A one-pot diastereoselective synthesis of cis-3-hexene-1,6-diols via an unusually reactive organozinc intermediate

Article abstract of DOI:10.1021/ja029449d

A highly diastereoselective method for the synthesis of cis-3-hexene-1,6-diols has been developed. This new reaction proceeds with excellent control of diastereoselectivity over four stereocenters and the double bond geometry. The diols are made in a one-pot procedure involving hydroboration of a terminal alkyne and transmetalation to zinc to give a divinylzinc intermediate. This intermediate undergoes reductive elimination, forming a C=C bond. In the absence of a trapping reagent, diene is liberated (70% yield); however, in the presence of ketones or aldehydes, the proposed intermediate metallocyclopentene is trapped via a double insertion of the carbonyl substrate. Workup provides the diols in 47-86% yield. Copyright

Full text of DOI:10.1021/ja029449d

Published on Web 02/25/2003
A One-Pot Diastereoselective Synthesis of cis-3-Hexene-1,6-diols via an
Unusually Reactive Organozinc Intermediate
Celina Garc´ıa, Eric R. Libra, Patrick J. Carroll, and Patrick J. Walsh*
P. Roy and Diane T. Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received November 22, 2002 ; E-mail: pwalsh@sas.upenn.edu
Table 1. Vinyl Coupling/Carbonyl Insertion Products from
Scheme 2
Use of readily available reagents to create densely functionalized
structures in a highly diastereoselective fashion is important to
enhance synthetic efficiency. As part of our program to develop
carbon-carbon bond forming reactions to prepare allylic,1 homo-
allylic,2 and tertiary alcohols3 with high enantioselectivities, we set
out to design a method for the asymmetric vinylation of ketones.
Our approach was akin to the vinylation of aldehydes developed
by Oppolzer4,5 involving hydroboration of a terminal alkyne,
transmetalation to zinc, and carbonyl addition to form the C-C
bond (Scheme 1). This process gives excellent enantioselectivities
Scheme 1. Enantioselective Synthesis of Allylic Alcohols
with aldehydes1,5,6 using Noyori’s DAIB7 or Nugent’s MIB ligand,8
but is currently unknown for ketones.
In the process of studying the vinylation of ketones (in the
absence of MIB), we trapped an unusually reactive organozinc
species. This transient intermediate arises via reductive coupling
of vinyl groups. It is trapped by insertion of 2 equiv of ketone or
aldehyde, resulting in generation of two new C-C single bonds
and a C-C double bond (Scheme 2). In most cases, this multistep
Scheme 2. Synthesis Symmetric (3a-10c) and Unsymmetric
(6c′-7c′) Enediols
2 and 3). To evaluate the reactivity of the organozinc intermediate,
less reactive benzophenone derivatives were employed as substrates.
Use of 4,4′-dimethylbenzophenone or 4,4′-dichlorobenzophenone
in Scheme 2 also gave the 1,6-diol products (entries 4-8). A single
diastereomer of the product was detected in entries 1-8.
Use of unsymmetric ketones led to generation of two additional
stereocenters with variable diastereoselectivity at the quaternary
positions. Reaction of acetophenone with vinyl borane 2c resulted
in formation of the symmetric and unsymmetric diastereomers 6c
and 6c′ in a 5.5:1 ratio (Scheme 2). The syn disposition of the
phenyl groups from the phenylacetylene in 6c was established by
an X-ray diffraction study of the major product (Figure 1). To
minimize steric crowding during the ketone insertion step, the
phenyl groups of acetophenone orient opposite those derived from
the alkyne. The minor, unsymmetric product (6c′) also has a cis-
double bond based on the olefinic coupling in the 1H NMR spectrum
(11.0 Hz) but differs in the stereochemistry of one of the quaternary
centers. Use of 3-methylacetophenone with 1-hexyne, cyclopro-
pylacetylene, and phenylacetylene resulted in generation of 1:1 to
2:1 mixtures of the symmetric and unsymmetric diastereomers
(entries 10-12).
process proceeds with excellent diastereoselectivity in the establish-
ment of the cis-double bond geometry and relative stereochemistries
at up to four centers.
Diethylzinc reacts very slowly with benzaldehyde at 0 °C (1%
conversion in 8 h)9 and shows virtually no reaction with ketones
at this temperature. Combination of diethylzinc and cyclohexanone
at 0 °C followed by addition of the alkenylborane 2a, derived from
hydroboration of 1-hexyne, led to formation of a single diastereomer
(3a) in 77% yield (Scheme 2, Table 1, entry 1). The cis-olefin
geometry and the relationship between the stereogenic centers were
established by NMR spectroscopy and X-ray crystallography, as
outlined below. Analogous products were generated from cyclo-
hexanone using cyclopropylacetylene and phenylacetylene (entries
9
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10.1021/ja029449d CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
ditionally, use of 1-hexyne in Scheme 2 in the presence of 1,4-
diphenyl-1,3-butadiene gave 3a (no 3c was detected). This indicates
that the diene did not exchange with the proposed metallocyclo-
pentene intermediate (13, Scheme 3). Additionally, mixing 1,4-
diphenyl-1,3-butadiene, zinc powder, and cyclohexanone resulted
in no reaction.
In summary, we have generated an unusually reactive organozinc
species that smoothly adds to ketones and aldehydes. Using this
procedure, simple, readily available materials can be converted into
complex, densely functionalized meso-1,6-enediol products with
excellent control over diastereoselectivity. Desymmetrization of
meso compounds16 is proving to be a powerful tool in the synthesis
of complex natural products, because it simplifies synthesis and
provides a method for establishing stereochemistry at several centers
simultaneously.17-22 Efficient desymmetrization of these diols can
potentially lead to enantiopure material with two, four, or even more
stereocenters.16 On the basis of the observed reactivity and
selectivity, we propose that the intermediate in Scheme 3 is a
metallocyclopentene complex.
Figure 1. Structure of cis-enediol 6c.
When the reaction of vinyl borane 2c, diethylzinc, benzaldehyde,
and (-)-MIB was conducted under the conditions in Scheme 2,
the vinyl addition product was isolated in 67% yield with 91% ee.
Less than 10% of the reductive coupling product 8c was isolated.
In the absence of MIB, however, the coupling product 8c
predominated and was isolated in 47% yield, while the vinylation
product was isolated in 21% yield (based on aldehyde). The product
distribution is determined by the relative rates of the vinyl addition
vs reductive coupling (Scheme 3). The action of the catalyst derived
Acknowledgment. This paper is dedicated to the memory of
Professor Antonio Gonza´lez, a pioneer in natural product chemistry
in the Canary Islands, Spain. We thank Dr. Ivan Keresztes and
Prof. Don Berry for helpful discussions. This work was supported
by the NIH (GM58101).
Scheme 3. Proposed Reaction Mechanism
Supporting Information Available: Procedures, full characteriza-
tion of 1,6-diols, and details of the structure of 6c (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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