Highly symmetrical amino acid-derived N,N′-diacylated sulfodiimines

Article abstract of DOI:10.1055/s-2005-861843

A mild and efficient method for the coupling of sulfodiimines with N-protected amino acids has been developed, yielding the corresponding N,N′-diacylated sulfodiimines with up to 94% yield.

Full text of DOI:10.1055/s-2005-861843

1058
SHORT PAPER
Highly Symmetrical Amino Acid-Derived N,N¢-Diacylated Sulfodiimines
H
ighly Sy
u
mmetrical
A
a
mino
A
cid-
n
D
erived N, N¢-Diac
R
ylated Sulfodiim
.
ines Dehli, Carsten Bolm*
Institut für Organische Chemie der RWTH Aachen, Professor-Pirlet-Str. 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: carsten.bolm@oc.rwth-aachen.de
Received 13 December 2004
HN NH
N
R'
4
R*
HN
R
acylation
Abstract: A mild and efficient method for the coupling of sulfodi-
imines with N-protected amino acids has been developed, yielding
the corresponding N,N¢-diacylated sulfodiimines with up to 94%
yield.
+
S
R*-COOH
S
R
R'
O
prochiral
sulfodiimine 2
enantiopure
acid 3
Key words: coupling, amino acids, acylations, peptides, sulfodi-
imines, asymmetric synthesis
Scheme 1 Concept for the stereodifferentiation of a prochiral sul-
fodiimine using an enantiopure carboxylic acid 3 as acylating agent
N-protected amino acids, which are available in high
structural variability from the chiral pool, was initially in-
vestigated. Utilizing the mild carbodiimide-mediated pro-
tocol that we had previously applied for couplings
between sulfoximines and N-protected amino acids,10 we
disappointingly noted that the reaction between 2a and N-
Boc-phenylalanine (6a) in the presence of N,N¢-dicyclo-
hexylcarbodiimide (DCC) as coupling reagent and 1-hy-
droxybenzotriazole (HOBt) as activator, did not lead to
the expected product at all. Instead, compound 5
(Figure 2) was obtained in almost quantitative yield, most
likely from direct nucleophilic attack of HOBt on the ben-
zylic position of the starting sulfodiimine.
During the last decades the chemistry of sulfoximines, 1,
has thoroughly been investigated.1 As a consequence, a
number of derivatives have found application in biologi-
cal chemistry2 and asymmetric catalysis.3–5 In many of
such systems the presence of a C2 axis plays an important
role for the effectiveness of the molecule.5 Surprisingly,
sulfodiimines 2 (Figure 1), the nitrogen analogues of sulf-
oximines, have been much less studied.6 Despite their
high stability towards hydrolysis and thermal decomposi-
tion, they have only found limited application in synthe-
sis.7 Furthermore, sulfodiimines with two unsubstituted
nitrogen atoms are achiral rendering this particular build-
ing block inappropriate for asymmetric synthesis.8
N
O
R
NH
R'
HN NH
S
HN NH
N
S
S
R
R'
N
Me
1
2
O
2a
5
Figure 1 General structure of sulfoximines 1 and sulfodiimines 2
Figure 2 Product 5 from the attempted coupling of 2a and N-Boc-
phenylalanine in the presence of DCC and HOBt (for details see text)
Haake has shown that sulfodiimines can react with strong
acylating agents, such as acyl chlorides and anhydrides, in
the presence of triethylamine.9 With only one equivalent
of the acylating agent, the weakly nucleophilic sulfodi-
imines yield monoacyl derivatives, whereas with an ex-
cess of reagent the corresponding disubstituted
compounds are obtained. We now wondered if upon using
an enantiopure acylating agent such a process could be
used for the stereodifferentiation of the two nitrogens of a
prochiral sulfodiimine (2 with R π R¢). As products dia-
stereomeric N-acylated sulfodiimines 4 would result
(Scheme 1), which we envisaged to be valuable interme-
diates for both building blocks for biologically interesting
molecules and ligands for asymmetric catalysis.
HOBt is used in DCC-mediated coupling reactions of car-
boxylic acids with amines in order to avoid the racemiza-
tion or epimerization of base-labile stereogenic centers.11
Since the basicity of N-unsubstituted sulfodiimines is sig-
nificantly lower than the one of amines, we wondered if a
(stereochemistry-retaining) coupling could also be per-
formed in the absence of HOBt. Gratifyingly we found
that this was indeed the case. Thus, under these condi-
tions, N-monoacyl sulfodiimine 7 was obtained in 98%
yield (Scheme 2). Unfortunately, however, an almost
equimolar mixture of diastereomers was formed, indicat-
ing that the chiral recognition between the two coupling
partners during the acylation had been rather low. More-
over, we were unable to separate the diastereomers of 7 by
conventional flash chromatography or preparative HPLC.
For studying the stereoselective acylation reaction, the
coupling between readily accessible S-benzyl-S-methyl-
sulfodiimine (2 with R = Bn, R¢ = Me)6 and enantiopure
At this stage, we began to consider the possibility of using
the sulfodiimine sulfur not as stereogenic center, but as
‘linker’ between two chiral units. As described above,
Haake had shown that treatment of sulfodiimines with
SYNTHESIS 2005, No. 7, pp 1058–1060
Advanced online publication: 10.03.2005
DOI: 10.1055/s-2005-861843; Art ID: Z23504SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
5

SHORT PAPER
Highly Symmetrical Amino Acid-Derived N,N¢-Diacylated Sulfodiimines
1059
Ph
Table 1 Synthesis of N,N-Diacylated Sulfodiimines 8 by DCC-Me-
diated Couplings with Chiral Carboxylic Acids
Ph
DCC
HN NH
+
HN
Me
N
Boc
S
HO
Me
Boc CH2Cl2
N
S
N
H
Entry Substrate Acid 6
R¢¢ in 6
and 8
Product Yield
(%)
O
H
Ph
O
Ph
2a
6a
7
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2b
2b
2b
2b
Boc-Phe-OH
Boc-Ala-OH
Boc-Val-OH
Boc-Leu-OH
Boc-Phe-OH
Boc-Ala-OH
Boc-Val-OH
Boc-Leu-OH
Bn
8a
8b
8c
8d
8e
8f
76
93
75
94
39
48
41
44
Scheme 2 Coupling between sulfodiimine 2a and amino acid 6a
Me
i-Pr
i-Bu
Bn
strong acylating agents in excess led to N,N¢-disubstituted
derivatives. To our delight we found that this transforma-
tion also occurred in the DCC-mediated coupling with N-
Boc-protected amino acids. Thus, using sulfodiimine 2a
and 2.2 equiv of N-Boc phenylalanine (6a) as starting ma-
terials and following the conditions shown in Scheme 3,
diacylated product 8a was obtained in 76% yield. Careful
analysis of the 1HNMR spectrum of 8a confirmed that the
reaction had proceeded without epimerization as indicat-
ed by the AB system for the benzylic methylene group at
sulfur (consisting of two diastereotopic protons). This pat-
tern also proved the pseudo-C2 symmetry of the product,
since a hypothetical epimerization at one of the amino
acid-derived substituents would have led a meso-isomer,
whose methylene group (with two enantiotopic protons)
would appear as a singlet in the 1H NMR spectrum.
Me
i-Pr
i-Bu
8g
8h
O
O
H
N
H
N
N
N
N
Boc
Boc
N
S
H
H
O
O
O
Me
Ph
Ph
Ph
9
Me
Me
N
N
S
R''
O
Me
Ph
HN NH
HO
Boc
+
S
N
R
R'
H
10
O
2a: R = Me, R' = Bn
2b: R = R' = Me
6 (2.2 equiv)
Figure 3 Sulfodiimines 9 and 10 stemming from couplings with a
dipeptide and ibuprofen, respectively
DCC (2.2 equiv)
CH2Cl2, r.t., 24 h
yield, respectively) (Figure 3) demonstrating the chemical
flexibility of the developed approach.
R''
R''
Boc
N
R
N
Boc
N
N
S
H
H
In summary, the previously developed methodology for
the coupling of sulfoximines with N-protected amino ac-
ids and peptides has been adapted for the case of sulfodi-
imines. Under appropriate conditions a nucleophilic
attack at the labile C–S bond leading to a destruction of
the sulfodiimine unit can be avoided. Although the cou-
pling itself is non-stereoselective, it can be used for the
preparation of highly symmetrical compounds with sul-
fur-based bidirectional core units. For such C2- and pseu-
do-C2-symmetric compounds we foresee a wide variety of
applications in asymmetric synthesis and catalysis.
R'
O
O
8
Scheme 3 Synthesis of N,N¢-diacylated sulfodiimines 8
As revealed by the results summarized in Table 1, the
DCC-mediated double coupling reaction was quite gener-
al. Other N-Boc-protected amino acids reacted with 2a to
give the corresponding N,N¢-diacylated products 8 in up to
94% yield (entries 1–4). Complementary to this, using
S,S-dimethylsulfodiimine (2b) as starting material afford-
ed C2-symmetric sulfodiimines in up to 48% yield (entries
All reactions were carried out under argon using standard Schlenk
5–8). In this case, the two methyl groups at sulfur ap- techniques. CH2Cl2 (free of alcohols as stabilizing agents) was dis-
1
tilled over calcium hydride and stored under argon. NH-sulfodi-
peared as a singlet in the H NMR spectrum, which con-
imines were prepared according to the literature.6 All other starting
firmed the stereochemical integrity of the product.12
materials were obtained from commercial suppliers and used with-
As an extension of the substrate scope, S-benzyl-S-methyl
sulfodiimine (2a) was coupled with two other chiral car-
boxylic acids. First, dipeptide N-Boc-Phe-Gly-OH and,
second, non-proteinogenic carboxylic acid 2-(4-iso-bu-
tylphenyl)propionic acid (ibuprofen) were applied as a
coupling partner. In both cases the corresponding prod-
ucts 9 and 10 were obtained in high yields (91 and 83%
out further purification. NMR spectra were recorded in CDCl3 with
TMS as internal standard on a Varian Gemini 300 spectrometer
(300 and 75 MHz for 1H and 13C NMR spectra, respectively), FTIR
spectra on a Perkin-Elmer PE-1760 FT apparatus and MS spectra on
a Varian MAT 212 using a chemical ionization technique.
Representative Procedure
To a well stirred solution of the sulfodiimine (1.0 mmol) and the N-
Boc-protected amino acid (2.2 mmol) in CH2Cl2 (10 mL) at 0 °C, a
Synthesis 2005, No. 7, 1058–1060 © Thieme Stuttgart · New York

1060
J. R. Dehli, C. Bolm
SHORT PAPER
solution of DCC in CH2Cl2 (1 M; 2.2 mL, 2.2 mmol) was slowly
added. The suspension was allowed to warm up to r.t. and after 24
h of stirring the CH2Cl2 was removed under reduced pressure. The
precipitate was then suspended in EtOAc and filtered through
Celite. After column chromatography on silica gel (pentane–EtOAc
gradient) the product was obtained as a white solid.
References
(1) Reviews: (a) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(b) Mikolajczk, M.; Drabowicz, J.; Kielbasinski, P. Chiral
Sulfur Reagents; CRC Press: Boca Raton, 1997. (c) Pyne,
S. Sulfur Reports 1992, 12, 57. (d) Haake, M. In Houben–
Weyl, Methoden der organischen Chemie, Vol. E11;
Klamann, D., Ed.; Thieme: Stuttgart, 1985, 1299.
(e) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341.
(f) Johnson, C. R. Aldrichimica Acta 1985, 18, 3.
(2) For some recent examples stemming from this group, see:
(a) Bolm, C.; Müller, D.; Dalhoff, C.; Hackenberger, C. P.
R.; Weinhold, E. Bioorg. Med. Chem. Lett. 2003, 13, 3207.
(b) Bolm, C.; Müller, D.; Hackenberger, C. P. R. Org. Lett.
2002, 4, 893. (c) Bolm, C.; Moll, G.; Kahmann, J. D.
Chem.–Eur. J. 2001, 7, 1118.
(3) Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482.
(4) For recent examples, see: (a) Langner, M.; Bolm, C. Angew.
Chem. Int. Ed. 2004, 43, 5984. (b) Bolm, C.; Martin, M.;
Simic, O.; Verrucci, M. Org. Lett. 2003, 5, 427. (c) Bolm,
C.; Verrucci, M.; Simic, O.; Cozzi, P. G.; Raabe, G.;
Okamura, H. Chem. Commun. 2003, 2816. (d) Bolm, C.;
Simic, O. J. Am. Chem. Soc. 2001, 123, 3830. (e) Bolm, C.;
Simic, O.; Martin, M. Synlett 2001, 1878. (f) Harmata, M.;
Ghosh, S. K. Org. Lett. 2001, 3, 3321. (g) See also: Bolm,
C.; Martin, M.; Gescheidt, G.; Palivan, C.; Neshchadin, D.;
Bertagnolli, H.; Feth, M.; Schweiger, A.; Mitrikas, G.;
Harmer, J. J. Am. Chem. Soc. 2003, 125, 6222.
(S,S)-S-Benzyl-S-methyl-N,N¢-bis[2-(N-tert-butoxycarbonyl-
amino)-3-phenylpropanoyl]sulfodiimine (8a)
Yield: 76%.
IR: 3431, 1709, 1640 cm–1.
1H NMR: d = 1.42 (s, 18 H), 3.0–3.3 (m, 7 H), 4.55 (m, 2 H), 4.97/
5.07 (AB system, J = 13.1 Hz, 2 H), 5.14 (br s, 2 H), 7.1–7.5 (m, 15
H).
13C NMR: d = 28.4 (CH3), 35.6 (CH3S), 38.7 (CH2), 57.5 (CH2S),
57.7 (CH), 79.5 (C), 125.4 (C), 126.7 (CH), 128.3 (CH), 129.3
(CH), 129.7 (CH), 130.3 (CH), 131.7 (CH), 137.0 (C), 155.2 (CO),
180.5 (CO).
MS: m/z (%) = 663 [(M + H)+, 1], 255 (52), 91 (100).
Anal. Calcd for C36H46N4O6S: C, 65.23; H, 6.99; N, 8.45. Found: C,
64.91; H, 7.14; N, 8.33.
(S,S)-S,S-Dimethyl-N,N¢-bis[2-(N-tert-butoxycarbonylamino)-
3-phenylpropanoyl]sulfodiimine (8e)
Yield: 39%.
IR: 3431, 1705, 1640 cm–1.
1H NMR: d = 1.34 (s, 18 H), 2.95–3.20 (m, 4 H), 3.30 (s, 6 H), 4.40–
4.55 (m, 2 H), 5.09 (d, J = 6.7 Hz, 2 H), 7.05–7.25 (m, 10 H).
(5) Harmata, M. Chemtracts: Org. Chem. 2003, 16, 660.
(6) Review: Haake, M. In Topics in Sulfur Chemistry; Senning,
A., Ed.; Thieme: Stuttgart, 1976, Vol. 1, 185.
(7) Diederich, W. E.; Haake, M. J. Org. Chem. 2003, 68, 3817;
13C NMR: d = 28.4 (CH3), 38.7 (CH2), 39.2 (CH3S), 57.5 (CH), 79.6
(C), 126.8 (CH), 128.3 (CH), 129.7 (CH), 136.9 (C), 155.2 (CO),
180.4 (CO).
and references therein.
(8) To the best of our knowledge, there is only one single report
on the synthesis of a non-racemic sulfodiimine, and in this
case, the enantiomer ratio has not been determined:
Christensen, B. W.; Kjær, A. J. Chem. Soc., Chem. Commun.
1975, 784.
MS: m/z (%) = 587 [(M + H)+, 2], 487 (18), 255 (93), 120 (100).
Anal. Calcd for C30H42N4O6S: C, 61.41; H, 7.21; N, 9.55. Found: C,
61.07; H, 7.35; N, 9.30.
(9) Haake, M.; Fode, H.; Eichenauer, B. Liebigs Ann. Chem.
1972, 759, 107.
Acknowledgment
(10) Hackenberger, C. P. R.; Raabe, G.; Bolm, C. Chem.–Eur. J.
2004, 10, 2942; and references therein.
(11) For reviews on coupling reagents, see: (a) Han, S.-Y.; Kim,
Y.-A. Tetrahedron 2004, 60, 2447. (b) Klausner, Y. S.;
Bodansky, M. Synthesis 1972, 453.
(12) In this case, the meso-product resulting from an
epimerization would possess two diastereotopic methyl
groups. Those would be in rather different chemical and
electronic environments and, therefore, two different
chemical shifts would be likely to occur in the 1H NMR
spectrum.
We gratefully acknowledge the Deutsche Forschungsgemeinschaft
(SFB 380) and the Fonds der Chemischen Industrie for financial
support. J. R. D. thanks the European Commission for a Marie Curie
postdoctoral fellowship (contract HPMF-CT-2002-01855). We also
thank Prof. Dr. Manfred Haake (Philipps University Marburg) and
Dr. Christian Hackenberger for helpful discussions.
Synthesis 2005, No. 7, 1058–1060 © Thieme Stuttgart · New York