CATALYTIC ASYMMETRIC-SYNTHESIS OF QUATERNARY CARBON CENTERS - EXPLORATORY STUDIES OF INTRAMOLECULAR HECK REACTIONS OF (Z)-ALPHA,BETA-UNSATURATED ANILIDES AND MECHANISTIC INVESTIGATIONS OF ASYMMETRIC HECK REACTIONS PROCEEDING VIA NEUTRAL INTERMEDIATES

Intramolecular Heck reactions of seven (Z)-alpha,beta-unsaturated 2-io doanilides catalyzed by Pd-BINAP were surveyed using two reaction cond itions: (1) silver-promoted cyclizations in the presence of 2 equiv of Ag3PO4 and (2) base-promoted cyclizations in the presence of 4 equiv of 1,2,2,6,6-pentamethylpiperidine (PMP). A comparison of these result s with the outcome of the corresponding intramolecular Heck reactions of the E stereoisomers leads to the following conclusions: (1) (E)- an d (Z)-alpha,beta-unsaturated 2-iodoanilides give opposite enantiomers of the Heck product when Ag3PO4 is the HT. acceptor (cationic pathway) ; the absolute configuration of the product is independent of alkene g eometry when the KI acceptor is PMP (neutral pathway). (2) When the 2- substituent is Me or prim-alkyl, stereoinduction is optimal in PMP-pro moted insertions of Z substrates which occur with ee's as high as 97%. (3) When the 2-substituent is large, stereoinduction is optimal in in sertions of E substrates carried out in the presence of Ag3PO4. (4) Co ntributions from the P-alkene substituent are minor. The neutral Heck reaction manifold can be entered from triflate substrates by carrying out the cyclization in the presence of added halide salts. The ability to vary both the alkene geometry and the Heck reaction pathway allows chiral 3,3-disubstituted-2-oxindoles having a wide range of substitue nts at the quaternary carbon (Me, prim-alkyl, tert-alkyl, and aryl) to be prepared with useful levels of enantioselection (72-97% ee). A num ber of studies were carried out aimed at clarifying the mechanism of t he neutral Heck reaction pathway. Key results are the following: (1) C hiral amplification studies show that the catalyst is monomeric Pd-BIN AP. (2) Investigations of monophosphine analogues of BINAP, which were designed to mimic a partially dissociated BINAP chelate, support the conclusion that BINAP is chelated during the enantioselective step. (3 ) Enantioselectivity is insensitive to solvent polarity. From these da ta, we propose that the stereochemistry determining step of the neutra l pathway occurs during the process in which iodide is displaced by th e tethered alkene (Figure 2, 41 --> 47 --> 45). In light of the variet y of pentacoordinate intermediates that could be involved, it is prema ture to advance a model to rationalize stereoinduction in asymmetric H eck reactions proceeding by the neutral pathway. Nonetheless, the find ing that the enantioselective step of asymmetric Heck reactions taking place by the neutral pathway involves five-coordinate intermediates s ignificantly broadens the vista for design of asymmetric ligands for t his and related reactions.