Sulfenic acids from L-cysteine involved in the synthesis of alliin analogues

Article abstract of DOI:10.1080/10426500590910792

L-cysteine is a stimulating starting product for the generation of transient sulfenic acids that add to suitable acceptors, allowing formation of sulfoxides showing a biologically active residue. For instance, N-(tert-butoxycarbonyl)-L-cysteine methyl ester furnished in few steps (R)-2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethanesulfenic acid, which was readily converted into (R,S_S)-(2-tert-butoxycarbonylamino-2- methoxycarbonyl-ethylsulfinyl)ethene, the methyl ester of Boc-protected nor-alliin. Copyright Taylor & Francis Inc.

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Sulfenic Acids from L-Cysteine
Involved in the Synthesis of
Alliin Analogues
Maria Chiara Aversa a , Anna Barattucci a , Paola
Bonaccorsi a & Placido Giannetto a
a Dipartimento di Chimica organica e biologica,
Università degli Studi di Messina , Messina, Italy
Published online: 16 Aug 2006.
To cite this article: Maria Chiara Aversa , Anna Barattucci , Paola Bonaccorsi &
Placido Giannetto (2005) Sulfenic Acids from L-Cysteine Involved in the Synthesis of
Alliin Analogues, Phosphorus, Sulfur, and Silicon and the Related Elements, 180:5-6,
1203-1208, DOI: 10.1080/10426500590910792
To link to this article: http://dx.doi.org/10.1080/10426500590910792
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Phosphorus, Sulfur, and Silicon, 180:1203–1208, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500590910792
Sulfenic Acids from L-Cysteine Involved in the Synthesis
of Alliin Analogues
Maria Chiara Aversa
Anna Barattucci
Paola Bonaccorsi
Placido Giannetto
Dipartimento di Chimica organica e biologica, Universita` degli Studi
di Messina, Messina, Italy
L-cysteine is a stimulating starting product for the generation of transient
sulfenic acids that add to suitable acceptors, allowing formation of sulfoxides
showing a biologically active residue. For instance, N-(tert-butoxycarbonyl)-L-
cysteine methyl ester furnished in few steps (R)-2-tert-butoxycarbonylamino-2-
methoxycarbonyl-ethanesulfenic acid, which was readily converted into (R,SS)-
(2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethylsulfinyl)ethene, the methyl
ester of Boc-protected nor-alliin.
Keywords Alliin analogues; L-cysteine derivatives; stereoselection; sulfenic acids;
sulfoxides
INTRODUCTION
The importance of sulfenic acids RSOH as transient intermediates in
biological processes is widely recognised.1 Sulfenic acids are also very
useful as intermediates in the synthesis of a large number of sulfoxides.
In fact the addition of RSOH to alkenes or alkynes allows an easy and
stereocontrolled introduction of a sulfinyl group into a suitably unsat-
urated substrate.2
In continuing our previous studies on the addition of enantiopure
sulfenic acids to appropriate unsaturated molecules,2 we envisioned
Received July 9, 2004; accepted October 5, 2004.
This work was carried out under the auspices of the national project “Stereose-
lezione in sintesi organica, metodologie e applicazioni” supported by MIUR (Ministero
dell’Istruzione, dell’Universita` e della Ricerca), Rome, Italy. The work was also supported
by the University of Messina (funds for selected topics of interdisciplinary research).
Address correspondence to Anna Barattucci, Dipartimento di Chimica organica e
biologica, Universita` degli Studi di Messina, Salita Sperone 31 (vill. S. Agata), 98166
Messina, Italy. E-mail: annab@isengard.unime.it
1203

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M. C. Aversa et al.
that L-cysteine derivatives could represent convenient chiral starting
products for the generation of the desired sulfenic acids. L-cysteine is
easily accessible in various protected forms and possesses functional
groups that can be ulteriorly transformed. Using this kind of starting
products, we have performed the synthesis of a number of enantiopure
molecules, analogues to alliin and isoalliin, containing both the sulfinyl
and amino acidic moieties.
RESULTS AND DISCUSSION
Commercial N-(tert-butoxycarbonyl)-L-cysteine methyl ester (1a) and
N-acetyl-L-cysteine methyl ester (1b) were adopted as starting ma-
terials for preparing sulfoxides 2–4 bearing alkyl residues with β-
hydrogens to the sulfinyl group and electron-withdrawing substituents
in suitable position to help the thermal syn-elimination of sulfenic acid
(Scheme 1). Acetyl and tert-butoxycarbonyl are among the most popu-
lar protecting groups of the amine function in amino acid compounds.
Therefore we found the comparison of synthetic results in the steps
required for the preparation of sulfoxides 3a and 3b meaningful.
In the first instance, we chose 2-methyl-1-buten-3-yne as trapping
agent of sulfenic acids 5 and 6 because the completely chemo- and re-
gioselective addition of 5 and 6 onto the triple bond of the enyne leads
to enantiopure 2-sulfinylbuta-1,3-dienes, epimeric at the sulfur atom
(7 and 8 from 3, and 9 and 10 from 4). On the basis of our previous
studies2 sulfinyl dienes 7–10 are expected to be effective partners in
asymmetric Diels–Alder cycloadditions.
The structural features of 1a attracted our attention from the be-
ginning because its conversion in sulfoxides 2 and 3a occurs with
maintenance, in the cysteine residue, of a β-proton to SO group whose
mobility is guaranteed by the presence of both the ester and amine func-
tions on the same carbon atom. These characteristics posed a problem
of chemoselectivity in the elimination of sulfenic acid. Indeed, when
we warmed sulfoxides 2, in refluxing toluene and in the presence of
2-methyl-1-buten-3-yne, we obtained amino ester 11,3 as an unique,
isolated product of the syn-elimination of sulfenic acid 12.
LAH reduction of the ester moiety of the cysteine derivative 1a to the
hydroxymethyl function in 13 led to a significant modification of the ini-
tial structural features of 1a, because the acidic character of the geminal
hydrogen to NHBoc decreased in the cysteine-like residue, and a hy-
droxy function was introduced in the chiral auxiliary. It has been well
demonstrated that the involvement of the sulfur-linked oxygen atom
in intramolecular hydrogen bonding can prevent self-condensation of
the sulfenic acid, enhance the stereoselectivity of the sulfenic acid

Sulfenic Acids from L-Cysteine
1205
SCHEME 1
addition in some cases, and facilitate the chromatographic separa-
tion of the obtained diastereoisomeric sulfoxides.2a Sulfoxides 4 under-
went thermolysis in the presence of 2-methyl-1-buten-3-yne in refluxing
toluene for 2.5 h and the addition of sulfenic acid 6 to the triple bond
of the enyne led to a mixture of sulfinyl dienes 9 and 10 in 70% total
yield. The considerable difference in chromatographic mobility between
the two epimeric dienes 9 and 10 confirmed the presence of an impor-
tant intramolecular hydrogen bonding between the sulfoxide oxygen
and the hydroxy group. Therefore, the absolute configuration at sulfur
atom in dienes 9 and 10 was assigned on the basis of intramolecular
hydrogen bonding, related conformational preferences, and chromato-
graphic mobility, as previously stated.4

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M. C. Aversa et al.
The introduction of a highly and suitably substituted alkyl group
such as the 1,1-diethoxycarbonyl-2-methylprop-2-yl residue5 into the
cysteine derivatives 1 enabled, finally, the generation of sulfenic acids
5 that retain amine and carboxy function, typical of the cysteine. Two
epimers at the sulfur atom were obtained in a 1:1 ratio for sulfoxides
3a and 1:2 for sulfoxides 3b. This low stereoselectivity was the only sig-
nificant difference induced by the protective group Ac instead of Boc.
Thermolysis of sulfoxides 3 in refluxing dichloromethane generated the
transient species 5, which added to the triple bond of 2-methyl-1-buten-
3-yne, giving sulfinyl dienes 7 and 8 in very good yields, isolated in
enantiomerically pure form by column chromatography. Compounds 7
and 8 still possess a “masked” sulfenic acid function, which was ex-
pected to be producible from the cysteine moieties by their heating
at moderate temperature. Thermolysis of the mixture of sulfinyl di-
enes 7a and 8a in refluxing toluene led indeed to amino ester 11. The
isolation of 11 represents indirect evidence of the elimination, from
7a + 8a, of sulfenic acid 14, which self-condensates to volatile thio-
sulfinates whose structural features are greatly related to the alkenyl
thiosulfinates, produced in Allium species by enzymic reaction when
they are cut or ruptured, and characterizing the aroma profile of these
vegetables.1
SCHEME 2

Sulfenic Acids from L-Cysteine
1207
Sulfenic acid 5a, generated in situ from sulfoxides 3a, was also added
to the functionalized triple bond of commercially available alkynes 15c–
e (Scheme 2). The reactions were performed in dichloromethane and led
to sulfoxides 16c–e and 17c–e in good yields. All the additions occurred
with complete regioselectivity, and the mixtures of sulfoxides were sep-
arated by column chromatography, furnishing vinylsulfinyl L-cysteine
derivatives 16 and 17 in enantiomerically pure form. Protodesilylation
of compounds 17c, 16e, and 17e with tetrabutylammonium fluoride
and CuI6 led to the formation of 18, 19, and 20, respectively, and rep-
resented the last step of an easy route of access to some enantiopure
alliin analogues.
We assigned the absolute configuration of sulfur atom in sul-
foxides 7, 8, 16, and 17 (Schemes 1 and 2), moving from the X-
ray analysis of (R, E, SS)-trimethyl-[2-(2-tert-butoxycarbonylamino-2-
methoxycarbonyl-ethylsulfinyl)vinyl]silane (17c).7
CONCLUSIONS
L-cysteine represents a versatile source of sulfenic acids that can easily
furnish several enantiopure sulfoxides. Both compounds 3a and 3b can
act as convenient starting products for introducing L-cysteine S-oxide
moiety into a suitable acceptor, via sulfenic acids 5. Application of this
strategy to the synthesis of alliin analogues 18–20 in enantiomerically
pure form illustrates the versatility of this procedure. Moreover, the
elimination of sulfenic acid 14 from the mixture 7a + 8a suggests that
complex sulfoxides, such as 7 and 8, obtained by addition of sulfenic
acids 5 to unsaturated acceptors, can be stereoselectively derivatized
and warmed again to eliminate enamine 11 and simultaneously gen-
erate a new sulfenic acid moiety, useful in subsequent stereoselective
transformations toward still more complex and enantiopure sulfoxides.
This last application can be regarded as a further stimulating develop-
ment of this chemistry.
REFERENCES
[1] a) L. A. G. M. Van Den Broek, L. P. C. Delbressine, and H. C. J. Ottenheijm, in The
Chemistry of Sulphenic Acids and Their Derivatives, S. Patai, Ed. (John Wiley &
Sons; Chichester, 1990); b) E. Block, Angew. Chem., Int. Ed. Engl., 31, 1135 (1992);
c) A. Claiborne, J. I. Yeh, T. C. Mallett, J. Luba, E. J. Crane III, V. Charrier, and D.
Personage, Biochemistry, 38, 15407 (1999); d) S. Imai, N. Tsuge, M. Tomotake, Y.
Nagatome, H. Sawada, T. Nagata, and H. Kumagai, Nature, 419, 685 (2002).
[2] a) M. C. Aversa, A. Barattucci, P. Bonaccorsi, P. Giannetto, and D. N. Jones, J. Org.
Chem., 62, 4376 (1997); b) M. C. Aversa, A. Barattucci, P. Bonaccorsi, P. Giannetto,
and M. Policicchio, ibid., 66, 4845 (2001); c) V. Aucagne, M. C. Aversa, A. Barattucci,

1208
M. C. Aversa et al.
P. Bonaccorsi, P. Giannetto, P. Rollin, and A. Tatiboue¨t, ibid., 67, 6925 (2002);
d) M. C. Aversa, A. Barattucci, P. Bonaccorsi, and P. Giannetto, Arkivoc, 79 (2002)
and references therein.
[3] D. H. Rich and J. P. Tam, J. Org. Chem., 42, 3815 (1977); L. A. Adams, V. K.
Aggarwal, R. V. Bonnert, B. Bressel, R. J. Cox, J. Shepherd, J. de Vicente, M. Walter,
W. Whittingham, and C. L. Winn, ibid., 68, 9433 (2003).
[4] M. C. Aversa, P. Bonaccorsi, P. Giannetto, S. M. A. Jafari, and D. N. Jones, Tetrahe-
dron: Asymmetry, 3, 701 (1992).
[5] H. Adams, J. C. Anderson, R. Bell, D. N. Jones, M. R. Peel, and N. C. O. Tomkinson,
J. Chem. Soc., Perkin Trans. 1, 3967 (1998) and references therein.
[6] B. M. Trost, Z. T. Ball, and T. Jo¨ge, J. Am. Chem. Soc., 124, 7922 (2002).
[7] M. C. Aversa, A. Barattucci, P. Bonaccorsi, and P. Giannetto, J. Org. Chem., 2005, in
press, http://dx.doi.org/10.1021/jo048662K.