Facile synthesis of hybrid sulfonophosphinodipeptides composing of taurines and 1-aminoalkylphosphinic acids

Article abstract of DOI:10.1007/s00726-011-1098-5

Both sulfonopeptides and phosphonopeptides are important analogs of naturally occurring peptides and have been widely used as enzyme inhibitors and haptens for producing catalytic antibodies due to their tetrahedrally structural features. A series of hybr

Full text of DOI:10.1007/s00726-011-1098-5

Amino Acids (2012) 43:423–429
DOI 10.1007/s00726-011-1098-5
ORIGINAL ARTICLE
Facile synthesis of hybrid sulfonophosphinodipeptides composing
of taurines and 1-aminoalkylphosphinic acids
•
Fanhua Meng Fengdan He Xiuqing Song
•
•
•
•
•
Leilei Zhang Wenxiang Hu Gang Liu
Jiaxi Xu
Received: 1 August 2011 / Accepted: 19 September 2011 / Published online: 4 October 2011
Ó Springer-Verlag 2011
Abstract Both sulfonopeptides and phosphonopeptides
are important analogs of naturally occurring peptides and
have been widely used as enzyme inhibitors and haptens for
producing catalytic antibodies due to their tetrahedrally
Introduction
Phosphonopeptides and phosphinopeptides are important
phosphorus analogs of naturally occurring peptides. Sulf-
onopeptides are significant sulfur analogs of naturally
occurring peptides. All of them have been widely used as
enzyme inhibitors and as haptens for catalytic antibody
research because they can be considered as stable mimetics
of tetrahedral transition states in ester and amide hydrolysis
and formation (Kafarski and Lejczak 2000b; Yiotakis et al.
2004; Cunningham et al. 2008; Xu 2003; Carson et al.
1997). Several phosphonopeptides have also shown
potent antibacterial activity (Kafarski and Lejczak 2000b;
Atherton et al. 1986).
structural features.
A series of hybrid sulfonopho-
sphinodipeptides composing of taurines and 1-aminoalkyl-
phosphinic acids were first and conveniently synthesized in
satisfactory to good yields via a Mannich-type reaction of
N-benzyloxycarbonylaminoalkanesulfonamides, aldehydes,
and aryldichlorophosphines, and subsequent hydrolysis. The
current method provides an efficient and direct synthesis of
hybrid sulfonophosphinodipeptides.
Keywords Aminoalkanesulfonamide Á Mannich
reaction Á Peptide Á Phosphinopeptide Á Synthesis
Phosphonopeptides, including phosphonamidate and
phosphinamidate linkages, have been synthesized generally
via the reaction of phosphonochloridates with amino acid
esters or peptide esters (Kafarski and Lejczak 2000a), via
the direct condensation of phosphonate monoesters with
amino acid esters or peptide esters in the presence of
coupling reagents (Galeotti et al. 1996; Campbell and
Bermak 1994a, b; Karanewsky and Badia 1986), and via
our Mannich-type condensation of benzyl carbamate,
aldehydes, alkyl dichlorophosphite, and subsequent ami-
nolysis with amino esters (Fu et al. 2006), or of N-Cbz
protected amino amides/peptide amides, aldehydes, aryl-
dichlorophosphines, and subsequent aminolysis with amino
acid esters/peptide esters (Li et al. 2007; He et al. 2009).
Sulfonopeptides have been generally prepared from the
reaction of N-protected aminoalkanesulfonyl chlorides with
amino acid esters or peptide esters (Xu 2003; Lowik and
Liskamp 2000; Gennari et al. 1994) or from the conden-
sation of N-protected aminoalkanesulfinyl chlorides and
amino esters or peptide esters, followed by subsequent
oxidation (Xu 2003; Moree et al. 1993, 1995). Recently,
F. Meng Á J. Xu (&)
State Key Laboratory of Chemical Resource Engineering,
Department of Organic Chemistry, Faculty of Science,
Beijing University of Chemical Technology, Beijing 100029,
People’s Republic of China
e-mail: jxxu@mail.buct.edu.cn
F. He Á W. Hu
Department of Chemistry, Capital Normal University,
Beijing 100048, China
X. Song
College of Life Science and Bio-engineering, Beijing University
of Technology, Beijing 100124, China
L. Zhang Á G. Liu
Institute of Materia Medica, Chinese Academy of Medical
Sciences, Beijing 100050, China
123

424
F. Meng et al.
some sulfino amino acid derivatives, considered as mimetics
of sulfonopeptides, have been synthesized (Kukhar et al. 2009;
Sorochinsky and Soloshonok 2010).
Cbz-Cl,NaOH
CbzHN
CbzHN
NH2
OH
S
O
H2N
OH
S
R1 O
O
R1 O
Phosphinopeptides containing C-terminal a-amin-
oalkylphosphinic acids have been synthesized by coupling
of N-protected amino acids or their active esters with alkyl
a-aminoalkylphosphinates (Vassiliou et al. 2008; Rava-
schino et al. 2006; Atherton et al. 1986), or with free
a-aminoalkylphosphinic acids in organic media or in aque-
ous-organic media (Kafarski and Lejczak 1988; Solodenko
et al. 1991; Lukas et al. 2002). All of these methods used
phosphinic acid derivatives as starting materials, which were
generally synthesized in multi-step procedure (Kukhar et al.
1994; Soloshonok et al. 1992; Xu and Yu 1999). Recently,
we reported novel methods for the preparation of a-amin-
oalkylphosphonic acid derivatives via the phosphorus-
Mannich-type reactions of carbamates, aldehydes, and
chlorophosphites (Xu and Fu 2000, 2001; Xu and Wei 2001;
Liu and Xu 2005; Xu and Gao 2005; Liu et al. 2006). We also
prepared phosphinopeptides via the Mannich-type conden-
sation of N-Cbz protected amino amides/peptide amides,
aldehydes, aryldichlorophosphines, and subsequent ami-
nolysis with amino acid esters/peptide esters (Li et al. 2007)
and sulfonophosphinopeptides via the Mannich-type con-
densation of N-Cbz protected amino alkanesulfonamides,
aldehydes, aryldichlorophosphines, and subsequent ami-
nolysis with amino acid esters/peptide esters (He et al. 2009).
The method has been applied to synthesize phosphinopep-
tides containing C-terminal a-aminoalkylphosphinic acids
via the Mannich reaction and subsequent hydrolysis (Meng
and Xu 2010). We herein present the facile synthesis of
hybrid sulfonophosphinodipeptides composing of b-amin-
oalkanesulfonic acids and C-terminal a-aminoalkylphos-
phinic acids (Scheme 1).
SOCl2
NH3 H2O
S
R1 O
O
1
CbzHN
CbzHN
CbzHN
NH2
+R2CHO+ArPCl2
S
MeCN
O
1
O
R1
Ar
O
H
N
H2O
P
S
Cl
R1 O
R2
Ar
O
2
O
H
N
P
S
OH
R1 O
R2
O
3
Scheme 1 Facile synthesis of hybrid sulfonophosphinodipeptides
petroleum ether (60–90°C)/ethyl acetate (1:1, v/v), and the
plates were visualized with UV light.
Aryldichlorophosphines were prepared according to lit-
erature procedure (Buchner and Lockhart 1951) and their
analytical data are identical to reported ones (Buchner and
Lockhart 1951; Weinberg 1975). Aminoalkanesulfonic
acids were prepared synthesized from vicinal amino alco-
hols according to our reported method (Zhang et al. 2008).
2-Benzyloxycarbonylaminoalkanesulfonic acids were pre-
pared from benzyl chloroformate and 2-aminoalkanesulf-
onic acids according to our reported method (He et al.
2009). Acetonitrile was refluxed with calcium hydride and
freshly distilled prior to use. All reactions were performed
under a nitrogen atmosphere.
Materials and methods
General procedure for the preparation
of N-Cbz-aminoalkanesulfonamides
Melting points were obtained on a Yanaco melting point
1
apparatus and are uncorrected. The HNMR, 13C NMR,
and 31P NMR spectra were recorded on a Varian Mercury
Plus 300 (300 MHz) or Bruker 400 (400 MHz) spectrom-
eter with TMS as an internal standard in the CDCl3
solution. 31P NMR spectra were obtained with use of
A solution of 2-Cbz-aminoalkanesulfonic acid (54 mmol)
and DMF (0.5 mL) was added to thionyl chloride (50.3 g,
30 mL, 422 mmol). The resulting solution was refluxed
under stirring for about 4 h. The cooled reaction mixture
was passed through a Celite column with dry dichloro-
methane as an eluent. After removal of solvent, the residue
was dissolved in dry dichloromethane and the solvent was
removed twice to remove residual thionyl chloride. Pure
2-Cbz-aminoalkanesulfonyl chloride was obtained. It was
dissolved in dichloromethane and the resulting solution
was added dropwise into ammonia (50 mL) under stirring
at -10°C. After addition, the resulting mixture was stirred
for another 30 min at 5°C. Precipitates was collected after
1
broad-band H decoupling; chemical shifts are reported as
ppm referenced to 85% phosphoric acid with positive shift
downfield. IR spectra were determined on a Nicolet
AVATAR 330 FT-IR spectrometer. HRMS data were
obtained with an Agilent LC/MSD TOF mass spectrome-
ter. Optical rotations were measured on a PerkinElmer
Model 341 polarimeter with a thermally jacketed 10 cm
cell (concentration c expressed as g/100 mL). TLC sepa-
rations were performed on silica gel G plates with
123

Facile synthesis of hybrid sulfonophosphinodipeptides
425
(S)-2-Benzyloxycarbonylamino-4-methylpentanesulfonamide
(1e) Colorless crystals, m.p. 128–129°C. Yield 50%.
Rf = 0.77 (Silica gel plate, ethyl acetate:hexanes 1:1, v/v).
[a]2D0 = -7.5 (c, 1.0, MeOH).
filtration and crystallized from water or methanol to give
colorless crystals (2-Cbz-aminoalkanesulfonamides).
2-Benzyloxycarbonylaminoethanesulfonamide (1a) Col-
orless needle crystals, m.p. 138.5–140°C. Lit. m.p.
138.5–140°C (He et al. 2009). Yield 42%. Rf = 0.26
(Silica gel plate, ethyl acetate:hexanes 1:1, v/v).
1H NMR (400 MHz, DMSO-d6) d: 3.12 (t, J = 7.0 Hz,
2H, CH2), 3.40 (dt, J = 6.8, 7.0 Hz, 2H, CH2), 5.02 (s, 2H,
CH2), 6.90 (s, 2H, NH2), 7.30–7.39 (m, 6H, ArH, NH).
13C NMR (100.6 MHz, DMSO-d6) d: 36.2, 54.4, 66.0,
128.2, 128.3, 128.8, 137.4, 156.5.
IR v (cm-1): 1,683 (C=O), 1,326 and 1,152 (SO2).
1H NMR (300 MHz, DMSO-d6) d: 0.86 (d, J = 6.3 Hz,
6H, 2CH3), 1.42–1.48 (m, 2H, CHCH2), 1.56–1.65 (m, 1H,
CH(CH3)2), 3.04 (dd, J = 6.0, 13.8 Hz, 1H in CH2SO2),
3.22 (dd, J = 6.3, 13.8 Hz, 1H in CH2SO2), 3.94–4.05 (m,
1H, CHN), 5.02 (s, 2H, CH2Ph), 6.81 (s, 2H, NH2),
7.29–7.36 (m, 6H, ArH and NH).
13C NMR (75 MHz, DMSO-d6) d: 21.4, 23.1, 24.1, 42.7,
45.4, 59.2, 65.1, 127.5, 127.7, 128.2, 137.1, 155.5.
HRMS (ESI) Calcd. for C14H22N2O4S [M ? H]? m/z
315.1373; Found 315.1370.
(S)-2-Benzyloxycarbonylaminopropanesulfonamide (1b)
Colorless needle crystals, m.p. 150–151°C. Yield 43%.
Rf = 0.57 (Silica gel plate, ethyl acetate:hexanes 1:1, v/v).
[a]2D0 = ?10.8 (c, 1.0, MeOH).
IR v (cm-1): 1,668 (C=O), 1,342 and 1,142 (SO2).
1H NMR (300 MHz, DMSO-d6) d: 1.24 (d, J = 6.6 Hz,
3H, CH3), 3.04 (dd, J = 7.5, 13.9 Hz, 1H in CH2SO2),
3.25 (dd, J = 5.3, 13.9 Hz, 1H in CH2SO2), 4.01(ddq,
J = 5.3, 7.5, 6.6 Hz, 1H, CHN), 5.03 (s, 2H, OCH2), 6.90
(s, 2H, NH2), 7.28–7.42 (m, 6H, ArH and NH).
13C NMR (75 MHz, DMSO-d6) d: 20.4, 43.2, 59.8, 65.3,
127.7, 127.8, 128.3, 137.0, 155.2.
General procedure for the synthesis of hybrid
sulfonophosphinodipeptides
To a solution of Cbz-aminoalkanesulfonamide (1.9 mmol)
and aldehyde (2.0 mmol) in dried acetonitrile (10 mL) was
added arylphosphine dichloride (2.0 mmol) under the
nitrogen atmosphere. The resulting solution was stirred at
45°C for 12 h. After cooling and addition of water
(0.5 mL), the reaction mixture was stirred for another 2 h.
After removal of solvent, the residue was dissolved in ethyl
acetate. The solution was washed with saturated aqueous
sodium bicarbonate. The aqueous solution was adjusted to
pH 1. Colorless precipitates appeared. After filtration and
washing with water, the solid was crystallized in ethyl
acetate or in methanol to afford colorless powder crystals.
HRMS (ESI) Calcd. for C11H17N2O4S [M ? H]? m/z
273.0904; Found 273.0902.
(S)-2-Benzyloxycarbonylamino-3-phenylpropanesulfonamide
(1c) Colorless crystals, m.p. 168–170°C. Lit. m.p.
168–170°C (He et al. 2009). Yield 30%. Rf = 0.57 (Silica
gel plate, ethyl acetate:hexanes 1:1, v/v). [a]2D0 = -14.4
(c, 1.0, MeOH).
1H NMR (400 MHz, DMSO-d6) d: 2.83–3.03 (m, 2H,
CH2), 3.15–3.38 (m, 2H, CH2), 4.18 (s, 1H, CH), 4.99 (s,
2H, CH2), 6.91 (s, 2H, NH2), 7.23–7.40 (m, 11H, ArH,
NH).
13C NMR (100.6 MHz, DMSO-d6) d: 39.8, 49.3, 58.6,
65.6, 126.8, 127.9, 128.1, 128.7, 128.8, 129.7, 137.6,
138.6, 155.9.
Phenyl[(R,S)-N-[N-benzyloxycarbonylaminoethanesulfonyl]-
1-aminophenylmethyl]phosphinic acid (3a) Colorless
crystals, m.p. 140–143°C, yield 81%. Rf = 0.42 (Silica gel
plate, CH2Cl2:MeOH:HOAc 20:1:1, v/v).
IR v (cm-1): 1,713 (C=O), 1,313 and 1,185 (SO2), 1,246
(P=O).
1H NMR (400 MHz, DMSO-d6) d: 2.72 (s, 2H,
SO2CH2), 3.20–3.21 (m, 2H, NCH2), 4.43 (dd, J = 8.5,
15.9 Hz, 1H, NCH), 5.01 (s, 2H, OCH2), 7.13–7.74 (m,
17H, ArH and 2NH).
(S)-2-Benzyloxycarbonylamino-3-methylbutanesulfonamide
(1d) Colorless crystals, m.p. 113–114°C. Yield 60%.
Rf = 0.66 (Silica gel plate, ethyl acetate:hexanes 1:1, v/v).
[a]2D0 = ?17.2 (c, 1.0, MeOH).
13C NMR (100.6 MHz, DMSO-d6) d: 35.1, 52.2, 58.7
(d, JP-C = 97.6 Hz), 65.2, 126.2, 127.1,127.2, 127.6,
128.1, 128.2, 130.1, 131.9, 132.0, 137.0, 138.3, 155.7.
31P NMR (162.0 MHz, DMSO-d6) d: 25.5.
IR v (cm-1): 1,696 (C=O), 1,327 and 1,143 (SO2).
1H NMR (300 MHz, DMSO-d6)d: 0.82 (d, J = 6.4 Hz,
6H, 2CH3), 1.81–1.90 (m, 1H, CH(CH3)2), 3.10 (d,
J = 6.0 Hz, 2H, CH2SO2), 3.85–3.94 (m, 1H, CHN),
5.03 (s, 2H, OCH2), 6.81 (s, 2H, NH2), 7.30–7.36 (m, 6H,
ArH and NH).
HRMS (ESI) Calcd. for C23H26N2O6PS [M ? H]? m/z
489.1249; Found 489.1260.
13C NMR (75 MHz, DMSO-d6) d: 17.3, 18.6, 31.6, 51.9,
56.0, 65.1, 127.5, 127.6, 128.3, 137.2, 155.8.
HRMS (ESI, m/z) Calcd. for C13H21N2O4S [M ? H]?
m/z 301.1217; Found 301.1214.
4-Methylphenyl[(R,S)-N-[N-benzyloxycarbonylaminoe-
thanesulfonyl]-1-amino-phenylmethyl]phosphinic acid
(3b) Colorless crystals, m.p. 196–202°C, yield 80%; major
rotamer:minor rotamer = 79:21.
123

426
F. Meng et al.
Rf = 0.5 (Silica gel plate, CH2Cl2:MeOH:HOAc 20:1:1,
v/v).
IR v (cm-1): 1,714 (C=O), 1,337 and 1,176 (SO2), 1,244
(P=O).
1H NMR (400 MHz, DMSO-d6) d: 2.31 (s, 3H, CH3,
minor), 2.33 (s, 3H, CH3, major), 2.54–2.64 (m, 2H,
SO2CH2), 3.08–3.14 (m, 2H, NCH2), 4.68 (dd, J = 9.8,
17.2 Hz, 1H, PCH), 5.00 (s, 2H, OCH2), 7.12–7.59 (m,
15H, ArH and NH), 8.21 (d, J = 9.8 Hz, 1H, SNH).
13C NMR (100.6 MHz, DMSO-d6) d: 20.8 (minor), 21.0
(major), 34.9, 52.7, 57.4 (d, JP-C = 102.3 Hz, minor), 57.5
(d, JP-C = 105.7 Hz, major), 65.3, 127.3, 127.7, 127.74,
127.8, 128.3, 128.4, 128.5, 128.6, 129.2, 131.9, 131.96,
132.3, 132.4, 136.0, 136.9, 141.7, 155.7.
31P NMR (162.0 MHz, DMSO-d6) d: 32.7.
HRMS (ESI) Calcd. for C20H28N2O6PS [M ? H]? m/z
455.1406; Found 455.1403.
Phenyl[(R,S)-N-[(S)-N-benzyloxycarbonyl-2-aminopropane-
sulfonyl]-1-aminophenylmethyl]phosphinic acid (3e) Col-
orless crystals, m.p. 192–197°C; (S,S):(S,R) = 54:46.
Rf = 0.38 (Silica gel plate, CH2Cl2:MeOH:HOAc 20:1:1,
v/v). [a]2D0 = ?5.8 (c, 1.0, MeOH).
IR v (cm-1): 1,718 (C=O), 1,312 and 1,249 (SO2), 1,193
(P=O).
1H NMR (400 MHz, DMSO-d6) d: 0.91 [d, J = 6.4 Hz,
3H, CH3, (S,S)] and 0.98 [d, J = 6.4 Hz, 3H, CH3, (S,R)],
2.33–2.38 (m, 1H in CH2SO2), 2.67–2.78 (m, 1H in
CH2SO2), 3.72–3.82 (m, 1H, NCH), 4.67–4.74 (m, 1H,
CHP), 4.99 (s, 2H, OCH2), 7.15–7.53 (m, 15H, 15ArH),
7,67–7.71 [m, 2H, 2NH, (S,S)], 8.11 [s, br, 1H, NH, (S,R)],
8.19 [d, J = 10.8 Hz, 1H, NH, (S,R)].
13C NMR (100.6 MHz, DMSO-d6) d: 20.2, 42.46 (S,R),
42.52 (S,S), 57.4 [d, Jp-c = 105.1 Hz, (S,R)], 57.5 [d,
Jp-c = 105.1 Hz, (S,S)], 58.5 (S,R), 58.53 (S,S), 65.1,
127.2, 127.26, 127.52, 127.55, 127.6, 127.72, 127.74,
127.8, 127.9, 128.2, 128.37, 128.4, 128.47, 128.5, 131.1,
131.2, 131.6, 131.78, 131.8, 131.9, 132.4, 132.5, 136.0,
136.9, 154.8, 154.9.
31P NMR (162.0 MHz, DMSO-d6) d: 29.9 (minor), 29.7
(major).
HRMS (ESI) Calcd. for C24H28N2O6PS [M ? H]? m/z
503.1406; Found 503.1410.
Phenyl[(R,S)-N-[N-benzyloxycarbonylaminoethanesulfonyl]-
1-amino-(4-methylphenyl)methyl]phosphinic acid (3c) Col-
orless crystals, m.p. 199–203°C, yield 78%. Rf = 0.39
(Silica gel plate, CH2Cl2:MeOH:HOAc 20:1:1, v/v).
IR v (cm-1): 1,714 (C=O), 1,337 and 1,176 (SO2), 1,176
(P=O).
1H NMR (400 MHz, DMSO-d6) d: 2.27 (s, 3H, CH3),
2.57–2.68 (m, 2H, SO2CH2), 3.12–3.13 (m, 2H, NCH2),
4.68 (dd, J = 10.2, 16.9 Hz, 1H, PCH), 4.99 (s, 2H,
OCH2), 7.08–7.72 (m, 15H, ArH and NH), 8.13 (d,
J = 10.0 Hz, 1H, SNH).
31P NMR (162.0 MHz, DMSO-d6) d: 29.3 (S,R), 29.5
(S,S) (85% H3PO4 as an external standard).
HRMS (ESI) Calcd. for C24H28N2O6PS [M ? H]? m/z
503.1400; Found 503.1409.
Phenyl[(R,S)-N-[(S)-N-benzyloxycarbonyl-2-amino-3-phe-
nylpropanesulfonyl]-1-aminophenylmethyl]phosphinic acid
(3f) Colorless crystals, m.p. 201–203°C, yield 72%;
(S,S):(S,R) = 57:43. Rf = 0.45 (Silica gel plate, CH2Cl2:
MeOH:HOAc 20:1:1, v/v). [a]2D0 = ?14.0 (c, 0.1, MeOH).
IR v (cm-1): 1,714 (C=O), 1,337 and 1,176 (SO2), 1,176
(P=O).
13C NMR (100.6 MHz, DMSO-d6) d: 20.6, 34.9, 52.7,
57.1 (d, JP-C = 106.5 Hz), 65.3, 127.7, 127.74, 127.8,
128.0, 128.3, 128.33, 128.37, 128.4, 131.2, 131.7, 131.8,
131.9, 132.5, 132.8, 136.5, 136.9, 155.7.
31P NMR (162.0 MHz, DMSO-d6) d: 29.6.
HRMS (ESI) Calcd. for C24H28N2O6PS [M ? H]? m/z
503.1406; Found 503.1410.
1H NMR (400 MHz, DMSO-d6) d: 2.50–2.64 (m, 2H,
PhCH2), 2.71–2.98 (m, 2H, SO2CH2), 3.98–4.02 (m, 1H,
NCH), 4.29–4.33 (m, 1H, PCH), 4.97 (dd, J = 12.0,
13.1 Hz), 7.07–7.61 (m, 22H, ArH and 2NH).
13C NMR (100.6 MHz, DMSO-d6) d: 35.7, 42.0, 44.0,
57.8 (d, JP-C = 106.8 Hz), 65.8, 126.8, 127.8, 128.2, 128.7,
128.8, 130.7, 132.5, 137.6, 138.9, 156.3.
Phenyl[(R,S)-N-[N-benzyloxycarbonylaminoethanesulfonyl]-
1-amino-2-methylpropyl]phosphinic acid (3d) Colorless
crystals, m.p. 165–170°C, yield 80%. Rf = 0.42 (Silica gel
plate, CH2Cl2:MeOH:HOAc 20:1:1, v/v).
IR v (cm-1): 1,716 (C=O), 1,145 (P=O), 1,309 and
1,178 (SO2).
1H NMR (400 MHz, DMSO-d6) d: 0.92 (d, J = 6.6 Hz,
3H, CH3), 0.94 (d, J = 6.6 Hz, 3H, CH3), 1.97–2.09 (m, 1H,
CH(CH3)2), 2.63–2.75 (m, 2H, SO2CH2), 3.17–3.30 (m, 2H,
NCH2), 3.55 (ddd, J = 3.2, 10.4, 13.2 Hz, 1H, PCH), 5.00(s,
2H, OCH2), 7.25–7.78 (m, 12H, ArH and 2NH).
31P NMR (162.0 MHz, DMSO-d6) d: 20.8.
HRMS (ESI) Calcd. for C30H31N2O6PS [M ? H]?
579.1719; Found 579.1712.
Phenyl[N-(R,S)-[(S)-N-benzyloxycarbonyl-2-amino-3-methy-
lbutanesulfonyl]-1-aminophenylmethyl]phosphinic acid
(3 g) Colorless crystals, m.p. 172–176°C, yield 71%;
13C NMR (100.6 MHz, DMSO-d6) d: 17.9 (d, JP-C
=
2.8 Hz), 20.9 (d, JP-C = 10.9 Hz), 28.0 (d, JP-C = 4.8 Hz),
35.2, 52.9, 57.9 (d, JP-C = 108.8 Hz), 65.3, 127.6, 127.7,
128.0, 128.1, 128.2, 131.6, 131.61, 131.63, 131.7, 132.3,
133.5, 136.9, 155.7.
(S,S):(S,R) = 59:41.
Rf = 0.6
(Silica
gel
plate,
CH2Cl2:MeOH:HOAc 20:1:1, v/v). [a]2D0 = ?18.0 (c, 0.1,
MeOH).
123

Facile synthesis of hybrid sulfonophosphinodipeptides
427
IR v (cm-1): 1,698 (C=O), 1,330 and 1,144 (SO2), 1,218
(P=O).
128.1, 128.4, 128.5, 131.4, 131.8, 131.9, 136.2, 137.1, 155.1
(S,R), 155.3 (S,S).
1H NMR (400 MHz, DMSO-d6) d: 0.57 (d, J = 16.5 Hz,
6H, 2CH3), 1.48 (br, 1H, CH(CH3)2), 2.37–2.74 (m, 2H,
SO2CH2), 3.66 (s, 1H, NHCH), 4.75 (s, br, 1H, CHP), 5.00 (s,
2H, OCH2), 7.21–8.19 (m, 17H, ArH and 2NH).
13C NMR (100.6 MHz, DMSO-d6) d: 17.0 (S,S), 17.1
(S,R),18.3 (S,S), 18.4 (S,R), 31.7 (S,S), 31.71 (S,R),
50.9 (S,S), 51.1 (S,R), 54.8 (S,R), 55.0 (S,S), 57.4 [d,
JP-C = 105.9 Hz, (S,R)], 57.5 [d, Jp-c = 105.5, (S,S)], 64.9
(S,S), 65.0 (S,R), 127.4, 127.6, 127.8, 128.0, 128.2, 128.6,
131.7, 131.8, 131.9, 136.1, 137.2, 155.6, 155.8.
31P NMR (162.0 MHz, DMSO-d6) d: 29.5 (S,S), 29.7
(S,R) (85% H3PO4 as an external standard).
31P NMR (162.0 MHz, DMSO-d6) d: 28.8 (85% H3PO4
as an external standard).
HRMS (ESI) Calcd. for C27H34N2O6PS [M ? H]? m/z
545.1870; Found 545.1868.
Results and discussion
First, N-benzoxylcarbonyl protected taurine was prepared
from taurine and benzyl chloroformate under basic condi-
tions and it was further converted into 2-(N-benzoxycar-
bonylamino)ethanesulfonyl chloride with thionyl chloride.
After aminolysis with ammonia, 2-(N-benzoxycarbonyla-
mino)ethanesulfonamide (1a) was obtained according to the
reported method (He et al. 2009). It was used as an amine
component in the Mannich-type reaction with benzaldehyde,
phenyldichlorophosphine in anhydrous acetonitrile, and
subsequent hydrolysis with water to afford a hybrid sulfo-
nophosphinodipeptide 3a in a good yield (Table 1, entry 1).
Benzyl carbamate and toluenesulfonamide was also used as
an amine component in the Mannich-type reaction to prepare
N-tolyl-aminobenzylphosphinic acid previously (Zhang
et al. 1993; Chen and Dai 1995). In the current method, an
aminoalkanesulfonic acid and an aminoalkylphosphinic acid
were linked together to generate the hybrid sulfonopho-
sphinodipeptide in a one-pot pseudo-four component con-
densation reaction. The current route provides a new and
efficient pathway to synthesize sulfonophosphinopeptides
via the Mannich-type reaction. To our best knowledge, this is
the first synthesis of the hybrid sulfonophosphinodipeptides.
The synthetic method is a convergent and atom-economic
strategy for synthesis of hybrid sulfonophosphinopeptides.
Following the procedure, a series of hybrid sulfonopho-
sphinodipeptides were prepared by the use of different
HRMS (ESI) Calcd. for C26H32N2O6PS [M ? H]? m/z
531.1713; Found 531.1714.
Phenyl[N-(R,S)-[(S)-N-benzyloxycarbonyl-2-amino-4-meth-
ylpentanesulfonyl]-1-aminophenylmethyl]phosphinic acid
(3 h) Colorless crystals, m.p. 119–125°C, yield 80%,
(S,S):(S,R) = 66:34. Rf = 0.55 (Silica gel plate, CH2Cl2:
MeOH:HOAc 20:1:1, v/v). [a]2D0 = ?1.0 (c, 0.1, MeOH).
IR v (cm-1): 1,700 (C=O), 1,327 and 1,145 (SO2), 1,225
(P=O).
1H NMR (400 MHz, DMSO-d6) d: 0.74 (s, 6H, 2CH3),
0.96–1.24 (m, 2H in CH2CH), 1.35–1.41 (m, 1H in
CH(CH3)2), 2.30–2.35 (m, 1H in CH2SO2), 2.61–2.76 (m,
1H in CH2SO2), 3.78 (m, 1H, NCH), 4.69 (dd, J = 9.6,
16.8 Hz, 1H, CHP), 5.05 (s, 2H, OCH2), 7.12–7.51
(m, 15H, ArH), 7.68 (t. J = 8.8 Hz, 2H, 2NH), 7.93
(d, J = 10.8 Hz, 1H, NH, epimer), 8.11 (d, J = 10.0 Hz,
1H, NH, epimer).
13C NMR (100.6 MHz, DMSO-d6) d: 21.2 (S,S), 21.3
(S,R), 22.8 (S,R), 22.9(S,S), 23.8 (S,S), 23.9 (S,R), 42.6 (S,S),
42.8 (S,R), 44.7 (S,R), 44.8 (S,S), 57.5 [d, JP-C = 102.7 Hz,
(S,S)], 57.6 [d, JP-C = 104.3 Hz, (S,R)], 57.51(S,R), 58.12
(S,S), 64.9, 127.1, 127.13, 127.3, 127.4, 127.5, 127.6, 127.7,
aldehydes,
2-N-Cbz-aminoalkanesulfonamides,
and
Table 1 Facile synthesis of hybrid sulfonophosphinodipeptides
Entry
Dipeptide
R1
R2
Ar
Ph
Yield (%)
Dr (S,S):(S,R)
1
2
3
4
5
6
7
8
a
3a
3b
3c
3d
3e
3f
H
Ph
81
80
78
80
75
72
71
80
–
–
–
–
H
Ph
p-MePh
H
p-MePh
iPr
Ph
Ph
Ph
Ph
Ph
Ph
H
Me
Bn
iPr
iBu
Ph
54:46a (59:41b)
57:43c
59:41a
Ph
3g
3h
Ph
Ph
66:34c
Diastereomeric ratio value on the basis of integration in 31P NMR analysis
b
c
1
Diastereomeric ratio value on the basis of integration in H NMR analysis
Diastereomeric ratio value on the basis of integration in 13C NMR analysis
123

428
F. Meng et al.
Scheme 2 Formation
O
S
O
HO
Cl
Cl
O
S
O
O
mechanism and stereostructures
of diastereomeric hybrid
sulfonophosphinodipeptide 3g
Cl
Cl
P
P
PhCHO
CbzHN
N
Ph
CbzHN
NH2
Ph
-HCl
Ph
attack from the back
H
Ph
H
P
O
O
O
O
Cl
OH
Re additon
favorably
S
P
S
CbzHN
N
Ph
CbzHN
CbzHN
N
Ph
Ph
H
Ph
Ph
O
S
O
Ph
O
O
H2O
OH
S
Cl
O
CbzHN
N
P
N
P
H
O
H
Ph
)-3g
major (S,S
attack from the front
H
O
H
O
S
O
O
S
Cl
OH
Si additon
P
CbzHN
Ph
N
H
Ph
CbzHN
CbzHN
N
Ph
unfavorably
Ph
Cl
Ph
P
O
S
O
Ph
O
O
H2O
OH
O
S
Cl
CbzHN
N
H
P
N
P
Ph
O
H
Ph
O
3g
minor (S,R )-
aryldichlorophosphines. The results are summarized in
Table 1. The results indicated that different aldehydes, 2-N-
Cbz-aminoalkanesulfonamides, and aryldichlorophosphines
do not affect the yields obviously. All reactants used work
very well for the reaction (Table 1, entries 1–8). The struc-
tures of all sulfonophosphinopeptides 3 were characterized
by 1H NMR, 13C NMR, 31P NMR, and MS spectrometries.
On stereochemistry of the product sulfonopho-
sphinodipeptides, for N-Cbz-taurine amide, racemic sulfo-
nophosphinodipeptides 3a–d were obtained. However,
interestingly, two stereostructural isomers of product 3b were
determined in all NMR spectra, revealing that two different
rotamers rather than epimers exist in its solution because
there is only one chiral carbon atom in the racemic product.
For optically active (S)-N-Cbz-2-aminoalkanesulfonamides
1b–e, low degree of asymmetric induction was observed in
each of cases because the chiral center is too far away from
the reactive center in the addition step of the aryl-
chlorophosphonous acid to the N-alkanesulfonyl imine in the
reaction (Scheme 2). The diastereomeric ratio of products
was determined on the basis of integration in NMR analysis.
The (S,S)-epimer of the products was assumed as major
diastereomer in the products on the basis of the reaction
mechanism (Scheme 2). The reaction of (S)-2-Benzylox-
ycarbonylamino-3-methylbutanesulfonamide (1d), benzald-
ehyde, and phenyldichlorophosphine was selected as an
example to illustrate the reaction mechanism and diastere-
oselectivity. The sulfonamide, benzaldehyde, and phenyldi-
chlorophosphine react to produce an N-sulfonylimine and
phenylchlorophosphonous acid similar to previous reports
(Li et al. 2007; He et al. 2009). The phenylchlorophospho-
nous acid then attacks the imine favorably from its Re side
due to the existence of steric isopropyl group, and subsequent
proton transfer affords the key intermediate as the N-sulfo-
nylaminoalkylphosphinic chloride, which undergoes
hydrolysis to generate the product hybrid sulfonophosphino-
dipeptide (S,S)-3g with S,S configuration as major product.
Similarly, the phenylchlorophosphonous acid attacks the
imine disfavorably from its Si side to afford the sulfono-
phosphinodipeptide (S,R)-3g with S,R configuration as minor
product (Scheme 2).
Conclusion
In conclusion, a series of novel hybrid sulfonopho-
sphinodipeptides composing of 2-aminoalkanesulfonic
acids and 1-aminoalkylphosphinic acids were synthesized
in good yields in a facile and one-pot Mannich-type reac-
tion of N-Cbz-2-aminoalkanesulfonamides, aldehydes, and
aryldichlorophosphines, and subsequent hydrolysis. The
current method is the first, convergent, and atom-economic
synthesis of hybrid sulfonophosphinodipeptides.
Acknowledgments The project was supported by National Natural
Science Foundation of China (No. 20092013 and 20772005), Beijing
Natural Science Foundation (No. 2092022), and University Innova-
tive Research Grant award (10Si003), BUCT, 2010.
123

Facile synthesis of hybrid sulfonophosphinodipeptides
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