Requirements for an Effective Chiral Auxiliary Enolate Alkylation 1. Xc must be low cost, and available in both enentiomeric forms 2. The cleavage of Xc from the substrate must occur under mild enough conditions so that racemization is avoided. 3. The pi-facial selectivity of electrophile attack on the enolate will be dictated by sterics. 4. Either E or Z enolate should be formed exclusively 5. tal ion chelation provides a rigid template and a single conformation, so that the sterics of the auxiliary can enforce facial bias in electrophile attack on the enolate
Early examples of Chiral auxiliaries for enolate alkylation 2-xazolines as Carbonyl Equivalents phenyl shields top face EtI E + 6 Cl yers, JACS, 1976, 567. 78% ee Prolinol amides: Cl 2 Br TL, 1980, 4233 JACS, 1990, 5290. tertiary amides generally form Z-enolates -> acyl migration, general base cat. hydrolysis 76% de 1 Cl/ ac 3
Enantiocomplementary Reagents: Evans Chiral Auxiliary JACS, 1982, 104, 1737. Acylaton provides imides, closer to esters in terms of acidity, enolate nucleophilicity, and cleavage chemistry: n-bu PrCCl TF, -78 Z-enolates are formed with very high selectivity due to sterics; metal chelated geometry presumed in ground and transition states Br Br >99:1 >99:1
Less Reactive Electrophiles: Use sodium enolate amds EtI 94:6 Alternatively, use triflate: Tf >95% de Enolate xidation- use Davis xaziridine: JACS, 1985, 4346 C 2 a(tms) 2 S 2 C 2 Aziridination: Amino acid synthesis: JACS, 1990, 4011. tbu KMDS ArS 2 3 3 tbu P 3 tbu 2
Pseudoephedrine as a Chiral Auxiliary cheap, commercially available chiral amino alcohols R,R-(-)-pseudoephedrine S,S-(+)-pseudoephedrine Myers, JACS, 1997, 119, 6496. X R R 1. 1.95 Cl 2. R'X R' R 1,4- syn relationship >99% de (solvent) (solvent) R electrophile enters from the same face as methyl group epoxides and alkyl halides attack opposite faces of the enolate due to lithium coordination of the epoxide Myers, JC, 1996, 61, 2428 R'X
Challenge:Remove Chiral Auxiliary w/o Racemization 2 S 4 >99%de C 4 9 dioxane reflux C 4 9 nbu 4, tbu 2, reflux C 4 9 basic conditions lead to facile epimerization of!-aryl substituted carbonyls Reduction: 2 B 3 C 4 9 LAB, TF C 4 9 TL, 1996, 3623 Al(Et) 3 C 4 9 2.4 eq. C 4 9 JACS, 1997, 6496.
Iterative Synthesis of 1,3 n-substituted Carbon Chains X c I X c LAB P 3, I 2 imidazole I Synlett, 1997, 5, 457. X d X c I as above X c X c repeat cycle as above I repeat cycle
Camphor-Based Auxiliaries S 2 elmchen Chiral Ester Enolate S 2 S 2 El + S 2 TF E enolate dr 99:1 El S 2 S 2 El + S 2 El TF/MPA 4:1 Z enolate dr 94:6 MPA breaks up higher order lithium enolate aggregates! Enolization leakage in the presence of MPA ACIEE, 1981, 20, 207 ACIEE, 1984, 23, 60 TL, 1983, 24, 1235 TL, 1983, 24, 3213
Camphor-Based Auxiliaries ppolzer Camphorsultam a a(tms) 2 S C 2 CCl S S a E + Br, MPA ppolzer, TL, 1989, 41, 5603 2 2 S 97% de no racemization under these hydrolysis conditions
Chiral talloenamines and tallated ydrazones I 3 + yers, JACS, 1981, 103, 3081. C 2 t-bu C 2 BMCl C 2 C 2 aq. CuCl 84% 94% ee Enders, Syn Comm. 1999, 29, 27.
C-2 Symmetric Amine Auxiliaries MM MM MM EtI MM MM MM Z-enolate de>95% Yamaguchi, TL, 1984, 25, 857. 1 Cl reflux
Catalytic thods for Asymmteric Alkylation Br - chiral phase-transfer catalyst 1 Corey, TL, 1998, 39, 5347. tbu + R-X 1, 10mol% Cs 2 R tbu R= -(C 2 ) 4 Cl -(C 2 ) 2 C 2 -(C 2 ) 2 CEt %ee 99 95 91 99