The phosphorus-mediated oligomerization of glycinesters

Article abstract of DOI:10.1080/10426500600762755

The catalytic polymerization of α-aminoacids or stable α-aminoesters in the presence of a phosphorus template is proposed as an alternative to that of sensitive N-carboxyanhydrides for the synthesis of polyaminoacids. The synthesis of methane thiophosphon

Full text of DOI:10.1080/10426500600762755

This article was downloaded by: [McMaster University]
On: 27 October 2014, At: 12:37
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
The Phosphorus-Mediated
Oligomerization of Glycinesters
S. Alibert-Fouet a & M. Mulliez a
a Laboratoire Synthèse et Physicochimie de
Molécules d'Intérêt Biologique , Université Paul
Sabatier , France
Published online: 01 Feb 2007.
To cite this article: S. Alibert-Fouet & M. Mulliez (2006) The Phosphorus-Mediated
Oligomerization of Glycinesters, Phosphorus, Sulfur, and Silicon and the Related
Elements, 181:11, 2555-2563, DOI: 10.1080/10426500600762755
To link to this article: http://dx.doi.org/10.1080/10426500600762755
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.

This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 181:2555–2563, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600762755
The Phosphorus-Mediated Oligomerization
of Glycinesters
S. Alibert-Fouet
M. Mulliez
Laboratoire Synthe`se et Physicochimie de Mole´cules d’Inte´reˆt
Biologique, Universite´ Paul Sabatier, France
The catalytic polymerization of α-aminoacids or stable α-aminoesters in the pres-
ence of a phosphorus template is proposed as an alternative to that of sensitive N-
carboxyanhydrides for the synthesis of polyaminoacids. The synthesis of methane
thiophosphonyl derivatives of polyglycine (an average of ten residues) was actually
carried out in polar solvents (dimethylformamide, acetonitrile) in the presence of
diazabicycloundecene and trimethylsilyldiethylamine.
Keywords Cyclization; peptides; phosphorus; polycondensation; silicon
INTRODUCTION
Polyaminoacids constitute a class of polymers with interesting appli-
cations. As a simplified protein model, they have, firstly, contributed
to elucidating the secondary structure of proteins.1 More recently
they have been used as antigens,2 as biodegradable substrates releas-
ing active components,3 or, when formed with amino acids possess-
ing a functional side-chain (particularly serine or lysine), as anchors
for various chemical groups.4 Typically, their synthesis involves N-
carboxyanhydride polymerization.5,6 However, these heterocycles are
very fragile, and alternative methods using more stable compounds are
therefore attractive. Indeed a different approach using α-aminoesters,
the salts of which are stable and easy to prepare, has recently been
published. Their polymerization is affected intramolecularly within a
metal complex.7 In fact, the principle of this method is identical to
what we published previously8 with a phosphorus template instead of a
metal template, and even more advantageously, with free (unprotected)
Received July 29, 2005; accepted April 5, 2006.
Address correspondence to Michel Mulliez, Laboratoire Synthe´se et Physicochimie de
Mole´cules d’Inte´reˆt Biologique, UMR CNRS n∗5068, Universite´ Paul Sabatier, 118 Route
de Narbonne, 31062 Toulouse Cedex 09, France. E-mail: mulliez@chimie.ups-tlse.fr
2555

2556
S. Alibert-Fouet and M. Mulliez
α-aminoacids in place of α-aminoesters. As success was limited to a low
degree of polymerization,7 it is of interest to examine also whether with
the phosphorus template8 the size of the oligomers could be enhanced.
RESULTS AND DISCUSSION
Our aforementioned peptide synthesis method8 requires the repetition
of two reactions (Scheme 1), with only one, the second, for the steps
comprising the displacement of the peptide link and the attachment of
the next α-amino acid, which are otherwise separated:7
SCHEME 1
In Aꢀ the arrangement is the same as in A, with permutation of the
respective positions of the growing peptide chain and of the amino acid:
The two reactions can be repeated alternately, ad. libitum. Moreover,
implicitly, the synthesis is regulated by the use of different media for
each reaction: for example, cyclization (1) in acid, and aminolysis (2) in a
basic medium. Conversely, if each reaction can be carried out under the
same conditions, the synthesis is unregulated: Polyaminoacids should
then be obtained.8b
Many years ago, in the search for such a medium, we first considered
operating with amino acids in carboxylic acids, since in those they are
sufficiently soluble, while their amino function is still reactive toward
such strong acylating reagents as trifluoraocetic anhydride9 or mixed
formic-acetic anhydride.10 As for the aminolysis (2), cyclization (1) may
also be a priori carried out in them in light of the known acid cat-
alyzed conversion11 of thiocarbamoyl amino acids into thiohydantoins

The Oligomerization of Glycinesters
2557
(analogous to B by replacing RP(Y) with CS). Nevertheless, in practice,
this was not feasible: In the presence of amines and acetic acid, hetero-
cycles B react exclusively with the acetic acid.12 They are also extremely
easily hydrolyzed (water is produced by the assumed cyclization reac-
tion). Furthermore, phosphonic acid diamides A are not very stable in
an acidic medium.8,13
At this stage we considered two alternatives:8 (1) the intramolecular
catalysis of the aminolysis of B, making possible the use of free amino
acids in a carboxylic acid medium, as previously mentioned. This study
was started recently and is in progress.14−18 (2) The second alterna-
tive was the use of aminoesters: each reaction (Scheme 1) may then be
affected in the same medium, i.e., an aprotic organic solvent. The prob-
lem is that in reaction (l) an alcohol will be released, which is known
to react much more easily with B than amines.12 In order to suppress
this alcoholysis, the use of alcohol trapping reagents may be considered.
Of course, they could also react with the aminoesters. We therefore se-
lected aminosilanes as it is known that they react with amines in a
displaced equilibrium19 (i.e., leaving, as required, some free, reactive
amino groups), unlike the way they react with alcohols; hexamethyld-
isilazane was discarded because free ammonia would react easier with
phosphorus than aminoesters. Trimethylsilyldiethylamine (TMSDEA)
was chosen because the more bulky secondary amine should not inter-
fere in the course of the reaction. We operated in three steps.
First, we examined (Scheme 2) the feasibility of the synthesis of B.
As it had already been prepared in another way,20 we chose heterocy-
cle 5, starting from phenyl phosphonic diamide 4. This isopropylester,
pure and easily crystallized, was prepared using Seebach’s method21
SCHEME 2

2558
S. Alibert-Fouet and M. Mulliez
from ethylester 3 in its crude state. Silylated heterocycle 5 was actu-
ally obtained under the following conditions (which are similar to those
already described for the synthesis of phosphorus heterocycles derived
from β-amino amides15 or sarcosamide22): (1) catalytic amounts of the
strong base Diazabicycloundecene (DBU) (triethylamine proved to be
inefficient); (2) a polar solvent such as DMF (in which the nucleophilicity
of anions is known to be enhanced) or acetonitrile; and (3) the TMSDEA
trapping reagent.
After an addition of a large excess (8 equivalents) of benzylamine,
which is a good model for a glycinester, and heating to 65◦C, aminoly-
sis leading to 6 by the attack on phosphorus12 was completed in only
a week. Clearly, these conditions preclude the use of α-aminoesters,
particularly of glycine derivatives, because of their well-known easier
self-condensation in dioxopiperazine.23
Second, in order to obtain the required free phosphorus access ac-
celerating aminolysis, we turned to the less crowded methyl phospho-
namide 7 (Scheme 3), previously prepared in the laboratory.24 Indeed
this proved to be considerable: Reaction at phosphorus of heterocycle
8 is completed in only a few hours at r.t. A second, slower, aminolysis
(performed overnight) of transient benzylester 8 leading eventually to
phosphondiamide 10 was also observed. The cyclization of 7 was also
faster (2 h at 60◦C) than that of 4, while being slower than the aminol-
ysis of 8.
SCHEME 3
Third, instead of benzylamine we used esters of glycine (Scheme 3,
left). Since their self-condensation reaction must be slower than reac-
tions (1) and (2) (Scheme 1), we did not employ the ethylester used
by Hoffmu¨ller et al.7 (leading, by transesterification [MeOH, NEt3],
to the methylester, even more prone to self-condensation25), which is
known to lead very easily to dioxopiperazine,25 and even to polyglycine

The Oligomerization of Glycinesters
2559
in the absence of template.26 Rather, we used isopropylester (easily pre-
pared from hydrochloride using Hillman’s excellent method27) and tert-
butylester.28 They are known to be, respectively, rather25 and very28 re-
sistant to self-condensation, while the cyclization (1) remains possible.8
Moreover, we checked that in the most favorable case for this reac-
tion (i.e., with isopropylester), no dioxopiperazine was produced, as the
stable29 N-silylated aminoester was formed. Finally, NMR analysis of
the insoluble material produced showed that it was a mixture of poly-
mers with an average number of ten glycine residues (nearly eight in
the experiment of Hoffmu¨ller et al.7).
In conclusion, the relatively low degree of polymerization obtained
confirms the explanation given by Hoffmu¨ller et al.:7 “notoriously in-
soluble polyglycine peptides in organic solvents.” (p. 730) Work is in
progress to improve the solubility by using more lipophilic aminoesters
derived from other α-aminoacids, provided the increase of steric bulk
does not drastically reduce the aminolysis reaction,30. and phospho-
nyl templates, which are more electrophilic than MEPS (e.g., CF3PO).
These are expected to improve both reactions in Scheme 1, particu-
larly cyclization, thus avoiding the use of DBU prone to racemizing the
synthesized polymers.
EXPERIMENTAL31
The general conditions are the same as indicated elsewhere.18
Phosphondiamide Ethylester 3
To a pyridine (20 mL) solution of 1 (0.58 g, 2.8 mmol), under vigor-
ous magnetic stirring and ice cooling, a pyridine (20 mL) solution of
benzylamine (0.3.3 g, 1.1 equiv.) was added dropwise during 20 min.
The resulting solution was added dropwise at r.t. under stirring dur-
ing 35 min to a pyridine (6 mL) and triethylamine (0.85 g, 3.35 equiv.)
suspension of Gly-OEt.HCl (0.55 g, 1.4 equiv.). After stirring overnight
and concentration, an addition of CCl4 (50 mL), extraction with water,
10% citric acid, and 5% NaHCO3 solutions (30 mL each), the CCl4 was
evaporated, and the residue dissolved in a mixture of pyridine (35 mL)
and water (2.5 mL). After 4 days, the solution was concentrated to dry-
ness; the residue was dissolved in ether (60 mL) and extracted with a
5% NaHCO3 solution (3 × 20 mL). After removal of the water (Na2SO4)
and concentration to dryness, the raw product (83% of the phosphorus
content) was used for the following transesterification reaction. Crys-
tals (m.p. 42–44◦C) were obtained from diisopropylether after 2 months.

2560
S. Alibert-Fouet and M. Mulliez
νmax 3337, 1737 cm−1; δH (CDCl3): 8 (m, 2H, 2 H ortho C6H5PS), 7.4 (m,
3H, 2 H meta + H para C6H5PS), 7.27 (s, 5H, C6H5CH2),4.3 (m, 4H,
ethyl and benzyl CH2), 3.78 (dd, JHH 6.2, JPH 11.4, 2H, CH2Gly), 3
(broad s, 2H, 2NH), 1.22 (t, JHH 7.1, 3H, CH3); δC (CDCl3): 171.5 (d,
JPC 8.1, CO), 138.5 (d, JPC 8.7, quart. C benzyl), 134.5 (d, JPC 123.1, C
ipso), 131.9 (d, JPC 2.8, CH para PhPS), 131.0 (d, JPC 11.2, 2CH meta
PhPS), 128.6 (d, JPC 13.4, 2CH ortho PhPS), 127.7 and 128.7 (2 × 2CH
ortho/meta benzyl), 127.4 (CH para benzyl), 61.5 (CH2 ethyl), 45.4 (CH2
benzyl), 42.8 (CH2 Gly), 14.2 (CH3); δP (CDCl3): +66.3.
Phosphondiamide Isopropylester 4
Isopropanol (90 mL), raw 3 (14 g; 40 mmol), and Ti(OiPr)4 (3.46
g, 0.3 equiv.) were heated for 24 h at 70◦C. After work-up as
described,21 the product crystallized rapidly from diisopropylether: col-
orless crystals, mp 70–71◦C. (Found: C, 58.73; H, 6.58; N, 7.70; S, 8.63.
C18H23N2O2PS requires C, 58.65; H, 6.40; N, 7.73; S, 8.85); νmax 3364,
3326, 1724 cm−1; δH (CDCl3): 7.85 (m, 2 H, 2H ortho PhPS), 7.40 (m, 3H,
2H meta +H para PhPS), 7.27 (s, 5H, C6H5CH2),5.00 (sept., JHH 6.3,
1H, CH isopropyl), 4.12 (dd, JHH 6.6, JPH 8.6, 2H, CH2 benzyl), 3.75 (dd,
JHH 6.1, JPH 11.3, 2H, CH2 Gly), 1.2 (d, JHH 6.3, 6H, 2CH3); δC (CDCl3):
171.0 (d, JPC 8.1, CO), 138.5 (d, JPC 8.7, quart. C benzyl), 134.5 (d, JPC
122.9, C ipso), 131.8 (d, JPC 2.9, CH para), 131.0 (d, JPC 11.2, 2 CH meta
PhPS), 128.6 (d, JPC 13.7, 2CH ortho PhPS), 128.6 and 127.7 (2 × CH
ortho/meta benzyl), 127.4 (CH para benzyl), 68.3 (CH isopropyl), 45.4
(CH2 benzyl), 43.0 (CH2 Gly), 21.8 (2 CH3); δP (CDCl3): +66.7.
Dibenzylamide 6
In an NMR tube filled with argon we added a capillary of deuteriated
benzene, DMF (0.4 mL), DBU (25 mg, 1.4 equiv.), and TMSDEA (85
mg, 5.5 equiv.), and after 20 h (time allowed for dehydration of the
medium), 4 (44 mg, 0.12 mmol). After 2 h at r.t., 31P NMR showed
two peaks δ 78.2 (silylated 5) and 67.2 (4) in a 38:61 ratio. A sep-
tum connected with a syringe filled with CaCl2 was then adapted,
the tube was heated at 65◦C. Ratio 5/4: 61:38 after 1 h 30 min; 81:8
after 6 h 30 min; 88:2 after 20 h. A mixture (118 mg) of benzy-
lamine (80%: 7.8 equiv.) and bis(silyl)acetamide (10%) was then added
at r.t. 31P NMR showed practically two peaks. δ 78.1 (5), 68.1 (6) in
the ratio 81:13, 63:31 after 6 h, 11:85 after 2 days, and 5:81 after
3 days. After 1 week, CH2Cl2 (40 mL) was added. After extractions
with 50% then 10% citric acid, 5% NaHCO3 solutions (20 × 30 mL

The Oligomerization of Glycinesters
2561
each), removal of water (Na2SO4), and concentration to dryness, 6 was
obtained as an oil in an 83% yield. After a year at −15◦C in a satu-
rated EtOAc/diisopropylether solution the product crystallized: white
powder, mp 72–73◦C. (Found: C, 64.28; H, 5.88; N, 8.83. C22H24N3OPS
requires C, 64.54; H, 5.81; N, 10.26). νmax 3376, 1662 cm−1; δH (CDCl3):
8.00 (m, 2H, 2H ortho PhPS), 7.45 (m, 3H, 2H meta + H para PhPS),
7.25 (s, 10H, 2 C6H5 benzyl), 6.62 (broad s, 1H, NH carboxamide), 4.34
(d, JHH 5.8, 2H, CH2 benzylcarboxamide), 4.08 (dd JHH 6.2, JPH 10,4,
2H, CH2 benzylphosphonamide), 3.68 (nonsymmetric dd, JHH 7.3, JPH
12.3, 2H, CH2 Gly), 3.34 (m, 1H, NH), 3.02 (m, 1H, NH); δC (CDCl3):
170.2 (d, JPC 6.1, CO), 138.2 (d, JPC 7.8, quart. C benzylphosphonamide).
137.8 (quart. C benzylcarboxamide), 134.1 (d, JPC 121.8, C ipso), 132.2–
127.6 (m, 15 C, 15 aromatic CH), 45.4 and 43.5 (2s, 2CH2); δP (CDCl3):
+66.7.
Dibenzylamide 10
In an NMR tube, as previously described, an acetonitrile (0.6 mL) so-
lution of 7 (85 mg, 0.24 mmol), DBU (33 mg, 0.8 equiv.) and TMSDEA
(130 mg, 3.7 equiv.) was heated for 3 h to 70◦C (31P NMR: δ + 87, 8).
Benzylamine (168 mg, 6.5 equiv.) was then added. After 20 h at r.t. (31P
NMR showed practically one signal at δ +68.3), the reaction mixture
was concentrated and diluted with CH2Cl2 (25 mL). The solution was
extracted with 10% citric acid and 5% NaHCO3 solutions (3 × 20 mL
each), dried (Na2SO4), and concentrated to dryness leaving an oil as a
mixture of 10 (72% yield) and trimethylsilylated benzylalcohol. After a
year at −15◦C in a saturated EtOAc/ether solution, the product crys-
tallized: small white balls. νmax 3280, 1647 cm−1; δH (CDCl3): 7.54 (t,
JHH 5.5, 1H, NH carboxamide), 7.30 (m, 11H, 2C6H5 + 1 NH carboxam-
ide), 4.31 (d, JHH 5–8, s with D2O, 2H, CH2 benzylcarboxamide), 4.04
(dd, JHH 5.8, JPH 11.6, 2H, CH2 benzylphosphonamide), 3.84 (d, JHH
5.7, s with D2O, 2H, CH2 carboxamide), 3.5 (m, 3H, 2H with D2O, CH2
Gly phosphonamide + NH phosphonamide), 3.30 (m, 1H, disappeared
with D2O, NH phosphonamide), 1.72 (d, JPH 14.2, 3H, CH3); δC (CDCl3):
171.8 (d, JPC 5.1, CO Gly linked to phosphorus), 168.3 (CO other Gly),
138.5 and 138.0 (2 quart. C), 128.7–126.6 (m, aromatic CH, two phenyl
groups), 45.1, 43.8, 43.3, 43.0 (4 s, 4 CH2), 21.8 (d, JPC 88.8, CH3); δP
(CDCl3): +68.6.
When the reaction was stopped after 2 h 30 min, a mixture of
trimethylsilylated benzylalcohol, 10 (40%), and 8 (60%) was obtained.
The latter product was identified by IR (additional νCO 1745 cm−1),
1H NMR (a characteristic low-field signal of the methylene protons of a

2562
S. Alibert-Fouet and M. Mulliez
benzylic ester at δ 5.13; methyl protons at δ 1.87 JPH 14.2), and 31P NMR
(δ 68.7, slighty upfield compared to 8).
Polycondensation
An NMR tube, as previously described, was loaded with acetonitrile (0.4
mL), 7 (71 mg, 0.17 mmol), TMSDEA (132 mg, 0.81 mmol, 5.34 eq.), and
DBU (25 mg, 0.17 mmol). The addition of Glycine-tert-butylester (Lan-
caster) was effected in successive sections of 75 mg (0.57 mmol, 3.3 eq.).
In this way, 31P NMR enabled the control of both aminolysis (δ ∼ + 70,
several hours at r.t.) and the cyclization (δ ∼ 87, 3 h at 60◦C: slightly
slower than with benzylester 7). After three cycles of this treatment, a
gel-like substance appeared; at the same time 31P signals became less
intense. Subsequently, this phenomenon became more and more pro-
nounced, and in the end no clear signals were observed. Finally, after
an addition of 12 equivalents of aminoester, the mixture was concen-
trated to dryness, and the residue was taken up in ether, in particular
in order to remove DBU and silylated alcohols. The IR spectrum of
the insoluble material (74% yield in 11) showed an intense carbonyl
absorption at 1630–1650 cm−1 (amide) and a weak one at 1737 cm−1
(ester). The 31P NMR spectrum in DMSO-d6 indicated the presence
1
not of cyclic products (δ ∼ 87) but of diamides (δ ∼ 70). The H NMR
spectrum proved, as for 10, the lack of a signal at 5.2 ppm characteris-
tic for benzylester: This confirmed that there were two tert-butylesters
present. The ratio of integration of glycine CH2 (at δ ∼ 3.2 ppm) and
of tert-butylesters CH3 confirmed polycondensation, with an average
number of 10 glycine residues.
The same result was also obtained with isopropylester or with an
addition of 25 tert-butylester equivalents. It is important to note that
by means both of IR and NMR no dioxopiperazine, which has a very
characteristic spectrum, was observed.
REFERENCES
[1] (a) G. D. Fasman, Poly-α-Aminoacids, Protein Models for Conformational Studies,
(Marcel Dekker, New York, 1967); (b) For a recent reference: O. Pieroni, A Fissi, N.
Angelini, and F. Lenci, Acc. Chem. Res., 34, 8 (2001).
[2] M. Sela, S. Fuchs, and R. Arnon, Biochem. J., 85, 223 (1962).
[3] K. R. Sidman, J. Membr. Sci., 7, 277 (1980).
[4] See for example: (a) M. Nanasawa and H. Karnogawa, Bull. Chem. Soc. Jpn., 48,
2588 (1975); (b) S. Alibert-Fouet, PhD thesis, Universite´ Paul Sabatier, Toulouse
(France), (2001).
[5] E. Wu¨nsch, In Methoden der Organischen Chemie (Houben-Weyl), (Georg Thieme
Verlag, Stuttgart, 1974).

The Oligomerization of Glycinesters
2563
[6] H. R. Kricheldorf, α-Aminoacid-N-Carboxy-Anhydrides and Related Heterocycles,
(Springer Verlag, Berlin, 1987).
[7] W. Hoffmu¨ller, M. Maurus, K. Severin, and W. Beck, Eur. J. Inorg. Chem., 728 (1998).
[8] (a) M. Mulliez, Tetrahedron, 37, 2027 (1981); (b) M. Mulliez, PhD thesis, Universite´
Paris Sud (France), (1978).
[9] F. Weygand and R. Geiger, Chem. Ber., 88, 647 (1956).
[10] J. C. Sheehan and D. D. Young, J. Am. Chem. Soc., 80, 1154 (1958).
[11] See for example: D. T. Elmore and P. A. Toseland, J. Chem. Soc., 4533 (1954).
[12] M. Mulliez and M. Wakselman, Phosphorus and Sulfur, 8, 41 (1980).
[13] N. E. Jacobsen and P. A. Bartlett, J. Am. Chem. Soc., 105, 1613 (1983).
[14] F. Dujols, P. Jollet, and M. Mulliez, Phosphorus, Sulfur, and Silicon, 134–135, 231
(1998).
[15] F. Dujols and M. Mulliez, Phosphorus Sulfur, and Silicon, 157, 165 (2000).
[16] F. Dujols and M. Mulliez, J. Heterocycl. Chem., 475 (2001).
[17] F. Dujols, PhD thesis, Universite´ Paul Sabatier, Toulouse (France), (1999).
[18] F. Dujols, L. Marty, and M. Mulliez, Org. Biomol. Chem., 3, 227 (2005).
[19] J. Hills, V. Hagen, H. Ludwig, and K. Ru¨hlmann, Chem. Ber., 88, 776 (1966).
[20] M. Mulliez and M. Wakselman, Synthesis, 478 (1977).
[21] D. Seebach, E. Hungerbu¨hler, R. Naef, P. Schurrenberger, B. Weidmann, and
M. Za¨ger, Synthesis, 138 (1982).
[22] S. Alibert, D. Crestia, F. Dujols, and M. Mulliez, Tetrahedron Lett., 38, 8841 (1998).
[23] J. P. Greenstein and M. Winitz, In Chemistry of the Amino Acids, Vol. 2, p. 782,
Wiley, New York, 1961.
[24] M. Mulliez, Phosphorus and Sulfur, 8, 208 (1980).
[25] E. Abderhalden and S. Suzuki, Hoppe Seyler’s Z. Physiol. Chem., 176, 101 (1931).
[26] M. Frankel and E. Katchalski, J. Am. Chem. Soc., 64, 2264 (1942).
[27] G. Hillmann, Z. Naturforsch., 1, 682 (1946).
[28] G. W. Anderson and F. M. Callahan, J. Am. Chem. Soc., 82, 3358 (1960).
[29] See for example: H. R. Kricheldorf and G. Greber, Chem. Ber., 104, 3131 (1971) and
references cited therein.
[30] In that case, the aminolysis will still be easier with the participation of the sulfon-
amido group18 by intramolecular nucleophilic catalysis.14
[31] More details are available in ref. 4b (chapter 3).