inositol and cyclitol synthe-
sis matured, more complex structures were
targeted. Dihydronaphthalenediol-derived
analogs such as 123 were synthesized from the
epoxydiol 122, and were shown to have inter-
esting molecular and biological
properties.116 Dimeric ethers and amines of
type 124 (Figure 17) were also recently
prepared via cis-dihydronaphthalenediol, and
were shown to have interesting solid-state
properties.117,118
The oligomers of L-chiro-inositols such as
127 are made by iterative coupling of primary
synthons 125 with vinyl oxiranes 45.
Compound 127 possesses a natural β-turn in
its secondary structure.119,120 The amino cyclitol
dimeric ether 128, prepared similarly, chelates
calcium ions and forms helical assemblies in
the solid state (Figure 17).120 The chemistry of
the higher inositol conjugates (an octamer has
recently been synthesized) and their derivatives
is likely to have a major impact on medicinal
and materials chemistry in the near future.
5.3. Carbohydrates
To execute a general and exhaustive design
of carbohydrates, it is necessary that the cyclo-
hexene ring be cleaved at a selected location
and the resulting compound reductively
cyclized in a premeditated fashion. The place-
ment of heteroatoms other than oxygen onto
the periphery of the dienediol also provides
access to heterosugars. By simple oxidation
of the periphery of the dienediol, followed by
selective reductive cyclizations, many permu-
tations of hexoses become possible, as shown
in Figure 18. Notice that, even though there
are two options for 6- and 5-membered-ring
closures, the resulting sugars will be
diastereomeric, depending on the definition of
peripheral stereochemistry prior to cleavage
and recyclization. Thus, all 16 isomers of
single hexoses are available from a single pre-
cursor as a function of detailed planning,
usually from primary synthons such as
epoxides or diols.
A detailed analysis of this strategy has been
published,11,13-17 and most examples have been
reduced to practice. The first application
involved the two-carbon oxidative scission of
26 to provide protected erythruronolactone 135
in 51% yield in just 3 steps from bromo- or
chlorobenzene.121,122 A periodate cleavage of
chloroepoxide diol 48 gave lactone 135, a syn-
thon with a proenantiotopic plane of symmetry,
in 38% overall yield (Figure 19).123
Both enantiomers of erythrose (136), as
well as L-ribonolactone (137), have been made
from 135. Because of its symmetry, the latter
compound was found to be a useful synthon for
pyrrolizidine alkaloid synthesis (see Figure 24).
Azasugars were synthesized from azido
alcohols of type 138 (all four diastereomers of
this synthon were prepared124) by oxidative
cleavage of C6–C1 followed by recyclization of
the reduced nitrogenous function, as in the
synthesis of mannojirimycin (139) (Figure 20).125
Reductive cyclization employing different
hydroxyl groups results in the selective
Figure 13. All conduritols, conduramines, and inositols.
Figure 14. Conduritol and con-
duramine synthesis.
44 Vol. 32, No. 2, 1999

syntheses of 2-, 3-, or 4-aminosugars, the
latter made from the isomeric azidohydrin
140. Glucosamine (141) and deoxyamino-
mannose 142 are prepared in this fashion.126
Sphingosines 143 (all four isomers) have been
prepared via azidoerythroses 144 by succes-
sive cleavage of C6–C1 and C2–C3 in
intermediates 138 and 140, after the stereo-
chemistry of the alcohol and azido groups
had been defined (Figure 20).124,127
Deuteromannose derivative 145 was
prepared from pentadeuterobromobenzene by
this strategy.128
Following the principal strategy of f irst
precisely defining the peripheral substitution
and then applying oxidative cleavage/reduc-
tive cyclization, deoxyfluorosugars also
become available, as exemplified by the
glucose and mannose derivatives 147 and 148,
respectively.129
Deoxysugars such as pseudo-β-
D-altropyranose (149)130 and a pseudosugar-
inositol conjugate, 150,131 were prepared as
shown in Figure 21. These examples demon-
strate the enormous power of the reductive
cyclization technology as a fully exhaustive
method of synthesis for any carbohydrate
derivative. The technique relies on the
definition of stereochemistry on the cyclic
precursor prior to oxidative cleavage. Its
various iterations have since been used by
Banwell to construct sugars such as
nonulosonic acid derivative 152 from
chlorobenzene,132 and by Johnson in the
synthesis of azasugars and analogs.133,134 The
rationale for the exhaustive strategy for
carbohydrate synthesis has been delineated in
detail on several occasions.11,14,15,17
Cleavage and reductive cyclization of
conduramines, such as 59, obtained by lipase-
mediated resolution, led to 1-deoxygalacto-
nojirimycin (153), as reported by Johnson
(Figure 22).133
A combination of Suzuki-type coupling
with oxidoreductive recyclization strategy has
been exploited by Johnson in the preparation
of various glycomimetics, e.g., aza-C-
disaccharides (Figure 22).134 It is expected
that applications such as these will grow as the
complexity of the targets that are attained
increases.
5.4. Alkaloid Synthesis
Certain oxygenated alkaloids lend
themselves quite naturally to considerations
involving the incorporation of cis-dihy-
droarenediols into their design. In addition,
the enantiodivergent design that furnished
both enantiomers of pinitol has also been
found to be applicable to erythruronolactone,
which possesses the same proenantiotopic
plane of symmetry.
Thus, either conduramine 58, cyclitol 60,
or erythruronolactone 135 can be manipulated
directly into both enantiomers of a target com-
pound by principles of the commutative law of
algebra (Figure 23). This law states that the
summation of a set of numbers is independent
Hudlicky's syntheses of (+)- and (-)-pinitol.
Ley's syntheses of (+)- and (-)-pinitol
X
O
O
OH
OH
MeO
HO
OH
OH
OH
OH
HO
MeO
OH
OH
O
O
O
O
O
OH
HO
OH
OH
OH
HO
OH
MeO
OBz
OBz
OH
HO
O
MeO
OR
OR
OH
HO
O
(+)-pinitol (7)
114 115
51 26, X = Br, Cl 56
(+)-7 (-)-7
proenantiotopic plane
O COCl
(–)-menthoxyacetyl
Figure 15. Enantiodivergent syntheses of pinitols.
Figure 16. Analogs of conduritols, conduramines, and inositols.
Vol. 32, No. 2, 1999 45

of the order of addition of individual numbers.
Thus, it is the precise ordering of chemical
events (otherwise identical in the pathways to
each enantiomer) that determines the symme-
try of the product.
Figure 24 displays another application of
this principle to the synthesis of trihydroxy-
heliotridanes.122,135 Erythruronolactone (135)
was converted to D- and L-erythroses by taking
advantage of different rates of reaction at the
carboxylate vs. aldehyde termini.121,122 Wittig
synthesis of the diene, followed by conversion
of the remaining alcohol to the azide, allowed
the formation of vinylaziridines 158 in both
enantiomeric series. In both series, these were
formed as diastereoisomeric pairs from E/Z
dienes in a 5:1 ratio. Thermolysis generated
the pyrrolizidines in an overall [4+1] intramol-
ecular pyrrolizine annulation,136 whose devel-
opment and history have been reviewed.110
Pyrrolizidine alkaloids synthesized by this
method in our laboratory in the racemic series
included platynecine, hastanecine, turne-
forcidine, dihydroxyheliotridane, supinidine,
isoretronecanol, and trachelanthimidine,
validating the [4+1] pyrrolizine annulation as
a fully general method of synthesis.135,136
Because of the endo mode of cyclization of
the intermediate ylide, 160, that is generated
by thermolysis, the diastereomers of vinyl-
aziridines converged stereoselectively to
single isomers of pyrrolizidines in each series.
In 1992, taking advantage of the rapid gen-
eration of conduramines by the acylnitroso
Diels–Alder reaction, we synthesized lycorici-
dine from bromobenzene in nine steps
(Figure 25).87,95 Oxazine 50 was reduced and
acylated to the functionalized conduramine
derivative 161. The abnormal Heck cycliza-
tion followed by deprotection yielded (+)-
lycoricidine 162. The racemate of the natural
product was also synthesized by Martin along
a similar pathway from cis-dihydrobenzenedi-
ol.137
Kifunensine (165), an unusual indolizidine
alkaloid, which also classifies as a hydroxylat-
ed piperidine (or azasugar), has been obtained
in conjunction with our projects in carbohy-
drate chemistry involving oxidative cleavage
of the functionalized cyclohexene 163 and its
appropriate reductive cyclization (Figure
26).138,139 Azido alcohol 163 was selectively
transformed first to the azamannosolactone or
mannojirimycin intermediate 139, whose
cyclization with oxalylamide did not yield
kifunensine; however, the furanose form
of azidomannose 164 was successfully
transformed to kifunensine138,139 by a known
literature procedure.140
Our interest in amaryllidaceae alkaloids
led us to the first asymmetric synthesis of
pancratistatin (169), attained in 13 steps from
bromobenzene via the addition of arylcuprate
Figure 17. Inositol oligomers synthesized via iterative coupling.
Figure 18. Examples of permutations in oxidoreductive cyclizations for
carbohydrates.
O
HO
HO
OH
O
OH
OH
HO
O
OH
OH
O
HO
O
O
O
OH
HO
C
l
O
O
O
O
HO
O
O
X
1. O3
2. DMS
NaIO4,
H2O
38%#
51%#
26 135 48
(#) Overall yields are from cis-chlorodihydrobenzenediol
L- D-
erythrose (136)
L-ribonolactone (137)
Figure 19. Enantiodivergent synthesis of erythroses.
46 Vol. 32, No. 2, 1999

166 to vinylaziridine 47 (Figure 27). In this
first-generation synthesis,141 the robust aryl
amide and tosyl amide moieties had to be
manipulated to intermediate 168, whose treat-
ment in refluxing water under pH controlled
conditions (catalytic amount of sodium
benzoate) furnished the target alkaloid in a
remarkable sequence of five consecutive
reactions.141-143
In the second-generation attempt,142 aimed
at 7-deoxypancratistatin (173), some major
improvements were realized by taking advan-
tage of the potential electrophilicity of the
carbamate group in aziridines 171 in order to
avoid using the robust benzamide moiety. The
modified Bischler–Napieralski cyclization of
172 under the conditions reported by
Banwell144 gave the cyclic amide and eventual-
ly led to an 11-step synthesis of 7-deoxy-
pancratistatin (Figure 27).142,143 The enan-
tiomers of both alkaloids can be prepared
from 4-substituted iododiols 26 by the appli-
cation of the "racemic switch" method of
Boyd.65 ent-7-Deoxypancratistatin has recent-
ly been synthesized from 26 via an additional
lipase-catalyzed enrichment procedure.145
The recognition that amaryllidaceae
alkaloids as well as morphine alkaloids may
be viewed as oxygenated biphenyls (Figure
28) led us to consider a design in which
synthons such as 177 would be made by either
direct enzymatic oxidation of the correspond-
ing biphenyls, or by a Suzuki-type coupling
of cis-halodihydrobenzenediols with the
appropriate aryl fragment. Such thinking led
us to design the synthesis of narciclasine
(Figure 29).146
The synthesis took advantage of the unique
symmetry found in 178—the metabolite
obtained by biooxidation of m-dibromo-
benzene—and its subsequent cycloaddition
with acylnitroso carbamate to oxazine 179.
Suzuki coupling of 179 with arylboronic acid
followed by reductive cleavage of 180 did not
generate the expected hydroxycarbamate.
Instead, the unsaturated ketone 181 was
formed and then transformed into the anti
alcohol by means of directed hydride reduc-
tion, or standard reduction followed by
Mitsunobu inversion (Figure 29). Finally,
closure of the B ring was made through the
Bischler–Napieralski-type reaction as in the
case of 7-deoxypancratistatin synthesis.142,146
The enzymatic dioxygenation of biphenyls
was pursued, and a number of metabolites
have been identified, among them the desired
diol 182 that is derived from 2,3-dimethoxy-
biphenyl.147 An approach to morphine was
envisioned, where the stereochemistry of the
C–14 and C–9 centers would be controlled by
the outcome of a sigmatropic process, which
would transfer the configuration of one of the
OH groups to a carbon center. Ideally suited
Figure 20. Design of aza-, amino-, fluorodeoxy-, and perdeuterosugars by oxida-
tive cleavage–reductive cyclization strategy.
Figure 21. Synthesis of deoxysugar analogs.
Vol. 32, No. 2, 1999 47

for this purpose is the Kazmaier modifica-
tion148 of the Claisen rearrangement of the
corresponding glycine enolates, and we have
applied it to glycinate 183 (Figure 30).72
Amino acid esters generally fail to rearrange
under standard Ireland conditions, but react
successfully in the presence of a Lewis acid,
such as ZnCl2or SnCl4. To fully control the
relative stereochemistry of C–9 and C–14,
184, which was generated as a 4:1 mixture of
stereoisomers, was transformed into lactone
185 in which the bulky NHBoc group would
be epimerized to the exo surface of the
bicyclic ring system.
Diols 186, derived from β-bromoethyl and
o-bromo-β-bromoethylbenzene, comprised
the starting point for a tandem radical cycliza-
tion approach to morphine in the former case
and a stepwise cyclization in the latter (Figure
31). In the tandem as well as the stepwise
approach, the bromocatechol unit required for
the aromatic ring of morphine was made
enzymatically from bromobenzene with
an organism that also expressed the
second enzyme in the pathway, namely, the
diol dehydrogenase.149,150
The tandem process, modeled after
Parker’s approach,151 provided low yields of
the pentacyclic precursor 188, with the epi
configuration at C–14 (Figure 31).149,150 When
o-bromo-β-bromoethylbenzene was first
converted to the isoquinoline derivative 189,
through a single radical cyclization followed
by attachment of the bromocatechol (in an ent
configuration), ent-morphinan (190) was
attained.150 The isoquinoline formation was
nonstereospecific with respect to C–9 (mor-
phine numbering) and resulted in a 2:1
mixture of isomers (α/β). However, the
isoquinoline in the correct enantiomeric series
was obtained selectively via acid-catalyzed
cyclization of the acyliminium salt 191.152
Dibenzoate 191 yields 192 stereospecifically,
and the trans isomer of 191 gives accordingly
the α-isomer of 192, thus providing for a fully
enantiodivergent approach to morphine. The
mechanistic details of the acid-catalyzed
cyclization of 191 and its trans isomer have
recently been published.153 Further refine-
ments in this multigeneration process are
ongoing and include the generation of
precursors for 191 by electrochemical
oxidations.152 Additional routes to morphine
are being pursued via Diels–Alder cycloaddi-
tions of compounds related to 85 and 88, but
containing the required elements of the
aromatic ring of morphine.
5.5. Miscellaneous Natural
Products
The incorporation of certain cis-dihy-
droarenediols into synthetic sequences results
almost always in a signif icant shortening of
the routes to the desired targets. We recog-
nized such advantages in our pursuit of the
total syntheses of natural products, even
during the very first project that we undertook
in this area.71 The protected dihydroxylated
Figure 22. Syntheses of nojirimycin analogs and carbon-tethered glycomimetics.
O
O
O
O
HO
O
O
O
X
X
OR
OR
58, X = NHCbz,
NHCO2Me
60, X = OH, OR
25, R = H
26, R+R = C(CH3)2
135
Figure 23. Synthons containing a proenantiotopic plane.
Figure 24. Enantiodivergent synthesis of oxygenated pyrrolizidine alkaloids.
48 Vol. 32, No. 2, 1999

cyclopentenone 194 has been used by
Johnson in a triply convergent synthesis of
prostaglandin PGE2α(195) (Figure 32).154,155
The starting enone itself is available in
several steps from arabinose by published
methods,156-158 only two of which employ the
diols derived from either chlorobenzene158 or
toluene.71,158 Ozonolysis of the diol derived
from toluene provides ketoaldehyde 193,
which is dehydrated with alumina to provide
the important enone, 194, in just three
operations from toluene.71 An alternative to
this process (sometimes not easily repro-
duced because of the nature of the aluminum
oxide catalyst) has been developed by
using the diol derived from chlorobenzene
and its high-yielding ozonolysis to
erythruronolactone (135); intermediate 135
was converted to 194 by the method of
Borchardt (Figure 32).156
The bicyclic enone, 194, is a very useful
five-carbon synthon (every carbon is differ-
entially functionalized), and we have used it
in a synthesis of specionin (200), an
antifeedant for the spruce budworm.159 This
particular approach relied on the [2+3] inter-
molecular cyclopentene annulation devel-
oped in our laboratories,160 and provided
specionin via vinylcyclopropane 197
and its rearrangement (thermal or fluoride
ion-catalyzed)160 products, cyclopentenes
198 or 199 (Figure 33). Noteworthy in this
synthesis is the fact that the initial
biochemically installed asymmetry is
propagated through the synthesis and is
later destroyed in the final elaboration
to the bisacetal ring in 200.
The unusual natural product zeylena
(80), containing a trans-diol unit, has been
investigated in connection with the
antitumor properties of related cyclohexene
oxides. We approached its synthesis from
the diol derived from styrene by "protecting"
the reactive triene unit via its Diels–Alder
reaction with diethyl azodicarboxylate
(DEAD) (Figure 34).
Following the Mitsunobu inversion of the
distal hydroxyl with cinnamic acid, the
triene was liberated; intramolecular
Diels–Alder reaction with cinnamate set the
required bicyclo[2.2.2]octane framework.
Further oxidative adjustments of the
styrene double bond led to the synthesis of
zeylena.161
Methyl shikimate (206) was synthesized
by Johnson104,162 from the meso diol of
benzene via lipase resolution (Figure 35).
Both enantiomers have been obtained
by transforming the resolved conduritol
A derivative, 204, into the iodoenone 207.
Vandewalle163 reported a synthesis of
shikimate as portrayed in Figure 35. In this
synthesis, the protected conduritol 209 was
transformed via Mitsunobu elimination and
subsequent epoxide opening to dithiane 210
and further to methyl shikimate (206).
Coupling of synthons derived from 25 to
C2-symmetric derivatives and preparation of
phenanthrene-type ring systems has been
reported recently.164
Banwell synthesized tropolones from
dihydrobenzene- or dihydrotoluenediols88 by
taking advantage of the cyclopropanation
of the double bonds in the dienediol
(Figure 36).
The meso-diol 25 (X = H) was
cyclopropanated, the diol unit deprotected,
oxidized, and rearranged with Lewis acid
to tropolone 213. In the case of dihydro-
toluenediol, the selectivity of the cyclo-
propanation favored the more electron-rich
(i.e., methyl-bearing) olefin; this was also
the case with bromodihydrobenzenediol
(214). This particular application, followed
by the two-carbon oxidative-scission strate-
gy outlined earlier, gave a differentially
functionalized cyclopropane suitable for
elaboration into chrysanthemates or other
pyrethroids, such as deltamethrin (219).89
Banwell applied the anion-accelerated
oxy-Cope rearrangement of bicyclo[2.2.2]-
octanes, derived from cis-dihydrotoluene-
diol, to the synthesis of the taxane AB
ring system (Figure 37). The required
bicyclo[2.2.2]octane framework was
generated by iminoketene addition to
yield 220. The Cope rearrangement
generated the oxygenated core of the AB
ring system of taxol, 222. In a more
advanced study, the initial adduct, 224, was
subjected to transannular cyclization to
provide the tricyclic skeleton 225, the
fragmentation of which, modeled after
Holton’s taxane synthesis, furnished the ring
A allylic alcohol, 226.74
Figure 25. Synthesis of lycoricidine.
Figure 26. Kifunensine synthesis.
Vol. 32, No. 2, 1999 49

5.6. Recent Applications of
Commercial Significance
Several applications of commercial value
of the cis-cyclohexadienediols have already
been reduced to practice. In addition to the
pioneering work of ICI (now Zeneca) on the
commercial synthesis of polyphenylene3,4
from benzene via the corresponding meso
diol, and the medium-scale preparation of
several inositols (D-chiro-, L-chiro-, allo-,
muco-, and neo-) published by our group,
there are other examples as shown in
Figure 38.
Merck considered the biocatalytic
production of dihydroindenediol for incorpo-
ration into the AIDS drug indinavir.165
Genencor manufactures indigo by a combina-
tion of metabolic engineering of the aromatic
amino acid pathway and naphthalene
dioxygenase-mediated oxidation of indole to
cis-dihydroindolediol, which dehydrates to
indoxyl, the precursor of indigo.166,167 The
preparation of D-chiro-inositol and other
inositols has been performed on a medium
scale (50–100 g) and can be considered easily
scalable to multikilogram quantities.108 It is
expected that other targets of commercial
significance will soon employ some of the
metabolites discussed in this review in their
synthetic sequences.
Quite recently, both chloro- and
bromodihydrobenzenediols have been used
in reactions on polymer supports.168
Ketalization was accomplished on polystyrene
resin via benzyl ether linkers, as depicted in
Figure 38. Many diverse structures have been
generated by these methods and freed from the
resin by CF3CO2H. The yields reported are
comparable to those from the solution-phase
synthesis of similar compounds.
6. Conclusion and Outlook
It is evident that a tremendous amount of
work has been accomplished in the utilization
of metabolites derived from aromatics. The
pioneering work of Gibson, Ribbons, and the
EPA group in Pensacola (associated with the
University of Minnesota) made it possible to
lay the groundwork for the synthetic commu-
nity to take full advantage of the rich potential
of these compounds. Yet, the expansion of
chemoenzymatic methods in general, and the
use of cis-dihydroarenediols in particular, has
hardly begun, as evidenced by the relatively
few groups worldwide involved in this area.6,14
The applications to synthesis have so far orig-
inated in only a few of the diols listed in the
tables. More complex strategies, as well as the
use of tandem reaction sequences and an
expanded reservoir of polyfunctional metabo-
lites, should support further growth of this
discipline. Without a single exception, all
Figure 27. First asymmetric synthesis of pancratistatin and
second-generation synthesis of (+)- and (–)-7-deoxypancratistatin
177
R1O
O
R2O
NMe
H
O
O
R
HN
O
HO OH
OH
O
O
R
HN
O
HO
OH
OH
OH
morphine (175), R1 = R2 = H
codeine (176); R1 = Me, R2 = H
pancratistatin (169), R = OH
7-deoxypancratistatin (173), R = H
narciclasine (174), R = OH
lycoricidine (162), R = H
OH
OH
OR
OR
RO
Figure 28. Disconnection of morphine and amaryllidaceae alkaloids to
oxygenated biphenyls.
50 Vol. 32, No. 2, 1999

total syntheses (certainly those from our
laboratory) that incorporate a cis-diol in the
sequence toward the target molecule are
considerably shorter than the traditional
approaches in the literature. This trend will no
doubt continue with new applications. The
readers are invited to view the collection of
structures in the tables and apply them in their
own innovative designs.
7. Acknowledgments
The authors are grateful to the many
coworkers who participated in the ventures
described in this review during the period
1988–1998, and whose names are listed in the
citations. The generous financial support for
this work came from NSF (CHE-9315684,
CHE-9521489 and CHE-9615112),
EPA R82613, Genencor International,
Mallinckrodt Specialty Chemicals, Jeffress
Trust Fund, TDC Research, Inc., TDC
Research Foundation, and NIH (support of
Gibson’s work only). Several outside
postdoctoral fellowships (Michel Desjardins,
Kurt Konigsberger, and Jacques Rouden)
are also acknowledged. Logistical help
from Dr. Gregg Whited, from Genencor
International, Inc., is greatly appreciated.
The authors are also in debt to Prof.
Gustavo Seoane (Universidad de la
República, Montevideo, Uruguay) for his
initial input. Careful proofreading and
many suggestions for the final draft
were provided by Dr. Josie Reed, Prof.
Douglas Ribbons, and Dr. Sol Resnick.
To all these individuals go our heartfelt
thanks. Last, but not least, one of us (TH)
is indebted to Dr. Larry Kwart, whose
convincing arguments and practical advice led
to the establishment of microbial oxidation
technology in the group. Without his initial
input, none of the work described in this
review would have ever come to fruition.
N
O
OMe
O
O
O
O
Br
CO2Me
OH
O
O
OH
OH
NH
OH
OOMe
O
O
O
O
O
NHCO2Me
CO2Me
N
Br
O
O
O
Br
B(OH)2
OMe
O
O
Br
Br
OH
OH Pd(PPh3)4, Na2CO3,
EtOH, PhH
TTMSS, AIBN
or Mo(CO)6
179178 180
181
174
Figure 29. Synthesis of narciclasine.
Figure 30. Claisen rearrangement approach to morphine.
Figure 31. Tandem vs. stepwise radical cyclization approach to morphine.
Vol. 32, No. 2, 1999 51

8. References and Notes
(†) In Tables 1–5, compounds are pictured exactly
as reported in the literature. In some cases, the
absolute stereochemistry is inferred but not
necessarily proven beyond doubt. Compounds
in brackets imply that the actual diol has not
been isolated. Compounds in color are those
that have been exploited in synthetic ventures.
1. Gibson, D. T.; Koch, J. R.; Schuld, C. L.;
Kallio, R.E. Biochemistry 1968, 7, 3795.
2. Motherwell, W. B.; Williams, A. S. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2031.
3. Ballard, D. G. H.; Courtis, A.; Shirley, I. M.;
Taylor, S. C. J. Chem. Soc., Chem. Commun.
1983, 954.
4. Ballard, D. G. H.; Courtis, A.; Shirley, I. M.;
Taylor, S.C. Macromolecules 1988, 21, 294.
5. Ley, S. V.; Sternfeld, F.; Taylor, S. Tetrahedron
Lett. 1987, 28, 225.
6. The latest count revealed the following groups
actively participating in this field: Australia:
Banwell; Austria: Griengl; Japan:
Suemone; India: Mereyala; Italy: Bossetti,
Di Gennaro, Nicolosi, Orsini, Sello; Spain:
Noheda; UK: Boyd, Carless, Carnell, Crout,
Dalton, Ley, Page, Ribbons, Roberts,
Stephenson, Widdowson; Uruguay: Seoane;
U.S.: Chapman, Eaton, Gibson, Grubbs,
Gunsalus, Hudlicky, Johnson, Martin, Olivo,
Selifonov, Wackett, Whited, Wiest, Ziffer.
7. Widdowson, D. A.; Ribbons, D. W.; Thomas,
S. D. Janssen Chimica Acta 1990, 8, 3.
8. Carless, H. A. J. Tetrahedron: Asymmetry
1992, 3, 795.
9. Sheldrake, G. N. In Chirality and Industry;
Collins, A. N., Sheldrake, G. N., Crosby, J.,
Eds.; John Wiley and Sons, Ltd.: Chichester,
U.K., 1992; p 127.
10. Brown, S. M.; Hudlicky, T. In Organic
Synthesis: Theory and Applications; Hudlicky,
T., Ed.; JAI Press: Greenwich, CT, 1993; Vol.
2, p 113.
11. Hudlicky, T.; Reed, J.W. In Advances in
Asymmetric Synthesis; Hassner, A., Ed.; JAI
Press: Greenwich, CT, 1995; p 271.
12. Grund, A.D. SIM News 1995, 45, 59.
13. Hudlicky, T.; Thorpe, A. J. Chem. Commun.
1996, 1993.
14. Hudlicky, T. Chem. Rev. 1996, 96, 3.
15. Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.;
Thorpe, A. J. Chem. Rev. 1996, 96, 1195.
16. Hudlicky, T. In Green Chemistry: Designing
Chemistry for the Environment; Anastas, P. T.,
Williamson, T. C., Eds.; ACS Symposium
Series; American Chemical Society:
Washington, DC, 1996; Vol. 626, p 180.
17. Hudlicky, T. In Green Chemistry: Frontiers in
Benign Chemical Syntheses and Processes;
Anastas, P. T., Williamson, T. C., Eds.; Oxford
University Press: Oxford, UK, 1998; Chapter
10, p 166.
18. Boyd, D. R.; Sheldrake, G. N. Nat. Prod. Rep.
1998, 309.
19. Gibson, D. T.; Koch, J. R.; Kallio, R. E.
Biochemistry 1968, 7, 2653.
20. Jerina, D. M.; Daly, J. W. B.; Zaltzman-
Niremberg, P.; Udenfriend, S. Arch. Biochem.
1968, 128, 176.
21. Gibson, D. T.; Cardini, G. E.; Maseles, F. C.;
Kallio, R. E. Biochemistry 1970, 9, 1631.
Figure 32. Two approaches to a prostaglandin intermediate.
Figure 33. Synthesis of specionin.
Figure 34. Synthesis of zeylena.
52 Vol. 32, No. 2, 1999

22. Gibson, D. T.; Hensley, M.; Yoshioka, H.;
Mabry, T. J. Biochemistry 1970, 9, 1626.
23. Ziffer, H.; Jerina, D. M.; Gibson, D. T.; Kobal,
V. M. J. Am. Chem. Soc. 1973, 95, 4048.
24. Gibson, D. T.; Gschwendt, B.; Yeh, W. K.;
Kobal, V. M. Biochemistry 1973, 12, 1520.
25. Ziffer, H.; Kabuto, K.; Gibson, D. T.; Kobal, V.
M.; Jerina, D. M. Tetrahedron 1977, 33, 2491.
26. Gibson, D. T.; Mahadevan, V.; Davey, J. F. J.
Bacteriol. 1974, 119, 930.
27. Ziffer, H.; Gibson, D. T. Tetrahedron Lett.
1975, 2137.
28. Gibson, D. T. Crit. Rev. Microbiol. 1971, 1,
199.
29. Jerina, D. M.; Daly, J. W.; Jeffrey, A. M.;
Gibson, D. T. Arch. Biochem. Biophys. 1971,
142, 394.
30. Jeffrey, A. M.; Yeh, H. J. C.; Jerina, D. M.;
Patel, T. R.; Davey, J. F.; Gibson, D. T.
Biochemistry 1975, 14, 575.
31. Gibson, D. T.; Roberts, R. L.; Wells, M. C.;
Kobal, V. M. Biochem. Biophys. Res.
Commun. 1973, 50, 211.
32. Khan, A. A.; Wang, R.-F.; Cao, W.-W.;
Franklin, W.; Cerniglia, C. E. Int. J. Syst.
Bacteriol. 1996, 46, 466.
33. Akhtar, M. N.; Boyd, D. R.; Thompson, N. J.;
Koreeda, M.; Gibson, D. T.; Mahadevan, V.;
Jerina, D. M. J. Chem. Soc., Perkin Trans. 1
1975, 2506.
34. Koreeda, M.; Akhtar, M. N.; Boyd, D. R.;
Neill, J. D.; Gibson, D. T.; Jerina, D. M.
J. Org. Chem. 1978, 43, 1023.
35. Jerina, D. M.; van Bladeren, P. J.; Yagi, H.;
Gibson, D. T.; Mahadevan, V.; Neese, A. S.;
Koreeda, M.; Sharma, N. D.; Boyd, D. R. J.
Org. Chem. 1984, 49, 3621.
36. Boyd, D. R.; Sharma, N. D.; Agarwal, R.;
Resnick, S. M.; Schocken, M. J.; Gibson, D.
T.; Sayer, J. M.; Yagi, H.; Jerina, D. M. J.
Chem. Soc., Perkin Trans. 1 1997, 1715.
37. Reiner, A. M.; Hegeman, G. D. Biochemistry
1971, 10, 2530.
38. Reineke, W.; Otting, W.; Knackmuss, H.-J.
Tetrahedron 1978, 34, 1707.
39. Reineke, W.; Knackmuss, H.-J. Biochim.
Biophys. Acta 1978, 542, 412.
40. DeFrank, J. J.; Ribbons, D. W. J. Bacteriol.
1977, 129, 1356.
41. DeFrank, J. J.; Ribbons, D. W. J. Bacteriol.
1977, 129, 1365.
42. Jenkins, G. N.; Ribbons, D. W.; Widdowson,
D. A.; Slawin, A. M. Z.; Williams, D. J. J.
Chem. Soc., Perkin Trans. 1 1995, 2647.
43. Resnick, S. M.; Lee, K.; Gibson, D. T. J. Ind.
Microbiol. 1996, 17, 438.
44. Gibson, D. T.; Subramanian, V. In Microbial
Degradation of Organic Compounds; Gibson,
D. T., Ed.; Marcel Dekker: New York, NY
1984; Vol. 13, p 181.
45. Gibson, D. T. In Microbial Metabolism and
the Carbon Cycle; Hagedorn, S. R., Hanson,
S. H., Kunz, D. A., Eds.; Hardwood Academic
Publisher: New York, NY, 1988; p 33.
46. Gibson, D. T. In Degradation of Synthetic
Organic Molecules in the Biosphere; National
Academy of Sciences: Washington, DC, 1971;
p 117.
47. Hudlicky, T.; Stabile, M. S.; Whited, G.
Gibson, D. T. Org. Synth. 1999, 76, 77.
48. Barnsley, E. A. J. Gen. Microbiol. 1975, 88,
193.
Figure 35. Synthesis of methyl shikimate and shikimic acid.
Figure 36. Synthesis of tropolones and synthons for chrysanthemates.
Vol. 32, No. 2, 1999 53

49. Mahaffey, W. R.; Gibson, D. T.; Cerniglia, C.
E. Appl. Environ. Microbiol. 1988, 54, 2415.
50. Gibson, D. T.; Resnick, S. M.; Lee, K.; Brand,
J. M.; Torok, D. S.; Wackett, L. P.; Schocken,
M. J.; Haigler, B. E. J. Bacteriol. 1995, 177,
2615.
51. Lee, K.; Gibson, D. T. Appl. Environ.
Microbiol. 1996, 62, 3101.
52. Gibson, D. T.; Kle
h
ka, G. M. Unpublished
results.
53. Kle
h
ka, G. M.; Gibson, D. T. Biochem. J.
1979, 180, 639.
54. Zylstra, G. J.; Gibson D. T. J. Biol. Chem.
1989, 264, 14940.
55. Simon, M. J.; Osslund, T. D.; Saunders, R.;
Ensley, B. D.; Suggs, S.; Harcourt, A.; Suen,
W. C.; Cruden, D. L.; Gibson, D. T.; Zylstra,
G. J. Gene 1993, 127, 31.
56. Mondello, F. J. J. Bacteriol. 1989, 171, 1725.
57. Butler, C. S.; Mason, J. R. Adv. Microbiol.
Phys. 1997, 38, 47.
58. Kauppi, B.; Lee, K.; Carredano, E.; Parales,
R. E.; Gibson, D. T.; Eklund, H.; Ramaswamy,
S. Structure 1998, 6, 571.
59. Stewart, J. D.; Hudlicky, T.; Novak, B. H.
Unpublished results, 1996.
60. Stewart J. D.; Reed, K. W.; Kayser, M. M. J.
Chem. Soc., Perkin Trans. 1 1996, 755.
61. Furstoss, R. Use of Biooxygenation in Fine
Organic Synthesis. In Microbial Reagents in
Organic Synthesis; Servi, S., Ed.; Kluwer
Academic Publishers: Dordretch,
Netherlands, 1992; p 333.
62. Taschner, M. J.; Peddada, L.; Cyr, P.; Chen,
Q.-Z.; Black, D. J. The Enzymatic
Baeyer–Villiger Oxidation. In Microbial
Reagents in Organic Synthesis; Servi, S., Ed.;
Kluwer Academic Publishers: Dordretch,
Netherlands, 1992; p 347.
63. Boyd, D. R.; Dor rity, M. R. J.; Hand, M. V.;
Malone, J. F.; Sharma, N. D.; Dalton, H.; Gray,
D. J.; Sheldrake, G. N. J. Am. Chem. Soc.
1991, 113, 666.
64. Resnick, S. M.; Gibson, D. T. In Abstr. of the
96th Gen. Meet. of the Am. Soc. For
Microbiol, 1996.
65. Allen, C. C. R.; Boyd, D. R.; Dalton, H.;
Sharma, N. D.; Brannigan, I.; Kerley, N. A.;
Sheldrake, G. N.; Taylor, S. C. J. Chem. Soc.,
Chem. Commun. 1995, 117.
66. Johnson, C. R.; Adams, J. P.; Collins, M. A. J.
Chem. Soc., Perkin Trans. 1 1993, 1.
67. Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda,
T. J. Am. Chem. Soc. 1990, 112, 9439.
68. Hudlicky, T.; Rulin, F.; Tsunoda, T.; Luna, H.;
Andersen, C.; Price, J. D. Isr. J. Chem. 1991,
31, 229.
69. Boyd, D. R.; Sharma, N. D.; Dalton, H.;
Clarke, D. A. Chem. Commun. 1996, 45.
70. McKibben, B. P.; Barnosky, G. S.; Hudlicky,
T. Synlett 1995, 806.
71. Hudlicky, T.; Luna, H.; Barbieri, G.; Kwart, L.
D. J. Am. Chem. Soc. 1988, 110, 4735.
72. Gonzalez, D.; Schapiro, V.; Seoane, G.;
Hudlicky, T.; Abboud, K. J. Org. Chem. 1997,
62, 1194.
73. Resnick, S. M.; Torok, D. S.; Gibson, D. T. J.
Org. Chem. 1995, 60, 3546.
74. Banwell, M. G.; Darmos, P.; McLeod, M. D.;
Hockless, D. C. R. Synlett 1998, 897.
75. Hudlicky, T.; McKibben, B. P. Unpublished
results, 1994: Pivalic aldehyde has been used
as a protective group.
76. Stephenson, G. R.; Howard, P. W.; Taylor, S.
C. J. Chem. Soc., Chem. Commun. 1991, 127.
77. Howard, P. W.; Stephenson, G. R.; Taylor, S.
C. J. Chem. Soc., Chem. Commun. 1988,
1603.
78. Braun, H.; Burger, W.; Kresze, G.;
Figure 37. Approaches to taxanes.
nucleophilic
opening Stille
coupling
231 232; X = Cl, Br
Glucose
Indinavir (227)
(Merck)
Indigo (230)
(Genencor International)
23 24
228 229
NH
OH
OH
NH
N
N
N
NH
t-
Bu
O
NH
OH
OH
OH
OH
O
OO
X
O
O
MeO OMe
H
N
O
NH
O
O
Figure 38. Potential commercial applications of cis-dihydroarenediols.
54 Vol. 32, No. 2, 1999

P. putida UV4
(ref. 170)
P. putida 39/D
E. coli JM109(pDTG601A)
( ref. 219)
P. putida 39/D
P. putida UV4
(ref. 22,63,180)
P. putida 39/D
P. putida UV4
(ref. 25,169)
P. putida 39/D
(ref. 1,25)
P. putida UV4
(ref. 63,184)
P. putida 39/D
E. coli JM109(pDTG601A)
(ref. 219)
P. putida 39/D
E. coli JM109(pDTG601A)
(ref. 219)
P. putida UV4
E. coli JM109(pDTG601A)
(ref. 170)
P. putida
(ref. 25,39)
P. putida UV4
E. coli JM109(pDTG601A)
(ref. 169, 170)
P. putida UV4
(ref. 63,184)
P. putida 39/D,
(ref. 19,21) E. coli JM109(pDTG601A)
(ref. 218)
P. putida 39/D
P. putida UV4
(ref. 25,63,184)
P. putida UV4
E. coli JM109 (pDTG601A)
(ref. 63,184)
E. coli JM109(pDTG601A)
(ref. 126,170)
E. coli JM109(pDTG601A)
(ref. 146)
P. putida 39/D
P. putida UV4
(ref. 161,184)
P. putida UV4
(ref. 170)
P. putida UV4
E. coli JM109 (pDTG601A)
(ref. 145,170)
P. putida UV4
(ref. 170)
P. putida UV4
(ref. 170)
P. putida UV4
(ref. 169)
P. putida UV4
E. coli JM109(pDTG601A)
(ref. 145,169)
OH
OH
Br
Br
OH
OH
D
OH
OH
I
Cl
OH
OH
I
Br
OH
OH
I
Br
OH
OH
I
Cl
OH
OH
Br
D
OH
OH
Br
OH
OH
Cl
OH
OH
H
OH
OH
F
OH
OH
CH3
Br
OH
OH
I
H3C
OH
OH
I
CH3
OH
OH
CF3
Br OH
OH
Br
F3C
OH
OH
I
OH
OH
CH3
Cl
OH
OH
CH3
F
OH
OH
CH3
OH
OH
Br
F
F
OH
OH
I
F
OH
OH
I
FOH
OH
I
F
OH
OH
CN
OH
OH
CO2H
CH3
HO
OH
OH
CO2H
CH3
OH
OH
CO2H
Cl
CH3
OH
OH
CO2H
CF3
OH
OH
HO2C
CF3OH
OH
CO2H
H3C
Br
OH
OH
HO2C
CH3
HO
HO COOH
CH3
OH
OH
HO2C
CH3
OH
OH
CF3
CH3
OH
OH
CO2H
H3C
F
OH
OH
Br
Br
OH
OH
Br
OH
OH
X
OH
OH
N3
E. coli JM109(pDTG601A)
(ref. 242)
X = CN, SCN, NCS, OAc, OH
E. coli JM109(pDTG601A)
(ref. 242)
P. putida 39/D
E. coli JM109(pDTG601A)
(ref. 192)
P. putida 39/D
E. coli JM109(pDTG601A)
(ref. 193)
P. putida JT107
(ref. 40)
P. putida UV4
(ref. 169)
A. eutrophus B9
(ref. 38,175)
Pseudomonas sp. B13
(ref. 39,175)
A. eutrophus B9
Pseudomonas sp. B13
(ref. 38,39,175)
P. putida JT107
(ref.40)
P. putida mt-2 +
A. eutrophus B9
(ref. 183)
P. putida JT107
(ref. 177)
P. putida JT107
(ref. 40)
P. putida JT107
(ref. 40)
P. putida JT107
(ref. 40)
Table 1. Diols Derived from Monocyclic Aromatics
Vol. 32, No. 2, 1999 55

P. putida 39/D
(ref. 24)
Micrococcus sp. 12B
(ref. 186)
P. putida JT107
(ref. 40)
P. putida
(ref. 181)
P. putida
(ref. 181)
Pseudomonas sp. B1
(ref. 175)
unidentified strain
(ref. 195)
P. putida
(ref. 194, 196)
P. desmolytica
P.convexa
(ref. 175,196)
P. putida 39/D
(ref. 26)
P. putida 39/D
(ref. 24)
P. putida 39/D
(ref. 24)
P. putida UV4
(ref. 191,231)
P. putida UV4
(ref. 191,231)
P. acidovorans
(ref. 203)
P. putida RE213
(ref. 232)
P. putida 39/D
(ref. 26)
Micrococcus sp. 12B
(ref. 186)
P. putida UV4
(ref. 231)
OH
OH
OH
OH
OH
CO2H
HO2C
OH
OH
CH3
H3C
OH
OH
H3CCH3
OH
OH
OH
HO
OH
OH
O
OH
OH
CH3
CH3
OH
OH
OH
OH
OH
OH
NH2
CO2H
CH3
OH
H3C
OH
HO2C
CH2CH3
OH
OH
HO2C
CH3
OH
OH
HO2C
CH3
OH
OH
CO2H
H3C
CH3
OH
OHBuO2C
CO2Bu
OH
OH
OH
OH
OH
OH
P. putida 39/D
(ref. 189)
X = Cl, Br
P. putida 39/D
(ref. 187-189)
P. putida 39/D
(ref. 71,192)
P. putida 39/D
(ref. 187)
P. putida 39/D
(ref. 186,187)
P. putida 39/D
(ref. 187)
X = H, Cl
P. putida 39/D
(ref. 71,135,187)
P. putida 39/D
(ref.187)
OH
OH
Cl
OH
OH
X
HO OH
Cl
OH
HO
Cl
HO OH
Cl
OH
OH
OH
OH
Cl
OH
OH
X
OH
HO
Br
P. putida 39/D
(ref. 187)
HO
A. eutrophus B9
(ref. 38,39)
P. putida UV4
P. putida 39/D
(ref. 63,174,229)
P. putida,
A. eutrophus B9
(ref. 37-39,175,181)
A. eutrophus B9
Pseudomonas sp. B13
(ref. 38,39)
A. eutrophus B9
(ref. 37,38)
P. fluorescens
A. eutrophus B9
(ref. 37,38,175,178)
P. putida NCIB12190
(ref. 174)
P. putida NCIB12190
(ref. 174)
P. putida UV4
(ref. 169)
OH
OH
CF3
I
OH
OH
CF3
F
OH
OH
CF3
F
OH
OH
HO2C
Cl
OH
OH
CO2H
X
OH
OH
HO2C
Cl
OH
OH
HO2C
Br
OH
OH
HO2C
OH
OH
CF3HO
HO COOH
Br
X = Cl, Br, I, CF3
P. putida JT107
(ref. 40,177)
Table 1. Diols Derived from Monocyclic Aromatics (cont.)
56 Vol. 32, No. 2, 1999

E. coli JM109(pDTG601A)
(ref. 241)
A. eutrophus B9
(ref. 38)
Pseudomonas sp. WR91
A. eutrophus B9
(ref. 37,179)
A. eutrophus B9
(ref. 37,38,39)
A. eutrophus B9
(ref. 37,38)
P. putida JT107
(ref. 40)
P. putida JT107
(ref. 40)
Pseudomonas sp. B13
(ref. 175)
A. eutrophus B9
(ref. 38,175)
P. putida JT103
(ref. 173,176)
P. putida JT103
(ref. 176)
P. putida JT103
(ref. 176)
P. putida 39/D
E. coli JM109(pDTG601A)
(ref. 227)
P. putida 39/D
E. coli JM109(pDTG601A)
P. putida UV4
(ref. 184,220,228)
P. putida UV4
P. putida 39/D
E. coli JM109(pDTG601A)
(ref. 63,184,228)
OH
OH
HO2C
F
OH
OH
HO2C
F
F
HO
HO
F
COOH
F
OH
OH
HO2C
FF
OH
OH
HO2C
Cl Cl
OH
OH
HO2C
Cl
Cl
OH
OH
CO2H
Cl
Cl
OH
OH
CO2H
HO
HO COOH
F
OH
OH
HO2C
F
HO
HO COOH
Cl
OH
OH
O
OH
OH
O
OH
OH
OCF3
OH
OH
Br
Table 1. Diols Derived from Monocyclic Aromatics (cont.)
P. putida NCIB 9816/11
(ref. 222)
P. putida NCIB 9816/11
(ref.197)
P. putida NCIB 9816/11
(ref. 197)
P.putida UV4, P. putida 119
P. putida NCIB 9816/11
A. quadruplicatum
E. coli JM109(pDTG601A)
(ref. 29,30,117,198,199,200,234)
P. putida NCIB 9816/11
(ref. 197)
P. putida NCIB 9816/11
(ref. 222)
P. putida 39/D
P. putida NCIB 9816/11
E. coli JM109 (pDTG601A)
E. coli JM109 (pDTG141)
S. yanoikuyae B8/36
(ref. 223)
P. putida 39/D
E. coli JM109 (pDTG601A)
(ref. 223)
P. testosteroni
(ref. 201)
P. testosteroni
(ref. 201)
Beijerinckia sp.
(ref. 205)
P. putida 119
S. yanoikuyae B8/36
(ref. 33,212)
P. putida 119
S. yanoikuyae B8/36
(ref. 34,212)
P. putida 119
S. yanoikuyae B8/36
(ref. 34,212)
A. quadruplicatum PR/6
(ref. 213)
OH
OH
OH
OH
OH
HO
OH
OH
HO OH
OH
OH
OCH3
OH
OH
CO2H
OH
OH
MeO
OH
HO
MeO
OH
OH
MeO
OH
OH
OH
OH
Br
OH
OH
OH
OH
Br
Br OH
OH
OH
OH
P. putida 39/D
P. putida NCIB 9816/11
E. coli JM109 (pDTG601A)
E. coli JM109 (pDTG141)
S. yanoikuyae B8/36
(ref. 223)
Table 2. Diols Derived from Fused Aromatic Systems
Vol. 32, No. 2, 1999 57

Schmidtchen, F. P.; Vaerman, J. L.; Viehe, H.
G. Tetrahedron: Asymmetry 1990, 1, 403.
79. Hudlicky, T.; Boros, E. E.; Olivo, H. F.;
Merola, J. S. J. Org. Chem. 1992, 57, 1026.
80. Pittol, C. A.; Pryce, R. J.; Roberts, S. M.;
Ryback, G.; Sik, V.; Williams, J. O. J. Chem.
Soc., Perkin Trans. 1 1989, 1160.
81. Ley, S. V.; Redgrave, A. J.; Taylor, S. C.;
Ahmed, S.; Ribbons, D. W. Synlett 1991, 741.
82. Hudlicky, T.; Boros, C. H. Tetrahedron Lett.
1993, 34, 2557.
83. Hudlicky, T.; Luna, H.; Olivo, H. F.; Andersen,
C.; Nugent, T.; Price, J. D. J. Chem. Soc.,
Perkin Trans. 1 1991, 2907.
84. Banwell, M. G.; Dupuche, J. R.; Gable, R. W.
Aust. J. Chem. 1996, 49, 639.
85. Hudlicky, T.; McKibben, B. P. J. Chem. Soc.,
Perkin Trans. 1 1994, 485.
86. Banwell, M. G.; Dupuche, J. R. Chem.
Commun. 1996, 869.
87. Hudlicky, T.; Olivo, H. F.; McKibben, B. J.
Am. Chem. Soc. 1994, 116, 5108.
88. Banwell, M. G.; Collis, M. P. J. Chem. Soc.,
Chem. Commun. 1991, 1343.
89. Banwell, M. G.; Forman, G. S. J. Chem. Soc.,
Perkin Trans. 1 1996, 2565.
90. Banwell, M. G.; Collis, M. P; Mackay, M. F.;
Richards, S. L. J. Chem. Soc., Perkin Trans. 1
1993, 1913.
91. Banwell, M. G.; Corbett, M.; Mackay, M. F.;
Richards, S. L. J. Chem. Soc., Perkin Trans. 1
1992, 1329.
92. Banwell, M. G.; Bridges, V. S.; Dupuche, J.
R.; Richards, S. L.; Walter, J. M. J. O rg.
Chem. 1994, 59, 6338.
93. Cotterill, I. C.; Finch, H.; Reynolds, D. P.;
Roberts, S. M.; Rzepa, H. S.; Short, K. M.;
Slawin, A. M. Z.; Wallis, C. J.; Williams, D. J.
J. Chem. Soc., Chem. Commun. 1988, 470.
94. Carless, H. A. J.; Oak, O. Z. Tetrahedron Lett.
1989, 30, 1719.
95. Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc.
1992, 114, 9694.
96. Olivo, H. F., Ph.D. Dissertation, Virginia
Tech., Blacksburg, VA, 1992. Diss. Abstr. Vol.
53 07B, p 3487.
97. Yang, N. C.; Noh, T.; Gan, H.; Halfon, S.;
Hrnjez, B. J. J. Am. Chem. Soc. 1988, 110,
5919.
98. Balci, M.; Sütbeyaz, Y.; Seçen, H.
Tetrahedron 1990, 46, 3715.
99. Balci, M. Pure Appl. Chem. 1997, 69, 97.
100. Hudlicky, T.; Boros, C. H.; Boros, E. E.
Synthesis 1992, 174.
101. Butora, G.; Gum, A. G.; Hudlicky, T.; Abboud,
K. A. Synthesis 1998, 275.
102. Carless, H. A. J. J. Chem. Soc., Chem.
Commun. 1992, 234.
103. Hudlicky, T.; Price, J. D. Synlett 1990, 159.
104. Johnson, C. R.; Ple, P. A.; Su, L.; Heeg, M. J.;
Adams, J. P. Synlett 1992, 388.
105. Ley, S. V.; Sternfeld, F. Tetrahedron 1989, 45,
3463.
106.Mandel, M.; Hudlicky, T.; Kwart, L. D.;
Whited, G. M. J. Org. Chem. 1993, 58, 2331.
107. Hudlicky, T.; Mandel, M.; Rouden, J.; Lee, R.
S.; Bachmann, B.; Dudding, T.; Yost, K. J.;
Merola, J. S. J. Chem. Soc., Perkin Trans. 1
1994, 1553.
108. Brammer, L. E., Jr.; Hudlicky, T. Tetrahedron:
Asymmetry 1998, 9, 2011.
109 Desjardins, M.; Brammer, L. E., Jr.; Hudlicky,
T. Carbohydr. Res. 1997, 304, 39.
110. Hudlicky, T.; Cebulak, M. Cyclitols and Their
Derivatives: A Handbook of Physical,
Spectral, and Synthetic Data, VCH Publisher:
Weinheim, Germany, 1993.
111. Nguyen, B. V.; York, C.; Hudlicky, T.
Tetrahedron 1997, 53, 8807.
112. Pingli, L.; Vandewalle, M. Tetrahedron 1994,
50, 7061.
113. Oppong, K. A.; Hudlicky, T.; Yan, F.; York, C.;
Nguyen, B. V. Tetrahedron 1999, 55, 2875.
114. Billington, D. C.; Perrou-Sierra, F.; Picard, I.;
P. putida UV4
(ref. 238)
P. putida NCIB 9816/11
E. coli JM109(pDTG141)
(ref. 235)
S. yanoikuyae B8/36
(ref. 35,214)
S. yanoikuyae B8/36
S. capricornicum (green algae)
(ref. 35,214,216)
S. yanoikuyae B8/36
S. capricornicum (green algae)
(ref. 35,214,216)
P. putida NCIB 9816/11
E. coli JM109(pDTG141)
(ref. 235)
P. putida NCIB 9816/11
E. coli JM109(pDTG141)
(ref. 235)
S. yanoikuyae B8/36
(ref. 35,214)
S. yanoikuyae B8/36
(ref. 35,214)
S. yanoikuyae B8/36
(ref. 35,214)
S. yanoikuyae B8/36
(ref. 35,214)
S. yanoikuyae B8/36
(ref. 243)
S. yanoikuyae B8/36
(ref. 243, 244)
OH
OH
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
OH
OH
HO
OH
OH
OH
OH
OH
OH
HO
OH
HO
OH
OH
OH
Table 2. Diols Derived from Fused Aromatic Systems (cont.)
58 Vol. 32, No. 2, 1999

Beaubras, S.; Duhault, J.; Espinal, J.; Challal,
S. Bioorg. Med. Chem. Lett. 1994, 4, 2307.
115. Kara, Y.; Balci, M.; Bourne, S. A.; Watson, W.
H. Tetrahedron Lett. 1994, 35, 3349.
116. Lallemand, M.-C.; Desjardins, M.; Freeman,
S.; Hudlicky, T. Tetrahedron Lett. 1997, 38,
7693.
117. Desjardins, M.; Lallemand, M.-C.; Hudlicky,
T.; Abboud, K. A. Synlett 1997, 728.
118. Desjardins, M.; Lallemand, M.-C.; Freeman,
S.; Hudlicky, T.; Abboud, K. A. J. Chem. Soc.,
Perkin Trans. 1 1999, 621.
119. Hudlicky, T.; Abboud, K. A.; Bolonick, J.;
Maurya, R.; Stanton, M. L.; Thorpe, A. J.
Chem. Commun. 1996, 1717.
120. Hudlicky, T.; Abboud, K. A.; Entwistle, D. A.;
Fan, R.; Maurya, R.; Thorpe, A. J.; Bolonick,
J.; Myers, B. Synthesis 1996, 897.
121. Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F.
Tetrahedron Lett. 1989, 30, 4053.
122. Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. J.
Org. Chem. 1990, 55, 4683.
123.Mandel, M.; Hudlicky, T.; Kwart, L. D.;
Whited, G. M. Collect. Czech. Chem.
Commun. 1993, 58, 2517.
124. Nugent, T. C.; Hudlicky, T. J. Org. Chem.
1998, 63, 510.
125. Hudlicky, T.; Rouden, J.; Luna, H. J. O rg.
Chem. 1993, 58, 985.
126. Pitzer, K.; Hudlicky, T. Synlett 1995, 803.
127. Hudlicky, T.; Nugent, T.; Griffith, W. J. Org.
Chem. 1994, 59, 7944.
128. Hudlicky, T.; Pitzer, K. K.; Stabile, M. R.;
Thorpe, A. J.; Whited, G. M. J. Org. Chem.
1996, 61, 4151.
129. Yan, F.; Nguyen, B. V.; York, C.; Hudlicky, T.
Tetrahedron 1997, 53, 11541.
130. Entwistle, D. A.; Hudlicky, T. Tetrahedron
Lett. 1995, 36, 2591.
131. Hudlicky, T.; Thorpe, A. J. Synlett 1994, 899.
132. Banwell, M. G.; De Savi, C.; Watson, K.
Chem. Commun. 1998, 1189.
133. Johnson, C. R.; Golebiowski, A.; Sundram,
H.; Miller, M. W.; Dwaihy, R. L. Tetrahedron
Lett. 1995, 36, 653.
134. Johns, B. A.; Pan, Y. T.; Elbein, A. D.;
Johnson, C. R. J. Am. Chem. Soc. 1997, 119,
4856.
135. Hudlicky, T.; Seoane, G.; Price, J. D.;
Gadamasetti, K. G. Synlett 1990, 433.
136. Hudlicky, T.; Frazier, J. O.; Seoane, G.; Tiedje,
M.; Seoane, A.; Kwart, L. D.; Beal, C. J. Am.
Chem. Soc. 1986, 108, 3755.
137. Martin, S. F.; Tso, H.-H. Heterocycles 1993,
35, 85.
138. Rouden, J.; Hudlicky, T. J. Chem. Soc., Perkin
Trans. 1 1993, 1095.
139. Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J.
Am. Chem. Soc. 1994, 116, 5099.
140. Kayakiri, H.; Kasahara, C.; Nakamura, K.;
Oku, T.; Hashimoto, M. Chem. Pharm. Bull.
1991, 39, 1392.
141. Tian, X.; Hudlicky, T.; Konigsberger, K. J. Am.
Chem. Soc. 1995, 117, 3643.
142. Tian, X.; Maurya, R.; Konigsberger, K.;
Hudlicky, T. Synlett 1995, 1125.
143.Hudlicky, T.; Tian, X.; Konigsberger, K.;
Maurya, R.; Rouden, J.; Fan, B. J. Am. Chem.
Soc. 1996, 118, 10752.
144. Banwell, M. G.; Bissett, B. D.; Busato, S.;
Cowden, C. J.; Hockless, D. C. R.; Holman, J.
W.; Read, R. W.; Wu, A. W. J. Chem. Soc.,
Chem. Commun. 1995, 2551.
145. Hudlicky, T.; Akgun, H., Tetrahedron Lett.
1999, 308.
146. Hudlicky, T.; Gonzalez, D.; Martinot, T.
Tetrahedron Lett. 1999, 3077.
147. Gonzalez, D.; Schapiro, V.; Seoane, G.;
Hudlicky, T. Tetrahedron: Asymmetry 1997, 8,
975.
148. Kazmaier, U. Liebigs Ann./Recl. 1997, 285;
and references cited therein.
149. Butora, G.; Hudlicky, T.; Fearnley, S. P.; Gum,
A. G.; Stabile, M. R.; Abboud, K. A.
Tetrahedron Lett. 1996, 37, 8155.
150. Butora, G.; Hudlicky, T.; Fearnley, S. P.;
Stabile, M. R.; Gum, A. G.; Gonzalez, D.
Synthesis 1998, 665.
151. Parker, K. A.; Fokas, D. J. Org. Chem. 1994,
59, 3933.
152. Endoma, M. A.; Butora, G.; Claeboe, C. D.;
Hudlicky, T.; Abboud, K. A. Tetrahedron Lett.
1997, 38, 8833.
153. Bottari, P.; Endoma, M. A.; Hudlicky, T.;
Ghiviringa, I.; Abboud, K. A. Coll. Czech.
Chem. Commun. 1999, 64, 203.
154. Johnson, C. R.; Penning, T. D. J. Am. Chem.
Soc. 1986, 108, 5655.
155. Johnson, C. R.; Penning, T. D. J. Am. Chem.
Soc. 1988, 110, 4726.
156. Borcherding, D. R.; Scholtz, S. A.; Borchardt,
R. T. J. Org. Chem. 1987, 52, 5457.
157. Bestmann, H. J.; Roth, D. Synlett 1990, 751.
158. Hudlicky, T.; Natchus, M. G.; Nugent, T. C.
Synth. Commun. 1992, 22, 151.
Pseudomonas sp. POB 310
(ref. 211)
Pseudomonas NCIB 9816,
S. yanoikuyae B8/36
(ref. 204)
Pseudomonas sp. HH69
(ref. 206)
S. yanoikuyae B8/36
(ref. 207)
S. yanoikuyae B8/36
(ref. 207)
Pseudomonas sp. HH69
(ref. 206)
S. yanoikuyae B8/36
(ref. 208)
E. coli JM109(pDTG601A)
(ref. 224)
E. coli JM109(pDTG601A)
(ref. 147)
S. yanoikuyae B8/36
E. coli JM109(pDTG601A)
(ref. 31,147,209)
Pseudomonas sp. LB400
(ref. 56,237)
Pseudomonas sp. LB400
(ref. 237)
E. coli JM109(pDTG601A)
(ref. 147)
Pseudomonas sp. LB400
(ref. 237)
Brevibacterium DPO 1361
(ref. 211)
P. putida JT107
(ref. 40)
OH
HO
CO2H
HO2C
OH OH
HO
HO
OH
OH
Cl
Cl
Cl
Cl
HO OH
OMe
HO OH
Cl
Cl
HO OH
Cl
HO OH
HO OH
OMe
MeO
HO OH
O
O
S
HO OH
OOH OH O
OH
OH
O
HO OH
O
O
OH
HO O
OOH
OH
O
OH
OH
HO2C
HO OH
HO OH
Pseudomonas sp.
(ref. 226)
Table 3. Diols Derived from Linked Aromatic Systems
Vol. 32, No. 2, 1999 59

159. Hudlicky, T.; Natchus, M. J. Org. Chem. 1992,
57, 4740.
160. For details of this methodology, see: Hudlicky,
T.; Heard, N. E.; Fleming, A. J. Org. Chem.
1990, 55, 2570.
161. Hudlicky, T.; Seoane, G.; Pettus, T. J. Org .
Chem. 1989, 54, 4239.
162. Johnson, C. R.; Ple, P. A.; Adams, J. P. J.
Chem. Soc., Chem. Commun. 1991, 1006.
163. Dumortier, L.; Van der Eycken, J.;
Vandewalle, M. Synlett 1992, 245.
164. Noheda, P.; Garcia-Ruiz, G.; Pozuelo, M. C.;
Abbassi, K.; Pascual-Alfonso, E.; Alonso, J.
M; Jimenez-Barbero, J. J. Org. Chem. 1998,
63, 6772.
165. (a) D avies, I. W.; Senanayake, C. H.;
Castonguay, L.; Larsen, R. D.; Verhoeven, T.
R.; Reider, P. J. Tetrahedron Lett. 1995, 36,
7619. (b) See also: Davies I. W.; Reider P. J.
Chem. Ind. (London) 1996, 412.
166. Ensley, B. D.; Ratzkin, B. J.; Osslund, T. D.;
Simon, M. J.; Wackett, L. P.; Gibson, D. T.
Science 1983, 222, 167.
167. Whited, G. Presented at Biotrans '95,
University of Warwick, 1995.
168. Wendeborn, S.; De Mesmaeker, A.; Brill, W.
K. D. Synlett 1998, 865.
169. Boyd, D. R.; Sharma, N. D.; Hand, M. V.;
Groocock, M. R.; Kerley, N. A.; Dalton, H.;
Chima, J.; Sheldrake, G. N. J. Chem. Soc.,
Chem. Commun. 1993, 974.
170. Boyd, D. R.; Sharma, N. D.; Barr, S. A.;
Dalton, H.; Chima, J.; Whited, G.; Seemayer,
R. J. Am. Chem. Soc. 1994, 116, 1147.
171. Torok, D. S.; Resnick, S. M.; Brand, J. M.;
Cruden, D. L.; Gibson, D. T. Appl. Environ.
Microbiol. 1995, 177, 5799.
172. Hogn, T.; Jaenicke, L. Eur. J. Biochem. 1972,
30, 369.
173. Cass, A. E. G.; Ribbons, D. W.; Rossiter, J. T.;
Williams, S. R. FEBS Lett. 1987, 220, 353.
174. Schofield, J. A. (Shell Internationalle)
European Patent 252567, 1986.
175. Knackmuss, H.-J. Chem. Ztg. 1975, 99, 213.
176. Rossiter, J. T.; Williams, S. R.; Cass, A. E. G.;
Ribbons, D. W. Tetrahedron Lett. 1987, 28,
5173.
177. Taylor, S. J. C.; Ribbons, D. W.; Slawin, A. M.
Z.; Widdowson, D. A.; Williams, D. J.
Tetrahedron Lett. 1987, 28, 6391.
178. Dorn, E.; Hellwig, M.; Reineke, W.;
Knackmuss, H.-J. Arch. Microbiol. 1974, 99,
61.
179. Hartmann, J.; Reineke, W.; Knackmuss, H.-J.
Appl. Environ. Microbiol. 1979, 37, 421.
180. Kobal, V. M.; Gibson, D. T.; Davis, R. E.;
Garza, A. J. Am. Chem. Soc. 1973, 95, 4420.
181. Whited, G. M.; McCombie, W. R.; Kwart, L.
D.; Gibson, D. T. J. Bacteriol. 1986, 166,
1028.
182. Geary, P. J.; Pryce, R. J.; Roberts, S. M.;
Ryback, G.; Winders, J. A. J. Chem. Soc.,
Chem. Commun. 1990, 204.
183. Engesser, K. H.; Cain, R. B.; Knackmuss, H.-
J. Arch. Microbiol. 1988, 149, 188.
184. Boyd, D. R.; Sharma, N. D.; Byrne, B.; Hand,
M. V.; Malone, J. F.; Sheldrake, G. N.;
Blacker, J.; Dalton, H. J. J. Chem. Soc., Perkin
Trans. 1 1998, 1935.
185. Boyd, D. R.; Sharma, N. D.; Boyle, R.;
McMordie, R. A. S.; Chima, J.; Dalton, H.
Tetrahedron Lett. 1992, 33, 1241.
186. Eaton, R. W.; Ribbons, D. W. J. Bacteriol.
1982, 151, 48.
187. Hudlicky, T.; Boros, E. E.; Boros, C. H.
Tetrahedron: Asymmetry 1993, 4, 1365.
188. Hudlicky, T.; Boros, E. E.; Boros, C. H.
Synlett 1992, 391.
189. Konigsberger, K.; Hudlicky, T. Tetrahedron:
Asymmetry 1993, 4, 2469.
190. Bestetti, G.; Galli, E.; Benigni, C.; Orsini, F.;
Pellizzoni, F. Appl. Microbiol. Biotechnol.
1989, 30, 252.
191. Boyd, D. R.; Sharma, N. D.; Stevenson, P. J.;
Chima, J.; Gray, D. J.; Dalton, H. Tetrahedron
Lett. 1991, 32, 3887.
192. Stabile, M. R.; Hudlicky, T.; Meisels, M. L.
Tetrahedron: Asymmetry 1995, 6, 537.
193. Stabile, M. R.; Hudlicky, T.; Meisels, M. L.;
Butora, G.; Gum, A. G.; Fearnley, S. P.;
Thorpe, A. J.; Ellis, M. R. Chirality 1995, 7,
556.
194. Omori, T.; Jigami, Y.; Minoda, Y. Agr. Biol.
Chem. 1974, 38, 409.
195. Buck, R.; Eberspacher, J.; Lingens, F. Hoppe-
Seyler's Z. Physiol. Chem. 1979, 360, 957.
196. Omori, T.; Jigami, Y.; Minoda, Y. Agr. Biol.
Chem. 1975, 39, 1781.
197. Hudlicky, T.; Endoma, M. A. A.; Butora, G.
Tetrahedron: Asymmetry 1996, 7, 61.
198. Cerniglia, C. E.; Gibson, D. T.; Van Baalen, C.
J. Gen. Microbiol. 1980, 116, 485.
199. Cerniglia, C. E.; Gibson, D. T.; Van Baalen, C.
J. Gen. Microbiol. 1980, 116, 495.
200. Cerniglia, C. E.; Gibson, D. T.; Van Baalen, C.
Biochem. Biophys. Res. Commun. 1979, 88,
50.
201. Knackmuss, H.-J.; Beckmann, W.; Otting, W.
Angew. Chem., Int. Ed. Engl. 1976, 15, 549.
202. Boyd, D. R.; McMordie, R. A. S.; Sharma, N.
D.; Dalton, H.; Williams, P.; Jenkins, R. O. J.
Chem. Soc., Chem. Commun. 1989, 339.
203. Baaggi, G.; Castelani, D.; Galli, E.; Treccani,
V. Biochem. J. 1972, 126, 1091.
204. Kle
h
ka, G. M.; Gibson, D. T. Appl. Environ.
Microbiol. 1980, 39, 288.
205. Shocken, M. J.; Gibson, D. T. Appl. Environ.
Microbiol. 1976, 48, 10.
206. Fortnagel, P.; Harms, H.; Wittich, R. M.;
Krohn, S.; Meyer, H.; Sinwell, V.; Wilkes, H.;
Francke, W. Appl. Environ. Microbiol. 1990,
56, 1148.
207. Cerniglia, C. E.; Morgan, J. C.; Gibson, D. T.
Biochem. J. 1979, 180, 175.
208. Laborde, A. L.; Gibson, D. T. Appl. Environ.
Microbiol. 1977, 34, 783.
209. Catelani, D.; Sorlini, C.; Treccani, V.
P. putida UV4
(ref. 240)
P. putida UV4
(ref. 240)
P. putida UV4
(ref. 240)
P. putida UV4
(ref. 231)
P. putida UV4
(ref. 231)
P. putida UV4
(ref. 225)
P. putida UV4
(ref. 225)
P. putida UV4
(ref. 225)
P. putida UV4
(ref. 239)
P. putida UV4
(ref. 239)
P. putida UV4
(ref. 239)
P. putida UV4
(ref. 225)
P. putida UV4
(ref. 225)
P. putida UV4
(ref. 225)
P. putida UV4
(ref. 217)
P. putida UV4
(ref. 231)
P. putida UV4
(ref. 217)
P. putida UV4
(ref. 231)
P. putida UV4
(ref. 185)
P. putida UV4
(ref. 217)
P. putida UV4
(ref. 231)
P. putida UV4
(ref. 231)
P. putida UV4
(ref. 225)
S. yanoikuyae B8/36
(ref. 243)
S. yanoikuyae B8/36
(ref. 243)
S. yanoikuyae B8/36
(ref. 243)
S. yanoikuyae B8/36
(ref. 243)
OH
OH
N
OH
OHN
N
N
N
OH
OH
OH
OH
N
OH
OH
N
N
OH
OH
N
OH
OH
O
OH
OH
O
OH
HO
S
OH
OH
O
OH
HO
O
OH
OH
S
OH
HO
S
OH
OH
S
OH
HO
N
OH
OH
Cl
N
OH
OHCl
N
H
O
OH
OH
S
OH
OH
S
OH
OH
O
OH
OH
O
OH
OH
S
OH
OH
N
OH
HO
NOH
OH
S
OH
HO
S
HO
HO OH
OH
H
N
OH
OH
E. coli HB101(pE317)
P. putida 39/D and G7
(ref. 166)
Table 4. Diols Derived from Aromatic Heterocycles
60 Vol. 32, No. 2, 1999

Experientia 1971, 27, 1173.
210. Selifonov, S. A.; Grifoll, M.; Gurst, J. E.;
Chapman, P. J. Biochem. Biophys. Res.
Commun. 1993, 193, 67.
211. Engesser, K. H.; Fietz, W.; Fischer, R.;
Schulte, P.; Knackmuss, H.-J. FEMS
Microbiol. Lett. 1990, 69, 317.
212. Jerina, D. M.; Selander, H.; Yagi, H.; Wells,
M. C.; Davey, J. F.; Mahadevan, V.; Gibson, D.
T. J. Am. Chem. Soc. 1976, 98, 5988.
213. Narro, M. L.; Cerniglia, C. E.; Van Baalen, C.;
Gibson, D. T. Appl. Environ. Microbiol. 1992,
58, 1351.
214. Gibson, D. T.; Mahadevan, V.; Jerina, D. M.;
Yagi, H.; Yeh, H. J. C. Science 1975, 189, 295.
215. Eaton, S. L.; Resnick, S. M.; Gibson, D. T.
Appl. Environ. Microbiol. 1996, 62, 4388.
216. Lindquist, B.; Warshawsky, D. Experientia
1985, 41, 767.
217. Boyd, D. R.; Sharma, N. D.; Boyle, R.;
McMurray, B. T.; Evans, T. A.; Malone, J. F.;
Dalton, H.; Chima, J.; Sheldrake, G. N. J.
Chem. Soc., Chem. Commun. 1993, 49.
218. Reddy, G. D.; Wiest, O.; Hudlicky, T.;
Schapiro, V.; Gonzalez, D. J. Org. Chem.
1999, 64, 2860.
219. Hudlicky, T.; Gonzalez, D.; Stabile, M.;
Endoma, M. A.; Deluca, M.; Parker, D.;
Gibson, D. T.; Resnick, S. M.; Whited, G. M.
J. Fluor. Chem. 1998, 89, 23.
220. Astley, S. T.; Meyer, M.; Stephenson, G. R.
Tetrahedron Lett. 1993, 34, 2035.
221. Allen, C. C. R.; Boyd, D. R.; Dalton, H.;
Sharma, N. D.; Haughey, S. A.; McMordie, R.
A. S.; McMurray, B. T.; Sheldrake, G. N.;
Sproule, K. J. Chem. Soc., Chem. Commun.
1995, 119.
222. Deluca, M. E.; Hudlicky, T. Tetrahedron Lett.
1990, 31, 13.
223. Whited, G. M.; Downie, J. C.; Hudlicky, T.;
Fearnley, S. P.; Dudding, T. C.; Olivo, H. F.;
Parker, D. Bioorg. Med. Chem. 1994, 2, 727.
224. Hudlicky, T.; Gonzalez, D.; Schilling, S.
Unpublished results, 1997.
225. Boyd, D. R.; Sharma, N. D.; Dorrity, M. R. J.;
Hand, M. V.; McMordie, R. A. S.; Malone, J.
F.; Porter, H. P.; Dalton, H.; Chima, J.;
Sheldrake, G. N. J. Chem. Soc., Perkin Trans.
11993, 1065.
226. Kimura, K.; Kato, H.; Nishi, A.; Furukawa, K.
Biosci. Biotech. Biochem. 1996, 60, 220.
227. Resnick, S. M.; Gibson, D. T. Unpublished
results.
228. Resnick, S. M.; Gibson, D. T. Biodegradation
1993, 4, 195.
229. Nadeau, L. J.; Sayler, G. S.; Spain, J. C. Arch.
Microbiol. 1998, 171, 44.
230. Boyd, D. R.; Dorrity, M. R. J.; Malone, J. F.;
McMordie, R. A. S.; Sharma, N. D.; Dalton,
H.; Williams, P. J. Chem. Soc., Perkin Trans. 1
1990, 489.
231. Boyd, D. R.; Sharma, N. D.; Brannigan, I. F.;
Haughey, S. A.; Malone, J. F.; Clarke, D. A.;
Dalton, H. Chem. Commun. 1996, 2361.
232. Eaton, R. W.; Selifonov, S. A. Appl. Environ.
Microbiol. 1996, 62, 756.
233. Resnick, S. M.; Gibson, D. T. Appl. Environ.
Microbiol. 1996, 62, 1364.
234. Boyd, D. R.; Sharma, N. D.; Kerley, N. A.;
McMordie, R. A. S.; Sheldrake, G. N.;
Williams, P.; Dalton, H. J. Chem. Soc., Perkin
Trans. 1 1996, 67.
235. Resnick, S. M.; Gibson, D. T. Appl. Environ.
Microbiol. 1996,62, 3355.
236. Wackett, L. P.; Kwart, L. D.; Gibson, D. T.
Biochemistry 1988, 27, 1360.
237. Haddock, J. D.; Horton, J. R.; Gibson, D. T. J.
Bacteriol. 1995, 177, 20.
238. Bowers, N. I.; Boyd, D. R.; Sharma, N. D.;
Kennedy, M. A.; Sheldrake, G. N.; Dalton, H.
Tetrahedron: Asymmetry 1998,9, 1831.
239. Boyd, D. R.; Sharma, N. D.; Carroll, J. G.;
Malone, J. F.; Mackerracher, D. G.; Allen, C.
C. R. Chem. Commun. 1998, 683.
240. Boyd, D. R.; Sharma, N. D.; Boyle, R.; Evans,
T. A.; Malone, J. F.; McCombe, K. M.; Dalton,
H.; Chima, J. J. Chem. Soc., Perkin Trans. 1
1996, 1757.
241. Novak, B. H.; Hudlicky, T. Tetrahedron:
Asymmetry 1999, 10, in press.
242. Hudlicky, T.; Endoma, M. A. A.; Butora, G. J.
Chem. Soc., Perkin Trans. 1 1996, 2187.
243. Boyd, D. R.; Sharma, N. D.; Hempestall, F.;
Kennedy, M. A.; Malone, J. F.; Allen, C. C. R.;
Resnick, S. M.; Gibson, D. T. J. Org. Chem.
1999, 64, 4005.
Note Added in Proof
Total Syntheses
1. Banwell, M.; McLeod, M. Chemoenzymatic
total synthesis of the sesquiterpene
(–)-patchoulenone Chem. Commun. 1998,
1851.
2. Banwell, M.; Blakey, S.; Harfoot, G.;
Longmore, R. W. First synthesis of L-ascorbic
acid (vitamin C) from a non-carbohydrate
source. J. Chem. Soc., Perkin Trans. 1 1998,
3141.
3. Banwell, M. G.; Blakey, S.; Harfoot, G.;
Longmore, R. W. cis-1,2-Dihydrocatechols in
chemical synthesis: First synthesis of L-ascor-
bic acid (vitamin C) from a non-carbohydrate
source. Aust. J. Chem. 1999, 52, 137.
P. putida NCIB 9816/11
P. putida NCIMB 8859
(ref. 50,65)
P. putida UV4
P. putida 39/D
(ref. 65,171,202)
P. putida NCIB 9816/11
P. putida NCIMB 8859
S. yanoikuyae B8/36
(ref. 65,171,215)
P. putida NCIB 9816/11
P. putida NCIMB 8859
S. yanoikuyae B8/36
(ref. 50,65,233)
P. putida 39/D
(ref. 135)
P. putida UV4
(ref. 221)
P. putida BM2
(ref. 182)
P. putida JT107
(ref. 40)
P. putida UV4
P. putida 39/D
(ref. 65,202,230,233)
P. putida BM2
(ref. 182)
P. putida UV4
P. putida 39/D
(ref. 65,202,236)
A. eutrophus A5
(ref. 229)
Pseudomonas sp. F274
(ref. 210)
HO
OH
HO OH
OH
OH
CO2H
CH3
H3C
OHHO
OH
OH
SS
OH
OH
O
HO OH
OH
OH
OH
OH
OH
OH
OH
OH
CCl3
H
Cl
Cl
OH
OH
OOH OH
Table 5. Miscellaneous Diols
Vol. 32, No. 2, 1999 61
OH
OH
Me
OOBn
HO
(-)-patchoulenone
OH
OH
Cl
O
O
O
OH
OOH
Ph
H
O
OH
OH
OOH
OH
H
L-ascorbic acid

Synthetic Methodology and Biochemical
Discoveries
4. Boyd, D. R.; Sharma, N. D.; Byrne, B.; Hand,
M. V.; Malone, J. F.; Sheldrake, G. N.;
Blacker, J.; Dalton, H. Enzymatic and
chemoenzymatic synthesis and stereochemi-
cal assignment of cis-dihydrodiol derivatives
of monosubstituted benzenes. J. Chem. Soc.,
Perkin Trans. 1 1998, 1935.
5. Boyd, D. R.; Sharma, N. D.; Carroll, J. G.;
Malone, J. F.; Mackerracher, D. G.; Allen, C.
C. R. Dioxygenase-catalysed cis-dihydrodiol
formation in the carbo- and heterocyclic rings
of quinolines. Chem. Commun. 1998, 683.
6. Barr, S. A.; Bowers, N.; Boyd, D. R.; Sharma,
N. D.; Hamilton, L.; Austin, R.; McMordie,
S.; Dalton, H. The potential role of cis-dihy-
drodiol intermediates in bacterial aromatic
hydroxylation and the NIH Shift. J. Chem.
Soc., Perkin Trans. 1 1998, 3443.
7. O'Dowd, C. R.; Boyd, D. R.; Sharma, N. D.
Enantiopure synthesis of syn and anti arene
dioxides. Abstr. Pap.—Am. Chem. Soc. 1998,
216, U470.
8. Lakshman, M. K.; Chaturvedi, S.; Zajc, B.;
Gibson, D. T.; Resnick, S. M. A general
chemoenzymatic synthesis of enantiopure cis-
β-amino alcohols from microbially derived
cis-glycols. Synthesis 1998, 1352.
9. Parales, R. E.; Emig, M. D.; Lynch, N. A.;
Gibson, D. T. Substrate specificities of hybrid
naphthalene and 2,4-dinitrotoluene dioxyge-
nase enzyme systems. J. Bacteriol. 1998, 180,
2337.
10. Parales, J. V.; Parales, R. E.; Resnick, S. M.;
Gibson, D. T. Enzyme specificity of 2-nitro-
toluene 2,3-dioxygenase from Pseudomonas
sp. strain JS42 is determined by the C-termi-
nal region of the αsubunit of the oxygenase
component. J. Bacteriol. 1998, 180, 1194.
11. Allen, C. C. R.; Boyd, D. R.; Hempestall, F.;
Larkin, M. J.; Sharma, N. D. Contrasting
effects of a nonionic surfactant on the bio-
transformation of polycyclic aromatic hydro-
carbons to cis-dihydrodiols by soil bacteria.
Appl. Environ. Microbiol. 1999, 65, 1335.
12. Brovetto, M.; Schapiro, V.; Cavalli, G.;
Padilla, P.; Sierra, A.; Seoane, G.; Suescun, L.;
Mariezcurrena, R. Osmylation of chiral cis-
cyclohexadienediols. New J. Chem. 1999, 23,
549.
13. Jiang, H. Y.; Parales, R. E.; Gibson, D. T. The
αsubunit of toluene dioxygenase from
Pseudomonas putida F1 can accept electrons
from reduced Ferredoxin(TOL) but is catalyt-
ically inactive in the absence of the βsubunit.
Appl. Environ. Microbiol. 1999, 65, 315.
14. Nojiri, H.; Nam, J. W.; Kosaka, M.; Morii, K.
I.; Takemura, T.; Furihata, K.; Yamane, H.;
Omori, T. Diverse oxygenations catalyzed
by carbazole 1,9a-dioxygenase from
Pseudomonas sp. strain CA10. J. Bacteriol.
1999, 181, 3105.
15. Parales, R. E.; Parales, J. V.; Gibson, D. T.
Aspartate 205 in the catalytic domain of naph-
thalene dioxygenase is essential for activity. J.
Bacteriol. 1999, 181, 1831.
About the Authors
Tomas Hudlicky was born in 1949 in
Prague, Czechoslovakia, where he received
his elementary and middle school education.
After several years of working as a process
chemist apprentice and in other odd jobs in
pharmaceutical chemistry, it became apparent
that higher education opportunities were
closed to him. In 1968, he emigrated to the
U.S. with his parents and sister. Hudlicky’s
educational experience continued at
Blacksburg High School, from which he
dropped out in the spring of 1969. Accepted
as a probational student at Virginia Tech the
following autumn, he received his B.S. in
chemistry in 1973, and went on to pursue
graduate studies at Rice University under the
direction of Professor Ernest Wenkert in the
field of indole alkaloid total synthesis, earning
his Ph.D. in 1977. He then spent a year at the
University of Geneva working under the late
Professor Wolfgang Oppolzer on the synthesis
of isocomene. In 1978, he joined the faculty
at the Illinois Institute of Technology as an
Assistant Professor, and began the first phase
of his research career in the field of general
methods of synthesis for triquinane terpenes
and other natural products containing five-
membered rings by [4+1] cyclopentene,
pyrroline, and dihydrofuran annulation
methodologies. He returned to his alma
mater, Virginia Tech, in 1982, and rose to the
rank of Professor in 1988. One year later, at
the 20-year class reunion of the Blacksburg
High School class of 1969, he received his
High School Diploma. The next phase of his
research involved the investigation of cis-
cyclohexadienediols in enantioselective syn-
thesis, as summarized in this review.
In 1995, he moved to his present position
at the University of Florida in Gainesville.
His current research interests include the
development of enantioselective synthetic
methods, bacterial dioxygenase-mediated
degradation of aromatics, design and synthe-
sis of fluorinated inhalation anesthetic agents,
synthesis of morphine and amaryllidaceae
alkaloids, and design of unnatural oligo-
saccharide conjugates with new molecular
properties. His hobbies include skiing, hock-
ey, martial arts, and music.
David Gonzalez was born in Montevideo,
Uruguay in 1965. He attended elementary
and middle school at Instituto Crandon, and
received his undergraduate education at the
School of Chemistry of the Uruguayan public
University (Universidad de la República). He
performed undergraduate research in the
Natural Products laboratory of Professor
Patrick Moyna, where he later worked as a lab
technician. In 1994, with the aid of a grant
from SAREC and a master’s fellowship from
CONICYT, he obtained his master’s degree in
the area of bioactive marine natural products
under the orientation of Professor Eduardo
Manta. He was later accepted as a graduate
student at the University of Florida, where he
completed his doctoral degree in Professor
Tomas Hudlicky’s group. His current research
interests involve the use of microbial biotrans-
formations as a tool in organic synthesis. The
results of his research have been presented at
several meetings and have led to seven
publications.
Dr. David T. Gibson was born in
Wakef ield, Yorkshire, England. He received a
B.Sc. degree (First Class Honors) in
Biochemistry in 1961 from the University of
Leeds, England. He obtained his Ph.D. in
1964 in the same department under the guid-
ance of the late Stanley Dagley. His disserta-
tion research played a major role in the eluci-
dation of the meta ring-fission pathway used
by bacteria to degrade aromatic compounds.
Dr. Gibson’s initial postdoctoral studies were
conducted in the laboratory of Dr. Charles J.
Sih in the College of Pharmacy at the
University of Wisconsin, where he worked on
the microbial degradation of the steroid A
ring. He then began studies on the bacterial
oxidation of hydrocarbons with the late Dr.
Reino E. Kallio in the Department of
Microbiology at the University of Illinois. In
1967, he joined the faculty of the Department
of Microbiology at the University of Texas at
Austin as an assistant professor. The follow-
ing year, he worked as a Research Biochemist
in the Pharmaceuticals Division of Imperial
Chemical Industries at Alderly Edge,
Cheshire, England. In 1969, he returned to the
Department of Microbiology at the University
of Texas, rising through the ranks to Professor
of Microbiology in 1975, and Director of the
Center for Applied Microbiology in 1981.
During this period, he studied the chemistry
and enzymology of the reactions used by
bacteria, fungi, and algae to initiate the degra-
dation of aromatic hydrocarbons. In 1988, he
was appointed to his current position as
Foundation Professor in Microbiology and
Biocatalysis at the University of Iowa. Dr.
Gibson’s current interests focus on the
structure and function of bacterial enzymes
that catalyze the asymmetric dihydroxylation
of aromatic hydrocarbons. He is the author of
more than 150 publications and the mentor of
22 graduate students. He has served on the
editorial boards of the Journal of Biological
Chemistry, the Journal of Bacteriology, and
Biodegradation. From 1981–1988, he was a
member of the Scientific Advisory Board of
AMGEN. In 1997, he received the Proctor
and Gamble Award in Applied and
Environmental Microbiology from the
American Society for Microbiology.
62 Vol. 32, No. 2, 1999

Chiral Nonracemic cis-Dienediols
and Derivatives
Building Blocks with a Remarkable Scope
The cis-dienediol functionality offers researchers a fantastic opportunity for the manipulation of these building blocks into a
variety of products. Chiral nonracemic cis-dienediols can undergo a variety of reactions such as oxidative cleavage, cycloaddi-
tions, electrophilic additions, and sigmatropic rearrangements.
Aldrich now offers an extensive line of cis-dienediols and their derivatives. To place an order, please call 800-558-9160 (USA)
or contact your local Sigma-Aldrich office.
48,949-2* (1S-cis)-3-Bromo-3,5-cyclohexadiene-1,2-diol, 96%
48,950-6* (1S-cis)-3-Chloro-3,5-cyclohexadiene-1,2-diol, 98%
48,963-8* (1S-cis)-3-Phenyl-3,5-cyclohexadiene-1,2-diol, 98%
49,032-6* (1R-cis)-1,2-Dihydro-1,2-naphthalenediol, 98%
49,035-0 [3aS-(3aα,4α,5α,7aα)]-7-Bromo-3a,4,5,7a-tetrahydro-2,2-dimethyl-1,3-benzodioxole-4,5-diol, 99%
49,038-5 [3aS-(3aα,4α,5α,7aα)]-3a,4,5,7a-Tetrahydro-2,2-dimethyl-1,3-benzodioxole-4,5-diol, 98%
49,085-7 [3aS-(3aα,5aβ,6aβ,6bα)]-4-Bromo-3a,5a,6a,6b-tetrahydro-2,2-dimethyloxireno[e]-1,3-benzodioxole, 98%
49,088-1 [3aR-(3aα,5aβ,6aβ,6bα)]-3a,5a,6a,6b-Tetrahydro-2,2-dimethyloxireno[e]-1,3-benzodioxole, 96%
49,340-6 [3aS-(3aα,4α,5β,7aα)]-5-Azido-7-bromo-3a,4,5,7a-tetrahydro-2,2-dimethyl-1,3-benzodioxol-4-ol, 99%
49,388-0 (3aS,7R,7aS)-7,7a-Dihydro-7-hydroxy-2,2-dimethyl-1,3-benzodioxol-4(3aH)-one, 98%
49,389-9 (3aS,7R,7aS)-7-(Carbobenzyloxyamino)-7,7a-dihydro-2,2-dimethyl-1,3-benzodioxol-4(3a
H
)-one, 98%
49,390-2 (3aR,4S,7R,7aS)-7-(Carbobenzyloxyamino)-3a,4,7,7a-tetrahydro-2,2-dimethyl-1,3-benzodioxol-4-ol, 98%
49,391-0 (3aR,4S,7R,7aS)-3a,4,7,7a-Tetrahydro-7-(methoxycarbonylamino)-2,2-dimethyl-1,3-benzodioxol-4-ol 4-acetate, 98%
* All these products are offered as a suspension in phosphate buffer. The unit size corresponds to the actual amount of product and not the total
volume. The label provides simple instructions on how to extract the product from the suspension prior to use. The chemical purity of each
product was determined on the pure crystals prior to suspending them in the phosphate buffer.
OH
OH
Br
OH
OH
Cl
OH
OH
OH
OH
O
O
Br
HO
OH
O
O
HO
OH
O
O
Br
OO
O
O
O
O
Br
N3
OH
O
OH
O
O
O
NH
O
O
O
OPh NH
O
O
O
OPh
OH
NH
O
O
O
O
Me
OAc
48,949-2 48,950-6 48,963-8 49,032-6
49,035-0 49,038-5 49,085-7 49,088-1 49,340-6
49,388-0 49,389-9 49,390-2 49,391-0
Chiral Nonracemic cis-Dienediols
and Derivatives
Building Blocks with a Remarkable Scope

Uses of Mg*
Reactant Product Ref.
M
etal-enhanced organic synthesis via organometallic intermediates is a widely used process
for the preparation of thousands of organic compounds. However, in some cases, ordinar y
bulk metal forms fail to react with organic substrates. Fortunately, Professor Reuben Rieke and
co-workers have developed highly active metal forms (M*) that react ef ficiently with a variety of
organic substrates. Listed in the tables below are some applications for Rieke®Highly Active
Metals taken from recent publications.
For a complete listing of Rieke®products available from Aldrich, please contact our Technical
Services Department at 800-231-8327 (USA) or your local Sigma-Aldrich of fice, or visit us on the
Web at www.sigma-aldrich.com.
R
ieke®Highly Reactive Zinc reacts with carbon–halide bonds to give Rieke®Organozinc Reagents
(RZnX, where R=alkyl, aryl; X=halide)1-4 —a class of compounds that are reasonably stable as
solutions in tetrahydrofuran. These reagents have different reactivity and selectivity proper ties
than the analogous Grignard Reagents, and are employed in cross-coupling reactions,5-7 Michael
additions, and electrophilic amination reactions.8
Rieke®Organozinc Reagents are now available in research quantities exclusively from Aldrich.
The reagents listed below are the first in an extensive line of Rieke®Organozinc Reagents that will
be available from Aldrich shortly.
Rieke is a registered trademark of Rieke Metals, Inc.
49,760-6 1-Adamantylzinc bromide
49,751-7 Benzylzinc bromide
52,165-5 3-Bromobenzylzinc bromide
49,946-3 4-Bromobenzylzinc bromide
49,766-5 5-Bromo-2-thienylzinc bromide
49,775-4
tert
-Butylzinc bromide
49,776-2 4-Chlorobenzylzinc chloride
49,777-0 4-Chlorobutylzinc bromide
49,779-7 6-Chlorohexylzinc bromide
49,781-9 5-Chloropentylzinc bromide
49,783-5 4-Chlorophenylzinc iodide
49,789-4 4-Cyanobutylzinc bromide
49,790-8 2-Cyanoethylzinc bromide
49,796-7 3-Cyanopropylzinc bromide
49,803-3 Cyclohexylzinc bromide
49,804-1 Cyclopentylzinc bromide
49,807-6 3,5-Dichlorophenylzinc iodide
49,842-4 3,5-Dimethylphenylzinc iodide
49,944-7 2-Ethoxybenzylzinc chloride
49,945-5 4-Ethoxybenzylzinc chloride
49,846-7
3-(Ethoxycarbonyl)phenylzinc iodide
49,847-5
4-(Ethoxycarbonyl)phenylzinc iodide
49,849-1
4-Ethoxy-4-oxobutylzinc bromide
49,850-5
6-Ethoxy-6-oxohexylzinc bromide
49,851-3
5-Ethoxy-5-oxopentylzinc bromide
49,852-1
3-Ethoxy-3-oxopropylzinc bromide
49,855-6 2-Ethylhexylzinc bromide
49,857-2 4-Ethylphenylzinc iodide
49,860-2 4-Fluorobenzylzinc chloride
49,896-3 Isobutylzinc bromide
49,878-5 2-Methoxybenzylzinc chloride
49,883-1 3-Methoxyphenylzinc iodide
49,885-8 4-Methoxyphenylzinc iodide
49,905-6
exo
-2-Norbornylzinc bromide
49,907-2 4-Pentenylzinc bromide
49,928-5 Pentylzinc bromide
49,933-1 Phenylzinc iodide
49,937-4 Propylzinc bromide
Introducing...
Rieke®Organozinc Reagents and Rieke®Highly Reactive Metals
Available exclusively from Aldrich!
49,957-9
Magnesium, highly reactive Rieke®metal (2.5g Mg* in 100mL tetrahydrofuran)
49,955-2 Zinc, highly reactive Rieke®metal (5g Zn* in 100mL tetrahydrofuran)
References: (1) Erdik, E.
Organozinc Reagents in Organic Synthesis
; CRC Press, Inc.: Boca Raton, FL, 1996; Aldrich Catalog Number Z28,012-7. (2) Rieke, R. D.; Hanson, M. V.
Tetrahedron
1997,
53
, 1925. (3) Hanson, M. V.; Brown, J. D.; Rieke, R. D.; Niu, Q.J.
Tetrahedron Lett
. 1994,
35
, 7205. (4) Cintas, P.
Activated Metals in Organic Synthesis
; CRC
Press, Inc.: Boca Raton, FL, 1993; Aldrich Catalog Number Z24,607-7. (5) Miller, J. A.; Farrell, R. P.
Tetrahedron Lett
. 1998,
39
, 7275. (6) Zhu, L.; Wehmeyer, R. M.; Rieke, R.
D.
J. Org. Chem
. 1991,
56
, 1445. (7) Negishi, E.; King, A. O.; Okukado, N.
ibid
. 1977,
42
, 1821. (8) Velarde-Ortiz, R.; Guijarro, A.; Rieke, R. D.
Tetrahedron Lett
. 1998,
39
,
9157. (9) Rieke, R.D.; Kim, S-H.; Wu, X.
J. Org. Chem
. 1997,
62
, 6921. (10) Rieke, R.D.; Sell, M.S.; Xiong, H.
J. Am. Chem. Soc
. 1995,
117
, 5429. (11) Wu, X.; Chen, T-A.;
Rieke, R.D.
Macromolecules
1995,
28
, 2101. (12) Chou, W-N.; Clark, D.L.; White, J.B.
Tetrahedron Lett
. 1991,
32
, 299. (13) Rieke, R.D.; Hanson, M.V.
Tetrahedron
1997,
53
,
1925; and references cited therein. (14) Sell, M.S.; Klein, W.R.; Rieke, R.D.
J. Org. Chem
. 1995,
60
, 1077.
All Rieke
®
Organozinc Reagents are 0.5
M
Solutions in Tetrahydrofuran.
FCO2H
O
CH3
CH3
OH
NPh
Ph
H
13
10
10
14
Uses of Zn*
Reactant Product Ref.
Br
Ph
O
S
I
S
Ph
Me
OHH
H
TMS Me
TMS
OH
S
S(
n
-C6H13)
BrBr S
S(
n
-C6H13)
n
13
9
12
11
Introducing...
Rieke®Organozinc Reagents and Rieke®Highly Reactive Metals
Available exclusively from Aldrich!

Inositols
66 Vol. 32, No. 2, 1999
The inositols and their phosphates constitute an
extremely important class of compounds. They have
been used in the development of metabolically stable insulin
mediators, inhibitors, and modulators of important meta-
bolic functions such as glycolysis. Inositols are stable to
degradative enzymes in vivo because they lack a hydrolyti-
cally labile glycosidic linkage. This feature is important for
the development of metabolically stable insulin mediators.
Aldrich now offers a variety of the more rare inositols,
such as D-chiro-, allo-, and neo-inositols. For more
information, please call our Technical Services department
at 800-231-8327 (USA).
References: (1) Potter, B.V.L. Nat. Prod. Rep.1990, 7, 1. (2) Bellington, D.C.
Chem. Soc. Rev.1989, 18, 83. (3) Berridge, M.J.; Irvine, R.F. Nature 1989,
341, 197. (4) Hudlicky, T.; Cebulak, M. Cyclitols and Their Derivatives. A
Handbook of Physical, Spectral, and Synthetic Data; VCH: New York, 1993.
(5) Hudlicky, T. et al. Chem. Rev.1996, 96, 1195. (6) Hudlicky, T. et al.
Synthesis 1996, 897.
46,808-8
allo
-Inositol
, 97%
46,805-3 L-(–)-
chiro
-Inositol
, 95%
46,804-5 D-(+)-
chiro
-Inositol
, 95%
I-665-2
Inositol
(
myo
-inositol)
44,125-2 D-Pinitol
, 95%
36,060-0 (–)-Quebrachitol
, 97%
51,616-3
neo
-Inositol
, 95%
HO OH
OH
OH
HO
HO
HO OH
OH
OH
HO
HO
HO OH
OH
OH
HO
HO
HO OH
OMe
OH
HO
HO
HO OH
OH
OH
MeO
HO
HO OH
OH
OH
HO
HO
allo
-Inositol L-(–)-
chiro
-Inositol D-(+)-
chiro
-Inositol
(–)-Quebrachitol
D-PinitolInositol
(
myo
-inositol)
Inositols
21,666-6
Tetrakis(triphenylphosphine)palladium(0), 99%
Now available in 500 gram BULK units
from stock!
Pd
Ph3P
Ph3P PPh3
PPh3
ALDRICH VARIABLE TAKE-OFF SPLITTER HEADS
Solve common set-up problems
Easy Access Design
•No interference with cold finger &
thermometer position
•Increased clearance for receiver
flask & distillation column
•Accessibility to metering valve
Features
•Easy & accurate drip counting
•Positive draining for no holdup
•Easy-action J.Young Teflon®valves
•Removable cold finger condenser
for easy cleaning
Micro distilling head
The column and receiver joints are C14/20 with a C10/18
thermometer joint.
Description Cat. No.
Jacketed Z41,309-7
Unjacketed Z41,310-0
Standard distilling head
The column and receiver joints are C24/40 with a C10/30
thermometer joint.
Description Cat. No.
Jacketed Z41,339-9
Unjacketed Z41,340-2
Teflon is a registered trademark of E.I. du Pont de Nemours & Co., Inc.
OMCVD PRECURSORS
Custom manufactured by Aldrich
to your individual purity specifications!
Cu, Si, Ti, and W precursors (up to 6N purity!)
Several packaging options are available.
For more information, please call 800-252-1879 (USA) or
contact your local Sigma-Aldrich office.
For pricing, please contact
Sigma-Aldrich Fine Chemicals at
800-336-9719 (USA) or your local Sigma-Aldrich office

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68 Vol. 32, No. 2, 1999
Teflon is a registered trademar k of E.I. du Pont de Nemours & Co., Inc. Sure/Seal, Pure-Pac, and Mini-Bulk are trademarks of Sigma-Aldrich Co.
Anhydrous Solvents from Aldrich
As the innovative leader in anhydrous solvent technology,
Aldrich just made the best even better by guaranteeing still
lower water specifications on more of our anhydrous sol-
vents. Aldrich continues to add to the list of IMPROVED
anhydrous products that have a low water content of
<0.0010% to <0.0030% and a low residue on evaporation
of <0.0005%, and are still being offered at the same
Mini-Bulk
TM
and Pure-Pac™
Containers
•Ideal for development- and pilot-scale quantities (18, 90, 200, 400
and 850 L).
•Closed system minimizes worker and environmental exposure.
•Reusable to minimize waste disposal costs.
•Cylinders are product-dedicated to guarantee safety and purity.
•NO RENTAL FEE; only a returnable deposit.
•Additional literature is available. Contact us for special bulletin
514-001.
Something Great Just Keeps Getting Better!
competitive prices! Combined with our selection of more than
80 different anhydrous solvents and time-tested Sure/SealTM
packaging, it's easy to see that Aldrich solvents are simply
the best for your moisture-sensitive reactions. A sampling
of our anhydrous solvents is shown below. For a complete
list, please call our Technical Services Department at
(800) 231-8327 (USA).
All solvents are available in 100mL, 1L, 2L, 6 x 1L, and 4 x 2L Sure/SealTM bottles. 100mL units have water content
≤
0.005%. Most are also available in 18L Pure-PacTM drums. Pure-PacTM drums require a deposit.
Exclusive Packaging for Aldrich Anhydrous Solvents
Sure/Seal
TM
Bottles
•Crimp-top Sure/Seal™ system is time-tested; provides all
the assurance you need.
•Research quantities (most materials are available in sizes
from 100 to 2,000 mL).
•Reagent comes in contact with only glass and Teflon®.
•Standard syringe and cannula techniques are used to
transfer contents.
•Additional literature is available. Contact us for
Technical Bulletin AL-134.
Aldrich Sure/Seal™ Septum-
Inlet Adapter (Z40,718-6)
•Economical closure for use with 100mL and 1L Sure/Seal™
bottles to permit repeated dispensing of product via syringe and
reliable long-term storage.
• Adapter allows the use of either an 8mm septum cap (included)
or standard rubber septum (Z10,072-2 or Z12,435-4).
• Also available: the Oxford Sure/Seal™ valve-cap (Z40,626-0)
to ensure positive valve closure during use and closure.
Cat. No. Product Water Content
27,100-4 Acetonitrile, 99.8% 10 ppm
40,176-5 Benzene, 99.8% 30 ppm
30,697-5
tert
-Butyl methyl ether, 99.8% 30 ppm
28,911-6 Carbon tetrachloride, 99.5+% 20 ppm
28,830-6 Chloroform, 99+% 10 ppm
27,099-7 Dichloromethane, 99.8% 10 ppm
29,630-9 1,4-Dioxane, 99.8% 30 ppm
45,984-4 Ethyl alcohol, 99.5%, non-denatured (TAX-PAID) 30 ppm
27,764-9 Ethyl alcohol, reagent, denatured 30 ppm
25,952-7 Ethylene glycol dimethyl ether, 99.5% 30 ppm
24,665-4 Heptane, 99% 10 ppm
22,706-4 Hexanes 20 ppm
29,699-6 Methyl acetate, 99.5% 30 ppm
32,241-5 Methyl alcohol, 99.8% 20 ppm
27,438-0 Methyl sulfide, 99+% 30 ppm
31,032-8 Propylene carbonate, 99.7% 30 ppm
27,097-0 Pyridine, 99.8% 30 ppm
18,656-2 Tetrahydrofuran, 99.9% 30 ppm
24,451-1 Toluene, 99.8% 20 ppm

Sunday, August 22, 1999
INORGANIC DIVISION SYMPOSIUM
(ORGN, CO-SPONSOR)
AM Session Chair: L. Barton
9:00 AM
S. Strauss
Selective Fluorination of B–H Bonds
9:30 AM
R. Grimes
Small Metallacarboranes in Synthesis: Beyond
Metallocenes
10:00 AM
F. Hawthorne
Synthetic Challenges and Structural Victories in
Polyhedral Borane Chemistry
10:30 AM
L. Sneddon
Metal-Catalyzed Syntheses of New Polyborane
Monomers and Polymers
11:00 AM
T. Fehlner
Utilization of Monoboranes in the Syntheses of
Metallaboranes of Groups 5–9
11:30 AM
K. Wade
Recent Studies of Icosahedral Carboranes
PM Session Chair: S. Krishnamurthy
1:30 PM
H. C. Brown
Organoboranes for Organic Syntheses: Recent
Advances in the Syntheses of Amines
2:00 PM
P. Knochel
Stereoselective Rearrangement of Organoboranes:
A New Method of Cyclic and Acyclic Stereocontrol of
Adjacent Carbon Centers
2:30 PM
A. Suzuki
Cross-Coupling Reactions of Organoboron Compounds
with Organic Electrophiles
3:00 PM
D. Matteson
A Mystery Story of Ligand Transfer on Boron
3:30 PM
K. Smith
Selective Polymeric Organoborohydride Agents—
Synthesis and Applications
4:00 PM
P. K. Jadhav
Enantioselective Allylboration Reaction with
Diisopinocampheylborane Reagents
4:30 PM
M. Zaidlewicz
Organoborane Dienophiles as 1-Alkene Equivalents,
Ter penylboranes and Catalytic Hydroboration of Dienes
and Enynes
Monday, August 23, 1999
INORGANIC DIVISION SYMPOSIUM
(ORGN, CO-SPONSOR)
AM Session Chair: K. Wade
8:30 AM
S. Shore
Cyclic Organohydroborate Metallocene Complexes
9:00 AM
H. Noth
N
- and
B
-Metalated Borazines: Will There Be a
Renaissance in Borazine Chemistry?
9:30 AM
R. Contreras
Boron in Optically Active Heterocycles
10:00 AM
L. Barton
Reactions of Metallaboranes: From Cluster
Degradation to the Formation of Linked Clusters
10:30 AM
N. Hosmane
Organometallics Derived from Carboranes and
Boranes
11:00 AM
W. Sieber t
Hydroboration and Diboration of Unsaturated
Compounds
11:30 AM
R. B. King
Analogies Between the Chemical Bonding in
Deltahedral Boranes and Planar Aromatic
Hydrobcarbons
PM Session Chair: C. Recatto
1:30 PM
M. Cook
Borane Chemistries through Sodium Borohydride
2:00 PM
J. Bruening
Borane Reagents for the Pharmaceutical Industry:
CalSelect™ Reducing Agents
2:30 PM
C. Goralski
Lithium Aminoborohydrides: Reagents with Multiple
Personalities
3:00 PM
M. Srebnik
The Chemistry and Applications of C-1 Bridged
Phosphorus Boronates
3:30 PM
M. Periasamy
New Organic Synthetic Methods Using Sodium
Borohydride/Iodine System
4:00 PM
J. S. Cha
Alkylboranes as Selective Reducing and Hydroborating
Agents
4:30 PM
N. N. Joshi
Oxazaborolidine-Catalyzed Reduction of Functionalized
Ketones
Wednesday, August 25, 1999
ORGANIC DIVISION SYMPOSIUM
(INOR, CO-SPONSOR)
AM Session Chair: P. V. Ramachandran
8:30 AM
A. Pelter
Some Alkene Syntheses via Organoboranes
9:00 AM
N. Miyaura
Rhodium-Catalyzed Addition of Organoboronic Acids to
Aldehydes and Enones
9:30 AM
H. Yamamoto
Designer Lewis Acid Catalysts of Boron
10:00 AM
I. Paterson
Stereocontrolled Synthesis of Concanamycin F Using
Chiral Boron Enolates
10:30 AM
R. Hoffmann
Synthesis of Heterocyclic Compounds by Domino-
Hydroformylation-Allylboration-Hydroformylation Reactions
11:00 AM
E. I. Negishi
Hydrometalation and Carbometalation of Alkynyl- and
Alkenylboranes and Hydroboration of Alkynyl- and
Alkenylmetals
11:30 AM
A. Soloway
Boranes in Developing of Tumor Targeting Agents for
Boron Neutron Capture Therapy
PM Session Chair: D. Matteson
1:00 PM
N. Petasis
Synthesis of Amine Derivatives from Organoboronic
Acids
1:30 PM
G. Kabalka
Solventless Suzuki Coupling Reactions on Alumina
2:00 PM
J. Soderquist
New Asymmetric Organoborane Conversions with 10-
TMS-9-BBD Systems
2:30 PM
K. K. Wang
Synthesis of Conjugated Dienes, Diene-allenes, Ene-diynes,
Enyne-allenes, and Related Compounds via Organoboranes
3:00 PM
Y. Yamamoto
Tr is(pentafluorophenyl)boron-Catalyzed Reduction of
Alcohols and Ethers with Hydrosilanes
3:30 PM
T. Cho
Catalytic Asymmetric Reduction of α-Functionalized
Ketones
4:00 PM
P. V. Ramachandran
Organoboranes for Fluoro-Organic Synthesis: Transition Metal
Catalyzed Hydroboration of Perfluoroalkyl(aryl)ethylenes
4:30 PM
N. M. Yoon
Borohydride Exchange Resin–Nickel Boride,
A Versatile Reagent for Organic Synthesis
5:00 PM Concluding Remarks
Aldrich Chemical Company, Inc. is proud to be a corporate sponsor of this symposium
CalSelect is a trademark of Callery Chemical Company, Inc.
Organic and Inorganic Syntheses via Boranes
A Symposium sponsored by the Inorganic and Organic Divisions of the American Chemical Society
218th National Meeting, New Orleans, LA
August 22–25, 1999
Organizer: Professor P. V. Ramachandran – Purdue University
Organic and Inorganic Syntheses via Boranes
A Symposium sponsored by the Inorganic and Organic Divisions of the American Chemical Society
218th National Meeting, New Orleans, LA
August 22–25, 1999
Organizer: Professor P. V. Ramachandran – Purdue University

70 Vol. 32, No. 2, 1999
Aldrich. ..Your One-Stop Source
for Stable Isotopes
49,166-7 Acetone-13C3, 99 atom % 13C
48,516-0 Acetonitrile-1-13C, 99 atom % 13C
48,517-9 Acetonitrile-1-13C-15N, 99 atom % 13C, 99 atom % 15N
48,521-7 Acetonitrile-13C2, 99 atom % 13C
49,167-5 Acetonitrile-13C2-15N, 99 atom % 13C, 99 atom % 15N
49,168-3 Acetonitrile-2-13C-15N, 99 atom % 13C, 99 atom % 15N
48,533-0 Benzene-d5, 99 atom % D
48,563-2 Benzene-13C, 99 atom % 13C
48,540-3 Chloroform-13C, 99 atom % 13C
49,218-3 Dichloromethane-13C, 99 atom % 13C
49,219-1 Dichloromethane-d, 95 atom % D
48,551-9 Methyl-13Csulfoxide, 99 atom % 13C
48,618-3 Pyridine-15N, 99 atom % 15N
48,621-3 Toluene-2,3,4,5,6-d5, 98 atom % D
48,707-4 Toluene-α,α,α-d3, 99 atom % D
48,708-2 Toluene-α-13C, 99 atom % 13C
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Protective Groups in Organic
Synthesis
3rd ed., T.W. Greene and P.M. Wuts, John
Wiley & Sons, New York, NY, 784pp.
Hardcover. Details the use of protecting
groups in synthetic organic chemistry.
Expanded by more than 50%, provides
readers with a compendium of 1,050 of the
most useful protective groups as well as
5,350 references to original publications.
Z41,242-2
Stereoselectivity in Synthesis
T. Ho, John Wiley & Sons, New York, NY,
1999. Hardcover. Shows how to choose
the best method for a given synthesis.
Provides readers with a thorough under-
standing of stereoselectivity in organic and
medicinal chemistry as well as the pharma-
ceutical, agricultural, and food industries.
Z41,243-0
Organic Coatings: Science and
Technology
2nd ed., Z.W. Wicks, F.N. Jones, and S.P.
Pappas, John Wiley & Sons, New York, NY,
1999, 630pp.Hardcover. Combines a pre-
sentation of contemporary scientific know-
ledge in the field of organic coatings with a
summary of its applied technology. This
new self-contained volume is more acces-
sible and contains new developments in the
field since the publication of the first edition.
Z41,244-9
Flavourings
E. Ziegler and H. Ziegler, Eds., Wiley-VCH,
Weinheim, Germany, 1998, 710pp.
Hardcover. Provides a comprehensive
insight into the production, processing, and
applications of various food flavourings.
Focuses on the conventional and new ana-
lytical methods employed in the field.
Covers food legislation as well as quality
control.
Z41,253-8
Kirk-Othmer Encyclopedia of
Chemical Technology
4th ed., Concise, M. Grayson and D.
Eckroth, Eds., John Wiley & Sons, New York,
NY, 1999. Hardcover. This abridged version
of a 28-volume set contains information
about 1,100 topics of interest to chemists.
Z41,246-5
Polymer Handbook
4th ed., J. Brandrup, E. Immergut and E.A.
Grulk, Eds., John Wiley & Sons, Somerset,
NJ, 1999, 2336pp. Hardcover. Contains
information pertaining to polymerization,
depolymerization, and characterization in
solution or in the solid state. Explores
developments in the field since 1989, such
as new PVT relationships and new copoly-
mer reactivity parameters.
Z41,247-3
Measure for Measure
R. Young and T. Glover, Blue Willow, Inc.,
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comprehesive conversion factor reference
that contains over 39,000 conversions for
over 5100 different units. Designed specif-
ically for engineers, scientists, students,
and teachers. Comes in a convenient size
(4in. W x 6in. H x 1in. D) with a durable
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Z41,248-1
Advanced Inorganic Chemistry
6th ed., F.A. Cotton and G. Wilkinson, John
Wiley & Sons, New York, NY, 1999.
Hardcover. Incorporates many new chemi-
cal developments, particularly recent theo-
retical advances in the interpretation of
bonding and reactivity in inorganic com-
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ters devoted to the elements form the core
and are covered in periodic table
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Z41,245-7
Chemistry of Advanced Materials:
An Overview
L.V. Interrante and M.J. Hampden-Smith,
Eds., Wiley-VCH, New York, NY, 1998,
580pp.Hardcover. Advanced materials are
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The Systematic Identification of
Organic Compounds
7th ed., R.L. Shriner, C.F. Hermann, T.C.
Morrill, D.Y. Curtin, and R.C. Fuson, John
Wiley & Sons, New York, NY, 1997, 669pp.
Hardcover. Updated edition explores the
fundamentals of organic qualitative analysis.
Provides protocols for both wet and spectro-
scopic methods of analysis. Includes one
chapter of identification exercises.
Z40,642-2
Fragrances: Beneficial and Adverse
Effects
P.J. Frosch, J.D. Johansen, and I.R. White,
Eds., Springer-Verlag, New York, NY, 1998,
234pp.Hardcover. Presents numerous
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From
the
Aldrich
Bookshelf
Vol. 32, No. 2, 1999 71
Lexotone is a registered trademark of The Holliston Mills.

FIRESTONE VALVE
A rapid, efficient, and foolproof purge valve for
100% replacement of air in reaction vessels.
Automatically controls gas flow and pressure. No
special fittings needed. Connect reaction vessel,
house vacuum, and purge gas to the Firestone
valve via 10mm o.d. connections. Conserve
expensive gases by decreasing flow to almost
zero after purging.
Z10,361-6
Scientific Glassware
... clearly the finest
LET THE ALDRICH GLASS SHOP HELP YOU WITH YOUR CUSTOM GLASSWARE NEEDS: SPECIAL APPARATUS✶JOINT MODIFICATIONS✶NON-STANDARD CATALOG ITEMS
CONTACT US AT ALDGLASS@SIAL.COM OR (414) 273-3850 EXT. 7483
ALDRICH MNNG DIAZOMETHANE GENERATOR WITH SYSTEM 45 CONNECTION
MNNG (1-methyl-3-nitro-1-nitrosoguanidine; cat. no. 12,994-1) is probably the most convenient precursor to diazo-
methane, because it is stable and crystalline, and generates diazomethane upon treatment with aqueous alkali.
This newly designed apparatus incorporates System 45 technology that eliminates glass joints, clamps, and grease
and permits the preparation of diazomethane without the need for codistillation with ether (see below). Request
Technical Information Bulletin No. AL-180.
The screw thread closure and PTFE adapter provide an efficient, gas-tight connection between the inner tube and
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syringe. Supplied complete with threaded body, threaded inner tube, PTFE adapter, 32mm cap, O-ring, lock nut,
septum, and 8mm open-top cap.
Typical Generator Setup
•1mmol (133mg) or less of MNNG reagent is placed in the inside tube through the 8mm open-top screw cap
along with 0.5mL of water to dissipate any heat generated.
•Ether (~3mL) is placed in the outside tube and the two parts are assembled and held together by tightening
the 32mm screw cap.
•Immerse the lower part in an ice bath and inject (dropwise, very slowly to prevent frothing or possible buildup
of back pressure) about 0.6mL of 5Nsodium hydroxide through the PTFE-faced silicone septum via a syringe
with a narrow gauge needle (No. 22) to prevent diazomethane leakage around the shank. (See below for
syringe ordering information.)
•Diazomethane collects in the ether ready for use.
Diazoethane, despite its lower volatility, can be generated similarly from ENNG (1-ethyl-3-nitro-1-nitrosoguanidine; cat. no. E4,160-5).
This apparatus is also useful for the generation of radioactive or deuterated diazomethane because it is a closed system.
WARNING: MNNG is mutagenic and exposure may cause skin sensitivity. While MNNG is more convenient for the generation
of small quantities of diazomethane, Diazald is the preferred reagent for large-scale production of diazomethane. However, it has
recently been reported that Diazald can be used in place of MNNG in the above apparatus. See: F. Ngan and M. Toofan Journal
of Chromatographic Science 1991, 29, 8. Diazomethane has been reported to be explosive, particularly on contact with ground-
glass joints during distillation.
ALDRICH SAFE-PURGE VALVES
For the safe and
efficient purging of
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Vessel, vacuum, and
purge gas lines con-
nect to 10mm o.d.
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•Built-in check valve prevents oil and air from
being pulled into system
•Rear hose connector vents toxic gases from
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•Sturdy, high-performance construction
With manually adjustable Teflon®valve
Z22,532-0
With spring-loaded automatic valve
Z22,533-9
Teflon is a registered trademark of E.I. du Pont de Nemours & Co., Inc.
Description Cat. No.
MNNG diazomethane generator Z41,173-6
Replacement parts
O-ring seal Z41,174-4
PTFE-faced silicone septum, 32mm Z41,175-2
PTFE-faced silicone septum, 8mm Z41,176-0
Screw cap with hole, 8mm Z41,177-9
Disposable syringes
All PE/PP, 1mL (order needles below) Z23,072-3
Disposable needles, 22 gauge, 1in. L Z11,806-0
72 Vol. 32, No. 2, 1999

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Tel: 414-273-3850
Fax: 414-273-4979
E-mail: aldrich@sial.com
Sigma Chemical Company
3050 Spruce Street
St. Louis, Missouri 63103
Toll Free Tel: 1-800-521-8956
Toll Free Fax: 1-800-325-5052
Tel: 314-771-5765
Fax: 314-771-5757
E-mail: sigma@sial.com
Sigma-Aldrich Worldwide Locations
ˆ

ALDRICH CHEMICAL COMPANY, INC.
P.O. BOX 355
MILWAUKEE, WISCONSIN 53201 USA
®
1999/2000
Laboratory Chemicals
and Analytical Reagents
Announcing a powerful
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The new combined catalog
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including:
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protected Amino Acids
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Polystyrene Resins for
Combinatorial Chemistry
•Shearwater Polymers
•Maldi GC-MS Matrix
Substances
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