Urethane N-carboxyanhydrides from β-amino acids

Article abstract of DOI:10.1021/jo001583y

A general method has been developed for the synthesis of N-tert-butyloxycarbonyl N-carboxyanhydrides from β-amino acids using Vilsmeier complex. These β-UNCA are stable, and the reactivity with different nucleophiles (alcohol, amine, lithium enolate) was studied.

Full text of DOI:10.1021/jo001583y

J . Org. Chem. 2001, 66, 6541-6544
6541
Ur eth a n e N-Ca r boxya n h yd r id es fr om â-Am in o Acid s
Mary McKiernan, J acques Huck, J ean-Alain Fehrentz, Marie-Louise Roumestant,*,†
Philippe Viallefont, and J ean Martinez
UMR 5810-CNRS, LAPP Universite´s Montpellier I et II, Place Euge`ne Bataillon,
34095 Montpellier Cedex 5, France
roumestant@crit.univ-montp2.fr
Received November 6, 2000
A general method has been developed for the synthesis of N-tert-butyloxycarbonyl N-carboxyan-
hydrides from â-amino acids using Vilsmeier complex. These â-UNCA are stable, and the reactivity
with different nucleophiles (alcohol, amine, lithium enolate) was studied.
In tr od u ction
â-Amino acids are found as components of peptidic8 and
natural products9 with antibiotic, antifungal, and cyto-
toxic properties. Recently, significant progress has been
made in elucidating the conformational properties10 of
short polymers of â-amino acids; â-peptides are promising
antimicrobial candidates11 because they offer a choice of
secondary structures and because the unnatural â-pep-
tide backbone is resistant to protease degradation.12
The intent of this study was to synthesize N-tert-
butyloxycarbonyl-protected N-carboxyanhydride deriva-
tives of â-amino acids. Should their synthesis be success-
ful, we hoped to carry out further studies to understand
the stability and utility of these compounds. Alterna-
tively, we decided to investigate the synthesis of N-
carboxyanhydride derivatives of â-amino acids, starting
first with â-alanine.
The use of N-carboxyanhydride (NCA) derivatives in
peptide synthesis is a particularly attractive strategy and
has been quite extensively used.1 There is literature
precedence for formation of five-membered N-carboxy-
anhydrides, with the most conventional procedure in-
volving reaction of an amino acid with a large excess of
phosgene.2 This method is unattractive primarily because
of the toxicity of phosgene and because of the harsh
temperatures required to drive the reaction. However,
the interest in NCA’s has resulted in alternative proce-
dures being explored. Some examples include trichlo-
romethyl carbamate3 and bis trichloromethyl carbonate,4
both of which are phosgene precursors, and phosphorus
trichloride,2,5 which enables the reaction to occur at lower
temperatures. However, results reported are very sub-
strate dependent.
Resu lts
The tendency of NCA derivatives to polymerize has
stimulated the synthesis of UNCA’s in which the nitrogen
is protected by a carbamate group.6 Urethane N-carboxy-
anhydrides (UNCA’s) are attractive target molecules for
medicinal chemists as they have incorporated into their
structure an activated carboxylate group and a protected
amino group. Such molecules are highly reactive and lend
themselves to facile stepwise peptide synthesis and solid-
phase synthesis. One of the most successful strategies
employed to incorporate R-amino acids into biologically
active compounds is via the corresponding urethane
N-carboxyanhydrides, which are very reactive compounds
and react with nucleophiles to yield readily removable
side products. Moreover, urethane N-carboxyanhydrides
can be considered as starting material for the synthesis
of various amino acid derivatives.7 Recently considerable
attention has been directed toward understanding the
biological activity of â-amino acids and their derivatives.
â-Alanine N-carboxyanhydride 4 was selected as the
primary target as it was considered to be the most
synthetically challenging, due to its flexibility.
The synthesis of N-carboxyanhydrides from â-amino
acids using phosgene was first reported 45 years ago by
L. Birkofer,13-15 followed by H. R. Kricheldorf,16 who also
studied their polymerization with basic catalysts, and
recently (during this work) by T. J . Deming.17
The first procedure we applied to the formation of
â-alanine N-carboxyanhydride was “Leuch’s method”,6
which utilizes phosphorus trichloride. Several reactions
failed to afford the desired six-membered NCA 4 (Scheme
1). An alternative Lewis acid was employed, PBr3.
The first attempt successfully afforded â-Ala-NCA 4;
unfortunately the unstablility of this molecule was real-
(8) Michael, J . P.; Pattenden, G. Angew. Chem., Int. Ed. Engl. 1993,
32, 1.
(9) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117.
(10) (a) Seebach, D.; Overhand, M.; Kuhnle, F. N. M.; Martinoni,
B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1996, 79,
913. (b) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (c) De Grado,
W. F.; Schneider, J . P.; Hamuro, Y. J . Pept. Res. 1999, 54, 206.
(11) (a) Hamuro, Y.; Schneider, J . P.; De Grado, W. F. J . Am. Chem.
Soc. 1999, 121, 12200. (b) Porter, E. A.; Wang, X.; Lee, H. S.; Weisblum,
B., Gellman, S. H. Nature 2000, 404, 565.
† Tel: (33) 04 67 14 37 61. Fax: (33) 04 67 14 48 66.
(1) Kricheldorf, H. R. R-aminoacid-N-carboxyanhydrides and Related
Heterocycles; Springer-Verlag: 1986.
(2) Kricheldorf, H. R. Chem. Ber. 1970, 103, 3353.
(3) (a) Oya, M.; Katakai, R.; Nakai, H. Chem. Lett. 1973, 1143. (b)
Katakai, R.; Iizuka, Y. J . Org. Chem. 1985, 50, 715.
(4) (a) Daly, W. H.; Poche, D. Tetrahedron Lett. 1988, 29, 5859. (b)
Wilder, R.; Mobashery, S. J . Org. Chem. 1992, 57, 2755.
(5) Berger, A.; Kurtz, J .; Katchalski, E. J . Org. Chem. 1954, 76, 5552.
(6) Fuller, W. D.; Cohen, M. P.; Shabankerah, M.; Blair, R. K.;
Goodman, M.; Naider, F. R. J . Am. Chem. Soc. 1990, 112, 7414.
(7) Pothion, C.; Fehrentz, J . A.; Aumelas, A.; Loffet, A.; Martinez,
J . Tetrahedron Lett. 1996, 37, 1027 and references cited
(12) Habermann, E. Science 1972, 177, 314.
(13) Birkofer, L.; Kachel, H. Naturwissenschaften 1954, 41, 576.
(14) Birkofer, L.; Modic, R. Liebigs Ann. Chem. 1957, 604, 56.
(15) Birkofer, L.; Modic, R. Liebigs Ann. Chem. 1959, 628, 162.
(16) Kricheldorf, H. R. Makromol. Chem. 1973, 173, 13-41.
(17) Cheng, J .; Ziller, J . W.; Deming, T. J . Org. Lett. 2000, 13, 1943.
10.1021/jo001583y CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/12/2001

6542 J . Org. Chem., Vol. 66, No. 20, 2001
McKiernan et al.
Sch em e 1a
Ta ble 1. Op tim iza tion of th e Rea ction Con d ition s
time at
-20 °C
time at
0 °C
time at
rt
equiv of
imide salt
yield
(%)
no.
1
2
3
4
5
6
2 h
2 h
2 h
2 h
30 min
30 min
30 min
30 min
30 min
30 min
30 min
4 h
4 h
4 h
4 h
3 h
2 h
2
4
6
2
1.1
6
63
54
62
55
0
69 crude
a
t
Reagents and conditions: i, (Boc)2O, NaOH, H2O, BuOH, 30
°C, 18 H, 73%; ii, NaOH, H2O, C6H5O2CCl, rt, 18 h; iii, PBr3,
CH2Cl2, 0 °C, 4 h.
Sch em e 3a
Sch em e 2a
a
Reagents and conditions: i, (Boc)2O, DMAP (10%), CH3CN,
12-48 h; ii, NaOH, dioxane/H2O; iii, ClCOCOCl, DMF, CH3CN,
at -20 °C, then addition of 21 or 22, pyr., CH3CN, -20 °C for 2 h,
then 0 °C for 1 h followed by 4 h at rt.
Sch em e 4
a
t
Reagents and conditions: i, (Boc)2O, NaOH, H2O, BuOH, 30
°C, 18 H, 73%; ii, Cs2CO3, MeOH/H2O, then BnBr, DMF, 18H, rt,
18 h; iii, (Boc)2O, DMAP (10%), CH3CN, 12-24 h; iv, Pd/C, H2, 1
H, rt; v, ClCOCOCl, DMF, CH3CN, at -20 °C, then addition of 13
or 14 or 15, pyr., CH3CN, -20 °C for 2 h, then 0 °C for 1 h followed
by 4 h at rt.
ized (air and temperature sensitive). To synthesize N-tert-
butyloxycarbonyl-protected N-carboxyanhydride derived
from â-alanine we carried out the procedure outlined by
Wakselman18 (Scheme 2), affording the desired UNCA
in varying yields. A slight modification to the formation
of the dimethylformamide-imide salt resulted in much
improved yields, 8-40% to 55-60%, using the more
conventional DMF/oxalyl chloride in acetonitrile. After
addition of the pyridinium salt of the chosen bis Boc
amino acid to the imide salt, the corresponding Boc
N-carboxyanhydride was afforded in good yield after
recrystallization from EtOAc/hexane at low temperature
(55-60%).
This synthetic scheme was applied to the synthesis of
N-Boc-â-Ala N-carboxyanhydride 16, N-Boc-â-methyl-â-
alanine N-carboxyanhydride 17 and racemic N-Boc-R-
methyl-â-alanine N-carboxyanhydride 18 from respec-
tively â-alanine, DL-3-aminobutyric acid, and DL-3-
aminoisobutyric acid according to Scheme 2. We tried to
optimize the yields and particularly step v (Scheme 2)
by varying the conditions; the results for 17 are reported
in Table 1. For the â-sustituted â-alanine derivatives,
greater reaction times at low temperature failed to
improve the yields. Presently the optimal conditions
require 2 equiv of the imide salt and just 15 min at -20
°C, followed by 2 h at rt. The synthetic route employed
to obtain the asymmetric N-Boc â-alanine N-carboxyan-
hydride is shown in Scheme 3.
Having sucessfully formed several â-alanine N-tert-
butyloxycarbonyl N-carboxyanhydrides, we were inter-
ested in understanding the utility of these compounds.
Nucleophilic attack of benzylamine, benzyl alcohol, and
the lithium enolate of ethyl acetate on the UNCA
derivatives of â-amino acids including 16, 17, and 18
proved to be very rapid, and a clean reaction was
obtained (Scheme 4). We19 have described that reduction
of UNCA derivatives of R-amino acids with LiAlH4
produced the corresponding aldehydes in fairly good
conditions. Reduction of the UNCA derivatives of â-amino
acids (e.g., Boc-â-Ala NCA) under the same conditions
yielded only the corresponding alcohol instead of the
desired aldehydes.
(18) Saurda, J .; Chertanova, L.; Wakselman, M. Tetrahedron 1994,
50, 5309.
(19) Fehrentz, J . A.; Pothion, C.; Califano, J . C.; Loffet, A.; Martinez,
J . Tetrahedron Lett. 1994, 35, 9031.

Urethane N-Carboxyanhydrides from â-Amino Acids
J . Org. Chem., Vol. 66, No. 20, 2001 6543
(CDCl3) δ 7.40-7.32 (5H, m, ArH), 5.18 (2H, s, CH2C6H5), 4.91
(1H, br s, NH), 3.21-3.45 (2H, m), 2.72-2.69 (1H, m), 1.45
Con clu sion
t
A general strategy for the synthesis of N-tert-butyloxy-
carbonyl â-amino acid N-carboxyanhydrides has been
accomplished; these derivatives are crystalline and stable.
However they showed a high reactivity toward nucleo-
philes. We have begun to understand the stability and
reactivity of these compounds; however, there is still
much work to be done to fully understand the utility of
N-protected â-alanine N-carboxyanhydrides.
(9H, s, Bu), 1.24 (3H, d, J ) 6.8, CHCH3).
Ben zyl 3-(Di-ter t-bu tyloxyca r bon yla m in op r op ion a te)
(N-Bis-Boc-â-a la n in e ben zyl ester , 10). N-Boc-â-alanine
benzyl ester (384 mg, 1.4 mmol) was dissolved in freshly
distilled acetonitrile (8 mL). Di-tert-butyl dicarbonate (326 mg,
1.5 mmol) was added to the solution, followed by DMAP (16
mg, 5% w/w). After 12 h of stirring at room temperature,
starting material remained, so a further 2 equiv of Boc-
anhydride and DMAP were added at 12 h intervals. The
reaction was treated with H2O (10 mL) and the product
extracted into EtOAc (3 × 10 mL). The combined organic
phases were dried (MgSO4) and evaporated under vacuum to
give 320 mg (61%) of N-bis Boc-â-alanine benzyl ester: Rf 0.46
Exp er im en ta l Section
All reactions were conducted under a positive pressure of
argon at ambient temperature unless otherwise indicated.
Temperatures designated 0, -20, or -30 °C are approximate
and refer to bath temperature. Silica gel (70-230) mesh was
used for column chromatography. Acetonitrile was distilled
from CaH2 immediately before use. 1H NMR spectra were
recorded on a Bruker at 200 MHz in CDCl3 unless otherwise
indicated. Mass spectra were recorded on J EOL DX 300 and
SX 102. Infrared spectra were performed on a Perkin-Elmer
Paragon 1000. Melting points are uncorrected.
1
(hex/EtOAc, 4:1); m/z (ES) 380 (M+ + 1); H NMR (CDCl3) δ
7.40-7.30 (5H, m, ArH), 5.12 (2H, s, CH2C6H5), 3.94 (2H, t, J
t
) 7,6), 2.69 (2H, t, J ) 7,0), 1.51 (18H, s, 2 × Bu).
Using the same procedure, 11 and 12 were obtained.
Ben zyl 3-(d i-ter t-bu tyloxyca r bon yla m in o)bu tyr a te (N-
bis-Boc-â-m eth yl-â-a la n in e ben zyl ester , 11): 60%; Rf 0.60
1
(hex/EtOAc, 6:1); m/z (ES) 390 (M+ + 1); H NMR (CDCl3) δ
7.38-7.29 (5H, m, ArH), 5.33 (1H, AB d, J ) 12.3), 5.14 (1H,
AB d, J ) 12.3), 4.85-4.67 (1H, m, CHCH3), 3.04 (1H, dd, J )
3-(ter t-Bu t yloxyca r b on yla m in o)p r op ion ic Acid (N-
Boc-â-a la n in e, 2). To a solution of â-alanine (2.0 g, 22 mmol)
in H2O (12 mL) were added di-tert-butyl dicarbonate (4.85 g,
22 mmol), sodium hydroxide (1.0 g, 25 mmol) in H2O (10 mL),
and 2-methyl-2-propanol (16.5 mL). The reaction mixture was
heated to 30 °C and stirred at room temperature. After 18 h,
the solution was evaporated in vacuo and H2O added (50 mL).
The product was extracted into EtOAc (3 × 30 mL), dried
(MgSO4), and evaporated to dryness under vacuum to afford
3.10 g (73%) of the desired product: Rf 0.85 (EtOH/NH4OH,
3:2); vmax cm-1 (film) 3438 (N-H), 2967 (C-H), 1704 (CdO),
t
15.7, 7.5), 2.77 (1H, dd, J ) 15.6, 7.2), 1.51 (9H, s, Bu), 1.38
(3H, d, J ) 6.9, CHCH3).
Ben zyl 2-m et h yl-3-(d i-ter t-b u t yloxyca r bon yla m in o)-
p r op ion a te (N-bis-Boc-r-m eth yl-â-a la n in e ben zyl ester ,
12): 81%; Rf 0.57 (hex/EtOAc, 4:1); m/z (ES) 390 (M + H+);
1H NMR (CDCl3) δ 7.37-7.29 (5H, m, ArH), 5.17 (1H, AB d, J
) 12.5, CH2C6H5), 5.09 (1H, AB d, J ) 12.5, CH2C6H5), 3.83
(1H, dd, J ) 14.0, 6.5), 3.68 (1H, dd, J ) 14.0, 7.3), 2.96-2.86
t
(1H, m, CHCH3), 1.49 (18H, s, 2 × Bu), 1.19 (3H, d, J ) 7.0).
3-(Di-ter t-bu tyloxyca r bon yla m in o)p r op ion ic Acid (N-
Bis-Boc-â-a la n in e, 13). A solution of N-bis-Boc-â-alanine
benzyl ester (320 mg, 0.8 mmol) in methanol (9 mL) was added
to a suspension of palladium hydroxide on carbon (32 mg, 10%
w/w) in methanol (10 mL), and the solution was hydrogenated.
After 2 h, the suspension was filtered through Celite and the
filtrate evaporated to dryness to afford the desired compound
as a white powder (239 mg, 98%): Rf 0.48 (MeOH/CH2Cl2, 95:
5); mp 102-103 °C; m/z (ES) 312 (M+ + Na); 1H NMR (CDCl3)
δ 3.90 (2H, t, J ) 7.0), 2.72 (2H, t, J ) 7.5), 1.52 (18H, s, 2 ×
tBu).
1
1510, 1238; H NMR (CDCl3) δ 10.10 (1H, br s, CO2H), 5.12
(1H, br s, NH), 3.06-3.77 (2H, m), 2.39-2.84 (2H, m), 1.46
t
(9H, s, Bu).
Using the same procedure, 5 and 6 were prepared.
3-(ter t-Bu tyloxyca r bon yla m in o)bu tyr ic Acid (N-Boc-
â-m eth yl-â-a la n in e, 5): 99%; Rf 0.24 (MeOH/CH2Cl2, 95:5);
1H NMR (CDCl3) δ 5.00 (1H, br s, NH), 4.06-4.09 (1H, m,
CHCH3), 2.51-2.59 (2H, m), 1.47 (9H, s, tBu), 1.29 (3H, t, J )
6.8).
2-Meth yl-3-(ter t-bu tyloxycar bon ylam in o)pr opion ic acid
(N-Boc-R-m eth yl-â-a la n in e, 6): 99%; Rf 0.74 (EtOH/NH4-
Using the same procedure, 14 and 15 were prepared.
3-(Di-ter t-bu tyloxyca r bon yla m in o)bu tyr ic a cid (N-bis-
Boc-â-m eth yl-â-a la n in e, 14): 82%; mp 79-80 °C; Rf 0.52
(MeOH/CH2Cl2, 95:5); m/z (ES) 304 (M+ + 1); 1H NMR (CDCl3)
δ 4.63-4.80 (1H, m), 3.06 (1H, dd, J ) 16.3, 7.5), 2.74 (1H,
1
OH, 4:1); H NMR (CDCl3) δ 7.30 (1H, br s, CO2H), 5.06 (1H,
br s, NH), 3.47-3.25 (2H, m), 2.82-2.63 (2H, m), 1.46 (9H, s,
tBu), 1.29 (3H, d, J ) 7.7, CH3).
Ben zyl 3-(ter t-Bu tyloxyca r bon yla m in o)p r op ion a te (N-
Boc-â-a la n in e ben zyl ester , 7). N-Boc-â-alanine (400 mg,
2.1 mmol) was dissolved in MeOH/H2O (10/1, 22 mL) and
treated with cesium carbonate (342 mg, 1.05 mmol) until the
solution was neutralized. The resulting cesium salt was
evaporated to dryness and redissolved in DMF (8 mL). Benzyl
bromide (251 µL, 2.1 mmol) was added dropwise to the cesium
salt. After 22 h, the DMF was evaporated and the residue
treated with H2O (30 mL) and EtOAc (3 × 25 mL). The
combined organic phases were dried (MgSO4) and evaporated
under vacuum to give 534 mg (90%) of N-Boc-â-alanine benzyl
ester: Rf 0.38 (hex/EtOAc, 4:1); m/z (ES) 581 (2M+ + Na), 279
t
dd, J ) 16.3, 7.0), 1.51 (18H, s, 2 × Bu), 1.38 (3H, d, J ) 6.9,
CHCH3).
2-Met h yl-3-(d i-ter t-b u t yloxyca r b on yla m in o)p r op ion -
ic a cid (N-bis-Boc-r-m eth yl-â-a la n in e, 15): white powder
(86%); Rf 0.64 (MeOH/CH2Cl2, 4:1); mp 49-50 °C; m/z (ES)
t
304 (M+ + 1), 248 (M+ - Bu), 204 (M+ - Boc); 1H NMR
(CDCl3) δ 3.97 (1H, dd, J ) 14.1, 7.3), 3.72 (1H, dd, J ) 14.1,
t
7.0), 2.96-2.78 (1H, m, CHCH3), 1.50 (18H, s, 2 × Bu), 1.18
(3H, d, J ) 7.1, CHCH3).
3-ter t-Bu t yloxyca r b on yl-4,5-d ih yd r o-1,3-oxa zin e-2,6-
d ion e (N-Boc-â-a la n in e N-ca r b oxya n h yd r id e, 16). To a
cooled (-20 °C) solution of DMF (804 µL, 10.4 mmol) in freshly
distilled acetonitrile (5 mL) was added dropwise oxalyl chloride
(907 µL, 10.4 mmol). After 30 min of stirring at -20 °C, a
cooled solution (-20 °C) of N-bis-Boc-â-alanine (500 mg, 1.7
mmol) and pyridine (140 µL, 1.73 mmol) in acetonitrile (3 mL)
was added dropwise. The solution was stirred at -20 °C for 2
h and then allowed to warm to room temperature (over 1 h)
and stirred for a further 4 h. The reaction was quenched by
pouring onto ice and the product extracted into EtOAc (3 ×
10 mL), dried (MgSO4), and evaporated under vacuum to afford
the desired Boc-â-Ala NCA as a crude oil; recrystallization
from ethyl acetate gave 231 mg (62%): mp 102-103 °C; m/z
(FAB positive) 216 (M + H+) (found: C, 50.31, H, 6.07, N, 6.49;
C9H13NO5 requires C, 50.23, H, 6.09, N, 6.51); vmax cm-1 (film)
(M+ + 1), 179 (-Boc); H NMR (CDCl3) δ 7.28-7.40 (5H, m,
ArH), 5.18 (2H, s, CH2C6H5), 5,10 (1H, br s, NH), 3.45 (2H, t,
J ) 6.0), 2.61 (2H, t, J ) 6.0), 1.45 (9H, s, Bu).
1
t
Using the same procedure, 8 and 9 were synthesized.
Ben zyl 3-(ter t-bu tyloxyca r bon yla m in o)bu tyr a te (N-
Boc-â-m eth yl-â-a la n in e ben zyl ester , 8): 91%; Rf 0.39 (hex/
EtOAc, 6:1); m/z (ES) 294 (M+ + 1), 179 (-tBu); 1H NMR
(CDCl3) δ 7.40-7.37 (5H, m, ArH), 5.15 (2H, s, CH2C6H5), 4.92
(1H, br s, NH), 4.11-4.01 (1H, m, CHCH3), 2.60 (2H, ddd, J
t
21.0, 15.5, 5.5, CH2), 1.45 (9H, s, Bu), 1.24 (3H, d, J 6.8,
CHCH3).
Ben zyl 2-m eth yl-3-(ter t-bu tyloxyca r bon yla m in o)p r o-
p ion a te (N-Boc-r-m eth yl-â-a la n in e ben zyl ester , 9): 84%;
Rf 0.36 (hex/EtOAc, 6:1); m/z (ES) 294 (M+ + 1); 1H NMR

6544 J . Org. Chem., Vol. 66, No. 20, 2001
McKiernan et al.
1
2982, 2935, 1825, 1787, 1745; H NMR (CDCl3) δ 3.94 (2H, t,
(S)-3-ter t-Bu tyloxyca r bon yl-4-ben zyl-4,5-d ih yd r o-1,3-
oxa zin e-2,6-d ion e (Boc-â-h om o-p h en yla la n in e N-ca r -
boxya n h yd r id e, 24). Following the procedure described for
16, Boc-â-homo-phe-Ala NCA was obtained as a crude oil and
recrystallized from ethyl acetate (65%): mp 114-115 °C; m/z
(ES positive) 306 (M+ + 1), 291 (M+ - 15), 279 (M+ - 27), 250
(M+ - 56), 206 (M+ - 100); C16H19NO5 requires C, 62.94, H,
6.27, N, 4.54 (found C, 63.17, H, 6.35, N, 4.58); 1H NMR
(CDCl3) δ 7.42-7.18 (5H, m), 4.72-4.61 (1H, m), 3.20 (1H, dd,
t
J ) 6.2), 2.90 (2H, t, J ) 6.4), 1.57 (18H, s, 2 × Bu).
Using the same procedure, 17 and 18 were prepared.
3-ter t-Bu tyloxyca r bon yl-4-m eth yl-4,5-d ih yd r o-1,3-ox-
a zin e 2,6-d ion e (â-m et h yl-â-a la n in e N-ca r b oxya n h y-
d r id e, 17): white needles, (62%); mp 144-145 °C; m/z (FAB)
230 (M+ +1) (found: C, 52.19, H, 6.72, N, 6.13; C10H15NO5
requires C, 52.40, H, 6 0.60, N, 6.11); vmax cm-1 (film) 2980,
2928, 1814, 1792, 1774; 1H NMR (CDCl3) δ 4.71-4.57 (1H, m,
CHCH3), 3.05 (1H, dd, J ) 16.6, 5.9), 2.82 (1H, dd, J ) 16.6,
J ) 13.4, 5.4), 2.82 (2H, d, J ) 3.9), 2.78 (1H, dd, J ) 13.5,
t
2.0), 1.59 (9H, s, Bu), 1.40 (3H, d, J ) 6.7, CHCH3).
t
7.8), 1.56 (9H, s, Bu); [R]20 ) -38 (c ) 1, CH2Cl2).
D
3-ter t-Bu tyloxyca r bon yl-5-m eth yl-4,5-d ih yd r o-1,3-ox-
a zin e-2,6-d ion e (N-Boc-r-m eth yl-â-a la n in e N-ca r boxy-
a n h yd r id e, 18): 62%; mp 89-90 °C; m/z (FAB) 230 (M+ + 1)
(found: C, 52.21, H, 6.72, N, 6.21; C10H15NO5 requires C, 52.40,
H, 6.60, N, 6.11); 1H NMR (CDCl3) δ 4.20 (1H, dd, J 13.2, 5.8),
3.49 (1H, dd, J ) 13.1, 11.8), 3.00-2.73 (1H, m), 1.52 (9H, s,
tBu), 1.39 (3H, d, J ) 6.9).
Rea ction s of N-ter t-Bu tyloxyca r bon yl N-Ca r boxya n -
h yd r id es w it h Nu cleop h iles. R ea ct ion w it h Ben zyl-
a m in e. To a solution of Boc-â-alanine NCA 16 (63 mg, 0.29
mmol) in THF (1 mL) was added benzylamine (32 µL, 0.29
mmol). After 10 min, the CO2 evolution ceased, the reaction
was quenched with H2O (2 mL), and the product was extracted
into EtOAc (2 × 5 mL). The organic phases were combined,
washed with brine, dried (MgSO4), and evaporated to dryness
to afford 63 mg (78%) of the desired product 25 as a white
powder: Rf 0.38 (hex/EtOAc, 4:1); mp 121-122 °C; m/z (ES)
279 (M + H); 1H NMR (CDCl3) δ 7.28-7.39 (5H, m, ArH), 6.03
(1H, br s NH), 5.22 (1H, br s, NH), 4.49 (2H, d, J ) 5.7), 3.5
(S)-Meth yl 3-(d i-ter t-bu tyloxyca r bon yla m in o)bu tyr a te
(bis-Boc-â-m eth yl-â-a la n in e m eth yl ester , 19) was pre-
pared by following the procedure described for 10. Purification
by column chromatography (4:1, hexane/EtOAc) afforded the
desired product (50% conversion) and starting material: Rf 0.51
(hex/EtOAc, 6:1); m/z (ES) 286 (M + H+); H NMR (CDCl3) δ
1
t
4.80-4.63 (1H, m, CHCH3), 3.68 (3H, s, CO2CH3), 2.96 (1H,
(2H, q, J ) 5.6), 2.51 (2H, t, J ) 5.8), 1.49 (9H, s, Bu).
dd, J ) 15.6, 7.5, CH2), 2.71 (1H, dd, J ) 15.6, 7.2, CH2), 1.53
From the same procedure starting from 17 (54 mg, 0.24
mmol) in THF (1 mL), benzylamine (26 mL, 0.24 mmol) gave
26. The reaction was stirred overnight until a white precipitate
formed; then the reaction was quenched as before to afford 66
mg (96%) of the desired product 26 as a white powder: Rf 0.38
(hex/EtOAc, 4:1); mp 142-143 °C; m/z (ES) 293 (M + H+); 1H
NMR (CDCl3) 7.26-7.41 (5H, m, ArH), 6.17 (1H, br s NH),
5.19 (1H, br s, NH), 4.48 (2H, d, J ) 5.7), 4.03-3.90 (1H, m),
(18H, s, 2 × Bu), 1.32 (3H, d, J ) 6.9); [R]20 ) +27 (c ) 1,
t
D
CH2Cl2).
(S)-3-(Di-ter t-bu tyloxycar bon ylam in o)bu tyr ic Acid (Bis-
Boc-â-m et h yl-â-a la n in e, 21). Bis-Boc-â-methyl-â-alanine
methyl ester (179 mg, 0.6 mmol) was added to a solution of
sodium hydroxide (28 mg, 0.7 mmol) in dioxane/H2O (1 mL,
1:9), and the solution was stirred at rt overnight. The dioxane
was removed under vacuum, and then the residue was treated
with 10% citric acid followed by EtOAc (3 × 5 mL). The organic
phases were combined, dried (MgSO4), and evaporated under
vacuum to afford 137 mg (95%) of the product as a white
powder: mp 79-80 °C; 1H NMR (CDCl3) δ 4.80-4.63 (1H, m,
CHCH3), 3.07 (1H, dd, J ) 16.4,7.5, CH2), 2.75 (1H, dd, J )
t
2.48 (2H, dd, J ) 5.9, 2.9), 1.44 (9H, s, Bu), 1.28 (3H, d, J )
6.7); νmax cm-1 (film) 1678, 1528.
Rea ction w ith Ben zyl Alcoh ol. To a solution of Boc-â-
alanine NCA 16 (32 mg, 0.15 mmol) in THF (1 mL) was added
benzyl alcohol (16 µL, 0.29 mmol). After 1 h, the reaction was
quenched with H2O (2 mL) and the product was extracted into
EtOAc (3 × 5 mL). The organic phases were combined, washed
with brine, dried (MgSO4), and evaporated. Chromatography
of the residue using hexane/ethyl acetate (9/1) as eluent yielded
the desired product 7, 29 mg (79%): Rf 0.38 (hex/EtOAc, 4/1);
m/z (ES) M+ 280; 1H NMR (CDCl3) δ 7.28-7.40 (5H, m, ArH),
5.18 (2H, s, CH2C6H5), 5.10 (1H, bs, NH), 3.45 (2H, t, J ) 6.0),
t
16.4, 7.0, CH2), 1.52 (18H, s, 2 × Bu), 1.39 (3H, d, J ) 6.9);
[R]20 ) +32 (c ) 1, CH2Cl2).
D
(S)-3-ter t-Bu tyloxyca r bon yl-4-m eth yl-4,5-d ih yd r o-1,3-
oxa zin e-2,6-d ion e (Boc-â-m eth yl-â-a la n in e N-ca r boxy-
a n h yd r id e, 23). Following the procedure described for 16,
Boc-â-methyl-â-Ala NCA was obtained as a crude oil. Recrys-
tallization from ethyl acetate gave white needles (53%): m/z
(ES positive) 481 (2M+ + Na), 252 (M+ + Na), 230 (M+ + 1),
174 (M+ - 56). Spectroscopic data obtained were the same as
t
2.61 (2H, t, J ) 6.0), 1.45 (9H, s, Bu).
given for compound 17. [R]20 ) -68 (c ) 1, CH2Cl2).
Rea ction w ith th e Lith iu m En ola te of Eth yl Aceta te.
To a solution of ethyl acetate (0.1 mL, 1.05 mmol) in THF (1
mL) was added a solution of lithium diisopropyl amide (1.5
mL, solution at 2 mol/L). After 30 min, the solution was added
to a cooled solution (-80 °C) of 18 (172 mg, 0.75 mmol) in THF
(3 mL). After 2 h, the reaction was quenched with H2O (5 mL)
and the product was extracted into EtOAc (3 × 20 mL). The
organic phases were combined, washed with brine, dried
(MgSO4), and evaporated. Chromatography of the residue
using hexane/ethyl acetate (9:1) as eluent gave the desired
product 27: 110 mg (54%); Rf 0.3 (hex/EtOAc, 4:1); m/z (ES)
D
(S)-Meth yl 3-(Di-ter t-bu tyloxyca r bon yla m in o)-4-p h en -
ylbu tyr a te (Bis-Boc-â-h om o-p h en yla la n in e m eth yl ester ,
20). Following the procedure described for 10 and purification
carried out using column chromatography in hexane/EtOAc
(5:1) afforded the desired product (45%) and starting mate-
rial: Rf 0.52 (hex/EtOAc, 6:1); m/z (ES) 394 (M+ + 1), 338 (M+
- 56), 382 (M+ - 112); H NMR (CDCl3) δ 7.16-7.34 (5H, m,
1
ArH), 4.91-4.81 (1H, m, CHCH3), 3.23 (1H, dd, J ) 13.4, 8.7),
3.07-2.88 (2H, m), 2.73 (1H, dd, J ) 15.8, 6.2), 1.45 (18H, s,
2 × Bu); [R]20 ) -38 (c ) 1, CH2Cl2).
t
D
1
(S)-3-(Di-ter t-bu tyloxyca r bon ya m in o)-4-p h en ylbu tyr -
ic a cid (bis-Boc-â-h om o-p h en yla la n in e, 22) was prepared
by following the procedure described for 21: 68%; Rf 0.6
(MeOH/CH2Cl2, 6:1); 1H NMR (CDCl3) δ 9.91 (1H, br s, CO2H),
274 (M + H); H NMR (CDCl3) δ 4.90 (1H, br m, NH), 4.15
(2H, q, J ) 7.2, O-CH2-CH3), 3.40 (2H, s, CO-CH2-CO), 3.20
(2H, m, CH-CH2-NH), 2.9 (1H, m, CH3-CH-CH2), 1.4 (9H, s,
tBu), 1.25 (3H, t, J ) 7.2, O-CH2-CH3), 1.1 (3H, d, J ) 7.2,
CH-CH3).
7.19-7.31 (5H, m), 4.94-4.84 (1H, m), 3.20-2.90 (3H, m), 2.75
(1H, dd, J ) 16.6,6.1), 1.44 (18H, s, 2 × Bu.); [R]20 ) -30 (c
t
D
) 1, CH2Cl2).
J O001583Y