readily synthesized either by phosgenation of free R-amino
acids (Fuchs-Farthing method) or through the cyclization
of NR-urethane-protected R-amino acids (Leuchs method).4
These methods are not universally applicable for the synthesis
of â-NCAs since the kinetics of ring closure and the
thermodynamic stability of NCAs decreases as ring size
increases from 5 (R-NCAs) to 6 (â-NCAs).4 For instance,
when â-amino acids are treated with phosgene, the major
isolated products are uncyclized N-chloroformyl â-amino
acids rather than the desired â-NCAs (Scheme 1).5 Treatment
which were derived from a small pool of readily available
precursors. However, these polymers were not synthesized
from â-NCAs but were prepared using either the ring-
opening polymerization of â-lactams7 or polycondensation
of carboxyl-activated R-alkyl-L-aspartates.8 We sought to
develop methods for the general preparation of optically pure
poly(â-peptides) utilizing recently developed chemistry that
provides a wide variety of optically pure â-amino acids.
These â-amino acid starting materials (2a-k) were synthe-
sized according to the methods developed by Seebach,2
namely, the Arndt-Eistert homologation of NR-protected
R-amino acids (1a-k) to the intermediate diazo ketones,
followed by Wolff rearrangement of the diazo ketones to
give the desired products (2a-k) in good yield (60-90%
overall, Scheme 2). The only exception was the conversion
of 1e to 2e, which could only be obtained in 15% overall
yield.
Scheme 1. Reactions of â-Amino Acids with Phosgene
Following literature precedent,6 PBr3 was used to cyclize
the acids, 2a-k, into the corresponding â-NCAs, 3a-f (eq
2). The â-NCA structure was confirmed by the X-ray
structural determination of 3a.9 With stoichiometric PBr3
(0.34 equiv), consumption of the starting material was found
to be slow and the reactions did not go to completion. Use
of 0.6 equiv of PBr3 was found to be optimal for giving both
high conversion and minimal side reactions (i.e., amine
deprotection by liberated acid) (Table 1). Reactions in
of these compounds with base (e.g., Et3N) generally results
in low yields of â-NCAs unless they are N-substituted. The
poor yields are due to isocyanate formation, which competes
with the ring closure.5 The Fuchs-Farthing method is thus
not very useful for â-NCA synthesis since it is the N-
unsubstituted derivatives that are desired due to their ability
to form H-bonded secondary structures. The formation of
N-unsubstitued â-NCAs is best accomplished using the
Leuchs method of NCA synthesis, specifically cyclization
of Nâ-Boc and Nâ-Cbz â-amino acids using PBr3 (eq 2).6
Table 1. Synthesis of â-NCAs (3a-f) from Urethane-Protected
â-Amino Acid Precursors (2a-k). Yields Are for Purified,
Isolated Products
entry substrate [substrate] (M) product â-NCA yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2a
2a
2a
2b
2c
2d
2e
2f
0.5
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
3a
3a
3a
3b
3c
3d
3e
3f
43
47a
95
80
85
75
54
45
58a
93
88
74
70
52
64a
2f
3f
2g
2h
2i
2j
2k
2k
3a
3b
3c
3d
3e
3e
All previous â-NCA preparations using the Leuchs method
were limited to synthesis of racemic NCAs, primarily since
only racemic â-amino acids were readily available.5b,6 The
random stereocopolymers derived from polymerization of
these monomers were not particularly useful since their
irregularity prevents the adoption of stable secondary struc-
tures. In fact, the number of optically active poly(â-peptides)
that have been reported is quite small. Most of these
examples contain a limited set of side-chain functionalities,
a Triethylamine (1 equiv) was added to these reactions.
different solvents (toluene, dioxane, THF, and CH2Cl2)
revealed that CH2Cl2 consistently gave the highest yields of
(7) (a) Graf, R.; Lohaus, G.; Bo¨rner, K.; Schmidt, E.; Bestian, H. Angew.
Chem. 1962, 74. 523. (b) Bestian, H. Angew. Chem. 1968, 80, 304. (c)
Schmidt, E. Angew. Makromol. Chem. 1970, 14, 185-202 (d) Chen, F.;
Lopero, G.; Goodman, M. Macromolecules. 1974, 7, 779-783. (e) Garc´ıa-
Alvarez, M.; Mart´ınez De Ilarduya, A.; Lo´pez-Carrasquero, F.; Ferna´ndez-
Sant´ın, J. M.; Mun˜oz-Guerra, S. J. Polym. Sci. Polym. Chem. 1996, 34,
1959-1968. (f) Ilarduya, A. M.; Alaman, C.; Garcia-Alvarez, M.; Lo´pez-
Carrasquero, F.; Mun˜oz-Guerra, S. Macromolecules, 1999, 32, 3257-3263.
(3) Gung, B. W.; Zou, D.; Stalcup, A. M.; Cottrell, C. E. J. Org. Chem.
1999, 64, 2176-2177.
(4) Kricheldorf, H. R-Aminoacid-N-Carboxyanhydrides and Related
Heterocycles; Springer-Verlag: 1987; pp 11-16.
(5) (a) Birkofer, L.; Modic, R. Liebigs Ann. Chem. 1957, 604, 56. (b)
Zilkha, A.; Burstein, Y. Biopolymers 1964, 2, 147-161.
(6) Birkofer, L.; Modic, R. Liebigs Ann. Chem. 1959, 628, 162-172.
1944
Org. Lett., Vol. 2, No. 13, 2000