"-Amino Acids: Function and Synthesis # Conformations of "-Peptides # Biological Significance # Asymmetric Synthesis Sean Brown MacMillan Group eting ovember 14, 2001 Lead eferences: Cheng,. P.; Gellman, S..; DeGrado, W. F. Chem. ev. 2001, 101, 3219-3232. Enantioselective Synthesis of "-Amino Acids; Juaristi, E., Ed.; Wiley-VC: ew York, 1997. Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015. Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.!-Amino Acids vs. "-Amino Acids!-Amino acids "-Amino acids 3 5 2 1 3 substitution positions 2 configurations: (), (S) 2 2 4 2 3 5 substitution positions 1 2 8 configurations: (2), (2S), (3), (3S), (,), (,S), (S,), (S,S) 2 "-Amino acids allow for greater diversity. Extra C-C bond potenially allows for increased diversity in secondary structures. Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015. 1
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! 3 Substituted!-Amino Acids Arndt-Eistert eaction 1) ClC 2, 3, TF 2) C 2 2, 2, 80% 2 Ag 2C, 3, 95% Wolff earrangement + - 2 Enantiomercally pure!-amino acids are prepared from the appropriate "-amino acid. earrangement occurs with retention of stereochemistry. Epimerization is rarely observed. Enantioselective Synthesis of!-amino Acids; Juaristi, E., Ed.; Wiley-VC: ew York, 1997.! 2,3 Substituted!-Amino Acids 2 eq. LDA / LiCl Li Li I 95% yield Li Li Electrophile approaches from above! 3 -Amino acids derived from the Arndt-Eistert method can be further elaborated to! 2,3 -amino acids. igh diastereoselectivities are observed in alkylations. Enantioselective Synthesis of!-amino Acids; Juaristi, E., Ed.; Wiley-VC: ew York, 1997.! 2 Substituted!-Amino Acids TiCl 4, 3 BzC 2Cl Bz ydrolysis 2 Ti Electrophile approaches from below Evans' chiral auxiliary alkylation produces! 2 -amino acids of high enantiomeric purity. Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215. Catalytic Asymmetric Addition of -Benzylhydroxylamine 30 mol% MgBr 2, Ligand 2 (1.1 eq), C 2Cl 2 =,,, and i-pr 74-80% yield 87-95% ee This is the first highly enantioselective catalytic conjugate amine addition. The other enatiomeric series can be accessed through use of Y(Tf) 3 or Yb(Tf) 3 though ee's are below 60%. Substitution on olefin limited to alkyl groups. igh catalyst loading. Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615. 3
Kinetic esolution of!-amino Amide 100 mol% MgBr 2, Ligand 2 (0.5 eq), C 2Cl 2 racemic 47% yield 34% yield 47% ee () 60% ee (S) ee of entioselective reaction increases over time but yield decreases. Minor enantiomer undergoes aminolysis faster than major enantiomer. Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615. Amine Conjugate Additions to Cinnamates 30 mol% MgX 2, Ligand Ar (2.2 eq), C 2Cl 2 Ar 53-87% yield 60-96% ee X= I, (Cl 4) First highly enantioselective conjugate amine addition to cinnamates. -Benzylhydroxylamine is more reactive than -benzylhydroxylamine and the pyrrolidinone cinnamate also more reactive than the corresponding pyrazole substrate. Sibi, M. P.; Liu, M. rg. Lett. 2000, 2, 3393. 4
rganocatalytic Addittion of Azide TMS 3, C 2, catalyst 3 Toluene, 25 C i-pr % yield % ee 97 63 91 71 84 82 Boc tbu cy 79 85 85 71 Boc Catalyst is an organic molecule which gives it obvious benefits.!-turn is necessary for selectivity. Guerin, D. J.; orstmann, T. E.; Miller, S. Angew. Chem. Int. Ed. 2000, 39, 3635. rganocatalytic Approach To Cyclic!-Amino Acids Cl ac 3, 2/ 2 68% yield 89% ee 1) acl 2, i-butene, a 2P 4 2; 98% 2) Br, DBU 3) s 4, M; 86%.C. gives quick access to highly functionalized!-amino acids. Wipf, P.; Wang, X. Tetrahedron. Let. 2000, 41,8747-8751. rgano Catalytic Approachs To "-Amino Carbonyls, -30 C Cl 4 91% yield 98% ee > 100:1 dr Z - + 1 2/ 2, -20 C Cl 4 Z 1 C 70-98% yield 90-99% ee a, eflux, 2.5 hrs. 80% yield TBS Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874-9875. Summary Lengthening!-amino acids by one carbon does not lead to chaos, but new secondary folding structures. "-Peptides form secondary structures with greater stability than!-peptides. The metabolic stability of "-peptides can be utilized in drug design. Asymmetric catalysis should provide inexpensive and quick access to novel "-amino acids. 5