Enantioselective synthesis of propargylic alcohols by addition of enantiopure cyclopentadienyldialkoxyallyltitanium complexes to acetylenic aldehydes

Article abstract of DOI:10.1016/S0040-4039(00)01597-5

The enantioselective synthesis of propargylic alcohols was achieved by enantioselective allyltitanation of acetylenic aldehydes. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01597-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8877–8880
Enantioselective synthesis of propargylic alcohols by
addition of enantiopure
cyclopentadienyldialkoxyallyltitanium complexes to
acetylenic aldehydes
Samir BouzBouz,a,* Fabienne Pradaux,a Janine Cossy,a,*
Clotilde Ferroudb and Annie Falguie`resb
aLaboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
bLaboratoire de Chimie Organique associe´ au CNRS, CNAM, 292 rue Saint Martin, 75141 Paris Cedex 03, France
Received 1 August 2000; accepted 15 September 2000
Abstract
The enantioselective synthesis of propargylic alcohols was achieved by enantioselective allyltitanation of
acetylenic aldehydes. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: allyltitanation; acetylenic aldehydes; propargylic alcohols.
The production of enantiomerically enriched intermediates from achiral starting materials by
means of chiral reagents and catalysts has been of increasing interest in recent years.1 One of the
most widely studied goals in this field has been an efficient synthesis of enantioenriched
carbinols. Recently, we became interested in the synthesis of chiral secondary propargylic
alcohols as these compounds are useful building blocks for the synthesis of biologically2 and
structurally interesting compounds.3 The methods that have been used for the synthesis of such
alcohols involve the enantioselective alkynylation of aldehydes.4 Stoichiometric reduction of
acetylenic ketones with chirally modified metal hydrides5 as well as catalytic asymmetric
reduction6 or enzymatic reduction7 of acetylenic ketones have also been employed to produce
these alcohols. Other methods such as cleavage of chiral acetylenic acetals,8 enantioselective
carbonyl-ene reactions with glyoxylates,9 and enantioselective aldol addition reaction to a,b-
ynals,10 in the presence of a chiral catalyst have also found applications.
Additions of chiral allylboranes to a,b-acetylenic aldehydes11 is one of the more general routes
to enantioenriched propargylic alcohols. Here, we report a related approach which utilizes the
* Corresponding authors. Fax: 33-1-40-79-46-60; e-mail: janine.cossy@espci.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01597-5

8878
cyclopentadienyldialkoxyallyltitanium complexes (R,R)-I or (S,S)-II12 in such additions. These
reagents exhibit remarkably high facial discrimination for such aldehydes despite the relatively
small steric requirements of the alkynyl group.
The asymmetric allyltitanation proceeds under neutral conditions at −78°C. Aldehydes 113
(1 mmol, 1 equiv.) were added to an etheral solution of the cyclopentadienyldialkoxyallyltita-
nium complex (1.1 equiv.). After 3 h, the reaction mixture was quenched and the propargylic
alcohols 2 were isolated in moderately high yield and excellent enantiomeric excess. For each
propargylic alcohol, the enantiomeric purity was determined by chiral HPLC.14 The results are
reported in Table 1.
Table 1
Enantioselective allyltitanation of acetylenic aldehydes
Entry
Aldehyde 1
Reagent
Product 2
Ee (%)14
d
R
Yield (%)
[h]D
Configuration
a
b
c
d
e
f
g
h
t-Bu(CH3)2Siꢀ
t-Bu(CH3)2Siꢀ
Phꢀ
CH3ꢀ(CH2)6ꢀ
CH3ꢀ(CH2)6ꢀ
TrOꢀ(CH2)2ꢀ
THPOꢀCH2ꢀ
o-AcOꢀC6H4ꢀ
(R,R)-I
(S,S)-II
(R,R)-I
(R,R)-I
(S,S)-II
(R,R)-I
(R,R)-I
(R,R)-I
53
64
70
71
55
70
60
61
−28
+27
−11
−19
+12
−5
96
95
93
98
95
93
95
95
(S)a
(R)b
(S)c
(S)a
(R)a
(S)a
(S)a
(S)a
−18
−23
1
a Determined by H NMR analysis of the O-methylmandelates.
b Determined by comparison of the [h]D of (−)-2a and (+)-2b.
c Determined by chemical correlation.
d The optical rotations for compounds 2a–h were recorded in CHCl3 at 25°C, with a similar concentration (c=1).

8879
When the propargylic aldehyde 1a was treated with the (R,R)-I complex, alcohol (−)-2a was
isolated in 53% yield (ee=96%). The absolute configuration was determined by analysis of the
1H NMR spectra of the corresponding O-methylmandelates.15 The allylic protons of the
(R)-O-methylmandelate appear at higher field than those of the (S)-O-methylmandelate (0.3
ppm) consistent with the (S) configuration for the propargylic alcohol. In a similar manner,
when 1c, 1d, 1f, 1g, and 1h were treated with the (R,R)-I complex, the corresponding
propargylic alcohols were isolated in 60–70% yield with high enantioselectivity (ee>93%).
In each case, the absolute configuration was determined as before by analysis of the
corresponding O-methylmandelates except for alcohol (−)-2c. For this compound, the determin-
ation of the absolute configuration was achieved by reduction of the propargylic alcohol (−)-2c
with LiAlH4 in THF and the vinylcarbinol (+)-3 was obtained in 90% yield ([h]D=+18, c 2,
ether; lit.16: compound (−)-3, [h]D=−19.3, c 1.33, ether). This chemical correlation allowed us to
attribute the (S) configuration to compound (−)-2c.
Addition of the (S,S)-I complex to aldehyde 1b led to alcohol (+)-2b in 60% yield (ee=95%).
By comparison of the [h]D of (−)-2a ([h]D=−28) and (+)-2b ([h]D=+27), we can assign the (R)
configuration to (+)-2b. When aldehyde 1e was treated with (S,S)-II, the propargylic alcohol
(+)-2e with the (R) configuration (determined from the O-methylmandelate derivatives),15 was
obtained in 55% yield.
Allyltitanation of a,b-acetylenic aldehydes with the (R,R)-I and (S,S)-II complexes proceeds
with consistent and predictable stereochemistry to give propargylic alcohols of high optical
purity (93–98%). The use of this reaction for the synthesis of biologically active compounds is
in progress and will be reported in due course.
Acknowledgements
The authors are indebted to Dr R. O. Duthaler for a generous gift of CpTiCl3.
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