Conversion of allylic alcohols to stereodefined trisubstituted alkenes: A complementary process to the claisen rearrangement

Article abstract of DOI:10.1021/ja8074242

A stereoselective method for the conversion of allylic alcohols to (Z)-trisubstituted alkenes is presented. Overall, the reaction sequence described is stereochemically complementary to related Claisen rearrangement reactions □ processes that typically deliver the stereoisomeric trisubstituted alkene containing products. Copyright

Full text of DOI:10.1021/ja8074242

Published on Web 11/20/2008
Conversion of Allylic Alcohols to Stereodefined Trisubstituted Alkenes: A
Complementary Process to the Claisen Rearrangement
Justin K. Belardi and Glenn C. Micalizio*
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
Received September 19, 2008; E-mail: glenn.micalizio@yale.edu
Methods for the synthesis of geometrically defined trisubstituted
olefins define a pillar of modern synthetic organic chemistry. From
a target-based perspective, these stereodefined structural motifs are
ubiquitous in natural products and molecules of biomedical and
physical relevance (Figure 1). From a reactivity-based perspective,
related reductive cross-coupling process could define a stereose-
lective convergent pathway to isolated di- and trisubstituted olefins.
To accomplish such a transformation, we targeted a reductive cross-
coupling reaction between allylic alcohols and vinylsilanes.5
Figure 1. Natural products possessing stereodefined (Z)-trisubstituted
alkenes.
geometrically defined olefins serve as a foundation for stereose-
lective synthesis. These factors have driven the invention of a large
variety of chemical methods for the convergent synthesis of
stereodefined olefins. While many of these methods proceed from
carbonyl addition chemistry or alkyne functionalization, the use of
allylic alcohol derivatives in sigmatropic processes defines a
powerful means to access a subset of stereodefined polysubstituted
olefins.1 Of these, Claisen-based methods have been particularly
effective at establishing stereodefined (E)-trisubstituted olefins.
Here, we describe a metal-mediated reductive cross-coupling
reaction that defines a stereochemically complementary means of
converting allylic alcohols to products related to those derived from
Claisen rearrangement (Figure 2). While describing a unique
stereoselective transformation for complex molecule synthesis, this
study also defines a novel reductive cross-coupling reaction between
alkenes and allylic alcohols.2,3
Figure 3. Preliminary study of stereoselection in reductive cross-coupling
of allylic alcohols with vinylsilanes.
Our initial studies, depicted in Figure 3, provided some hope
that the desired stereoselective transformation would be possible.
In general, the preformed lithium alkoxide of an allylic alcohol
was combined with vinyltrimethylsilane in Et2O, cooled, and treated
with the combination of ClTi(Oi-Pr)3 and C5H9MgCl (-78 to 0
°C).6 While cross-coupling of allylic alkoxides 1 and 4 with
vinyltrimethylsilane (2) provided cross-coupled products 3 and 5
in 58-66% yield, these reactions proceeded without stereoselection
(E/Z ) 1:1). In contrast, reductive cross-coupling of the (Z)-
disubstituted alkene 6 with 2 provided the (E)-alkene 7 in 64%
yield (E/Z ) 9:1). Highest levels of (E)-selectivity were observed
in the reaction of 8 with 2. This process provided 9 in 69% yield
with g20:1 selectivity; defining a stereoselective transformation
that also establishes a quaternary center.7
While the cross-coupling reaction of terminally substituted allylic
alcohols (i.e., 6 and 8) delivers stereodefined (E)-disubstituted
alkenes, the reaction of allylic alcohols bearing a 1,1-disubstituted
olefin proceeds in a stereochemically unique manner. Reductive
cross-coupling of 10 with 2 delivers 11 in 50% yield, with g20:1
selectivity, favoring the formation of the central stereodefined (Z)-
trisubstituted alkene. Similarly, the coupling of the trisubstituted
allylic alcohol 12 with 2 provides 13 in 65% yield (Z:E g 20:1).
While preliminary studies investigating the coupling of simple
acyclic- and cyclic alkenes with vinyltrimethylsilane indicate that
this reaction is flexible and stereoselective (Figure 3 and Table 1,
entries 1-3), we searched to identify a coupling partner that would
allow for facile oxidation of the C-Si bond resident in the products.
The combination of these two reactions, cross-coupling and
oxidation, would then define a means to access stereodefined
products related to those derived from Claisen rearrangment.1
Figure 2. A stereochemically unique method for the synthesis of stereo-
defined trisubstituted alkenes from allylic alcohols.
Recently, we demonstrated that allylic alcohols are useful
substrates in titanium-mediated reductive cross-coupling reactions
with internal alkynes.4 In these reactions, 1,4-dienes result from
C-C bond formation between preformed titanium-alkyne com-
plexes and allylic alkoxides. While quite useful for the stereose-
lective synthesis of substituted 1,4-dienes, we wondered whether a
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2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1
Figure 5. A stereochemically complementary process with respect to the
Claisen rearrangement. Reaction conditions: (a) Johnson o-ester Claisen
rearrangement; (b) reduction;9 (c) 20, ClTi(Oi-Pr)3, c-C5H9MgCl, Et2O (-78
to -50 °C), then cool to -78 °C and add lithium alkoxide of 10 (-78 to
0 °C) then, HCl (1 N) (75%, Z/E g 20:1); (d) t-BuOOH, CsOH ·H2O, TBAF,
DMF, 70 °C.
similarly stereoconvergent manner, indicating a potential role of
the PMB ether in the stereochemical course of this reaction (entry
8).12
Reaction conditions: (a) n-BuLi (1 equiv), vinylsilane (3 equiv),
The regio- and stereochemical control observed in this allylic
alcohol functionalization process is consistent with the empirical
model depicted in Figure 6. In short, preassociation of the allylic
alkoxide with a preformed titanacyclopropane (derived from the
vinylsilane) produces an intermediate mixed titanate ester capable
of rearrangement via formal metallo-[3,3]-rearrangement.4 While
the C-C bond formation proceeds with allylic transposition,
stereochemical control is thought to derive from minimization of
ClTi(Oi-Pr)3 (3 equiv), C5H9MgCl (6 equiv) (-78 to 0°C), then HCl (1
N); (b) n-BuLi (2 equiv), vinylsilane (3 equiv), ClTi(Oi-Pr)3 (3 equiv),
C5H9MgCl (6 equiv) (-78 to 0°C), then HCl (1 N).
As illustrated in Figure 4, reductive cross-coupling of allylic
alcohols 6 and 12 with vinyldimethylchlorosilane5 (20) proceeds
in a stereoselective manner, and delivers the corresponding si-
lylethers 21 and 22 in 53% and 75% yield (E/Z ) 10:1 to g20:1).
Oxidation of the C-Si bond under standard conditions8 then
delivers the stereodefined unsaturated primary carbinol (i.e., 22 f
23). While products like 23 could be derived from 12 by the
application of well-known Claisen rearrangement-based procedures,
the cross-coupling reaction described here has the potential to
deliver stereodefined products not readily accessible with these
robust [3,3]-sigmatropic rearrangement processes. For example,
Claisen rearrangement of 10, followed by carbonyl reduction,
provides the (E)-trisubstituted olefin 24 with high levels of
stereoselection (E/Z g 20:1).9 In this complementary process,
reductive cross-coupling of 10 with vinyldimethyl-chlorosilane (20),
followed by oxidation, provides the isomeric (Z)-trisubstituted olefin
25 in 58% yield (Z/E g 20:1).10
Table 2.
As illustrated in Table 2, this (Z)-selective reductive cross-
coupling reaction is useful for the stereoselective functionalization
of a variety of allylic alcohols (entries 1-5). Additionally,
stereochemically defined products can be prepared from the
coupling of mixtures of isomeric allylic alcohols (i.e., entries 6 and
7). Interestingly, coupling of 36 with 20 does not proceed in a
a Yield reported is over the two-step process: (1) Reductive
cross-coupling (20, ClTi(Oi-Pr)3, c-C5H9MgCl, Et2O (-78 to -50 °C),
then cool to -78 °C and add lithium alkoxide of the allylic alcohol
(-78 to 0 °C) then, HCl (1 N)); (2) oxidation (t-BuOOH, CsOH·H2O,
TBAF, DMF, 70 °C).
Figure 4. Cross-coupling reactions with vinyldimethylchlorosilane.
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C O M M U N I C A T I O N S
[2,3]-Wittig rearrangement to access related products, see: (j) Still, W. C.;
nonbonded steric interactions in a boatlike conformation (i.e., A′
and B′) where the σC-Ti bond is aligned with the πCdC bond.13
Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927–1928.
(2) For metal-mediated dimerization of terminal alkenes, see: (a) Isakov, V. E.;
Kulinkovich, O. G. Synlett 2003, 967–970. (b) Lee, J. C.; Sung, M. J.;
Cha, J. K. Tetrahedron Lett. 2001, 42, 2059–2061. (c) Reference 5. For
dimerization of, or coupling with, ethylene in route to metallacyclopentanes,
see: (d) McDermott, J. X.; Wilson, M. E.; Whitesides, G. M. J. Am. Chem.
Soc. 1976, 98, 6529–6536. (e) Grubbs, R. H.; Miyashita, A. J. Chem. Soc.,
Chem. Commun. 1977, 864–865. (f) Cohen, S. A.; Auburn, P. R.; Bercaw,
J. E. J. Am. Chem. Soc. 1983, 105, 1136–1143. (g) Mashima, K.; Takaya,
H. Organometallics 1985, 4, 14641466;(h) Mashima, K.; Sakai, N.; Takaya,
H. Bull. Chem. Soc. Jpn. 1991, 64, 2475–2483. (i) Thorn, M. G.; Hill,
J. E.; Waratuke, S. A.; Johnson, E. S.; Fanwick, P. E.; Rothwell, I. P. J. Am.
Chem. Soc. 1997, 119, 8630–8641 For the dimerization of chalcones, see:
(j) Schobert, R.; Maaref, R.; Du¨rr, S. Synlett 1995, 83–84 For cross-coupling
of 1,3-dienes with R-olefins, see: (k) Waratuke, S. A.; Thorn, M. G.;
Fanwick, P. E.; Rothwell, A. P.; Rothwell, I. P. J. Am. Chem. Soc. 1999,
121, 9111–9119.
(3) For titanium alkoxide-mediated coupling reactions of allylic alcohols and
ethers with Grignard reagents, see: (a) Kulinkovich, O. G.; Epstein, O. L.;
Isakov, V. E.; Khmel’nitskaya, I. A. Synlett 2001, 49–52. (b) Matyushenkov,
E. A.; Churikov, D. G.; Sokolov, N. A.; Kulinkovich, O. G. Russian J.
Org. Chem. 2003, 39, 478–485 For Cp2ZrCl2-catalyzed carbomagnesiation
of allylic alcohols and ethers, see: (c) Hoveyda, A. H.; Xu, Z. J. Am. Chem.
Soc. 1991, 113, 5079–5080. (d) Houri, A. F.; Didiuk, M. T.; Xu, Z.; Horan,
N. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1993, 115, 6614–6624. (e)
Hoveyda, A. H.; Morken, J. P. Angew. Chem., Int. Ed. Engl. 1996, 35,
1262–1284.
(4) (a) Kolundzic, F.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 15112–
15113 For reductive cross-coupling of allenic alcohols with alkynes via
formal metallo-[3,3] rearrangement, see: (b) Shimp, H. L.; Hare, A.;
McLaughlin, M.; Micalizio, G. C. Tetrahedron 2008, 64, 3437–3445 For
reductive cross-coupling of allenic alcohols with aromatic imines via formal
metallo-[3,3] rearrangement, see: (c) McLaughlin, M.; Shimp, H. L.;
Navarro, R.; Micalizio, G. C. Synlett 2008, 735–738.
(5) For the first report documenting the ability of vinylsilanes to participate in
the ligand exchange reaction with presumed alkoxytitanacyclopropane
intermediates, see : Mizojiri, R.; Urabe, H.; Sato, F. J. Org. Chem. 2000,
65, 6217–6222.
Figure 6. Model of stereoselection.
In sum, we have described a new regio- and stereoselective
reductive cross-coupling reaction between allylic alcohols and
vinylsilanes. This reaction proceeds with allylic transposition,
delivers products with stereodefined di- and trisubstituted olefins,
and provides a means to establish allylic tertiary and quaternary
carbon centers. In addition to defining a novel olefin functional-
ization reaction and metal-mediated reductive cross-coupling pro-
cess,14 this reaction provides a stereochemically unique pathway
to functionalized acyclic products not readily accessible with
modern [3,3]-sigmatropic rearrangement reactions.1 Future study
will explore both the utility of this process in target-oriented
synthesis and the interplay between allylic alcohol substitution and
selectivity.
(6) For the use of cycloalkylmagnesium halide reagents to generate presumed
alkoxytitanacyclopropane intermediates for intermolecular Kulinkovich
cyclopropanation, see: Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996,
118, 4198–4199.
(7) For reviews on the construction of quaternary carbon centers, see: (a) Martin,
S. F. Tetrahedron 1980, 36, 419–460. (b) Corey, E. J.; Buzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388–401. (c) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105–10146.
(8) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044–6046.
(9) Abouabdellah, A.; Bonnet-Delpon, D. Tetrahedron 1994, 50, 11921–11932.
(10) Titanium-mediated reductive cross-coupling reactions of allylic alcohols
with internal alkynes proceed with a similar sense of stereoselection. See
ref 4a for details.
(11) Derived from the addition of 2-propenylmagnesium bromide to the
corresponding chiral aldehyde. See Supporting Information for details.
Acknowledgment. We gratefully acknowledge financial support
of this work by the American Cancer Society (Grant RSG-06-117-
01), the Arnold and Mabel Beckman Foundation, Boehringer
Ingelheim, Eli Lilly & Co., and the National Institutes of
HealthsNIGMS (Grant GM80266).
Note Added in Proof. During the course of our studies, a related
process was published by Professor Jin K. Cha: Lysenko, I. L.; Kim,
K.; Lee, H. G.; Cha, J. K. J. Am. Chem. Soc., published online
November 6, 2008 http://dx.doi.org/10.1021/ja806440m.
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.
(12) The stereochemistry of the major/minor isomer was not determined. Future
studies will examine the relationship of the relative stereochemistry of 36
on the stereochemical course of the reductive cross-coupling reaction.
(13) This empirical model does not yet address the number of ligands present
on the metal center in the transition state. Others have suggested-ate
complexes as reactive intermediates in the Kulinkovich reaction: (a)
Kulinkovich, O. G.; Kanonovich, D. G. Eur. J. Org. Chem. 2007, 212,
1–2132. (b) Kananovich, D. G.; Kulinkovich, O. G. Tetrahedron 2008,
64, 1536–1547 For the proposal of related intermediates in the reductive
ethylation of allylic ethers, see: (c) Matyushenkov, E. A.; Churikov, D. G.;
Sokolov, N. A.; Kulinkovich, O. G. Russ. J. Org. Chem. 2003, 39, 478–
485.
(14) While this reaction has not yet been rendered catalytic in the metal (Ti),
the process provides a stereochemically unique transformation of great
potential utility in organic synthesis. Like the Claisen rearrangement, these
reactions proceed by substrate control, thereby eliminating the necessity
to control stereochemistry by reagent- or catalyst-based methods. Finally,
due to the low cost of the metal-containing reagents, and benign nature of
the byproducts (TiO2 and magnesium(II) salts), the reaction in its current
form should be of great utility in organic chemistry.
References
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