L-cysteine, a versatile source of sulfenic acids. Synthesis of enantiopure alliin analogues

Article abstract of DOI:10.1021/jo048662k

(Chemical Equation Presented) L-Cysteine is a stimulating starting product for the generation of transient sulfenic acids, such as 4, 6, 9, and 15, which add to suitable acceptors, allowing formation of sulfoxides showing a biologically active residue. These sulfoxides are easily isolated in enantiomerically pure form. For instance, N-(tert-butoxycarbonyl)-L-cysteine methyl ester (1a) furnished in few steps sulfenic acid 9a, which was readily converted into (R,S_S)-(2-tert-butoxycarbonylamino-2-methoxycarbonyl- ethylsulfinyl)ethene (22), the methyl ester of Boc-protected nor-alliin. Moreover, the addition of 9a to 2-methyl-1-buten-3-yne has led to a sulfur epimeric and separable mixture of (CR)-2-(2-tert-butoxycarbonylamino-2- methoxycarbonyl-ethylsulfinyl)-3-methyl-buta-1,3-dienes 10a and 11a, still possessing a "masked" sulfenic acid function, producible from their cysteine moieties once the dienes have been converted into the desired derivatives.

Full text of DOI:10.1021/jo048662k

L-Cysteine, a Versatile Source of Sulfenic Acids. Synthesis of
Enantiopure Alliin Analogues
Maria C. Aversa,* Anna Barattucci, Paola Bonaccorsi,* and Placido Giannetto
Dipartimento di Chimica Organica e Biologica, Universita` degli Studi di Messina,
Salita Sperone 31 (vill. S. Agata), 98166 Messina, Italy
mariachiara.aversa@unime.it; paolab@isengard.unime.it
Received August 3, 2004
L-Cysteine is a stimulating starting product for the generation of transient sulfenic acids, such as
4, 6, 9, and 15, which add to suitable acceptors, allowing formation of sulfoxides showing a
biologically active residue. These sulfoxides are easily isolated in enantiomerically pure form. For
instance, N-(tert-butoxycarbonyl)-L-cysteine methyl ester (1a) furnished in few steps sulfenic acid
9a, which was readily converted into (R,SS)-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-
ethylsulfinyl)ethene (22), the methyl ester of Boc-protected nor-alliin. Moreover, the addition of 9a
to 2-methyl-1-buten-3-yne has led to a sulfur epimeric and separable mixture of (R)-2-(2-tert-
butoxycarbonylamino-2-methoxycarbonyl-ethylsulfinyl)-3-methyl-buta-1,3-dienes 10a and 11a, still
possessing a “masked” sulfenic acid function, producible from their cysteine moieties once the dienes
have been converted into the desired derivatives.
Introduction
tightly connected with reactions of self-condensation and
rearrangement of sulfenic acids that originate from (SS)-
S-allyl-L-cysteine S-oxide (alliin) and (SS,E)-S-(1-pro-
penyl)-L-cysteine S-oxide (isoalliin) by the action of
specific enzymes.3
The importance of sulfenic acids RSOH as transient
intermediates in biological processes is widely recognized.
Oxidation of thiol groups in living systems and much of
the chemistry of the penicillin sulfoxides have been
considered to involve sulfenic acid chemistry.1 There is
evidence for functional Cys-SOH in native proteins such
as NADH peroxidase and oxidase. Cys-SOH forms of
protein tyrosine phosphatases and glutathione reductase
play key roles in important biological processes. In
general, functional Cys-SOHs participate in diverse
cellular processes, including signal transduction, oxida-
tive stress response, and transcriptional regulation.2 The
recognized therapeutical properties of garlic, its typical
flavor, and the disagreeable smell of breath and sweat
after its ingestion or the lachrymatory factor of onion are
In continuing our study on the syn-addition of enan-
tiopure sulfenic acids to appropriate unsaturated mol-
ecules,4 we envisaged that L-cysteine derivatives could
represent convenient chiral starting products for the
generation of various sulfenic acids and their involvement
in stereocontrolled processes that allow the introduction
of a cysteine S-oxide residue into a suitably chosen
acceptor. Cysteine S-oxides are known for their cancero-
protective and antioxidant potential,5 L-cysteine is easily
accessible in various protected forms and possesses
functional groups that can be further transformed, but
most of all, the L-cysteine S-oxide framework represents
a kind of chiral auxiliary where the stereodifferentiating
moiety is also a biologically active residue, so that it could
be convenient to not remove the cysteine S-oxide group
once it has played its auxiliary role. L-Cysteine deriva-
* To whom correspondence should be addressed. M.C.A.: Tel +39-
090-6765165. Fax +39-090-393895. P.B.: Tel +39-090-6765187. Fax
+39-090-393895.
(1) Van Den Broek, L. A. G. M.; Delbressine, L. P. C.; Ottenheijm,
H. C. J. In The Chemistry of Sulphenic Acids and their Derivatives;
Patai, S., Ed.; John Wiley & Sons: Chichester, 1990; pp 701-721.
(2) ) Claiborne, A.; Yeh, J. I.; Mallett, T. C.; Luba, J.; Crane, E. J.,
III; Charrier, V.; Personage, D. Biochemistry 1999, 38, 15407-15416.
(3) Block, E. Angew. Chem., Int. Ed. Engl. 1992, 31, 1135-1178.
Imai, S.; Tsuge, N.; Tomotake, M.; Nagatome, Y.; Sawada, H.; Nagata,
T.; Kumagai, H. Nature 2002, 419, 685.
10.1021/jo048662k CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/16/2004
1986
J. Org. Chem. 2005, 70, 1986-1992

L-Cysteine as a Source of Sulfenic Acids
SCHEME 1
SCHEME 2
tives, obtained via sulfenic acids, can be therefore in-
volved in asymmetric processes offering stimulating
opportunities of synthetic applications.
In this paper we report the generation of enantiopure
sulfenic acids from L-cysteine derivatives and the in-
volvement of some of them in the stereoselective synthe-
sis of enantiopure alliin analogues, such as (R,SS)-(2-
tert-butoxycarbonylamino-2-methoxycarbonyl-ethylsulfi-
nyl)ethene (22) and both sulfur epimers 21 and 23 of (R)-
2-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethyl-
sulfinyl)propene.6
Results and Discussion
Commercial N-(tert-butoxycarbonyl)-L-cysteine methyl
ester (1a) and N-acetyl-L-cysteine methyl ester (1b) were
adopted as starting materials for preparing sulfoxides 3,
8, and 13 bearing alkyl residues with â-hydrogens to the
sulfinyl group and electron-withdrawing substituents in
suitable position to help the thermal syn-elimination of
sulfenic acid (Schemes 1 and 2). Acetyl and tert-butoxy-
carbonyl are among the most popular protecting groups
of the amine function in amino acid compounds. There-
fore we found meaningful the comparison of synthetic
(4) ) (a) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.;
Jones, D. N. J. Org. Chem. 1997, 62, 4376-4384. (b) Aversa, M. C.;
Barattucci, A.; Bonaccorsi, P.; Giannetto, P.; Nicolo`, F. J. Org. Chem.
1999, 64, 2114-2118. (c) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.;
Giannetto, P.; Policicchio, M. J. Org. Chem. 2001, 66, 4845-4851. (d)
Aucagne, V.; Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto,
P.; Rollin, P.; Tatiboue¨t, A. J. Org. Chem. 2002, 67, 6925-6930. (e)
Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P. Arkivoc
2002, 79-98.
results in the steps required for the preparation of
sulfoxides 8a and 8b.
In a first instance, we chose 2-methyl-1-buten-3-yne
as trapping agent of sulfenic acids 9a, 9b, and 15 because
the completely chemo- and regioselective addition of
sulfenic acid onto the triple bond of the enyne leads to
enantiopure 2-sulfinylbuta-1,3-dienes, epimeric at sulfur
atom (10a and 11a from 8a, 10b and 11b from 8b in
Scheme 1, 16 and 17 from 13 in Scheme 2). On the basis
of our previous studies4a,b,7 sulfinyl dienes 10, 11, 16, and
(5) ) Krest, I.; Keusgen, M. Anal. Chim. Acta 2002, 469, 155-164.
Helen, A.; Krishnakumar, K.; Vijayammal, P. L.; Augusti, K. T.
Pharmacology 2003, 67, 113-117.
(6) ) Authors decided to name the new compounds privileging the
preservation in any case of the same indices for cysteine-like residues,
instead of strictly applying IUPAC conventions.
J. Org. Chem, Vol. 70, No. 6, 2005 1987

Aversa et al.
17 are expected to be effective partners in asymmetric
Diels-Alder cycloadditions.
yield. The considerable difference in chromatographic
mobility between the two epimeric dienes 16 and 17
confirmed the presence of an important intramolecular
hydrogen bonding between the sulfoxide oxygen and the
hydroxy group. Therefore, the absolute configuration at
the sulfur atom in dienes 16 and 17 (Scheme 2) was
assigned on the basis of intramolecular hydrogen bond-
ing, related conformational preferences, and chromato-
graphic mobility, as previously stated.11 For this purpose
we decided to represent Newman projections of 16 and
17 flattening the sulfur atom onto the carbon stereogenic
center. The preferred hydrogen-bonded conformation was
considered to be (a), which led to the assignment of the
(RS) configuration to the more mobile epimer 16, whereas
for the corresponding (SS) isomer 17, intramolecular
hydrogen bonding should require the adoption of less
favorable conformations (b) and/or (c) with four bulky
substituents gauche to each other.
The structural features of 1a (Scheme 1) attracted our
attention from the beginning because its conversion in
sulfoxides 3 and 8a occurs with maintenance, in the
cysteine residue, of a â-proton to SO group whose
mobility is guaranteed by the presence of both the ester
and amine functions on the same carbon atom. These
characteristics posed a problem of chemoselectivity in the
elimination of sulfenic acid. Indeed, when we warmed
sulfoxides 3, in refluxing toluene and in the presence of
2-methyl-1-buten-3-yne, we obtained amino ester 5,8 as
unique isolated product of the syn-elimination of sulfenic
acid 4. Rich and Tam had reported8a dehydrosulfenylation
of Boc-protected 3-benzylsulfinyl amino acid derivatives,
meaningfully influenced by intramolecular hydrogen
bonding between the sulfoxide oxygen and the amide NH
group. Epimeric sulfoxides 3 were prepared by treatment
of cysteine derivative 1a with acrylonitrile and benzyl-
trimethylammonium hydroxide (Triton B) and subse-
quent oxidation with m-CPBA of sulfide 2,9 which was
obtained in 80% yield. m-CPBA oxidation of 2 to 3 was
nearly quantitative, and sulfoxides 3 were obtained as a
1:1 mixture of epimers at sulfur atom.
LAH reduction of the ester moiety of the cysteine
derivative 1a to the hydroxymethyl function in 12
(Scheme 2) led to a significant modification of the initial
structural features of 1a, since the acidic character of the
geminal hydrogen to NHBoc decreased in the cysteine-
like residue, and a hydroxy 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 in some cases
the stereoselectivity of the sulfenic acid addition, and
facilitate the chromatographic separation of the obtained
diastereoisomeric sulfoxides.4a Hydroxythiol 1210 was
reacted with acrylonitrile and Triton B to give sulfide 14
in 95% yield. Oxidation of 14 with m-CPBA furnished
the sulfur epimeric mixture 13 in 93% yield. Sulfoxides
13 underwent thermolysis in the presence of 2-methyl-
1-buten-3-yne in refluxing toluene for 2.5 h, and the
addition of sulfenic acid 15 to the triple bond of the enyne
led to a mixture of sulfinyl dienes 16 and 17 in 70% total
Thermolysis of sulfoxides to sulfenic acids is normally
accelerated by increasing the acidity of â-hydrogens with
the presence of electron-withdrawing and alkyl substit-
uents â and R, respectively, to SO.12 The introduction of
a highly and suitably substituted alkyl group such as the
1,1-diethoxycarbonyl-2-methylprop-2-yl residue into the
cysteine derivatives 1 enabled, finally, the generation of
sulfenic acids 9, which retain amine and carboxy func-
tion, typical of the cysteine (Scheme 1). Reaction of
cysteine derivatives 1a and 1b with diethyl isopropyl-
idenemalonate, in the presence of Triton B at -78 °C,
furnished sulfides 7a and 7b in 85% and 80% yield,
respectively. Sulfoxides 8a and 8b were obtained in 98%
and 92% yield, respectively, by oxidation of sulfides 7 in
the same conditions previously quoted for sulfides 2 and
14. Two epimers at the sulfur atom were obtained in 1:1
ratio for sulfoxides 8a and 1:2 ratio for sulfoxides 8b. This
low stereoselectivity was the only significant difference
induced by the protective group Ac instead of Boc.
Thermolysis of sulfoxides 8a and 8b in refluxing dichloro-
methane (40 °C) generated the transient species 9a and
9b, which added to the triple bond of 2-methyl-1-buten-
3-yne giving sulfinyl dienes 10 and 11 in very good yields.
Dienes 10a, 11a, 10b, and 11b were isolated in enan-
tiomerically pure form by column chromatography. Note-
worthy, compounds 10 and 11 still possess a “masked”
sulfenic acid function that was expected to be producible
(7) Adams, H.; Jones, D. N.; Aversa, M. C.; Bonaccorsi, P.; Giannetto,
P. Tetrahedron Lett. 1993, 34, 6481-6484. Aversa, M. C.; Bonaccorsi,
P.; Giannetto, P.; Jones, D. N. Tetrahedron: Asymmetry 1994, 5, 805-
808. Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Bruno, G.; Giannetto,
P.; Panzalorto, M. Tetrahedron: Asymmetry 1997, 8, 2989-2995.
Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.; Panzalorto,
M.; Rizzo, S. Tetrahedron: Asymmetry 1998, 9, 1577-1587. Aversa,
M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.; Nicolo`, F.; Rizzo,
S. Tetrahedron: Asymmetry 1999, 10, 3907-3917. Aranda, M. T.;
Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Carren˜o, M. C.; Cid, M.
B.; Garc´ıa Ruano, J. L. Tetrahedron: Asymmetry 2000, 11, 1217-1225.
Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Bruno, G.; Caruso, F.;
Giannetto, P. Tetrahedron: Asymmetry 2001, 12, 2901-2908.
(8) (a) Rich, D. H.; Tam, J. P. J. Org. Chem. 1977, 42, 3815-3820.
(b) Hermkens, P. H. H.; Van Maarseveen, J. H.; Ottenheijm, H. C. J.;
Kruse, C. G.; Scheeren, H. W. J. Org. Chem. 1990, 55, 3998-4006. (c)
Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.; Taylor, R. J.
K. J. Org. Chem. 2002, 67, 1802-1815. (d) Adams, L. A.; Aggarwal,
V. K.; Bonnert, R. V.; Bressel, B.; Cox, R. J.; Shepherd, J.; de Vicente,
J.; Walter, M.; Whittingham, W.; Winn, C. L. J. Org. Chem. 2003, 68,
9433-9440.
(11) Aversa, M. C.; Bonaccorsi, P.; Giannetto, P.; Jafari, S. M. A.;
Jones, D. N. Tetrahedron: Asymmetry 1992, 3, 701-704.
(12) Adams, H.; Anderson, J. C.; Bell, R.; Jones, D. N.; Peel, M. R.;
Tomkinson, N. C. O. J. Chem. Soc., Perkin Trans. 1 1998, 3967-3974
and references therein.
(9) Climie, I. J. G.; Evans, D. A. Tetrahedron 1982, 38, 697-711.
(10) Park, J.-K.; Choi, K. S.; Lee, H. W.; So, S. K.; Ham, W. F.; Oh,
C. Y.; Lee, K. Y.; Kim, Y. H.; Park, M. S. Jpn. Kokai Tokkyo Koho JP
2001233863, 2001; Chem. Abstr. 2001, 135, 195555.
1988 J. Org. Chem., Vol. 70, No. 6, 2005

L-Cysteine as a Source of Sulfenic Acids
SCHEME 3
(R,RS) configuration of 19c and (R,SS) configuration of
22, this last obtained by protodesilylation of 20c. Typical
NMR parameters were compared for sulfur epimeric
couples 10a and 11a, 19c-e and 20c-e, 21 and 23, all
characterized by the presence of (R)-2-tert-butoxycarbonyl-
amino-2-methoxycarbonyl-ethylsulfinyl moiety, therefore
showing analogous conformational preferences. We ob-
served that, on going from a (RS)-sulfoxide to its (SS)-
epimer, C-1′ resonance was shielded by 1 ppm and NH
resonance deshielded by about 0.13 ppm. More signifi-
cantly J1′A,2′, J1′B,2′, and J2′,NH assumed almost the same
values (6.6-4.8 Hz) for (RS)-sulfoxides, while J1′A,2′ was
almost the same as J2′,NH (8.0-7.4 Hz) and J1′B,2′ clearly
smaller (4.1-3.6 Hz) for (SS)-sulfoxides. Analogous spec-
tral trends allowed the assignment of configurations
shown in Scheme 1 for epimeric sulfinyl dienes 10b and
11b, characterized by NHAc moiety.15
from the cysteine moieties by their heating at moderate
temperature. Thermolysis of the mixture of sulfinyl
dienes 10a and 11a in refluxing toluene (110 °C) led
indeed to amino ester 5 (Scheme 1). The isolation of 5
represents indirect evidence of the elimination of sulfenic
acid 6, which self-condensates to volatile thiosulfinates
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.3,13
Sulfenic acid 9a, generated in situ from sulfoxides 8a
(Scheme 1), was also added to the functionalized triple
bond of (trimethylsilyl)acetylene (18c), 1-(trimethylsilyl)-
1-propyne (18d), and 3-(trimethylsilyl)-1-propyne (18e),
all of them commercially available (Scheme 3). The
reactions were performed in dichloromethane and led to
sulfoxides 19c-e and 20c-e in good yields. All the
additions occurred with complete regioselectivity, and the
mixtures of sulfoxides were separated by column chro-
matography, furnishing vinylsulfinyl L-cysteine deriva-
tives 19 and 20 in enantiomerically pure form. Protode-
silylation of compounds 20c, 19e, and 20e with tetrabutyl-
ammonium fluoride (TBAF) and CuI14 led to the forma-
tion of (R,SS)-(2-tert-butoxycarbonylamino-2-methoxycar-
bonyl-ethylsulfinyl)ethene (22) and (R,RS)- and (R,SS)-
2-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-
ethylsulfinyl)propene (21 and 23, respectively) and
represented the last step of an easy route of access to
some alliin analogues.
Conclusions
L-Cysteine represents a versatile source of sulfenic
acids that can easily furnish several enantiopure sulfox-
ides. Both compounds 7a and 7b can act as convenient
starting products for introducing L-cysteine S-oxide
moiety into a suitable acceptor, via sulfenic acids 9a and
9b. Application of this strategy to the synthesis of alliin
analogues 21-23 in enantiomerically pure form il-
lustrates the versatility of this procedure. Moreover, the
elimination of sulfenic acid 6 from the mixture 10a +
11a suggests that complex sulfoxides, such as 10 and 11,
obtained by addition of sulfenic acids 9 to unsaturated
acceptors, can be stereoselectively derivatized and warmed
again to eliminate an enamine such as 5 and simulta-
neously generate 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
development of this chemistry.
Experimental Section
General Methods. 1H and 13C NMR spectra were recorded
at 300 and 75 MHz, respectively, in CDCl3 solutions with TMS
as internal standard; J values are given in Hz. The assign-
ments are supported by Attached Proton Test (APT) and
homodecoupling experiments. Protons and carbon nuclei marked
with (′) pertain to the cysteine-like moieties. Mass spectra were
measured by FAB (m-nitrobenzyl alcohol as matrix). All
reactions were monitored by TLC on commercially available
precoated plates (silica gel 60 F 254), and the products were
visualized with acidic vanillin solution. Silica gel 60, 230-400
mesh, was used for column chromatography. Petrol refers to
light petroleum, bp 30-40 °C.
We assigned the absolute configuration of sulfur atom
in sulfoxides 10, 11, 19, and 20 (Schemes 1 and 3) moving
from the X-ray analysis of (R,E,SS)-trimethyl-[2-(2-tert-
butoxycarbonylamino-2-methoxycarbonyl-ethylsulfinyl)-
vinyl]silane (20c), mp 134-135 °C, synthesized together
with its sulfur epimer 19c by thermolysis of 8a in the
presence of (trimethylsilyl)acetylene (18c). The diffrac-
tometry results unambiguously support the (R,SS) con-
figuration of sulfoxide 20c and, as a consequence, the
(R)-2-tert-Butoxycarbonylamino-3-hydroxy-propane-
1-thiol (12).10 A solution of N-(tert-butoxycarbonyl)-L-cysteine
methyl ester (1a) (705 mg, 3.0 mmol) in anhydrous Et2O (7
(13) Xiao, H.; Parkin, K. L. J. Agric. Food Chem. 2002, 50, 2488-
2493. Higuchi, O.; Tateshita, K.; Nishimura, H. J. Agric. Food Chem.
2003, 51, 7208-7214.
(14) Trost, B. M.; Ball, Z. T.; Jo¨ge, T. J. Am. Chem. Soc. 2002, 124,
7922-7923.
(15) (R,RS)-2-(2-Acetylamino-2-methoxycarbonyl-ethylsulfinyl)-3-
methyl-buta-1,3-diene (10b): NH 6.80 ppm, C-1′ 55.0 ppm, J1′A,2′
)
J2′,NH 5.7 Hz, J1′B,2′ 5.5 Hz. (R,SS)-2-(2-Acetylamino-2-methoxycarbonyl-
ethylsulfinyl)-3-methyl-buta-1,3-diene (11b): NH 7.04 ppm, C-1′ 54.0
ppm, J1′A,2′ 6.9 Hz, J2′,NH 7.3 Hz, J1′B,2′ 3.9 Hz.
J. Org. Chem, Vol. 70, No. 6, 2005 1989

Aversa et al.
mL) was added dropwise to a LAH suspension (171 mg, 4.5
mmol) in anhydrous Et2O (10 mL) at -15 °C. After 15 min
the reaction appeared complete by TLC and LAH in excess
was carefully quenched by adding wet Et2O and H2O. The
organic phase was filtered, dried (Na2SO4), and concentrated
under reduced pressure to give the hydroxythiol 12 as an oil,
which did not need purification (560 mg, 2.7 mmol, 90%
yield): 1H NMR δ 5.03 (br d, NH), 3.8-3.7 (m, H-2, H2-3), 2.76
(m, H2-1), 1.50 (m, SH), 1.46 (s, CMe3); 13C NMR δ 156.0
(NHCO), 80.0 (CMe3), 62.8 (C-3), 53.5 (C-2), 28.2 (CMe3), 25.7
(C-1). Anal. Calcd for C8H17NO3S: C 46.35, H 8.27, N 6.76.
Found: C 46.38, H 7.95, N 6.84.
2-Cyanoethyl Sulfides 2 and 14. General Procedure.
Acrylonitrile (80 µL, 1.2 mmol) was added slowly to a solution
of thiol 1a or 12 (1.0 mmol) and Triton B (50 µL, 0.12 mmol,
40 wt % solution in MeOH) in anhydrous THF (4 mL) at -78
°C. When the reaction appeared complete by TLC, water was
added. The crude product was extracted with Et2O (3 × 15
mL) and dried (Na2SO4).
(R)-2-[1-(2-Acetylamino-2-methoxycarbonyl-ethylthio)-
1-methyl-ethyl]malonic Acid Diethyl Ester (7b). Diethyl
isopropylidenemalonate (0.81 mL, 4.0 mmol), N-acetyl-L-
cysteine methyl ester (1b) (177 mg, 1.0 mmol), and Triton B
(25 µL, 0.06 mmol, 40 wt % solution in MeOH) were reacted
as previously described for compound 7a. The crude residue
was purified by column chromatography (petrol/EtOAc 90:10
up to 20:80) to afford compound 7b as an oil (302 mg, 0.80
mmol 80% yield): [R]25D +26.4 (c 4.70, CHCl3); 1H NMR δ 6.56
(br d, J2′,NH 7.4, NH), 4.79 (dt, J1′A,2′ 5.1, J1′B,2′ 4.9, H-2′), 4.19
(two q) and 4.18 (two q) (Jvic 7.0, 2 × OCH2), 3.74 (s, OMe),
3.56 (s, H-2), 3.06 (AB dd, J1′A,1′B 12.6, HA-1′), 3.03 (AB dd,
HB-1′), 2.04 (s, MeCO), 1.52 (s, SCMe2), 1.26 (two t, 2 ×
CH2Me); 13C NMR δ 171.0 (CO2Me), 167.1, 167.05, and 167.03
(C-1,3, NHCO), 61.42 and 61.36 (OCH2), 60.4 (C-2), 52.6 (C-
2′), 51.6 (OMe), 45.6 (SCMe2), 30.1 (C-1′), 26.5 and 26.3
(SCMe2), 22.7 (MeCO), 13.9 and 13.8 (CH2Me); MS m/z (%) 378
(M + 1, 100), 318 (26), 218 (58), 201 (39), 178 (36), 176 (25),
155 (39), 144 (29), 99 (32). Anal. Calcd for C19H33NO8S: C
52.40, H 7.64, N 3.22. Found: C 52.22, H 7.69, N 3.34.
(R)-3-(2-tert-Butoxycarbonylamino-2-methoxycarbonyl-
ethylthio)propionitrile (2).9 The conversion of 1a to 2 was
complete after allowing the solution to spontaneously reach
-20 °C and remain at this temperature for 30 min. Evapora-
tion of the solvent gave an oily residue that was purified by
column chromatography. Elution with petrol/EtOAc 90:10
afforded compound 2 (80% yield) as an oil: 1H NMR δ 5.36 (br
d, J2′,NH 6.4, NH), 4.55 (m, H-2′), 3.79 (s, OMe), 3.09 (AB dd,
J1′A,1′B 14.0, J1′A,2′ 5.1, HA-1′), 3.01 (AB dd, J1′B,2′ 5.3, HB-1′),
2.82 (split t, Jvic 7.1, H2-3), 2.64 (split t, H2-2), 1.46 (s, CMe3);
13C NMR δ 171.0 (CO2Me), 155.0 (NHCO), 117.9 (C-1), 80.3
(CMe3), 53.3 (C-2′), 52.7 (OMe), 34.5 (C-1′), 28.2 (CMe3), 28.1
(C-3), 18.6 (C-2); MS m/z (%) 289 (M + 1, 10), 233 (63), 189
(58), 172 (20), 95 (50), 81 (55), 69 (74), 57 (100). Anal. Calcd
for C12H20N2O4S: C 49.98, H 6.99, N 9.71. Found: C 50.17, H
6.83, N 9.64.
(R)-3-(2-tert-Butoxycarbonylamino-3-hydroxy-propyl-
thio)propionitrile (14). The conversion of 12 to 14 was
complete after 15 min at -78 °C. Evaporation of the solvent
gave compound 14 as an oil not needing any purification (95%
yield): 1H NMR δ 5.07 (br d, NH), 3.8-3.7 (m, H-2′, H2-3′),
2.9-2.7 (m, H2-1′,2,3), 1.45 (s, CMe3); 13C NMR δ 155.8
(NHCO), 118.3 (C-1), 80.0 (CMe3), 62.9 (C-3′), 51.6 (C-2′), 33.1
(C-1′), 28.3 (CMe3), 27.8 (C-3), 18.8 (C-2); MS m/z (%) 261 (M
+ 1, 8), 205 (19), 81 (55), 95 (54), 69 (78), 57 (97), 55 (100).
Anal. Calcd for C11H20N2O3S: C 50.75, H 7.74, N 10.76.
Found: C 50.87, H 7.57, N 10.86.
(R)-2-[1-(2-tert-Butoxycarbonylamino-2-methoxycar-
bonyl-ethylthio)-1-methyl-ethyl]malonic Acid Diethyl
Ester (7a). Diethyl isopropylidenemalonate (0.61 mL, 3.0
mmol) was added to a stirred solution of N-(tert-butoxycarbo-
nyl)-L-cysteine methyl ester (1a) (235 mg, 1.0 mmol), and
Triton B (38 µL, 0.09 mmol, 40 wt % solution in MeOH) in
anhydrous THF (2.5 mL) at -78 °C. The reaction was slowly
brought to room temperature, and when it appeared complete
by TLC, after 2 h, water was added. The crude product was
extracted with Et2O (3 × 15 mL). The combined organic layers
were washed with saturated NaCl solution (3 × 15 mL) and
dried (Na2SO4). The solvent was removed under reduced
pressure, and the residue was purified by column chromatog-
raphy (petrol/EtOAc 95:5 up to 50:50) to afford compound 7a
as an oil (370 mg, 0.85 mmol, 85% yield): [R]25D +12.2 (c 4.82,
CHCl3); 1H NMR δ 5.37 (br d, J2′,NH 7.6, NH), 4.54 (br dt, J1′,2′
5.0, H-2′), 4.21 and 4.20 (two q, Jvic 7.1, 2 x OCH2), 3.76 (s,
OMe), 3.58 (s, H-2), 3.04 (d, H2-1′), 1.54 (s, SCMe2), 1.44 (s,
CMe3), 1.28 (two t, 2 × CH2Me); 13C NMR δ 171.2 (CO2Me),
166.9 (C-1,3), 155.1 (NHCO), 80.1 (CMe3), 61.4 (OCH2), 60.3
(C-2), 52.9 (C-2′), 52.5 (OMe), 45.8 (SCMe2), 30.8 (C-1′), 28.2
(CMe3), 26.53 and 26.48 (SCMe2), 14.0 (CH2Me); MS m/z (%)
436 (M + 1, 6), 380 (13), 336 (100), 318 (32), 247 (18), 220
(15), 201 (75), 176 (51), 155 (48), 127(15), 99 (33), 57 (39). Anal.
Calcd for C19H33NO8S: C 52.40, H 7.64, N 3.22. Found: C
52.18, H 7.61, N 3.40.
m-CPBA Oxidation of Sulfides 2, 7, and 14 to Sulfox-
ides 3, 8, and 13, Respectively. General Procedure.
m-CPBA (0.17 g 80%, 0.8 mmol) was dissolved in CH2Cl2 (6
mL) and added dropwise to a solution of the sulfide (0.8 mmol)
in CH2Cl2 (5 mL) at -50 °C. When the reaction appeared
complete by TLC, a 10% solution of Na2S2O3 was added (10
mL), and the organic layer was extracted and washed with a
saturated solution of NaHCO3 (2 × 10 mL) and water (2 × 10
mL).
(R)-3-(2-tert-Butoxycarbonylamino-2-methoxycarbonyl-
ethylsulfinyl)propionitriles 3. The conversion of 2 into 3
was complete after 20 min. Evaporation of the solvent under
reduced pressure gave sulfoxides 3 (95% yield, sulfur epimeric
ratio 1:1) as an oil usable for the next step without purifica-
tion: 1H NMR δ 5.65 (br m, NH), 4.66 (m, H-2′), 3.81 (s, OMe),
3.5-2.8 (m, H2-1,1′,2), 1.46 (s, CMe3); 13C NMR δ 170.5 and
170.1 (CO2Me), 155.3 (NHCO), 117.2 (C-1), 80.8 (CMe3), 54.3,
53.7, and 53.0 (C-2′, OMe), 49.5 and 49.3 (C-1′), 47.0 and 46.6
(C-3), 28.1 (CMe3), 11.1 and 10.9 (C-2). Anal. Calcd for
C12H20N2O5S: C 47.35, H 6.62, N 9.20. Found: C 47.00, H 6.62,
N 9.10.
(R)-2-[1-(2-tert-Butoxycarbonylamino-2-methoxycar-
bonyl-ethylsulfinyl)-1-methyl-ethyl]malonic Acids Di-
ethyl Esters 8a. The conversion of 7a into 8a was complete
after 5 min. Evaporation of the solvent under reduced pressure
gave sulfoxides 8a (98% yield, sulfur epimeric ratio 1:1) as an
oil usable for the next step without purification: 1H NMR δ
5.73 (br d, J2′,NH 9.0) and 5.69 (br d, J2′,NH 6.3) (NH), 4.74 (m,
H-2′), 4.3-4.2 (m, 2 × OCH2), 3.80 and 3.79 (two s, OMe), 3.72
(s, H-2), 3.3-3.0 (m, H2-1′), 1.48 and 1.46 (s, SCMe2), 1.45 and
1.44 (s, CMe3), 1.28 (m, 2 × CH2Me); 13C NMR δ 170.4 (CO2-
Me), 166.50, 166.46, 166.15, and 166.12 (C-1,3), 155.2 and
155.1 (NHCO), 80.4 (CMe3), 61.9, 61.82, 61.76, and 61.73
(OCH2), 58.1 (C-1′), 55.1 (C-2), 52.8 and 52.7 (C-2′), 50.3 and
50.2 (OMe), 47.3 and 46.5 (SCMe2), 28.2 (CMe3), 13.9 (CH2Me);
MS m/z (%) 452 (M + 1, 11), 396 (15), 368 (43), 329 (9), 201
(64), 155 (52), 81 (35), 69 (53), 57 (100). Anal. Calcd for C19H33-
NO9S: C 50.54, H 7.37, N 3.10. Found: C 50.83, H 7.40, N
3.16.
(R)-2-[1-(2-Acetylamino-2-methoxycarbonyl-ethylsul-
finyl)-1-methyl-ethyl]malonic Acids Diethyl Esters 8b.
The conversion of 7b into 8b was complete after 20 min.
Evaporation of the solvent under reduced pressure gave
sulfoxides 8b (92% yield, sulfur epimeric ratio 1:2) as an oil
usable for the next step without purification: 1H NMR δ 7.17
(br d, J2′,NH 8.1, NH of minor epimer), 6.87 (br d, J2′,NH 5.9,
NH of major epimer), 5.0-4.9 (m, H-2′), 4.23 (m, 2 × OCH2),
3.76 (s, OMe), 3.68 (s, H-2 of minor epimer), 3.67 (s, H-2 of
major epimer), 3.29 (AB dd, J1′A,1′B 12.9, J1′A,2′ 5.5, HA-1′ of
major epimer), 3.26 (AB dd, J1′A,1′B 13.0, J1′A,2′ 7.2, HA-1′ of
minor epimer), 3.15 (AB dd, J1′B,2′ 4.5, HB-1′ of major epimer),
3.00 (AB dd, J1′B,2′ 3.9, HB-1′ of minor epimer), 2.05 (s, MeCO
1990 J. Org. Chem., Vol. 70, No. 6, 2005

L-Cysteine as a Source of Sulfenic Acids
of minor epimer), 2.04 (s, MeCO of major epimer), 1.44, 1.40,
1.29, and 1.28 (four s, SCMe2), 1.3-1.2 (m, 2 × CH2Me); 13C
NMR δ 170.5 and 170.4 (CO2Me), 166.6, 166.5, 166.23, 166.16,
and 165.8 (C-1,3, NHCO), 61.95, 61.90, 61.84, 61.79, 60.7, and
58.1 (C-1′, OCH2), 55.1 and 55.0 (C-2), 52.9 and 52.8 (C-2′),
49.3, 49.2, 49.1, and 49.0 (OMe, SCMe2), 23.0 and 22.9 (MeCO),
17.8, 17.4, 17.2, and 17.1 (SCMe2), 14.0, 13.9, 13.8, and 13.7
(CH2Me); MS m/z (%) 394 (M + 1, 100), 201 (49), 194 (16), 176
(92), 155 (50), 144 (22), 99 (26). Anal. Calcd for C16H27NO8S:
C 48.84, H 6.92, N 3.56. Found: C 48.45, H 7.13, N 3.43.
(R)-3-(2-tert-Butoxycarbonylamino-3-hydroxy-propyl-
sulfinyl)propionitriles 13. The conversion of 14 into 13 was
complete after 20 min. Evaporation of the solvent under
reduced pressure gave sulfoxides 14 (93% yield, sulfur epimeric
ratio 1:1) as an oil usable for the next steps without purifica-
tion: 1H NMR δ 5.46 and 5.43 (two br d, NH), 4.1-3.7 (m,
H-2′, H2-3′), 3.2-2.9 (m, H2-1′,2,3), 1.45 (s, CMe3); 13C NMR δ
155.7 (NHCO), 117.2 (C-1), 80.5 (CMe3), 63.9 and 63.5 (C-3′),
56.1 and 53.7 (C-1′), 49.1 and 48.9 (C-2′), 46.9 and 46.2 (C-3),
28.2 (CMe3), 11.0 (C-2); MS m/z (%) 277 (M + 1, 15), 221 (49),
177 (42), 95 (38), 81 (44), 69 (61), 57 (100). Anal. Calcd for
C11H20N2O4S: C 47.81, H 7.29, N 10.14. Found: C 47.42, H
7.14, N 9.95.
Thermolysis of Sulfoxides 3, 8, and 13 in the Presence
of 2-Methyl-1-buten-3-yne. General Procedure. A solution
of the sulfoxides (0.72 mmol) and 2-methyl-1-buten-3-yne (1
mL, 10.4 mmol) in toluene (110 °C, 15 mL) or CH2Cl2 (40 °C,
15 mL) was maintained at reflux temperature. When the
reaction appeared complete by TLC (disappearance of starting
sulfoxides), the solvent was removed under reduced pressure.
Thermolysis of (R)-3-(2-tert-Butoxycarbonylamino-2-
methoxycarbonyl-ethylsulfinyl)propionitriles 3 in the
Presence of 2-Methyl-1-buten-3-yne. The reaction occurred
in toluene and afforded in 1 h methyl 2-(tert-butoxycarbonyl)-
aminoacrylate (5) as unique isolated product.8
raphy (petrol/EtOAc 60:40): MS m/z (%) 260 (M + 1, 43), 144
(86), 95 (29), 69 (69), 55 (100), 41 (90). First eluted was (R,RS)-
2-(2-acetylamino-2-methoxycarbonyl-ethylsulfinyl)-3-methyl-
buta-1,3-diene (10b) as an oil: [R]25 + 46.5 (c 3.06, CHCl3);
D
1H NMR δ 6.80 (br d, J1′A,2′ ) J2′,NH 5.7, NH), 6.01 (s, HA-1, cis
to SO), 5.87 (s, HB-1, trans to SO), 5.17 (br s, HA-4, trans to
3-Me), 5.05 (s, HB-4, cis to 3-Me), 4.90 (dt, J1′B,2′ 5.5, H-2′), 3.79
(s, OMe), 3.65 (AB dd, J1′A,1′B 13.7, HA-1′), 3.01 (AB dd, HB-1′),
2.09 (s, MeCO), 2.01 (d, J4A,Me 0.5, 3-Me); 13C NMR δ 170.3
and 170.2 (CO2Me, NHCO), 151.7 (C-3), 137.2 (C-2), 115.7 and
115.3 (C-1,4), 55.0 (C-1′), 52.8 (C-2′), 49.2 (OMe), 22.8 (MeCO),
21.7 (3-Me). Calcd for C11H17NO4S: C 50.95, H 6.61, N 5.40.
Found: C 50.76, H 6.61, N 5.41. Then (R,SS)-2-(2-acetylamino-
2-methoxycarbonyl-ethylsulfinyl)-3-methyl-buta-1,3-diene (11b)
was eluted as an oil: 1H NMR δ 7.04 (br d, J2′,NH 7.3, NH),
6.03 (s, HA-1, cis to SO), 5.91 (s, HB-1, trans to SO), 5.19 (br s,
HA-4, trans to 3-Me), 5.06 (s, HB-4, cis to 3-Me), 4.97 (ddd, J1′A,2′
6.9, J1′B,2′ 3.9, H-2′), 3.80 (s, OMe), 3.57 (AB dd, J1′A,1′B 13.6,
HA-1′), 2.90 (AB dd, HB-1′), 2.05 (s, MeCO), 2.02 (br s, 3-Me);
13C NMR δ 170.3 and 170.2 (CO2Me, NHCO), 151.7 (C-3), 137.3
(C-2), 115.9 and 115.4 (C-1,4), 54.0 (C-1′), 52.8 (C-2′), 49.8
(OMe), 22.9 (MeCO), 21.8 (3-Me). Anal. Calcd for C11H17-
NO4S: C 50.95, H 6.61, N 5.40. Found: C 50.60, H 6.87, N
5.48.
Thermolysis of (R)-3-(2-tert-Butoxycarbonylamino-3-
hydroxy-propylsulfinyl)propionitriles 13 in the Pres-
ence of 2-Methyl-1-buten-3-yne. The reaction, performed in
toluene, was complete after 2.5 h. The crude mixture of
sulfoxides 16 and 17 (70% yield, sulfur epimeric ratio 1:1) was
purified by column chromatography (petrol/EtOAc 60:40). First
eluted was (R,RS)-2-(2-tert-butoxycarbonylamino-3-hydroxy-
propylsulfinyl)-3-methyl-buta-1,3-diene (16) as an oil: [R]24
D
+62.3 (c 0.82, CHCl3); 1H NMR δ 6.06 (s, HA-1, cis to SO), 5.90
(s, HB-1, trans to SO), 5.54 (br d, NH), 5.17 (m, J4,Me 0.9, HA-4,
trans to 3-Me), 5.07 (br s, HB-4, cis to 3-Me), 4.1-3.7 (m, H-2′,
H2-3′), 3.69 (AB dd, J1′A,1′B 13.8, J1′A,2′ 6.0, HA-1′), 2.63 (AB dd,
J1′B,2′ 2.7, HB-1′), 2.01 (m, 3-Me), 1.45 (s, CMe3); 13C NMR δ
155.3 (NHCO), 150.8 (C-3), 137.5 (C-2), 116.0 and 115.5 (C-
1,4), 79.9 (CMe3), 63.7 (C-3′), 58.6 (C-1′), 49.5 (C-2′), 28.3
(CMe3), 21.8 (3-Me). Anal. Calcd for C13H23NO4S: C 53.95,
H 8.01, N 4.84. Found: C 54.31, H 7.97, N 4.91. Then (R,SS)-
2-(2-tert-butoxycarbonylamino-3-hydroxy-propylsulfinyl)-3-
Thermolysis of (R)-2-[1-(2-tert-Butoxycarbonylamino-
2-methoxycarbonyl-ethylsulfinyl)-1-methyl-ethyl]malon-
ic Acids Diethyl Esters 8a in the Presence of 2-Methyl-
1-buten-3-yne. The reaction, performed in CH2Cl2, was
complete after 20 h. The crude mixture of sulfoxides 10a and
11a (60% yield, sulfur epimeric ratio 1:1) was purified by
column chromatography (petrol/EtOAc 80:20): MS m/z (%) 318
(M + 1, 22), 262 (88), 218 (59), 102 (70), 57 (100). First eluted
was (R,RS)-2-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-
methyl-buta-1,3-diene (17) was eluted as an oil: [R]26 -4.3
D
1
(c 0.89, CHCl3); H NMR δ 6.03 (s, HA-1, cis to SO), 5.88 (s,
HB-1, trans to SO), 5.53 (br d, NH), 5.18 (m, HA-4, trans to
3-Me), 5.12 (br s, HB-4, cis to 3-Me), 4.1-3.3 (m, HA-1′, H-2′,
H2-3′), 2.72 (AB dd, J1′A,1′B 13.7, J1′B,2′ 5.3, HB-1′), 2.02 (t, J4,Me
0.6, 3-Me), 1.44 (s, CMe3); 13C NMR δ 155.8 (NHCO), 151.6
(C-3), 137.5 (C-2), 115.7 and 115.4 (C-1,4), 80.1 (CMe3), 64.3
(C-3′), 55.5 (C-1′), 49.9 (C-2′), 28.3 (CMe3), 21.9 (3-Me). Anal.
Calcd for C13H23NO4S: C 53.95, H 8.01, N 4.84. Found: C
53.80, H 8.36, N 4.99.
Thermolysis of (R)-2-[1-(2-tert-Butoxycarbonylamino-
2-methoxycarbonyl-ethylsulfinyl)-1-methyl-ethyl]malon-
ic Acids Diethyl Esters 8a in the Presence of Alkynes
18. General Procedure. A solution of sulfoxides 8a (402 mg,
0.89 mmol) and alkynes 18 (13.3 mmol) in CH2Cl2 (10 mL)
was maintained at reflux temperature. After 20 h the reaction
appeared complete by TLC (disappearance of sulfoxides 8a),
and the solvent was removed under reduced pressure.
Thermolysis of 8a in the Presence of (Trimethylsilyl)-
acetylene (18c). The column chromatography of the crude
product mixture, eluted with hexane/EtOAc 80:20, afforded
sulfoxides 19c and 20c (65% yield, sulfur epimeric ratio 1:1).
First eluted was (R,E,SS)-trimethyl-[2-(2-tert-butoxycarbony-
lamino-2-methoxycarbonyl-ethylsulfinyl)vinyl]silane (20c), mp
134-135 °C: [R]22D +58.2 (c 3.80, CHCl3); 1H NMR δ 6.91 (AB
d, J1,2 17.7, H-2), 6.69 (AB d, H-1), 5.78 (br d, J2′,NH 7.7, NH),
4.63 (m, H-2′), 3.76 (s, OMe), 3.30 (AB dd, J1′A,1′B 13.3, J1′A,2′
7.6, HA-1′), 3.00 (AB dd, J1′B,2′ 3.9, HB-1′), 1.42 (s, CMe3), 0.14
(s, SiMe3); 13C NMR δ 170.8 (CO2Me), 155.2 (NHCO), 144.5
(C-1), 138.8 (C-2), 80.4 (CMe3), 54.3 (C-1′), 52.8 (C-2′), 50.1
ethylsulfinyl)-3-methyl-buta-1,3-diene (10a) as an oil: [R]26
D
+42.5 (c 0.46, CHCl3); 1H NMR δ 6.02 (s, HA-1, cis to SO), 5.86
(s, HB-1, trans to SO), 5.67 (br d, J2′,NH 6.1, NH), 5.15 (br s,
HA-4, trans to 3-Me), 5.08 (br s, HB-4, cis to 3-Me), 4.65 (br
ddd, H-2′), 3.79 (s, OMe), 3.63 (AB dd, J1′A,1′B 13.5, J1′A,2′ 5.6,
HA-1′), 2.97 (AB dd, J1′B,2′ 4.8, HB-1′), 2.01 (t, J4,Me 0.7, 3-Me),
1.45 (s, CMe3); 13C NMR δ 170.6 (CO2Me), 154.9 (NHCO), 151.8
(C-3), 137.5 (C-2), 115.8 and 115.1 (C-1,4), 80.4 (CMe3), 55.7
(C-1′), 52.8 (C-2′), 49.7 (OMe), 28.2 (CMe3), 21.8 (3-Me). Anal.
Calcd for C14H23NO5S: C 52.98, H 7.30, N 4.41. Found: C
52.62, H 7.43, N 4.30. Then (R,SS)-2-(2-tert-butoxycarbonyl-
amino-2-methoxycarbonyl-ethylsulfinyl)-3-methyl-buta-1,3-diene
(11a) was eluted as an oil: [R]26 -15.5 (c 0.20, CHCl3); 1H
D
NMR δ 6.06 (s, HA-1, cis to SO), 5.89 (s, HB-1, trans to SO),
5.74 (br d, NH), 5.16 (br s, HA-4, trans to 3-Me), 5.07 (br s,
HB-4, cis to 3-Me), 4.67 (br ddd, H-2′), 3.79 (s, OMe), 3.56 (br
AB dd, J1′A,1′B 13.5, J1′A,2′ 7.4, HA-1′), 2.90 (AB dd, J1′B,2′ 3.7,
HB-1′), 2.01 (br s, 3-Me), 1.45 (s, CMe3); 13C NMR δ 170.7 (CO2-
Me), 155.2 (NHCO), 151.9 (C-3), 137.4 (C-2), 115.7 and 115.1
(C-1,4), 80.3 (CMe3), 55.2 (C-1′), 52.7 (C-2′), 50.5 (OMe), 28.1
(CMe3), 21.7 (3-Me). Anal. Calcd for C14H23NO5S: C 52.98, H
7.30, N 4.41. Found: C 52.79, H 7.16, N 4.07.
Thermolysis of (R)-2-[1-(2-Acetylamino-2-methoxycar-
bonyl-ethylsulfinyl)-1-methyl-ethyl]malonic Acids Di-
ethyl Esters 8b in the Presence of 2-Methyl-1-buten-3-
yne. The reaction, performed in CH2Cl2, was complete after
20 h. The crude mixture of sulfoxides 10b and 11b (67% yield,
sulfur epimeric ratio 1:1) was purified by column chromatog-
J. Org. Chem, Vol. 70, No. 6, 2005 1991

Aversa et al.
(OMe), 28.2 (CMe3), -1.7 (SiMe3); MS m/z (%) 350 (M + 1, 23),
294 (78), 250 (46), 77 (76), 73 (61), 57 (100). Anal. Calcd for
C14H27NO5SSi: C 48.11, H 7.79, N 4.01. Found: C 47.76, H
8.04, N 3.74. Then (R,E,RS)-trimethyl-[2-(2-tert-butoxycarbonyl-
amino-2-methoxycarbonyl-ethylsulfinyl)vinyl]silane (19c) was
eluted as an oil: 1H NMR δ 6.92 (AB d, J1,2 17.8, H-2), 6.75
(AB d, H-1), 5.62 (br d, J2′,NH 6.6, NH), 4.67 (m, H-2′), 3.80 (s,
OMe), 3.37 (AB dd, J1′A,1′B 13.5, J1′A,2′ 5.1, HA-1′), 3.09 (AB dd,
J1′B,2′ 5.9, HB-1′), 1.46 (s, CMe3), 0.17 (s, SiMe3); 13C NMR δ
170.4 (CO2Me), 155.0 (NHCO), 144.6 (C-1), 138.9 (C-2), 80.5
(CMe3), 55.2 (C-1′), 52.9 (C-2′), 49.7 (OMe), 28.2 (CMe3), -1.7
(SiMe3); MS m/z (%) 350 (M + 1, 14), 294 (49), 250 (43), 77
(66), 73 (81), 57 (100). Anal. Calcd for C14H27NO5SSi: C 48.11,
H 7.79, N 4.01. Found: C 47.72, H 7.63, N 3.92.
Thermolysis of 8a in the Presence of 1-(Trimethyl-
silyl)-1-propyne (18d). The column chromatography of the
crude product mixture, eluted with hexane/EtOAc 80:20,
afforded sulfoxides 19d and 20d (60% yield, sulfur epimeric
ratio 1:1): MS m/z (%) 364 (M + 1, 23), 308 (53), 264 (14), 250
(18), 178 (64), 146 (9), 113 (23), 73 (100), 57 (33). First eluted
as an oil was (R,E,SS)-trimethyl-[2-(2-tert-butoxycarbonylamino-
2-methoxycarbonyl-ethylsulfinyl)prop-1-enyl]silane (20d): 1H
NMR δ 6.49 (br s, H-1), 5.80 (br d, J2′,NH 7.7, NH), 4.63 (m,
H-2′), 3.79 (s, OMe), 3.32 (AB dd, J1′A,1′B 13.3, J1′A,2′ 8.0, HA-
1′), 2.88 (AB dd, J1′B,2′ 3.7, HB-1′), 1.99 (d, J1,3 1.0, H3-3), 1.45
(s, CMe3), 0.21 (s, SiMe3); 13C NMR δ 170.9 (CO2Me), 155.3
(NHCO), 152.3 (C-2), 130.5 (C-1), 80.3 (CMe3), 52.7 (C-2′), 52.4
(C-1′), 50.3 (OMe), 28.2 (CMe3), 14.4 (C-3), - 0.6 (SiMe3). Anal.
Calcd for C15H29NO5SSi: C 49.56, H 8.04, N 3.85. Found: C
49.60, H 7.99, N 3.87. Then (R,E,RS)-trimethyl-[2-(2-tert-
butoxycarbonylamino-2-methoxycarbonyl-ethylsulfinyl)prop-1-
enyl]silane (19d) was eluted as an oil: 1H NMR δ 6.45 (br s,
H-1), 5.60 (br d, J2′,NH 6.4, NH), 4.61 (m, H-2′), 3.79 (s, OMe),
3.40 (AB dd, J1′A,1′B 13.3, J1′A,2′ 4.8, HA-1′), 2.97 (AB dd, J1′B,2′
5.4, HB-1′), 1.98 (d, J1,3 1.0, H3-3), 1.45 (s, CMe3), 0.21 (s,
SiMe3); 13C NMR δ 170.6 (CO2Me), 155.1 (NHCO), 152.7 (C-
2), 130.9 (C-1), 80.5 (CMe3), 53.0 (C-1′), 52.9 (C-2′), 49.7 (OMe),
28.2 (CMe3), 14.1 (C-3), -0.6 (SiMe3). Anal. Calcd for C15H29-
NO5SSi: C 49.56, H 8.04, N 3.85. Found: C 49.58, H 8.06, N
3.84.
Thermolysis of 8a in the Presence of 3-(Trimethyl-
silyl)-1-propyne (18e). The column chromatography of the
crude product mixture, eluted with hexane/EtOAc 80:20,
afforded sulfoxides 19e and 20e (60% yield, sulfur epimeric
ratio 1:1). First eluted was (R,RS)-trimethyl-[2-(2-tert-butoxy-
carbonylamino-2-methoxycarbonyl-ethylsulfinyl)prop-2-enyl]-
silane (19e) as an oil: 1H NMR δ 5.73 (s, HA-3, cis to SO),
5.70 (br d, J1′A,2′ ) J1′B,2′ ) J2′,NH 5.5, NH), 5.46 (br s, HB-3,
trans to SO), 4.63 (q, H-2′), 3.79 (s, OMe), 3.45 (AB dd, J1′A,1′B
13.4, HA-1′), 3.02 (AB dd, HB-1′), 1.88 (AB d, J1A,1B 14.9, HA-
1), 1.45 (s, CMe3), 1.39 (AB dd, J1B,3B 0.9, HB-1), 0.09 (s, SiMe3);
13C NMR δ 170.6 (CO2Me), 155.1 (NHCO), 150.3 (C-2), 113.8
(C-3), 80.4 (CMe3), 53.6 (C-1′), 52.8 (C-2′), 49.9 (OMe), 28.2
(CMe3), 18.4 (C-1), -1.5 (SiMe3); MS m/z (%) 364 (M + 1, 46),
308 (96), 264 (46), 178 (20), 73 (100), 57 (40). Anal. Calcd for
C15H29NO5SSi: C 49.56, H 8.04, N 3.85. Found: C 49.62, H
8.23, N 4.04. Then (R,SS)-trimethyl-[2-(2-tert-butoxycarbonyl-
amino-2-methoxycarbonyl-ethylsulfinyl)prop-2-enyl]silane (20e)-
was eluted as an oil: 1H NMR δ 5.79 (br d, NH), 5.76 (s, HA-3,
cis to SO), 5.48 (br s, HB-3, trans to SO), 4.63 (m, H-2′), 3.80
(s, OMe), 3.38 (AB dd, J1′A,1′B 13.4, J1′A,2′ 7.8, HA-1′), 2.97 (AB
dd, J1′B,2′ 3.6, HB-1′), 1.90 (AB d, J1A,1B 14.6, HA-1), 1.46 (s,
CMe3), 1.39 (AB d, HB-1), 0.09 (s, SiMe3); 13C NMR δ 170.8
(CO2Me), 155.3 (NHCO), 150.2 (C-2), 113.6 (C-3), 80.3 (CMe3),
53.2 (C-1′), 52.7 (C-2′), 50.5 (OMe), 28.2 (CMe3), 18.5 (C-1), -1.5
(SiMe3); MS m/z (%) 364 (M + 1, 41), 436 (12), 308 (100), 264
(55), 178 (25), 73 (93), 57 (32). Anal. Calcd for C15H29NO5SSi:
C 49.56, H 8.04, N 3.85. Found: C 49.68, H 8.20, N 3.65.
Protodesilylation of Sulfoxides 19e, 20e and 20c.
General Procedure. A freshly prepared 1 M solution of
TBAF‚3H2O in THF (3 mL, 3.0 mmol) was added to a solution
of sulfoxide 19e, 20e, or 20c (1.0 mmol) and CuI (286 mg, 1.5
mmol) in THF (7 mL).14 The reaction appeared complete after
5 min for sulfoxides 19e or 20e, whereas in the case of 20c
the reaction was stopped after 24 h despite being unfinished.
The crude mixture was filtered through SiO2, and the solid
residue was washed with CH2Cl2 (20 mL). The solvent was
evaporated under reduced pressure.
(R,RS)-2-(2-tert-Butoxycarbonylamino-2-methoxycar-
bonyl-ethylsulfinyl)propene (21). The oily residue obtained
from 19e was purified by column chromatography eluting with
petrol/EtOAc 60:40 to give compound 21 as an oil (85% yield):
1H NMR δ 5.82 (br s, HA-1, cis to SO), 5.68 (br d, J1′A,2′ ) J1′B,2′
) J2′,NH 5.5, NH), 5.65 (br s, HB-1, trans to SO), 4.64 (q, H-2′),
3.79 (s, OMe), 3.39 (AB dd, J1′A,1′B 13.4, HA-1′), 3.12 (AB dd,
HB-1′), 1.99 (dd, J1,3 1.5 and 1.0, H3-3), 1.45 (s, CMe3); 13C NMR
δ 170.5 (CO2Me), 155.1 (NHCO), 147.8 (C-2), 118.5 (C-1), 80.5
(CMe3), 52.8 (C-2′), 52.7 (C-1′), 49.7 (OMe), 28.2 (CMe3), 14.0
(C-3). Anal. Calcd for C12H21NO5S: C 49.47, H 7.26, N 4.81.
Found: C 49.35, H 7.38, N 4.80.
(R,SS)-2-(2-tert-Butoxycarbonylamino-2-methoxycar-
bonyl-ethylsulfinyl)propene (23). The oily residue obtained
from 20e was purified by column chromatography eluting with
petrol/EtOAc 60:40 to give compound 23 as an oil (87% yield):
1H NMR δ 5.82 (br s, HA-1, cis to SO), 5.80 (br d, NH), 5.65
(br s, HB-1, trans to SO), 4.65 (dt, J1′A,2′ ) J2′,NH 7.8, H-2′), 3.79
(s, OMe), 3.29 (AB dd, J1′A,1′B 13.4, HA-1′), 3.07 (AB dd, J1′B,2′
3.9, HB-1′), 1.99 (dd, J1,3 1.5 and 1.0, H3-3), 1.44 (s, CMe3); 13
C
NMR δ 170.8 (CO2Me), 155.2 (NHCO), 147.8 (C-2), 118.1 (C-
1), 80.3 (CMe3), 52.8 (C-2′), 52.3 (C-1′), 50.2 (OMe), 28.2 (CMe3),
14.2 (C-3). Anal. Calcd for C12H21NO5S: C 49.47, H 7.26, N
4.81. Found: C 49.43, H 7.35, N 4.44.
(R,SS)-(2-tert-Butoxycarbonylamino-2-methoxycarbo-
nyl-ethylsulfinyl)ethene (22). The oily residue obtained
from 20c was purified by column chromatography. Elution
with hexane/EtOAc 70:30 gave as first eluted the amino ester
5 (15% yield), followed by unreacted sulfoxide 20c (50% yield).
Finally, elution with hexane/EtOAc 50:50 led to the isolation
of compound 22 (30% yield) as an oil: 1H NMR δ 6.68 (dd,
J1,2A 16.5, J1,2B 9.8, H-1), 6.16 (d, HA-2, cis to SO), 6.02 (d, HB-
2, trans to SO), 5.69 (br d, J1′A,2′ ) J2′,NH 7.4, NH), 4.68 (dt,
J1′B,2′ 4.1, H-2′), 3.80 (s, OMe), 3.32 (AB dd, J1′A,1′B 13.4, HA-
1′), 3.13 (AB dd, HB-1′), 1.45 (s, CMe3); 13C NMR δ 170.7 (CO2-
Me), 155.2 (NHCO), 140.4 (C-1), 122.6 (C-2), 80.6 (CMe3), 54.6
(C-1′), 52.9 (C-2′), 50.1 (OMe), 28.2 (CMe3). Anal. Calcd for
C11H19NO5S: C 47.64, H 6.91, N 5.05. Found: C 47.72, H 6.82,
N 5.05.
Acknowledgment. This work was carried out under
the auspices of the national project “Stereoselezione in
sintesi organica, metodologie ed applicazioni” supported
by MIUR (Ministero dell’Istruzione, dell’Universita` e
della Ricerca) Rome, Italy. Financial support from the
University of Messina is also acknowledged. We thank
dr. Cristina Faggi, Centro Interdipartimentale di Cri-
stallografia (CRIST), Universita` di Firenze, Italy for the
X-ray crystallographic analysis of compound 20c.
Supporting Information Available: X-ray crystallo-
graphic data of 20c (details of data collection, structure
refinement, crystal and unit-cell parameters, ORTEP view,
tables of atomic coordinates and thermal parameters, bond
lengths, bond angles, torsion angles, anisotropic displacement
parameters) in PDF and CIF files (CCDC deposition number
245984). This material is available free of charge via the
Internet at http://pubs.acs.org.
JO048662K
1992 J. Org. Chem., Vol. 70, No. 6, 2005