Bisoxazolidine-catalyzed enantioselective alkynylation of aldehydes

Article abstract of DOI:10.1021/ja062711o

A C₂-symmetric bisoxazolidine derived from aminoindanol has been successfully applied in the asymmetric alkynylation of aldehydes. The ligand is readily available, has a wide substrate scope, and catalyzes the formation of chiral propargylic alcohols with excellent yields and enantioselectivties. Copyright

Full text of DOI:10.1021/ja062711o

Published on Web 08/04/2006
Bisoxazolidine-Catalyzed Enantioselective Alkynylation of Aldehydes
Christian Wolf* and Shuanglong Liu
Department of Chemistry, Georgetown UniVersity, Washington, D.C. 20057
Received April 18, 2006; E-mail: cw27@georgetown.edu
Scheme 1. Synthesis and Single Crystal Structure of Ligand 1
The ever-increasing industrial and academic demand for enan-
tiopure chemicals has been accompanied by the development of
numerous asymmetric synthetic methods utilizing highly efficient
chiral catalysts and auxiliaries.1 Ideally, a practical asymmetric
catalyst is inexpensive, readily available in both enantiopure forms,
and provides high yields and enantioselectivities for a wide range
of substrates in various reactions. Among the many chiral catalysts
reported to date, a relatively small number derived from rigid C2-
symmetric ligands including BINOL, BOX, salen, DIOP, DUPHOS,
and TADDOL have proved to be exceptionally versatile and
effective. Despite the structural similarity to bisoxazoline ligands
which have been applied very successfully in catalytic asymmetric
Diels-Alder and ene reactions,2 Mukaiyama aldol reactions,3
cyclopropanations,4 and aziridinations,5 to the best of our knowledge
there have been no reports of asymmetric catalysts derived from
C2-symmetric bisoxazolidines. In analogy to chiral bisoxazolines
which are easily synthesized from readily available amino alcohols
and malonyl dichloride or derivatives thereof, we expected that
bisoxazolidines could be prepared in a single step by replacing the
diacyl halide with a 1,2-diketone. Herein, we provide the first
example of a chiral bisoxazolidine and describe its use for catalytic
asymmetric carbon-carbon bond formation.
tetrahydrofuran, diethyl ether, or dichloromethane were used as
solvent. We then varied the amount and ratio of both phenylacety-
lene and organozinc reagent and explored the use of diisopropyl-
and dimethylzinc. To our delight, we found that the latter effectively
impedes the competing alkylation reaction favoring alkynylation
when equimolar amounts of dimethylzinc and phenylacetylene were
employed in nonpolar solvents. Temperature and solvent composi-
tion proved to have a distinctive effect on yields and ee’s and were
carefully optimized. Best results were obtained using 10 mol % of
1 in a heptane-toluene mixture (5.6:1 v/v) at -4 °C (see Supporting
Information).
Having optimized the bisoxazolidine-catalyzed alkynylation of
benzaldehyde with phenylacetylene, we decided to screen a series
of aromatic and aliphatic aldehydes and acetylenes to evaluate the
scope of this reaction (Table 1). We were pleased to find that
alkynylation of electron-rich and electron-deficient aromatic alde-
hydes with phenylacetylene in the presence of 10 mol % of 1 gave
the corresponding propargylic alcohols in excellent yield and ee’s
(Table 1, entries 1-9). Importantly, our method is also suitable to
both linear and branched aliphatic alkynes (entries 10-14). For
example, alkynylation of benzaldehyde with cyclohexylacetylene
and 1-hexyne proceeded with 87-96% yield and 92% ee. Excellent
results were also observed with 1-ethynylcyclohexene and cyclo-
propylacetylene (entries 12 and 14) which compare favorably to
the 74-77% yield and 83-89% ee obtained with 10 mol % of an
In(III)/BINOL catalyst.11a Similarly, alkynylation of aliphatic
aldehydes gave the corresponding propargylic alcohols in high
yields and enantioselectivities (entries 15 and 16). The catalyst has
been recovered after asymmetric alkynylation of benzaldehyde with
phenylacetylene and successfully recycled (Table 1, entry 1).
Catalyst 1 was also employed in the asymmetric addition of
silylacetylenes to aldehydes under the same conditions (Figure 1).
The corresponding 3-silylpropargylic alcohols were obtained in up
to 88% yield and 99% ee. The efficient asymmetric synthesis of
these compounds is important because of the versatile use of
desilylated derivatives in alkylations and Sonogashira couplings.
Noteworthy, our procedure eliminates the need for commonly
used additives such as HMPA or titanium tetraisopropoxide while
premixing and stirring of the ligand and the organozinc reagent or
acetylene prior to addition of the aldehyde is not required. It should
be noted, however, that various other procedures avoid cumbersome
premixing and require only small amounts of inexpensive amine
additives.9a,11a,12
Employing (1R,2S)-cis-1-amino-2-indanol in the acid-promoted
reaction with 1,2-cyclohexanedione we obtained bisoxazolidine 1
in 90% yield and 99% de while other amino alcohols gave complex
isomeric mixtures (Scheme 1). However, 1 was produced with
excellent diastereoselectivity and exclusive formation of the (S,S)-
N,O-diketal was confirmed by crystallographic analysis.6 The ligand
possesses a C2-symmetric structure and an averaged separation of
2.35 Å between the nitrogen and oxygen atoms which should
facilitate bidentate binding to metal ions and organometallic
compounds. We therefore envisioned that 1 is a useful Lewis basic
catalyst for asymmetric reactions with organozinc reagents.
Since chiral secondary alcohols have been identified as versatile
building blocks for asymmetric synthesis,7 the enantioselective
addition of organozinc reagents to aldehydes has emerged as one
of the most important carbon-carbon bond forming reactions. To
date, asymmetric alkynylation of aldehydes has been realized using
stoichiometric amounts of chiral ligands8 and several catalytic
procedures have been reported.9 Many of these protocols focus on
the addition of phenylacetylene to aromatic aldehydes,10 while few
address the need to utilize nonaromatic substrates.11 It is therefore
desirable to further extend this reaction to both aliphatic aldehydes
and aliphatic alkynes. General drawbacks of currently existing
methods include the need for freshly distilled solvents and purified
reagents in addition to laborious and time-consuming procedures
requiring stepwise premixing of chiral ligand, organozinc reagent,
and acetylene in a certain order and stirring for extensive times, in
some cases several hours, prior to the addition of the aldehyde.
Initial studies using various amounts of diethylzinc, phenylacety-
lene, and benzaldehyde in the presence of 10 mol % of 1 revealed
that superior results can be obtained with nonpolar solvents such
as hexanes and toluene while both yields and ee’s dropped when
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J. AM. CHEM. SOC. 2006, 128, 10996-10997
10.1021/ja062711o CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Oxazolidine-Catalyzed Alkynylation
Table 1. Bisoxazolidine-Catalyzed Asymmetric Alkynylation of
Aldehydes
(1R,2S)-cis-1-amino-2-indanol-derived oxazolidine 2 using cyclo-
hexanone instead of cyclohexanedione and tested its catalytic
performance under the same reaction conditions. Alkynylation of
benzaldehyde with phenylacetylene in the presence of 10 mol %
of 2 gave the corresponding alcohol in only 76% yield and 17% ee
(Scheme 2).
In conclusion, we have prepared the first bisoxazolidine ligand
and showed its usefulness for asymmetric catalysis. Ligand 1 was
synthesized in high yields in a single step from inexpensive amino-
indanol which is available in both enantiomeric forms. The bisoxa-
zolidine ligand was successfully applied in the catalytic enantiose-
lective alkynylation of a range of aromatic and aliphatic aldehydes
generating chiral propargylic alcohols in high yields and enantio-
selectivities. The rigid, C2-symmetric structure and the simplicity
of the preparation of enantiopure 1 make this an attractive new chiral
ligand that may find multiple applications in asymmetric catalysis.
Supporting Information Available: Experimental procedures and
full characterization of 1 and all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Although monooxazolidines have been used for alkylation and
alkynylation of aldehydes,13 the C2-symmetry of bisoxazolidine 1
provides superior results and appears to be crucial for both catalytic
activity and asymmetric induction. For comparison, we prepared
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