C O M M U N I C A T I O N S
Table 3. Enantioselective Azidation/Cycloaddition Sequence
the asymmetric azidations reported herein, this improvement enabled
the development of a two-step sequence for the production of
optically enriched triazoles relying on 1,3-dipolar cycloadditions
of the azidation products. Asymmetric transformations that set up
further complexity-generating transformations have been shown to
be of value in both target-oriented and diversity-oriented synthetic
contexts. Studies along these lines are underway in our laboratory.
Acknowledgment. This research is supported by the NIH (GM-
57595). We are also grateful to the NSF (CHE-9874963), DuPont,
Eli Lilly, Glaxo-SmithKline, and Merck for research support. D.J.G.
would like to thank the Organic Division of the American Chemical
Society and the Bristol-Myers Squibb Foundation for a graduate
fellowship. S.J.M. is a Fellow of the Alfred P. Sloan Foundation,
a Cottrell Scholar of Research Corporation, and a Camille Dreyfus
Teacher-Scholar.
Supporting Information Available: Experimental procedures and
product characterization for all new compounds synthesized (PDF). This
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a Combined yield for two steps after silica gel chromatography. Ratio
in parentheses refers to ratio of regioisomers or diastereomers. b Determined
by chiral HPLC. See Supporting Information for details. Enantioselectivities
before and after the cycloaddition step were found to be (2% ee. c Heated
in the presence of the corresponding alkyne. See Supporting Information
for details. d Heated in the presence of N-methylmaleimide. See Supporting
Information for details. e The reported ee is for the azide precursor to 19.
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130 °C for 48 h then affords optically enriched triazole 19 in 76%
overall (entry 1). Similarly, methyl-substituted substrate 20 is
converted to triazole 21 in good overall yield and ee (86% ee, 83%
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converted by the same protocol to a number of cycloadducts with
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yields triazole 22 in 73% yield (92% ee, entry 3). Use of methyl
propiolate affords adduct 23 in 85% yield as a 4:1 mixture of
regioisomers (92% ee, entry 4). Cycloaddition with ethyl butynoate
yields adduct 24 in 78% overall yield as a 2:1 mixture of
regioisomers, again with no loss of ee (entry 5). Condensation with
bis(acetoxy)-2-butyne-diol produces triazole 25 in 77% overall yield
(92% ee, entry 6). Finally, cycloaddition with N-methylmaleimide
produces adduct 26 in 79% yield as a 1:1 mixture of diastereomers,
but with no loss of enantioselectivity (entry 7).
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The results presented herein indicate that introduction of sub-
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