Efficient catalytic asymmetric alkylations. 1. Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysis

Abstract

Efficient asymmetric alkylation reactions have been a longsought goal in organic synthesis. The recent literature1 reports elegant three-step sequences to achieve high enantiomeric excesses (ee's); however, these procedures are complex and require the use of stoichiometric quantities of chiral auxiliaries. Chiral phasetransfer-mediated alkylations offer a potentially simple, one-step solution to this problem. The first reports2 of such using cyclic i8-keto esters as substrates and ephedrinium halides as catalysts claimed ee's of only 15%. These results have subsequently been disputed.3

Direct and enantioselective α-allylation of ketones via singly occupied molecular orbital (SOMO) catalysis

“…Seminal work from Doyle and Jacobsen (5), Trost and co-workers (6-8), Stoltz and co-workers (9, 10), Braun and co-workers (11,12), and Hartwig and co-workers (13, 14) has introduced valuable previously undescribed technologies for (i) the enantioselective alkylation of preformed or in situ generated metal enolates (5,6,(11)(12)(13)(14)(15)(16)(17) and (ii) the asymmetric and decarboxylative conversion of allyl keto carbonates to α-allylated ketones (7-10). With these key advances in place, a goal now for asymmetric catalysis has become the direct α-allylation of simple ketone substrates (18,19), an elusive yet potentially powerful bond construction (Scheme 1).…”

Organocatalysis in Total Synthesis

“…Company in the mid-1980s [126]. The pioneering explored methodology was the methylation reaction of a cyclic ketone 23 in the presence of chiral ammonium salt G to create a chiral quaternary center.…”

Development of P-Spiro Chiral Aminophosphonium Salts as a New Class of Versatile Organic Molecular Catalyst

“…To examine this hypothesis, we conducted the reaction of a phenylalanine derived azlactone 11a with N tosyl imine 12a in the presence of a series of chiral aminophosphonium carboxylates (M,S) 2a (RCO 2 H) 2 (2 mol%), which were readily prepared from (M,S) 2a HCl through ion exchange, in THF at 40 (eq. 2 ] led to a substantial increase in the rate. This observation strongly suggests that the expected deprotonation protonation sequence infl uences the reaction.…”

“…The fi rst example of successful asymmetric catalysis of a chiral quaternary onium salt was reported in 1984: a cinchona alkaloid derived ammonium salt was used as a phase transfer catalyst for the enantioselective alkylation of an enolate under biphasic conditions. 2 Since then, the main interests in this fi eld of research have been the development of chiral quaternary ammonium salts and their catalyses. 3 A considerable number of effective and practical catalyst systems have been introduced and applied to a large variety of useful transformations.…”