2,4-Dinitrophenyl 4-Methoxybenzyl Disulfide: A New Efficient Reagent for the Electrophilic Sulfenylation of β-Amino Ester Enolates

Full text of DOI:10.1021/jo9623853

4848
J . Org. Chem. 1997, 62, 4848-4850
2,4-Din itr op h en yl 4-Meth oxyben zyl
Disu lfid e: A New Efficien t Rea gen t for th e
Electr op h ilic Su lfen yla tion of â-Am in o
Ester En ola tes
F igu r e 1. Sulfenylating agents reported in the literature.
Laurent Bischoff, Christelle David, Lo¨ıc Martin,
Herve´ Meudal, Bernard-Pierre Roques,* and
Marie-Claude Fournie´-Zaluski
De´partement de Pharmacochimie Mole´culaire et
Structurale, INSERM U266, CNRS URA D 1500,
Universite´ Rene´ Descartes, UFR des Sciences
Pharmaceutiques et Biologiques, 4 Avenue de
l’Observatoire, 75270 Paris Cedex 06, France
F igu r e 2. Symmetrical and unsymmetrical 4-methoxybenzyl-
derived disulfides.
Received December 20, 1996
Numerous membrane-bound zinc metallopeptidases
play a crucial role in the activation or inactivation of
regulatory peptides. There is considerable interest in the
development of potent inhibitors as potential therapeutic
agents as illustrated with captopril for angiotensin
converting enzyme and thiorphan for neutral endopep-
tidase.1 In most cases, the inhibitors contain a thiol
moiety as a zinc chelating group. In continuation of our
studies2 toward inhibitors of aminopeptidase A, we
required N,S-protected R-mercapto-â-amino acids. Such
compounds can be obtained by electrophilic sulfenylation3
of N-protected-â-amino esters, readily available via Arndt-
Eistert homologation4 of the corresponding R-amino acids.
There are few sulfenylating agents (Figure 1) described
in the literature. Thiram5a and sulfenylamines have
rather low reactivities, while sulfenyl chlorides are much
more reactive but more difficult to handle. An alkane-
sulfinate can also be used as a leaving group at the sulfur
position.5b Symmetrical disulfides are the most com-
monly used reagents, being especially reactive in the case
of diaryl disulfides. For instance, the latter were used
for the sulfenylation of indoles6 and aldehydes.7 Most
recently,8,9 a very efficient reagent in which the leaving
group consists of an arenesulfinate was proposed for the
sulfenylation of the â-aspartyl dianion.
F igu r e 3. Reagents and conditions: a: lithium diisopropyl-
amide, THF, -78 °C (2.4 or 3.4 equiv). (b) 1 (1.4 equiv) -78
°C, 30 min and then -40 °C, 30 min.
would be a much poorer nucleophile than the 4-meth-
oxybenzyl mercaptan. Therefore, 2,4-dinitrophenyl 4-
methoxybenzyl disulfide (1) was prepared on a multi-
gram-scale following Endo’s procedure described for other
unsymmetrical disulfides.10 Treatment of commercially
available 4-methoxy-R-toluenethiol with silver acetate led
to the corresponding silver thiolate which was filtered
off and reacted with 2,4-dinitrobenzenesulfenyl chloride.
1 was obtained as very pure bright yellow crystals (mp
) 144 °C) with an overall yield of 80%. It is not light
nor moisture-sensitive and could be stored for months
at 6 °C without any noticeable change.
Sulfenylation proceeded as follows (Figure 3). N-Pro-
tected-â-amino esters were treated with lithium diiso-
propylamide (2.4 or 3.4 equiv depending on whether the
side chain is bearing an acidic proton or not) at -78 °C
followed by addition of 1 as a solid at -78 °C. Rapid solu-
bilization was concomitant with the appearance of a deep
red color that we attributed to the conjugated 2,4-dini-
trothiophenate species. The reaction proceeded smoothly
between -78 and -40 °C and was quenched when no
starting material could be detected by HPLC (ca. 30 min).
As various side chains were required for extended
studies of aminopeptidases, sulfenylations of several
N-protected-â-amino esters were examined. Results are
listed in Table 1.
It is worth noting that sulfenylation only occurred at
the S-benzyl position, leading to a much better leaving
group than nucleophilic substitution at the other sulfur
atom. In addition, this position is more accessible steric-
ally.
Yields were moderate to good in most cases, even when
a trianion was formed (4d and 4e). Several examples
(4c-e) illustrate the higher reactivity of 1 compared to
the symmetrical disulfide 2. In the case of 4f, unidenti-
fied side products were obtained, but no other stereomer
was observed. In order to perform racemization-free acid
deprotection, the allyl ester was also prepared by decom-
position of the corresponding diazo ketone in a 1:2 allyl
In the course of our syntheses, we needed to introduce
the thiol moiety protected by a 4-methoxybenzyl group,
the latter being further removed by means of HF or TFA/
HgII treatment. Unfortunately in some of our cases,
bis(4-methoxybenzyl) disulfide (2) (Figure 2) used by
Gordon et al.3 exhibited a poor reactivity, leading to low
yields and degradation products. Thus, we anticipated
that replacement of one of the (4-methoxybenzyl)thio
groups by a more labile leaving group would be a way of
enhancing the reactivity of this species.
Resu lts a n d Discu ssion
Our attention was focused on a readily available
unsymmetrical disulfide, in which the leaving group
* Author to whom correspondence should be addressed at De´par-
tement de Pharmacochimie Mole´culaire et Structurale, Inserm U266,
CNRS URA D 1500, 4 Avenue de l’Observatoire, 75270 Paris Cedex
06, France. Tel: (33)-1-43.25.50.45. Fax: (33)-1-43.26.69.18.
(1) Roques, B. P.; Noble, F.; Dauge´, V.; Fournie´-Zaluski, M.-C.;
Beaumont, A. Pharmacol. Rev. 1993, 45, 87.
(2) Chauvel, E. N.; Coric, P.; Llorens-Corte`s, C.; Wilk, S.; Roques,
B. P.; Fournie´-Zaluski, M.-C. J . Med. Chem. 1994, 37, 1339, 2950.
(3) Gordon, E. M.; Godfrey, J . D.; Delaney, N. G.; Asaad, M. M.;
Von Langen, D.; Cushman, D. W. J . Med. Chem. 1988, 31, 2199.
(4) Ondetti, M. A.; Engel, S. L. J . Med. Chem. 1975, 18, 761.
(5) (a) Seebach, D.; Teschner, M. Chem. Ber. 1976, 109, 1601 and
references cited therein. (b) Scholz, D. Synthesis 1983, 944.
(6) Atkinson, J . G.; Hamel, P.; Girard, Y. Synthesis 1988, 480.
Anzai, K. J . Heterocyc. Chem. 1979, 16, 567.
(8) Shibata, N.; Baldwin, J . E.; J acobs, A.; Wood, M. E. Synlett 1996,
519.
(9) Shibata, N.; Baldwin, J . E.; J acobs, A.; Wood, M. E. Tetrahedron
1996, 52, 12839.
(10) Endo, T.; Tasai, H.; Ishigami, T. Chem. Lett. 1975, 813.
(11) Seebach, D.; Estermann, H. Tetrahedron Lett. 1987, 28, 3103.
(7) Chibale, K.; Warren, S. Tetrahedron Lett. 1994, 35, 3991.
S0022-3263(96)02385-7 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 14, 1997 4849
Ta ble 1. Yield s of Su lfen yla tion s of â-Am in o Ester
En ola tes u sin g 1 a n d 2
lation of chiral ester or amide enolates with this reagent.
In addition, this strategy may be used for the preparation
of various sulfenylating reagents, in which other protec-
tive groups at the sulfur position can be introduced.
These methods are believed to facilitate the design of zinc
ectopeptidase inhibitors.
compd
R
R′
P
yield (%)a anti:sync
4a
4b
4c
4d
4e
4f
iPr
Ph
Me
Me
Me
Me
Me
Me
Boc
Boc
Boc
Cbz
Cbz
Boc
69 (57)b
68 (72)b
49 (16)
57 (30)
69 (<10)
24 (0)
99:1
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
CH2OTBDMS
CH2SO2NHtBu
(CH2)3NHBoc
CH2COOtBu
CH2COOtBu
Exp er im en ta l Section
4g
Allyl Boc
20 (0)
General. All reactions were performed in vacuum-dried
glassware under an argon atmosphere. THF was distilled from
sodium/benzophenone, and starting materials were thoroughly
dried under vacuum prior to use. All experiments involving
diazomethane and diazoketone decomposition were carried out
behind a safety shield. HPLC analyses were run on a C8
Kromasil reverse-phase column (5 µm, 100 Å, using CH3CN:H2O:
TFA (70:30:0.015) as the mobile phase). Compositions of dia-
a
Figures in parentheses indicate the yields obtained when 2
was used as a sulfenylating agent. Reference 3. c In each case,
only one stereoisomer could be detected by means of 400 MHz
NMR and HPLC prior to purification.
b
1
tereomeric mixtures were determined by means of 400 MHz H
NMR and HPLC of the crude reaction mixtures after workup
before any purification. TLC were run using cyclohexane:AcOEt
) 4:1 (eluent A) and 1:1 (eluent B) unless otherwise indicated.
P r ep a r a tion of N-p r otected -â-amino esters was acom-
plished by slightly modified methods reported in the litterature.4
To a 0.5 M solution of N-protected amino acid in DME or THF
was added N-methylmorpholine (1.1 molar equiv), followed by
isobutyl chloroformate at -10 °C. After 20 min of stirring at
this temperature, the white precipitate was filtered off and
washed with THF. To this solution was added an etheral
solution of diazomethane (2.0 molar equiv), and the yellow
solution stirred at rt during 1 h. After evaporation of the excess
diazomethane and removal of the solvent under reduced pres-
sure, the diazo ketone was taken up in ethyl acetate, washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure.
It was dissolved in 99% methanol (or allyl alcohol:THF ) 1:2
when the allyl ester was required) and treated at room temper-
ature with a solution of 7 mol % silver benzoate (0.15 M in
triethylamine). A vigorous gas evolution was noted. After 30
min of stirring, Celite and brine were added and the black
suspension was filtered through Celite. Evaporation of the
solvents afforded the crude ester which was purified by means
of a column chromatography (EtOAc:cyclohexane ) 1:4 to 1:1).
Gen er a l P r oced u r e for th e r-Sulfenylation of N-Protected-
â-amino Ester Enolates. Ester 3a -g (1 mmol) was dissolved in
anhydrous THF (4 mL) and treated with 2 M lithium diisopro-
pylamide (ACROS, 2.4 or 3.4 molar equiv). The resulting
solution was stirred for 30 min at this temperature; then
disulfide 1 was added in one portion as a solid. Temperature
was kept at -78 °C during 30 min and then allowed to reach
-40 °C over 30 min. Then 3 mL of 2 N HCl was added and the
cold heterogeneous mixture taken up in ethyl acetate. After
decantation and further extractive workup, the combined organic
layers were washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. Flash chromatography on silica
gel (eluent A) afforded the pure R-sulfenylated ester 4a -g.
F igu r e 4. Assignment of the stereochemistry by formation
of a thiazolidine. Reagents and conditions: (a) CF3COOH, ani-
sole, rt, 1 h and then (CF3COO)2Hg, 0 °C, 30 min; (b) ethane-
dithiol, CH3COOH:H2O ) 4:1, 0 °C, 1 h; (c) acetone, reflux.
alcohol:THF mixture, leading to ester 3g. Sulfenylation
proceeded with a 20% yield, though the reaction was
much cleaner.
Diastereomeric excesses were measured by means of
reverse-phase HPLC and 400 MHz NMR. In the case of
R ) iPr, we prepared a racemic sample of 4a by complete
racemization with sodium methoxide. A comparison with
the data obtained for the optically pure sample gave
proper NMR and HPLC assignments of the other stereo-
isomer. Careful analysis of the crude reaction medium
before and after workup showed that the latter could not
be detected. Concerning compounds 4b-g, NMR spectra
showed the presence of only one stereomer but accurate
assignment of the other diastereomer was not performed.
In order to prove the stereochemical outcome of the
reaction, compound 4a as a model for the series was
converted to the corresponding thiazolidine 5 by means
of N,S-deprotection followed by acetone cyclization12
(Figure 4). The relative stereochemistry of the thiazoli-
dine was determined by means of NMR. A ROESY
experiment performed on compound 5 led to the conclu-
sion that there was a good spatial interaction between
protons Ha and Hb. Thus, we can conclude that the
configuration of compound 4a was 2S,3S, corresponding
to an anti sulfenylation of the enolate which can be
explained by the asymmetric induction brought by the
N-protected amino group. This result is consistent with
diastereoselective alkylations of N-protected-â-amino
ester enolates described by Seebach11 and can be com-
pared to the results obtained for the anti sulfenylation
of the aspartic acid side chain.9
4-Meth oxyben zyl 2,4-d in itr op h en yl d isu lfid e (1):9 ob-
tained in an 80% yield on a 15 g scale; 1H NMR (400 MHz,
CDCl3) 3.64 (3H, s), 3.89 (2H, s), 6.61 (2H, d, J ) 8.7 Hz), 7.05
(2H, d, J ) 8.7 Hz), 8.02 (2H, d, J ) 8.9 Hz), 8.10 (2H, dd, J )
8.9 and 2.4 Hz), 8.91 (2H, d, J ) 2.4 Hz); 13C NMR (67 MHz,
CDCl3) 43.7, 55.9, 114.8, 121.7, 127.2, 127.9, 129.8, 131.2, 145.8,
147.0, 160.2; TLC Rf ) 0.42 (eluent A); HPLC: tR ) 9.6 min.
Anal. Calcd for C14H12N2O5S2: C, 47.72; H, 3.43; N, 7.95.
Found: C, 47.69; H, 3.37; N, 8.04.
Con clu sion
Bis(4-m eth oxyben zyl d isu lfid e (2) was prepared according
We have developed a very reactive and versatile
reagent for the electrophilic sulfenylation of â-amino ester
enolates, thus providing a wide range of precursors of
aminopeptidase inhibitors bearing lipophilic or hydro-
philic side chains. The high reactivity of compound 1
makes it a good reagent for asymmetric synthesis, since
sulfenylation proceeded at low temperatures. Therefore
it would be interesting to study the asymmetric sulfeny-
to ref 3. Analytical data were consistent with those published.
Meth yl 3(S)-[(ter t-Bu toxyca r bon yl)a m in o]-5-m eth ylh ex-
a n oa te (3a ). Starting from 4.0 g (16 mmol) of leucine hydrate
(which was not dehydrated prior to use), 3.93 g (94%) was
obtained: 1H NMR (270 MHz, CDCl3) 0.8-0.9 (6 H, m), 1.1-
1.3 (1H, m), 1.3-1.45 (10 H, m + s), 1.5-1.65 (1H, m), 2.35-
2.55 (2H, m), 3.6 (3H, s), 3.9-4.0 (1H, m), 4.8 (1H, br d); 13C
NMR (67 MHz, CDCl3) 22.8, 23.6, 25.7, 29.1, 40.3, 44.4, 46.5,
52.2, 79.9, 156.0, 172.9; TLC Rf ) 0.38 (eluent A); HPLC tR
)
5.8 min; [R]21 ) -21.4 (c 1.03, absolute MeOH.) Anal. Calcd
D
for C13H25NO4: C, 60.35; H, 9.76; N, 5.42. Found: C, 60.21; H,
9.72; N, 5.40.
(12) Sheehan, J . C.; Yang, D.-D. H. J . Am. Chem. Soc. 1958, 80,
1158.

4850 J . Org. Chem., Vol. 62, No. 14, 1997
Notes
Meth yl 3(S)-[(ter t-Bu toxyca r bon yl)a m in o]-4-p h en ylbu -
ta n oa te (3b). Starting from Boc-Phe-OH (5 g, mmol), 5.19 g
(94%) was obtained. Analytical data were consistent with those
published.3
Met h yl 3(S)-[(ter t-Bu t oxyca r b on yl)a m in o]-5-[(ter t-b u -
tyld im eth ylsilyl)oxy]p en ta n oa te (3c). 3c was obtained from
Boc-Asp(OBzl)-OH by a homologation-debenzylation-reduc-
tion-silylation sequence: 1H NMR (270 MHz, DMSO) 0.03 (6H,
s), 0.85 (9H, s), 1.37 (9H, s), 1.52-1.62 (2H, m), 2.39 (2H, d, J )
5.6 Hz), 3.50-3.62 (5H, m), 3.80-3.92 (1H, m), 6.67 (1H, br d,
J ) 7 Hz); HPLC tR ) 8.5 min.
Met h yl 3(S)-[(ter t-b u t oxyca r b on yl)a m in o]-5-[(ter t-b u -
tyla m in o)su lfon yl]p en ta n oa te (3d ). Starting from 10.80 g
(29 mmol) of 2(S)-[(tert-butoxycarbonyl)amino]-4-[(tert-butylami-
no)sulfonyl]butanoic acid, 6.95 g (60%) was obtained: HPLC tR
) 4.1 min. Anal. Calcd for C18H28N2O6S: C, 53.98; H, 7.05; N,
6.99. Found: C, 53.96; H, 7.05; N, 6.95.
(49%) of 4c was obtained: 1H NMR (270 MHz, CDCl3) 0.01 (6H,
s), 0.89 (9H, s), 1.42 (9H, s), 1.60-1.82 (2H, m), 3.46 (1H, d, J )
4.4 Hz), 3.60 (2H, t, J ) 6.8 Hz), 3.71 (3H, s), 3.79 (5H, s), 4.02-
4.14 (1H, m), 5.36 (1H, d, J ) 9.7 Hz), 6.82 (2H, d, J ) 8.5 Hz),
7.23 (2H, d, J ) 8.5 Hz); HPLC tR ) 17.0 min.
Met h yl (2S,3S)-2-[(4-Met h oxyb en zyl)t h io]-3-[(ter t-b u -
t oxyca r b on yl)a m in o]-5-[(ter t-b u t yla m in o)su lfon yl]p en -
ta n oa te (4d ). Starting from 3d (249 mg, 0.62 mmol), 195 mg
(57%) of 4d was obtained: 1H NMR (270 MHz, CDCl3) 1.25 (9H,
s), 1.72-2.08 (2H, m), 2.94 (2H, t, J ) 6.5 Hz), 3.22 (1H, d, J )
4.4 Hz), 3.68 (3H, s), 3.72 (5H, s), 3.9-4.05 (5H, s), 4.95 (1H,
d(AB), J ) 12 Hz), 5.05 (1H, d(AB), J ) 12 Hz), 5.5 (1H, d, J )
10 Hz), 6.77 (2H, d, J ) 8.6 Hz), 7.18 (2H, d, J ) 8.6 Hz), 7.2-
7.3 (5H, m); TLC (cyclohexane:AcOEt:CH2Cl2 ) 1:1:1) Rf ) 0.42;
HPLC tR ) 6.9 min.
Met h yl (2S,3S)-2-[(4-Met h oxyb en zyl)t h io]-3-[[(b en zyl-
oxy)ca r bon yl]a m in o]-5-[(ter t-bu toxyca r bon yl)a m in o]h ep -
ta n oa te (4e). From 3e (634 mg, 1.55 mmol), 519 mg (69%) of
4e was obtained: 1H NMR (400 MHz, CDCl3) 1.18-1.44 (15H,
m), 2.97 (2H, m), 3.21 (1H, d, J ) 4.39 Hz), 3.65 (3H, s), 3.72
(2H, s), 3.73 (3H, s), 3.87-3.92 (1H, m), 4.48 (1H, br s), 4.99
(1H, d, J ) 12.3 Hz), 5.05 (1H, d, J ) 12.3 Hz), 5.43 (1H, d,
J ) 9.9 Hz), 6.78 (2H, d, J ) 8.6 Hz), 7.16-7.30 (2H, m), 7.22-
7.33 (5H, m); 13C NMR (67 MHz, CDCl3) accurate assignments
were obtained by means of a 1H/13C 2D experiment, 21.2 (C5),
26.5 (C(CH3)3), 27.5 (C6), 31.1 (C4), 34.0 (S-CH2), 38.3 (C7),
47.5 (C2), 50.2 (C3), 50.3 (CH3 ester), 53.3 (CH3 methoxy), 64.8
(CH2 Cbz), 77.1 (C(CH3)3), 112.1 (C3,C5 PMB), 126.0 (C2,C6
Cbz), 126.5 (C3,C4,C5 Cbz), 127.0 (C1 PMB), 128.3 (C2,C6 PMB),
134.7 (C1 Cbz), 154.1 (CdO Boc), 154.3 (CdO Cbz), 157.0 (C4
PMB), 170.2 (CdO ester); [R]21D ) -63.5 (c 1.13, absolute MeOH)
HPLC tR ) 8.1 min; MS (m/z): 561 (MH+). Anal. Calcd for
Meth yl 3(S)-[((Ben zyloxy)ca r bon yl)a m in o]-5-[(ter t-bu -
toxyca r bon yl)a m in o]h ep ta n oa te (3e). Starting from Cbz-
Lys(Boc)-OH (5.89 g, 15.5 mmol), 6.23 g (98%) was obtained:
1H NMR (270 MHz, DMSO) 1.1-1.4 (15H, m), 2.38 (2H, d, J )
5.6 Hz), 2.8-2.86 (2H, m), 3.5 (3H, s), 3.7-3.8 (1H, m), 4.9-5.0
(2H, m), 6.65 (1H, br t), 7.12 (1H, d), 7.2-7.3 (5H, m); 13C NMR
(67 MHz, CDCl3) 23.8, 29.1, 30.3, 34.7, 39.6, 40.8, 48.6, 52.3,
67.3, 79.7, 128.7, 129.1, 137.2, 156.6, 156.7, 172.6; TLC Rf ) 0.5
(eluent B); HPLC tR ) 5.1 min; [R]21 ) -7.5 (c 1.01, absolute
D
MeOH). Anal. Calcd for C21H32N2O6: C, 61.75; H, 7.89; N, 6.86.
Found: C, 61.69; H, 7.87; N, 6.80.
Meth yl (3S)-5-(ter t-Bu toxyca r bon yl)-3-[(ter t-bu toxyca r -
bon yl)a m in o]p en ta n oa te (3f). Starting from Boc-Glu(OtBu)-
OH (1.87 g, 6.20 mmol), 1.89 g (92%) was obtained: 1H NMR
(400 MHz, CDCl3) 1.36 and 1.37 (18H, 2s), 1.73 (2H, q, J ) 7.2
Hz), 2.23 (2H, t, J ) 7.3 Hz), 2.46 (2H, d, J ) 5.4 Hz), 3.61 (3H,
s), 3.85 (1H, m), 4.92 (1H, br d, J ) 8.9 Hz); 13C NMR (67 MHz,
CDCl3) 28.8, 29.0, 30.1, 33.1, 40.1, 48.1, 52.3, 80.0, 81.2, 156.0,
C
29H40N2O7S: C, 62.12; H, 7.19; N, 5.00. Found: C, 62.06; H,
7.19; N, 5.02.
Meth yl (2S,3S)-2-[(4-Meth oxyben zyl)th io]-5-(ter t-bu toxy-
ca r bon yl)-3-[(ter t-bu toxyca r bon yl)a m in o]-p en ta n oa te (4f).
This material was prepared using the same procedure as that
for 4a -e, except that the anion was reacted during 1.5 h at -78
°C. From 3f (278 mg, 0.68 mmol), 79 mg (24%) of 4f was
obtained: 1H NMR (270 MHz, CDCl3) 1.35 and 1.37 (18H, 2s),
1.56-1.63 (1H, m), 1.75-1.82 (1H, m), 2.17 (2H, t, J ) 7.5 Hz),
3.23 (1H, d, J ) 4.5 Hz), 3.66 (3H, s), 3.72 and 3.73 (5H, 2s),
3.84-3.92 (1H, m), 5.14 (1H, br d, J ) 10.0 Hz), 6.78 (2H, d, J
172.5, 173.2. TLC Rf ) 0.75 (eluent B); [R]21 ) -12.7 (c 0.9,
D
absolute MeOH); HPLC tR ) 6.2 min. Anal. Calcd for
C
16H29NO6: C, 57.99; H, 8.82; N, 4.23. Found: C, 58.44; H, 8.91;
N, 4.17.
Allyl (3S)-5-(ter t-Bu toxyca r bon yl)-3-[(ter t-bu toxyca r bo-
n yl)a m in o]p en ta n oa te (3g). Starting from Boc-Glu(OtBu)-OH
(8.41 g, 27.9 mmol), 8.88 g (89%) was obtained: 1H NMR (270
MHz, CDCl3) 1.35 and 1.36 (18H, 2s), 1.73 (2H, q, J ) 7.3 Hz),
2.22 (2H, t, J ) 7.3 Hz), 2.48 (2H, d, J ) 5.4 Hz), 3.8-3.9 (1H,
m), 4.50-4.52 (2H, m), 4.93 (1H, br d, J ) 8.9 Hz), 5.15-5.27
(2H, m), 5.78-5.88 (1H, m); 13C NMR (67 MHz, CDCl3) 28.8,
29.0, 30.1, 33.0, 40.1, 48.1, 65.9, 80.0, 81.2, 119.2, 132.7, 156.0,
) 8.6 Hz), 7.19 (2H, d, J ) 8.6 Hz); [R]21 ) -60.9 (c 0.67,
D
absolute MeOH); HPLC tR ) 13.1 min; MS (m/z) 484 (MH+).
Anal. Calcd for
C24H37NO7S: C, 58.61; H, 7.71; N, 2.90.
Found: C, 58.67; H, 7.59; N, 2.89.
Allyl (2S,3S)-2-[(4-Meth oxyben zyl)th io]-5-(ter t-bu toxy-
ca r bon yl)-3-[(ter t-bu toxyca r bon yl)a m in o]p en ta n oa te (4g).
This material was prepared using the same procedure as that
for 4a -e, except that the dianion was reacted during 1.5 h at
-78 °C.
171.7, 173.2; [R]21 ) -11.1 (c 1.03, absolute MeOH); HPLC tR
D
) 7.8 min. Anal. Calcd for C18H31NO6: C, 60.48; H, 8.74; N,
3.92. Found: C, 60.66; H, 8.70; N, 3.95.
Met h yl (2S,3S)-2-[(4-Met h oxyb en zyl)t h io]-3-[(ter t-b u -
toxyca r bon yl)a m in o]-5-m eth ylh exa n oa te (4a ). From 3a
(414 mg, 1.60 mmol), 454 mg (69%) of 4a was obtained: 1H NMR
(400 MHz, CDCl3) 0.76 (3H, d, J ) 6.65 Hz), 0.81 (3 H, d, J )
6.52 Hz), 1.15-1.29 (2H, m), 1.36 (9H, s), 1.46-1.53 (1H, m),
3.22 (1H, d, J ) 4.3 Hz), 3.66 (3H, s), 3.73 (5H, s), 3.94-3.99
(1H, m), 5.08 (1H, d, J ) 9.86 Hz), 6.78 (2H, d, J ) 8.6 Hz), 7.19
(2H, d, J ) 8.6 Hz); 13C NMR (67 MHz, CDCl3) 19.9, 21.0, 22.9,
26.3, 33.8, 40.4, 47.7, 48.2, 50.0, 53.1, 76.9, 111.9, 127.0, 128.1,
153.4, 156.9, 170.1; TLC (eluent A) Rf ) 0.42; HPLC tR ) 12.7
From 3g (544 mg, 1.52 mmol), 157 mg (20%) of 4g was
obtained: 1H NMR (270 MHz, CDCl3) 1.35 and 1.37 (18H, 2s),
1.56-1.63 (1H, m), 1.75-1.82 (1H, m), 2.17 (2H, t, J ) 7.5 Hz),
3.22 (1H, d, J ) 4.5 Hz), 3.73 (5H, s), 3.86-3.93 (1H, m), 4.53-
4.60 (2H, m), 5.17-5.33 (3H, m), 5.82-5.91 (1H, m), 6.77 (2H,
d, J ) 8.6 Hz), 7.18 (2H, d, J ) 8.6 Hz); 13C NMR (67 MHz,
CDCl3) 28.8, 29.0, 32.9, 36.6, 50.3, 52.0, 55.9, 66.6, 77.9, 80.3,
81.2, 114.7, 119.7, 129.6, 130.9, 132.3, 156.4, 159.6, 172.2, 173.1;
TLC Rf ) 0.31 (eluent A); [R]21D ) -64.9 (c 0.51, absolute MeOH);
HPLC tR ) 16.1 min; MS (m/z) 510 (MH+). Anal. Calcd for
min; [R]21 ) -112.7 (c 0.7, absolute MeOH); MS (m/z) 412
D
(MH+). Anal. Calcd for C21H33NO5S: C, 61.29; H, 8.08; N, 3.40.
Found: C, 61.11; H, 8.07; N, 3.40.
C
26H39NO7S: C, 61.10; H, 7.69; N, 2.77. Found: C, 61.27; H,
7.71; N, 2.75.
Met h yl (2S,3S)-2-[(4-Met h oxyb en zyl)t h io]-3-[(ter t-b u -
toxycar bon yl)am in o]-4-ph en ylbu tan oate (4b). Starting from
3b (2.02 g, 6.90 mmol), 2.09 g (68%) of 4b was obtained: 1H
NMR (400 MHz, CDCl3) 1.33 (9H, s), 2.66 (1H, dd, J ) 13.7,
7.94 Hz), 2.84 (1H, dd, J ) 13.7, 6.8 Hz), 3.15 (1H, d, J ) 4.9
Hz), 3.64-3.67 (5H, m), 3.73 (3H, s), 4.05-4.12 (1H, m), 5.35
(1H, d, J ) 9.7 Hz), 6.69 (2H, d, J ) 8.5 Hz), 6.99 (2H, d, J )
6.5 Hz), 7.06 (2H, d, J ) 8.5 Hz), 7.12-7.18 (3H, m); 13C NMR
(67 MHz, CDCl3) 26.4, 33.9, 37.6, 45.7, 50.4, 51.3, 53.3, 77.5,
112.0, 124.6, 126.5, 126.9, 127.3, 128.2, 135.3, 153.4, 156.9, 170.5;
TLC Rf ) 0.35 (eluent A); [R]21D ) -75.2 (c 0.57, absolute MeOH);
MS (m/z) 446 (MH+). Anal. Calcd for C24H31NO5S: C, 64.69;
H, 7.01; N, 3.14. Found: C, 62.67; H, 6.86; N, 3.03.
Ack n ow led gm en t. This work was supported by
CNRS and INSERM fundings. We thank the MESR for
a grant to Christelle David and Lo¨ıc Martin. Sophie
Cornet is gratefully acknowledged for a multigram-scale
preparation of 1.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
of most compounds of the series 3a -g and 4a -g (24 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
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Met h yl (2S,3S)-2-[(4-Met h oxyb en zyl)t h io]-3-[(ter t-b u -
toxyca r bon yl)a m in o]-5-[(ter t-bu tyld im eth ylsilyl)oxy]p en -
ta n oa te (4c). Starting from 3c (201 mg, 0.56 mmol), 140 mg
J O9623853