E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing

Abstract

Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a 24-membered ring, en route to the cytotoxic natural product dolabelide C.

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Articles
https://doi.org/10.1038/s41557-022-00935-y
1Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA. 2Supramolecular Science and Engineering Institute, University of Strasbourg and
CNRS, Strasbourg, France. 3Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. ✉e-mail: romiti@unistra.fr;
amir.hoveyda@bc.edu
It is a sign of the power of macrocyclic ring-closing metathesis
(MRCM)1,2 that, despite being often inefficient, it is used regu-
larly to synthesize bioactive trisubstituted cyclic alkenes3. What
makes this yet more remarkable is that only in rare cases does
MRCM deliver one alkene isomer preferentially4–7 and even then
it might not be the desired one8,9 (see Supplementary Information
for an extended bibliography). The stereochemical outcome of an
MRCM hinges on subtle energy differences between a substrate’s
conformers, making it difficult—if not impossible—to predict
whether it will be selective and, if so, to what degree and/or which
isomer might be favoured. Making matters more difficult, typically,
high catalyst loadings (for example, up to 60 mol%), elevated reac-
tion temperatures (up to 100 °C) and/or extended reaction times
(up to a week) are necessary6,7,10–12.
Progress towards development of kinetically controlled MRCM13
has been confined to transformations that afford a disubstituted
alkene14,15. Although a few methods for preparation of trisubsti-
tuted olefins by cross-metathesis exist16–18, there appears to be no
kinetically controlled MRCM method for accessing trisubstituted
macrocyclic olefins. One approach might involve alkyne metath-
esis, followed by stereoselective conversion of a macrocyclic alkyne
to trisubstituted alkene derivatives19. However, a directing group
(such as a propargylic alcohol) is needed to convert the alkyne into
a trisubstituted alkene, only one of the two stereoisomers can be
accessed and a macrocyclic alkyne might be too strained to form
in high yield.
In an earlier foray, in connection to synthesis of fluvirucin B1
(Fig. 1a), we showed that MRCM of diene 1a can be performed
with 20 mol% bis-alkoxide complex Mo-1 (Fig. 1e) to afford
14-membered ring 2a in 91% yield and >98:2 Z:E ratio20; catalytic
reduction afforded the desired methyl-substituted carbon ste-
reogenic centre with complete stereocontrol. Later investigations
revealed that the high Z:E ratio, resulting from conformational
preferences of the starting material (substrate control) was a coinci-
dence and is atypical. For instance, MRCM of regioisomeric 1b with
20 mol% Ru-1 (Fig. 1e) afforded 2b (C7–C8 versus C6–C7 alkene in
2a) with just a slight preference for the E isomer21,22.
Subsequent efforts towards identifying a more general strategy
led to the discovery of Mo-2 (Fig. 1e). With 7.5 mol% Mo-2, triene
3 was converted to Z-trisubstituted macrocyclic alkene 4 (Fig. 1b),
the precursor to epothilone D, in 73% yield and 91:9 Z:E selectiv-
ity23. Stereoselective epoxidation of 4 afforded epothilone B24. This
was an improvement compared to the previous attempts, which
demanded 20 mol% Mo-1 (86% yield)24 and led to the formation
of isomeric mixtures. Nonetheless, molybdenum bisaryloxide cata-
lysts proved not to be broadly applicable, as manifested by severe
inefficiency of MRCM with sparsely functionalized dienes. As an
example, none of the desired products were detected in the reaction
with 5 to afford macrolactone 6 (Fig. 1c), namely, the macrocyclic
core of epothilones without substituents. It did not matter whether a
molybdenum or ruthenium complex was used. Only homocoupling
by-products, generated from reaction at the monosubstituted alkene
terminus, were observed. Unlike processes that afford disubstituted
macrocyclic alkenes25–28, MRCM that afford a trisubstituted alkene
without substantial entropic assistance29 are rare and the known
examples are either low-yielding or hardly stereoselective20,30. This
shortcoming is consequential because minimally functionalized
trisubstituted macrocyclic olefins are musks31,32. Furthermore, facile
and stereoselective preparation of unsaturated large rings, regard-
less of their substitution pattern and/or stereochemical identity,
is important to the art of framework editing33,34 and drug devel-
opment35,36. Whether a macrocycle contains an E- or a Z-alkene
impacts its three-dimensional shape and ability to recognize and
bind a particular receptor site.
The reliability of MRCM is especially crucial when it is intended
as a late-stage operation in a multistep route that leads to a complex
molecule, such as the naturally occurring anticancer compounds
dolabelides A–D (Fig. 1d)37,38. There are two known total synthe-
ses of these 24- and 22-membered unsaturated lactone macrocy-
clic alkenes, one delivering dolabelide C39 and the other dolabelide
E- and Z-trisubstituted macrocyclic alkenes for
natural product synthesis and skeletal editing
Yucheng Mu 1, Felix W. W. Hartrampf1, Elsie C. Yu 1, Katherine E. Lounsbury2, Richard R. Schrock3,
Filippo Romiti 1,2 ✉ and Amir H. Hoveyda 1,2 ✉
Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient
and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations
require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we
introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form,
regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, includ-
ing complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by
two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam
related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a
24-membered ring, en route to the cytotoxic natural product dolabelide C.
NATURE CHEMISTRY | VOL 14 | JUNE 2022 | 640–649 | www.nature.com/naturechemistry
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