Organic Letters
Letter
Scheme3. (A)Experiment Determiningtheeebeforeandafter
the Reaction; (B) Experiment to Test for Product
Racemization with Exogenous Product Added
ACKNOWLEDGMENTS
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We thank the National Institutes of Health (NIH) for financial
support (Award Number GM58160). We thank Aldrich for a gift
of t-BuBrettPhos (L1). We thank Dr. Yiming Wang (MIT) and
Dr. Michael Pirnot (MIT) for assistance in the preparation of this
manuscript. We thank Anni Zhang (MIT), Dr. Tom Kinzel
(MIT), Dr. Aaron C. Sather (MIT), and Dr. Meredeth A.
McGowan (MIT) for providing aryl triflate starting materials for
the project. The Varian 500 MHz instrument used for portions of
this work was supported by the National Science Foundation
(Grant No. CHE 9808061). The content of this manuscript is
solely the responsibility of the authors and does not necessarily
represent the official views of the NIH.
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does not occur to a significant extent. In an additional experiment,
theN-arylationofphenylalaninetert-butylester5awasconducted
under the optimized reaction conditions, and the yield and
enantiomeric excess of the product 6a were monitored as a
function of reaction time (see SI, Table S5). The enantiomeric
excess of 6a decreased as a function of time, which is consistent
with our understanding that racemization in this reaction is
mainly due to racemization of the starting material 5a and not of
the product.
In summary, we have developed a general method for the N-
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to the development of this method was the use of (1) DOE
analysis for reaction optimization and (2) t-BuBrettPhos Pd G3
(P1) and G4 (P3) precatalysts, which enabled the use of mild
reaction conditions and resulted in minimal racemization of the
amino acid ester. Given the importance of the N-aryl amino acid
core structure in medicinal agents, we anticipate the adoption of
this protocol in diverse contexts as a practical and improved
method for their synthesis.
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ASSOCIATED CONTENT
* Supporting Information
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Experimental procedures along with experimental and
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AUTHOR INFORMATION
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Corresponding Author
Notes
Theauthorsdeclarethefollowingcompetingfinancialinterest(s):
MIThaspatentsonsomeoftheligandsandprecatalystsdescribed
in this work from which S.L.B. as well as former or current co-
workers receive royalty payments.
D
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