Preparation of chiral propargylic alcohols from α,β-unsaturated esters

Article abstract of DOI:10.1016/S0040-4039(02)01968-8

A series of chiral propargylic alcohols with high enantiomeric excess was prepared by asymmetric dihydroxylation of α,β-unsaturated esters, conversion of the diols to 4-(chloromethyl)-1,3-dioxolane intermediates, and base-induced elimination.

Full text of DOI:10.1016/S0040-4039(02)01968-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8043–8045
Preparation of chiral propargylic alcohols from a,b-unsaturated
esters
Jiong Chun, Hoe-Sup Byun and Robert Bittman*
Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, NY 11367-1597,
USA
Received 14 August 2002; revised 6 September 2002; accepted 12 September 2002
Abstract—A series of chiral propargylic alcohols with high enantiomeric excess was prepared by asymmetric dihydroxylation of
a,b-unsaturated esters, conversion of the diols to 4-(chloromethyl)-1,3-dioxolane intermediates, and base-induced elimination.
© 2002 Elsevier Science Ltd. All rights reserved.
Chiral propargylic alcohols are widely used synthons
for many natural products.1 Among the methods for
preparing chiral propargylic alcohols are addition of
organometallic reagents to a,b-acetylenic aldehydes in
the presence of chiral ligands,2 enantioselective aldol
additions to a,b-ynals,3 asymmetric reduction of a,b-
ynones,4 enzymatic resolution,5 base-mediated double
elimination of substrates [1-chloro-2,3-epoxy6 and 4-
(chloromethyl)-1,3-dioxolane7], elimination of chiral
vinyl sulfoxides,8 alkynylation of aldehydes catalyzed
by a chiral ligand,9 and reductive cleavage of a,b-
alkynyl acetals.10 However, some of these methods
provide low enantiomeric excess (ee), especially for the
synthesis of long-chain propargylic alcohols. For exam-
ple, Alpine-Borane reduction of a long-chain ynone
gave the E analog of 1a in only 60–65% ee.11 Further-
more, when we used ynone reduction (LiAlH4 in the
presence of Darvon alcohol4a or (R)-Alpine-Borane4b)
to prepare 1c (an important synthon for ceramide
synthesis), an unsatisfactory optical purity (<80% ee)
was obtained. Since it is well known that a,b-unsatu-
rated esters are excellent substrates for the asymmetric
dihydroxylation (AD) reaction (giving high yield and
very high ee),12 we have developed a new method for
the preparation of 4-(chloromethyl)-1,3-dioxolane inter-
mediates from a,b-unsaturated esters. These dioxolane
intermediates are easily converted to chiral propargylic
alcohols via double elimination. The configuration at
C-3 of the product is established during the AD reac-
tion and remains intact in this reaction sequence. We
demonstrate here the utility of this method by prepar-
ing a series of representative propargylic alcohols 1a–e
(Scheme 1) in high chiral purity.
The Horner–Wadsworth–Emmons (HWE) reaction of
aldehydes with a phosphonate reagent provides a,b-
unsaturated esters.13 Compounds 2a,14 2c,15 and 2d
were prepared via HWE reaction of the aldehydes with
(i-PrO)2P(O)CH2CO2Et. Compound 2e was synthesized
as previously described.16
Compound 1a is the Z analog of eicos-(4E)-en-1-yn-3-
ol. The E isomer, which was isolated from a marine
sponge, has been synthesized;11,17 it exhibits immuno-
suppressive and antitumor activities.18 Analog 1a,
which may be useful for establishing structure–function
relationships, was obtained in geometrically pure form
by the reaction sequence illustrated in Scheme 2. The
AD reaction of a,b-unsaturated esters 2b–e provided
diols 3b–e in high yield (ꢀ90%). However, diol 3a was
obtained in low yield under the normal AD reaction
conditions. The yield of 3a was markedly improved (to
80%) by supplementation of the reaction mixture with
additional osmium reagent (K2OsO4·2H2O) and chiral
ligand [(DHQ)2-PHAL]. After conversion of diol 3a to
acetonide ester 4a, reduction with DIBAL-H provided
alcohol 5a in 92% yield (two steps from 3a). Reduction
of 5a with Lindlar catalyst in MeOH provided cis
compound 6a, which was converted to chloride 7a
(NCS, Ph3P).19 (Z)-Alcohol 1a was obtained by treat-
ment of 7a with n-BuLi in the presence of HMPA7
(81% yield, 96% ee).20 Application of the method used
to prepare alcohol 1a also afforded 1b–e with high ee
(Scheme 1).21
Keywords: asymmetric dihydroxylation; propargyl secondary alco-
hols.
* Corresponding author. Tel.: (718) 997-3279; fax: (718) 997-3349;
e-mail: robert bittman@qc.edu
–
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01968-8

8044
J. Chun et al. / Tetrahedron Letters 43 (2002) 8043–8045
Scheme 1. Outline of the preparation of chiral alcohol 1 from ester 2.
Scheme 2. Representative example of the conversion of ester 2a to alcohol 1. Reagents and conditions: (a) AD-mix-a (more
K2OsO4·2H2O and (DHQ)2-PHAL were added), MeSO2NH2, t-BuOH/H2O 1:1, rt; (b) Me2C(OMe)2, p-TsOH, CH2Cl2, rt; (c)
DIBAL-H, THF, 0°C–rt; (d) H2, Pd-CaCO3 (cat.), MeOH, rt; (e) NCS, Ph3P, CH2Cl2, 0°C–rt; (f) n-BuLi, HMPA, THF,
−42°C–rt.
In summary, we have developed an efficient method
that affords both R and S propargylic alcohols in high
ee. AD reaction of an a,b-unsaturated ester with either
AD-mix a or b, followed by acetonide formation,
DIBAL-H reduction, conversion of the resultant pri-
mary alcohol to 4-(chloromethyl)-1,3-dioxolane, and
elimination with n-BuLi in the presence of HMPA gave
chiral propargylic alcohols 1a–e in high ee.
2. See, for example: BouzBouz, S.; Pradaux, F.; Cossy, J.;
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1990, 937–943; (b) Singer, R. A.; Shepard, M. S.; Car-
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Acknowledgements
This work was supported by National Institutes of
Health Grant HL 16660.
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J. Chun et al. / Tetrahedron Letters 43 (2002) 8043–8045
8045
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