Catalytic Asymmetric Synthesis of Quaternary Carbon Centers. Exploratory Studies of Intramolecular Heck Reactions of (Z)-,
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- 作者：Atsuyuki Ashimori ; Benoit Bachand ; Michael A. Calter ; Steven P. Govek ; Larry E. Overman ; and Daniel J. Poon
- 刊名：Journal of the American Chemical Society
- 出版年：1998
- 出版时间：July 8, 1998
- 年：1998
- 卷：120
- 期：26
- 页码：6488 - 6499
- 全文大小：319K
- 年卷期：v.120,no.26(July 8, 1998)
- ISSN：1520-5126
文摘
Intramolecular Heck reactions of seven(Z)-
fchars/alpha.gif" BORDER=0>,fchars/beta2.gif" BORDER=0 ALIGN="middle">-unsaturated 2-iodoanilides catalyzed byPd-BINAPwere surveyed using two reaction conditions: (1) silver-promotedcyclizations in the presence of 2 equiv ofAg3PO4 and (2) base-promoted cyclizationsin the presence of 4 equiv of1,2,2,6,6-pentamethylpiperidine(PMP). A comparison of these results with the outcome of thecorresponding intramolecular Heck reactionsof the E stereoisomers leads to the following conclusions:(1) (E)- and (Z)-fchars/alpha.gif" BORDER=0>,fchars/beta2.gif" BORDER=0 ALIGN="middle">-unsaturated2-iodoanilidesgive opposite enantiomers of the Heck product whenAg3PO4 is the HI acceptor (cationicpathway); the absoluteconfiguration of the product is independent of alkene geometry when theHI acceptor is PMP (neutral pathway).(2) When the 2-substituent is Me or prim-alkyl,stereoinduction is optimal in PMP-promoted insertions ofZsubstrates which occur with ee's as high as 97%. (3) When the2-substituent is large, stereoinduction is optimalin insertions of E substrates carried out in the presence ofAg3PO4. (4) Contributions from thefchars/beta2.gif" BORDER=0 ALIGN="middle">-alkenesubstituent are minor. The neutral Heck reaction manifold can beentered from triflate substrates by carryingout the cyclization in the presence of added halide salts. Theability to vary both the alkene geometry and theHeck reaction pathway allows chiral 3,3-disubstituted-2-oxindoleshaving a wide range of substituents at thequaternary carbon (Me, prim-alkyl, tert-alkyl,and aryl) to be prepared with useful levels ofenantioselection(72-97% ee). A number of studies were carried out aimed atclarifying the mechanism of the neutral Heckreaction pathway. Key results are the following: (1) Chiralamplification studies show that the catalyst ismonomeric Pd-BINAP. (2) Investigations of monophosphineanalogues of BINAP, which were designed tomimic a partially dissociated BINAP chelate, support the conclusionthat BINAP is chelated during theenantioselective step. (3) Enantioselectivity is insensitive tosolvent polarity. From these data, we proposethat the stereochemistry determining step of the neutral pathway occursduring the process in which iodide isdisplaced by the tethered alkene (Figure 2, 41 
f"> 47f"> 45). In light of the variety ofpentacoordinateintermediates that could be involved, it is premature to advance amodel to rationalize stereoinduction inasymmetric Heck reactions proceeding by the neutral pathway.Nonetheless, the finding that the enantioselectivestep of asymmetric Heck reactions taking place by the neutral pathwayinvolves five-coordinate intermediatessignificantly broadens the vista for design of asymmetric ligands forthis and related reactions.
fchars/alpha.gif" BORDER=0>,fchars/beta2.gif" BORDER=0 ALIGN="middle">-unsaturated 2-iodoanilides catalyzed byPd-BINAPwere surveyed using two reaction conditions: (1) silver-promotedcyclizations in the presence of 2 equiv ofAg3PO4 and (2) base-promoted cyclizationsin the presence of 4 equiv of1,2,2,6,6-pentamethylpiperidine(PMP). A comparison of these results with the outcome of thecorresponding intramolecular Heck reactionsof the E stereoisomers leads to the following conclusions:(1) (E)- and (Z)-fchars/alpha.gif" BORDER=0>,fchars/beta2.gif" BORDER=0 ALIGN="middle">-unsaturated2-iodoanilidesgive opposite enantiomers of the Heck product whenAg3PO4 is the HI acceptor (cationicpathway); the absoluteconfiguration of the product is independent of alkene geometry when theHI acceptor is PMP (neutral pathway).(2) When the 2-substituent is Me or prim-alkyl,stereoinduction is optimal in PMP-promoted insertions ofZsubstrates which occur with ee's as high as 97%. (3) When the2-substituent is large, stereoinduction is optimalin insertions of E substrates carried out in the presence ofAg3PO4. (4) Contributions from thefchars/beta2.gif" BORDER=0 ALIGN="middle">-alkenesubstituent are minor. The neutral Heck reaction manifold can beentered from triflate substrates by carryingout the cyclization in the presence of added halide salts. Theability to vary both the alkene geometry and theHeck reaction pathway allows chiral 3,3-disubstituted-2-oxindoleshaving a wide range of substituents at thequaternary carbon (Me, prim-alkyl, tert-alkyl,and aryl) to be prepared with useful levels ofenantioselection(72-97% ee). A number of studies were carried out aimed atclarifying the mechanism of the neutral Heckreaction pathway. Key results are the following: (1) Chiralamplification studies show that the catalyst ismonomeric Pd-BINAP. (2) Investigations of monophosphineanalogues of BINAP, which were designed tomimic a partially dissociated BINAP chelate, support the conclusionthat BINAP is chelated during theenantioselective step. (3) Enantioselectivity is insensitive tosolvent polarity. From these data, we proposethat the stereochemistry determining step of the neutral pathway occursduring the process in which iodide isdisplaced by the tethered alkene (Figure 2, 41 f"> 47f"> 45). In light of the variety ofpentacoordinateintermediates that could be involved, it is premature to advance amodel to rationalize stereoinduction inasymmetric Heck reactions proceeding by the neutral pathway.Nonetheless, the finding that the enantioselectivestep of asymmetric Heck reactions taking place by the neutral pathwayinvolves five-coordinate intermediatessignificantly broadens the vista for design of asymmetric ligands forthis and related reactions.