Highly enantio- and diasfereoselective one-pot synthesis of acyclic epoxy alcohols with three contiguous stereocenters

Article abstract of DOI:10.1021/ja046750g

Two highly enantio- and diastereoselective one-pot procedures for the synthesis of epoxy alcohols with up to three contiguous stereocenters are reported. Route one involves asymmetric addition of an alkylzinc reagent to an enal followed by diastereoselect

Full text of DOI:10.1021/ja046750g

Published on Web 10/05/2004
Highly Enantio- and Diastereoselective One-Pot Synthesis of Acyclic Epoxy
Alcohols with Three Contiguous Stereocenters
Alice E. Lurain, Aaron Maestri, Ann Rowley Kelly, Patrick J. Carroll, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received June 2, 2004; E-mail: pwalsh@sas.upenn.edu
Scheme 1. Tandem Asymmetric Addition/Diastereoselective
Epoxidations
Two of the most significant developments in the history of
asymmetric catalysis were the introduction of the Sharpless
asymmetric epoxidation of prochiral allylic alcohols1-3 and the
application of this reaction to the kinetic resolution of racemic allylic
alcohols (eqs 1 and 2).4 The products of these processes, enantio-
enriched epoxy alcohols, are among the most valuable and versatile
intermediates in organic synthesis,5 because they readily undergo
regioselective ring-opening reactions.6 As a result, the Sharpless
asymmetric epoxidation has found extensive utility in the synthesis
of natural products.3
of the crude products and are shown in Table 1, along with the
combined yields of both diastereomers after chromatography.
The rate of addition of dimethylzinc to aldehydes with MIB and
related amino alcohol-based catalysts is slow at room temperature.9
We therefore employed bis(sulfonamide) ligand 210,11 in the methyl
addition reactions at room temperature (Scheme 1, Table 1)10
followed by exposure to dioxygen.11
The levels of enantioselectivity in the asymmetric addition of a
variety of alkyl groups were very high (85-99%, Table 1).
Moderate to excellent dr’s were found and, in most cases, were
better than those we observed on epoxidation of the isolated allylic
alcohols with Ti(O-iPr)4/TBHP, VO(acac)2/TBHP or m-CPBA.
Allylic alkoxide intermediates possessing A1,2-strain in one of the
diastereomeric transition states afford mainly the erythro products
(entries 1-4 and 7-9), while those with A1,3-strain primarly furnish
the threo diastereomers (entries 5, 6, and 10-12).12 The stereo-
chemistry of the product in entry 5 was confirmed by X-ray
crystallography (Supporting Information).
Despite the enduring success of the Sharpless kinetic resolution,
there remain significant limitations. If the desired product is the
epoxy alcohol, the kinetic resolution must be quenched at low
conversion to ensure product of high ee.6 Alternatively, the resolved
allylic alcohol is often isolated and epoxidized in a separate step.
Of course, an inherent problem with kinetic resolutions is that the
maximum yield is 50%.
In this communication, we disclose a method to address these
limitations. We have developed a highly enantio- and diastereo-
selective method to synthesize acyclic epoxy alcohols with three
contiguous stereocenters in good to excellent yields. This protocol
entails an enantioselective C-C bond-forming reaction to generate
allylic alkoxides that are subsequently epoxidized diastereoselec-
tively via a directed epoxidation using dioxygen.7 In this process,
three new bonds are formed, allowing efficient assembly of complex
chiral building blocks.
The second route to epoxy alcohols entailed the addition of
divinylzinc reagents 3 and 4 to aliphatic and aromatic aldehydes,
as illustrated in eq 3. The divinylzinc reagents are easily prepared
Our first route is based on the highly enantioselective alkyl
addition to R,â-unsaturated aldehydes promoted by a catalyst
generated from Nugent’s (-)-MIB8 (1, Scheme 1). The ee’s of the
allylic alcohols formed on quenching the reaction with aqueous
NH4Cl are recorded in Table 1. In the tandem addition/epoxidation
procedure, the newly formed allylic alkoxide is exposed to 1 atm
of dioxygen at 0 °C (30 min). It is then cooled to -20 °C, and
titanium tetraisopropoxide (20 mol %) is added. Epoxidation is
complete in 18 h at this temperature. We believe the oxidant is
formed upon insertion of dioxygen into a Zn-C bond to generate
the peroxy species R-Zn-OOR. Subsequent transmetalation to the
titanium allylic alkoxide intermediate is followed by directed
and purified by sublimation.13 To conserve the divinylzinc reagents,
3.1 equiv of diethylzinc was added before the aldehyde. This likely
results in formation of ethyl vinyl zinc species, in which the more
reactive vinyl group is preferentially transferred. As displayed in
Table 2 (entries 1-5), the enantio- and diastereoselectivities with
1
epoxidation. After workup, the dr’s were determined by H NMR
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J. AM. CHEM. SOC. 2004, 126, 13608-13609
10.1021/ja046750g CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis of Epoxy Alcohols from Enals
Table 2. Synthesis of Epoxy Alcohols from Divinylzinc Reagents
a Stereochemistry indicated corresponds to that of the major diastereomer.
b Determined by chiral HPLC or GC analysis. c Determined by 1H NMR
analysis.
a Stereochemistry indicated corresponds to that of the major diastereomer.
b Determined by chiral HPLC or GC analysis. c Determined by 1H NMR
analysis.
Supporting Information Available: A cif file containg crystal-
lographic data for the product in entry 5 of Table 1, text giving
procedures and full characterization of new compounds and conditions
for determining the enantiomeric excess for the compounds, and figures
giving 1H and 13C{1H} NMR spectra for the compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
divinylzinc reagent 3 are excellent, and the yields are high. Like-
wise, reaction of the 2,2′-dimethyl divinylzinc reagent 4 resulted in
very high enantio- and diastereoselectivities, except with unbranched
aldehydes, where the enantioselectivities were around 80%.
In summary, two expedient routes for the synthesis of acyclic
epoxy alcohols containing up to three stereogenic centers have been
presented. They involve initial asymmetric C-C bond formation
followed by diastereoselective epoxidation. The advantages of these
methods are (1) that they circumvent the need to prepare and isolate
either racemic or enantioenriched allylic alcohols, (2) the oxidant
is generated under the reaction conditions from organozinc reagents
and dioxygen, (3) the enantio- and diastereoselectivities are very
high for almost all classes of substrates, and (4) the asymmetric
C-C bond-forming step can be catalyzed by literally hundreds of
catalysts.14 Like the epoxy alcohols prepared by the Sharpless
asymmetric epoxidation, we anticipate that the epoxy alcohols
outlined here will find widespread utility in enantioselective
synthesis.
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Acknowledgment. This work was supported by the NIH
(GM58101) and the NSF (CHE-0315913). We are also grateful to
Azko Nobel for the gift of alkyl zinc reagents. This work is
dedicated to Prof. Lars Hellberg (SDSU and Instituto Tecnolo´gico
de Tijuana) on the occasion of his 75th birthday.
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