Rapid procedure for N-phthaloylation of α-amino carboxamides, α-amino alcohols, α-amino esters and dipeptide derivatives

Article abstract of DOI:10.1055/s-2001-17710

A rapid, one-pot synthesis and mild procedure for the N-phthaloylation of α-amino carboxamides is described. In acetonitrile, these derivatives react with mono-methylphthalate in the presence of BOP and i-Pr₂NEt to afford the intermediate N^α-[(o-methoxycarbonyl)benzoyl]amino carboxamides, which undergo rapid cyclization in the presence of aqueous sodium carbonate to afford the corresponding N^α-phthaloylamino carboxamides in excellent yields. The reaction also works efficiently with α-amino esters, α-amino alcohols and dipeptide esters or amides.

Full text of DOI:10.1055/s-2001-17710

PAPER
1985
Rapid Procedure for N-Phthaloylation of -Amino Carboxamides, -Amino
Alcohols, -Amino Esters and Dipeptide Derivatives
R
apid Pro
.
cedure for
NR
a
Laboratoire de Chimie Immunologique, UPR 9021 CNRS (IBMC), 15 rue René Descartes, 67084 Strasbourg cedex, France
b
Department of Organic Chemistry, Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050 Brussels, Belgium
Fax +33(3)88610680; E-mail: CASIMIR.Richard@wanadoo.fr
Received 15 May 2001; revised 19 June 2001
dures.13 In particular, the reaction of amino acids with
phthalic anhydride requires heating and can cause racem-
ization.14-16 Although this latter problem was thought to be
resolved by the introduction of the well-known N-(ethox-
Abstract: A rapid, one-pot synthesis and mild procedure for the N-
phthaloylation of -amino carboxamides is described. In acetoni-
trile, these derivatives react with mono-methylphthalate in the pres-
ence of BOP and i-Pr2NEt to afford the intermediate N -[(o-
methoxycarbonyl)benzoyl]amino carboxamides, which undergo ycarbonyl)phthalimide by Nefkens et al,6 low yields have
rapid cyclization in the presence of aqueous sodium carbonate to af-
been experienced when this reagent was used with amino
alcohols or sterically hindered amino acids.7,17–19
ford the corresponding N -phthaloylamino carboxamides in excel-
lent yields. The reaction also works efficiently with -amino esters,
In our ongoing work on the synthesis of 4-amino-2-benza-
zepin-3-ones,20,21 we required a mild and rapid method for
the sythesis of N -phthaloylamino carboxamides. Howev-
er, only 50-60% yields of the desired phthaloylated prod-
ucts were obtained when the Nefkens’ procedure was
repeated with -amino carboxamides. For this reason, we
decided to investigate new methods for the protection of
these compounds.
-amino alcohols and dipeptide esters or amides.
Key words: phthaloyl protection -amino carboxamides, mono-
methylphthalate -amino alcohols, cyclization
N-Phthaloylation is a widely used methodology for pro-
tecting the primary amino groups in amino acids and pep-
tides. In addition to the fact that N-phthaloylated
compounds are stable and easily recrystallized, the phtha-
loyl protection can be easily removed under mild condi-
tions using methylhydrazine, phenylhydrazine, or
hydrazine.1–3 However, although the phthaloylation of -
amino acids, carboxamides, esters, nitriles, and alcohols
are well documented,3–12 low yields and low optical puri-
ties have been experienced with the literature proce-
In this paper, we report a rapid and mild procedure for the
preparation of N -phthaloylamino carboxamides, which is
also applicable to N-phthaloylation of -amino alcohols,
-amino esters, and dipeptide derivatives.
The procedure is based on the activation of 2-(methoxy-
carbonyl)benzoic acid 1 with BOP [benzotriazole-1-yl-
oxy-tris-(dimethylamino)-phosphoniumhexafluorophos-
O
O
OMe
R1
HCl H2N
H
OMe
OH
a
H
+
N
R2
R2
R1
H
O
O
2a-m
3a-m
1
b
66-100%
O
R1
H
N
R2
O
4a-m
a. MeCN, BOP, i-Pr2NEt, r.t., 30 min. b. Na2CO3/H2O, r.t., 30-240 min.
Scheme
Synthesis 2001, No. 13, 08 10 2001. Article Identifier:
1437-210X,E;2001,0,13,1985,1988,ftx,en;Z05001SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1986
J. R. Casimir et al.
PAPER
Table BOP-Na2CO3 Promoted N-Phthaloylation of -Amino
Carboxamides, Esters, Alcohols and Dipeptide Derivatives
phate] in acetonitrile containing ethyl-diisopropylamine,
followed by reaction with -amino carboxamides 2a–f
(Table) to afford the intermediate phthalamic derivatives
3a–f (scheme). As demonstrated by C18 RP-HPLC analy-
sis of the reaction mixture after 30 min, compounds 2a–f,
were rapidly converted to the corresponding intermedi-
ates 3a–f. However, in these conditions, the transforma-
tion of these intermediates into the desired phthaloylated
derivatives 4a–f, proceeded very slowly, showing that
stronger bases were needed to accelerate the cyclization
process. The miscibility of acetonitrile with water enabled
us to take advantage of inorganic bases which could ulti-
mately be removed from the reaction mixture by aqueous
washings. Indeed, the intermediates 3a–f, were rapidly
converted to the N-phthaloyl derivatives 4a–f when aque-
ous sodium carbonate was added to the mixture. In the
case of -amino carboxamides, the cyclization reaction
was completed in less than 30 min and the desired prod-
ucts were isolated in very good yields (66–100%, Table)
after dilution with ethylacetate, aqueous washings, and
elimination of the solvents under reduced pressure. This
implies phthalimides 4a–f formed in this manner are sta-
ble to the aqueous sodium carbonate solution used and
that only water-soluble by-products are formed during the
reaction.
Prod- R1 (chirality)
uct
R2
Time Rt
Yield
(min)a (min)b(%)c,d
4a
4b
CONH2
CONH2
30 12.61 78
30 12.43 96
30 13.12 78
4c
4d
4e
CONH2
CONH2
CONH2
30 12.52 77
30 15.18 69
4f
CO2Bn
CO2Me
CO2t-Bu
30 11.34 66
210 17.29 100e
120 15.00 88e
In order to evaluate the applicability of the procedure to
the phthaloylation -amino alcohols, -amino esters and
dipeptide esters, compounds 2g–m were allowed to react
with 2-(methoxycarbonyl)benzoic acid (1) under the con-
ditions described above. As shown in the Table, the de-
sired phthaloylated compounds 4g–m were obtained in
very good yields, although the cyclization proceeded less
rapidly with benzyl and methyl valinates.
4g
4h
4i
4j
CO2t-Bu
30 15.79 97
30 13.63 76
As demonstrated by GITC (1,3,4,6-tetra-O-acetyl- -D-
glucopyranosyl isothiocyanate) analysis of compounds 4b
and 4d after removal of the phthaloyl protection by hy-
drazinolysis,4,22,23 only the S-isomers were obtained show-
ing that no racemization takes place during the course of
the reaction.
CH2OH
4k
30 14.56 66
In conclusion, we report a rapid and racemization-free
procedure for the preparation of phthaloyl derivatives of
-amino carboxamides, -amino alcohols, -amino esters,
and dipeptides derivatives. We believe that this mild and
simple procedure will be very useful for protecting the
amino groups in a wide range of compounds.
4l
30 15.66 100
30 17.29 67f
4m
Analytical grade CH3CN was used without further purification for
all experiments. Melting points were measured on a Büchi 530 in-
strument and were not corrected. Optical rotations were determined
at 22 °C on a Perkin-Elmer 241 polarimeter. Mass spectra (positive
mode) were recorded on a linear MALDI-TOF instrument (Bruker
Bremen) using -cyano-4-hydroxycinnamic acid as a matrix. Exact
mass measurements (EMM) were recorded at low resolution using
electrospray ionization and a quadrupole VG Quattro II mass spec-
trometer (EI+, conevoltage 40) with poly(ethyleneglycol)monome-
thylether as standard.24 1D NMR spectra were recorded in DMSO-
d6 or CDCl3 on a Bruker AC 200 MHz spectrometer. Analytical
HPLC was recorded at 30 °C on a Nucleosil C18 column (8 m, 3.9
150 mm) using a linear gradient of 0–100% of B (0.08% TFA in
a Time taken for the cyclization of intermediates 2a–k into 4a–k.
b Determined by C18 RP-HPLC.
c Yields of isolated products.
d All products are white solids, except 4g and 4h.
e Colourless oil.
f Obtained after purification by flash chromatography in hex-
anes–ethyl acetate 70:30.
Synthesis 2001, No. 13, 1985–1988 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Rapid Procedure for N-Phthaloylation
1987
MeCN) in A (0.1% TFA in H2O) for 20 min at a flow rate of 1.2 mL/
min with UV detection at 214 nm, except for GITC experiments
where a gradient of 20–50% of B in A was used with UV detection
at 250 nm. TLC was performed on aluminium sheets coated with
silica gel 60 F254 (Merck, Darmstadt) in hexanes–EtOAc–HOAc,
70:30:5.
13C NMR (50 MHz, DMSO-d6): = 33.7 (CH2), 54.2 (CH), 122.9
(CH), 126.3 (CH), 128.2 (CH), 128.6 (CH), 131.2 (C), 134.4 (CH),
137.7 (C), 167.4 (C), 169.6 (C).
MS: m/z = 295 (M+ + H), 317 (M+ + Na), 333 (M+ + K).
N -Phthaloyl-(S)-O-benzyltyrosinamide (4e).
White solid (1.38 g, 69%); mp 158 °C; Rf = 0.26; HPLC Rt = 15.18
min; [ ]D –162.1 (c = 1.0, MeOH).
1H NMR (200 MHz, DMSO-d6): = 3.41 (m, 2 H), 4.94 (dd, 1 H, J
= 11.7, 4.7 Hz), 5.0 (s, 2 H), 6.84 (d, 2 H , J = 8.6 Hz), 7.08 (d, 2 H,
J = 8.6 Hz), 7.33–7.43 (m, 6 H), 7.75 (s, 1 H), 7.85 (s, 4 H).
13C NMR (50 MHz, DMSO-d6): = 32.8 (CH2), 54.4 (CH), 68.9
(CH2), 114.5 (CH), 122.9 (CH), 127.5 (CH), 128.2 (CH), 129.5
(CH), 129.8 (C), 131.2 (C), 134.3 (CH), 136.9 (C), 156.8 (C), 167.4
(C), 169.6 (C).
N-Phthaloylation of -Amino Carboxamides and Dipeptides;
Typical Procedure
A solution of 2-(methoxycarbonyl)benzoic acid 1 (0.90 g, 5.0
mmol), -amino carboxamide, -amino ester or dipeptides 2 (5.0
mmol), BOP (2.26 g, 5.0 mmol), and i-Pr2NEt (3.4 mL, 20.0 mmol)
in CH3CN (40 mL) were stirred at r.t. for 30 min. A solution of
Na2CO3 (1.06 g, 10 mmol) in H2O (20 mL) was then added and stir-
ring was continued for 0.5–4 h (Table). After evaporation of the
CH3CN and dilution with EtOAc (100 mL), the organic phase was
washed with saturated NaHCO3 solution (3 50 mL), 1 N HCl (1
50 ml), H2O (1 50 mL), dried with Na2SO4, and evaporated to af-
ford the pure product in very good yield.
MS: m/z = 423 (M+ + Na), 439 (M+ + K).
EMM (m/z): [M + H]+ calcd for C24H20N2O4, 401.1501; found,
401.1510.
N -Phthaloyl-(S)-leucinamide (4a)
White solid (1.02 g, 78%); mp 160–161 °C; Rf = 0.37; HPLC Rt =
12.61 min; [ ]D –13.2 (c = 1.1, MeOH).
1H NMR (200 MHz, DMSO-d6): = 0.87 (d, 3 H, J = 6.6 Hz), 0.88
(d, 3 H, J = 6.5 Hz), 1.37 (m, 1 H), 1.90 (m, 1 H), 2.20 (m, 1 H),
4.67 (dd, 1 H, J =11.8, 4.3 Hz), 7.23 (s, 1 H), 7.62 (s, 1 H), 7.89 (m,
4 H).
N -Phthaloyl-(S)-valinamide (4f)
White solid (0.81 g, 66%); mp 194–195 °C; Rf = 0.36; HPLC Rt =
11.34 min; [ ]D –21.0 (c = 0.7, MeOH).
1H NMR (200 MHz, DMSO-d6): = 0.77 (d, 3 H, J = 6.8 Hz), 1.02
(d, 3 H, J = 6.7 Hz), 2.69 (m, 1 H), 4.29 (d, 1 H, J = 8.6 Hz), 7.11
(s, 1 H), 7.50 (s, 1 H), 7.88 (m, 4 H).
13C NMR (50 MHz, DMSO-d6): = 19.2 (CH3), 20.9 (CH3), 27.1
(CH), 58.4 (CH), 123.1 (CH), 131.3 (C), 134.5 (CH), 167.6 (C),
169.4 (C).
13C NMR (50 MHz, DMSO-d6): = 20.7 (CH3), 23.1 (CH3), 24.8
(CH), 36.5 (CH2), 51.3 (CH), 123.1 (CH), 131.5 (C), 134.4 (CH),
167.7 (C), 170.4 (C).
MS: m/z = 247 (M+ + H), 269 (M+ + Na), 285 (M+ + K).
MS: m/z = 261 (M+ + H), 283 (M+ + Na), 299 (M+ + K).
Benzyl N -Phthaloyl-(S)-valinate (4g)
Colourless oil (1.69 g, 100%); Rf = 0.70; HPLC Rt = 17.29 min; [ ]D
–47.4 (c = 1.0, MeOH).
N -Phthaloyl-(S)-iso-leucinamide (4b)
White solid (1.25 g, 96%); mp 227–228 °C; Rf = 0.41; HPLC Rt =
12.43 min; [ ]D +4.4 (c = 0.9, HOAc).
1H NMR (200 MHz, DMSO-d6): = 0.80 (d, 3 H, J = 6.8 Hz), 1.02
(d, 3 H, J = 6.7 Hz), 2.60 (m, 1 H), 4.62 (d, 1 H, J = 7.9 Hz), 5.09
(s, 2 H), 7.22 (s, 5 H), 7.86 (m, 4 H).
1H NMR (200 MHz, DMSO-d6): = 0.79 (t, 3 H, J = 7.1 Hz), 0.90
(m, 1 H), 0.99 (d, 3 H, J = 6.7 Hz), 1.38 (m, 1 H), 2.52 (m, 1 H),
4.36 (d, 1 H, J = 9.0 Hz), 7.14 (s, 1 H), 7.51 (s, 1 H), 7.89 (m, 4 H).
13C NMR (50 MHz, DMSO-d6): = 18.9 (CH3), 20.4 (CH3), 28.0
(CH), 56.9 (CH), 66.3 (CH2), 123.4 (CH), 127.6 (CH), 127.9 (CH),
128.2 (CH), 130.8 (C), 134.9 (CH), 135.4 (C), 167.3 (C), 168.1 (C).
13C NMR (50 MHz, DMSO-d6): = 10.6 (CH3), 16.6 (CH3), 25.2
(CH2), 32.8 (CH), 57.9 (CH), 123.1 (CH), 131.2 (C), 134.5 (CH),
167.6 (C), 169.5 (C).
MS: m/z = 360 (M+ + Na), 376 (M+ + K).
MS: m/z = 261 (M+ + H), 283 (M+ + Na), 299 (M+ + K).
EMM (m/z): [M + H]+ calcd for C20H19NO4, 338.1392; found,
338.1489.
N -Phthaloyl-(S)-O-benzylserinamide (4c)
White hygroscopic solid (1.27 g, 78%); Rf = 0.28; HPLC Rt = 13.12
min; [ ]D –32.1 (c = 1.0, MeOH).
1H NMR (200 MHz, CDCl3): = 3.88 (dd, 1 H, J = 6.0, 9.6 Hz),
4.39 (m, 1 H), 4.61 (d, 2 H, J = 4.0 Hz), 5.04 (dd, 1 H, J = 6.0, 8.7
Hz), 6.34 (s, 1 H), 6.89 (s, 1 H), 7.31 (s, 5 H), 7.67–7.85 (m, 4 H).
13C NMR (50 MHz, CDCl3): = 52.0 (CH), 67.6 (CH2), 73.4 (CH2),
123.6 (CH), 127.9 (CH), 128.1 (CH), 128.6 (CH), 131.8 (C), 134.3
(CH), 137.0 (C), 167.8 (C), 169.8 (C).
Methyl N -Phthaloyl-(S)-valinate (4h)
Colourless oil (1.15 g, 88%); Rf = 0.68; HPLC Rt = 15.00 min; [ ]D
–69.7 (c = 1.0, MeOH).
1H NMR (200 MHz, CDCl3): = 0.88 (d, 3 H, J = 6.8 Hz), 1.12 (d,
3 H, J = 6.7 Hz), 2.71 (m, 1 H), 3.68 (s, 3 H), 5.54 (d, 1 H, J = 8.3
Hz), 7.70–7.76 (m, 2 H), 7.77–7.87 (m, 2 H).
13C NMR (50 MHz, DMSO-d6): = 19.4 (CH3), 20.9 (CH3), 28.6
(CH), 52.4 (CH), 57.6 (CH3), 123.4 (CH), 131.7 (C), 134.2 (CH),
167.7 (C), 169.3 (C).
MS: m/z = 347 (M+ + Na), 363 (M+ + K).
EMM (m/z): [M + H]+ calcd for C18H16N2O4, 325.1188; found,
MS: m/z = 262 (M+ + H), 284 (M+ + Na).
325.1192.
t-Butyl N -Phthaloyl-(S)-alaninate (4i)
N -Phthaloyl-(S)-phenylalaninamide (4d)
White solid (1.34 g, 97%); mp 67–69 °C; Rf = 0.72; HPLC Rt =
15.79 min; [ ]D –10.3(c = 1.1, MeOH).
White solid (1.13 g, 77%); mp 226–228 °C; Rf = 0.27; HPLC Rt =
12.52 min; [ ]D –20.4 (c = 1.0, MeOH).
1H NMR (200 MHz, CDCl3): = 1.43 (s, 9 H), 1.64 (d, 3 H, J = 7.3
Hz), 4.87 (q, 1 H, J = 7.3 Hz), 7.70–7.88 (m, 4 H).
13C NMR (50 MHz, CDCl3): = 15.3 (CH3), 27.9 (CH3), 48.4 (CH),
82.3 (C), 123.4 (CH), 132.0 (C), 134.1 (CH), 167.6 (C), 168.7 (C).
1H NMR (200 MHz, DMSO-d6): = 3.34 (dd, 1 H, J = 14.0, 11.8
Hz), 3.53 (dd, 1 H, J = 14.0, 4.8 Hz), 4.93 (dd, 1 H, J =11.8, 4.8 Hz),
7.12 (m, 5 H), 7.32 (s, 1 H), 7.72 (s, 1 H), 7.80 (s, 4 H).
Synthesis 2001, No. 13, 1985–1988 ISSN 0039-7881 © Thieme Stuttgart · New York

1988
J. R. Casimir et al.
PAPER
MS: m/z = 298 (M+ + Na), 314 (M+ + K).
EMM (m/z): [M + Na]+ calcd for C15H17NO4, 298.1055; found,
13.0 (CH), 131.5 (C), 134.3 (CH), 136.9 (C), 157.8 (C), 168.0 (C),
168.5 (C), 172.1 (C).
MS: m/z = 515 (M+ + H), 537 (M+ + Na), 553 (M+ + K).
298.1094.
EMM (m/z): [M + H]+ calcd for C30H30N2O6, 515.2182; found,
515.2189.
N -Phthaloyl-(S)-phenylalaninol (4j)
White solid (1.07 g, 76%); mp 104–106 °C; Rf = 0.41; HPLC Rt =
13.63 min; [ ]D –134.1(c = 1.1, MeOH).
1H NMR (200 MHz, CDCl3): = 3.16 (m, 2 H), 3.29 (bs, 1 H), 3.88
(dd, 1 H, J =11.6, 4.0 Hz), 4.07 (m, 1 H), 4.61 (m, 1 H), 7.15 (m, 5
H), 7.56–7.74 (m, 4 H).
13C NMR (50 MHz, CDCl3): = 34.8 (CH2), 55.3 (CH), 62.6 (CH2),
123.3 (CH), 126.7 (CH), 128.5 (CH), 129.0 (CH), 131.6 (C), 134.0
(CH), 137.5 (C), 169.0 (C).
Acknowledgement
J.R.C. acknowledges financial support from the European Commu-
nity. The authors thank Dr. G. Laus for exact mass measurements
(EMM).
References
MS: m/z = 282 (M+ + H), 288 (M+ + Li), 304 (M+ + Na).
EMM (m/z): [M + H]+ calcd for C17H15NO3, 282.1130; found,
282.1157.
(1) Kukolja, S.; Lammert, S. R. J. Am. Chem. Soc. 1975, 97,
5582.
(2) Schumann, I.; Boissonnas, R. A. Helv. Chim. Acta. 1952, 35,
2235.
(3) Sheehan, J. C.; Chapman, D. W.; Roth, R. W. J. Am. Chem.
Soc. 1952, 74, 3822.
(4) Casimir, J. R.; Guichard, G.; Briand, J.-P. Synthesis 2001,
75.
(5) Billman, J. H.; Harting, W. F. J. Am. Chem. Soc. 1948, 70,
1473.
(6) Nefkens, G. H. L.; Tesser, G. I.; Nivard, R. J. F. Recl.
Trav.Chim. Pays-Bas 1960, 79, 688.
N -Phthaloyl-(S)-O-benzylserinyl-(S)-iso-leucinamide (4k)
White solid (1.44 g, 66%); mp 164–165 °C; Rf = 0.27; HPLC Rt =
14.56 min; [ ]D –43.9(c = 0.9, MeOH).
1H NMR (200 MHz, DMSO-d6): = 0.69 (t, 3 H, J = 7.3 Hz), 0.74
(d, 3 H, J = 7.0 Hz), 0.97 (m, 2 H), 1.65 (m, 1 H), 3.92–4.15 (m, 3
H), 4.36 (d, 1 H, J = 12.1 Hz), 4.48 (d, 1 H, J = 12.1 Hz), 5.00 (dd,
1 H, J = 9.4, 5.9 Hz), 6.98 (s, 1 H), 7.14 (m, 5 H), 7.38 (s, 1 H), 7.83
(m, 4 H), 8.16 (d, 1 H, J = 8.8 Hz).
13C NMR (50 MHz, DMSO-d6): = 10.7 (CH3), 15.4 (CH3), 24.1
(CH2), 35.8 (CH), 51.8 (CH), 56.8 (CH), 66.4 (CH2), 71.7 (CH2),
123.0 (CH), 127.3 (CH), 128.1 (CH), 131.7 (C), 134.4 (CH), 137.9
(C), 166.2 (C), 167.5 (C), 172.7 (C).
MS: m/z = 460 (M+ + Na).
EMM (m/z): [M + H]+ calcd for C24H27N3O5, 438.2029; found,
(7) McArthur, C. R.; Worster, P. M.; Okon, A. U. Synth.
Commun. 1983, 13, 311.
(8) Hoogwater, D. A.; Reinhoudt, D. N.; Lie, T. S.; Gunneweg,
J. J.; Beyerman, H. G. Recl. Trav.Chim. Pays-Bas 1973, 92,
819.
(9) Sheehan, J. C.; Goodman, M.; Hess, G. J. Am. Chem. Soc.
1956, 78, 1367.
(10) Reddy, P. Y.; Kondo, S.; Toru, T.; Ueno, Y. J. Org. Chem.
1997, 62, 2652.
438.2106.
Methyl N -Phthaloyl-(S)-phenylalanyl-(S)-valinate (4l)
White solid (2.04 g, 100%); mp 88-89°C; Rf = 0.49; HPLC Rt =
15.66 min; [ ]D –27.4 (c = 0.7, MeOH).
1H NMR (200 MHz, CDCl3): = 0.83 (d, 3 H, J = 6.9 Hz), 0.92 (d,
3 H, J = 6.9 Hz), 2.14 (m, 1 H), 3.42–3.60 (m, 2 H), 3.67 (s, 3 H),
4.58 (dd, 1 H, J = 4.7, 8.6 Hz), 5.18 (dd, 1 H, J = 6.8, 9.9 Hz), 6.69
(d, 1 H, J = 8.6 Hz), 7.06–7.19 (m, 5 H), 7.66–7.80 (m, 4 H).
13C NMR (50 MHz, CDCl3): = 17.7 (CH3), 18.9 (CH3), 31.4 (CH),
35.1 (CH2), 52.2 (CH), 56.0 (CH), 57.4 (CH3), 123.6 (CH), 127.0
(CH), 128.7 (CH), 128.9 (CH), 131.5 (C), 134.3 (CH), 136.6 (C),
168.0 (C), 168.4 (C), 172.1 (C).
(11) Aguilar, N.; Moyano, A.; Pericàs, M. A.; Riera, A. Synthesis
1998, 313.
(12) Damm, W.; Hoffmann, U.; Macko, L.; Neuburger, M.;
Zehnder, M.; Giese, B. Tetrahedron 1994, 50, 7029.
(13) Fling, M.; Minard, F. N.; Fox, S. W. J. Am. Chem. Soc. 1947,
69, 2466.
(14) Shealy, Y. F.; Opliger, C. E.; Montgomery, J. A. J. Pharm.
Sci. 1968, 57, 757.
(15) Sato, H.; Kusumi, T.; Imaye, K.; Kakisawa, H. Bull. Chem.
Soc. Jpn. 1976, 49, 2815.
(16) Hoffmann, E.; Schiff-Shenhav, H. J. Org. Chem. 1962, 27,
4686.
(17) Worster, P. M.; Leznoff, C. C.; McArthur, C. R. J. Org.
Chem. 1980, 45, 174.
MS: m/z = 409 (M+ + H), 431 (M+ + Na), 447 (M+ + K).
EMM (m/z): [M + H]+ calcd for C23H24N2O5, 409.1763; found,
(18) Adriaens, P.; Meesschaert, B.; Janssen, G.; Dumon, L.;
Eyssen, H. Recl. Trav. Chim. Pays-Bas. 1978, 97, 260.
(19) Wicks, Z. W. Jr.; Chen, G.-F. J. Org. Chem. 1979, 44, 1244.
(20) Casimir, J. R.; Tourwé, D.; Iterbeke, K.; Guichard, G.;
Briand, J.-P. J. Org. Chem. 2000, 65, 6487.
(21) Casimir, J. R.; Iterbeke, K.; van den Nest, W.; Trescol-
Biémont, M.-C.; Dumortier, H.; Muller, S.; Gerlier, D.;
Rabourdin-Combe, C.; Tourwé, D.; Paris, J. J. Peptide Res.
2000, 56, 398.
409.1769.
Methyl N -Phthaloyl-(S)-O-benzyltyrosinyl-(S)-valinate (4m)
White solid (1.77 g, 67%); mp 113–115 °C; Rf = 0.42; HPLC Rt =
17.29 min; [ ]D –114.9 (c = 1.1, MeOH).
1H NMR (200 MHz, CDCl3): = 0.88 (d, 3 H, J = 6.9 Hz), 0.97 (d,
3 H, J = 6.9 Hz), 2.20 (m, 1 H), 3.53–3.58 (m, 2 H), 3.70 (s, 3 H),
4.63 (dd, 1 H, J = 8.62, 4.75 Hz), 4.98 (s, 2 H), 5.18 (dd, 1 H, J =
9.71, 6.96 Hz), 6.77 (m, 1 H), 6.83 (d, 2 H, J = 8.6 Hz), 7.15 (d, 2
H, J = 8.6 Hz), 7.38 (m, 5 H), 7.70–7.85 (m, 4 H).
(22) Nimura, N.; Ogura, H.; Kinoshita, T. J. Chromatogr. 1980,
202, 375.
13C NMR (50 MHz, CDCl3): = 17.7 (CH3), 18.9 (CH3), 31.3 (CH),
34.3 (CH2), 52.2 (CH3), 56.1 (CH), 57.4 (CH), 70.0 (CH2), 115.1
CH), 123.6 (CH), 127.4 (CH), 127.9 (CH), 128.5 (CH), 128.9 (C),
(23) In both cases, the ratio L/D was >99:1.
(24) Tyler, A. N.; Clayton, E.; Green, B. N. Anal. Chem. 1996,
68, 3561.
Synthesis 2001, No. 13, 1985–1988 ISSN 0039-7881 © Thieme Stuttgart · New York