SN2-type nucleophilic opening of β-thiolactones (thietan-2-ones) as a source of thioacids for coupling reactions

Article abstract of DOI:10.1021/jo9001728

β-Thiolactones monosubstituted in the 3-position by alkyl and carbamoyl groups undergo nucleophilic ring opening by arenethiolates through a process involving an S_N2-type attack at the 4-position leading to 3-arylthiopropionates substituted in the 2-position. These thiocarboxylates can be trapped in situ by Mukaiyama's reagent or Sanger's reagent through a nucleophilic aromatic substitution process leading to highly activated thioesters that are then allowed to react further with primary or secondary amines leading, overall, to one-pot, three-component syntheses of 3-arylthiopropionamides carrying various substituents in the 2-position. Alternatively, the trapping combination of an electron deficient aryl halide and an amine may be replaced by a 2,4-dinitrobenzenesulfonamide, resulting in the formation of the same products overall with the incorporation of the latent amine in the sulfonamide into the final amide product. In another embodiment, the thiocarboxylate intermediate is allowed to react with a sulfonyl azide, resulting overall in N-arenesulfonyl 3-arylthiopropionamide derivatives.

Full text of DOI:10.1021/jo9001728

SN2-Type Nucleophilic Opening of ꢀ-Thiolactones (Thietan-2-ones)
as a Source of Thioacids for Coupling Reactions
David Crich*,†,‡ and Kasinath Sana†
Department of Chemistry, Wayne State UniVersity, 5101 Cass AVenue, Detroit, Michigan 48202, and
Centre de Recherche CNRS de Gif-sur-YVette, Institut de Chimie des Substances Naturelles, AVenue de la
Terrasse, 91198 Gif-sur-YVette, France
dcrich@icsn.cnrs-gif.fr
ReceiVed January 26, 2009
ꢀ-Thiolactones monosubstituted in the 3-position by alkyl and carbamoyl groups undergo nucleophilic
ring opening by arenethiolates through a process involving an SN2-type attack at the 4-position leading
to 3-arylthiopropionates substituted in the 2-position. These thiocarboxylates can be trapped in situ by
Mukaiyama’s reagent or Sanger’s reagent through a nucleophilic aromatic substitution process leading
to highly activated thioesters that are then allowed to react further with primary or secondary amines
leading, overall, to one-pot, three-component syntheses of 3-arylthiopropionamides carrying various
substituents in the 2-position. Alternatively, the trapping combination of an electron deficient aryl halide
and an amine may be replaced by a 2,4-dinitrobenzenesulfonamide, resulting in the formation of the
same products overall with the incorporation of the latent amine in the sulfonamide into the final amide
product. In another embodiment, the thiocarboxylate intermediate is allowed to react with a sulfonyl
azide, resulting overall in N-arenesulfonyl 3-arylthiopropionamide derivatives.
SCHEME 1. Differing Modes of Reactivity for
ꢀ-Thiolactones and ꢀ-Lactones toward Benzylamine
Introduction
Unlike the widely appreciated ꢀ-lactones,1 the ꢀ-thiolactones
(thietan-2-ones) have seen little use in synthesis. We speculated
that one of the lesser employed facets of ꢀ-lactone chemistry,
ring opening by an SN2-type attack at the 4-position by soft
nucleophiles,2 might be extended to the ꢀ-thiolactones when it
would provide a novel entry to thioacids, a functional group
whose chemistry is of current interest.3 Although the reactivity
of ꢀ-thiolactones has been relatively little explored, it was known
that one of the simplest, 3-methylthietan-2-one (1), on reaction
with benzylamine undergoes apparent exclusive ring opening
by an attack at the carbonyl position.4 In contrast, the close
all-oxygen analogue, 4-methyloxetan-2-one (2), displays both
modes of reactivity despite the more highly substituted nature
of its 4-position (Scheme 1).5
† Wayne State University.
‡ Institut de Chimie des Substances Naturelles.
(1) (a) Pommier, A.; Pons, J.-M. Synthesis 1993, 441–459. (b) Pommier,
A.; Pons, J.-M. Synthesis 1995, 729–744. (c) Lowe, C.; Vederas, J. C. Org.
Prep. Proced. Int. 1995, 27, 305–346. (d) Wang, Y.; Tennyson, R. L.; Romo,
D. Heterocycles 2004, 64, 605–658. (e) Yang, H. W.; Romo, D. Tetrahedron
1999, 55, 6403–6434.
(2) (a) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc.
1985, 7105–7109. (b) Arnold, L. D.; Drover, J. C. G.; Vederas, J. C. J. Am.
Chem. Soc. 1987, 109, 4649–4659. (c) Ratemi, E. S.; Vederas, J. C. Tetrahedron
Lett. 1994, 35, 7605–7608.
In spite of this observation, we reasoned that softer nucleo-
philes than amines, to wit, thiols, might still allow us to access
the SN2-ring opening mode of the ꢀ-thiolactones. As we describe
herein, this supposition has been reduced to practice and
provides a novel entry to thioacids and three-component
coupling sequences.
10.1021/jo9001728 CCC: $40.75
Published on Web 03/27/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3389–3393 3389

Crich and Sana
SCHEME 4. Synthesis of an Amino Acid Synthon
Results and Discussion
Substrate Preparation. Simple ꢀ-thiolactones were readily
accessed by conjugate addition of thioacetic acid to acrylic acid
derivatives branched at the 2-position, followed by acidolysis
and then ring closure with isobutyl chloroformate (Scheme 2).4
The moderate yield reported for the parent substance is mainly
due to the volatility of this substance.
observed in the formation of 16 as determined with the aid of
chiral shift reagents.
With these ꢀ-thiolactones in hand, we investigated a reaction
sequence involving reaction with an aromatic thiolate followed
by trapping of the intended thiocarboxylate by nucleophilic
aromatic substitution with Mukaiyama’s reagent (2-chloro-N-
methylpyridinium iodide)7 to give a highly active thioester
(17).3l The thioester was then subjected to reaction with an
amine, resulting overall in a one-pot, three-component coupling
process (Scheme 5). A directly analogous protocol employed
Sanger’s reagent (2,4-dinitrofluorobenzene)8 in the place of
Mukaiyama’s reagent and involved the alternative intermediate
thioester 18 (Scheme 5).3l In a third series of experiments the
thiocarboxylate intermediate was intercepted by a set of 2,4-
dinitrobenzenesulfonamides in a process that involves nucleo-
philic aromatic substitution leading to the formation of active
ester 18 and concomitant liberation of the latent amine in the
sulfonamide for the final amide bond forming step.3h,i,k A final
protocol relied on trapping of the intermediate thiocarboxylate
with a sulfonyl azide,3a-e again resulting in the formation of
the amide bond.
SCHEME 2. Preparation of Simple ꢀ-Thiolactones
A spirocyclic version, 2-thiaspiro[3.5]nonan-1-one (14), was
prepared from methyl 1-(acetylthiomethyl)cyclohexanecarboxylate
(13), which was obtained from methyl cyclohexanecarboxylate
(11) by the literature procedure (Scheme 3).6
SCHEME 5. Three-Component Coupling Processes
SCHEME 3. Synthesis of 2-Thiaspiro[3.5]nonan-1-one
The carbamoyl derivative 16 was prepared from N-Boc-L-
cysteine by cyclization with isobutyl chloroformate in the usual
manner (Scheme 4). No loss of stereochemical integrity was
With a series of aromatic thiols as nucleophiles in the
presence of cesium carbonate as a base, the reaction followed
the anticipated course, resulting, after addition of Mukaiyama’s
reagent or Sanger’s reagent and an amine, in the formation of
a range of 3-arylthiocarboxamides (Table 1).
As is clear from Table 1, entries 1-11, the general protocol
of a reaction of an aromatic cesium thiolate with ꢀ-thiolactone
itself or with analogues monosubstituted in the 3-position
followed by capture by an electron-deficient arene and ultimate
introduction of an amine follows the anticipated route. This
sequence of reactions enables the one-pot formation of both
secondary and tertiary 3-arylmercaptocarboxamides in a straight-
forward manner and proceeds effectively with either Mukaiya-
ma’s or Sanger’s reagent as the electron-deficient arene.
The examples employing the cysteine derived ꢀ-thiolactone
16 (Table 1, entries 12-17) are particularly interesting. The
(3) (a) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J. J. Am.
Chem. Soc. 2003, 125, 7754–7755. (b) Merkx, R.; Brouwer, A. J.; Rijkers,
D. T. S.; Liskamp, R. M. J. Org. Lett. 2005, 7, 1125–1128. (c) Barlett, K. N.;
Kolakowski, R. V.; Katukojvala, S.; Williams, L. J. Org. Lett. 2006, 8, 823–
826. (d) Kolakowski, R. V.; Shangguan, N.; Sauers, R. R.; Williams, L. J. J. Am.
Chem. Soc. 2006, 128, 5695–5702. (e) Merkx, R.; Van Haren, M. J.; Rijkers,
D. T. S.; Liskamp, R. M. J. J. Org. Chem. 2007, 72, 4574–4577. (f) Gulevich,
A. V.; Balenkova, E. S.; Nenajdenko, V. G. J. Org. Chem. 2007, 72, 7878–
7885. (g) Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. H. Science
1994, 266, 776–779. (h) Messeri, T.; Sternbach, D. D.; Tomkinson, N. C. O.
Tetrahedron Lett. 1998, 39, 1673–1676. (i) Messeri, T.; Sternbach, D. D.;
Tomkinson, N. C. O. Tetrahedron Lett. 1998, 39, 1669–1672. (j) Crich, D.;
Bowers, A. A. Org. Lett. 2007, 9, 5323–5325. (k) Crich, D.; Sana, K.; Guo, S.
Org. Lett. 2007, 9, 4423–4426. (l) Crich, D.; Sharma, I. Angew. Chem., Int. Ed.
2009, 48, 2355–2358.
(4) Lee, H. B.; Park, H.-Y.; Lee, B.-S.; Kim, Y. G. Magn. Reson. Chem.
2000, 38, 468–471.
(5) (a) Griesbeck, A.; Seebach, D. HelV. Chim. Acta 1987, 70, 1326–1332.
(b) Seebach, D.; Estermann, H. Tetrahedron Lett. 1987, 28, 3103–3106.
(6) Hannah, D. R.; Dyke, H. J.; Sharpe, A.; Baxter, A. D. PCT Int. Appl.
851145, 2001.
(7) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163–1166.
(8) (a) Sanger, F. Biochem. J. 1945, 39, 507–515. (b) Eisen, H. N.; Belman,
S.; Carsten, M. E. J. Am. Chem. Soc. 1953, 75, 4583–4585.
3390 J. Org. Chem. Vol. 74, No. 9, 2009

SN2-Type Nucleophilic Opening of ꢀ-Thiolactones
TABLE 1. ꢀ-Thiolactone-Based, Three-Component Coupling Process
a Ar ) 2,4-dinitrophenyl.
products are obtained in highly enantiomerically enriched form,
thereby distinguishing the chemistry presented here from the
more classical point of entry to such derivatives involving
conjugate addition to dehydroalanine derivatives followed by
standard amide bond forming protocols.9 An especially note-
worthy example is that involving the cysteine ꢀ-thiolactone 16
with capture by the dinitrobenzenesulfonamide of the methyl
L-phenylalaninate that couples the nucleophilic ring opening of
the thiolactone with a peptide bond forming step (Table 1, entry
16). In the case of the spirocyclic ꢀ-thiolactone 14 (Table 1,
entry 18) the highly sterically hindered neopentyl-like nature
of the 4-position effectively prevents the SN2 mode of ring
opening, paving the way for the ultimate attack of the amine
on the carbonyl carbon with subsequent ring opening. The
thiolate generated in the course of this process is then captured
by the intended coupling reagent, Sanger’s reagent, to afford a
product differing only by the subsitutents on the arylthio moiety
from the one intended, albeit by a completely different route.
The attempted use of alkanethiols and/or thiolates as nucleo-
philes in this chemistry was unproductive under a variety of
conditions and resulted only in the formation of complex
reaction mixtures.
Finally, we investigated briefly the possibility of replacing
the thiolate nucleophile by an amine (Table 1, entry 19) but
were unable to divert the chemistry away from an attack at the
ꢀ-thiolactone carbonyl carbon as had been described previously
in the literature for this class of nucleophile (Scheme 1).
We suggest that the differing reactivity between the ꢀ-thi-
olactones and their all-oxygen counterparts, apparent from the
literature (Scheme 1) and highlighted by the contrast among
entries 1-17, 18, and 19 of Table 1, is likely due to the much-
reduced resonance of the ring heteroatom with the carbonyl
group in the case of the thiolactones. The reduced resonance
may be attributed to the weakness of the carbon-sulfur double
(9) For example, see: (a) Zhu, Y.; van der Donk, W. A. Org. Lett. 2001, 3,
1189–1192. (b) Bernardes, G. J. L.; Chalker, J. M.; Errey, J. C.; Davis, B. G.
J. Am. Chem. Soc. 2008, 130, 5052–5053.
J. Org. Chem. Vol. 74, No. 9, 2009 3391

Crich and Sana
SCHEME 6. Reduced Resonance Delocalization in the
Thiolactones
the solvent followed by column chromatography provided the
products as described below.
General Procedure (B) for Multicomponent Coupling
Reactions Using 3-Methylthietan-2-one (1), Thietan-2-one (9),
3-Benzylthietan-2-one (10), and Sanger’s Reagent. To a stirred
solution of 3-substituted-thietan-2-one (1, 9, or 10; 1.0 equiv) in
DMF (0.15-0.2 M) were added thiol (1.5 equiv) and Cs2CO3 (1.0
equiv) at room temperature. The reaction mixture was allowed to
stir for 2 h, after which time the reaction mixture had turned a
faint yellow color. Then 1-fluoro-2,4-dinitrobenzene (1.5 equiv) was
added, followed immediately by 0.9 equiv of amine. Upon addition
of the 2,4-dinitrofluorobenzene and amine, the reaction mixture
turned dark red in color and further deepened in color as the reaction
continued. The reaction mixture was allowed to stir for 2 h, after
which the DMF was removed under high vacuum, and the crude
mixture was dissolved in EtOAc, washed with water and brine,
and dried. Evaporation of solvent followed by column chromatog-
raphy provided the coupled products as described below.
N-Phenethyl-3-(phenylthio)propanamide (19): Following the
general procedure A, using thietan-2-one and eluting with 30% ethyl
acetate in hexane, 19 was obtained in 66% yield. White solid,
crystallized from chloroform/hexane, mp: 74.5-75.0 °C. 1H NMR
(300 MHz) δ: 7.34-7.16 (m, 10H), 5.63 (s, 1H), 3.54-3.48 (q, J
) 6.6 Hz, 2H), 3.21-3.16 (t, J ) 7.5 Hz, 2H), 2.83-2.78 (t, J )
6.6, 2H), 2.43-2.39 (t, J ) 7.5 Hz, 2H). 13C NMR (75 MHz) δ:
171.0, 139.0, 135.6, 129.8, 129.3, 129.0, 128.9, 126.8, 126.6, 40.9,
36.4, 35.8, 29.6. ESI-HRMS: calcd for C17H19NOS [M + Na]+,
308.1085; found, 308.1078.
bond10 and has the effect of making the 4-position softer and
less reactive toward hard nucleophiles (Scheme 6).
Experimental Section
2-Thiaspiro[3.5]nonan-1-one (14): Methyl 1-acetylsulfanylm-
ethylcyclohexane carboxylate6 (3.92 g, 17 mmol) was dissolved in
22 mL of Claisen’s alkali (6.25 mol/L KOH in a mixture of CH3OH
and H2O (v/v: 3/1)), heated to reflux for 3 h, and then cooled to 0
°C. The reaction mixture was acidified with 1 N HCl to pH ) 1,
and dichloromethane was added; the organic layer was extracted,
washed with water and brine, and dried. Evaporation of the solvent
afforded crude 1-(mercaptomethyl)cyclohexane carboxylic acid,
which was taken forward for cyclization without purification.
To a stirred solution of the crude 1-(mercaptomethyl)cyclohexane
carboxylic acid (2.8 g, 16.1 mmol) and triethylamine (2.6 mL, 17.6
mmol) in dichloromethane (70 mL) at -10 °C was added dropwise
iso-butyl chloroformate (2.4 mL, 17.6 mmol). After the addition
was complete, the reaction mixture was allowed to come to 0 °C
over a period of 45 min. The resulting mixture was neutralized at
0 °C, with 1 N HCl at pH ∼ 4, and the organic layer was extracted,
dried, and concentrated. Chromatographic purification using 2%
ethyl acetate in hexane afforded 14 (1.08 g, 43%). Colorless liquid.
3-(4-Chlorophenylthio)-2-methyl-N-phenethylpropanamide (24):
Following general procedure B, using 3-methylthietan-2-one and
eluting with 25% ethyl acetate in hexane, 24 was obtained in 67%
yield. White solid, crystallized from chloroform/hexane, mp:
1
93.0-94.0 °C. H NMR (500 MHz) δ: 7.33-7.30 (t, J ) 7.5 Hz,
2H), 7.27-7.19 (m, 7H), 5.47 (s, 1H), 3.58-3.48 (m, 2H),
3.23-3.18 (dd, J ) 8.0, 13.5 Hz, 1H), 2.92-2.88 (dd, J ) 6.5,
13.5 Hz, 1H), 2.84-2.81 (t, J ) 6.5 Hz, 2H), 2.33-2.26 (m, 1H),
1.22-1.20 (d, J ) 7.0 Hz, 3H). 13C NMR (125 MHz) δ: 174.4,
139.0, 134.8, 132.4, 130.9, 129.4, 129.1, 128.9, 126.8, 41.5, 40.7,
37.8, 35.8, 17.9. ESI-HRMS: calcd for C18H20NOSCl [M + Na]+,
356.0852; found, 356.0859.
1
IR (CHCl3): 2931, 2854, 1771, 1745 cm-1. H NMR (500 MHz)
δ: 2.81 (s, 2H), 1.88-1.79 (m, 4H), 1.74-1.70 (m, 2H), 1.52-1.50
(m, 1H), 1.41-1.30 (m, 1H). 13C NMR (125 MHz) δ: 199.2, 77.1,
32.9, 29.5, 25.0, 22.2. EI-HRMS: calcd for C8H12OS [M]+,
156.0609; found, 156.0615.
(S)-O-(tert-Butyl) N-(Thietan-2-on-3-yl) Carbamate (16): Fol-
lowing the same procedure as for the preparation of 2-thiaspiro-
[3.5]nonan-1-one, using N-tert-butoxycarbonyl-L-cysteine as sub-
strate and eluting with 20% ethyl acetate in hexane, 16 was obtained
in 38% yield. White solid, crystallized from ethyl acetate/hexane,
mp: 140.5-141.5 °C. [R]22D -40.3 (c 1.2). IR (CHCl3): 3352, 2927,
1747, 1716, 1682 cm-1. 1H NMR (500 MHz) δ: 5.44 (s, 1H), 5.35
(bs, 1H), 3.44-3.41 (t, J ) 7.5 Hz, 1H), 3.34-3.31 (t, J ) 7.5
Hz), 1.46 (s, 9H). 13C NMR (125 MHz) δ: 193.7, 154.4, 81.4, 72.5,
28.4. ESI-HRMS: calcd for C8H13NO3S [M + Na]+, 226.0514;
found, 226.0502.
General Procedure (A) for Multicomponent Coupling
Reactions Using 3-Methylthietan-2-one (1), Thietan-2-one (9),
3-Benzylthietan-2-one (10), and Mukaiyama’s Reagent. To a
stirred solution of 3-substituted-thietan-2-one (1, 9, or 10; 1.0 equiv)
in DMF (0.15-0.2 M) were added aromatic thiol (1.5 equiv) and
Cs2CO3 (1.0 equiv) at room temperature. The reaction mixture was
allowed to stir for 2 h, after which time the reaction mixture had
turned a faint yellow color. Then 2-chloro-1-methylpyridinium
iodide (1.5 equiv) was added, followed immediately by 0.9 equiv
of amine. Upon addition of the 2-chloro-1-methylpyridinium iodide
and amine, the reaction mixture became a dark yellow color and
further deepened in color as the reaction continued. The reaction
mixture was allowed to stir for 5 h, after which the DMF was
removed under high vacuum, and the crude mixture was dissolved
in EtOAc, washed with water and brine, and dried. Evaporation of
General Procedure (C) for Multicomponent Coupling Reac-
tions Using (S)-O-(tert-Butyl) N-(Thietan-2-on-3-yl) Carbam-
ate (16): To a stirred solution of 16 (1.0 equiv) in DMF (0.15-0.2
M) were added aromatic thiol (1.2 equiv) and Cs2CO3 (1.0 equiv)
at room temperature. The reaction mixture was allowed to stir for
6 h, after which time the reaction mixture had turned a faint yellow
color. Then 2,4-dinitrobenbenzene sulfonamide (1.2 equiv) was
added to the reaction mixture. Upon addition of the sulfonamide
the reaction mixture became a dark red color and further deepened
in color as the reaction continued. The reaction mixture was allowed
to stir for 1 h, after which the DMF was removed under high
vacuum, and the crude mixture was dissolved in EtOAc, washed
with water and brine, and dried. Evaporation of solvent followed
by column chromatography provided the coupled products as
described below.
(R)-O-(tert-Butyl) N-(3-(4-Chlorophenylthio)-1-(phenethylami-
nocarbonyl)propan-2-yl) Carbamate (30): Following general pro-
cedure C, eluting with 30% ethyl acetate in hexane, 30 was obtained
in 70% yield. White solid, crystallized from ethyl acetate/hexane,
mp: 116.5-117.5 °C. [R]22D -6.0 (c 1.2). 1H NMR (500 MHz) δ:
7.32-7.22 (m, 7H), 7.19-7.17 (d, J ) 7.0 Hz, 2H), 6.25 (s, 1H),
5.25 (s, 1H), 4.20 (bs, 1H), 3.55-3.40 (m, 2H), 3.26-3.21 (m,
2H), 2.80-2.77 (t, J ) 7.0 Hz, 2H), 1.43 (s, 9H). 13C NMR (125
MHz) δ: 170.2, 155.5, 138.7, 133.5, 133.0, 131.4, 129.5, 129.0,
128.9, 126.9, 80.7, 54.1, 41.0, 36.5, 35.7, 28.5. ESI-HRMS: calcd
for C22H27N2O3SCl [M + Na]+, 457.1329; found, 457.1313.
Methyl N-tert-Butoxycarbonyl-(4-chlorophenylsulfanyl)-L-alani-
nyl-L-phenylalaninate (36): Following general procedure C, eluting
with 25% ethyl acetate in hexane, 36 was obtained in 62% yield.
(10) Hadad, C. M.; Rablen, P. R.; Wiberg, K. B. J. Org. Chem. 1998, 63,
8668–8681.
3392 J. Org. Chem. Vol. 74, No. 9, 2009

SN2-Type Nucleophilic Opening of ꢀ-Thiolactones
1
Colorless syrup. [R]22 +15.6 (c 1.1). H NMR (500 MHz) δ:
vacuum, and the crude mixture was purified by column chroma-
tography using 5% methanol in dichloromethane to give 38 (57
mg, 68%). White solid, crystallized from ethyl acetate/hexane, mp:
169.0-170.0 °C. [R]22D -13.1 (c 0.1, MeOH). 1H NMR (500 MHz,
MeOH-d4) δ: 7.92-7.90 (d, J ) 8.5 Hz, 2H), 7.74-7.73 (d, J )
8.0 Hz, 2H), 7.31-7.26 (m, 4H), 4.15 (bs, 1H), 3.23-3.19 (dd, J
) 5.5, 13.5 Hz, 1H), 3.09-3.05 (dd, J ) 7.5, 13.0 Hz, 1H), 2.16
(s, 3H), 1.39 (s, 9H). 13C NMR (125 MHz, MeOH-d4) δ: 170.9,
156.1, 143.7, 134.3, 133.9, 132.5, 132.0, 131.5, 129.2, 129.1, 129.0,
118.8, 79.8, 54.8, 35.5, 27.5, 22.9. ESI-HRMS: calcd for
C22H26N3O6S2Cl [M + Na]+, 550.0849; found, 550.0826.
D
7.33-7.25 (m, 7H), 7.10-7.08 (d, J ) 7.0 Hz, 2H), 6.67-6.65 (d,
J ) 7.5 Hz, 1H), 5.18 (s, 1H), 4.79-4.76 (q, J ) 6.0 Hz, 1H),
4.21 (s, 1H), 3.73 (s, 3H), 3.24 (bs, 2H), 3.16-3.12 (dd, J ) 6.0,
13.8 Hz, 1H), 3.10-3.06 (dd, J ) 5.5, 13.5 Hz, 1H), 1.44 (s, 1H).
13C NMR (125 MHz) δ: 171.6, 169.9, 155.4, 135.8, 133.4, 133.2,
131.8, 129.5, 128.8, 127.4, 80.8, 54.0, 53.6, 52.6, 38.1, 36.6, 28.5.
ESI-HRMS: calcd for C24H29N2O5SCl [M + Na]+, 515.1383; found,
515.1371.
(R)-O-(tert-Butyl) N-3-(4-Chlorophenylthio)-1-(4-acetamidophe-
nylsulfonamido)propan-2-yl) Carbamate (38): To a stirred solution
of 16 (40 mg, 0.2 mmol) in DMF (1 mL) were added 4-chlo-
rothiophenol (34 mg, 0.24 mmol) and Cs2CO3 (64 mg, 0.2 mmol)
at room temperature. The reaction mixture was allowed to stir for
6 h, after which time the reaction mixture had turned a faint yellow
color. 4-Acetamidobenzenesulfonyl azide (38 mg, 0.16 mmol) was
added to the reaction mixture. The reaction mixture was allowed
to stir for 1 h, after which the DMF was removed under high
Supporting Information Available: Full experimental details
and copies of 1H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO9001728
J. Org. Chem. Vol. 74, No. 9, 2009 3393