Chemoselective reductive cross-coupling of 1,5-diene-3-ols with alkynes: A facile entry to stereodefined skipped trienes

Article abstract of DOI:10.1021/ja103836h

A convergent synthesis of highly substituted and stereodefined skipped polyenes is described from the reductive cross-coupling of substituted 1,5-diene-3-ols with alkynes. The control of site selectivity in functionalization of the substituted diene is a central feature of this complex fragment union reaction.

Full text of DOI:10.1021/ja103836h

Published on Web 06/29/2010
Chemoselective Reductive Cross-Coupling of 1,5-Diene-3-ols with Alkynes: A
Facile Entry to Stereodefined Skipped Trienes
Peter S. Diez and Glenn C. Micalizio*
Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458
Received May 5, 2010; E-mail: micalizio@scripps.edu
Abstract: A convergent synthesis of highly substituted and stereo-
defined skipped polyenes is described from the reductive cross-
coupling of substituted 1,5-diene-3-ols with alkynes. The control of
site selectivity in functionalization of the substituted diene is a central
feature of this complex fragment union reaction.
Skipped polyenes are structural motifs that are present in a vast
array of natural products of biological significance. While stere-
ochemically homogeneous skipped polyenes are a central feature
of a variety of natural polyunsaturated fatty acids,1 skipped polyenes
of diverse stereochemistry and substitution are also abundant, with
examples including natural products that are of potential value as
antibiotic, antifungal, and anticancer agents (Figure 1).2 Despite
their frequent occurrence in natural products, and potential utility
in organic chemistry, there remains a great dearth of efficient
methods for the synthesis of stereodefined skipped polyenes.3 We
Figure 2. Convergent coupling reactions for skipped triene synthesis.
describe here a highly selective convergent pathway to skipped
trienes via chemo-, regio-, and stereoselective reductive cross-
coupling of substituted 1,5-dienes and alkynes.
of NH4Cl) led to the formation of the skipped triene 3. While we
were delighted to isolate a skipped triene from this coupling
reaction, both the site selectivity and stereoselectivity for this
process were poor (1.4:1 and 1:1, respectively). Moving on, reaction
of the Me-substituted 1,5-diene 4 with alkyne 1 delivered the 1,7-
diene 5 in 50% yield, with no trace of a skipped triene being
produced (entry 2).
To our delight, when both alkenes of the 1,5-diene are substituted,
reductive cross-coupling reactions uniformly proceed with high
selectivity for the formation of stereodefined skipped trienes. The
generality of this process can be seen in entries 3-6, where skipped
trienes bearing two or three stereodefined alkenes (7, 9, 11, and
13) are produced with g20:1 selectivity for C-C bond formation
at the allylic alcohol terminus of the 1,5-diene. Notably, these
coupling reactions proceed with very high levels of stereoselectivity,
do not disturb the preset stereochemistry of the 1,5-diene starting
material, and provide a foundation of evidence that supports the
ability to control site selectivity in reductive cross-coupling reactions
of dienes with alkynes.
Advancing beyond a simple exploration of the 1,5-diene partner,
we shifted our attention to employing this bond construction for
regioselective coupling of unsymmetrical alkynes.8 While TMS-
alkynes were expected to behave in a predictable manner, with C-C
bond formation occurring distal to the TMS group, we were
delighted to see that TMS-substituted enynes (14 and 16) were
compatible substrates in this chemoselective reductive cross-
coupling reaction (Table 2, entries 1-2). Here, selective activation
of the alkyne of 14 and 16 is followed by chemo- and stereoselective
C-C bond formation with substituted 1,5-dienes. Even alkynes that
boast a modest level of steric differentiation (Me- vs TIPSOEt-)
result in regioselective cross-coupling (entry 3); here, the stereo-
defined triene 19 is produced in 54% yield (rs ) 9:1). Use of a
more sterically differentiated internal alkyne results in skipped
Figure 1. Natural products housing skipped polyenes.
In efforts aimed at providing a solution to problems associated
with the synthesis of stereochemically heterogeneous skipped
polyenes, we previously described a reductive cross-coupling of
substituted vinylcyclopropanes with alkynes.4 This reaction, de-
picted in Figure 2A, furnishes skipped trienes bearing a central (E)-
alkene, with the potential to install a flanking (E)- or (Z)-disubstituted
alkene. We hypothesized that a related reductive cross-coupling of
1,5-dienes with alkynes may define a more convenient and
stereochemically complementary pathway to related skipped trienes
(Figure 2B). That said, such a process would require control of
chemoselectivity defined by the competition between reaction paths
depicted in Figure 2C: (1) Site selective reductive cross-coupling
at the allylic alcohol (Path A),5 (2) site selective reductive cross-
coupling via the homoallylic alcohol (Path B),6 or (3) reaction at
both alkenes of the 1,5-diene.
Our initial investigations were focused on determining whether
structural features on the 1,5-diene could be used to control site
selective C-C bond formation. As depicted in entry 1 of Table 1,
coupling of the parent unsubstituted diene 2 with symmetrical
alkyne 1 (by treatment of the alkyne with the combination of Ti(Oi-
Pr)4 and c-C5H9MgCl,7 followed by addition of the lithium alkoxide
of 2 and subsequent hydrolysis with a saturated aqueous solution
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C O M M U N I C A T I O N S
Table 1
Table 2
a Reaction conditions: alkyne (2-3 equiv), Ti(Oi-Pr)4 or ClTi(Oi-Pr),
c-C5H9MgCl, PhMe (-78 to -35 °C), then cool to -78 °C and add Li
alkoxide of the allylic alcohol as a solution in THF (warm to 0 °C).
b Yield reported is over two steps: chemoselective reductive
cross-coupling and silyl deprotection with TBAF in THF.
a Reaction conditions: 1 (2-3 equiv), Ti(Oi-Pr)4, c-C5H9MgCl, PhMe
(-78 to -35 °C), then cool to -78 °C and add Li alkoxide of the
allylic alcohol as a solution in THF (warm to 0 °C). b In cases where
selectivity is reported as g20:1, no evidence was found for products
derived from C-C bond formation by a different path. c In cases where
selectivity is reported as g20:1, no evidence was found for the
formation of stereoisomeric products. d Olefin geometry of the major
products was assigned by analogy to previous examples. e Yield reported
is after HPLC purification.
unexpected and points to a potentially powerful aspect of the present
reductive cross-coupling reaction. We look forward to advances
that follow from these initial findings.
trienes with even higher levels of regioselection. As depicted in
entry 4, union of alkyne 20 with diene 10 produces triene 21 in
65% yield with g20:1 rs. Substitution is also tolerated in the 1,5-
diene partner. As illustrated in entry 5, union of alkyne 18 with
diene 22 results in the formation of triene 23, a stereodefined
skipped polyene possessing one (E)-trisubstituted, one (Z)-trisub-
stituted, and one (Z)-disubstituted alkene, while also establishing a
1,4-diene bearing a central stereodefined alkyl substituent.
Acknowledgment. The National Institutes of HealthsNIGMS
supported this study (GM80266 and GM80266-04S1).
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.
References
(1) (a) Krey, G.; Braissant, O.; L’Horset, F.; Kalkhoven, E.; Perroud, M.; Parker,
M. G.; Wahli, W. Mol. Endocrinol. 1997, 11, 779. (b) Ringbom, T.; Huss,
U.; Stenholm, Å; Flock, S.; Skattebøl, L.; Perera, P.; Bohlin, L. J. Nat. Prod.
2001, 64, 745. (c) Hamilton, J. A. Prostag. Leukotr. Ess. 2006, 67, 65. (d)
Yaqoob, P. Trends Immunol. 2003, 24, 639. (e) Lie Ken Jie, M. S. F.; Pasha,
M. K.; Syed-Rahmatullah, M. S. K. Nat. Prod. Rep. 1997, 14, 163.
(2) (a) Irschik, H.; Augustiniak, H.; Gerth, K.; Höefle, G.; Reichenback, H. J.
Antibiot. 1995, 48, 787. (b) Gerth, K.; Washausen, P.; Höefle, G.; Irschik,
H.; Reichenback, H. J. Antibiot. 1996, 49, 71.
In conclusion, we have described a convenient synthetic pathway
to a range of stereochemically defined skipped trienes by the union
of 1,5-dienes with disubstituted alkynes. This achievement docu-
ments the ability to control chemoselectivity in reductive cross-
coupling reactions of dienes, where alkene substitution and location
of a pendant alkoxide combine to dictate the course of C-C bond
formation.9 A mechanistic feature that has been revealed in the
course of these studies is the increased sensitivity of homoallylic
alcohol-alkyne reductive cross-coupling reactions to alkene substitu-
tion in comparison to allylic alcohol-alkyne coupling processes. In
all cases explored, where each alkene of a 1,5-diene is disubstituted,
chemoselective reductive cross-coupling proceeds by a pathway that
exploits the enhanced reactivity of an allylic alcohol in preference
to a homoallylic alcohol; a mechanistic rationale for this divergent
reactivity awaits further experimentation. Finally, we have dem-
onstrated that this coupling reaction is useful for the selective union
of unsymmetrical coupling partners, including substrates that display
only minor steric differences (i.e., 18); this observation was
(3) For a review of methods for the synthesis of (Z, Z)-1,4-dienes, see: (a)
Durand, S.; Parrain, J.-L.; Santelli, M. J. Chem. Soc., Perkin Trans. 1 2000,
253. For carbonyl olefination-based methods to access skipped alkenes, see:
(b) Fu¨rstner, A.; Larionov, O.; Flu¨gge, S. Angew. Chem., Int. Ed. 2007, 46,
5545. For recent reviews, see: (c) A¨ıssa, C. Eur. J. Org. Chem. 2009, 1831.
(d) Demeunier, R.; Marko, I. E. In Modern Carbonyl Olefination; Takeda,
T., Ed.; Wiley-VCH: Weinheim, 2004, p 104. For a route to 1,4-dienes by
1,5-hydrogen migrations in cis-vinylcyclopropanes, see: (e) Ellis, R. J.; Frey,
H. M. P. Chem. Soc. London 1964, 221. (f) Parziale, P. A.; Berson, J. A.
J. Am. Chem. Soc. 1990, 112, 1650. (g) Parziale, P. A.; Berson, J. A. J. Am.
Chem. Soc. 1991, 113, 4595.
(4) Macklin, T. K.; Micalizio, G. C. Nature Chem. 2010, 2, doi:10.1038/
nchem.665.
(5) (a) Kolundzic, F.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 15112.
See also: (b) Lysenko, I. L.; Kim, K.; Lee, H. G.; Cha, J. K. J. Am. Chem.
Soc. 2008, 130, 15997.
(6) Reichard, H. A.; Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46, 1440.
9
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C O M M U N I C A T I O N S
(7) For reviews of metal-π complexes from Ti(Oi-Pr)4, see: (a) Kulinkovich,
O. G.; Meijere, A. Chem. ReV. 2000, 100, 2789. (b) Sato, F.; Urabe, H.;
Okamoto, S. Chem. ReV. 2000, 100, 2835.
(9) In Ni-catalyzed reductive cross-coupling of enynes with aldehydes, Jamison
has demonstrated that the pendent alkene plays a role in regioselective
functionalization of the alkyne; see: Miller, K. M.; Jamison, T. F. J. Am.
Chem. Soc. 2004, 126, 15342. The method described herein does not rely
on similar alkene direction and is tolerant of diverse alkene substitution and
stereochemistry.
(8) Regioselection in reductive cross-coupling is often challenging to control.
For a recent review, see: (a) Reichard, H. A.; McLaughlin, M.; Chen, M. Z.;
Micalizio, G. C. Eur. J. Org. Chem. 2010, 391. For a recent example of
ligand-controlled regioselective reductive cross-coupling of internal alkynes
with aldehydes, see: (b) Malik, H. A.; Sormunen, G. J.; Montgomery, J.
J. Am. Chem. Soc. 2010, 132, 6304.
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