Modular and stereoselective formal synthesis of MeBmt, an unusual amino acid constituent of cyclosporin A

Article abstract of DOI:10.1016/j.tet.2004.01.088

A convergent, flexible and stereoselective formal synthesis of MeBmt, the nonproteinogenic amino acid constituent of cyclosporin A is disclosed. The sulfinyl moiety has been exploited as the internal nucleophile to stereo- and regioselectively functionalize an allylic carbamate.

Full text of DOI:10.1016/j.tet.2004.01.088

Tetrahedron 60 (2004) 3059–3065
Modular and stereoselective formal synthesis of MeBmt,
an unusual amino acid constituent of cyclosporin Aq
*
Sadagopan Raghavan and M. Abdul Rasheed
Organic Division I, Indian Institute of Chemical Technology, Habsiguda, Hyderabad 500 007, India
Received 19 September 2003; revised 2 January 2004; accepted 29 January 2004
Abstract—A convergent, flexible and stereoselective formal synthesis of MeBmt, the nonproteinogenic amino acid constituent of cyclo-
sporin A is disclosed. The sulfinyl moiety has been exploited as the internal nucleophile to stereo- and regioselectively functionalize an
allylic carbamate.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
additional steps for the N-methylation of the final amino
acid, thereby limiting their potential for the large scale
preparation of MeBmt. As part of our interest in employing
the sulfinyl moiety as an internal nucleophile5 to stereo- and
regioselectively functionalize allylic olefins and use of
the resulting bromohydrins as intermediates for the
synthesis of bioactive target molecules,6 we detail herein a
stereoselective and modular synthesis of MeBmt.
Cyclosporin A is a cyclic undecapeptide isolated from
the fungus Tolypocladium inflatium Gams.,1 possessing
immunosuppressive activity, thus preventing organ rejec-
tion after transplantation. The structure of cyclosporin A
is characterized by the presence of many N-methylated
a-amino acids and a unique g-alkyl-b-hydroxy-a-amino
acid, MeBmt (1). MeBmt itself does not show any
bioactivity, however modification of the MeBmt moiety in
cyclosporin greatly affects its immunosuppressive activity.
Many routes have been reported for the synthesis of MeBmt,
employing starting materials from the chiral pool,2 chiral
epoxides3 and the aldol reaction4 in the key step of the
reaction sequence. The syntheses employing the aldol
reaction as the key step require chiral a-alkyl branched
aldehyde and a chiral glycine synthon for good diastereo-
selection. The other syntheses require expensive catalysts or
2. Results and discussion
MeBmt has three contiguous chiral centers, an N-Me group
and a trans double bond. By retrosynthetic analysis (Scheme
1), MeBmt can be derived from the retron 2, the forward
sequence would require chain extension by a propenyl
cuprate followed by oxidation of the primary hydroxy group
and hydrolysis of the oxazolidinone. The oxazolidinone 2
Scheme 1.
q IICT Communication No. 030210.
Keywords: MeBmt; Sulfoxide; Neighbouring group participation; Bromohydrin.
*
Corresponding author. Tel.: þ91-04027160123; fax: þ91-04027160512; e-mail address: sraghavan@iict.ap.nic.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.088

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S. Raghavan, M. A. Rasheed / Tetrahedron 60 (2004) 3059–3065
Scheme 2. (a) LiAlH4/AlCl3, THF/ether 0 8C, 1 h, 93%; (b) NaIO4, CH3OH/H2O, rt, 16 h, 95%; (c) TBDPSCl, imidazole, CH2Cl2, rt, 2 h, 95%; (d) CH3NCO,
Et3N, CH2Cl2, rt, 6 h, 14, 90%, 12, 95%; (e) NBS, H2O, toluene, rt, 30 min, 9, 80% 15, 80%; (f) K2CO3, CH3OH, rt, 1 h, 10, 95%, 12, 95%; (g) TBAF/AcOH,
THF, rt, 2 h, 85%; (h) NaHMDS, THF, 0 8C, 30 min, 95%.
can itself be derived from bromohydrin 3 which in turn can
be readily obtained from the olefinic substrate 4. In the
proposed strategy, the methyl group would serve to
introduce the other two chiral centers stereoselectively by
asymmetric induction.
product 9 has three stereocenters other than the sulfoxide,
that are disposed both in a relative and an absolute sense as
in MeBmt; the N-Me group therefore needed to be
introduced by a double inversion procedure. Toward that
direction, subjecting a methanolic solution of 9 to treatment
with K2CO3 in methanol afforded the epoxide 10.
Deprotection of the silyl group by treatment with buffered
TBAF7 in anhydrous THF afforded epoxy alcohol 11.
Reaction of the epoxy alcohol 11 with methyl isocyanate
afforded the carbamate 12, which when subjected to
treatment with NaHMDS in anhydrous THF afforded the
rearranged oxazolidinone8 13 exclusively (Scheme 2).
The synthesis began with the unsaturated ester 5,6b which
was reduced with alane, generated in situ, to afford the
primary alcohol 6. Oxidation of the sulfide with NaIO4
afforded an inseparable equimolar mixture of sulfoxides 7,
which was transformed into the silyl ether 8 by treatment
with t-butyldiphenylchloro silane. No efforts were made to
separate the epimeric sulfoxides 8, since the sulfur chirality
was of no consequence in the subsequent steps of the
synthesis.5b Treatment of the sulfoxide 8 with NBS in
toluene in the presence of water afforded bromohydrin 9, the
structure of which has been rigorously established.5b The
It occurred to us that if the bromohydration could be done on
the allylic carbamate 14, two steps could be reduced in the
overall synthetic sequence. Homoallylic carbamates have
been reported to function as internal nucleophiles and afford
Scheme 3. (a) Ac2O, Et3N, cat. DMAP, CH2Cl2, rt, 30 min, 95%; (b) TFAA, Et3N, CH3CN, rt, 30 min, then aq. NaHCO3, NaBH4, at 0 8C, 30 min, 65%;
(c) TsCl, Et3N, cat. DMAP, CH2Cl2, rt, 1 h, 85%; (d) 1-(E)-propenylmagnesium bromide, CuI, THF, 278 8C to rt, 2 h, 70%; (e) PhI(OAc)2, TEMPO,
CH3CN/H2O, rt, 2 h, then ethereal CH2N2, rt, 10 min, 80% for 2 steps.

S. Raghavan, M. A. Rasheed / Tetrahedron 60 (2004) 3059–3065
3061
iodocarbonates upon treatment with iodine in a biphasic
system after a prolonged reaction period. A single example
of a carbamate derived from an allyl alcohol was reported to
yield the iodocarbonate in moderate yield under similar
reaction conditions.9 We were therefore not certain if the
carbamate or the sulfinyl moiety would function as the
intramolecular nucleophile in the reaction of 14 with NBS.
Gratifyingly, reaction of 14, prepared from alcohol 7 by
treatment with methyl isocyanate, with NBS in toluene
afforded exclusively, the bromohydrin 15, as an epimeric
mixture, within a period of 30 min. Subjecting bromohydrin
15 to treatment with K2CO3 in methanol afforded epoxy
carbamate 12 identical to that prepared from the allyl
silylether 8. The cyclization of epoxycarbamate 12 to yield
13 not only served to introduce the N-methyl substituent
but also served to simultaneously protect the hydroxy and
amino groups. Having access to the oxazolidinone 13, the
next step of the synthesis called for the introduction of the
olefinic side chain and oxidation of the primary hydroxy
group. Acetylation of the hydroxy group in 13 afforded
compound 16 which was more conveniently obtained in a
one pot operation from 12 by quenching the reaction with
Ac2O. Subjecting 16 to Pummerer rearrangement10 con-
ditions followed by treatment of the resulting intermediate
17 with sat. aq. NaHCO3 and NaBH4 afforded alcohol 18
in an one pot operation. Tosylation of the hydroxy
group yielded product 19 which upon treatment with excess
(E)-propenyl magnesium bromide in the presence of cat.
amount of CuI afforded olefinic alcohol2a 20 by concomitant
deprotection of the acetyl group. The primary hydroxy
group was oxidized by treatment with PhI(OAc)2/TEMPO11
to yield the acid which was esterified by treatment with
excess of diazomethane to afford the ester 21. Compound 21
had physical and spectroscopic properties similar to that
reported in the literature.2a Oxazolidinone 21 has been
transformed to MeBmt2a,4a,g and thus we have completed a
formal synthesis of the unusual amino acid, MeBmt
(Scheme 3).
spectrometer. 1H NMR and 13C NMR samples were
internally referenced to TMS (0.00 ppm). Insufficient
resonances in the 13C NMR data of the diastereomeric
mixture of compounds is due to resonance overlap. Melting
points are uncorrected.
3.1.1. 4-Methyl-5-phenylsulfanyl-(Z,4S)-2-pentene-1-ol
6. To the suspension of LiAlH4 (0.91 g, 24 mmol) in dry
ether (20 mL) maintained at 0 8C was added the solution of
AlCl3 (1.07 g, 8 mmol) in anhydrous ether (37 mL) and the
reaction mixture stirred at the same temperature for 30 min.
The solution of the ester 56b (3.78 g, 16 mmol) in anhydrous
ether (37 mL) was then added to reaction mixture and the
stirring continued at 0 8C for a further 30 min. The reaction
mixture was diluted with ether and quenched by adding ice
pieces. The reaction mixture was passed through a small pad
of celite and the filtrate evaporated under reduced pressure
to afford the crude product which was purified by column
chromatography using 30% EtOAc/petroleum ether (v/v) as
the eluent to yield allyl alcohol 6 (3.1 g, 14.9 mmol) in 93%
yield. Viscous oil. Rf 0.3 (10% EtOAc/petroleum ether).
[a]2D5¼221.0 (c 1.0, CHCl3). ms LSIMS 209 [MþH]þ. IR
1
(neat) 3554, 2889, 1087, 954, 690. H NMR (200 MHz,
CDCl3) d 7.38–7.10 (m, 5H), 5.68 (m, 1H), 5.35 (t, J¼
8.3 Hz, 1H), 4.20–3.95 (m, 2H), 3.0–2.70 (m, 3H), 1.13 (d,
J¼6.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 20.8, 32.1,
40.8, 58.3, 126.0, 128.9, 129.2, 136.1, 136.6. Anal. calcd for
C12H16OS: C, 69.19; H, 7.74; S, 15.39. Found: C, 69.35; H,
7.56; S, 15.25.
3.1.2. 4-Methyl-5(SS)-phenylsulfinyl-(Z,4S)-2-pentene-1-
ol and 4-methyl-5(RS)-phenylsulfinyl-(Z,4S)-2-pentene-
1-ol 7. To the solution of the sulfide 6 (3.0 g, 14.5 mmol), in
1:1 MeOH/THF (146 mL) was added the solution of NaIO4
(3.4 g, 15.9 mmol) in water (73 mL) and the reaction
mixture stirred at rt for 16 h. The precipitated solid was
removed by filtration and the filtrate evaporated under
reduced pressure. The aq. layer was extracted with ethyl
acetate and the combined organic layers washed with water,
brine and dried over Na2SO4. The organic layer was
evaporated under reduced pressure to afford the crude
product which was purified by column chromatography
using 50% EtOAc/petroleum ether (v/v) as the eluent to
yield sulfoxide 7 (3.08 g, 13.77 mmol) as a 1:1 diastereo-
meric mixture in 95% yield. Viscous oil. Rf 0.2 (50%
EtOAc/petroleum ether). ms LSIMS 225 [MþH]þ. IR (neat)
In summary, we have disclosed a novel, modular and
stereoselective synthesis of MeBmt. The key steps in the
reaction sequence include regio- and stereoselective bromo-
hydration of a double bond utilizing the sulfinyl group as an
internal nucleophile, the use of a carbamate as an internal
nucleophile to open the epoxide to yield the required trans
oxazolidinone and the use of the sulfoxide as a masked
hydroxyl group.
3327, 2953, 1651, 1598, 1047, 968 cm21 1H NMR
.
(200 MHz, CDCl3) d 7.60–7.48 (m, 10H), 5.90 (m, 1H),
5.75 (m, 1H), 5.39 (t, J¼10.4 Hz, 1H), 5.25 (t, J¼10.4 Hz,
1H), 4.40–3.90 (m, 4H), 3.42–3.0 (m, 2H), 2.95–2.75 (m,
2H), 2.61–2.40 (m, 2H), 1.20 (d, J¼7.8 Hz, 3H), 1.10 (d,
J¼7.8 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 20.5, 20.8,
27.4, 27.7, 57.8, 57.9, 64.3, 64.6, 123.8, 123.9, 129.1, 129.2,
129.3, 131.0, 131.1, 133.7, 134.6, 143.5, 143.7. Anal. calcd
for C12H16O2S: C, 64.25; H, 7.19; S, 14.29. Found: C,
64.16; H, 7.04; S, 14.12.
3. Experimental
3.1. General
All air or moisture sensitive reactions were carried out under
nitrogen atmosphere. Solvents were distilled freshly over
Na/benzophenone ketyl for THF, over P2O5 followed by
CaH2 for DCM and over P2O5 for toluene. Commercially
available reagents were used without further purification
except NBS, which was freshly recrystallized from hot
water before use. Thin layer chromatography was per-
formed with precoated silica gel plates. Column chroma-
tography was carried out using silica gel (60–120 mesh).
NMR spectra were recorded on a 200, 300 or 400 MHz
3.1.3. 1(SS)-[5-tert-Butyldiphenylsiloxy-2-methyl-(2S,
3Z)-3-pentenylsulfinyl]-benzene and 1(RS)-[5-tert-butyl-
diphenylsiloxy-2-methyl-(2S,3Z)-3-pentenylsulfinyl]-
benzene 8. To the solution of the alcohol 7 (0.45 g, 2 mmol)
in dry DCM (3.8 mL) was added imidazole (204 mg,
3 mmol) followed by the addition of TBDPS-Cl (0.56 mL,

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S. Raghavan, M. A. Rasheed / Tetrahedron 60 (2004) 3059–3065
2.2 mmol). The reaction mixture was stirred at rt for 3 h
under an atmosphere of nitrogen. The reaction mixture was
diluted with DCM (30 mL) and washed successively with
water, brine and dried over Na2SO4. The organic layer was
evaporated under reduced pressure to afford the crude
product which was purified by column chromatography on
silica gel using 10% EtOAc/pet. ether (v/v) as the eluent to
yield 8 (0.71 g, 1.54 mmol) in 78% yield. A small amount of
the epimeric sulfoxide was separated for characterization
purposes into 8a and 8b.
Anal. calcd for C28H35BrO3SSi: C, 60.09; H, 6.30; S, 5.73.
Found: C, 60.18; H, 6.46; S, 5.98.
Compound 9b. Viscous oil. Rf 0.2 (20% EtOAc/petroleum
ether). [a]2D5¼263.6 (c 0.5, CHCl3). ms (FAB) 559, 501. IR
1
(neat) 3326, 2943, 1554, 1043, 972, 698, 625 cm21. H
NMR (200 MHz, CDCl3) d 7.72–7.63 (m, 6H), 7.58–7.40
(m, 9H), 4.12–3.86 (m, 3H), 3.57 (d, J¼8.8 Hz, 1H), 3.22
(dd, J¼12.6, 4.0 Hz, 1H), 2.61 (dd, J¼12.6, 7.0 Hz, 1H),
2.41 (m, 1H), 1.55 (d, J¼6.3 Hz, 3H) 1.06 (s, 9H). 13C NMR
(50 MHz, CDCl3) d 16.6, 19.2, 26.8, 34.7, 57.9, 62.4, 65.6,
73.2, 124.1, 127.9, 129.3, 130.0, 131.0, 133.2, 135.5, 135.6,
144.3. Anal. calcd for C28H35BrO3SSi: C, 60.09; H, 6.30; S,
5.73. Found: C, 60.26; H, 6.43; S, 5.87.
Compound 8a. Liquid. Rf 0.3 (20% EtOAc/petroleum
ether). [a]2D5¼238.6 (c 1.0, CHCl3). ms (EI) 405 (Mþ2
C4H9). IR (neat) 2953, 1655, 1595, 1032, 968, 854,
1
690 cm21. H NMR (200 MHz, CDCl3) d 7.68–7.30 (m,
15H), 5.56 (m, 1H), 5.23 (m, 1H), 4.19 (d, J¼6.38 Hz, 2H),
2.77 (m, 1H), 2.73 (dd, J¼12.7, 5.1 Hz, 1H), 2.50 (dd, J¼
12.7, 8.9 Hz, 1H), 1.13 (d, J¼6.3 Hz, 3H), 1.03 (s, 9H). 13C
NMR (50 MHz, CDCl3) d 19.6, 20.3, 26.9, 27.9, 60.2, 65.1,
124.1, 127.7, 129.2, 129.6, 130.9, 133.7, 135.6, 144.0. Anal.
calcd for C28H34O2SSi: C, 72.68; H, 7.41; S, 6.93. Found: C,
72.52; H, 7.73; S, 7.28.
3.1.5. 2-tert-Butyldiphenylsilyloxymethyl-3-[1-methyl-
2(SS)-phenylsulfinyl-(1S)-ethyl]-(2R,3S)-oxerane and
2-tert-butyldiphenylsilyloxymethyl-3-[1-methyl-2(RS)-
phenylsulfinyl-(1S)-ethyl]-(2R,3S)-oxerane 10. To the
solution of bromohydrin 9 (0.44 g, 0.8 mmol) in methanol
(4 mL) was added K2CO3 (0.22 g, 1.6 mmol) at 0 8C and
stirred for 2 h at rt The reaction mixture was diluted with
ether and filtered through a small pad of celite and the
solvent evaporated under reduced pressure. The crude
product was purified by column chromatography using
20% EtOAc/petroleum ether (v/v) as the eluent to afford 10
(0.38 g, 0.8 mmol) as a 1:1 epimeric mixture in quantitative
yield. Gummy liquid. Rf 0.3 (30% EtOAc/petroleum ether).
ms LSIMS 479 [MþH]þ. IR (neat) 2961, 2932, 1588, 1471,
Compound 8b. Liquid. Rf 0.25 (20% EtOAc/petroleum
ether). [a]2D5¼þ135.8 (c 1.0, CHCl3). ms (EI) 405
[Mþ2C4H9]. IR (neat) 2953, 1655, 1595, 1032, 968, 854,
1
690 cm21. H NMR (200 MHz, CDCl3) d 7.70–7.30 (m,
15H), 5.70 (m, 1H), 5.25 (m, 1H), 4.30 (d, J¼6.3 Hz, 2H),
2.92 (m, 1H), 2.73 (dd, J¼13.2, 5.1 Hz, 1H), 2.40 (dd, J¼
13.2, 9.1 Hz, 1H), 1.04 (bs, 12H). 13C NMR (50 MHz,
CDCl3) d 19.1, 20.9, 26.8, 28.3, 60.3, 65.7, 123.8, 127.5,
127.6, 129.1, 129.5, 130.9, 133.8, 135.5, 144.8. Anal. calcd
for C28H34O2SSi: C, 72.68; H, 7.41; S, 6.93. Found: C,
72.84; H, 7.65; S, 7.30.
1428, 1062, 823, 698, 625 cm21 1H NMR (300 MHz,
.
CDCl3) d 7.65–7.35 (m, 30H), 3.90–3.60 (m, 4H), 3.20–
3.0 (m, 4H), 2.85–2.55 (m, 4H), 2.0 (m, 1H), 1.75 (m, 1H),
1.25 (d, J¼7.0 Hz, 3H), 1.20 (d, J¼7.0 Hz, 3H), 1.05 (s,
18H). 13C NMR (50 MHz, CDCl3) d 16.1, 19.2, 26.8, 28.6,
57.4, 59.9, 60.3, 61.8, 63.1, 124.2, 127.8, 129.2, 129.9,
131.0, 133.0, 135.5, 144.0. Anal. calcd for C28H34O3SSi: C,
70.25; H, 7.16; S, 6.7. Found: C, 70.12; H, 7.24; S, 6.43.
3.1.4. 2-Bromo-1-tert-butyldiphenylsilyloxy-4-methyl-
5(SS)-phenylsulfinyl-(2R,3R,4S)-pentan-3-ol and 2-bro-
mo-1-tert-butyldiphenylsilyloxy-4-methyl-5(RS)-phenyl-
sulfinyl-(2R,3R,4S)-pentan-3-ol 9. To the solution of the
sulfoxide 8 (0.56 g, 1.2 mmol) in dry toluene (4.8 mL) was
added water (32 mL, 1.8 mmol), followed by NBS (256 mg,
1.44 mmol) and the reaction mixture stirred at rt for 1 h. The
reaction was quenched by the addition of an aq. saturated
NaHCO3 solution. The layers were separated and the aq.
layer extracted with EtOAc (2£25 mL). The combined
organic layers were washed with water, brine and dried over
Na2SO4. The organic layer was evaporated under reduced
pressure to afford the crude product which was purified by
column chromatography using 20% EtOAc/pet. ether (v/v)
as the eluent to yield bromohydrin 9 (0.5 g, 0.9 mmol) in
75% yield. Viscous oil. A small sample of the epimeric
mixture of bromohydrins was separated into the individual
isomers for the purpose of characterization.
3.1.6. 3-[1-Methyl-2(SS)-phenylsulfinyl-(1S)-ethyl]-
(2R,3S)-oxiran-2-ylmethanol and 3-[1-methyl-2(RS)-phe-
nylsulfinyl-(1S)-ethyl]-(2R,3S)-oxiran-2-ylmethanol 11.
To the solution of compound 10 (0.34 g, 0.71 mmol) in
dry tetrahydrofuran (1.4 mL) was added acetic acid
(0.13 mL, 2.13 mmol) and tetrabutylammonium fluoride
(1.0 mL, 1 M in THF 1.0 mmol) at 0 8C and stirred for 2 h.
The reaction mixture was then diluted with ether, washed
successively with water, brine, dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The
crude product was purified by column chromatography
using 40% EtOAc/petroleum ether (v/v) as the eluent to
afford 11 (0.154 g, 0.64 mmol) as a 1:1 epimeric mixture in
90% yield. Gummy liquid. Rf 0.2 (50% EtOAc/petroleum
ether). ms (EI) 208 [Mþ]. IR (Neat) 3354, 2964, 2932, 1586,
1462, 1425, 1047, 862, 625 cm21 1H NMR (200 MHz,
.
Compound 9a. Viscous oil. Rf 0.25 (20% EtOAc/petroleum
ether). [a]2D5¼þ49.1 (c 1.0, CHCl3). ms (FAB) 559, 501. IR
CDCl3) d 7.70–7.40 (m, 10H), 3.95–3.6 (m, 4H), 3.25–
3.05 (m, 4H), 2.95–2.75 (m, 4H), 2.65–2.50 (m, 2H), 2.35–
2.15 (m, 1H) 2.10–1.90 (m, 1H), 1.30 (d, J¼7.0 Hz, 3H),
1.15 (d, J¼7.0 Hz, 3H).
1
(neat) 3326, 2943, 1554, 1043, 972, 698, 625 cm21. H
NMR (200 MHz, CDCl3) d 7.70–7.58 (m, 6H), 7.52–7.33
(m, 9H), 4.15–3.94 (m, 3H), 3.66 (d, J¼8.6 Hz, 1H), 3.10
(dd, J¼13.1, 3.8 Hz, 1H), 2.92 (dd, J¼13.1, 3.8 Hz, 1H),
2.39 (m, 1H) 1.06 (s, 9H), 1.02 (d, J¼6.7 Hz, 3H). 13C NMR
(50 MHz, CDCl3) d 17.3, 19.8, 26.9, 34.7, 57.9, 61.2, 65.5,
72.4, 124.2, 127.9, 129.3, 129.9, 131.1, 133.7, 135.6, 144.0.
3.1.7. 2-N-Methylcarbonyloxymethyl-3-[1-methyl-2(SS)-
phenylsulfinyl-(1S)-ethyl]-(2R,3S)-oxirane and 2-N-
methylcarbonyloxymethyl-3-[1-methyl-2(RS)-phenyl-
sulfinyl-(1S)-ethyl]-(2R,3S)-oxirane 12. To the solution of

S. Raghavan, M. A. Rasheed / Tetrahedron 60 (2004) 3059–3065
3063
compound 11 (0.12 g, 0.5 mmol) in dry CH2Cl2 (2 mL) was
added Et3N (0.2 mL, 1.5 mmol) and CH3NCO (0.1 mL,
1.6 mmol) at rt and stirred for 2 h. The reaction mixture was
then cooled to 0 8C, quenched by adding 10% aq. NaHCO3
solution and diluted with ether. The organic layer was
separated and washed successively with water, brine, dried
over anhydrous Na2SO4 and evaporated under reduced
pressure. The crude product was purified by column
chromatography using 30% EtOAc/petroleum ether (v/v)
as the eluent to afford 12 (0.13 g, 0.45 mmol) as a 1:1
epimeric mixture in 90% yield. Gummy liquid. Rf 0.2 (50%
EtOAc/petroleum ether). ms LSIMS 298 [MþH]þ. IR
(Neat) 3330, 2964, 1798, 1714, 1538, 1142, 1086, 1016,
5.98 mmol) as a 1:1 epimeric mixture in 80% yield. Gummy
liquid. Rf 0.2 (50% EtOAc/petroleum ether). ms LSIMS 378
[MþH]þ. IR (Neat) 3319, 2969, 1798, 1714, 1538, 1086,
1016, 750, 690 cm21. 1H NMR (200 MHz, CDCl3) d 7.70–
7.50 (m, 10H), 5.50 (bs, 1H), 4.90 (bs, 1H), 4.60–4.10 (m,
8H), 3.50 (bs, 2H), 3.20–2.90 (m, 4H), 2.80 (d, J¼4.5 Hz,
6H), 2.63 (m, 1H), 2.45 (m, 1H), 1.30 (d, J¼7.4 Hz, 3H),
1.10 (d, J¼7.4 Hz, 3H). 13C NMR (50 MHz, CDCl3) d 16.8,
17.2, 27.5, 29.2, 34.2, 34.8, 54.9, 61.1, 62.0, 65.1, 65.5,
72.1, 74.2, 123.9, 124.0, 129.3, 131.2, 143.9, 156.8. Anal.
calcd for C14H20BrNO4S: C, 44.45; H, 5.33; N, 3.70; S,
8.48. Found: C, 44.26; H, 5.30; N, 3.56; S, 8.29.
1
750, 690 cm21. H NMR (200 MHz, CDCl3) d 7.70–7.50
3.1.10. N-Methylcarbonyloxymethyl-3-[1-methyl-2(SS)-
phenylsulfinyl-(1S)-ethyl]-(2R,3S)-oxerane and 2-N-
methylcarbonyloxymethyl-3-[1-methyl-2(RS)-phenyl-
sulfinyl-(1S)-ethyl]-(2R,3S)-oxerane 12. To the solution of
compound 15 (2.2 g, 5.82 mmol) in methanol (58 mL) was
added K2CO3 (0.88 g, 6.4 mmol) and the mixture stirred at
rt for 1 h. The reaction mixture was diluted with ether,
filtered through a small pad of celite and the solvent
evaporated under reduced pressure. The residue was
purified by column chromatography using 30% EtOAc/
petroleum ether (v/v) as the eluent to afford 12 (1.64 g,
5.53 mmol) as a 1:1 epimeric mixture in 95% yield which
was identical to the sample obtained from 11.
(m, 10H), 5.50 (bs, 2H), 4.43–4.30 (m, 2H), 4.16–3.98 (m,
2H), 3.31–3.20 (m, 2H), 2.96–2.86 (m, 4H), 2.80 (d, J¼
5.2 Hz, 6H), 2.70–2.55 (m, 2H), 2.20–1.90 (m, 2H), 1.30
(d, J¼6.7 Hz, 3H), 1.17 (d, J¼6.7 Hz, 3H). 13C NMR
(50 MHz, CDCl3) d 15.8, 16.6, 28.4, 29.0, 54.2, 54.9, 59.4,
59.9, 61.9, 62.9, 63.5, 123.6, 123.9, 129.1, 131.0, 143.7,
144.4, 156.4. Anal. calcd for C14H19NO4S: C, 56.55; H,
6.44; N, 4.71; S, 10.78. Found: C, 56.47; H, 6.21; N, 4.62; S,
10.63.
3.1.8. 1(SS)-[5-N-Methylcarbonyloxy-2-methyl-(2S,3Z)-
3-pentenylsulfinyl]-benzene and 1(RS)-[5-N-methylcar-
bonyloxy-2-methyl-(2S, 3Z)-3-pentenylsulfinyl]-benzene
14. To the solution of compound 7 (1.9 g, 8.48 mmol) in dry
CH2Cl2 (34 mL) was added Et3N (3.5 mL, 25.4 mmol) and
CH3NCO (1.5 mL, 25.4 mmol) at rt and stirred for 2 h. The
reaction mixture was then cooled to 0 8C, quenched by
adding 10% aq. NaHCO3 solution and diluted with ether.
The organic layer was separated and washed successively
with water, brine, dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The crude product was
purified by column chromatography using 30% EtOAc/
petroleum ether (v/v) as the eluent to afford 14 (2.14 g,
7.63 mmol) as a 1:1 epimeric mixture in 90% yield. Gummy
liquid. Rf 0.3 (50% EtOAc/petroleum ether). ms LSIMS 282
[MþH]þ. IR (Neat) 3321, 2963, 1712, 1537, 1446, 1263,
1037, 821 cm21. 1H NMR (200 MHz, CDCl3) d 7.60–7.40
(m, 10H), 5.80–5.60 (m, 2H), 5.50–5.30 (m, 2H), 4.70–
4.50 (m, 4H), 3.30 (m, 2H), 3.0–2.40 (m, 10H), 1.30 (d,
J¼6.7 Hz, 3H), 1.10 (d, J¼6.7 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d 20.0, 21.3, 27.4, 28.5, 28.9, 60.3, 61.3, 65.7, 66.2,
123.8, 124.7, 125.9, 129.2, 129.9, 130.9, 135.8, 136.5, 144.3,
144.8, 156.7. Anal. calcd for C14H19NO3S: C, 59.76; H, 6.81;
N, 4.98; S, 11.39. Found: C, 59.87; H, 6.68; N, 4.73; S, 11.19.
3.1.11. 4-Hydroxymethyl-3-methyl-5-[1-methyl-2(SS)-
phenylsulfinyl-(1S)-ethyl]-(4R,5R)1,3-oxazolan-2-one
and 4-hydroxymethyl-3-methyl-5-[1-methyl-2(RS)-phe-
nylsulfinyl-(1S)-ethyl]-(4R,5R)1,3-oxazolan-2-one 13. To
the solution of compound 12 (1.6 g, 5.39 mmol) in dry THF
(108 mL) at 0 8C was added NaHMDS (3 mL, 2 M/THF,
6 mmol) and stirred for 30 min. The reaction mixture was
quenched by adding saturated aq. NH4Cl solution and
diluted with ether (60 mL). The organic layer was separated
and washed successively with water, brine, dried over
anhydrous Na2SO4 and the solvent evaporated under
reduced pressure to afford a residue which was purified by
column chromatography using 70% EtOAc/petroleum ether
(v/v) as the eluent to afford 13 (1.52 g, 5.12 mmol) as a 1:1
epimeric mixture in 95% yield. Viscous oil. Rf 0.1 (80%
EtOAc/petroleum ether). ms LSIMS 298 [MþH]þ. IR
(Neat) 3331, 2922, 1744, 1520, 1443, 1255, 1087, 1033,
1
754 cm21. H NMR (300 MHz, CDCl3) d 7.60–7.50 (m,
10H), 4.40–4.30 (m, 2H), 3.80–3.60 (m, 4H), 3.50–3.40
(m, 2H), 3.05–2.90 (m, 2H), 2.85 (s, 3H), 2.80 (s, 3H),
2.70–2.50 (m, 2H), 2.32 (m, 2H), 1.30 (d, J¼6.8 Hz, 3H),
1.0 (d, J¼6.8 Hz, 3H). Anal. calcd for C14H19NO4S: C,
56.55; H, 6.44; N, 4.71; S, 10.78. Found: C, 56.37; H, 6.53;
N, 4.79; S, 10.89.
3.1.9. 2-Bromo-1-N-methylcarbonyloxy-4-methyl-5(SS)-
phenylsulfinyl-(2R,3R,4S)-pentan-3-ol and 2-bromo-1-
N-methylcarbonyloxy-4-methyl-5(RS)-phenylsulfinyl-
(2R,3R,4S)-pentan-3-ol 15. To the solution of compound
14 (2.1 g, 7.47 mmol) in toluene (30 mL) at rt was added
water (0.23 mL, 12.7 mmol), N-bromosuccinimide (1.6 g,
8.96 mmol) and stirred for 30 min. When TLC examination
revealed completion of the reaction. The reaction mixture
was taken into ethyl acetate (70 mL) and washed success-
ively with 10% aq. NaHCO3, water and brine. The organic
layer was dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The crude reaction mixture was
purified by column chromatography using 30% EtOAc/
petroleum ether (v/v) as the eluent to afford 15 (2.26 g,
3.1.12. 3-Methyl-5-[1-methyl-2(SS)-phenylsulfinyl-(1S)-
ethyl]-2-oxo-(4R,5R)-1,3-oxazolan-4-yl-methylacetate
and 3-methyl-5-[1-methyl-2(RS)-phenylsulfinyl-(1S)-
ethyl]-2-oxo-(4R,5R)-1,3-oxazolan-4-yl-methylacetate
16. To the solution of compound 13 (1.48 g, 4.98 mmol) in
dry CH2Cl2 (20 mL) was added triethylamine (1.04 mL,
7.47 mmol) followed by acetic anhydride (0.52 mL,
5.48 mmol) and stirred at rt for 30 min. The reaction
mixture was diluted with EtOAc (20 mL) and washed
successively with water, brine and dried over Na2SO4. The
solvent was removed under reduced pressure to afford a

3064
S. Raghavan, M. A. Rasheed / Tetrahedron 60 (2004) 3059–3065
residue which was purified by column chromatography
using 50% EtOAc/petroleum ether (v/v) as the eluent to
afford 16 (1.6 g, 4.73 mmol) as a 1:1 epimeric mixture in
95% yield. Viscous oil. Rf 0.4 (80% EtOAc/petroleum
ether). ms LSIMS 340 [MþH]þ. IR (Neat) 2918, 1747,
3.1.15. (4R,5R)-4-Hydroxymethyl-3-methyl-5-[(E,1R)-1-
methyl-3-pentenyl)-oxazolidin-2-one 20. To the suspen-
sion of CuI (0.2 g, 1.04 mmol) in dry THF (2 mL) at 278 8C
was added compound 19 (0.4 g, 1.04 mmol) in dry THF
(2 mL) and stirred for 30 min. 1-(E)-propenylmagnesium
bromide (prepared from 0.49 g of Mg and 2.42 g of 1-(E)-
propenyl bromide in 40 mL of THF) was added dropwise
and the reaction mixture gradually allowed to attain rt and
stirred further for 2 h. The reaction mixture was cooled to
0 8C and decomposed with sat. aq NH4Cl solution. The
reaction mixture was diluted with EtOAc and washed suc-
cessively with water, brine, dried over anhydrous Na2SO4
and the solvent evaporated under reduced pressure. The
residue was purified by column chromatography using 30%
EtOAc/petroleum ether (v/v) as the eluent to yield 20
(155 mg, 0.73 mmol) in 70% yield. White solid. Mp 82–
83 8C. Rf 0.25 (50% EtOAc/petroleum ether). [a]2D5¼þ76.0
(c 0.85, CH2Cl2). (Lit.2a [a]D25¼þ76.9 (c 0.92, CH2Cl2). ms
LSIMS 214 [MþH]þ. IR (Neat) 3445, 1767, 1717, 1472,
1444, 1230, 1088, 1037, 755, 692 cm21
.
1H NMR
(200 MHz, CDCl3) d 7.60–7.50 (m, 10H), 4.40–4.02 (m,
6H), 3.73–3.54 (m, 2H), 3.05–2.45 (m, 4H), 2.90 (s, 3H),
2.80 (s, 3H), 2.50–2.30 (m, 2H), 2.10 (s, 6H), 1.40 (d, J¼
6.7 Hz, 3H), 1.0 (d, J¼6.7 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d 15.0, 15.9, 20.4, 20.5, 29.0, 29.1, 33.1, 33.2, 58.7,
58.9, 59.0, 59.6, 62.1, 62.3, 77.2, 78.4, 123.6, 123.8, 129.2,
129.3, 131.2, 143.2, 143.3, 156.8, 156.9, 170.2. Anal. calcd
for C16H21NO5S: C, 56.62; H, 6.24; N, 4.13; S, 9.45. Found:
C, 56.47; H, 6.14; N, 4.05; S, 9.36.
3.1.13. 5-[2-Hydroxy-1-methyl-(1R)-ethyl]-3-methyl-2-
oxo-(4R,5R)-1,3-oxazolan-4-yl-methylacetate 18. To the
solution of compound 16 (1.50 g, 4.42 mmol) in aceto-
nitrile (24 mL) at rt was added triethylamine (6.15 mL,
44.2 mmol) followed by trifluoroacetic anhydride (6.2 mL,
44.2 mmol) and stirred for 30 min. A solution of NaHCO3
(7.40 g, 88.4 mmol) in water (24 mL) was added at 0 8C
followed by solid NaBH4 (1.68 g, 44.2 mmol) and the
reaction mixture stirred for another 30 min. The reaction
mixture was then extracted into ethyl acetate and washed
successively with water, brine and dried over Na2SO4. The
solvent was removed under reduced pressure to afford a
residue which was purified by column chromatography
using 30% EtOAc/petroleum ether (v/v) as the eluent to
afford 18 (0.66 g, 2.87 mmol) in 65% yield. Viscous oil. Rf
0.3 (80% EtOAc/petroleum ether). [a]2D5¼þ24.6 (c 0.66,
CHCl3). ms LSIMS 232 [MþH]þ. IR (Neat) 3327, 2925,
1
980, 690 cm21. H NMR (300 MHz, CDCl3) d 5.60–5.30
(m, 2H), 4.20 (t, J¼6.2 Hz, 1H), 3.83–3.78 (dd, J¼12.2,
3.1 Hz, 1H), 3.56–3.50 (dd, J¼12.2, 3.4 Hz, 1H), 3.39 (m,
1H), 2.87 (s, 3H), 2.20 (m, 1H), 1.91–1.76 (m, 2H), 1.70 (d,
J¼5.0 Hz, 3H), 0.90 (d, J¼6.8 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d 13.9, 17.9, 29.3, 34.5, 37.4, 61.2, 61.6, 78.8,
127.7, 158.3. Anal. calcd for C11H19NO3: C, 61.95; H, 8.98;
N, 6.57. Found: C, 61.78; H, 8.85; N, 6.53.
3.1.16. Methyl-(4S,5R)-3-methyl-5-[(E,1R)-1-methyl-3-
pentenyl)-oxazolidin-2-one-4-carboxylate 21. To the solu-
tion of the compound 20 (100 mg, 0.47 mmol) in 1:1 aceto-
nitrile/H2O (3.0 mL) was added TEMPO (16 mg,
0.08 mmol) followed by PhI(OAc)2 (314 mg, 0.98 mmol).
The reaction mixture was stirred at rt for 2 h and the solvent
was evaporated under reduced pressure. The reaction
mixture was then extracted into ethyl acetate and washed
with water. The organic layer was washed with 10% aq.
NaHCO3. The bicarbonate layer was acidified to pH 2 with
5 N HCl and extracted with ethyl acetate. To the ethyl
acetate layer was added cold (0 8C) ethereal CH2N2,
generated in situ from N-methyl N-nitroso urea (0.28 g,
2.59 mmol) in ether (10 mL) and 50% aq. KOH (4 mL) at
0 8C, and stirred at rt for 10 min. The solvent was removed
under reduced pressure to afford a residue which was
purified by column chromatography using 30% EtOAc/
petroleum ether (v/v) as the eluent to afford 21 (90 mg,
0.38 mmol) in 80% overall yield for two steps. Clean oil. Rf.
0.5 (50% EtOAc/petroleum ether). [a]2D5¼þ37.0 (c 0.80,
CH2Cl2). (Lit.2a [a]D25¼þ39.2 (c 1.67, CH2Cl2). ms LSIMS
242 [MþH]þ. IR (neat) 1753, 1442, 1402, 1235, 1046, 986,
1
1741, 1442, 1233, 1141, 1038 cm21. H NMR (200 MHz,
CDCl3) d 4.35 (dd, J¼11.8, 4.1 Hz, 1H), 4.23 (t, J¼5.9 Hz,
1H), 4.06 (dd, J¼11.8, 4.1 Hz, 1H), 3.70–3.60 (m, 3H),
2.90 (s, 3H), 2.10 (s, 3H), 2.05–1.95 (m, 1H), 1.0 (d,
J¼7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 11.6, 20.7,
29.4, 39.2, 59.0, 62.8, 63.8, 77.5, 157.5, 170.2. Anal. calcd
for C10H17NO5: C, 51.94; H, 7.41; N, 6.06. Found: C, 51.74;
H, 7.32; N, 6.12.
3.1.14. 3-Methyl-5-[1-methyl-2-(4-methylphenylsulfonyl-
oxy)-(1R)-ethyl]-2-oxo-(4R,5R)-1,3-oxazolan-4-yl-
methylacetate 19. To the solution of compound 18 (0.6 g,
2.6 mmol) in dry DCM (11 mL), was added catalytic
amounts of DMAP, Et3N (0.54 mL, 3.9 mmol), p-toluene-
sulfonyl chloride (0.55 g, 2.86 mmol) and the mixture
stirred at rt for 2 h. The reaction mixture was diluted with
EtOAc (20 mL) and washed successively with water, brine,
dried over anhydrous Na2SO4 and the solvent evaporated
under reduced pressure. The residue was purified by column
chromatography using 40% EtOAc/petroleum ether (v/v)
as the eluent to yield 19 (0.85 g, 2.21 mmol) in 85% yield
and used immediately in the next step. Viscous oil. Rf 0.2
(50% EtOAc/petroleum ether). [a]2D5¼þ17.7 (c 0.23,
CHCl3). ms LSIMS 386 [MþH]þ. IR (Neat) 2987, 1747,
1
700 cm21. H NMR (300 MHz, CDCl3) d 5.55–5.31 (m,
2H), 4.28 (dd, J¼6.2, 4.8 Hz, 1H), 3.97 (d, J¼4.8 Hz, 1H),
3.82 (s, 3H), 2.91 (s, 3H), 2.25–2.17 (m, 1H), 2.0–1.83 (m,
2H), 1.66 (d, J¼6.0 Hz, 3H), 0.95 (d, J¼6.6 Hz, 3H). Anal.
calcd for C12H19NO4: C, 59.74; H, 7.94; N, 5.81. Found: C,
59.70; H, 7.80; N, 5.70.
1
1651, 1633, 1435, 1036, 969 cm21. H NMR (400 MHz,
CDCl3) d 7.76 (d, J¼7.0 Hz, 2H), 7.38 (d, J¼7.0 Hz,
2H), 4.32 (dd, J¼12.7, 3.2 Hz, 1H), 4.12 (dd, J¼12.7,
2.0 Hz, 1H), 4.05–3.95 (m, 3H), 3.70–3.60 (m, 1H),
2.85 (s, 3H), 2.46 (s, 3H), 2.20–2.05 (m, 4H), 1.0 (d, J¼
6.8 Hz, 3H).
Acknowledgements
S.R is thankful to Dr. J. S. Yadav, Director, IICT, for
constant support and encouragement; to Dr. A. C. Kunwar
for NMR spectra and Dr. Vairamani for the mass spectra.

S. Raghavan, M. A. Rasheed / Tetrahedron 60 (2004) 3059–3065
3065
28, 2849. (e) Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli,
C.; Weber, T. Helv. Chim. Acta 1987, 70, 237. (f) Aebi, J. D.;
Dhaon, M. K.; Rich, D. H. J. Org. Chem. 1987, 52, 2881.
(g) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108,
6757.
M.A.R. is thankful to CSIR (New Delhi) for the senior
research fellowship. Financial assistance from DST is
gratefully acknowledged.
5. (a) Raghavan, S.; Rasheed, M. A.; Joseph, S. C.; Rajender, A.
J. Chem. Soc., Chem. Commun. 1999, 1845. (b) Raghavan, S.;
Ramakrishna Reddy, S.; Tony, K. A.; Naveen Kumar, Ch.;
Varma, A. K.; Nangia, A. J. Org. Chem. 2002, 67, 5838.
6. (a) Raghavan, S.; Joseph, S. C. Tetrahedron: Asymmetry 2003,
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