Triphenylphosphonium salts bearing an L-alanyl substituent: Short synthesis and enantiomeric analysis by NMR

Article abstract of DOI:10.1016/S0040-4039(01)00650-5

A short, practical stereospecific synthesis of triphenylphosphonium salts bearing an L-(N-benzoyl)-alanyl substituent from L-serine is described. The key step is the ring opening of an oxazoline salt derived from serine with trimethylsilyl halide, giving

Full text of DOI:10.1016/S0040-4039(01)00650-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3981–3984
Triphenylphosphonium salts bearing an -alanyl substituent:
L
short synthesis and enantiomeric analysis by NMR
Franck Meyer,a Jacques Uziel,a Anne Marie Papinib and Sylvain Juge´a,*
aUnite´ mixte Universite´ Cergy Pontoise-ESCOM, FRE CNRS 2126, Synth. Org. Se´lective et Ch. Organome´t.,
Universite´ Cergy Pontoise, 5 mail Gay Lussac, 95031 Cergy Pontoise, France
bLab. Ch. Peptidi, Universita` degli Studi di Firenze, via Gino Capponi, 9, Florence, Italy
Received 5 April 2001; accepted 18 April 2001
Abstract—A short, practical stereospecific synthesis of triphenylphosphonium salts bearing an
L-(N-benzoyl)-alanyl substituent
from -serine is described. The key step is the ring opening of an oxazoline salt derived from serine with trimethylsilyl halide,
L
giving b-bromo or b-iodo alanine, which were used for the quaternization of triphenylphosphine. The phosphonium salts were
obtained in 80% overall yield from serine, and their enantiomeric purity was easily determined by 31P NMR in the presence of
a cinchona alcaloid. © 2001 Elsevier Science Ltd. All rights reserved.
application in hemisynthesis. The main synthetic
difficulty arises from the presence of the free carboxylic
acid group in compounds 2, which is necessary in order
to avoid elimination or racemization during the Wittig
process. Thus, while the quaternization of PPh3
requires a b-bromo or a b-iodo alanine derivative, the
free carboxylic acid group could not be obtained from
the benzyl ester by debenzylation, since hydrogenolysis
is unsuccessful with these phosphonium salts.10,13
Hemisynthetic methods are widely used for the prepara-
tion of enantiomerically pure unnatural or non-classical
a-aminoacids.1 The main synthetic route requires the
construction of CꢀC or CꢀX (X=heteroatoms) single
bonds by nucleophilic, electrophilic or radical reactions
at the b position of an alanine equivalent, e.g. b-
iodoalanine,2 b-lactone,3 a,b-aziridine,4 a,b-sulfami-
date5 or b-sulfone,6 derived from the readily available
D
- or L-serine. Although b,g-unsaturated-a-aminoacids
1 have attracted attention as antibiotic7 and potential
suicide enzyme inhibitors,8 or also as synthetic inter-
mediates,9,10 few hemisyntheses involving the direct
With this in mind, and continuing our work on the
oxazolines derived from serine as alanine b-cation
equivalents,14 we examined their application for the
formation of
a CbꢁCg double bond have been
described.10–12
Despite the pioneering work of Itaya, the Wittig
reagent 2 has not been extensively investigated, due in
particular to the low yield of the resulting olefination
(<43%).10 In addition, the seven-step preparation of the
synthon 2 from serine poses a serious obstacle for its
Scheme 1.
Keywords: amino acids and derivatives; phosphonium salts; NMR; enantiomeric purity.
* Corresponding author. Fax: 33 1 34 25 70 67; e-mail: sylvain.juge@chim.u-cergy.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00650-5

3982
F. Meyer et al. / Tetrahedron Letters 42 (2001) 3981–3984
synthesis of phosphonium derivatives. We report here a
short stereospecific synthesis of the N-protected amino
phosphonium salts could also be obtained by an alter-
native one-pot procedure, namely, reaction of the oxa-
zoline sodium salt 4 with a TMSBr/H2O (1:1) mixture
at room temperature for 48 h, followed by quaterniza-
tion with 2.5 equivalents of PPh3 in refluxing
chloroform.
acid phosphonium salts 2 (PG=Bz) from
L
-serine 3
and a practical 31P NMR method for the determination
of their enantiomeric purity.
The (S)-oxazoline sodium salt 4 was easily obtained in
90% overall yield from 3 by successive esterification
with methanol, condensation with the phenyl imino-
ether derived from benzonitrile and saponification
(Scheme 1).15
The enantiomeric purity of compound 2a was checked
by 31P NMR using a chiral phosphate anion,18a as
previously described for phosphonium salts.18b How-
ever, the analysis could also be performed by a simple
31P NMR experiment in the presence of cinchona
alcaloid. Thus, the NMR spectra of a sample of
racemic 2b with cinchonidine revealed two signals at
+23.2 and +23.3 ppm (Fig. 1b), while the compound
prepared above showed only one signal (Fig. 1a). In the
case of the bromide 2a, cinchonine gave better results in
the enantiomeric analysis.
Stirring the oxazoline sodium salt 4 with three equiva-
lents of a TMSBr/H2O (1:1) mixture in chloroform at
room temperature for 48 h, led to the corresponding
N-benzoyl-b-bromo-alanine 5a in 86% yield. No signifi-
cant elimination or racemization was detected under
these conditions, and compound 5a was of sufficient
chemical purity to allow its use in the following reac-
tion without further purification. Under similar condi-
tions, TMSI led to the corresponding b-iodo derivative
5b, which was isolated in 93% yield. Therefore, we
assume that the ring opening product 5 resulted mainly
from the reaction of the oxazoline sodium salt 4 with
the HBr (or HI), which is generated in situ by the
TMSX hydrolysis. Thus, the oxazolinium salt formed
by nitrogen protonation underwent attack by halide at
the C(5) position, leading to the ring opening by CꢀO
bond cleavage (Scheme 2).16
In summary, we have reported a short, practical
stereospecific synthesis of triphenylphosphonium salts
bearing
L
-(N-benzoyl)-alanyl substituents in 80% over-
-serine. The key step of the synthesis is
all yield from
L
the ring opening of the oxazoline salt derived from
serine with a trimethylsilyl halide, giving b-bromo or
b-iodo alanine in 93% yield. The advantage of this
pathway is the generation of HX under mild condi-
tions, allowing the reaction to occur without side-prod-
ucts or racemization. Moreover, triphenylphosphine is
cleanly quaternized by the N-benzoyl-b-halogeno-a-
amino acid, giving the desired phosphonium salt in 80%
overall yield from serine. The enantiomeric purity was
easily determined by 31P NMR of their diastereoiso-
meric salts formed in situ with cinchonine or cin-
chonidine. Further developments and applications of
the phosphonium salts and their ylides derivatives are
currently under study in our laboratory.
Quaternization of triphenylphosphine with the corre-
sponding N-benzoyl-b-halogeno-a-amino acid 5a or 5b
was achieved in refluxing chloroform to give the corre-
sponding phosphonium salts 2a and 2b in 95% yield.
The analytically pure phosphonium salts 2a and 2b17
were easily recovered by simple filtration and obtained
in 80% overall yield from -serine 3. Interestingly, the
L
Acknowledgements
We thank the Ministry of Research and the CNRS for
financial support, and Dr. J. Lacour (University of
Geneva) for the attempts at enantiomeric separation
using a chiral anion.
Scheme 2.
Figure 1. 31P NMR enantiomeric analysis of the phosphonium salt 2b in the presence of cinchonidine: (a) prepared using the
chemistry described above; (b) racemic sample.

F. Meyer et al. / Tetrahedron Letters 42 (2001) 3981–3984
3983
15. (a) Fry, E. M. J. Org. Chem. 1949, 14, 887–894; (b)
Stammer, C. H.; Wilson, A. N.; Spencer, C. F.; Bachelor,
F. W.; Holly, F. W.; Folkers, K. J. Am. Chem. Soc. 1957,
79, 3236–3240.
16. Typical procedure for the synthesis of the N-benzoyl-b-
halogeno-a-amino acid 5: 20 mmol of halogeno
trimethylsilane was added to a suspension of 2.13 g (10
mmol) oxazoline sodium salt 4 in 30 mL of CHCl3. The
mixture was stirred at room temperature for 48 h. The
solvent was removed under vacuum and the compound 5
was extracted with acetone. The acetone was removed
and the solid was washed with CH2Cl2 to give a white
powder.
References
1. Duthaler, R. O. Tetrahedron 1994, 50, 1539–1650.
2. (a) Adlington, R. M.; Baldwin, J. E.; Basak, A.; Kozy-
rod, R. P. J. Chem. Soc., Chem. Commun. 1983, 944–945;
(b) Bajgrowicz, J. A.; El Hallaoui, A.; Jacquier, R.;
Pigie`re, Ch.; Viallefont, Ph. Tetrahedron 1985, 41, 1833–
1843; (c) Jackson, F. W.; Wishart, N.; Wood, A.; James,
K.; Wythes, M. J. J. Org. Chem. 1992, 57, 3337–3404.
3. (a) Arnold, L. D.; Drover, J. C. G.; Vederas, J. C. J. Am.
Chem. Soc. 1987, 109, 4649–4659; (b) Arnold, L. D.;
May, R. G.; Vederas, J. C. J. Am. Chem. Soc. 1988, 110,
2237–2241.
4. (a) Nakajima, K.; Okawa, K. Bull. Chem. Soc. Jpn. 1983,
56, 1565–1566; (b) Sato, K.; Kosokowski, P. Tetrahedron
Lett. 1989, 30, 4073–4076; (c) Kuyl-Yeheskiely, E.; Lod-
der, M.; van der Marel, G. A.; van Boom, J. H. Tetra-
hedron Lett. 1992, 33, 3013–3016; (d) Baldwin, J. E.;
Spivey, A. C.; Schofield, C. J.; Sweeney, J. B. Tetrahedron
1993, 49, 6309–6330; (e) Baldwin, J. E.; Farthing, C. N.;
Russell, A. T.; Schofield, C. J.; Spivey, A. C. Tetrahedron
Lett. 1996, 37, 3761–3764.
(R)-(−)-2-(N-Benzoyl-amino)-3-bromo propanoic acid 5a:
White solid; mp=106°C; IR (KBr, w cm−1): 3378, 3285,
1
1717, 1635, 719; H NMR (250 MHz acetone-d6) l 7.97
(2H, dd, J=1.5, J=7, H arom.), 7.53 (3H, m, H arom.),
5.12 (1H, t, J=4.8, CH), 4.02 (2H, d, J=4.2, CH2Br);
13C NMR (62.9 MHz acetone-d6) l 171.1 (COPh), 168.5
(CO2H), 135, 133.3, 129.9, 129.1 (C arom.), 55.2 (CH),
33.9 (CH2Br). HRMS (FAB+) calcd for C10H11BrNO3
[M+1]: 271.9922; found: 271.9916.
5. Baldwin, J. E.; Spivey, A. C.; Schofield, C. J. Tetra-
hedron: Asymmetry 1990, 1, 881–884.
(R)-(−)-2-(N-Benzoyl-amino)-3-iodo propanoic acid 5b:
White solid; mp=127°C; IR (KBr, w cm−1): 3366, 1714,
1
6. (a) Sasaki, N. A.; Hashimoto, C.; Potier, P. Tetrahedron
Lett. 1987, 28, 6069–6072; (b) Sasaki, N. A.; Hashimoto,
C.; Pauly, R. Tetrahedron Lett. 1989, 30, 1943–1946; (c)
Sasaki, N. A.; Dockner, M.; Chiaroni, A.; Riche, C.;
Potier, P. J. Org. Chem. 1997, 62, 765–770.
7. (a) Greenlee, W. L. J. Org. Chem. 1984, 49, 2632–2634;
(b) Yonezawa, Y.; Shimizu, K.; Yoon, K.; Chin, C.
Synthesis 2000, 634–636.
1631, 1198, 712; H NMR (250 MHz acetone-d6) l 8.00
(3H, m, NH, H arom.), 7.64–7.49 (3H, m, H arom.), 4.95
(1H, td, J=4.5, J=7.3, CH), 3.89 (1H, dd, J=4.5,
J=10.4, CHHI), 3.80 (1H, dd, J=7.1, J=10.4, CHHI);
13C NMR (62.9 MHz acetone-d6) l 171.3 (COPh), 168.2
(CO2H), 135.5, 133.3, 130, 128.9 (C arom.), 55.6 (CH),
6.7 (CH2I). HRMS (FAB+) anal. calcd for C10H11INO3
[M+1]: 319.9784; found: 319.9771.
8. For selected examples of b,g-unsaturated aminoacids as
enzyme inhibitors, see: (a) Shannon, P.; Marcotte, P.;
Coppersmith, S.; Walsh, C. Biochemistry 1979, 18, 3917–
3920; (b) Andrews, M. D.; O’Callaghan, K. A.; Vederas,
J. C. Tetrahedron 1997, 53, 8295–8306 and references
cited therein.
9. For selected examples of b,g-unsatured aminoacids as
synthons, see: (a) Bartlett, P. A.; Tanzella, D. J.;
Barstow, J. F. Tetrahedron Lett. 1982, 23, 619–622; (b)
Bartlett, P. A.; Barstow, J. F. Tetrahedron Lett. 1982, 23,
623–626.
10. (a) Itaya, T.; Shimomichi, M.; Ozasa, M. Tetrahedron
Lett. 1988, 4129–4132; (b) Itaya, T.; Mizutani, A.; Iida,
T. Chem. Pharm. Bull. 1991, 39, 1407–1414; (c) Itaya, T.;
Iida, T.; Shimizu, S.; Mizutani, A.; Morisue, M.; Sugi-
moto, Y.; Tachinaka, M. Chem. Pharm. Bull. 1993, 41,
252–261; (d) Itaya, T.; Kanai, T.; Iida, T. Tetrahedron
Lett. 1987, 38, 1979–1982; (e) Itaya, T.; Kanai, T.; Iida,
T. Tetrahedron Lett. 1997, 38, 1979–1982.
17. Typical procedure for b-halogeno phosphonium salts 2:
1.05 g (4 mmol) of triphenylphosphine was added to 0.51
g (1.6 mmol) of iodo aminoacid 5b in 10 mL of CHCl3.
The mixture was heated under reflux for 48 h. A part of
the phosphonium salt 2b was recovered by filtration, the
residue was evaporated and was stirred in ether to extract
the phosphine excess. The combined precipitates gave a
white powder with 95% yield.
(R) - (−) - [2 - (Carboxy) - 2 - (N - benzoyl - amino] - ethyl tri-
phenylphosphonium bromide 2a:
White solid; mp=135°C; [h]2D0=−37.4 (c=0.76, MeOH)
e.e.=99%; IR (KBr, w cm−1): 3413, 2904, 1741, 1623,
1439, 747; 1H NMR (250 MHz CD3OD) l 7.93–7.42
(20H, m, H arom.), 5.06 (1H, ddd, J=2.7, J=10.4,
J=13.3, CH), 4.26 (1H, ddd, J=2.8, J=14.2, J=16.8
CHHP), 4.03 (1H, ddd, J=11.1, J=15.9, J=22.1,
CHHP); 13C NMR (62.9 MHz CD3OD) l 172.9 (d,
J=15.8, CO2H), 170.4 (COPh), 137.1, 135.8, 135.7,
135.3, 134.5, 134.1, 132.4, 132.2, 130.1, 129.3, 120.7,
119.3 (C arom.), 48.8 (CH), 26.3 (d, J=55, CH2P); 31P
NMR (101 MHz CD3OD) l 22.32. HRMS (FAB+) anal.
calcd for C28H25PNO3 [M−Br]: 454.1572; found:
454.1560.
11. Sibi, M. P.; Rutherford, D.; Renhowe, P. A.; Biqin, L. J.
Am. Chem. Soc. 1999, 121, 7509–7516.
12. (a) Blaskovich, M. A.; Lajoie, G. A. J. Am. Chem. Soc.
1993, 115, 5021–5030; (b) Luo, Y.; Blaskovitch, M. A.;
Lajoie, G. A. J. Org. Chem. 1999, 64, 6106–6111; (c)
Rose, N. G. W.; Blaskovitch, M. A.; Wong, A.; Lajoie,
G. A. Tetrahedron 2001, 57, 1497–1507.
13. Meyer, F. PhD thesis, Universite´ de Cergy Pontoise,
2000.
14. Laaziri, A.; Uziel, J.; Juge´, S. Tetrahedron: Asymmetry
1998, 9, 437–447.
(R)-(−)-[2-(Carboxy)-2-(benzoyl-amino]-ethyl triphenyl-
phosphonium iodide 2b:
White solid; mp=195°C; [h]2D0=−42 (c=1.03, MeOH)
e.e.=99%; IR (KBr, w cm−1): 3413, 2925, 1741, 1624,
1439, 746; 1H NMR (250 MHz CD3OD) l 7.92–7.38
(20H, m, H arom.), 5.10 (1H, ddd, J=2.7, J=10.6,
J=13.3, CH), 4.29 (1H, ddd, J=2.8, J=14.2, J=16.7,

3984
F. Meyer et al. / Tetrahedron Letters 42 (2001) 3981–3984
CHHP), 4.05 (1H, ddd, J=11, J=16, J=22, CHHP);
57.83; H, 4.30; N, 2.41; found: C, 57.99; H, 4.36; N, 2.29.
HRMS (FAB+) anal. calcd for C28H25PNO3 [M−I]:
454.1572; found: 454.1582.
13C NMR (62.9 MHz CD3OD) l 172.1 (d, J=15.1,
CO2H), 169.7 (COPh), 136.4, 136.3, 135, 134.9, 133.8,
133.3, 131.6, 131.4, 129.3, 128.4, 119.9, 118.5 (C arom.),
48.5 (CH), 25.6 (d, J=54.7, CH2P); 31P NMR (101 MHz
CD3OD) l 22.20. Anal. calcd for C28H25PINO3 (581): C,
18. (a) Lacour, J., unpublished work; (b) Ginglinger, C.;
Jeannerat, D.; Lacour, J.; Juge´, S.; Uziel, J. Tetrahedron
Lett. 1998, 39, 7495–7498.
.