Incorporation of α-substituted serine analog into peptide via a novel O,N-migration

Article abstract of DOI:10.1055/s-1998-1748

Peptides incorporating β-hydroxy-α,α-disubstituted-α-amino acids, (S)-α-methylserine ((S)-α-MeSer), (1R,2S)-1-amino-2-hydroxycyclohexanecarboxylic acid ((1R,2S)-Ahh), or (R)-α-benzyl-serine ((R)-α-BnSer), were efficiently synthesized using a novel 0,N-migration.

Full text of DOI:10.1055/s-1998-1748

June 1998
SYNLETT
609
Incorporation of α-Substituted Serine Analog into Peptide via a Novel O,N-Migration
a
b
M. Horikawa *, T. Nakajima and Y. Ohfune *
a
Suntory Institute for Bioorganic Research, Shimamoto-cho, Mishima-gun, Osaka 618, Japan
Fax: 81-75-962-2115; E-mail: LEE05541@niftyserve.or.jp
b
Department of Material Science, Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558, Japan
Fax: 81-6-605-3153; E-mail: ohfune@sci.osaka-cu.ac.jp
Received 20 March 1998
Abstract: Peptides incorporating β-hydroxy-α,α-disubstituted-α-amino
acids, (S)-α-methylserine ((S)-α-MeSer), (1R,2S)-1-amino-2-hydroxy-
cyclohexanecarboxylic acid ((1R,2S)-Ahh), or (R)-α-benzyl-serine ((R)-
α-BnSer), were efficiently synthesized using a novel O,N-migration.
Thus, Cbz-Val-OH was condensed with the Boc-(S)-α-MeSer methyl
ester 1a using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide
hydrochloride (EDCHCl) and a catalytic amount of 4-dimethylamino-
pyridine (DMAP) to give ester 2a. After removal of the Boc group,
treatment of the resulting amine with 10% aqueous ammonium
bicarbonate afforded the desired coupling product 3a in 92% overall
In recent years, there has been an increasing interest in α,α-
disubstituted-α-amino acids, in view of their important role in peptide
chemistry, which markedly affects not only the conformation of the
5
yield from 1a. The coupling of 1a with Cbz-Glu(γ-Bn)-OH produced
5
the dipeptide 3b in excellent yield. The reaction of 1b with Cbz-Val-
OH or Cbz-Glu(γ-Bn)-OH gave 3c or 3d, respectively, in good yields
1
peptide but also its biological activity. In particular, α-substituted
5
(Table 1). No racemization of the products was encountered based on
2a,c
2c
serine analogs 1a
and 1b have received considerable attention
1
the H NMR analyses.
because these amino acids can be viewed as conformational variants of
serine where the α-substituent or the carbocyclic ring fixed the hydroxy
group to a specific conformation. Prior to carrying out the peptide
coupling, it was considered that the free hydroxy group of serine often
required troublesome protection-deprotection steps, or the presence of
the sterically bulky α-substituent would decrease the yields of the
3
coupling product. Thus, our plan was the initial esterification of the
hydroxy group with the C-terminal of an N-protected amino acid and
4
subsequent intramolecular acyl-migration (O,N-migration) under mild
reaction conditions (Scheme 1). Although related examples have been
4
reported in the case of serine, it was uncertain whether the desired
migration would occur in the α-substituted cases.
It was of interest to examine the feasibility of the O,N-migration for the
synthesis of biologically active peptides such as enkephalin. Thus, we
2b
2
examined the incorporation of 1a and (R)-α-BnSer into the Gly and
4
Phe positions of Leu-enkephalin, respectively. The esters 4 and 6 were
prepared both in the liquid phase and on the solid supports. Successive
treatments of the ester 4, prepared by the esterification of Boc-Tyr(t-
Bu)-Gly-Gly-OH with Boc-(R)-α-BnSer-Leu-O-t-Bu, with (1) TFA and
(2) aqueous ammonium bicarbonate underwent initial removal of the
protecting groups and subsequent ester migration to give the enkephalin
6
analog 5 in 75% yield. The ester 6 attached to the solid support also
7
gave the desired peptide 7 in 78% yield (Scheme 2).
In summary, several types of the α-substituted serine analogs were
efficiently incorporated into a peptide by means of both the liquid and
solid phases. The O,N-migration method would provide valuable
advantages for incorporating β-hydroxy-α,α-disubstituted-α-amino
Scheme 1
Scheme 2

610
LETTERS
SYNLETT
acids into peptides in view of its high yields and with the protection the
hydroxy group being unnecessary.
Hz), 3.76 (3 H, s), 3.79 (1 H, d, J = 11.2 Hz), 4.05 (1 H, d, J = 11.2
Hz), 4.19 (1 H, dt, J = 5.6, 7.2 Hz), 5.10 (2 H, s), 5.12 (2 H, s),
5.66 (1 H, d, J = 5.6 Hz), 6.98 (1 H, s), 7.30-7.38 (10 H, m). 3b:
1
[α] -57.5° (c 1.41, CHCl ); H NMR (400 MHz, CDCl ) δ 0.96
D
3
3
Acknowledgment: We thank the New Energy and Industrial
Technology Development Organization (NEDO), Ministry of
International Trade and Industry, Japan, for financial support.
(3 H, d, J = 6.8 Hz), 0.99 (3 H, d, J = 6.8 Hz), 1.53 (3 H, s), 2.10
(1 H, dsep, J = 6.4, 6.8 Hz), 3.49 (1 H, brs), 3.78 (3 H, s), 3.79 (1
H, brd, J = 10.8 Hz), 3.89 (1 H, dd, J = 6.4, 6.8 Hz), 4.10 (1 H,
brd, J = 10.8 Hz), 5.08 (1 H, d, J = 14.4 Hz), 5.12 (1 H, d, J = 14.4
References and Notes
Hz), 5.28 (1 H, d, J = 6.4 Hz), 6.81 (1 H, s), 7.31-7.36 (5 H, m).
1
1.
Davies, J. S. Amino Acids, Peptides and Proteins; The Royal
Society of Chemistry 1997;28:166-232 and references cited
therein.
c
3c: [α] -77.8° ( 0.91, CHCl ); H NMR (400 MHz, CDCl ) δ
D
3
3
1.25-1.85 (7 H, m), 2.01 (1 H, dq, = 14.0, 7.2 Hz), 2.20 (1 H, bq,
J
J
= 14.0, 7.2 Hz), 2.32 (1 H, brd, = 13.2 Hz), 2.54 (1 H, dt, =
J
J
16.8, 6.8 Hz), 2.64 (1 H, dt, J = 16.8, 6.8 Hz), 3.70 (3 H, s), 3.75
(1 H, m), 3.95 (1 H, m), 4.33 (1 H, m), 5.07-5.16 (4 H, m), 5.71 (1
2.
(a) Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116, 7405-
7406. (b) Horikawa, M.; Nakajima, T.; Ohfune, Y. Synlett 1997,
253-254. (c) Ohfune, Y.; Horikawa, M. J. Syn. Org. Chem. Jpn.
1997, 55, 982-993.
H, d, J = 7.2 Hz), 6.76 (1 H, s), 7.31-7.35 (10 H, m). 3d: [α]
-
D
1
137° (c 0.12, CHCl ); H NMR (400 MHz, CDCl ) δ 0.96 (3 H, d,
3
3
J = 6.8 Hz), 1.01 (3 H, d, J = 6.8 Hz), 1.25-1.88 (7 H, m), 2.20 (1
H, dsep, J = 6.8, 6.4 Hz), 2.43 (1 H, brd, J = 13.6 Hz), 3,47 (1 H,
brs), 3.73 (3 H, s), 3.91 (1 H, m), 4.01 (1 H, dd, J = 6.4, 8.0 Hz),
5.10 (1 H, d, J = 12.0 Hz), 5.15 (1 H, d, J = 12.0 Hz), 5.29 (1 H,
m), 6.33 (1 H, s), 7.31-7.37 (5 H, m).
3.
4.
Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243-
2266 and literatures cited therein.
(a) Fujino, M.; Wakimasu, M.; Shinagawa, S.; Kitada, C.; Yajima,
H. Chem. Pharm. Bull. 1978, 26, 539-548. (d) Swerdloff, M. D.;
Anderson, S. B.; Sedgwick, R. D.; Gabriel, M. K.; Brambilla, R.
6.
7.
Ester 6 was prepared by the treatment of Boc-Tyr(t-Bu)-OH and
Boc-(R)-α-MeSer-Gly-Phe-Leu-Wang-resin, prepared by using
standard Fmoc chemistry, with DCC and a catalytic amount of
DMAP in CH Cl at room temperature.
J.; Hindelang, D. M.; Williams, J. I. Int. J. Peptide Protein Res.
1989, 33, 318-327.
1
5.
[α] Value and H NMR data of the compounds 3a-3d were as
D
1
2
2
follows; 3a: [α] -62.1° (c 0.68, CHCl ); H NMR (400 MHz,
D
3
CDCl ) δ 1.49 (3 H, s), 2.02 (1 H, dq, J = 14, 7 Hz), 2.14 (1 H, dq,
Biological activity of 5 and 7 to the opioid receptors is currently
3
J = 14, 7 Hz), 2.48 (1 H, dt, J = 17, 7 Hz), 2.58 (1 H, dt, J = 17, 7
under investigation.