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665
SYNTHESIS
April 1998
Toward a Practical Synthesis of Morphine. The First Several Generations of a Radical
Cyclization Approach
1
Gabor Butora, Tomas Hudlicky,* Stephen P. Fearnley, Michele R. Stabile, Andrew G. Gum, David Gonzalez
Department of Chemistry, University of Florida, Gainesville, Florida 32611–7200, USA
Fax +1(352)8461203; E-mail: hudlicky@chem.ufl.edu
Received 4 September 1997; revised 3 November 1997
Abstract:
A radical cyclization approach to the complete skeleton
of morphine was investigated in several iterations. The first attempt
at a radical cascade via a Bergman-type intermediate derived from
ene-diyne
10
failed during a model study in which 10-membered
silicon-tethered ene-diyne
17
proved inert to Bergman cyclization
conditions. A second model study involving ene-diyne
27
, function-
alized with an allyl group, underwent Claisen rearrangement to
32
in preference to a Bergman-type cyclization. Several simple model
studies were performed with bromophenols appended to protected
diols
40
and
50
, respectively, to determine the feasibility of
C12–C13 bond formation in the former case and the cascade clo-
sure C12–C13/C14–C9 in the latter via radical species generated
from the aryl halides. The second-generation approach employed
the diene diol
7a
derived biocatalytically from
β
-bromoethylben-
zene via oxidation with
E. coli
JM109(pDTG601), its conversion to
cyclization precursor
55
, and the radical cyclization to
56a
,
b
. The
conditions and the outcome of this process are discussed in detail
along with the rationalization of stereochemistry of the cyclization,
which furnished C14-
epi
configuration in
56a
in low yield.
The third-generation synthesis relied on stepwise radical cyclization
of vinyl bromide
67
derived from
o-
bromo-
β
-ethylbenzene (also by
biocatalytic means) and equipped with an oxazolidone as the radi-
cal acceptor group. Isoquinoline derivatives
68a
and
68b
were
obtained as a mixture of isomers, the major of which,
68a
, was con-
verted via a second tin-mediated cyclization to the pentacyclic com-
pound
78
, also possessing C14-
epi
configuration. The stepwise
radical cyclization proceeded in higher yields, produced cleaner
reaction mixtures, and was also performed with the more flexible
alcohol
87
, whose tin-mediated closure produced a 1:1 mixture of
C14 epimers, tetracyclic compounds
81
and
89
. Finally, tetracycle
80
or pentacycle
79
was converted to oxo aldehyde
83
and cyclized
to the complete morphinan skeleton,
84
, in the
ent
-C14-
epi
series.
Additionally, preliminary studies were performed on direct closures
of chloride
82
to
85
, via a C10/C11 alkylation of a
sp
3
-hybridized
center. The three generations of synthetic effort are discussed in
detail and physical and spectral data are provided for all new com-
pounds. The relative merits of tandem
vs
. stepwise radical cycliza-
tion are evaluated and projections for future work are indicated.
Key words:
enzymatic dioxygenation, radical cyclization, iso-
quinoline alkaloids, approach to (+)-morphine,
ent
-morphinans
Introduction
The consumption of morphine
1
(
1
) in the United States is
approaching one hundred metric tons annually.
2
The
world’s oldest drug on record,
3a
today used routinely as
both an analgesic and an anesthetic,
3b
is available by com-
mercial processing of raw opium from
Papaver somnifer-
um
grown in those latitudes that favor the biogenesis of
morphinans.
4
As of this writing, all morphine for medici-
nal as well as illicit use originates in natural sources. De-
spite years of research focused on plant tissue culture
production and microbial transformations of morphine
alkaloids
5
as well as the enzymology of morphine biogen-
esis,
6
the probability of large scale production by biologi-
cal means remains uncertain, at least for the foreseeable
future. Equally elusive has been the effort by the synthetic
community to furnish morphine in a manner that would ri-
val isolation in terms of economics. Morphine serves as a
convenient starting material for other medicinally impor-
tant substances (Figure 1) such as codeine (
2
), as well as
for the (illicit) production of heroin (
3
). Various antago-
nists, such as naloxone (
4
) and naltrexone (
5
), are chemi-
cally synthesized via noroxymorphone (
6
) and its
derivatives, themselves produced from morphine by semi-
synthesis.
Since Gates’ first synthesis
8a
of morphine in 1956 there
have been fewer than twenty total or formal total synthe-
ses of morphine
8
reported in the literature, all recently re-
viewed.
9
The most efficient to date, that of Rice,
8i
provided the title alkaloid in 29% overall yield, still not
sufficiently competitive with isolation. There have also
been many ingenious approaches to the architecturally
difficult skeleton of morphine.
10
It is clear from the com-
bined synthetic experience of those organic chemists who
have together committed 40+ years of serious effort to-
ward a concise and practical synthesis that morphine
stands out as a target of difficulty. In this manuscript, we
report the first few iterations of an approach based on a
cascade of bond-forming reactions which furnished the
skeleton of
1
in 13 steps: an accomplishment far removed
from the goal of achieving the entire synthetic sequence in
under 8 steps; nevertheless, it is a valuable first step.
Results and Discussion
We selected several topologically independent strategies
to approach the morphine synthesis in a practical manner.
Biomimetic in principle continues to be our approach via
the intramolecular Diels–Alder reaction, the initial
results
11
of and recent progress
12
of which, have been dis-
closed. The approach discussed herein evolved from con-
siderations of a radical cascade as the most efficient
means of the rapid assembly of the carbon skeleton (Fig-
Figure 1.
Common Morphine-Derived Alkaloids in Use Today
666
Papers
SYNTHESIS
ure 2). The question of stereoselectivity in such a cascade
was unclear, especially with respect to the C14 stereo-
center, which has proved notoriously difficult to control in
many of the reported syntheses. Nevertheless, we initially
placed the overall brevity of the assembly above stereose-
lectivity issues in ultimate importance.
The Bergman Cascade Approach
. The idea of simulta-
neously creating ring A and a phenyl radical for a cycliza-
tion cascade
13
is shown in Figure 2. The original concept
assumed that diene
7a
14a
would be derived via fermenta-
tion of
β
-bromoethylbenzene with
P. putida
15
and its re-
combinant organisms available through the efforts of
Gibson.
16
This particular diene diol and others derived
from
β
-substituted ethyl benzenes, have recently been
used in several synthetic ventures.
12,17,18
After alkylation of oxazolidone
8
with
7b
protected at
the distal hydroxyl, the free alcohol
was envisioned as a
nucleophilic partner for the coupling with diyne epoxide
9
in an overall equivalent of the Williamson ether syn-
thesis of the intermediate aryl ether
11
. Note that the
electronics of this design are opposite to those of tradi-
tional Williamson syntheses, i.e., the alkyl, not the aryl
unit bears the nucleophilic oxygen. The oxidation of the
trans
-diol derived from
9
would provide the hydrogen
bonded species
10
whose tendency toward Bergman cy-
clization should be the function of interatomic distance
c–d
between the acetylenic termini. The aryl diradical
11
would undergo cyclization and yield
12
after protodesi-
lylation of the silicon tethers introduced to control
c–d
distance in
9
and
10
. The precedent for cyclization of 10-
membered ene-diynes that possess the structural features
of
9
, found in compounds
13–16
, was indeed favorable
as shown in Figure 3. Molecular dynamics (Cache) per-
formed on a truncated version of
10
, namely
17
, predict-
ed a cyclization temperature of 60–75°C with
c–d
distance of 3.38 Å. From the literature data it is expected
that the ene-diynes having a
c–d
distance less than
3.20 Å suffer spontaneous closure while those with a
c–d
distance greater than 3.20–3.31Å are stable at ambient
temperature.
21
With this information we undertook the synthesis of a
model system with structural features of
10
as shown in
Scheme 1. The ene-diyne
21
was synthesized in yields not
exceeding ~20% by two rather laborious routes. In the
first of these, Vollhardt’s method of coupling
cis
-dichlo-
roethylene with trimethylsilyl acetylene
25
was adapted to
produce
18
which was subjected to desilylation in aque-
Figure 2.
Bergman Cyclization Approach to Morphine
Figure 3.
Cyclization Parameters of some Bergman Precursors
Reagents: i LiOH, THF, H
2
O, ii BuLi, THF, iii bis(chlorodimethylsi-
lyl)ethane, iv EtBr, Mg, v H
3
O
+
, vi CrO
3
, vii SmI
2
, viii Bu
2
SnO, allyl
bromide, ix Tf
2
O, pyridine, CH
2
Cl
2
then DBU, r.t., x CBr
4
, PPh
3
,
CH
2
Cl
2
, xi Na
2
S, xii MCPBA, xiii a) SO
2
Cl
2
, CH
2
Cl
2
, –78°C b)
MCPBA, CH
2
Cl
2
, 0°C, xiv MeLi.
Scheme 1
667
SYNTHESIS
April 1998
ous LiOH and the free bisacetylene 19 metalated with
BuLi. The dianion 20 was quenched to produce the ten-
membered ene-diyne 21 in low yields, with recovery of
the material complicated by its volatility. The second
route, Scheme 1, relied on the SmI
2
-mediated McMurry-
type coupling
26
of the known dialdehyde
27
24 derived by
oxidation of the corresponding diol. This material was
available in reasonable yield by a known procedure from
protected propargylic alcohol 23. Diol 25 was initially
subjected to several procedures for elimination, including
a Corey–Winter
28
reaction which had shown some success
for Semmelhack.
24
No ene-diyne was detected in any of
these reactions. We chose an alternate route from diol 24,
which was converted, via dibromide 28, to a cyclic sulfox-
ide, and ultimately taken to the Ramberg–Backlund pre-
cursor 31.
29
Treatment of the chlorosulfone with MeLi at
–78°C in diethyl ether afforded a low yield of 21 (<20%).
Disappointingly, it has been shown to be stable to ther-
molysis up to 225°C and no cycloaromatization to the ex-
pected and independently synthesized product 21a was
detected. Despite the predicted geometry and c–d dis-
tance, which bode favorably for a low reaction tempera-
ture, the material proved inert and this was attributed, at
least for the moment, to the electronic effect of tethering
silicon atoms. Several cases reported in the literature de-
scribe long-range effect of silicon tethers on the cycliza-
tion rates and attendant temperatures occasionally
requiring > 600°C.
27
The final evidence for the probable
lack of utility of this cascade approach became available
by thermolysis of enol ether 27, whose cyclization param-
eters portrayed, quite accurately, those foreseen in com-
pound 10. The enol ether was prepared from diol 25 by
monoallylation
30
and subsequent elimination of the allyl
mesylate. At the predicted cyclization temperature of
65°C this material was found completely inert. After
60 hours at 80°C the starting material was consumed. No
evidence of Bergman-type products was found but ketone
32 was isolated in 43% yield, indicating that the energet-
ics for the Claisen rearrangement in 27 are more favorable
than Bergman cyclization. The project was abandoned at
this point until such time that a solution to the detrimental
influence of silicon tethers is found.
The Tandem Radical Cyclization. Because of the failure
of the Bergman cyclization approach, in which the aryl
radical would have been generated in situ, we chose a
more direct route where the required radical species orig-
inated in the reduction of an aryl halide. One of the appar-
ent advantages of this approach, depicted in Figure 4, was
the possibility of incorporation of several enzymatic
transformations into the synthetic pathway. Diol 7a re-
mains accessible from
β
-bromoethylbenzene through the
first oxidation step in the natural degradation pathway of
arenes in the wild strains of Pseudomonas putida.
31
The second step in the pathway utilized by the wild strain
consists of further oxidation of the arene-cis-diol by cate-
chol dehydrogenase to a catechol which then suffers an ortho
cleavage and is ultimately channeled through further enzy-
matic steps to acetate as a carbon source for the organism.
Gibson developed not only blocked mutants
15
of Pseudomo-
nas but also recombinant strains
16
of E. coli in which further
enzyme expression beyond either the first step [P. putida 39/
D; E. coli JM109(pDTG601)] or the second step [E. coli
(pDTG602)]
16
is arrested. Thus the required catechol 33 can
be obtained from bromobenzene by the use of the latter mu-
tant organism and one further chemical step, namely selec-
tive alkylation of the “distal” phenol group.
Model Study: C12–C13 bond. To validate the chemistry
contained in this approach, we chose the simplest system,
capable of only a single radical closure, as shown in
Scheme 2. The required catechol 33 was prepared from
bromobenzene or 2-methoxyphenol as previously report-
ed by Hoshino
32
and used as a nucleophile in the second
Mitsunobu inversion
33
of the alcohol 42 derived from tol-
uene diol via alcohol 40.
11
For the initial model study the
thexyl derivative 38 was chosen because we had not yet
manufactured the catechol enzymatically and this material
was prepared by a protection/oxidation sequence from 36.
Figure 4. Tandem Radical Cyclization Approach
Reagents: i P. putida TG02C, ii JM109 (pDTG601), iii Jones oxidati-
on, iv MeI, acetone, v TMSI, vi THSCl, imidazole, DMF, vii oxalyl
chloride, DMSO, Et
3
N, -78°C to 0°C, viii potassium azodicarboxyla-
te, HOAc, ix benzoic acid, Bu
3
P, DEAD, THF, x NaOMe, MeOH, xi
38, Bu
3
P, DEAD, THF, xii H
3
O
+
, xiii benzyl bromide, K
2
CO
3
, ace-
tone, xiv Bu
3
SnH, AIBN, toluene, reflux.
Scheme 2
668
Papers
SYNTHESIS
The first Mitsunobu inversion provided the benzoate 41,
from which transesterification with NaOMe in MeOH lib-
erated the alcohol 42. The second Mitsunobu reaction of
alcohol 42 and thexyloxy bromophenol 38 gave ultimate-
ly derivative 44, after the labile thexyl group in the con-
densation product had been replaced by a benzyl moiety
in 43. The protected ether 44 was exposed to AIBN/
Bu
3
SnH in refluxing toluene to afford a 50 % yield of tri-
cycle 45 containing three of the five stereogenic centers of
morphine in the correct absolute configuration. With this
promising result we turned to the assembly of the entire
morphine skeleton.
Model Study: C14–C9 bond. To provide initial informa-
tion about the relative stereochemistry at C14–C9, tradi-
tionally the pitfall of most syntheses of morphine, we
designed a simple model cyclization shown in Scheme 3.
The less substituted alkene in diene diol 7b was reduced
with diimide and the C6-hydroxyl protected as a TBS-
ether (See structures 49 and 50, Scheme 4). Mitsunobu re-
action with o-bromophenol, followed by displacement of
the primary alkyl bromide with the sodium salt of oxazoli-
done 8, furnished the protected trans-diol 46 which was
exposed to Bu
3
SnH/AIBN in refluxing toluene to furnish
pentacyclic product 47 in approximately 10% yield.
1
H
NMR analysis established the relationship of the C14–H
and C9–H as trans; however, it was not possible to discern
the configuration relative to C5 or C6 and the product was
assigned as either 47a or 47b.
The results of the two aforementioned model studies val-
idated the premise of the tandem radical cyclization con-
sidered for the assembly of the morphine skeleton.
Conceptually similar to the strategy employed by Parker
8p
(except for the connectivity of C11–C10–C9 atoms) the
proposed sequence would create the two crucial bonds
(C12/C13 and C14/C9) in a cascade manner and it was as-
sumed that the C14/C9 stereochemistry would be subject
to some degree of control (vis-à-vis Parker’s experience).
The two novel issues in our approach were the anticipated
C10/C11 closure of an otherwise intact skeleton and the
incorporation of chirality into ring C by the enzymatic ox-
idation. [Note: The compounds synthesized in the course
of the model studies as well as those prepared during the
study of the Bergman cyclization (21, 25–32, 41–47) were
characterized only to permit the ultimate judgment as to
the future merits of that particular approach. All of the
compounds have either led to a dead end investigation or
validated the completion of a preliminary model study and
therefore were not characterized as fully as the intermedi-
ates in the subsequent application (see Experimental Sec-
tion for partial characterization of these intermediates)].
Tandem Radical Cyclization: First Generation. Based on
the results of the simple model studies we turned to the ob-
jective of assembling the entire morphine skeleton.
β
-Bro-
moethylbenzene was subjected to enzymatic dihy-
droxylation to yield the homochiral diol 7a
14a
which was
reduced to give 49,
14a
protected as a TBS-ether at the dis-
tal hydroxyl group (50) and further transformed via a Mit-
sunobu inversion to benzoate 51, in 85 % yield (Scheme
4). The alkylation of this material with oxazolidone 8 did
not proceed without problems. As reported in a prelimi-
nary communication, elimination to diene 53 took place
quite readily; in principle this diene could be “recycled”
via a hydroboration/oxidation/displacement sequence to
furnish better yields of 52 (See Scheme 6 for recycling of
a similar compound, 71
14b
). Hydrolysis of the benzoate
and Mitsunobu inversion of the alcohol with bromophenol
33 gave the penultimate precursor for the radical cycliza-
tion, ether 55, which was exposed to (TMS)
3
SiH/AIBN to
afford a complex mixture of more than six products. La-
borious chromatographic separation provided no more
than a modest 15% yield of the pentacyclic material 56a,
whose analysis by NMR techniques established the epi-
C14 configuration as shown. Although not identified un-
ambiguously, the isomer 56b was also isolated as a minor
Reagents: i potassium azodicarboxylate, AcOH, ii TBSOTf, iii o-bro-
mophenol, Bu
3
P, DEAD, THF, iv NaH, 2-oxazolidone, v Bu
3
SnH,
AIBN.
Scheme 3
Reagents: i JM109(pDTG601), ii potassium azodicarboxylate, AcOH,
iii TBDMSOTF, CH
2
Cl
2
, iPr
2
NEt, iv benzoic acid, nBu
3
P, DEAD,
THF, v 2-oxazolidone, NaH, DMSO, vi aq NaOH, vii 33, nBu
3
P,
DEAD, THF, viii (TMS)
3
SiH, AIBN, benzene, 140°C, sealed tube
Scheme 4
669
SYNTHESIS
April 1998
product. Among the various byproducts isolated from the
reaction mixture we also identified the enol ether 58
which probably originated in the hydrogen abstraction
route shown in Figure 5. The stereochemistry of the two
protons in 58, corresponding to C14 and C9 of morphine,
was established as trans, but the relative stereochemistry
with respect to C6 remained undetermined.
A few comments regarding the course of this cascade se-
quence are in order. First, the reaction produced complex
mixtures which proved very difficult to separate and mon-
itor by traditional methods (TLC, HPLC). Second, the
course of the crucial C14–C9 bond formation would be-
come extremely difficult to evaluate without the accurate
knowledge of the stereochemical identity of all products
which originated in the double closure. Third, the confor-
mations of the radical species at C14 prior to the closure
will depend on the bulk of the substituent at the C6 oxygen
as well as the exact placement of the oxazolidone ring at
the time of bond formation. (See Figure 6 for the likely
possible conformation of the intermediate radical species
59). Finally, the radical closure of a species derived from
the unreduced diene 60 would produce the allylic radical
61 (Figure 7) whose fate in further bond formation would
be affected by the additional 10–12 kcal/mol of allylic sta-
bilization. The comparison of the four possible conforma-
tions in both 56 and 62 indicates that the transition state
“b”, leading in both cases to the correct C14–C9 stereo-
chemistry, is the least concave of the four conformers.
The possibility for stereocontrol through the manipulation
of the peripheral protecting groups could be pursued in fu-
ture studies. The conformations of 56 and 62 illustrate the
difficulty in predicting the precise outcome of C14–C9
stereochemistry. Consequently, we turned to the examina-
tion of a stepwise radical cyclization approach in which
the C9 stereochemistry would be set in the first step and
the steric fate of C14 would become dependent on the fa-
cial selectivity of a hydrogen abstraction process, rather
than the relatively slower bond-forming process. As it
turned out following this particular study, the two strate-
gies can be related analytically with regard to the confor-
mations (See Figures 6 and 7).
Figure 5. Formation of Enol Ether 58 by Intramolecular H-Abstrac-
tion
Figure 6. Conformations of the Four Possible Isomers at C14/C5
Figure 7. Conformation of Isomers in Which Ring C Retains Unsatu-
ration
670
Papers
SYNTHESIS
Stepwise Radical Cyclization: Second Generation. The
biooxidation of o-bromo-
β
-bromoethylbenzene was ex-
amined with the expectation that the larger
β
-bromoethyl
group would direct the enzymatic placement of the cis-di-
ol. Fortuitously, this turned out to be the case and diol
64
14b
was isolated from the broth of fermentation of 63
with recombinant organism E. coli JM109(DTG601A),
(Scheme 5).
The structure and absolute stereochemistry of 64
14b
was
determined, along with the absolute stereochemistry of
7a,
14a
by correlation with the styrene-derived cis-diol
69,
34
whose absolute configuration has been firmly estab-
lished.
35
The yields of 64 were low and the mass balance
of 64 and starting material 63 proved extremely low. We
attributed this yield problem to the differences in the intra-
cellular transport rates for the two compounds. While the
yield of 7a is among the highest for any arene cis-diol
(>10 g/L), diol 64 became available in 200 mg/L with
over 50% of the fate of 63 unaccounted for. Nevertheless,
we proceeded with the synthesis under the assumption
that the biooxidation would be optimized in the future,
were this approach found synthetically viable. Note also
that the presence of benzofuran derivatives 70a and 70b
contributed to the low yield of either 64 or 65. In the latter
case 65 was regenerated from 70b as shown in Scheme 6
and as previously described.
14b
Exposure of 67 to Bu
3
SnH/AIBN provided octahydroiso-
quinolines 68a and 68b in a 2:1 ratio in favor of the isomer
possessing the epi-C9 configuration. The lack of selectiv-
ity in the closure may be attributed to the marginal steric
effect of the distant acetonide moiety. The combined yield
of the cyclization was high and the two compounds were
easily isolated from a clean reaction mixture. The stereo-
chemistry of 68a was determined by a single crystal X-ray
crystallography of the free diol 74.
1
Because of the greater availability of 68a we chose to pur-
sue the synthesis of the ent-morphine skeleton, since only
a single Mitsunobu inversion is required for the introduc-
tion of the catechol moiety. An assumption was made that
the synthesis of ent-morphine would be an appropriate
model study for the approach to the natural enantiomer
from 68b at such time as the control in setting the C9 cen-
ter would either be absolute in either direction, or at least
lead to a 1:1 mixture of isomers. In the latter event the syn-
thesis would be enantiodivergent from the same interme-
diate, mimicking the strategy of Rice.
8i
A Mitsunobu inversion with phenol 33 generated the pre-
cursor for the second cyclization, ether 76,
1
whose expo-
sure to Bu
3
SnH/AIBN gave a clean yield of pentacycle
78, Scheme 7.
1
The stereochemistry at C14 was deter-
mined to be in the epi configuration (the coupling constant
between C14 and C9 was found to be 11 Hz, see Experi-
mental Section), presumably because the final act of hy-
drogen atom abstraction occurred from the convex face of
the conformer 86a. A reasonable explanation of this stereo-
chemical outcome is to invoke the rigidity of the 6-5 sys-
tem and the reluctance to favor the conformation 86b in
which the concave face would be more accessible. That
Reagents: i JM109(pDTG601A), ii potassium azodicarboxylate,
AcOH, iii 2,2-dimethoxypropane, pTSA, iv 2-oxazolone, NaH,
DMSO, v nBu
3
SnH, AIBN, benzene, reflux, vi Cs
2
CO
3
, acetone,
vii Et
4
NBr, BF
3
.Et
2
O, CH
2
Cl
2
.
Reagents: i 2-oxazolone, NaH, DMSO, ii 9-BBN, THF, followed by
H
2
O
2
/NaOH, iii MsCl, iPr
2
NEt, CH
2
Cl
2
.
Scheme 6
Reduction of the diene in 64 with potassium azodicarbox-
ylate followed by the introduction of oxazolone provided
67 along with a substantial amount of styrene 71 resulting
from the base-induced elimination. This material was “re-
cycled” as shown in Scheme 6 by a hydroboration/oxida-
tion/mesylation sequence, to provide useful quantities of
the cyclization precursor.
Scheme 5
671
SYNTHESIS
April 1998
the reason for exclusive epi-C14 quench was not the pres-
ence of the bulky silyl group was ascertained by perform-
ing the cyclization on the free alcohol 77 and obtaining 79
with the same result: epi-C14
configuration, Scheme 7.
The above arguments became even more credible when
the cyclization was performed on the more flexible system
such as alcohol 87, Scheme 8. The reduction of the ox-
azolidone moiety, usually performed on 78 after the cy-
clization to generate 81 and prepare the C10 center for the
final connection to C11, was done with 76 instead, gener-
ating 87 which was subjected to the radical cyclization.
With this substrate, a 1:1 mixture of C14 epimers, 81 and
89, was isolated confirming the fact that the silyl group lo-
cated on the concave face of the intermediate radical 88
had no influence on the final quenching event. Rather it is
the increase in the flexibility of the system that allows 88
to adopt the less concave conformation leading to 89 in
addition to that leading to 81, Scheme 8. In future studies,
the control of stereochemistry will be enhanced by design-
ing a cyclization precursor that will favor maximization of
the conformation apparently operating in the formation of
89.
To complete the synthesis of the ent-morphinan skeleton,
the pentacyclic compound 78 was deprotected, the ox-
azolidone moiety was reduced to yield diol 80 which was
subjected to a double Swern oxidation to yield the rather
unstable oxo aldehyde 83. Exposure of this material to tri-
fluoromethanesulfonic acid led to the formation of alco-
hol 84, containing the complete morphinan skeleton. The
synthesis terminated here, even though a reduction of this
compound would furnish ent-epi-dihydrocodeine based
on the known stereochemistry of the reductions at C6. Ad-
ditionally, conversion of 81 via its mesylate to chloride 82
provided the opportunity to perform the first-ever closure
of a C10–C11 bond on an intermediate in which the ben-
zofuran bridge is in place and where C10 is sp
3
hybrid-
ized. A preliminary evidence [HRMS (CI/methane):
302.1812, (C
18
H
23
NO
3
+H) requires 302.1756; (FAB):
324.1574, (C
18
H
23
NO
3
+Na) requires, 324.1575] indicated
that upon exposure to AlCl
3
in benzene pentacycle 85 was
produced. The minute scale of the reaction precluded full
characterization of products. Future work will need to ad-
dress this procedure on a scale where manipulation of alu-
minum chloride catalyst proceeds without substantial
hydrolysis.
Stereochemistry of Radical Cyclization. From the results
obtained in the parallel experiments with 76, 77, and 87
several rationalizations can be extended also to the expla-
nations of results in the cascade cyclization. Figure 6
showed the four possible outcomes of a radical cyclization
that led to the formation of 56a and small amounts of 56b.
The transition state operating in the closure of the radical
59 may resemble the conformations of the product with a
substantial sp
2
character still connected at C14. In such a
case, the course of this cyclization would parallel the
events described for the transformations of 76 to 81 and
87 to 81 and 89. If this argument is correct, then perform-
ing the tandem cyclization on a more flexible system, such
as 91, may lead to the enhancement of the tendency to as-
sume conformations that will maximize production of
56b. The “open” form, 91, can be synthesized easily by a
conversion of halide or azide of the side chain to a car-
bamate and its condensation with
α
-bromoacetaldehyde
(or its dimethylketal), obtained by the method of Kraus by
ozonolysis of 1,4-dibromobut-2-ene.
36
The closure of the
radical such as 90 may lead to maximization of the correct
C14/C9 absolute stereochemistry through the less convex
shape.
Reagents: i TBSTf, iPr
2
NEt, CH
2
Cl
2
, –78°C, ii 33, nBu
3
P, DEAD,
THF, iii nBu
3
SnH, AIBN, benzene, reflux, iv TBAF, THF, v DIBAL-
H, CH
2
Cl
2
, vi oxalyl chloride, DMSO, Et
3
N, CH
2
Cl
2
, vii trifluorome-
thanesulfonic acid, viii MsCl, Et
3
N, THF, ix AlCl
3
, benzene, reflux.
Reagents: i DIBAL-H, CH
2
Cl
2
, ii nBu
3
SnH, AIBN, benzene, reflux.
Scheme 8
Scheme 7
672
Papers
SYNTHESIS
Another way in which the more “planar” (or less convex)
conformation required for 56b might be allowed would be
by performing the cyclization on 60 in which the original
double bonds of the arene cis-diol 7a have been retained,
Figure 7. Formation of radical 61 and its further behavior
should parallel the arguments offered above: in order to
maximize the conformation leading to the correct isomer
62b, the systems must attain a more “planar” configura-
tion. This can either be achieved by the introduction of the
additional sp
2
centers into the C ring or by not restricting
the flexibility of conformers with the rigid oxazolidone
ring. It is relatively easy to see in Figures 6 and 7 that of
the four conformations, the three that lead to the incorrect
epimers are all relatively convex while the one leading to
the correct configuration at C14 and C9 is relatively flat.
At this point, the best assumption for the next generation
improvement would be the following:
1. Perform the stepwise cyclization on the flexible hy-
droxy methyl compound and study the influence of hy-
drogen donor groups attached to the hydroxyl.
2. Perform the tandem cyclization of the “open form” of
oxazolidone which maintains the radical recipient
functionality (i.e., enol ether 90).
3. Devise other methods of cyclization for octahydroiso-
quinoline 68 (electrochemical or acid-catalyzed), and
study the stereochemical outcome.
The attainment of the correct configuration at C14 relative
to C9 constitutes one of the pivotal problems in morphine
synthesis as the majority of total syntheses attests to. The
multigeneration approach to the synthesis of this alkaloid
will hopefully resolve this problem adequately in the not
too distant future.
Conclusions
The first few steps that were necessary to evaluate the rad-
ical cyclization approach to the morphine skeleton have
been completed. The traditional problem of controlling
the C14 stereochemistry materialized in our approach as
well and in the future ameliorations serious attention will
be given to the events that control the conformations of ei-
ther the cyclization precursors (cascade approach) or the
cyclized radical species just before the hydrogen atom ab-
straction (stepwise approach). To achieve the promise of
a practical synthesis of this alkaloid, as insinuated in the
title of this paper, careful attention must also be given to
the overall number of operations and to the practical exe-
cution of each step. To this end, the enzymatic generation
of the key building blocks will almost certainly be re-
tained. On the other hand, more effective means will be
explored for the step-to-step manipulation of these syn-
thons in terms of both procedures and yield. Electrochem-
ical means of oxidation, reduction, and C–C bond
formation will specifically be looked at in this regard as a
promising replacement technology for the more tradition-
al methods. We look forward to reporting further results
of our quest for morphine synthesis in the future.
1,1,8,8-Tetramethyl-1,8-disilacyclodeca-2,6-diyne-4,5-diol (25):
The corresponding dialdehyde derived from diol 24 (2.4 g, 9.6 mmol)
was added neat to a solution of SmI
2
[320 mL, 31.6 mmol (0.1 M so-
lution in THF)], under vigorous stirring at r.t. The initial deep blue
color of the SmI
2
solution changed to dark orange within 30 seconds
following the addition of the dialdehyde. After stirring for 15 min, a
precipitate developed. The lanthanide species was then dissolved in
4 mL of 0.1 N aq HCl solution. Evaporation of the combined organic
layers afforded 25 (2.12 g, 87% crude) as a brown foam; mp
113–114°C (benzene/hexanes); R
f
= 0.3 (2:1 hexanes/EtOAc).
IR (CCl
4
):
ν
= 3375 (br), 3005, 2961, 1407 cm
–1
.
1
H NMR (400 MHz, CDCl
3
,):
δ =
4.40
(
d, J = 4.0 Hz, 2H), 2.25 (d, J
= 4.0 Hz, 2H), 0.74 (s, 4H), 0.17 (s, 12H).
13
C NMR (100 MHz, CDCl
3
,):
δ
= 104.5, 93.6, 68.9, 7.9, –2.5, –3.0.
MS: m/z = 252 (M
+
, 10), 235 (100), 145 (45).
1,1,8,8-Tetramethyl-1,8-disilacyclodeca-2,6-diyne-5-(2-propenyl-
oxy)-4-ol (26):
A 250 mL flask containing diol 25 (1.78 g, 7.06 mmol) was charged
with benzene and Bu
2
SnO (2.10 g, 8.48 mmol). The mixture was re-
fluxed overnight with azeotropic removal of H
2
O until the Bu
2
SnO
was completely dissolved, indicating the end of the reaction. After
evaporation of the solvent, 4 g of product were obtained which, with-
out further purification was dissolved in excess allyl bromide. After
2 days at reflux, the starting material was consumed and silica gel was
added to the mixture. The solvents were removed under reduced pres-
sure and the residue was purified by column chromatography (hex-
anes/EtOAc 4:1) to furnish the monoallyl ether 26 (740 mg, 36%) as
a yellow oil; R
f
= 0.5 (hexanes/EtOAc 10:1).
IR (neat):
ν
= 3400, 2945, 2900, 2160,1250 cm
–1
.
1
H NMR (400 MHz, CDCl
3
,):
δ
= 5.91
(
m, 1H), 5.33
(
d, J = 16 Hz,
1H), 5.23 (d, J = 12 Hz, 1H), 4.53 (dd, J = 7, 4 Hz, 1H), 4.29 (dd, J =
12.5, 6 Hz, 1H), 4.21 (d, J = 7 Hz, 1H), 4.03 (dd, J = 12.5, 6 Hz, 1H),
2.45 (d, J = 4 Hz, 1H), 0.74 (s, 2H), 0.72 (s, 2H), 0.16 (s, 6H), 0.15 (s,
6H).
13
C NMR (67.5 MHz, CDCl
3
,):
δ
= 133.7, 118.2, 103.5, 102.1, 94.3,
92.8, 75.1, 70.6, 67.2, 7.7, –2.3, –3.1.
MS: m/z = 292 (M
+
, 2%), 251 (18), 145 (100).
1,1,8,8-Tetramethyl-1,8-disilacyclodeca-2,6-diyne-5-(2-propenyl-
oxy)-4-ene (27):
To the allyl ether 26 (190 mg, 0.651 mmol) in CH
2
Cl
2
at 0°C was add-
ed pyridine (0.13 mL, 1.628 mmol) followed by dropwise addition of
triflic anhydride (0.16 mL, 0.976 mmol). After stirring at 0°C for
15 min, the mixture was poured into 1% HCl (10 mL), and extracted
with CH
2
Cl
2
. The combined organic phases were dried (Na
2
SO
4
), fil-
tered and evaporated. The mixture was quickly passed through a plug
of silica (hexanes/EtOAc 25:1) to give the corresponding triflate
(89.6 mg, 32%) as a colorless oil, which was used immediately in the
next reaction.
The triflate was dissolved in benzene (6 mL). DBU (0.035 mL,
0.212 mmol) was added dropwise at r.t. After stirring for 15 min, the
solution turned aquamarine in color, silica gel (100 mg) was added,
and the solvent was evaporated. The mixture was applied directly to
a flash silica column (hexanes/EtOAc 98:2) to yield 27 (28 mg, 48 %)
as a colorless oil; R
f
= 0.3 (hexanes/EtOAc 98:2).
IR (neat):
ν
= 2817, 2120 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ =
5.91
(
m, 1H), 5.31
(
s, 1H), 5.33 (d,
J = 16 Hz, 1H), 5.26 (d, J = 16, 1H), 4.39 (d, J = 5.6 Hz, 2H), 0.39 (s,
4H), 0.04 (s, 12H).
673
SYNTHESIS
April 1998
13
C NMR (67.5 MHz, CDCl
3
):
δ
= 148.1, 132.2, 118.5, 101.2, 98.8,
95.2, 84.1, 70.2 (di), 9.7, 7.9, –0.3, –2.3.
MS (EI): m/z = 274 (35%), 245 (41), 73 (100).
Bis[1,2-dimethylsilyl-2-(propynylbromo)]ethane (28):
To a stirred solution of diol 24 (11.0 g, 43.3 mmol) and CBr
4
(27 g,
86.6 mmol) in CH
2
Cl
2
(200 mL) at 0°C was added dropwise a solu-
tion of PPh
3
(34 g, 130 mmol) in CH
2
Cl
2
(100 mL). The mixture was
stirred overnight and the resulting orange solution was filtered and the
solvent evaporated. Filtration of the residue and trituration with Et
2
O
yielded 18 g of crude compound. The oil was purified by flash chro-
matography (hexanes/CH
2
Cl
2
4:1) to afford 28 (11.1 g, 68%) as a col-
orless oil; R
f
= 0.4 (hexanes/CH
2
Cl
2
4:1).
Found: C, 38.00; H, 5.36. (C
12
H
20
Br
2
Si
2
) requires: C, 37.90; H,
5.31%.
IR (neat):
ν
= 2960, 2170, 1245, 1200 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ =
3.92 (s, 4H), 0.58 (s, 4H), 0.16 (s,
12H
).
13
C NMR (67.5 MHz, CDCl
3
):
δ
= 100.5, 91.4, 14.6, 8.1, –2.6.
MS: m/z = 380 (M
+
, 2%), 223 (60), 175 (60), 147 (80).
5-Thia-1,1,8,8-tetramethyl-1,8-disilacyclodeca-2,6-diyne (29):
The dibromide 28 (1.0 g, 2.64 mmol) was dissolved in CH
2
Cl
2
(26 mL) and H
2
O (35 mL). After complete dissolution tetrabutylam-
monium bromide (0.27 g, 0.789 mmol) and Na
2
S.9H
2
O (0.76 g,
3.16 mmol) were added under vigorous stirring. After 2 h, the layers
were separated and the organic extract washed with H
2
O, dried and
removed under reduced pressure to afford a pale yellow solid. Purifi-
cation by flash column chromatography (hexanes/CH
2
Cl
2
4:1) afford-
ed 29 (120 mg, 18%) as a white solid; mp 118–121°C; R
f
= 0.4
(hexanes/CH
2
Cl
2
2:1).
Found: C, 55.44; H, 8.07. (C
12
H
20
SSi
2
.0.5.H
2
O) requires: C, 55.11;
H, 8.09 %.
IR (CCl
4
):
ν
= 2910, 2360, 2343, 1186 cm
–1
.
1
H NMR (270 MHz, CDCl
3
):
δ =
3.39 (s, 4H), 0.57 (s, 4H), 0.12 (s,
12H).
13
C NMR (67.5 MHz, CDCl
3
):
δ
= 101.1, 87.4, 19.9, 8.6, –2.3.
MS: m/z = 252 (M
+
, 1%), 224 (100), 209 (90), 147 (35).
5-Thia-1,1,8,8-tetramethyl-1,8-disilacyclodeca-2,6-diyne 5-Ox-
ide (30):
To a precooled (–30°C) solution of the sulfide 29 (1.4 g, 5.56 mmol)
in CH
2
Cl
2
(85 mL) was added MCPBA (1.6 g, 5.67 mmol). After
30 min, dimethyl sulfide (4 mL) was added and the mixture was
stirred for an additional 15 min. The reaction was concentrated under
reduced pressure, and the residue dissolved in Et
2
O. The organic so-
lution was washed with sat. NaHCO
3
(2 × 60 mL) and brine (1 ×
30 mL), dried (MgSO
4
), filtered, and evaporated to afford 1.3 g of a
light yellow semi-solid residue. Purification by flash column chroma-
tography (Et
2
O) afforded 30 (940 mg, 63%) as a white solid; mp
177–178°C; R
f
= 0.5 (Et
2
O).
Found: C, 53.67; H, 7.58. (C
12
H
20
OSSi
2
) requires: C, 53.66; H, 7.52 %.
IR (CCl
4
):
ν
= 2960, 2910, 2170, 2343, 1186 cm
–1
.
1
H NMR (270 MHz, CDCl
3
):
δ =
3.39 (s, 4H), 0.57 (s, 4H), 0.12 (s,
12H).
13
C NMR (67.5 MHz, CDCl
3
):
δ
= 101.1, 87.4, 19.9, 8.6, –2.3.
MS: m/z = 252 (M
+
, 1%), 224 (100), 209 (90), 147 (35).
5-Thia-1,1,8,8-tetramethyl-4-chloro-1,8-disilacyclodeca-2,6-
diyne 5,5-Dioxide (31):
To a –78°C solution of sulfoxide 30 (248 mg, 0.925 mmol) in CH
2
Cl
2
(20 mL) was added pyridine (0.26 mL, 3.24 mmol) followed by
SO
2
Cl
2
(1.9 mL of a 1 M solution in CH
2
Cl
2
, 1.94 mmol). After 1.5 h,
the solution was quenched with H
2
O (4 mL) and warmed to r.t. The
mixture was extracted with sat. NaHCO
3
solution (5 mL), H
2
O
(5 mL), sat. CuSO
4
solution (2 × 5 mL) and brine (10 mL). The organ-
ic solution was dried (MgSO
4
), filtered, and evaporated to afford a
residue that was dissolved in CH
2
Cl
2
, cooled to 0°C and treated with
MCPBA (495 mg, 2.87 mmol). The mixture was stirred overnight and
then two drops of Me
2
S were added. After stirring for 15 min, the
mixture was washed with NaHCO
3
solution (10 mL), and H
2
O
(10 mL), dried (MgSO
4
), filtered, and evaporated to afford 425 mg of
a foamy residue. Purification by flash column chromatography
(CH
2
Cl
2
/hexanes 10:1) afforded 31 (263 mg, 90%) as a pale yellow
solid; R
f
= 0.5 (CH
2
Cl
2
/hexanes 10:1).
Found: C, 43.55; H, 5.80. (C
12
H
20
ClO
2
SSi
2
.0.5.H
2
O) requires: C,
43.94; H, 6.14 %.
IR (CHCl
3
):
ν
= 2980, 2910, 2190, 1800 cm
–1
.
1
H NMR (270 MHz, CDCl
3
):
δ =
5.74 (dd, J = 12, 2.6, 1H), 4.32 (m,
1H), 4.15 (m, 1H), 0.66 (s, 4H), 0.18 (s, 12H).
13
C NMR (67.5 MHz, CDCl
3
):
δ
= 99.8, 94.4, 59.7, 42.9, 8.2, –2.8.
MS: m/z = 319 (2), 157 (28), 139 (100).
1,1,8,8-Tetramethyl-1,8-disilacyclodeca-2,6-4-ene (21):
To a –78°C solution of MeLi (0.47 mL of a 1.6 M solution in Et
2
O,
0.75 mmol) in Et
2
O (8 mL), was added sulfone 31 (200 mg,
0.63 mmol) dissolved in Et
2
O (15 mL). Immediately after the addi-
tion was complete, sat. aq ammonium chloride was added and the
mixture was diluted with pentane and H
2
O. The organic layer was
separated, dried (MgSO
4
), filtered, and evaporated to afford 140 mg
of an orange oil. Purification by flash column chromatography (pen-
tane/Et
2
O 98:2) afforded 21 (263 mg, 90%) as a colorless semi-solid;
R
f
= 0.3 (pentane/Et
2
O 98:2).
IR (neat):
ν
= 2900, 2110 cm
–1
.
UV (CH
3
CN):
λ
max
= 274, 290.
1
H NMR (270 MHz, CDCl
3
):
δ =
6.0 (s, 2H), 0.66 (s, 4H), 0.16 (s,
12H).
13
C NMR (67.5 MHz, CDCl
3
):
δ
= 121.8, 103.0, 100.2, 8.7.
1,1,8,8-Tetramethyl-1,8-disilacyclodeca-2,6-diyne-5-propenyl-4-
one (32):
Enediyne 27 (3 mg, 0.01 mmol) was dissolved in benzene-d
6
(0.8 mL)
and transferred to a thick-walled NMR tube. Cyclohexa-1,3-diene
(0.08 mL, 0.8 mmol) was added to the mixture, and the sample was
degassed for 30 min with a stream of Ar. After heating the sample at
55°C for 8 h, the starting material remained unchanged. The reaction
temperature was increased to 80°C, and after 60 h the starting mate-
rial was consumed. Evaporation of the solvents yielded 32 (1.3 mg,
43 %) as a yellow oil; R
f
= 0.5 (hexanes/EtOAc 10:1).
IR (neat):
ν
= 2810, 2100, 1725 cm
–1
.
1
H NMR (270 MHz, CDCl
3
):
δ =
5.84 (m, 1 H), 5.12 (m, 2H), 3.27
(m, 1H), 2.50 (m, 2H), 0.23 (s, 4H), 0.17 (s, 12 H).
13
C NMR (67.5 MHz, CDCl
3
):
δ
= 185.4, 133.6, 117.9, 106.7, 104.0,
100.1, 91.7, 48.1, 35.4, 7.9, –2.6, –3.3.
(1R,6R)-6-Thexyloxy-2-methylcyclohex-2-enyl-(2-phenylacetate)
(41):
A THF solution (5 mL) of a phosphine reagent [prepared from DEAD
(142 mg, 0.905 mmol) and tributylphosphine (225 mg, 0.905 mmol)]
was added dropwise to a precooled solution (0°C) of alcohol 40
(120.0 mg, 0.444 mmol) and benzoic acid (110.5 mg, 0.905 mmol) in
THF (5 mL) and stirred at r.t. for 20 h. The solvent was removed un-
der reduced pressure, and the residue was purified by column chroma-
tography (EtOAc/hexane 1:9) to yield 41 (113 mg, 68 %) as a viscous,
colorless oil; R
f
= 0.25 (EtOAc/hexane 1:9); [
α
]
D
25
+103.2 (c = 1.18,
CHCl
3
).
1
H NMR (400 MHz, CDCl
3
):
δ
= 8.08 (d, J = 1.2 Hz, 1H), 8.05, (d, J
= 1.4 Hz, 1H), 7.99 (tt, J = 7.8, 1.7 Hz, 2H), 7.66 (br t, J = 1.22 Hz,
1H), 7.55 (tt, J = 7.8, 1.2 Hz, 1H), 5.40 (d, J = 4.9 Hz, 1H), 4.00 (hept,
J = 5.2, 3.1, 2.2 Hz, 1H), 2.20 (m, 1H), 2.05 (m, 1H), 1.81 (m, 1H),
1.74 (m, 1H), 1.68 (br d, 1H), 1.56 (sep, J = 6.5 Hz, 1H), 0.82 (d, 6H),
0.78 (d, 6H), 0.10 (s, 3H), 0.08 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 162.3, 132.8, 130.5, 130.3, 129.7,
128.3, 126.8, 75.7, 69.7, 34.2, 27.9, 22.4, 20.2, 18.5, –2.7, –2.9.
(1R,6R)-6-Thexyloxy-2-methylcyclohex-2-en-1-ol (42):
A solution of ester 41 (214 mg, 0.571 mmol) in MeOH/NaOMe
(12 mL, trace) was stirred at r.t. for 46.5 h. The mixture was concen-
trated under reduced pressure to give a residue which was dissolved
in benzene and purified by column chromatography (EtOAc/hexane
674
Papers
SYNTHESIS
3:7) to afford alcohol 42 (143.9 mg, 93%) as a colorless, viscous oil;
R
f
= 0.60 (EtOAc/hexane 3:7).
1
H NMR (400 MHz, CDCl
3
):
δ
= 5.41 (br s, 1H), 3.87 (br s, 1H), 3.74
(ddd, J = 10.2, 6.7, 3.5 Hz, 1H), 2.06 (m, 2H), 1.99 (d, J = 4.1 Hz, 1H),
1.76 (m, 4H), 1.63 (m, 2H), 0.88 (br d, J = 6.9 Hz, 6H), 0.84 (s, 6H),
0.14 (s, 3H), 0.12 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 133.6, 123.8, 75.1, 74.0, 34.2, 29.7,
28.5, 23.6, 20.4, 19.4, 18.6, –2.3, –2.8.
3-Bromo-2-{[(1R,6S)-6-thexyloxy]-2-methylcyclohex-2-enyl}oxy-
phenol (43):
To a precooled solution (0°C) of alcohol 42 (75 mg, 0.277 mmol) and
Bu
3
P (112 mg, 0.554 mmol) in THF (2 mL) was added dropwise
DEAD (96.6 mg, 0.554 mmol). After stirring for 2 min a solution of
phenol 38 (110 mg, 0.333 mmol) in THF (2 mL) was added dropwise.
The cooling bath was removed and the mixture was stirred for 12.5 h.
The mixture was concentrated under reduced pressure to afford
42.6 mg of crude silyl protected 43. This was dissolved in THF (5
mL), and treated with TBAF (57 mg). After 9 h of stirring at r.t., H
2
O
(15 mL) was added, and the THF distilled off under reduced pressure.
The product was extracted with CH
2
Cl
2
(5 × 15 mL), dried (MgSO
4
),
and after filtration, the solvent was removed under reduced pressure
to give crude phenol 43 (~30 mg). The crude material was taken on
directly to the next step.
Benzyl (3-Bromo-2-{[(1R,6S)-6-thexyloxy-2-methylcyclohex-2-
enyl]oxy}phenyl Ether (44):
The solution of phenol 43 (34.5 mg, 0.0781 mmol) and benzyl bro-
mide (20.0 mg, 0.117 mmol) in acetone (2.5 mL) was treated with
K
2
CO
3
(55 mg, 0.390 mmol) and vigorously stirred. After 5 h, the sol-
id was filtered off and the filtrate was concentrated under reduced
pressure. The residue (41 mg) was purified by column chromatogra-
phy (EtOAc/hexanes 1:9) to afford 44 (21.4 mg, 51%) as a viscous,
colorless oil.
1
H NMR (400 MHz, CDCl
3
):
δ
= 7.37 (m, 5H), 7.14 (dd, J = 7.6,
1.8 Hz, 1H), 6.87 (m, 1H), 5.53 (br s, 1H), 5.07 (s, 2H), 4.87 (t, J =
5.4 Hz, 1H), 4.22 (br s, 1H), 2.09 (m, 1H), 1.82 (m, 1H), 1.79 (s, 3H),
1.62 (p, J = 6.9 Hz, 1H), 1.55 (s, 1H), 1.41 (m, 1H), 0.88 (s, 3H), 0.86
(s, 3H), 0.82 (s, 6H), 0.11 (s, 3H), 0.09 (s, 3H).
(5aR,6S,9aS)-9a-Methyl-6-thexyloxy-5a,6,7,8,9,9a-hexahydro-
dibenzo[b,d]furan-4-yl Benzyl Ether (45):
The solution of the bromide 44 (21.0 mg, 0.039 mmol) and Bu
3
SnH
(23.0 mg, 0.078 mmol) in refluxing toluene (3.0 mL) was treated with
AIBN. After 24 h of reflux, the reaction was concentrated under re-
duced pressure, and the residue was purified by column chromatogra-
phy (benzene) to yield tricyclic ether 45 (9.8 mg, 55%) as a colorless
oil.
1
H NMR (400 MHz, CDCl
3
):
δ
= 7.44 (m, 2H), 7.35 (m, 2H), 7.29 (m,
1H), 6.75 (m, 2H), 6.70 (dd, J = 6.3, 2.3 Hz, 1H), 5.18 (s, 2H), 4.38
(t, J = 4.9 Hz, 1H), 3.80 (m, 1H), 2.13 (m, 1H), 1.88 (m, 1H), 1.79 (m,
2H), 1.63 (m, 2H), 1.58 (s, 3H), 1.35 (m, 1H), 0.90 (s, 3H), 0.88 (s,
3H), 0.83 (d, J = 6.0 Hz, 6H), 0.08 (s, 3H), 0.05 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 147.0, 144.0, 140.0, 137.3, 128.5,
127.8, 127.4, 121.1, 114.7, 113.8, 88.8, 71.1, 66.5, 42.5, 34.1, 28.5,
24.8, 22.7, 20.2, 19.6, 18.6, –2.7, –2.9.
(3S,4S)-3-(1-Bromo-2-phenyloxy)-4-(tert-butyldimethylsilyloxy)-
2-[2-(3-oxazolone)ethyl]cyclohexene (46):
To a solution of alcohol 50 (204.3 mg, 0.609 mmol) and 2-bromophe-
nol (112.8 mg, 0.609 mmol) in THF (10 mL) was added the Mitsuno-
bu reagent [prepared from Bu
3
P (296 mg, 1.462 mmol) and DEAD
(255 mg, 1.462 mmol) in THF (10 mL) precooled to 0°C]. The cool-
ing bath was removed and the mixture was stirred for 5 h, at which
time TLC indicated disappearance of starting material. The solvent
was removed under reduced pressure and the crude product was dis-
solved in Et
2
O (50 mL). After washing with H
2
O (20 mL) and brine
(20 mL), the combined organic phase was dried (MgSO
4
), filtered,
and concentrated. The crude product was purified by column chroma-
tography (EtOAc/hexane 95:5) to yield the intermediate (3S,4S)-2-(2-
bromoethyl)-3-(1-bromo-2-phenyloxy)-4-(tert-butyldimethylsilyl-
oxy)cyclohexene (132 mg, 44%).
1
H NMR (400 MHz, CDCl
3
):
δ
= 7.53 (dd, J = 7.9, 1.5 Hz, 1H), 7.26
(m, 1H), 7.24 (dt, J = 7.2, 0.9, 1H), 6.83 (dt, J = 7.5, 1.4 Hz, 1H), 5.80
(br s, 1H), 4.63 (br d, J = 4.7 Hz, 1H), 4.04 (m, 1H), 3.41 (dd, J = 7.9,
6.9 Hz, 2H), 2.80 (m, 1H), 2.56 (m, 1H), 2.20 (m, 2H), 1.90 (m, 1H),
1.72 (m, 1H), 0.82 (s, 9H), 0.01 (s, 3H), –0.11 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 155.3, 133.5, 132.2, 129.5, 128.3,
122.1, 115.0, 112.7, 79.4, 70.0, 37.5, 31.9, 27.8, 25.7, 22.4, 18.9,
–5.0.
To a solution of oxazolone 8 (21 mg, 0.247 mmol) in DMSO (5 mL)
was added NaH (10 mg, 0.25 mmol). The mixture was stirred for
15 min to complete the formation of the sodium salt and the interme-
diate bromide (121 mg, 0.247 mmol) in DMSO (2 mL) was added
dropwise via syringe. After stirring at r.t. for 20 h, the reaction was
diluted with Et
2
O (50 mL) and quenched with H
2
O (30 mL). The or-
ganic phase was separated, washed with brine (2 × 20 mL), dried
(MgSO
4
), filtered and concentrated under reduced pressure. The
crude product was purified by column chromatography (EtOAc/hex-
ane 3:7) to afford 46 (68 mg, 56%) as a viscous oil.
1
H NMR (400 MHz, CDCl
3
):
δ
= 7.64 (dd, J = 7.8, 1.5 HZ, 1H), 7.36
(dt, J = 7.3, 1.7 Hz, 1H), 7.27 (dd, J = 8.2 Hz, 1H), 6.94 (br t, J =
7.8 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 5.79
(dt, J = 3.8 Hz, 1H), 4.80 (br d, J = 4.1 Hz, 1H), 4.13 (m, 1H), 3.74
(m, 2H), 2.70 (br m, 1H), 2.42 (br m, 1H), 2.28 (m, 1H), 2.16 (m, 1H),
2.00 (m, 1H), 1.80 (m, 1H), 0.91 (s, 9 H), 0.12 (s, 3H), 0.10 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 155.0, 133.5, 130.3, 130.3, 128.5,
122.2, 116.3, 115.0, 112.5, 79.5, 69.8, 42.7, 33.9, 27.6, 25.7, 22.4,
–4.9, –4.9.
10-tert-Butyldimethylsilyloxy-8,16,18-dioxazapentacyclo-
[11.7.0.0
1,9
.0
2,7
.0
14,18
]icosa-2(7),3,5-trien-17-one (47):
To a degassed (Ar sparge) solution of 46 (67 mg, 0.135 mmol) in tol-
uene (10 mL) was added Bu
3
SnH (78.9 mg, 73 µL, 0.271 mmol) and
AIBN (cat.). The reaction vessel was submerged into a preheated oil
bath (110°C) and allowed to reflux for 16 h. Two additional spatula
tips of AIBN were added and the reaction was stirred at reflux an ad-
ditional 5 h. The solvent was removed under reduced pressure, and
the crude product was purified by column chromatography (benzene/
Et
2
O 9:1). Two compounds with similar R
f
were isolated as a mixture,
which was further purified by preparative TLC (EtOAc/hexane 1:1)
to afford pentacycle 47 (5.5 mg, 10%) as a colorless oil.
1
H NMR (400 MHz, CDCl
3
):
δ
= 7.26 (m, 1H), 6.97 (br t, J = 7.3 Hz,
1H), 6.86 (m, 2H), 4.48 (t, J = 8.1 Hz, 1H), 4.18 (br s, 1H), 4.10 (dd,
J = 8.7, 5.5 Hz, 1H), 3.83 (ddd, J = 13, 6, 1 Hz, 1H), 3.40 (ddd, J =
10.1, 8, 5.6, 1H), 2.80 (dt, J = 12.8, 3.7 Hz, 1H), 2.65 (dm, J = 13 Hz,
1H), 2.20 (dt, J = 10.1, 5.9 Hz, 1H), 1.50–1.80 (bm, app 6H), 0.81 (s,
9H), –0.05 (s, 3H), –0.12 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 157.8, 129.5, 123.3, 121.5, 115.3,
66.8, 65.1, 60.1, 41.2, 40.2, 30.6, 29.0, 28.3, 26.8, 25.7, 24.6, 19.7,
17.3, 13.6, –2.4, –2.6.
MS (CI): m/z = 416 (M+H
+
, 28%), 358 (100), 313 (25), 190 (30), 151
(30),
HRMS: 416.2276, (C
23
H
33
NO
4
Si+H) requires, 416.2257.
(3R,4S)-2-(2-Bromoethyl)-4-(tert-butyldimethylsilyloxy)-3-hy-
droxycyclohexene (50):
To a stirred solution of the diol 49 (1.634 g, 7.39 mmol) in anhyd
CH
2
Cl
2
(50 mL) under Ar, was added diisopropylethylamine (2.70
mL, 15.52 mmol) and the mixture cooled to –78°C, resulting in a
white suspension. After 10 min, tert-butyldimethylsilyl triflate (1.87
mL, 8.13 mmol) was added dropwise, and stirring/cooling continued.
After 5 h, further TBSTf (0.85 mL, 3.70 mmol) was added dropwise,
and the stirred mixture allowed to slowly warm to r.t. overnight. After
20 h, H
2
O (80 mL) and saturated aqueous NH
4
Cl (30 mL) were add-
ed, and the resulting mixture extracted with further CH
2
Cl
2
(4 × 80
mL). The combined organic fractions were dried (MgSO
4
), filtered
and reduced in vacuo to yield a brown oil. Further purification by
675
SYNTHESIS
April 1998
flash chromatography (silica ratio 50:1, hexane/EtOAc, gradient elu-
tion, 50:1 to 20:1), yielded silyl ether 50 (1.166 g, 47% from 7a) as a
colorless oil; R
f
= 0.30 (hexane/EtOAc 19:1); [
α
]
D
25
= –42.0 (c = 1.0,
CHCl
3
).
IR: (thin film):
ν
= 3552, 2932, 1256, 1087 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 5.65 (m, 1H), 3.90 (t, J = 3.5 Hz,
1H), 3.81 (dt, J = 10.6, 2x 3.7 Hz, 1H), 3.53 (m, 2H), 2.76 (m, 1H),
2.63 (m, 2H), 2.18 (m, 1H), 2.03 (m, 1H), 1.78 (m, 1H), 1.57 (m, 1H),
0.92 (s, 9H), 0.11 (s, 6H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 134.7 (C), 127.7 (CH), 70.7 (CH),
68.6 (CH), 38.4 (CH
2
), 31.8 (CH
2
), 25.7 (3 × CH
3
), 25.4 (CH
2
), 23.9
(CH
2
), 18.0 (C), –4.5 (CH
3
), –4.9 (CH
3
).
MS (EI, 70 eV): m/z = 335 (M+H
+
, 10%).
HRMS: 335.1042, (C
14
H
28
O
2
79
BrSi) requires, 335.1042.
Also isolated, in varying amount, was the bis silylated compound; R
f
= 0.59 (hexane/EtOAc 19:1); [
α
]
D
25
–42.2 (c = 1.0, CHCl
3
).
IR (thin film):
ν
= 2995, 1470, 1255, 1090 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 5.65 (br t, J = 3.3 Hz, 1H), 3.96 (br
s, 1H), 3.72 (dt, J = 10.5, 2x 2.8 Hz, 1H), 3.42 (m, 2H), 2.57 (t, J =
7.9 Hz, 2H), 2.16 (m, 1H), 2.01 (m, 1H), 1.90 (m, 1H), 1.51 (m, 1H),
0.90 (s, 9H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07
(s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 136.4 (C), 125.9 (CH), 72.2 (CH),
71.2 (CH), 37.6 (CH
2
), 32.0 (CH
2
), 26.1 (6x CH
3
), 25.4 (CH
2
), 24.7
(CH
2
), 18.4 (2x C), -3.6 (CH
3
), –4.3 (CH
3
), –4.4 (CH
3
), –4.6 (CH
3
).
(3S,4S)-3-Benzoyloxy-4-tert-butyldimethylsilyoxy-2-(2-bromo-
ethyl)cyclohexene (51):
To stirred solution of alcohol 50 (4.609 g, 13.74 mmol) and benzoic
acid (1.846 g, 15.12 mmol) in anhyd THF (12 mL) at 0°C, was added
a solution of the Mitsunobu reagent [previously prepared by addition
of DEAD (4.786 g, 27.48 mmol) to a stirred solution of tributylphos-
phine (5.559 g, 27.48 mmol) in anhyd THF (10 mL) at 0°C], and the
mixture allowed to warm to r.t. with stirring. After 16 h, solvent was
removed in vacuo to yield a brown oil, which was prepurified by pas-
sage through a silica plug with benzene. Further purification by flash
chromatography (silica 300 g, benzene) yielded benzoate 51 (5.117 g,
84%) as a highly viscous, colorless oil, which solidified on prolonged
standing; mp 65–66°C (benzene); R
f
= 0.20 (hexane/EtOAc 19:1);
[
α
]
D
25
+102.0 (c = 1.0, CHCl
3
).
IR: (KBr disc):
ν
= 2930, 1710, 1260, 1110, 840 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 8.05 (dm, J = 8.5 Hz, 2H), 7.57 (ddt,
J = 7.9, 6.9, 1.4 Hz, 1H), 7.45 (tm, J = 7.6 Hz, 2H), 5.84 (br t, J =
3.6 Hz, 1H), 5.40 (d, J = 4.4 Hz, 1H), 4.02 (ddd, J = 7.0, 4.7, 2.9 Hz,
1H), 3.45 (m, 2H), 2.60 (m, 1H), 2.50 (m, 1H), 2.30 (m, 1H), 2.11 (m,
1H), 1.82 (m, 1H), 1.74 (m, 1H), 0.84 (s, 9H), 0.50 (s, 3H), 0.30 (s,
3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 166.1 (C), 133.0 (CH), 130.8 (C),
130.3 (CH), 130.1 (C), 129.7 (2 × CH), 128.4 (2 × CH), 73.4 (CH),
69.2 (CH), 37.5 (CH
2
), 31.1 (CH
2
), 27.2 (CH
2
), 25.6 (3 × CH
3
), 22.1
(CH
2
), 17.8 (C), –4.86 (CH
3
), –4.88 (CH
3
).
MS (EI, 70 eV): m/z 439 (M
+
, 10%), 359 (MH
+
, 100).
HRMS: 439.1291, (C
21
H
32
O
3
79
BrSi) requires, 439.1304.
(3S,4S)-3-Benzoyloxy-4-tert-butyldimethylsilyl-2-[2-(oxazol-2-
on-1-yl)ethyl]cyclohexene (52):
To a stirred suspension of NaH (0.3353 g, 1.40 mmol) in anhyd
DMSO (20 mL) was added, in one portion, the oxazolone 8 (1.1885 g,
13.97 mmol) and the resulting mixture stirred at r.t. for 20 min. After
this time, the mixture was cooled slightly (~10°C) and a solution of
bromide 51 (5.1168 g, 11.64 mmol) in DMSO (40 mL) was added
dropwise. The mixture was allowed to warm to r.t. with stirring. After
18 h, the reaction was cooled to 0°C and quenched with brine
(200 mL) and H
2
O (200 mL). The resulting mixture was extracted
with EtOAc (1 × 200 mL, 3 × 100 mL), the combined organic frac-
tions were washed with brine (1 × 50 mL), dried (Na
2
SO
4
) and the
solvent was removed in vacuo to yield a pale yellow oil. Further pu-
rification by flash chromatography (silica 200 g, EtOAc/hexane 1:1)
yielded pure ester 52 (3.683 g, 71%) as a highly viscous, colorless oil;
R
f
= 0.14 (hexane/EtOAc 4:1); [
α
]
D
25
+ 83.7 (c = 1.0, CHCl
3
).
IR (thin film):
ν
= 2930, 1750, 1720, 1260 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 8.07 (m, 2H), 7.59 (ddt, J = 8.0, 6.8,
2 × 1.3 Hz, 1H), 7.46 (m, 2H), 6.70 (d, J = 2.1 Hz, 1H), 6.53 (d, J =
2.1 Hz, 1H), 5.76 (br t, J = 4.0 Hz, 1H), 5.47 (d, J = 4.6 Hz, 1H), 4.05
(ddd, J = 7.4, 4.9, 2.7 Hz, 1H), 3.74 (ddd, J = 13.9, 7.3, 5.0 Hz, 1H),
3.60 (ddd, J = 14.2, 8.4, 7.0 Hz, 1H), 2.38 (m, 1H), 2.25 (m, 2H), 2.12
(m, 1H), 1.85 (m, 1H), 1.75 (m, 1H), 0.84 (s, 9H), 0.07 (s, 3H), 0.04
(s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 166.2 (C), 155.5 (C), 133.1 (CH),
131.0 (CH), 129.8 (C), 129.6 (2 × CH), 129.4 (C), 128.4 (2 × CH),
116.3 (CH), 73.3 (CH), 69.4 (CH), 42.2 (CH
2
), 33.1 (CH
2
), 27.3
(CH
2
), 25.6 (3 × CH
3
), 22.1 (CH
2
), 17.9 (C), –4.9 (2 × CH
3
).
MS (EI, 70 eV): m/z = 444 (M+H
+
, 20%), 428 (M-CH
3
+
, 42).
HRMS: 444.2204, (C
24
H
34
NO
5
Si) requires, 444.2206.
Also isolated was the elimination product, (3R)-Benzoyloxy-(4S)-
tert-butyldimethylsilyloxy-2-vinylcyclohexene (53): (0.459 g,
11%) as a colorless oil; R
f
= 0.49 (hexane/EtOAc 19:1); [
α
]
D
25
+ 246.4
(c = 1.0, CHCl
3
).
IR (thin film):
ν
= 2930, 2860, 1720, 1260, 1090 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 8.05 (m, 2H), 7.55 (m, 1H), 7.43 (m,
2H), 6.31 (dd, J = 17.6, 11.1 Hz, 1H), 6.11 (dd, J = 5.0, 3.0 Hz, 1H),
5.62 (d, J = 3.2 Hz, 1H), 5.11 (d, J = 17.7 Hz, 1H), 4.90 (d, J = 11.0
Hz, 1H), 4.10 (t, J = 4.9 Hz, 1H), 2.44 (m, 1H), 2.17 (dm, J = 18.9 Hz,
1H), 1.85 (dddd, J = 13.5, 10.7, 5.5, 2.0 Hz, 1H), 1.75 (m, 1H), 0.89
(s, 9H), 0.15 (s, 3H), 0.11 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 165.5 (C), 137.5 (CH), 134.1 (CH),
132.9 (CH), 131.7 (C), 130.3 (C), 129.7 (2 × CH), 128.3 (2 × CH),
111.2 (CH
2
), 68.7 (CH), 67.5 (CH), 25.7 (3 × CH
3
), 21.8 (CH
2
), 21.3
(CH
2
), 18.1 (C), –4.8 (CH
3
), –5.0 (CH
3
).
MS (CI/methane): m/z = 359 (M+H
+
, 1%), 237 (M-PhCO
2
+
, 52).
HRMS: 359.2030, (C
21
H
31
O
3
Si) requires, 359.2042.
(3R,4S)-3-[2-(1-Bromo-3-methoxy)phenyloxy]-4-(tert-butyldi-
methylsilyloxy)-2-[2-(3-oxazolone)ethyl]cyclohexene (55):
To a stirred solution of benzoate 52 (3.683 g, 8.30 mmol) in MeOH
(50 mL) at r.t., was added 1 M aq NaOH (20 mL), resulting in mild
emulsification. After 6 h, the MeOH was removed in vacuo, brine
(100 mL) was added, and the resulting mixture extracted with EtOAc
(3 × 150 mL). The combined organic fractions were dried (MgSO
4
),
filtered and reduced in vacuo to yield the intermediate alcohol 54 as a
highly viscous, colorless oil, which was used directly without further
purification.
1
H NMR (400 MHz, CDCl
3
):
δ
= 6.77 (d, J = 2.1 Hz, 1H), 6.54 (d, J
= 2.1 Hz, 1H), 5.39 (br t, J = 3.0 Hz, 1H), 3.94 (m, 1H), 3.87 (ddd, J
= 6.4, 7.6, 16.0 Hz, 1H), 3.74 (ddd, J = 3.2, 5.9, 9.1 Hz, 1H), 3.64 (dt,
J = 6.4 x 2, 13.9 Hz, 1H), 2.75 (d, J = 5.6 Hz, 1H), 2.52 (m, 1H), 2.37
(m, 1H), 2.10 (m, 1H), 1.98 (m, 1H), 1.77 (m, 1H), 1.60 (m, 1H), 0.9
(s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ =
156.1 (C), 132.7 (C), 127.8 (2 × C),
116.0 (CH), 73.62 (CH), 73.58 (CH), 43.13 (CH
2
), 34.2 (CH
2
), 27.5
(CH
2
), 25.8 (3 × CH
3
), 23.1 (CH
2
), 18.0 (C), –4.5 (CH
3
), –4.7 (CH
3
).
To a stirred solution of the alcohol 54 (2.54 g, 7.48 mmol) and phenol
33 (1.52 g, 7.48 mmol) in anhyd THF (10 mL) under Ar at 0°C, was
added dropwise a solution of the Mitsunobu reagent [previously pre-
pared by addition of DEAD (2.356 mL, 14.96 mmol) to a stirred so-
lution of Bu
3
P (3.727 mL, 14.96 mmol) in anhyd THF (30 mL) at
0°C], and the mixture was allowed to warm to r.t. with stirring. After
6 h, the solvent was removed in vacuo to yield a brown oil, which was
prepurified by passage through a silica plug (hexane/EtOAc 3:2). Fur-
ther purification by flash chromatography (silica ratio 200:1, hexane/
EtOAc 3:2) yielded aryl ether 55, (1.095 g, 28%) as a highly viscous,
colorless oil; R
f
= 0.22 (hexane/EtOAc 2:1); [
α
]
D
25
–179.5 (c = 1.0,
CHCl
3
).
IR (KBr disc):
ν
= 3150, 2960, 1750, 1470, 1260, 1120, 840 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 7.07 (dd, J = 7.2, 2.4 Hz, 1H), 6.79
(m, 2H), 6.70 (d, J = 1.8 Hz, 1H), 6.61 (d, J = 1.8 Hz, 1H), 5.58 (m,
1H), 5.13 (d, J = 2.9 Hz, 1H), 3.88 (s, 3H), 3.87 (m, 1H), 3.74 (m, 2H),
2.69 (m, J = ~7Hz, 1H), 2.55 (m, 1H), 2.44 (m, 1H), 2.21 (m, 1H),
2.04 (m, 1H), 1.58 (m, 1H), 0.60 (s, 9H), –0.10 (s, 3H), –0.28 (s, 3H).
676
Papers
SYNTHESIS
13
C NMR (100 MHz, CDCl
3
):
δ
= 155.9 (C), 151.8 (C), 146.6 (C),
131.6 (C), 131.2 (2 × CH), 125.6 (CH), 122.8 (CH), 117.5 (C), 116.8
(CH), 111.3 (CH), 78.2 (CH), 73.0 (CH), 55.6 (CH
3
), 43.1 (CH
2
),
35.2 (CH
2
), 25.7 (CH
2
), 25.6 (3 × CH
3
), 24.9 (CH
2
), 17.9 (C), –5.0
(CH
3
), –5.4 (CH
3
).
MS (EI, 70 eV): m/z = 524 (M
+
, 1%), 468 (M-tert-Bu
+
, 40).
HRMS: 524.1467, (C
24
H
35
NO
5
79
BrSi) requires, 524.1468.
10-tert-Butyldimethylsilyloxy-6-methoxy-(1S,10S,13S,14R)-
8,16,18-dioxazapentacyclo[11.7.0.0
1,9
.0
2,7
.0
14,18
]icosa-2(7),3,5-
trien-17-one (56a):
A large, heavy walled, resealable glass tube was fitted with a septum,
subjected to vacuum flame drying, Ar flooding three times, and al-
lowed to cool under Ar. Bromide 55 (215 mg, 0.410 mmol) was taken
up in anhyd benzene (3 × 14 mL) and added to the tube. The resulting
solution (~0.01 M) was rigorously degassed under a stream of Ar for
30 min. After that time, tris(trimethylsilyl)silane (190 µL,
0.615 mmol) was added, followed by a catalytic quantity of AIBN,
while taking precautions to exclude oxygen. The tube was sealed, and
the solution heated to 140°C in an oil bath. Further AIBN was added
over regular intervals (~5 h), and after 20 h, additional TTMSS (63
µL, 0.205 mmol). After 24 h total, heat was removed, the tube al-
lowed to cool, and opened. Solvent was removed in vacuo, and the
residue subjected to purification by a combination of flash chroma-
tography (silica ratio 100:1, hexane/EtOAc 3:2) and preparative
HPLC (Supelco C
18
reverse phase column, MeOH/H
2
O 90:10, 15
mL/min). Further purification of the enriched fractions yielded penta-
cycle 56a (15.4 mg, 8%) as a white solid; R
f
= 0.50 (hexane/EtOAc
1:1); [
α
]
D
25
–11.5 (c = 0.2, CHCl
3
).
1
H NMR (400 MHz, CDCl
3
):
δ
= 6.82 (t, J = 7.8 Hz, 1H), 6.74 (dd, J
= 8.1, 1.1 Hz, 1H), 6.60 (dd, J = 7.4, 1.1 Hz, 1H), 4.57 (d, J = 4.0 Hz,
1H), 4.53 (t, J = 8.3 Hz, 1H), 4.21 (td, J = 6.2, 6.2, 4.1 Hz, 1H), 3.99
(dd, J = 8.6, 5.7 Hz, 1H), 3.87 (s, 3H), 3.83 (ddd, J = 13.7, 5.0, 2.9 Hz,
1H), 3.74 (ddd, J = 11.0, 7.8, 5.8 Hz, 1H), 2.99 (ddd, J = 13.7, 12.1,
3.3 Hz, 1H), 2.01 (ddd, J = 10.9, 5.4, 2.7 Hz, 1H), 1.81 (m, 1H), 1.70
(ddd, J = 14.3, 12.3, 5.1 Hz, 1H), 1.65 (dt, J = 8.1, 6.0, 6.0 Hz, 1H),
1.23 (ddt, J = 14.3, 2 × 5.7, 2.7 Hz, 1H), 0.76 (s, 9H), 0.06 (s, 6H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 156.5 (C), 144.1 (C), 135.1 (C),
121.3 (CH), 113.6 (CH), 112.3 (CH), 110.4 (C), 87.1 (CH), 68.3
(CH
2
), 68.2 (CH), 55.9 (CH
3
), 55.5 (CH), 47.8 (CH
2
), 40.3 (CH), 37.6
(CH
2
), 36.4 (CH
2
), 25.7 (3 × CH
3
), 24.2 (CH
2
), 18.4 (C), –4.8 (CH
3
),
–5.0 (CH
3
).
Also isolated were various amounts of tetracyclic enol ether 58:
1
H NMR (400 MHz, CDCl
3
):
δ
= 6.92 (m, 2H), 6.82 (m, 2H), 4.46 (t,
J = 8.5 Hz, 1H), 4.25 (br s, 1H), 4.08 (dd, J = 8.9, 5.5 Hz, 1H), 3.89
(s, 3H), 3.80 (ddd, J = 13.0, 6.1, 1.4 Hz, 1H), 3.40 (ddd, J = 10.1, 7.9,
5.5 Hz, 1H), 2.75 (dt, J = 12.8, 3.7 Hz, 1H), 2.64 (br d, J = 14.2 Hz,
1H), 2.15 (m, 1H), 1.82 (m, 2H), 1.67 (m, 3H), 0.96 (s, 9H), –0.05 (s,
3H), –0.18 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 156.7, 148.7, 147.7, 147.1, 123.1,
121.9, 120.5, 114.4, 112.0, 66.8, 65.4, 60.1, 55.8, 41.4, 40.1, 30.7,
25.7, 24.6, 19.7, 17.9, –5.2, –5.3.
6-Bromo-7-(2-bromoethyl)-2,2-dimethyl-(3aS,7aR)-4,5-dihy-
drobenzo[d][1,3]dioxole (66):
The PAD reduced diol 65 (776 mg, 2.59 mmol) was dissolved in ac-
etone (10 mL). 2,2-Dimethoxypropane (6 mL) and a catalytic amount
of p-TsOH were added. After stirring the mixture at r.t. for 3 h the
contents were concentrated to afford 843 mg of a brown oil. Purifica-
tion by flash chromatography (10% deactivated silica gel, hexane/
EtOAc 9:1), yielded 66 (790 mg, 90%) as a pale yellow oil; R
f
= 0.21
(hexane/EtOAc, 20:1); [
α
]
D
25
+93.7 (c = 1.2, CHCl
3
).
Found: C, 39.18; H, 4.42. (C
11
H
16
O
2
Br
2
) requires: C, 38.85; H, 4.74%.
IR (neat):
ν
= 3100, 2900, 1100 cm
-1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 4.52 (d, J = 4.4 Hz, 1H), 4.38 (1m,
1H), 3.54 (m, 1H), 2.83 (m, 3H), 2.42 (ddd, J = 17.5, 4.3, 3.4 Hz, 1H),
2.03 (m, 1H), 1.87 (m, 1H), 1.37 (s, 3H), 1.35 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 132.0 (C), 126.2 (C), 109.1 (C),
75.7 (CH), 72.4 (CH), 37.2 (CH
2
), 31.7 (CH
2
), 27.8 (CH
3
), 26.5
(CH
2
), 26.2 (CH
2
).
MS: m/z = 342 (M
+2
, 4%), 340 (M
+
, 10), 259 (31), 183 (62), 55 (100).
HRMS: 337.9515, (C
11
H
16
O
2
79
Br
2
) requires, 337.9517.
3-[2-(6-Bromo-2,2-dimethyl-(3aS,7aR)-4,5-dihydroben-
zo[d][1,3]dioxol-7-yl)]ethyl-2,3-dihydro[1,3]oxazol-2-one (67):
A flame dried, Ar filled flask was charged with oxazol-2-one 8
(1.085 g, 12.75 mmol) and NaH (460 mg, 11.5 mmol, 60% susp., Ald-
rich) and cooled to 0°C. Anhyd DMSO (5 mL) was added via syringe
and the cooling bath was removed. After stirring for 15 min at r.t. (to
complete the salt formation), the mixture was placed in a ice bath and
allowed to partially solidify. The solution of the acetonide (2.168 g,
6.375 mmol) in DMSO (3 mL) was added dropwise. An additional
2 mL of DMSO was used to rinse the flask containing the acetonide and
was subsequently added to the mixture. The temperature was allowed
to rise gradually to r.t. overnight. The mixture was diluted with Et
2
O
(10 mL) and quenched with H
2
O/brine mixture (1:1, 10 mL). After fur-
ther extraction with Et
2
O (3 × 30 mL) and drying (MgSO
4
), the com-
bined organic extracts were filtered through a plug of Celite and
evaporated to dryness to give 2.4 g of a crude oil. Purification by flash
chromatography (hexane/EtOAc 7:3), yielded N-alkylated compound
67 (843 mg, 38%) and somewhat impure 71 (981.2 mg, 59%). The lat-
ter was used without purification in the hydroboration/oxidation se-
quence described below.
1
H NMR (400 MHz, CDCl
3
): δ = 6.82 (dd, J = 17.7, 11.3 Hz, 1Η),
5.60 (d, J = 16.6 Ηz, 1Η), 5.29 (d, J = 11.3 Ηz, 1Η), 4.81 (d, J
=
5.3 Hz, 1H), 4.39 (m, 1H), 2.54 (dt, J = 18, 5.3, Hz 1H), 2.02 (m, 1H),
1.86 (m, 1H), 1.41 (s, 3H), 1.39 (s, 3H).
In a similar procedure, starting with 73 the desired product 67 was ob-
tained in 60 % yield.
67: R
f
= 0.43 (hexane/EtOAc, 1:1); [
α
]
D
27
+42.4 (c = 0.83, CHCl
3
).
Found: C, 48.78; H, 5.27. (C
14
H
18
O
4
NBr) requires: C, 48.84; H,
5.28%.
IR (neat):
ν
= 3490, 3200, 1520, 1350 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 6.77 (d, J = 2.1 Hz, 1H), 6.57 (d, J
= 2.1 Hz, 1H), 4.54 (d, J = 5.5 Hz, 1H), 4.36 ( ddd, J = 5.3, 5.3, 3.0
Hz, 1H), 3.87 (m, 1H), 3.63 (m, 1H), 2.69 (m, 3H), 2.38 (ddd, J =
17.2, 4.6, 4.6 Hz, 3H), 1.97 (m, 1H), 1.86 (m, 1H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 155.6 (C), 130.4 (C), 127.4 (CH),
136.6 (CH), 115.8 (CH), 109.0 (C), 75.2 (CH), 72.5 (CH), 41.4 (CH
2
),
33.4 (CH
2
), 31.9 (CH
2
), 27.7 (CH
3
), 26.4 (CH
2
), 26.3 (CH
3
).
MS (EI): m/z = 344 (M+H
+
, 56%), 286 (100), 264 (48), 206 (62).
HRMS: 344.0520, (C
14
H
19
O
4
79
BrN) requires, 344.0498.
Procedure for regeneration of 67:
2-(6-Bromo-2,2-dimethyl-(3aS,7aR)-4,5-dihydrobenzo[d][1,3]di-
oxol-7-yl)ethanol (72):
The crude (3aR,7aS)-5-bromo-2-2-dimethyl-4-vinyl-3a,6,7,7a-tet-
rahydro-1,3-benzodioxole 71 (2.9 g, ~11.19 mmol) was dissolved in
anhyd THF (20 mL) and a solution of 9-BBN (54 mL, 27 mmol, 0.5 M
sol. in THF, Aldrich) was added via syringe. After stirring at r.t. for
20 h, the mixture was cooled to 0°C, and H
2
O (2 mL), an aqueous so-
lution of NaOH (6 mL, 3M), EtOH (10 mL) and H
2
O
2
(10 mL, 30%)
were added. The oxidation was complete after 30 min, and the mixture
was concentrated under reduced pressure. The residue was diluted with
H
2
O/brine mixture (1:1, 60 mL) and extracted with EtOAc (5 x 50 mL).
The combined organic phases were dried (MgSO
4
), filtered through a
plug of Celite, and evaporated to dryness. Flash column chromatogra-
phy (silica gel, 87 g, EtOAc/hexanes 1:1) afforded 72 (1.392 g, 45%);
R
f
= 0.50 (hexane/EtOAc 7:3); [
α
]
D
26
+87.4 (c = 1.00, CHCl
3
).
Found: C, 47.50; H, 6.30. (C
11
H
17
O
3
Br) requires: C, 47.67; H, 6.18%.
IR (neat):
ν
= 3400, 2950, 2930 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ =
4.52 (d, J = 5.6 Hz, 1H), 4.38 (m,
1H), 3.77 (m, 2H), 2.56 (m, 2H), 2.41 (m, 3H), 2.0 (m, 1H), 1.90 (m,
1H), 1.38 (s, 3H), 1.28 (s, 3 H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 132.0 (C), 126.2 (C), 109.0 (C),
76.1 (CH), 72.6 (CH), 60.9 (CH
2
), 38.1 (CH
2
), 32.0 (CH
2
), 27.6
(CH
3
), 26.8 (CH
2
), 26.2 (CH
3
).
MS (EI): m/z = 277 (M
+
, 80%), 261 (38), 200 (82), 139 (100).
HRMS: 277.0404, (C
11
H
18
79
BrO
3
) requires, 277.0439.
677
SYNTHESIS
April 1998
5-Bromo-4-(2-methanesulfonyloxyethyl)-2,2-dimethyl-
(3aS,7aR)-6,7-dihydrobenzo[d][1,3]dioxole (73):
A solution of (3aR,7aS)-4-(2-hydroxyethyl)-3a,6,7,7a-tetrahydro-
1,3-benzodioxole (1.297 g, 4.68 mmol) and diisopropylethylamine
(1.63 mL, 9.36 mmol) in anhyd CH
2
Cl
2
(20 mL) was cooled to 0°C,
and mesyl chloride (0.707 mL, 5.614 mmol) was added via syringe.
The mixture was allowed to warm up to r.t. over a period of 30 min
and was quenched with brine (30 mL). Extraction with CH
2
Cl
2
(3 × 50 mL), drying (MgSO
4
), filtration and evaporation of the sol-
vent afforded 1.78 g of crude product. Further purification by flash
chromatography (silica gel, 80 g, EtOAc/hexanes 1:1) gave the de-
sired mesylate 73 (1.595 g, 95%), which was immediately used in the
next step.
2,2-Dimethyl-(3aR,9aR,11aS)-4,5,10,11-tetrahydro[1,3]dioxo-
lo[4,5-f]oxazolo[4,3-a]isoquinolin-7-one (68a): and 2,2-Dimethyl-
(3aR,9aS,11aS)-4,5,10,11-tetrahydro[1,3]dioxolo[4,5-f]oxazo-
lo[4,3-a]isoquinolin-7-one (68b):
A flame dried round bottom flask was set under static Ar and charged
with the solution of 67 (2.75 g, 8.0 mmol) in freshly distilled benzene
(500 mL). After degassing, (stream of Ar, 30 min.) Bu
3
SnH (2.15 mL,
16.0 mmol) was added via glass pipette followed by AIBN (132 mg,
0.80 mmol). The mixture was heated to reflux for 1 h. The solvent was
evaporated and the crude product was disproportionated between
MeCN and hexane. The MeCN phase was evaporated to dryness, and
the residue was purified by flash chromatography (silica gel, 6:4 hex-
ane/EtOAc) to give 68a (1.193 g, 56%) as the major isomer and 68b
(0.633 g,31 %) as the minor isomer.
(68a) (Major Isomer):
R
f
= 0.16 (hexane/EtOAc 7:3); [
α
]
D
25
–100.8 (c = 0.66, CHCl
3
).
Found: C, 62.98; H, 7.25; N, 5.08. (C
14
H
19
NO
4
) requires: C, 63.34;
H, 7.22; N, 5.28%.
IR (neat):
ν
= 2980, 1760 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 4.49 (t, J = 8.8 Hz, 1H), 4.24 (m,
3H), 3.97 (m, 2H), 3.01 (ddd, J = 13.6, 11.6, 4.8 Hz, 1H), 2.32 (d, J =
12.4 Hz, 1H), 2.21 (m, 1H), 2.01 (m, 1H), 1.83 (m, 3H), 1.37 (s, 6H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 157.4 (C), 130.2 (C), 128.4 (C),
108.5 (C), 73.6 (CH), 72.7 (CH), 66.7 (CH
2
), 54.9 (CH), 38.3 (CH
2
),
28.0 (CH
3
), 26.2 (CH
3
), 25.4 (CH
2
), 24.1 (CH
2
), 21.0 (CH
2
).
MS (EI): m/z = 265 (M
+
, 8%), 190 (100), 151 (39), 105 (48).
HRMS: 266.1392, (C
14
H
20
NO
4
) requires, 266.1393
(68b) (Minor Isomer):
mp 102–105°C; R
f
= 0.09 (hexane/EtOAc, 7:3); [
α
]
D
26
+201.2 (c =
0.89, CHCl
3
).
Found: C, 63.31; H, 7.19; N, 5.27. (C
14
H
19
NO
4
)
requires C, 63.34; H,
7.22; N, 5.28%.
IR (neat):
ν
= 2980, 1720 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 4.47 (t, J = 8.5 Hz, 1H ), 4.35 (m,
1H), 4.26 (m, 1H), 3.98 (q, J = 6.6 Hz, 1H), 3.91 (t, J = 7.9 Hz, 1H),
3.01 (ddd, J = 13.3, 11.9, 4.7 Hz, 1H), 2.55 (m, 1H), 2.12 (m, 2H),
1.87 (d, J = 16.0 Hz, 1H), 1.71 (m, 1H), 1.36 (s, 3H), 1.31 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ =
129 (C), 128.3 (C), 108.9 (C), 75.7
(CH), 72.4 (CH), 66.8 (CH
2
), 55.0 (CH), 37.8 (CH
2
), 27.9 (CH
3
), 26.5
(CH
3
), 25.5 (CH
2
), 24.3 (CH
2
), 19.7 (CH
2
).
MS (EI): m/s = 265 (M
+
, 2%), 250 (28), 190 (51), 105 (100).
HRMS: 266.1394, (C
14
H
20
NO
4
) requires, 266.1393.
5-Bromo-4-(2-methanesulfonyloxyethyl)-2,2-dimethyl-
(3aS,7aR)-6,7-dihydrobenzo[d][1,3]dioxole (73):
1
H NMR (400 MHz, CDCl
3
):
δ
= 4.48 (br d, J = 5.3 Hz, 1H), 4.41 (m,
1H), 4.35 (m, 2H), 3.02 (s, 3H), 2.75 (m, 3H), 2.41 (dt, J = 17.0, 5.0
Hz, 1H), 2.02 (m 1H), 1.88 (m, 1H), 1.36 (s, 3H), 1.34 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 129.7, 126.8, 109.1, 75.8, 72.4,
67.3, 37.5, 33.6, 31.7, 27.8, 26.4, 26.2.
7,8-Dihydroxy-(7R,8S,10bR)-5,6,7,8,9,10-hexahydrooxazolo[4,3-
a]isoquinolin-3-one (74):
A suspension of the acetonide 68a (1.16 g, 4.37 mmol) and Dowex
50X8-100 strongly acidic resin (625 mg) in aq MeOH (50 mL, 90%)
was stirred at r.t. overnight. The mixture was filtered through a plug
of silica gel and evaporated to dryness. Purification by flash chroma-
tography (silica gel, EtOAc/EtOH 8:2) afforded pure diol 74 (923.2
mg, 94%); mp 150–153°C; R
f
= 0.43 (EtOAc/MeOH 4:1); [
α
]
D
30
–22.8 (c = 0.67, MeOH).
Found: C, 58.41; H, 6.75; N, 6.16. (C
11
H
16
NO
4
) requires: C, 58.66;
H, 6.71; N, 6.22%.
IR (KBr):
ν
= 2870, 1740 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ =
4.47 (t, J = 8.7 Hz, 1H), 4.25 (t, J =
6.7 Hz, 1H), 3.97 (m, 2H), 3.89 (s, 1H), 3.75 (s, 1H), 3.06 (ddd, J =
13, 11, 4.7 Hz, 1H), 2.61 (d, J = 4.7 Hz, 1H), 2.40 (m, 1H), 2.25 (m,
1H), 1.97 (s, 2H), 1.80 (m, 2H), 1.70 (s, 1H).
13
C NMR (100 MHz, CDCl
3
):
δ =
130.4 (C), 130.1 (C), 124.9 (C),
69.0 (CH), 68.3 (CH), 66.6 (CH
2
), 55.3(CH), 38.1 (CH
2
), 25.3 (CH
2
),
24.9 (CH
2
), 24.3 (CH
2
).
MS (CI): m/z = 226 (M
+
, 100%), 207 (18), 190 (29).
HRMS: 266.1064, (C
11
H
16
NO
4
) requires, 226.1072.
7-Hydroxy-8-tert-butyldimethylsilyloxy-(7R,8S,10bS)-
5,6,7,8,9,10-hexahydrooxazolo[4,3-a]isoquinolin-3-one (75):
The solution of the diol 74 (882.7 mg, 3.912 mmol) and diisopropyl-
ethylamine (1.363 mL, 7.824 mmol) in CH
2
Cl
2
(200 mL) was stirred
and cooled to –78°C. A solution of tert-butyldimethylsilyltrifluo-
romethanesulfonate (1.078 mL, 4.694 mmol) in CH
2
Cl
2
(50 mL) was
added dropwise during a period of 30 min and the stirring at –78°C
was continued for 4 h. The reaction was quenched at –78°C with H
2
O
(60 mL) and allowed to warm up to r.t. The CH
2
Cl
2
layer was sepa-
rated, and the aqueous phase was extracted with CH
2
Cl
2
(2 × 50 mL).
The combined organic extracts were dried (MgSO
4
), filtered through
Celite and evaporated to dryness. The crude product was dissolved in
a mixture of EtOAc/hexane (7:3, 50 mL) and passed through a plug
of silica gel. The filtrate was evaporated to dryness and purified by
flash chromatography (silica gel, EtOAc/hexane 7:3) to yield the de-
sired product 75 (1.135 g, 85.5%) and bis-protected 7,8-di(tert-bu-
tyldimethylsilyloxy)-(7R,8S,10bS)-5,6,7,8,9,10-hexahydro[1,3]oxa-
zolo[4,3-a]isoquinolin-3-one (173 mg, 10%). The latter was cleaved
using tetrabutylammonium fluoride to regenerate the starting diol 74.
(75):
mp 200–201°C; R
f
= 0.40 (EtOAc/hexane 7:3); [
α
]
D
24
–180.9 (c = 1.1,
CHCl
3
).
Found: C, 59.97; H, 8.63; N, 3.91. (C
17
H
29
NO
4
Si) requires: C, 60.14;
H, 8.61; N, 4.13%.
IR (KBr):
ν
= 3510, 2920, 2895, 2840, 1745, 1405, 1370, 1305, 1245,
1173, 1100, 1050, 973, 920, 820 cm
–1
.
1
H NMR (400 MHz, CDCl
3
):
δ
= 4.44 (t, J = 8.4 Hz, 1H), 4.21 (br t,
J = 6.9 Hz, 1H), 3.97 (d , J = 6.7 Hz, 1H), 3.94 (dd, J = 6.7 , 4.4 Hz,
1H), 3.73 (m, 2H), 3.06 (ddd, J = 13.6, 11.6, 4.88 Hz, 1H), 2.73 (br s,
1H), 2.37 (br dd, J = 17.1, 2.1 Hz, 1H), 2.24 (m, 1H), 1.87 (m, 3H),
1.60 (m, 1H), 0.9 (s, 9H), 0.1 (s, 6 H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 157.3 (C), 131.1 (C), 130.0 (C),
70.3 (CH), 68.5 (CH), 55.4 (CH), 38.0 (CH
2
), 25.7 (CH
3
), 24.9 (CH
2
),
24.4 (CH
2
), 18.0 (C), –4.5 (CH
3
), –4.9 (CH
3
).
MS (CI): m/z = 340 (M+H
+
, 100%), 322 (10), 282 (12), 208 (1), 191
(6), 190 (47).
HRMS: 340.1958, (C
17
H
30
NO
4
Si) requires, 340.1944.
7-(2-Bromo-6-methoxyphenyloxy)-8-tert-butyldimethylsilyloxy-
(7S,8S,10bR)-5,6,7,8,9,10-hexahydrooxazolo[4,3-a]isoquinolin-3-
one (76):
A solution of 75 (551 mg, 1.623 mmol) and 6-bromo-2-methoxyphe-
nol (346 mg, 1.704 mmol) in THF (10 mL) was cooled to 0°C with
stirring. To this solution, a reagent, prepared from Bu
3
P (657 mg,
3.246 mmol) and DEAD (565 mg, 3.246 mmol) in THF (10 mL), was
added dropwise and the mixture was stirred at 0°C for 90 min. The
reaction was quenched with MeOH (3 mL), and the solvent was evap-
orated at reduced pressure. The crude product (1.003 g) was further
purified by flash chromatography (silica gel, 86 g, EtOAc: hexane
1:1) to yield pure 76 (803 mg, 94%) as a viscous, colorless oil; R
f
=
0.23 (CH
2
Cl
2
/acetone 97:3); T
r
= 8.80 min., (Prodigy 5
µ
, 80%
MeCN/20% H
2
O, 5 mM Et
3
N.HOAc, 1.0 mL/min., UV
λ
max
236 nm);
[
α
]
D
27
–11.5 (c = 1.1, CHCl
3
).
678
Papers
SYNTHESIS
Found: C, 54.59; H, 6.41; N, 2.26. (C
24
H
34
BrNO
5
Si) requires: C,
54.96; H, 6.53; N, 2.67%.
IR (KBr):
ν
= 3440, 2930, 2850, 1760, 1570, 1470, 1450, 1440, 1260,
1120, 1080, 1030, 840, 750 cm
–1
.
1
H NMR (500 MHz, CDCl
3
):
δ
= 7.12 (dd, J = 1.5, 7.9 Hz, 1H), 6.92
(t, J = 2x 8.1 Hz, 1H), 6.85 (dd, J = 8.2, 1.5 Hz, 1H), 4.53 (d, J = 8.9,
8.1 Hz, 1H), 4.39 (br s 1H), 4.31 (br t, J = 8.9 Hz, 1H), 4.07 (m, 2H),
3.93 (dd, J = 13.1, 6.1 Hz, 1H), 3.84 (s, 3H), 3.01 (ddd, J = 13.1, 11.9,
4.4 Hz, 1H), 2.53 (m, 1H), 2.33 (m, 1H), 2.16 (m, 1H), 1.99 (br d, J =
16.9 Hz, 1H), 1.7 (m, 2H), 0.78 (s, 9H), –0.08 (s, 3H), –0.12 (s, 3H).
13
C NMR (125 MHz, CDCl
3
):
δ
= 157.1 (C). 153.4(C), 144.2 (C),
132.4 (C), 125.9 (C), 125.1 (CH), 124.9 (CH), 118.1 (CH), 111.5
(CH), 81.6 (CH), 67.5 (CH
2
), 66.9 (CH), 55.7 (CH
3
), 54.5 (CH), 38.1
(CH
2
), 27.9 (CH
2
), 25.6 (CH
3
), 25.1 (CH
2
), 20.5 (CH
2
), 18.0 (C), –5.1
(CH
3
), –5.2 (CH
3
).
MS (FAB): m/z = 524 (M
+
, 7%), 322 (65), 190 (100).
HRMS: 524.1450, (C
24
H
35
NO
5
79
BrSi) requires, 524.1468.
7-(2-Bromo-6-methoxyphenyloxy)-8-hydroxy-(7S,8S,10bR)-
5,6,7,8,9,10-hexahydrooxazolo[4,3-a]isoquinolin-3-one (77):
To a solution of silyl ether 76 (39 mg, 0.076 mmol) in THF (2 mL)
was added TBAF/silica (30 mg) and TBAF/H
2
O (30 mg). The mix-
ture was stirred at r.t. for 3.5 h. The crude mixture was concentrated
under reduced pressure and purified by column chromatography (sil-
ica gel, EtOAc) to afford alcohol 77 (31.2 mg, quant.) as an oil; R
f
=
0.30 (CH
2
Cl
2
/Et
2
O 8:2); T
r
= 6.86 min., (Prodigy 5
µ
, 35% MeCN/
65% H
2
O, 5 mM Et
3
N.HOAc, 1.0 mL/min., UV
λ
max
254 nm).
1
H NMR (400 MHz, CDCl
3
):
δ
= 7.13 (dd, J = 8.1, 1.7 Hz, 1H), 6.91
(t, J = 8.2 Hz, 1H), 6.85 (dd, J = 8.2, 1.5, 1H), 4.66 (br s, 1H), 4.50 (t,
J = 8.7 Hz, 1H), 4.30 (br t, J = 6.9 Hz, 1H), 4.18 (m, 1H), 4.04 (t, J =
8.1 Hz, 1H), 3.95 (dd, J = 13.1, 6.6 Hz, 1H), 3.84 (s, 3H), 3.02 (ddd,
J = 13.3 11.9, 4.4 Hz, 1H), 2.60 (m, 1H), 2.20 (m, 1H), 2.00 (m, 3H),
1.80 (m, 1H).
13
C NMR (100 MHz, CDCl
3
):
δ
= 157.0, 153.0, 144.8, 131.1, 127.7,
125.2, 124.8, 117.5, 111.7, 83.4, 69.4, 55.7, 54.8, 37.9, 27.3, 26.2,
22.1.
10-tert-Butyldimethylsilyloxy-6-methoxy-(1R,9S,10S,13S,14R)-
8,16,18-dioxazapentacyclo[11.7.0.0
1,9
.0
2,7
.0
14,18
]icosa-2(7),3,5-
trien-17-one (78):
A solution of 76 (747 mg, 1.425 mmol) in benzene (500 mL) was de-
gassed at r.t. with a stream of Ar (30 min.). Bu
3
SnH (1.659 g,
5.7 mmol, glass pipette), followed by AIBN (90 mg, 0.548 mmol)
was added and the reaction flask was submerged into a preheated
(100°C) oil bath. HPLC (Prodigy 5
µ
ODS2, 80% MeCN/20% H
2
O,
5 mM Et
3
N.AcOH buffer, UV
λ
max
210 nm, 1.0 mL/min.) indicated
complete reaction after 50 min. The solvent was removed in vacuo
and the remaining oil was distributed between MeCN (100 mL) and
hexane (200 mL). The MeCN phase was extracted with hexane
(2 × 100 mL), and the combined hexanes back-washed with MeCN
(100 mL). The combined MeCN extracts were evaporated in vacuo to
yield 833 mg of crude product. Column chromatography (silica gel,
86 g, CH
2
Cl
2
/acetone 97:3) gave the pure pentacycle 78 (297.1 mg,
47%); R
f
= 0.53 (EtOAc/hexanes 1:1); T
r
= 14.4 min., (Prodigy 5
µ
ODS2, 80% MeCN/20%H
2
O, 5 mM triethylammonium acetate,
UV
λ
max
210 nm, 1.0 mL/min.); [
α
]
D
28
+ 23.3 (c = 0.89, CHCl
3
).
Found: C, 64.26; H, 7.99; N, 3.20. (C
24
H
36
NO
5
Si) requires: C, 64.69;
H, 7.92; N, 3.14%.
IR (CHCl
3
):
ν
= 3010, 2930, 1750, 1620, 1450, 1270, 1120, 910,
840 cm
–1
.
1
H NMR (500 MHz, CDCl
3
):
δ
= 6.87 (dd, J = 8.1, 7.3 Hz, 1H), 6.79
(dd, J = 8.1, 1.1 Hz, 1H), 6.63 (dd, J = 7.5, 1.1 Hz, 1H), 4.49 (d, J =
5.6 Hz, 1H), 4.46 (t, J = 8.1 Hz, 1H), 4.08 (ddd, J = 11.1, 7.9, 5.5 Hz,
1H), 4.02 (dd, J = 8.4, 5.7 Hz, 1H), 3.86 (s, 3H), 3.79 (ddd, J = 13.9,
5.3, 2.0 Hz, 1H), 3.68 (ddd, J = 8.9, 5.5, 5.5 Hz, 1H), 3.09 (ddd, J =
13.3, 13.3, 2.9 Hz, 1H), 2.13 (ddd, J = 11.0, 5.3, 2.1 Hz, 1H), 1.78 (m,
1H), 1.67 (m, 1H), 1.55 (m, 2H), 1.47 (m, 1H), 1.35 (m, 1H), 0.9 (s,
9H), 0.14 (s, 3H), 0.02 (s, 3H).
13
C NMR (125 MHz, CDCl
3
):
δ
= 156.8, 145.8, 145.7, 135.6, 122.1,
113.5, 112.3, 89.4, 71.8, 67.6, 56.0, 54.0, 48.6, 38.5, 37.7, 35.4, 26.4,
25.8, 20.2, 18.0.
MS (FAB) m/z = 446 (M+H
+
, 100%), 388 (25), 312 (3), 270 (2), 209 (3).
HRMS: 446.2340, (C
24
H
36
NO
5
Si) requires, 446.2363.
10-Hydroxy-6-methoxy-(1R,9S,10S,13S,14R)-8,16,18-dioxaza-
pentacyclo[11.7.0.0
1,9
.0
2,7
.0
14,18
]icosa-2(7),3,5-trien-17-one (79):
The solution of TBS-pentacycle 78 (116 mg, 0.260 mmol) and tet-
rabutylammonium fluoride trihydrate (100 mg) in THF (5 mL) was
stirred at r.t. for 4 h. The mixture was filtered through Celite, washed
with MeOH and evaporated to dryness. The crude product was puri-
fied by flash chromatography (silica gel, 86 g, CH
2
Cl
2
/acetone 7:3) to
yield the desired alcohol 79 (86 mg, quant.).
Cyclization from 77: To a degassed (Ar sparge) solution of 77
(44.4 mg, 0.108 mmol) in benzene (25 mL) was added Bu
3
SnH (63 mg,
58 µl, 0.216 mmol) followed by AIBN (cat.). The reaction vessel was
submerged into a preheated oil bath and refluxed was maintained until
HPLC indicated the disappearance of starting material, approx. 80 min.
The solvent was evaporated under reduced pressure and the oily residue
was disproportionated between hexane (60 mL) and MeCN (30 mL).
The MeCN layer was extracted with hexane two additional times
(2 × 30 mL), and the MeCN was evaporated under reduced pressure.
The crude residue was purified by column chromatography (EtOAc/
EtOH/NH
4
OH 90:5:5) to afford alcohol 79 (10.3 mg, 29%), spectral
characteristics of which were identical to those obtained by the TBAF
mediated deprotection; mp 118–120°C; R
f
= 0.45 (benzene/dioxane/aq
NH
4
OH/H
2
O 50:40:5:5); T
r
= 6.88 min, (Prodigy 5
µ
ODS2, 30%
MeCN/70% H
2
O, 5 mM triethylammonium acetate, UV
λ
max
236 nm,
1.0 mL/min.); [
α
]
D
25
+31.3 (c = 0.38, CHCl
3
).
Found: C, 50.49; H, 4.94; N, 3.07. (C
18
H
21
NO
5
+CHCl
3
) 450.744
(Solvate with CHCl
3
, four analyses) requires: C, 50.63; H, 4.90; N,
3.10%.
IR (CHCl
3
): 2936, 1749, 1614, 1492, 1455, 1283, 1215, 908 cm
–1
.
1
H NMR (500 MHz, CDCl
3
):
δ
= 6.92 (t, J = 7.8 Hz, 1H), 6.80 (dd, J
= 8.7, 1.0 Hz, 1H), 6.65 (dd, J = 7.8, 1.0 Hz, 1H), 4.53 (d, J = 7.3 Hz,
1H), 4.52 (t, J = 8,8 Hz, 1H), 4.05 (dd, J = 8.8, 5.9 Hz, 1H), 3.89 (ddd,
J = 11.2, 8.1, 5.9 Hz, 1H), 3.88 (s, 3H), 3.80 (ddd, J = 13.9, 5.1,
1.7 Hz, 1H), 3.63 (ddd, J = 11.7, 7.3, 5.9 Hz, 1H), 3.07 (ddd, J = 13.4,
13.4, 3.8 Hz, 1H), 2.19 (ddd, J = 11.2, 4.6, 2.2 Hz, 1H), 1.81 (ddd, J
= 14.2, 2.4, 2.4 Hz, 1H), 1.75 (m, 1H), 1.65 (ddd, J = 13.7, 3.4, 3.4 Hz,
1H), 1.53 (ddd, J = 13.2, 11.7, 2.9 Hz, 1H), 1.46 (ddd, J = 14.7, 6.4,
3.4 Hz, 1H), 1.37 (ddd, J = 13.3, 13.2, 4.9 Hz, 1H).
13
C NMR (125 MHz, CDCl
3
):
δ
= 156.7 (C), 145.9 (C), 145.1(C),
135.5 (C), 122.4 (CH), 113.2 (CH), 112.0 (CH), 89.6 (CH), 71.7
(CH), 67.6 (CH
2
), 55.9 (CH
3
), 53.4 (CH), 49.0 (CH
2
), 38.6 (CH), 37.6
(C), 34.6 (CH
2
), 25.1 (CH
2)
, 21.1 (CH
2
).
MS (FAB): m/z = 332 (M
+
, 100%), 242 (9), 155 (36), 118 (57).
HRMS: 332.1500, (C
18
H
21
NO
5
+H) requires, 332.1498.
5-Hydroxymethyl-13-methoxy-4-methyl-(1R,5R,6S,9S,10S)-11,4-
oxazatetracyclo[8.7.0
1,6
.0
12,17
]heptadeca-12(17)13,15-trien-9-ol
(80):
A flame dried round-bottom flask was set under static Ar, and was
charged with the solution of the pentacyclic alcohol 79 (86 mg, 0.259
mmol) in CH
2
Cl
2
(20 mL). The stirred solution was cooled to 0°C and
solution of DIBAL-H in THF (2.6 mL, 1M, Aldrich) was added, drop-
wise. After 30 min., HPLC (Primesphere 5
µ
, C18HC, 30% MeCN/
70% H
2
O, 5 mM ammonium carbonate, 1.0 mL/min., UV
λ
max
284 nm) indicated complete conversion and the reaction was
quenched at 0°C with H
2
O (1.8 mL), followed by MeOH (1.8 mL)
and sat. aq NaHCO
3
(3.6 mL). The mixture was allowed to warm to
r.t. and the solid was filtered off and washed with CH
2
Cl
2
(4 ×
40 mL). The combined filtrates were dried (Na
2
SO
4
) and the solvent
was removed under reduced pressure. The crude product was purified
by flash chromatography (silica gel, 85 g, EtOAc/EtOH/aq NH
4
OH
75:20:5) to yield the pure product 80 (72 mg, 87 %) as a viscous, color-
less oil; R
f
= 0.4 (EtOAc/ EtOH/aq NH
4
OH 75:20:5); T
r
= 2.99 min.
(Primesphere 5
µ
, C18HC, 30% MeCN/70% H
2
O, 5mM ammonium car-
bonate, 1.0 mL/min., UV
λ
max
284 nm); [
α
]
D
26
+34.7 (c = 1.51, CHCl
3
).
IR (CHCl
3
):
ν
= 2960, 1380, 1130, 1220, 770 cm
–1
.
1H NMR (500 MHz, CDCl
3
):
δ
= 6.87 (t, J = 7.8 Hz, 1H), 6.75 (d, J
= 8.3 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 4.49 (d, J = 7.3 Hz, 1H), 3.89
679
SYNTHESIS
April 1998
(dd, J = 11.7, 2.9 Hz, 1H), 3.85 (s, 3H), 3.64 (dd, J = 11.7, 1.0 Hz,
1H), 3.58 (ddd, J = 11.7, 6.8, 5.8 Hz, 1H), 2.78 (ddd, J = 12.2, 3.4, 3.4
Hz, 1H), 2.57 (bdd, J = 10.7, 3.4, ~1.5 Hz, 1H), 2.54 (ddd, J = 12.2,
12.2, 2.0 Hz, 1H), 2.35 (s, 3H), 2.21 (br d, J = 10.7 Hz, 1H), 1.73 (m,
3H), 1.65 (m, 1H), 1.46 (m, 3H).
1
H NMR (500 MHz, benzene-d
6
):
δ
= 6.76 (t, J = 7.8 Hz, 1H), 6.59
(d, J = 3.2 Hz), 6.57 (d, J = 4.7 Hz, 1H), 4.47 (d, J = 7.1 Hz, 1H), 3.63
(dd, J = 11.7, 3.1 Hz, 1H), 3.47 (s, 3H), 3.46 (m, 1H), 3.43 (br d, J =
10.9 Hz, 1H), 2.58 (br d, J = 10.7 Hz, 1H), 2.26 (dt, J = 12.1, 3.6 Hz,
1H), 2.03 (td, J = 12.7, 2.2 Hz, 1H), 1.90 (s, 3H), 1.77 (br d, J =
10.9 Hz, 1H), 1.60 (dt, J = 13.8, 1.9 Hz, 1H), 1.35 (br m, 5H).
13
C NMR (125 MHz, CDCl
3
):
δ
= 145.7, 145.2, 137.3, 122.1, 113.5,
111.5, 90.0, 72.9, 63.4, 58.4, 55.9, 52.0, 49.2, 42.8, 35.6, 33.3, 25.8,
22.6.
MS (FAB): m/z = 320 (M+H
+
, 100%), 288 (38), 219 (3), 213 (3), 169
(5), 154 (10), 137 (15), 109 (21), 94 (44).
HRMS (FAB): 320.1877, (C
18
H
26
NO
4
+H) requires, 320.1862.
5-Hydroxymethyl-9-tert-butyldimethylsilyoxy-13-methoxy-4-
methyl-(1R,5R,6S,9S,10S)-11,4-oxazatetracyc-
lo[8.7.0.0
1,6
.0
12,17
]hep-tadeca-12(17),13,15-triene (81):
A solution of the pentacyclic substrate 78 (25.0 mg, 0.056 mmol) in
freshly distilled CH
2
Cl
2
(6 mL) was set under static Ar atmosphere,
and cooled with stirring to 0°C. A solution of DIBAL-H (281 µL, 1M
in CH
2
Cl
2
, Aldrich) was added via syringe. Stirring at 0°C was con-
tinued for 1 h, and the mixture was allowed to warm up to r.t. After
additional 2 h, the reaction was quenched with H
2
O (0.8 mL), fol-
lowed by MeOH (0.8 mL) and sat. aq NaHCO
3
(1.6 mL) and stirring
continued for 30 min. The solid was filtered off, washed with CH
2
Cl
2
(6 × 6 mL) and H
2
O (6 × 6 mL). The organic phase was separated,
dried (MgSO
4
), and the solvent was evaporated under reduced pres-
sure to yield the crude product (27 mg). HPLC analysis (Primesphere
5m C18HC, 70% MeCN/30% H
2
O, 5 mM triethylammonium acetate,
UV
λ
max
210 nm, 1.0 mL/min.) indicated 79% purity. Column chro-
matography (silica gel, 15 g, EtOAc/EtOH/NH
4
OH 70:25:5) gave
pure 81 (19.3 mg, 79%); R
f
= 0.53 (EtOAc/EtOH/NH
4
OH 70:25:5);
T
r
= 7.94 min. (Primesphere 5
µ
C18HC, 70% MeCN/30% H
2
O,
5 mM triethylammonium acetate, UV
λ
max
210 nm, 1.0 mL/min.).
1
H NMR (500 MHz, CDCl
3
):
δ
= 6.87 (dd, J = 8.1, 7.5 Hz, 1H), 6.77
(dd, J = 8.2, 1.1 Hz, 1H), 6.74 (dd, J = 7.3, 1.1 Hz, 1H), 4.45 (d, J =
6.6 Hz, 1H), 3.90 (dd, J = 11.9, 3.2 Hz, 1H), 3.86 (s, 3H), 3.64 (dd, J
= 11.6, 1.0 Hz, 1H), 3.57 (m, 1H), 2.77 (ddd, J = 12.1, 3.8, 3.8 Hz,
1H), 2.63 (ddd, J = 12.7, 12.7, 2.4 Hz, 1H), 2.57 (br d, J = 11.2 Hz,
1H), 2.38 (s, 3H), 2.33 (br d, J = 10.7 Hz, 1H), 1.76 (ddd, J = 14.2,
2.9, 2.9 Hz, 1H), 1.50 (m, 4H), 0.90 (s, 9H), 0.13 (s, 3H), 0.02 (s, 3H).
13
C NMR (125 MHz, CDCl
3
):
δ
= 145.7, 145.6, 137.6, 121.6, 113.5,
111.9, 90.7, 73.3, 63.5, 58.4, 55.9, 51.9, 49.1, 42.7, 35.8, 33.2, 27.6,
25.8, 22.6, 22.2, 18.1.
5-Chloromethyl-9-tert-butyldimethylsilyoxy-13-methoxy-4-
methyl-(1R,5R,6S,9S,10S)-11,4-oxazatetracyclo[8.7.0.0
1,6
.0
12,17
]
heptadeca-12(17),13,15-triene (82):
A flame dried round-bottom flask was set under static Ar atmosphere,
and was charged with LiCl (30 mg, 0.708 mmol). A solution of sub-
strate 81 (12.0 mg, 0.028 mmol) in CH
2
Cl
2
(3 mL) was introduced via
syringe, followed by Et
3
N (5.6 mg, 0.055 mmol, in 100 µL of CH
2
Cl
2
,
stock solution). The mixture was cooled with stirring to 0°C and a so-
lution of MsCl (2.57 µL, 0.033 mmol) in CH
2
Cl
2
(100
µL, stock solu-
tion) was added. The reaction was monitored via HPLC (Prodigy 5
µ
,
80% MeCN/20% H
2
O, 5 mM triethylammonium acetate, UV
λ
max
236 nm, 1.0 mL/min.). The starting material (T
r
= 5.16 min) disap-
peared within 1 h, and the mixture contained 72% of the (presumed)
mesylate (T
r
= 6.03 min.), and 9% of the desired chloride (T
r
= 12.5
min.). After a total of 6 h, HPLC indicated less than 3% of the mesylate
and solvent was removed under reduced pressure. Flash chromatogra-
phy (silica gel, 8.6 g, EtOAc, saturated with NH
4
OH) yielded pure 82
(10.9 mg, 87%) as a viscous oil; R
f
= 0.55 (EtOAc/EtOH/NH
4
OH
70:25:5); T
r
= 12.51 min. (Prodigy 5
µ
, 80 % MeCN/ 20 % H
2
O, 5 mM
triethylammonium acetate, UV
λ
max
236 nm, 1.0 mL/min.).
1
H NMR (500 MHz, CDCl
3
):
δ
= 6.87 (t, J = 7.81 Hz, 1H), 6.77 (d, J
= 7.6 Hz, 1H), 6.74 (d, J = 7.3 Hz, 1H), 4.46 (d, J = 6.6 Hz, 1H), 3.86
(s, 3H), 3.20 (ABq, J = 12.7 Hz, 2H), 3.60 (m, 1H), 3.05 (dd, J = 14.2,
7.1 Hz, 1H), 2.83 (ddd, J = 12.0, 3.9, 3.9 Hz, 1H), 2.53 (m, 3H), 2.41
(s, 3H), 2.30 (dddd, J = 11.2, 11.2, 3.7, 3.7 Hz, 1H), 1.95 (br d, J =
10.3 Hz, 1H), 1.6 (m, 3H), 0.90 (s, 3H), 0.14 (s, 3H), 0.01 (s, 3H).
13-Methoxy-4-methyl-9-oxo-(1R,5R,6S,10S)-11,4-oxazatetracy-
clo[8.7.0
1,6
.0
12,17
]heptadeca-12,(17),13,15-triene-5-carbaldehyde
(83):
A flame dried round-bottom flask was set under static Ar atmosphere,
charged with CH
2
Cl
2
(4 mL) and oxalyl chloride (86 µL, 2 M solution
in CH
2
Cl
2
, Aldrich, 0.172 mmol,). The mixture was cooled to –78°C
and a CH
2
Cl
2
solution of DMSO (344 µl, 1M, 0.344 mmol) was in-
troduced via syringe. After stirring for 10 min. a solution of the tetra-
cyclic diol 80 (5.5 mg, 0.0172 mmol) in CH
2
Cl
2
(1.0 mL) was added
and the temperature was allowed to warm up to 0°C during 4 h. A
CH
2
Cl
2
solution of Et
3
N (412 µL, 0.412 mmol, 1M) was added, the
cooling bath was removed and stirring was continued for an addition-
al 30 min. The reaction was quenched with sat. NaHCO
3
(2.0 mL,
1:10 solution), stirred for 5 min and the organic solvent was separat-
ed. The aqueous layer was further extracted with CH
2
Cl
2
(2 × 4 mL),
the combined organic phases were dried (Na
2
SO
4
) and the solvent
was removed under reduced pressure. Column chromatography (sili-
ca gel, 5.4 g, EtOAc/ethanol/aq NH
4
OH 90:5:5) gave the pure product
(3.6 mg, 66%) as a viscous oil, which was used immediately in the
next step; R
f
= 0.6 (EtOAc/EtOH/aq NH
4
OH 90:5:5); T
r
= 12.8 min.
(Primesphere 5
µ
, C18HC, 30 % MeCN / 70 % H
2
O, 5 mM ammoni-
um carbonate, UV
λ
max
283 nm, 1.0 mL/min.).
1
H NMR (500 MHz, CDCl
3
):
δ
= 9.45 (s, 1H), 6.93 (t, J = 7.8 Hz, 1H),
6.79 (d, J = 7.3 Hz, 1H), 6.70 (t, J = 7.8 Hz, 1H), 4.60 (s, 1H), 3.88
(s, 3H), 3.87 (m, 1H), 2.90 (br d, J = 12.2 Hz, 1H), 2.50 (m, 5H), 2.27
(s, 3H), 2.20 (m, 2H), 1.88 (ddd, J = 13.9, 2.4, 2.4 Hz, 1H), 1.77
(dddd, J = 14.9, 14.9, 7.6, 3.4 Hz, 1H).
10-Hydroxy-14-epi-ent-dihydrocodeinone (84):
The crude oxo aldehyde 83 (12.0 mg, 0.038 mmol) was dissolved in
trifluoromethanesulfonic acid (neat, 400
µ
L) at r.t. A deep red colored
solution resulted. The reaction progress was monitored by HPLC
(Prodigy 5
µ
, ODS2, MeCN/H
2
O 30:70, 5 mM ammonium acetate
buffer, 1.0 mL/min., UV
λ
max
210 nm), which, after 10 min indicated
complete disappearance of the starting material (T
r, SM
= 11.10 mins,
T
r
, product 3.97 min).
The mixture was diluted with CHCl
3
(8 mL), cooled to –5°C, and
carefully quenched with 5 g of ice. The aqueous layer was basified
(1.0 M KOH), and extracted with CHCl
3
(6 × 6 mL). The combined
organic extracts were dried (Na
2
SO
4
), and the solvent was removed
under reduced pressure to yield 9.3 mg of the crude base, as an vis-
cous oil. Column chromatography (silica gel, 7.0 g, CHCl
3
/MeOH/
NH
4
OH 90:9:1) gave 6.9 mg (58 %) of the pure morphinan; R
f
= 0.30
(CHCl
3
/MeOH/NH
4
OH 90:9:1);
λ
max
(MeCN): 286, 248, 236 and
214 nm.
1
H NMR (500 MHz, benzene-d
6
):
δ
= 6.84 (dd, J = 8.3, 0.7 Hz, 1H),
6.67 (d, J = 8.3 Hz, 1H), 4.80 (s, 1H), 4.18 (s, 1H), 3.65 (s, 3H), 2.77
(br d, J = 2.1 Hz, 1H), 2.28 (m, 1H), 2.20 (s, 3H), 2.10 (m, 1H), 2.08
(dd, J = 10.2, 6.2 Hz, 1H), 1.99 (dt, J = 12.2, 3.6 Hz, 1H), 1.86 (ddd,
J = 16.0, 10.6, 2.1 Hz, 1H), 1.76 (dt, J = 12.6, 5.7 Hz, 1H), 1.31 (m,
1H).
1
H NMR (500 MHz, MeOH-d
4
):
δ
= 6.95 (dd, J = 8.3, 0.7 Hz, 1H),
6.84 (d, J = 8.3 Hz, 1H), 4.98 (s, 1H), 4.97 (s, 1H), 3.88 (s, 3H), 2.99
(br d, J = 2.1 Hz, 1H), 2.77 (ddd, J = 13.1, 10.4, 6.2 Hz, 1H), 2.72 (dt,
J = 12.3, 3.5 Hz, 1H), 2.57 (dd, J = 11.8, 4.9 Hz, 1H), 2.53 (s, 3H),
2.47 (dt, J = 12.8, 5.3 Hz, 1H), 2.38 (m, 1H), 2.29 (dt, J = 12.2, 3.5
Hz, 1H), 1.89 (br dt, J = 13.0, 3.2 Hz, 1H), 1.75 (br d, J = 13.3 Hz,
1H), 1.60 (br d, J = 10.3 Hz, 1H).
MS (FAB-Glycerine): m/z = 316.1561 (52%), 298.1383 (100),
225.1987 (62), 207.0850 (10), 115.0453 (6), 98.0988 (5).
MS (FAB-NBA): m/z = 316.1546 (62%), 225.1802 (17), 107.0620
(21).
680
Papers
SYNTHESIS
MS (EI, 70 eV): m/z = 315.1511 (62%), 258.1210 (17), 224.1931
(18), 143.1195 (38), 98.0914 (56), 70.0646 (100).
HRMS (FAB-Glycerine): 316.1561 (1.2 mmu), (C
18
H
22
NO
4
+H) re-
quires, 316.1549. For (M+H)
+
– H
2
O: 298.1383 (6.0 mmu),
(C
18
H
22
NO
4
+H) – H
2
O requires 298.1443.
FAB-Nitrobenzyl alcohol: 316.1546 (0.3 mmu), (C
18
H
22
NO
4
+H) re-
quires 316.1549.
EI (70 eV): 315.1511 (-4 mmu), (C
18
H
21
NO
4
) requires, 315.1471.
The authors are grateful to Mallinckrodt Specialty Chemicals, TDC
Research, Inc., NSF (CHE-9315684, CHE-9521489, and CHE-
9615112) and the University of Florida for financial support of this
work. Special thanks are extended to Khalil A. Abboud (University of
Florida) for determination of the absolute stereochemistry of diol 74
and Matthew R. Ellis (Summer Undergraduate Research Participant)
for his assistance in preparation of some starting materials.
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