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DOI: 10.1055/s-0031-1289255
Synthesis of a γ-Secretase Modulator
Contributor(s):Philip KocienskiUniversity of California, Santa Barbara, USA
Highly Enantioselective Direct Alkylation of Arylacetic Acids with Chiral Lithium Amides as Traceless Auxiliaries
J. Am. Chem. Soc. 2011, 133: 11936-11939
Publication History
Publication Date:
19 October 2011 (online)
Key words
γ-secretase modulators - asymmetric alkylation - enediolates - chiral lithium amide bases - arylacetic acids
Significance
The synthesis of the γ-secretase modulator depicted illustrates an efficient enantioselective alkylation of enediolates derived from arylacetic acids using the chiral lithium amide base H as a stereodirecting agent. The chiral base is required in stoichiometric amounts, but it is recoverable and easily prepared in two steps from styrene oxide (M. J. Frizzle et al. Org. Process Res. Dev. 2007, 11, 215).
Comment
The scope of the asymmetric alkylation was established using 24 aryl- and heteroarylacetic acids and 12 alkylating agents (36 examples in total) with yields typically exceeding 70% (6 exceptions) and ee values typically exceeding 90% (5 exceptions). Under the standard conditions outlined above, simple alkanoic acids did not undergo highly enantioselective alkylation.