Turn formation initiated by a bissulfoximine motif: synthesis and structural investigation.

Article abstract of DOI:10.1021/ol017188r

[reaction: see text] Bissulfoximines containing heterochiral SulfCO-SulfCO units may be used as molecular templates, which induce U-shaped conformations in peptidelike structures. The synthesis of such molecules has been investigated, and the structural r

Full text of DOI:10.1021/ol017188r

ORGANIC
LETTERS
2002
Vol. 4, No. 6
893-896
Turn Formation Initiated by a
Bissulfoximine Motif: Synthesis and
Structural Investigation
Carsten Bolm,* Dirk Mu1ller, and Christian P. R. Hackenberger
Institut fu¨r Organische Chemie der RWTH Aachen, Professor-Pirlet-Str.1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received December 7, 2001
ABSTRACT
Bissulfoximines containing heterochiral SulfCO−SulfCO units may be used as molecular templates, which induce U-shaped conformations in
peptidelike structures. The synthesis of such molecules has been investigated, and the structural requirements of this new turn motif have
been identified.
Peptides containing unnatural amino acids or structural motifs
that mimic original elements of native peptides have attracted
much attention as a result of their potential pharmacological
properties, including resistance to peptidase degeneration.1
Much effort has been devoted toward the design and
synthesis of modified peptides, which lead to well-defined
secondary structures such as helices and sheets. Hence,
“foldamers”, entirely unnatural oligomers that have a predict-
able folding behavior, are of particular interest.2 Because turn
elements in proteins play a major role in the recognition of
receptors, antibodies, and enzymes,3 various nonpeptidic turn-
forming segments have been developed.4 Those conforma-
tional templates5 and molecular scaffolds force attached
peptide chains to adopt specific secondary structures (e.g.,
artifical â-sheets). Excellent recent examples have been
reported by Gellman,6 Gennari,7 and Nowick.8 In regard to
the work described here, Gellman’s hairpin formation with
â-peptides containing a heterochiral dinipecotic acid segment
is particularly noteworthy.6c,9
(5) For an early report on a template-nucleated helical conformation,
see: Kemp, D. S.; Curran, T. P.; Boyd, J. G.; Allen, T. A. J. Org. Chem.
1991, 56, 6683.
(6) (a) Fisk, J. D.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc.
2000, 122, 5443. (b) Langenhan, J. M.; Fisk, J. D.; Gellman, S. H. Org.
Lett. 2001, 3, 2559. (c) Chung, Y. J.; Huck, B. R.; Christianson, L. A.;
Stanger, H. E.; Krautha¨user, S.; Powell, D. R.; Gellman, S. H. J. Am.
Chem. Soc. 2000, 122, 3995. (d) Woll, M. G.; Lai, J. R.; Guzei, I. A.;
Taylor, S. J. C.; Smith, M. E. B.; Gellman, S. H. J. Am. Chem. Soc. 2001,
123, 11077.
(7) (a) Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico, C. Eur. J. Org.
Chem. 1999, 379. (b) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.;
Scolastico, C. Eur. J. Org. Chem. 1999, 389. (c) Belvisi, L.; Gennari, C.;
Madder, A.; Mielgo, A.; Potenza, D.; Scolastico, C. Eur. J. Org. Chem.
2000, 695.
(8) (a) Nowick, J. S. Acc. Chem. Res. 1999, 32, 287. (b) Nowick, J.
S.; Tsai, J. H.; Bui, Q.-C. D.; Maitra, S. J. Am. Chem. Soc. 1999, 121,
8409. (c) Holmes, D. L.; Smith, E. M.; Nowick, J. S. J. Am. Chem. Soc.
1997, 119, 7665. (d) Nowick, J. S.; Insaf, S. J. Am. Chem. Soc. 1997, 119,
10903.
(1) For leading references, see: (a) Ball, J. B.; Alewood, P. F. J. Mol.
Recog. 1990, 3, 55. (b) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl.
1993, 32, 1244. (c) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(d) Gillespie, P.; Cicariello, J.; Olsen, G. L. Biopolymers 1997, 43, 191.
(2) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(3) (a) Rizo, J.; Gierasch, L. M. Annu. ReV. Biochem. 1992, 61, 387. (b)
Rose, G. D.; Gierash, L. M.; Smith, J. A. AdV. Protein Chem. 1985, 37, 1.
(4) (a) For reviews on peptide secondary structure mimetics, see:
Tetrahedron (Symposia-in-Print, no. 50; Kahn, M., Ed.) 1993, 49, 3433.
(b) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789. (c) For â-turn mimics, see also: Fink, B. E.;
Kym, P. R.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1998, 120, 4334
and references therein.
10.1021/ol017188r CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/23/2002

Scheme 2a
Figure 1.
Our investigation was initiated after molecular modeling
studies had revealed that a sulfoximidoyl (SulfCO) moiety10
as in 1 led to a bending of the peptide chain, resulting in an
overall L-shaped conformation of the molecule. We then
prepared bissulfoximines 2, containing two consecutive
SulfCO-moieties in the peptidelike chain, to investigate
whether a sequence of two sulfoximidoyl units would give
a turn motif.
The synthesis of the pseudopeptide 1 with one SulfCO
group followed a reaction sequence in which the key step
was the coupling of â-sulfoximidoyl carboxylate 3 with
p-tosylate salts of protected amino acid esters 4 to give 5
(Scheme 1).11 Further functionalization of 5 afforded 1a-c
Scheme 1a
a (a) 1.03 equiv of DCC, 0.13 equiv of DMAP; (b) (1) lithium
cyclohexylisopropyl amide (LCHIPA), CO2, aq. workup; (2) 1.0
equiv of H-Ala-O(CH2)2CHdCH2, 1.0 equiv of pTosOH; 1.03 equiv
of DCC, 0.13 equiv of DMAP; (c) (1) TFA; (2) 1.0 equiv of
4-penten acid, 1.03 equiv of DCC, 1.03 equiv of HOBt. b The given
absolute configurations refer to those at sulfur only.
of 3 with p-tosylate salts of sulfoximines and allow the
introduction of sulfur-containg fragments with defined
absolute configuration. All four possible diastereomers of
2a and two diastereomers of 2b (hetero- and homochiral at
sulfur) were synthesized in the course of this study.
Route A involves the buildup of the SulfCO-SulfCO unit
through the combination of 3 and sulfoximine 612 prior to
peptide chain extensions on both sides. In Scheme 2 the
synthesis of 2a having S- and R-configuration at the SulfCO
units is shown. Analogously, the diastereomer of 2a with
R-configuration at both sulfurs was prepared. Route B is
more convergent and utilizes the coupling of two sulfox-
imines of about equal size. As a consequence, only two
further steps are required in the synthesis of 2a after 3 and
8 react to afford 9. This route was followed in the synthesis
of the two diastereomers of 2a having S,S-configuration (as
shown in Scheme 2) and R,S-configuration at the sulfur
atoms.
a (a) 1.03 equiv of DCC, 0.13 equiv of DMAP; (b) (1) TFA; (2)
1.0 equiv of 4-penten acid, 1.03 equiv of DCC, 1.03 equiv of HOBt;
(c) (1) TFA; (2) 1.0 equiv of Boc-Ala-OH, 1.03 equiv of DCC,
1.03 equiv of HOBt; (3) TFA; 1.0 equiv of 4-penten acid, 1.03
equiv of DCC, 1.03 equiv of HOBt.
in up to 50% and 1d in 8% yield (over five and six steps,
respectively).
Two synthetic strategies (routes A and B) were developed
for the synthesis of 2 (Scheme 2). Both rely on the coupling
894
Org. Lett., Vol. 4, No. 6, 2002

To probe the expected U-shape conformation of 2,
reactivity studies were performed. Assuming that molecules
that were preorganzied by a suitable turn motif would be
prone to undergo an intramolecular cyclization, we chose
the ring closing metathesis (RCM) reaction13 with Grubbs’
catalyst Cl2(PCy3)2RudCHPh as an analytical tool.14 Since
it was desired to have a broad basis for comparison, the
investigation included compounds 1a-d (with all-S con-
figurations) having a single SulfCO unit and various distances
between the reacting double bonds, as well as all four
diastereomers of bissulfoximine 2a, resulting from the
combination of R- and S-configurated sulfoximine units. The
latter part of this study was considered to be particularly
interesting, since we hoped to reveal the importance of the
absolute configuration at sulfur with respect to the overall
conformation of the molecules. The results of this investiga-
tion are summarized in Table 1. Cyclic products were only
1
Table 2. Selected H NMR Data for 2b and 9a
entry
compoundb
δ of Ha [ppm]
δ of Hb [ppm]
1
2
3
4
5
6
(R,S)-2b
(S,S)-2b
(S,R)-2b
(R,S)-9
(S,S)-9
7.65
7.64
7.82
7.80
7.79
7.81
5.34
5.05
5.44
5.42
4.82
4.88
(R,R)-9
a Use of 10 mg of peptide in 0.07 mL of CDCl3. b The absolute
configurations refer to those at sulfur only.
the following two factors are necessary for formation of a
U-shaped arrangement: first, the presence of two SulfCO
units and second, a heterochiral combination at sulfur.
The relevance of the second point was further supported
1
by H NMR spectroscopy data of various diastereomers of
2b and 9 (Table 2). A weak hydrogen bond was identified
between Hb and the CdO group of the other peptide chain
branch (Figure 2). Whereas in molecules 2b and 9 with
Table 1. RCM Reactions of 1a-d and 2aa
starting
ring size
yield of cyclized
product [%]
entry
materialb
of products
1
2
3
4
5
6
7
8
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S,S)-2a
(R,R)-2a
(S,R)-2a
(R,S)-2a
17
17
18
21
22
22
22
22
0
0
0
0
0
0
37
40
a Use of 15 mol % of Cl2(PCy3)2RudCHPh, DCM, 12 h, 40 °C. b The
absolute configurations refer to those at sulfur only.
Figure 2.
obtained from two diastereomers of 2a both haVing hetero-
chiral configurations at sulfur.15 Neither 1a-d nor the two
diastereomers of 2a with homochiral sulfur atoms led to
cyclized products. These results support the hypothesized
presence of a turn motif in 2 and reveal the conformational
impact of the sulfur atoms. Hence, it may be concluded that
homochiral sulfur atoms these protons resonate in the range
of 4.8 to 5.1 ppm (Table 2, entries 2, 5, and 6), the respective
chemical shifts in the heterochiral series of 2b and 9 have
values between 5.3 and 5.4 ppm (entries 1, 3, and 4). The
downfield shift of the latter protons is indicative for a more
pronounced Hb-carbonyl interaction in cases where the two
sulfur atoms of the SulfCO-SulfCO unit have opposite
absolute configurations. The strong downfield shift of the
Ha protons in all isomers of 2b and 9 (δ ) 7.64-7.82 ppm)
is analogous to the ones previously observed in studies of
structurally related pseudotripeptides.11b
Both the results of the reactivity studies and the 1H NMR
data can be explained by conformational arrangements of 2
(and 9) as depicted in Figure 2. A turn is only then initiated
when the two stereogenic centers at sulfur have opposite
absolute configurations (Figure 2, left). The resulting U-shape
of the molecule brings Hb and a distant carbonyl group into
proximitry, as indicated by the downfield shift of Hb in the
1H NMR spectrum. Since the H-bond acceptor is an ester
and not an amide group the H-bond-induced chemical shift
change is relatively small.16 If PG and PG′ contain terminal
double bonds as in 2a, those may be utilized in RCM
(9) For earlier studies on RCM of diastereomeric peptides, see: (a) Miller,
S. J. Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 5855. (b) Miller, S. J.;
Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606.
(10) Sulfoximines can easily be prepared on a multigramm scale. For a
recent review, see: Reggelin, M.; Zur, C. Synthesis 2000, 1.
(11) (a) Bolm, C.; Kahmann, J. D.; Moll, G. Tetrahedron Lett. 1997,
38, 1169. (b) Bolm, C.; Moll, G.; Kahmann, J. D. Chem. Eur. J. 2001, 7,
1118.
(12) Sulfoximine 6 is commercially available in both enantiomeric forms.
Alternatively, it can easily be synthesized following protocols described
in: (a) Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973, 95, 7418.
(b) Fusco, R.; Tericoni, F. Chem. Ind. (Milano) 1965, 47, 61. (c) Brandt,
J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909.
(13) Recent reviews on RCM in organic synthesis: (a) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (b) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413. (c) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012.
(14) For recent examples of the use of RCM in the synthesis of cyclic
peptides, see: (a) Reichwein, J. F.; Versluis, C.; Liskamp, R. M. J. J. Org.
Chem. 2000, 65, 6187. (b) Blackwell, H. E.; Sadowsky, J. D.; Howard, R.
J.; Sampson, J. N.; Chao, J. A.; Steinmetz, W. E.; O’Leary, D. J.; Grubbs,
R. H. J. Org. Chem. 2001, 66, 5291 and references therein.
(15) The E/Z ratio was approximately 1.6:1, which is similar to the ones
reported for macrocyclizations by RCM. Fu¨rstner, A.; Kindler, N. Tetra-
hedron Lett. 1996, 37, 7005.
Org. Lett., Vol. 4, No. 6, 2002
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reactions generating the corresponding cyclic products. In
contrast to this scenario, derivatives of 2, which contain
homochiral sulfur atoms, lead to stretched structures (Figure
2, right). Those do not form Hb/OdC hydrogen bonds and
hence may not undergo RCM reactions because of the
distance between the two reacting sites.
In conclusion, we have described a new turn motif for
peptidic structures and demonstrated the importance of the
stereogenic sulfur atoms for conformational control. Studies
focusing on the biological activities of those sulfoximine-
containing peptides are currently in progress.
Acknowledgment. We are grateful to the Deutsche
Forschungsgemeinschaft (SFB 380) and the Fonds der
Chemischen Industrie for continuous financial support of this
research project. C.P.R.H. acknowledges a scholarship from
the FCI and the BMBF. We also thank Professor Sam
Gellman, Madison, for valuable comments on the draft of
the manuscript.
Supporting Information Available: The preparation and
characterization of compounds 1-9 and full details of the
RCM reaction. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) At the present stage we can neither rigorously exclude structures
with H-bonds to the sulfur oxygen nor the formation of â-sheet pattern
resulting from interactions between Ha and other remote carbonyl groups.
Further studies to clarify these aspects are in progress.
OL017188R
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