Polyketide assembly by alkene-alkyne reductive cross-coupling: Spiroketals through the union of homoallylic alcohols

Article abstract of DOI:10.1021/ja102888f

A reaction sequence composed of regioselective formal hydroalkynylation, reductive ene-yne cross-coupling, and oxidative cyclization has been developed to prepare stereochemically dense spiroketals. Overall, the chemistry defines a three-component coupling process for the union of two homoallylic alcohol-based substrates with trimethylsilylacetylene.

Full text of DOI:10.1021/ja102888f

Published on Web 05/18/2010
Polyketide Assembly by Alkene-Alkyne Reductive Cross-Coupling:
Spiroketals through the Union of Homoallylic Alcohols
Daniel P. Canterbury and Glenn C. Micalizio*
Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458
Received April 6, 2010; E-mail: micalizio@scripps.edu
Spiroketal-containing natural products represent a rich class
of complex molecules that are known to possess potent and
diverse biological properties. Examples include molecules that
target HIV-1 protease, tubulin polymerization, protein phos-
phatases, and isoleucyl tRNA synthetase among other therapeuti-
cally interesting targets.1 As a result, the synthesis and evaluation
of spiroketal-containing molecules has been a topic of consider-
able interest in chemistry and medicine. Recent investigations
along these lines have led to the discovery of natural product-
inspired spiroketals that inhibit microtubule assembly, cause
apoptosis, inhibit phosphatases, modulate the tubulin cytoskel-
eton, and show promise as potential therapeutics for B-cell
chronic lymphocytic leukemia.2 As a result of their significant
potential in defining novel medicinally relevant small molecules,
it is not surprising that many chemical strategies have emerged
for the synthesis of stereodefined spiroketals.3 While recent
interest has focused on methods for controlling the stereochem-
istry of the acetal,4 few general and flexible strategies for
accessing the carbon skeleton have been advanced beyond
multistep aldol chemistry,5 which involves processes that
currently require numerous carbonyl redox and protecting-group
manipulations. Here we describe a highly convergent and concise
entry to substituted and stereodefined spiroketals by the union
of homoallylic alcohols with trimethylsilylacetylene (TMS-
acetylene) (2 + 3 + 4 f 1; Figure 1A). Because a variety of
methods for stereoselective allyl transfer exist,6 this spiroketal
synthesis defines a simple convergent pathway that proceeds by
the union of aldehydes (5 and 6) through a sequence that
establishes four C-C bonds and up to six new stereocenters.
With well-established allyl transfer chemistry in place, the
union of homoallylic alcohols 2 and 4 with TMS-acetylene (3)
en route to complex spiroketals 1 was targeted through a three-
step process, as depicted in Figure 1B. Initial functionalization
of homoallylic alcohol 2 by regioselective formal hydroalky-
nylation with TMS-acetylene would deliver alkyne 7. Subsequent
site- and stereoselective reductive cross-coupling between 7 and
the second homoallylic alcohol 4 would then deliver complex
diol 8. Finally, oxidative cleavage of the central alkene with
subsequent dehydrative cyclization would furnish complex
spiroketal 1.
Initial attempts to accomplish formal hydroalkynylation via
hydroboration of a terminal alkene followed by B-alkyl Suzuki
coupling with bromo-TMS-acetylene were met with failure.7
Turning our attention to classic alkynylborate chemistry,8 we
hypothesized that the desired bond construction could proceed by
the sequence depicted in Figure 2A. Initial hydroboration of 2 was
anticipated to deliver a trialkylborane intermediate that, although
capable of undergoing the desired alkynylborate chemistry, was
anticipated to be problematic, as selectivity in subsequent 1,2-alkyl
migration is known to proceed with competitive ring expansion of
the borabicyclononane system.9 Thus, we pursued site-selective
mono-oxidation of the resulting trialkylborane10 followed by
addition of Li-TMS-acetylide to deliver intermediate mixed lithium
alkynylborates having the general structure 9. Subsequent iodine-
initiated group-selective 1,2-alkyl migration and base-induced
elimination would then deliver 7, the product of formal hydroalky-
nylation of 2.
As illustrated in Figure 2B, this design for formal hydroalky-
nylation proved effective and general, providing coupled products
in 72-86% yield (eqs 1-6). Overall, the required sequence of
reactions was easy to perform in a one-pot process and provided
products bearing a range of stereodefined alkyl substitution (11,
13, 15, 17, 19, and 21).
Next, we explored the second C-C bond-forming process for
the proposed spiroketal construction: ene-yne cross-coupling
between stereodefined homoallylic alcohols and a suitably
functionalized TMS-alkyne (22; Figure 3). Building on our earlier
observations that culminated in a general method for ene-yne
cross-coupling,11 we explored titanium-mediated alkoxide-
directed reductive coupling as a means to accomplish the desired
bond construction. Initial formation of a Ti-alkyne complex
Figure 1. Convergent assembly of spiroketals by the selective union of
homoallylic alcohols.
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10.1021/ja102888f  2010 American Chemical Society

C O M M U N I C A T I O N S
Figure 3. Titanium-mediated reductive cross-coupling.
spiroketals. As illustrated in Figure 4, a three-step sequence
composed of reductive cross-coupling, oxidative cleavage, and acid-
promoted dehydration14 was pursued as a general strategy for the
synthesis of stereodefined spiroketals. Overall, complex and diverse
polysubstituted spiroketals 35-38 were generated with very high
levels of stereoselection from the union of a range of stereochemi-
cally defined homoallylic alcohols (23, 27, 29 and 31) with the
products of formal hydroalkynylation (13, 17 and 19), as shown in
eqs 13-16.15 While the overall yields for this three-step process
define an area for future improvement, the current efficiencies derive
from sequences of reactions with average yields per step ranging
from 68-80%.
In summary, we have developed a strategy for the convergent
assembly of highly substituted and stereodefined spiroketals that
proceeds through the union of two chiral homoallylic alcohols.
The chemical process defined here is based on merging well-
established stereoselective allyl transfer chemistry with (1) a
regioselective formal hydroalkynylation and (2) a metallacycle-
mediated reductive cross-coupling reaction between function-
alized homoallylic alcohols and TMS-alkynes (the product that
results from the hydroalkynylation reaction). While defining a
synthetic pathway to spiroketals that can accommodate substitu-
tion patterns not easily attained by other convergent methods
(based on aldol technology, allylmetal chemistry, cross-metath-
esis, and dithiane alkylation processes), these studies demonstrate
the potential utility of ene-yne reductive cross-coupling reac-
tions in the synthesis of complex molecules. We look forward
to advances that follow from these initial studies.
Figure 2. Formal hydroalkynylation by alkynylborate chemistry.
by exposure of 22 to the combination of Ti(Oi-Pr)4 and
c-C5H9MgCl,12 followed by addition of the lithium alkoxide of
homoallylic alcohol 23, provided the homologated product 24
in 87% yield as a single isomer (eq 7) after aqueous workup.
This ene-yne reductive cross-coupling proved to be effective
for a range of homoallylic alcohols (25, 27, 29, and 31),
delivering the corresponding cross-coupled products 26, 28, 30,
and 32 in 74-88% yield (eqs 8-11). Of these examples, eqs
10 and 11 highlight an interesting and powerful feature of this
coupling process. In these cases, the deoxypropionate architecture
was established in a highly stereoselective fashion through a
complex metallacycle-mediated coupling reaction that proceeds
with high levels of regioselectivity with respect to each
unsymmetrically disubstituted π system in concert with the
establishment of a new allylic stereogenic center (ds g 20:1).13
While we were delighted with the apparent generality of this
fragment union process, a limitation was observed in our initial
study. As depicted in eq 12, reductive cross-coupling of
homoallylic alcohol 33 with alkyne 22 did proceed, but product
34 could be isolated in only 22% yield. This limitation appears
to be associated with the use of a homoallylic alcohol substrate
containing both a disubstituted alkene and a sterically hindered
directing group.
With methods for regioselective hydroalkynylation and ene-yne
cross-coupling in hand, we turned our attention to the assembly of
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(14) On the basis of a reviewer’s suggestion, we add that these conditions are
typical for thermodynamic control in the stereoselective generation of the
spiroacetal. See the Supporting Information for additional details.
(15) In each case (eqs 13-16), no evidence was found for the production of
stereoisomeric spiroketals. This observation is in accord with the well-
established thermodynamic preference for the generation of spiroketals that
are stabilized by a double anomeric effect. See the Supporting Information
for additional details.
Figure 4. Spiroketal synthesis by the convergent union of homoallylic
alcohols.
Acknowledgment. We gratefully acknowledge financial sup-
port of this work by the American Cancer Society (RSG-06-
117-01) and the NIGMS of the National Institutes of Health
(GM80266).
Supporting Information Available: Experimental procedures and
tabulated spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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