Direct, stereospecific generation of (Z)-disubstituted allylic alcohols

Article abstract of DOI:10.1021/ja061973n

A one-pot method to prepare highly functionalized (Z)-disubstituted allylic alcohols is introduced. Hydroboration of a variety of 1-bromo-1-acetylenes with dicyclohexyl borane, reaction with t-BuLi, and transmetalation to zinc generates a (Z)-disubstituted vinylzinc reagent. In situ reaction of this reagent with aldehydes generates (Z)-disubstituted allylic alcohols in high yields (81-97%). Addition to chiral protected α- or β-oxygenated aldehydes proceeds with diastereoselectivities between 6:1 and 18:1. The anti-Felkin product is obtained in most cases. Copyright

Full text of DOI:10.1021/ja061973n

Published on Web 07/12/2006
Direct, Stereospecific Generation of (Z)-Disubstituted Allylic Alcohols
Sang-Jin Jeon, Ethan L. Fisher, Patrick J. Carroll, and Patrick J. Walsh*
P. Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received March 31, 2006; E-mail: pwalsh@sas.upenn.edu
Table 1. One-Pot Synthesis of (Z)-Disubstituted Allylic Alcohols
The catalytic asymmetric addition of vinylzinc reagents to
aldehydes has recently engendered a great deal of attention.1 The
resulting allylic alcohols are versatile building blocks for the
synthesis of enantioenriched allylic amines,2 R-amino acids,2
γ-unsaturated â-amino acids,3 cyclopropyl alcohols,4 epoxy
alcohols,5-7 and natural products.8,9 The majority of asymmetric
aldehyde vinylations have employed (E)-disubstituted vinylzinc
reagents generated via hydroboration10 or hydrozirconation11 of
terminal alkynes and transmetalation to zinc. Analogous methods
to produce (Z)-disubstituted vinylzinc reagents, and therefore (Z)-
allylic alcohols, are lacking.
Herein we introduce a practical and general one-pot stereospecific
method to generate elaborate (Z)-disubstituted allylic alcohols. The
basis of our chemistry is Zweifel’s addition of nucleophiles to
1-bromo vinylboranes, which forms a C-C bond with inversion at
the vinylic center (eq 1).12 Addition of hydride sources was later
examined by Negishi13 (LiBEt3H, KB(sec-Bu)3H), Molander14
(t-BuLi), and Brown15 (KB(OiPr)3H) (eq 2). The resulting (Z)-
vinylboranes have seldom been applied in organic synthesis due
to their inherently low reactivity.
We envisaged that transmetalation of the vinylboranes in eqs 1
and 2 to zinc would dramatically increase their reactivity and enable
one-pot generation of (Z)-trisubstituted16 and (Z)-disubstituted allylic
alcohols. To generate (Z)-disubstituted allylic alcohols, we initially
employed t-BuLi as the hydride source and toluene as the solvent.
Thus, hydroboration of 1-bromoalkynes with HBCy2 generated
analogous 1-bromo vinylboranes (eq 2). Subsequent addition of
t-BuLi at -78 °C followed by warming to room temperature formed
the (Z)-disubstituted vinylboranes. Treatment of the vinylborane
with Et2Zn generated the reactive vinylzinc intermediates to which
an aldehyde was added. The desired (Z)-allylic alcohols were
obtained, albeit in low yield with cyclohexyl migrated (Z)-
trisubstituted allylic alcohol as a major product. We speculated that
a lithium borate complex generated in the course of reaction was
unstable in the nonpolar toluene. THF was examined in the hope
that it would stabilize the proposed borate intermediate. Use of THF
to form the (Z)-vinylborane was followed by removal of the volatile
materials. Toluene, Et2Zn, and the aldehyde were added to the
vinylzinc reagent at low temperature (-78 to 0 °C). The reaction
mixture was allowed to warm to room temperature and stirred
for 12 h. To our delight, the desired (Z)-allylic alcohols were
isolated in high yields with no detectable contamination of the
a Numbers in parentheses are yields from the reactions using KB(OiPr)3H
as the hydride source.
C-H’s exhibit an 11 Hz coupling constant in the 1H NMR
spectra, indicative of the cis geometry.
The broad scope of our tandem reaction is illustrated in Table
1. Aromatic, aliphatic, and R,â-unsaturated aldehydes react smoothly
with in situ generated (Z)-vinylzinc reagents to provide the
corresponding allylic alcohols in high yields (81-97%). Particularly
noteworthy is the stereospecific generation of the (Z)-double bond
in the presence of alkynes (entries 5, 9, and 12). These propargylic
alcohols could not be prepared by conventional Lindlar reduction
of diynols. Additionally, it is known that sulfur-containing com-
pounds can poison hydrogenation catalysts. The thiophene deriva-
tives in entries 11 and 13 are readily prepared with this tandem
1
(E)-diastereomer by H NMR spectroscopy (eq 3). The olefinic
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10.1021/ja061973n CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
To our surprise, the anti-Felkin product was obtained.22-24 The
stereochemistry of the remaining products was assigned by 1H NMR
analysis of the Mosher ester derivatives.25 Chelation-controlled
addition with TBS-protected R- and â-hydroxy aldehydes is rare,
due to the steric demands of the TBS group. In our case, the
preferential anti-Felkin addition (entries 1-8) can be overridden
by employing the very bulky TIPS protecting group (entry 9). We
are currently investigating the origin of the increased anti-Felkin
product upon addition of a monodentate Lewis acid (BF3‚OEt2).
In summary, we have developed a simple and efficient one-pot
procedure for the synthesis of elaborate (Z)-disubstituted allylic
alcohols from readily available 1-bromoalkynes. An advantage of
our method is the generation of the (Z)-double bond isomer without
contamination from the undesired (E)-product. The (Z)-vinylzinc
reagents have also been shown to undergo addition to chiral R-
and â-oxygenated aldehydes with good to excellent control over
diastereoselectivity. This tandem addition reaction enables the
synthesis of allylic alcohols previously difficult to access, opening
up new avenues for complex molecule synthesis. We are currently
developing an enantioselective version of these reactions.
Table 2. Diastereoselective Additions to Chiral Aldehydes
Acknowledgment. This work was supported by the NIH
(GM58101) and the NSF (CHE-0615210).
Supporting Information Available: Procedures and full charac-
terization, stereochemical assignments, and X-ray determinations of new
compounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
a Absolute configurations of secondary alcohols were determined by
X-ray crystallography or Mosher ester derivatization method (see Supporting
Information). b Diastereomeric ratio based on crude 1H NMR. c Two
equivalents of BF3‚OEt2 was premixed with aldehyde at -78 °C for 2 min
then added to the reaction mixture. d Two equivalents of ZnBr2 was added
to the reaction mixture before addition of aldehyde.
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