Beta aminoácids
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"-Amino Acids: Function and Synthesis# Conformations of "-Peptides # Biological Significance # Asymmetric Synthesis
Sean Brown MacMillan Group Meeting November 14, 2001
Lead References: Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219-3232.
Enantioselective Synthesis of "-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New 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
H N R2 O OH R1 R5
"-Amino acids
2 H R N
R1 OH O
R3
R4
R3
3 substitution positions 2 configurations: (R), (S)
5 substitution positions 8 configurations: (2R), (2S), (3R), (3S), (R,R), (R,S), (S,R), (S,S)
O H2N OH
H2N H2N O OH O
OH
H N
O OH HN O H2N O OH OH
H N O
OH
• "-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
2
!3 Substituted !-Amino Acids
Arndt-Eistert Reaction
Me Cbz N H OH O
1) ClCO2Et, NEt3, THF 2) CH2N2, Et2O, 80%
Me Cbz N H N2 O
AgO2CPh, NEt3
Cbz
Me N H
O OMe
MeOH, 95%
Wolff Rearrangement
O R H N+ N– O O • H R H
-N2
R
MeOH
R
O OMe
• Enantiomercally pure !-amino acids are prepared from the appropriate "-amino acid. • Rearrangement occurs with retention of stereochemistry. • Epimerization is rarely observed.
Enantioselective Synthesis of !-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
!2,3 Substituted !-Amino Acids
OLi Cbz Ph NH O OMe
2 eq. LDA / LiCl
BnO Ph
N
OLi OMe
OLi Cbz
MeI 95% yield
NH
O OMe Me
BnO Ph
N
Li
O OMe
Ph
Electrophile approaches from above
• !3-Amino acids derived from the Arndt-Eistert method can be further elaborated to !2,3-amino acids. • High diastereoselectivities are observed in alkylations.
Enantioselective Synthesis