First and convergent synthesis of hybrid sulfonophosphinopeptides

Article abstract of DOI:10.1021/ol901543y

Figure Presented Hybrid sulfonophosphinopeptides were first and convergently synthesized in satisfactory to good yields via the Mannich-type reaction of N-protected 2-aminoalkanesulfonamides, aromatic aldehydes, and aryldichlorophosphines and subsequent aminolysis with amino esters.

Full text of DOI:10.1021/ol901543y

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3922-3925
First and Convergent Synthesis of
Hybrid Sulfonophosphinopeptides
Fengdan He,‡ Fanhua Meng,† Xiuqing Song,§ Wenxiang Hu,‡ and Jiaxi Xu*,†
State Key Laboratory of Chemicial Engineering Resource, Faculty of Science, Beijing
UniVersity of Chemical Technology, Beijing 100029, P. R. China, Department of
Chemistry, Capital Normal UniVersity, Beijing100048, P. R. China, and College of
Life Science and Bio-engineering, Beijing UniVersity of Technology,
Beijing100124, China
jxxu@mail.buct.edu.cn
Received July 6, 2009
ABSTRACT
Hybrid sulfonophosphinopeptides were first and convergently synthesized in satisfactory to good yields via the Mannich-type reaction of
N-protected 2-aminoalkanesulfonamides, aromatic aldehydes, and aryldichlorophosphines and subsequent aminolysis with amino esters.
Phosphonopeptides and phosphinopeptides have been widely
used as enzyme inhibitors, haptens for production of catalytic
antibodies, and antibacterial and herbicidal agents during the
last two decades.1 To date, several efficient synthetic routes
have been developed for synthesis of phosphonopeptides and
phosphinopeptides.2 The formation methods of the phosphi-
namide bond in phosphinopeptides generally include the
reaction of N-protected aminoalkylphosphinic chlorides with
amino acid esters or peptide esters,3 the direct condensation
of aminoalkylphosphinic acids and amino esters or peptide
esters in the presence of coupling reagents, such as DCC,
BOP, DPPA, with additives HOBt or DMAP, in low yields,4
the enzyme-catalyzed coupling reaction of ethyl aminoalky-
lphosphinate and amino esters in satisfactory yields,5 and
the Mannich ligation of amino amides, aldehydes, aryldi-
chlorophosphines, and amino/peptide esters.6
Sulfonopeptides, as a class of more stable analogues of
naturally occurring or synthetic peptides, have also been used
as enzyme inhibitors.7 The sulfonopeptide bond has been
generally formed through two pathways. One is the reaction
of N-protected aminoalkanesulfonyl chlorides with amino
acid esters or peptide esters.8 The other is the condensation
of N-protected aminoalkanesulfinyl chlorides and amino
esters or peptide esters, followed by subsequent oxidation.9
However, no hybrid sulfonophosphonopeptide, composed of
amino acid, aminoalkylphosphonic acid or aminoalkylphos-
‡ Capital Normal University.
† Beijing University of Chemical Technology.
§ Beijing University of Technology.
(1) (a) For a review, see: Kafarski, P.; Lejczak, B. The Biological
Activity of Phosphono- and Phosphinopeptides. In Aminophosphonic and
Aminophosphinic Acids: Chemistry and Biological ActiVity; Kukhar, V. P.,
Hudson, H. R., Eds.; John Wiley: Chichester, 2000; Chapter 12, pp
404-442. (b) For a recent example, see: Ravaschino, E. L.; Docampo, R.;
Rodriguez, J. B. J. Med. Chem. 2006, 49, 426–435. (c) Ntai, I.; Phelan,
V. V.; Bachmann, B. O. Chem. Commun. 2006, 4518–4520. (d) Cunning-
ham, E.; Drag, M.; Kafarski, P.; Bell, A. Antimicrob. Agents Chemother.
2008, 52, 3221–3228.
(2) For a review, see: Kafarski, P.; Lejczak, B. The Biological Activity
of Phosphono- and Phosphinopeptides. In Aminophosphonic and Amino-
phosphinic Acids: Chemistry and Biological ActiVity; Kukhar, V. P., Hudson,
H. R., Eds.; John Wiley: Chichester, 2000; Chapter 12, pp 173-204.
(3) (a) Moree, W. J.; van der Marel, G. A.; van Boom, J. H.; Liskamp,
R. M. J. Tetrahedron 1993, 49, 11055–11064. (b) Mucha, A.; Kafarski, P.;
Plenat, F.; Cristau, H.-J. Tetrahedron 1994, 50, 12743–12754.
(4) Elhaddadi, M.; Jacquier, R.; Petrus, C.; Petrus, F. Phosphorus Sulfur
Silicon 1991, 63, 255–259.
(5) Natchev, I. A. Tetrahedron 1991, 47, 1239–1248.
(6) Li, B. N.; Cai, S. Z.; Du, D. M.; Xu, J. X. Org. Lett. 2007, 9, 2257–
2260.
10.1021/ol901543y CCC: $40.75
Published on Web 08/10/2009
 2009 American Chemical Society

phinic acid, and aminoalkanesulfonic acid residues, has been
synthesized until now. Herein, we report the first and
convergent synthesis of sulfonophosphinopeptides via the
Mannich-type reaction of N-protected 2-aminoalkanesulfona-
mides, aldehydes, and aryldichlorophosphines and subsequent
aminolysis with amino esters.
anhydrous acetonitrile and subsequent aminolysis with ethyl
glycinate hydrochloride or ethyl glycinate (Scheme 2, R1 )
Scheme 2. Synthesis of Sulfonophosphinopeptides 3
Previously, we used the Mannich-type reactions of car-
bamates or amino amides, aldehydes, and chlorophosphites,
or aryldichlorophosphines and subsequent aminolysis with
amino or peptide esters to prepare phosphonopeptides10 and
phosphinopeptides6 or alcoholysis with hydroxyl esters or
hydrolysis to give rise to depsiphosphonopeptides.10,11 In the
current method, we have substituted sulfonamides as the
amine component in the Mannich-type reaction with alde-
hydes and aryldichlorophosphines to generate hybrid sul-
fonophosphinopeptides in a one-pot pseudo-four-component
condensation reaction (Scheme 2). To the best of our
knowledge, this is the first synthesis of hybrid sulfonophos-
phinopeptides. The synthetic method is a convergent and
atom-economic strategy for synthesis of sulfonophosphi-
nopeptides.
H, R2 ) Ph, Ar ) 4-MePh, AA ) Gly). After several
attempts (Table 1, entries 1-3), a hybrid sulfonophosphi-
We have recently reported several efficient routes to prepare
structurally diverse substituted taurines (2-aminoalkanesulfonic
acids).12 In a manner similar to the previously reported
method,13 N-protected 2-aminoalkanesulfonamides 1a and 1b
were prepared from the corresponding 2-aminoalkanesulfonic
acids by protection of the amino group with benzyl chlorofor-
mate under basic conditions, conversion of the sulfonic acid to
the sulfonyl chloride with thionyl chloride, and subsequent
aminolysis with ammonia (Scheme 1).
Table 1. Synthesis of Sulfonophosphinopeptidesa
entry peptide R1
R2
Ar
AA
yieldb (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3b
3c
3d
3e
3e
3f
H
H
H
H
H
H
Ph
Ph
Ph
Ph
4-MePh Gly
4-MePh Gly
4-MePh Gly
30c
43d
75
65
74
Ph
Gly
4-MePh Ph
4-ClPh
Gly
Ph
Ph
Ph
Ph
Ph
Gly
70
Bn Ph
Bn Ph
Bn 4-ClPh
Bn Ph
ꢀ-Ala
ꢀ-Ala
Gly
62
60e
60
Scheme 1. Synthesis of N-Protected
2-Aminoalkanesulfonamides 1
10
3g
(S)-Leu
56
a The reaction was conducted in a molar ratio of sulfonamide/aldehyde/
ArPCl2 of 1.9:2.0:2.0 at 45 °C for 12 h first and then stirred for 24 h after
addition of an amino ester (6.0 mmol) and TEA (8.0 mmol). b Isolated yield.
c The reaction was conducted in a molar ratio of sulfonamide/aldehyde/
ArPCl2 of 2.4:2.7:2.7 with GlyOEt···HCl (8.0 mmol) and TEA (8.0 mmol).
d The reaction was conducted as in footnote c with GlyOEt (8.0 mmol).
e DIPEA was used instead of TEA.
nopeptide 3a was obtained in good yield (Table 1, entry 3).
We then explored the use of other N-protected 2-aminoal-
kanesulfonamide, aromatic aldehyde, aryldichlorophosphine,
and amino acid ethyl ester components in this reaction (Table
1). The results indicate that different aromatic aldehydes and
aryldichlorophosphines show similar reactivity (Table 1,
entries 3-6). However, the product yield obviously depends
on the steric hindrance of aminoalkanesulfonamides and
amino esters (Table 1, entries 4, 7, 9, and 10). 2-Aminoet-
hanesulfonamide (1a) and ethyl glycinate show higher yields
than (S)-2-amino-3-phenylpropanesulfonamide (1b) and ethyl
(S)-leucinate.
We initially optimized the reaction of the sulfonamide 1a
with benzaldehyde and 4-methylphenyldichlorophosphine in
(7) (a) For a review, see: Xu, J. X. Chin J. Org. Chem. 2003, 23, 1–9.
(b) For an example, see: Carson, K. G.; Schwender, C. F.; Shroff, H. N.;
Cochran, N. A.; Gallant, D. L.; Briskin, M. J. Bioorg. Med. Chem. Lett.
1997, 7711-714.
(8) (a) Lowik, D. W. P. M.; Liskamp, R. W. J. Eur. J. Org. Chem.
2000, 1219–1228. (b) Luisi, G.; Calcagni, A.; Pinnen, F. Tetrahedron Lett.
1993, 34, 2391–2392. (c) Gude, M.; Piarulli, U.; Potenza, D.; Salom, B.;
Gennari, C. Tetrahedron Lett. 1996, 47, 8589–8592. (d) Gennari, C.; Salom,
B.; Potenza, D.; Williams, A. Angew. Chem., Int. Ed. Engl. 1994, 33, 2067–
2069.
(9) (a) Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J.
Tetrahedron Lett. 1991, 32, 409–412. (b) Moree, W. J.; van Gent, L. C.;
van der Marel, G. A.; Liskamp, R. M. J. Tetrahedron 1993, 49, 1133–
1150. (c) Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J. Tetrahedron
Lett. 1992, 33, 6389–6392. (d) Moree, W. J.; van der Marel, G. A.; Liskamp,
R. M. J. J. Org. Chem. 1995, 60, 5157–5169.
(10) Fu, N. Y.; Zhang, Q. H.; Duan, L. F.; Xu, J. X. J. Peptide Sci.
2006, 12, 303–309.
(11) (a) Xu, J. X.; Gao, Y. H. Synthesis 2005, 783–788. (b) Liu, H.;
Cai, S. Z.; Xu, J. X. J. Peptide Sci 2006, 12, 337–340.
Org. Lett., Vol. 11, No. 17, 2009
3923

As for the reaction mechanism, in a manner similar to
previous one in the synthesis of phosphinopeptides,6 it was
assumed that a sulfonamide first attacks an aldehyde to form
an N-sulfonylaminohydrin adduct, which further reacts with
an aryldichlorophosphine to produce an aryl chlorophosphite.
The phosphite undergoes an elimination to give rise to an
N-sulfonylimine and an arylchlorophosphonous acid. The
arylchlorophosphonous acid undergoes an addition to the N-
sulfonylimine to produce the key intermediate as the ami-
noalkylphosphinic chloride, which undergoes an aminolysis
with an amino ester to generate the final product hybrid
sulfonophosphinopeptide (Scheme 3).
no obvious stereoselectivity was observed because the chiral
center is too far away from the reactive center in the addition
step of the arylchlorophosphonous acid to the N-sulfo-
nylimine. The similar stereoselectivity was also observed in
the synthesis of phosphinopeptides in our previous investiga-
tion.6 The newly formed stereocenters in sulfonophosphi-
nopeptides 3 are generated in the addition step in the
mechanism. Thus, their configurations could be deduced from
the addition mechanism (shown in Scheme 4). In the addition
Scheme 4
.
Stereochemical Control in Synthesis of
Sulfonophosphinopeptides
Scheme 3. Proposed Mechanism in the Formation of Hybrid
Sulfonophosphinopeptides in the Mannich-Type Reaction
1H, 13C, and 31P NMR spectra of sulfonophosphinopeptides
3a-d show that only one of the two possible diastereomeric
pairs was produced, indicating that only a pair of enantiomers
was generated in each of the reactions for 2-aminoethane-
sulfonamide (1a). However, for reactions with (S)-2-amino-
3-phenylpropanesulfonamide (1b) as the amine component,
a pair of peaks were observed in 31P NMR spectra of its
products in each of reactions, indicating that a pair of
diastereomers were generated for sulfonophosphinopeptides
3e-g. On the basis of the integretion of 31P NMR spectra,
(12) (a) Xu, J. X. Tetrahedron: Asymmetry 2002, 13, 1129–1134. (b)
Xu, J. X.; Xu, S. Synthesis 2004, 276–282. (c) Huang, J. X.; Wang, F.; Du,
D. M.; Xu, J. X. Synthesis 2005, 2122–2128. (d) Huang, J. X.; Du, D. M.;
Xu, J. X. Synthesis 2006, 315–319. (e) Hu, L. B.; Zhu, H.; Du, D. M.; Xu,
J. X. J. Org. Chem. 2007, 72, 4543–4546. (f) Zhang, W.; Wang, B. Y.;
Chen, N.; Du, D. M.; Xu, J. X. Synthesis 2008, 197–200. (g) Wang, B. Y.;
Zhang, W.; Zhang, L. L.; Du, D. M.; Liu, G.; Xu, J. X. Eur. J. Org. Chem.
2008, 350–355. (h) Yu, H.; Cao, S. L.; Zhang, L. L.; Liu, G.; Xu, J. X.
Synthesis 2009, 2205–2209. (i) Chen, N.; Zhu, M.; Zhang, W.; Du, D. M.;
Xu, J. X. Amino Acids 2009, 37, 309–313.
step, the arylchlorophosphonous acid could attack the N-
sulfonylimine from either its Re side or Si side via a five-
membered ring transition state formed through a hydrogen
bond (N-H-O), producing (R,R)- and (S,S)-arylaminoaryl-
methylphosphinic acid chloride 2. (R,S)- and (S,R)-isomers
cannot be generated due to the five-membered transition state
control. For reactions with (S)-2-amino-3-phenylpropane-
sulfonamide (1b) as the amine component, because the chiral
(13) (a) Hara, T.; Durell, S. R.; Myers, M. C.; Appella, D. H. J. Am.
Chem. Soc. 2006, 128, 1995–2004. (b) Brouwer, A. J.; Merks, R.;
Dabrowska, K.; Rijkers, D. T. S.; Liskamp, R. M. J. Synthesis 2006, 455–
460.
3924
Org. Lett., Vol. 11, No. 17, 2009

center is too far away from the reactive center no obviously
steric difference is generated in Re and Si additions. The
hydrogen bond plays a crucial role in the stereochemical
control in the addition step in the mechanism. After nucleo-
philic displacement with amino acid esters, sulfonophosphi-
nopeptides 3 were obtained. Thus, arylaminoarylmethylphos-
phinic acid residues in sulfonophosphinopeptides should be
(R,R) or (S,S). That is, sulfonophosphinopeptides 3a-d are
a pair of enantiomers with (R,R) and (S,S) configurations.
Sulfonophosphinopeptides 3e-f are a pair of diastereomers
with (S,R,R) and (S,S,S) configurations. And sulfonophos-
phinopeptide 3g is a pair of diastereomers with (S,R,R,S)
and (S,S,S,S) configurations.
N-protected 2-aminoalkanesulfonamides, aromatic aldehydes,
and aryldichlorophosphines, and subsequent aminolysis with
amino esters. The current synthetic route is a convergent and
atom-economic method. It is an efficient pathway to prepare
hybrid sulfonophosphinopeptides from simple starting ma-
terials.
Acknowledgment. This work was supported in part by
the National Natural Science Fundation of China and the
Beijing Natrual Science Foundation (Project No. 2092022).
Supporting Information Available: Experimental pro-
cedure, analytical data, and copies of 1H NMR and 13C NMR
spectra of N-protected 2-aminoalkanesulfonamides and sul-
fonophosphinopeptides. This material is available free of
charge via the Internet at http://pubs.acs.org.
In summary, a series of hybrid sulfonophosphinopeptides,
composed of amino acid, aminoalkylphosphinic acid, and
aminoalkanesulfonic acid residues, were synthesized in
satisfactory to good yields via the Mannich-type reaction of
OL901543Y
Org. Lett., Vol. 11, No. 17, 2009
3925