Syntheses of biologically relevant reactive sulfur species by utilizing a primary alkyl steric protection group

Article abstract of DOI:10.1080/10426507.2010.538778

A novel primary alkyl steric protection group (BpqCH₂ group) bearing a cavityshaped framework was designed and successfully applied to the stabilization of a sulfenyl iodide. The sulfenyl iodide showed remarkable stability, demonstrating that the BpqCH₂ group is very effective for kinetic stabilization of primary-alkyl-substituted reactive species. Copyright Taylor and Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.538778

Phosphorus, Sulfur, and Silicon, 186:1255–1258, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.538778
SYNTHESES OF BIOLOGICALLY RELEVANT REACTIVE
SULFUR SPECIES BY UTILIZING A PRIMARY ALKYL
STERIC PROTECTION GROUP
Kei Goto, Noriaki Abe, Yohei Aoki, and Shohei Sase
Department of Chemistry, Graduate School of Science and Engineering,
Tokyo Institute of Technology, Tokyo, Japan
Abstract A novel primary alkyl steric protection group (BpqCH2 group) bearing a cavity-
shaped framework was designed and successfully applied to the stabilization of a sulfenyl
iodide. The sulfenyl iodide showed remarkable stability, demonstrating that the BpqCH2 group
is very effective for kinetic stabilization of primary-alkyl-substituted reactive species.
Keywords Cysteine models; reactive sulfur species; steric protection; sulfenyl iodides
INTRODUCTION
While there are a variety of biologically important chemical species derived from
cysteine thiols, some of them are notoriously unstable because of facile bimolecular de-
composition, such as dimerization, self-condensation, and disproportionation reactions.1
As chemical models for the reactive species derived from a –CH2SH side chain of cysteine
residues, compounds bearing a primary alkyl substituent are considered to be the most
appropriate. However, it is a common idea that the synthesis of primary-alkyl derivatives
of such reactive species is difficult because the steric demands of primary alkyl groups
are too small to prevent the bimolecular decomposition of reactive species. A new molec-
ular design for steric protection with a primary alkyl group is required for modeling the
cysteine-derived reactive species. We have recently developed an aromatic steric protec-
tion group, a Bpq group, with a nanosized cavity-shaped framework and applied it to the
stabilization of various highly reactive species.2 It is expected that a large cavity of the Bpq
group could include the CH2X (X = reactive functionality) moiety in its inside and confer
sufficient kinetic stability upon the reactive species (Figure 1). In this article, we report the
development of an effective primary alkyl steric protection group, a BpqCH2 group, and its
Received 29 September 2010; accepted 4 November 2010.
This work was partly supported by Grants-in-Aid for the Global COE Program for Education and Research
Center for Emergence of New Molecular Chemistry and for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. We also acknowledge supports from Toray Science Foundation
and The Society of Iodine Science.
Address correspondence to Kei Goto, Department of Chemistry, Graduate School of Science and Engi-
neering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8551, Japan. E-mail: goto@
chem.titech.ac.jp
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K. GOTO ET AL.
Figure 1 Schematic representation of a cavity-shaped molecule with a primary alkyl group.
application to the synthesis of a stable sulfenyl iodide (R-SI), a sulfur-containing reactive
species of biological importance.3
RESULTS AND DISCUSSION
Thiol 1 bearing a BpqCH2 group was prepared by the route shown in Scheme 1, in
which the m-phenylene framework of the Bpq group was constructed via a Suzuki–Miyaura
coupling reaction of the terphenylboronic acid and 2,6-dibromobenzaldehyde.
Scheme 1
Sulfenyl iodides have been recognized as important intermediates in various types
of modification of protein thiols.4 However, they are usually very unstable because of the
ready disproportionation reaction to give disulfide and iodine. While we previously reported
the synthesis of stable sulfenyl iodides bearing an aromatic substituent,2a,5 isolation of a
primary alkyl derivative is only limited to that bearing a poly(benzyl ether) dendrimer-type
framework reported by Takaguchi et al.,6 and its crystal structure has not been determined.
The reaction of thiol 1 with N-iodosuccinimide (NIS) afforded sulfenyl iodide 2, which
was successfully isolated as red crystals in 96% yield (Scheme 2). The structure of 2
was established by X-ray crystallographic analysis (Figure 2). This is the first example of
a crystallographic analysis of a primary-alkyl-substituted sulfenyl iodide. The S I bond
length of 2 is 2.3743(17) Å, which is comparable to those of the arenesulfenyl iodides we
Scheme 2

REACTIVE SULFUR SPECIES UTILIZING STERIC PROTECTION
1257
Figure 2 ORTEP drawing of 2 (50% probability). Hydrogen atoms are omitted for clarity. Selected bond lengths
(Å) and bond angle (deg): S I, 2.3743(17); C S, 1.808(6); C I, 101.62(18).
S
reported previously.2a,5 The shortest intermolecular S I distance is 8.79 Å, indicating that
2 is monomeric in the crystalline state. The CH2SI moiety is incorporated in the large
cavity of the Bpq group, and it is expected that disulfide formation by disproportionation of
2 would be difficult due to the peripheral steric protection by the cavity-shaped framework.
In fact, sulfenyl iodide 2 exhibited remarkably high thermal stability. Heating of 2 in
toluene-d8 at 80◦C for 9 days resulted in no decomposition, indicating the effectiveness of
the BpqCH2 group.
. . .
Treatment of 2 with benzylamine readily afforded sulfenamide 3 in a good yield
(Scheme 3). This is in sharp contrast to the result reported by Takaguchi et al. that the
sulfenyl iodide bearing a poly(benzyl ether) dendrimer-type framework does not react with
the same nucleophile.6 These results demonstrate that there is a space around the central
functional group of 2, which is large enough to allow the reaction with a relatively small
reagent.
Scheme 3
The application of this novel primary alkyl steric protection group to the synthesis of
other reactive species is currently in progress.
REFRERENCES
1. (a) Winterbourn, C. C.; Hampton, M. B. Free Radical Biol. Med. 2008, 45, 549–561; (b) Forman,
H. J.; Fukuto, J. M.; Torres, M. Am. J. Physiol. Cell. Physiol. 2004, 287, C246–C256.
2. (a) Goto, K.; Yamamoto, G.; Tan, B.; Okazaki, R. Tetrahedron Lett. 2001, 42, 4875–4877; (b) Shi-
mada, K.; Goto, K.; Kawashima, T.; Takagi, N.; Choe, Y. K.; Nagase, S. J. Am. Chem. Soc. 2004,

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126, 13238–13239; (c) Goto, K.; Sonoda, D.; Shimada, K.; Sase, S.; Kawashima, T. Angew.
Chem., Int. Ed. 2010, 49, 545–547.
3. Goto, K.; Aoki, Y.; Abe, N.; Sase, S. Chem. Lett. 2009, 38, 1188–1189.
4. (a) Fraenkel-Conrat, H. J. Biol. Chem. 1955, 217, 373–381; (b) Thomas, E. L.; Aune, T. M.
Biochemistry 1977, 16, 3581; (c) Cunningham, L. W.; Crews, B. C.; Gettins, P. Biochemistry
1990, 29, 1638–1643.
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