N-aminosulfamide peptide mimic synthesis by alkylation of aza-sulfurylglycinyl peptides

Article abstract of DOI:10.1021/ol3001987

N-Aminosulfamides are peptidomimetics in which the C_αH and the carbonyl of an amino acid residue are both respectively replaced by a nitrogen atom and a sulfonyl group. Aza-sulfurylglycinyl tripeptide analogs were effectively synthesized from amino acid building blocks by condensations of N-protected amino hydrazides and p-nitrophenylsulfamidate esters. The installation of N-alkyl chains and access to other aza-sulfuryl amino acid residues were effectively achieved by chemoselective alkylation.

Full text of DOI:10.1021/ol3001987

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1318–1321
N-Aminosulfamide Peptide
Mimic Synthesis by Alkylation
of Aza-sulfurylglycinyl Peptides
ꢀ
Stephane Turcotte, Samir H. Bouayad-Gervais, and William D. Lubell*
ꢀ
Departement de chimie, Universite de Montreal, C.P. 6128, Succursale Centre-Ville,
Montreal, Quebec H3C 3J7, Canada
ꢀ
ꢀ
ꢀ
ꢀ
william.lubell@umontreal.ca
Received January 25, 2012
ABSTRACT
N-Aminosulfamides are peptidomimetics in which the CRH and the carbonyl of an amino acid residue are both respectively replaced by a nitrogen
atom and a sulfonyl group. Aza-sulfurylglycinyl tripeptide analogs were effectively synthesized from amino acid building blocks by condensations
of N-protected amino hydrazides and p-nitrophenylsulfamidate esters. The installation of N-alkyl chains and access to other aza-sulfuryl amino
acid residues were effectively achieved by chemoselective alkylation.
The biological activityand physicalproperties ofpeptide
structures are inherently contingent on backbone geometry
and side chain functionality, such that attempts to mod-
ulate natural function are challenged to consider innate
form. For example, replacement of a peptide amide by a
phosphonamide1 or a silanediol2 may effectively mimic the
tetrahedral transition states common in enzyme-catalyzed
reactions and produce enzyme inhibitors. Although the
Figure 1. N-Aminosulfamidopeptide1 and proteinase inhibitor2.
respective amide to sulfonamide exchange may appear
promising, the resulting R-sulfonamido peptides have been
reported to be unstable.3
N-Aminosulfamido peptides 1 in which both the
CRH and the carbonyl of an amino acid residue are re-
spectively replaced by a nitrogen atom and a sulfonyl
group have proven to be more stable (Figure 1). Moreover,
aza-sulfurylphenylalaninyl (Asf) peptide 2 was reported to
inhibit the human immunodeficiency virus-1 (HIV-1) pro-
teinase, presumably by imitating the transition state for
amide bond hydrolysis.4
Aza-sulfurylpeptide analogs combine the characteristics
of aza- and R-sulfonamido peptides, thus offering inter-
esting potential for modifying backbone geometry. The
sulfonyl group possesses a tetrahedral sulfur, which adopts
ω torsion angle values around (60° and (100° (instead of
(1) Hirschmann, R.; Yager, K. M.; Taylor, C. M.; Witherington, J.;
Sprengeler, P. A.; Phillips, B. W.; Moore, W.; Smith, A. B., III J. Am.
Chem. Soc. 1997, 119, 8177–8190 and refs 1ꢀ18 cited therein.
(2) Chen, C. A.; Sieburth, S. M. N.; Glekas, A.; Hewitt, G. W.;
Trainor, G. L.; Erickson-Viitanen, S.; Garber, S. S.; Cordova, B.; Jeffry,
S.; Klabe, R. M. Chem. Biol. 2001, 8, 1161–1166.
(4) Cheeseright, T. J.; Daenke, S.; Elmore, D. T.; Jones, J. H.
J. Chem. Soc., Perkin Trans. 1 1994, 1953–1955.
(3) Gilmore, W. F.; Lin, H. J. J. Org. Chem. 1978, 43, 4535–4537.
r
10.1021/ol3001987
Published on Web 02/13/2012
2012 American Chemical Society

amide cis-(E) and trans-(Z) conformations at respectively
0° and (180°) separated by a lower SꢀN rotational barrier
(ΔG‡ ≈ 35 kJ/mol), relative to the amide CꢀN (ΔG‡ ≈
75 kJ/mol).5 Furthermore, the SꢀN bond length is longer
thanthe CꢀN, duetolackofanamide bond resonance and
greater sp3 versus sp2 character of the sulfonamide nitro-
gen (Figure 2).
of an aza-sulfurylglycine intermediate and subsequent
chemoselective alkylation. 4-Nitrophenyl chlorosulfate 9
has been used effectively in the synthesis of sulfamides11
and was thus studied for the selective synthesis of N-
aminosulfamides.
Scheme 2. Synthesis of the p-Nitrophenylsulfamidate Esters
15ꢀ19
Figure 2. Sulfonamide6 and amide7 bond lengths and angles.
In light of their interesting conformational and biologi-
cal properties, the synthesis of N-aminosulfamides has
apparently restricted their application in peptide mimicry.4
To the best of our knowledge, only one method has been
reported for constructing acyclic N-aminosulfamides and
employs sulfuryl chloride (SO2Cl2) to combine hydrazide
and amine components (Scheme 1).8
Scheme 1. Reported Synthesis of N-Aminosulfamides
Initial attempts to prepare sulfamidates from hydra-
zones and chlorosulfate 9 gave however azines. In contrast,
the corresponding sulfamidates were prepared successfully
from various amino esters, i.e., L-Ala-OBn (10), L-Ala-
OMe (11), L-Leu-OBn (12), D- and L-Phe-Ot-Bu [(R)- and
(S)-13], and L-Val-OMe (14) (Scheme 2).
A 2 equiv amount of 4-nitrophenol was necessary as an
additive to avoid formation of symmetric sulfamide. Ad-
ditionally, 2 equiv of chlorosulfate 9 were also crucial for
sulfamidate formation. Lower yields of 15 and 16 were in-
curred during purification on silica gel and using aq.
NaHCO3 washings to remove 4-nitrophenol (Supporting
Information). Relative to sulfuryl chloride, which needs to
be distilled prior to use, chlorosulfate 9 was a convenient
solid. Similarly, except for sulfamidate 18, the p-nitrophe-
nylsulfamidates were solids, which could be stored for
several months without decomposition.
Coupling was relatively sluggish, in spite of the addi-
tion of catalytic amounts of toxic antimony pentachloride
(SbCl5), such that, in the synthesis of N-aminosulfamide 7,
reaction of 2 equiv of the amine component with sulfuryl
chloride competed to produce symmetric sulfamide 8 as a
majorsideproduct. Inaddition, introduction ofside chains
onto the N-aminosulfamide residue required synthesis of
N-alkyl protected hydrazide precursors.8
Inspired by our past applications of sulfamidates
as synthetic intermediates,9 as well as the application
of aza-glycine alkylation in the submonomer synthesis
of azapeptides,10 we have pursued an approach to
N-aminosulfamide peptides featuring convergent synthesis
(9) (a) Wei, L.; Lubell, W. D. Can. J. Chem. 2001, 79, 94–104.
(b) Atfani, M.; Wei, L.; Lubell, W. D. Org. Lett. 2001, 3, 2965–2968.
(c) Jamieson, A. G.; Boutard, N.; Beauregard, K.; Bodas, M. S.; Ong,
H.; Quiniou, C.; Chemtob, S.; Lubell, W. D. J. Am. Chem. Soc. 2009,
131, 7917–7927. (d) Boutard, N.; Turcotte, S.; Beauregard, K.; Quiniou,
C.; Chemtob, S.; Lubell, W. D. J. Pept. Sci. 2011, 17, 288–296. (e)
(5) Baldauf, C.; Gunther, R.; Hofmann, H. J. THEOCHEM 2004,
675, 19–28.
ꢀ
Melendez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581–2616.
(6) Bharatam, P. V.; Gupta, A.; Kaur, D. Tetrahedron 2002, 58,
1759–1764.
(7) Hamilton, W. C. Acta Crystallogr. 1965, 18, 866–870.
(8) Cheeseright, T. J.; Edwards, A. J.; Elmore, D. T.; Jones, J. H.;
Raissi, M.; Lewis, E. C. J. Chem. Soc., Perkin Trans. 1 1994, 1595–1600.
(10) (a) Sabatino, D.; Proulx, C.; Klocek, S.; Bourguet, C. B.;
Boeglin, D.; Ong, H.; Lubell, W. D. Org. Lett. 2009, 11, 3650–3653.
(b) Bourguet, C. B.; Proulx, C.; Klocek, S.; Sabatino, D.; Lubell, W. D.
J. Pept. Sci. 2010, 16, 284–296. (c) Sabatino, D.; Proulx, C.; Pohankova,
P.; Ong, H.; Lubell, W. D. J. Am. Chem. Soc. 2011, 133, 12493–12506.
Org. Lett., Vol. 14, No. 5, 2012
1319

To further examine conformational properties, sulfa-
midate 19 was crystallized from EtOAc on diffusion of
hexane vapors (Figure 3 and Supporting Information).
The crystal structure shows that the sulfamidate (ꢀNꢀ
S(O2)ꢀOꢀ) adopts a distorted tetrahedral structure and
ing orthogonally protected building blocks 35ꢀ41 for
incorporation into longer peptides (Scheme 4). Initially,
N-Boc-Ala-Asg-Ala-OMe (28) was treated with potassium
tert-butoxide and propargylbromide to provide azasulfur-
yl tripeptide 35, albeit in 20% yield with recovered starting
material. By switching to the phosphazene base, tert-
butylimino-tri(pyrrolidino)-phosphorane (BTPP), the al-
kylation yield was improved to 73%. Subsequent reactions
were performed with BTPP. Bis-alkylation was minimized
by employing stoichiometric amounts of base and alkylat-
ing reagent.
˚
that the NꢀS bond length (1.593 A) is longer than an
amide bond (Figure 2). Furthermore, the ω torsion angle
(62.2°) was close to the ideal theoretical value (60°) for
sulfonamides.5
Scheme 3. Synthesis of the N-Aminosulfamides 25ꢀ34
Figure 3. Crystal structure of sulfamidate 19, showing the atom-
ic numbering system employed.
N-Aminosulfamides 25ꢀ34 were synthesized by reaction
of sulfamidates 16ꢀ19 respectively with benzophenone
hydrazone (20), tert-butyl and benzyl carbazates (6 and
21), and N-(Boc)-L-Ala, L-Phe, and L-Pro hydrazides
(22ꢀ24) (Scheme 3).
Microwave irradiation proved important in the for-
mation of the N-aminosulfamides and favored coupling
between the two precursors. In contrast to the 80% yield
using microwave heating, synthesis of N-aminosulfa-
mide 25 in DCM using conventional heating at reflux
for 24 h gave only a 36% yield and recovered starting
material.
Although side chains may in principle be introduced
onto the N-aminosulfamide moiety by employing N0-
alkylhydrazides, inspired by our submonomer approach
to azapeptides,10 chemoselective alkylation was pursued to
provide a combinatorial approach to aza-sulfuryl amino
acid residues. Initially, attempts to employ hydrazone and
carbazate derivatives 25ꢀ27 in chemoselective alkylation/
deprotection sequences failed, likely due to sulfonyl hy-
drazide decomposition.12
The position of alkylation was ascertained by NMR
experiments on tripeptide 35 (Supporting Information). In
the 2D COSY spectrum, through-bond correlations were
observed between the alanine NꢀH and CRꢀH protons. In
the 2D HMBC spectrum, through-bond correlation was
observed between the hydrazide NH and carbonyl carbon.
The position of alkylation was assigned for analogs 36ꢀ
41 based on analogy to 35, because of the relatively
1
similar chemical shifts for the NꢀH signals in the H
NMR spectra.
Chemoselective alkylation of aza-sulfurylglycinyl (Asg)
peptides 28ꢀ30 and 32 proved effective for prepar-
In order to ascertain if epimerization had occurred
during the alkylation of aza-sulfurylglycine, (S,R)-
and (S,S)-diastereoisomers of aza-sulfurylallylglycinyl
(11) Fettes, K. J.; Howard, N.; Hickman, D. T.; Adah, S.; Player,
M. R.; Torrence, P. F.; Micklefield, J. J. Chem. Soc., Perkin Trans. 1
2002, 485–495.
(12) Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838–
1841.
(13) The presence of <10% diastereomeric aza-sulfurylglycinyl tri-
peptide 30 may likely be caused by racemization during formation of the
N-(Boc)-L-Ala hydrazide. See: Benoiton, N.; Kuroda, K.; Chen, F. M. F.
Int. J. Pept. Protein Res. 1982, 20, 81–86.
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Org. Lett., Vol. 14, No. 5, 2012

tripeptide 36 were synthesized and analyzed by 1H
NMR spectroscopy. The diastereoisomeric ratio ob-
served for the alkylated product 36 was consistent with
the starting aza-sulfurylglycinyl tripeptide diastereo-
mers 30, indicating no epimerization.13 Furthermore,
treatment of aza-sulfurylallylglycinyl tripeptide (S,R)-
36 with 1 equiv of BTPP at room temperature for 3 h
failed to cause epimerization.
In conclusion, a new method for the synthesis of
N-aminosulfamides has been developed featuring the
coupling of p-nitrophenylsulfamidatesandN-(Boc)-amino
acid hydrazides under microwave irradiation. Chemose-
lective alkylation of the aza-sulfurylglycinyl peptides was
used to add side-chain diversity and prepare other aza-
sulfuryl amino acid residues. This method avoids sym-
metric sulfamide formation as well as the use of N0-alkyl
hydrazides in the synthesis of the N-aminosulfamide pep-
tides. The crystallization of sulfamidate 19 confirmed the
tetrahedral nature of the sulfur and the 60° ω-torsion
angle. We are currently working on crystallizing the
N-aminosulfamides to validate the potential for mimicry
of the transition state of amide bond hydrolysis. In addi-
tion, insertion of the N-aminosulfamide tripeptidebuilding
blocks into biologically active peptides is being pursued to
study structureꢀactivity relationships.
Scheme 4. Chemoselective Alkylation of Aza-sulfurylglycinyl
Peptides
Acknowledgment. This research was supported by the
Natural Sciences and Engineering Research Council of
ꢀ
Canada (NSERC) and the Fonds Quebecois de la Recherche
sur la Nature et les Technologies (FQRNT). S.T. would
liketothank the FQRNTfor graduate student fellowships.
€ €
The authors also thank Dr. A. Furtos, K. Venne, and
ꢀ
M.-C. Tang (Universite de Montreal) for the HR-MS
analysis, Sylvie Bilodeau (Universite de Montreal) for the
ꢀ
ꢀ
ꢀ
ꢀ
NMR experiments on compound 35 and Francine Belanger
(Universite de Montreal) for the crystallographic data.
ꢀ
ꢀ
Supporting Information Available. Experimental pro-
cedures, NMR data for all compounds, and cif file for
compound 19. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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