process when compared against the typical organozinc
additions,2 we have embarked on a more extensive study of
this reaction. We document herein a study of the reaction
conducted with reagent grade toluene (84-1000 ppm H2O)
that provides adducts for a wide range of substrates in high
yields and enantioselectivities (Table 1).3 In general, given
the absence of CdO addition processes involving putative
organozinc reagents that can be carried out without recourse
to conditions that rigorously exclude moisture and oxygen,
the results we describe are unique and provide a benchmark
for the further development of related chemical processes.
Each of the reactions that form the basis of this study was
carried out in ACS reagent grade toluene whose water
content was quantified using Karl Fischer titration. Although
entirely unnecessary, the reaction vessel and stirbar were
oven-dried prior to use, to properly control the amount of
moisture in the system. As shown in Table 1, the addition
reactions may be conducted on a wide range of substrates
including aromatic and unsaturated aldehydes. Additionally,
the structure of the terminal acetylene can be considerably
varied leading to numerous adducts; thus, trimethyl silyl-,
alkyl-, and aryl-acetylenes participate successfully in the
reaction. The enantioselectivity as well as the yield of the
adducts tabulated herein are comparable to those we have
previously reported when the reaction had been conducted
with rigorous exclusion of moisture and oxygen.
Table 1. Optically Active Propargylic Alcohols from Scheme
1a
We hypothesize that the unique aspects of this system vis-
a´-vis the typical dialkyl and dialkynyl-zinc reagents stems
from the fact that the process involves the intermediacy of
a monoalkynylzinc species. As a result of the electron-
deficient character of such a monosubstituted organozinc,
the C-Zn bond is considerably kinetically less labile and
thus seemingly compatible with limited amount of moisture
and oxygen.
We have documented an extensive study of enantioselec-
tive addition reactions to aldehydes by terminal acetylenes
utilizing reagent grade solvent (84-1000 ppm H2O as
measured by Karl Fischer titration) without recourse to inert
atmosphere. This aspect of the reaction provides for a process
that is convenient to execute. The identification of additional
C-C bond forming reactions that lead to useful, optically
active building blocks for asymmetric synthesis remains an
important goal of our program. Mechanistic and preparative
studies are underway and will be reported as results become
available.
a The addition reactions were conducted following the general protocol
previously reported (see ref 1b), except that reagent grade toluene was used
directly from a bottle and during the reaction setup and course no measures
were taken to exclude ambient atmosphere. General procedure: 1.1 equiv
of Zn(OTf)2, 1.2 equiv of (+)-N-methyl ephedrine, and 1.2 equiv of Et3N
in toluene (0.3 M) at 23 °C. The enantiomeric excess was determined by
HPLC as described previously. In all cases, the product chromatograms
were compared against a known racemic mixture. Absolute configuration
of the products was established by correlation with known compounds
previously reported or through independent syntheses utilizing known
methods.
Acknowledgment. We thank the ETH for an internal
research grant.
OL026282K
(2) For reviews, see: (a) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757.
(b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833.
(3) In all cases, product yields are reported for analytically pure material,
that has been subjected to the usual battery of methods for characterization.
2606
Org. Lett., Vol. 4, No. 15, 2002
Boyall, Dean
