Synthesis of enantiopure bis-aziridines, bis-epoxides, and aziridino-epoxides from d-mannitol

Article abstract of DOI:10.1016/j.tet.2006.08.035

A practical synthesis of enantiopure bis-aziridines 11 and 15, bis-epoxides 12 and 17, and aziridino-epoxides 27 and 30 is reported using inexpensive d-mannitol as the starting material. The key transformation involves the reductive cleavage of bis-benzyl

Full text of DOI:10.1016/j.tet.2006.08.035

Tetrahedron 62 (2006) 10162–10170
Synthesis of enantiopure bis-aziridines, bis-epoxides, and
aziridino-epoxides from D-mannitol
,y
*
Devarajulu Sureshkumar, Susama Maity and Srinivasan Chandrasekaran
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012, Karnataka, India
Received 26 April 2006; revised 26 July 2006; accepted 10 August 2006
Available online 6 September 2006
Abstract—A practical synthesis of enantiopure bis-aziridines 11 and 15, bis-epoxides 12 and 17, and aziridino-epoxides 27 and 30 is reported
using inexpensive D-mannitol as the starting material. The key transformation involves the reductive cleavage of bis-benzylidene acetal 3 to
form dimesylate 4, which was further converted to monoazides and diazides followed by reduction, mesylation, and cyclization to furnish the
required compounds in good yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
yield in two steps. Using a procedure developed by Baskaran
et al.,11 a highly regio- and chemoselective reductive cleav-
age of bis-benzylidene acetal 3 with BF3$Et2O/Et3SiH in dry
CH2Cl2 furnished C2-symmetric diol 4 (78%), which was
then converted to the acetonide 5 in 80% yield. Nucleophilic
substitution of the dimesylate 5 with NaN3 afforded the
corresponding diazide11b 6, which was subjected to chemo-
selective reduction using Lindlar’s catalyst to furnish the
bis-amine 7. Compound 7 was converted to the ditosylate
8 followed by deprotection using FeCl3$6H2O12 in dry
CH2Cl2 to give the diol 9. Finally, mesylation of diol 9
and intramolecular cyclization using NaH in THF af-
forded enantiopure C2-symmetric 2,4-bis-aziridine 11 in
23% overall yield from D-mannitol. The structure of com-
pound 1113 was confirmed by single crystal X-ray analysis
(Fig. 2).
D-Mannitol is a naturally occurring inexpensive chiral build-
ing block used for the synthesis of many biologically active
and pharmaceutically important natural products.1,2 In gen-
eral the bis-aziridines, bis-epoxides, and aziridino-epoxides
derived from mannitol are key intermediates in the synthesis
of various nitrogen, sulfur, and selenium heterocycles with
potential biological activity.4–8 Though Depezay et al.3 re-
ported the first synthesis of enantiopure 1,5-bis-aziridine
and 1,5-bis-epoxide from D-mannitol in 1986, there are no
alternate synthetic procedures available for the synthesis
of chirally pure 1,5-bis-aziridines, 1,5-bis-epoxides, and
2,4-bis-epoxides. Additionally there are no reports on the
synthesis of 2,4-bis-aziridines, 1,5-aziridino-epoxides, and
2,4-aziridino-epoxides from D-mannitol in the literature.
The main problem with Depezay’s procedure is the difficulty
in the removal of triphenyl phosphine oxide byproduct.
Herein, we report simple alternative procedures for the syn-
thesis of optically pure 1,5-bis-aziridine, 1,5-bis-epoxide,
2,4-bis-aziridine, 2,4-bis-epoxide, 1,5-aziridino-epoxide,
and 2,4-aziridino-epoxide starting from the same intermedi-
ate, bis-benzylidene acetal 2, derived from D-mannitol.
2.2. Synthesis of 2,4-bis-epoxide 12
In order to synthesize the 2,4-bis-epoxide 12 from D-manni-
tol, dimesylate 4 was directly treated with NaH in THF. It
underwent cyclization to afford the required enantiopure
2,4-bis-epoxide14 12 in 47% overall yield from D-mannitol
(Scheme 2). Bis-epoxide 12 is a useful starting material
for the synthesis of C2-symmetric, diol-based HIV-1 prote-
ase inhibitors.15
2. Results and discussion
2.1. Synthesis of 2,4-bis-aziridine 11
2.3. Synthesis of 1,5-bis-aziridine 15
The bis-benzylidene acetal 29 derived from D-mannitol was
converted to the dimesylate 310 (Scheme 1; Fig. 1) in 71%
In order to synthesize the 1,5-bis-aziridine 15, the inter-
mediate ditosylate 8 (from Scheme 1) was subjected to hy-
drogenolysis (10% Pd/C, H2, 1 atm, MeOH) to furnish diol
13 in 90% yield. Treatment of 13 with methane sulfonyl
chloride followed by intramolecular cyclization using NaH
in dry THF gave C2-symmetric bis-aziridine3 15 in 24%
overall yield from D-mannitol (Scheme 3).
Keywords: Bis-benzylidene acetal; Bis-aziridines; Bis-epoxides; Aziridino-
epoxides.
* Corresponding author. Tel.: +91 80 2293 2404; fax: +91 80 2360 2423;
e-mail: scn@orgchem.iisc.ernet.in
Honorary Professor, Jawaharlal Nehru Center for Advanced Scientific
y
Research, Jakkur, Bangalore.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.035

D. Sureshkumar et al. / Tetrahedron 62 (2006) 10162–10170
Ph
10163
Ph
OMs
OH OH OH
OH OH OH
1
OH
O
O
OMs O
O
HO
HO
OBn
OBn
Et3N, MsCl
BF3.Et2O, Et3SiH
CH2Cl2, 1 h
78%
PhCHO, DMF
CH Cl , 0
C
°
2
2
2 h
Con. H2SO4
rt, 5 days
86%
O
O
OH
O
O
OMs
OMs
4
82%
Ph
Ph
D-Mannitol
3
2
2,2-DMP, PTSA (cat)
rt, 5 h, acetone
80%
NHTs
OBn
OMs
N3
NH2
Lindlar's catalyst
H2 (1 atm)
OBn
OBn
OBn
OBn
OBn
OBn
O
O
O
O
O
NaN3, DMF
TsCl, Py
110 C, 24 h
°
0
C to rt
MeOH, rt, 4 h
95%
°
3 h
O
O
O
OBn
NHTs
8
91%
OMs
5
N3
6
NH2
7
86%
FeCl3.6H2O
CH2Cl2, rt, 30 min
86%
NHTs
NHTs
OBn
NTs
TsN
TsN
OBn
HO
HO
MsO
MsO
OBn
OBn
MsCl, Py
NaH, THF
OBn
0 °C to rt
3 h
91%
BnO
TsN
0 °C to rt, 12 h
OBn
NHTs
9
OBn
NHTs
10
88%
11
Scheme 1. Synthesis of C2-symmetric N-tosyl-2,4-bis-aziridine 11.
2.4. Synthesis of 1,5-bis-epoxide 17
The synthesis of 1,5-bis-epoxide 17 utilizes dimesylate 5 as
the starting material, which upon hydrogenolysis (10%
Pd/C, H2, 1 atm, MeOH) afforded diol 16 in 86% yield. Sub-
sequent intramolecular cyclization using NaH in THF gave
the bis-epoxide3 17 in 32% overall yield from D-mannitol
(Scheme 4). The bis-aziridine 15 and bis-epoxide 17 are
the key intermediates in the synthesis of thiepane deriva-
tives, which are potential glycosidase7a and HIV protease8
inhibitors. The structure of bis-epoxide 1716 was confirmed
by X-ray analysis (Fig. 3).
2.5. Synthesis of 2,4-aziridino-epoxide 27
In order to synthesize the aziridino-epoxide 27, bis-benzyl-
idene acetal 2 was reacted with 1 equiv TsCl in pyridine
to furnish the monotosylate 18 in 62% yield. Compound
18 was converted to acetate 19, which on reductive
cleavage with BF3$Et2O/Et3SiH in dry CH2Cl2 gave the
diol 20 in 78% yield. Next, diol 20 was protected as the
corresponding acetonide 21. Formation of the correspond-
ing azide 22 and reduction using Lindlar’s catalyst pro-
vided amine 23 in 91% yield. Amine 23 was converted
to the tosylate 24, which on hydrolysis resulted in the
formation of diol 25. Finally, diol 25 was converted into
dimesylate 26 and intramolecular cyclization using NaOMe
in MeOH afforded the 2,4-aziridino-epoxide 27 in 15%
overall yield from D-mannitol (Scheme 5).
Figure 1. Solid ꢀstate structure of compound 3 and C–H/O (C9–H9B/O:
˚
2.485 A; 140.08 ) interactionsthat form chainlike structurethrough‘b’ axis.

10164
D. Sureshkumar et al. / Tetrahedron 62 (2006) 10162–10170
ꢀ
˚
Figure 2. Solid state structure of compound 11 and C–H/O (C33–H33/O6: 2.570 A; 137.44 ) interactions that form chain like structure through ‘a’ axis.
O
OMs
NaH, THF
O
O
BnO
4
OBn
OH
OH
O
O
°
0
C to rt, 6 h
85%
O
O
O
NaH, THF
10% Pd/C, H2
5
12
0
C to rt, 7 h
85%
°
MeOH, rt, 4 h
86%
OMs
16
Scheme 2. Synthesis of C2-symmetric 2,4-bis-epoxide 12.
17
Scheme 4. Synthesis of C2-symmetric 1,5-bis-epoxide 17.
2.6. Synthesis of 1,5-aziridino-epoxide 30
To synthesize the unsymmetrical 1,5-aziridino-epoxide 30,
acetate 24 was subjected to hydrogenolysis (10% Pd/C,
H2, 1 atm, MeOH) to afford the diol 28 in 83% yield. Com-
pound 28 on treatment with methane sulfonyl chloride gave
the dimesylate 29, which upon intramolecular cyclization
using NaOMe in MeOH (0 ꢀC, 1 h) furnished the 1,5-aziri-
dino-epoxide 30 in 15% overall yield from D-mannitol
(Scheme 6).
3. Conclusion
In conclusion, we have demonstrated here the development
of simple but efficient synthesis of enantiopure bis-aziri-
dines 11 and 15, bis-epoxides 12 and 17, and aziridino-
epoxides 27 and 30 from readily available and inexpensive
D-mannitol.
NHTs
NHTs
NTs
OMs
O
O
O
O
OH
O
O
Et3N, MsCl
NaH, THF
10% Pd/C, H2
MeOH, rt, 12 h
90%
8
CH2Cl2, 0 °C
2 h
0 °C, 1 h
87%
OMs
NHTs
14
OH
NHTs
13
NTs
15
92%
Scheme 3. Synthesis of C2-symmetric 1,5-bis-aziridine 15.

D. Sureshkumar et al. / Tetrahedron 62 (2006) 10162–10170
10165
procedures. Analytical TLC was performed on commercial
plates coated with silica gel GF254 (0.25 mm). Silica gel
(230–400 mesh) was used for column chromatography.
Melting points determined are uncorrected. Yields refer to
chromatographically and spectroscopically (1H NMR) ho-
mogeneous materials, unless otherwise stated. NMR spectra
were recorded on 300 or 400 MHz instrument and calibrated
using residual undeuterated solvent as an internal reference.
The following abbreviations explain the multiplicity: s¼
singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, and
br¼broad. IR spectra were recorded on a FTIR spectrometer.
4.1.1. (S)-2-(Benzyloxy)-1-((4R,5R)-5-((S)-2-(benzyloxy)-
1-(tosylamino)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-N-
tosylethanamine 8. The azide 6 was synthesized from
D-mannitol according to the literature procedure.11 Lindlar’s
catalyst (0.115 g, 20 wt %) was added to the stirred solution
of azide 6 (1 g, 2.2 mmol) in methanol (20 mL). The reac-
tion flask was evacuated and flushed with H2 gas. The resul-
tant mixture was stirred under hydrogen atmosphere
(balloon) at room temperature (28 ꢀC) for 4 h. After comple-
tion of the reaction, the catalyst was filtered through a pad of
Celite, washed with methanol (50 mL) and the filtrate was
concentrated under reduced pressure. To the crude residue
(0.84 g, 2.1 mmol) in pyridine (15 mL) at 0 ꢀC was added
tosyl chloride (0.88 g, 4.5 mmol) slowly. After 3 h stirring
at room temperature, the reaction mixture was poured into
ice cold solution of 1 M HCl and extracted with diethyl ether
thrice (100 mL). The combined organic layers were washed
with brine and dried over anhydrous Na2SO4. Removal of
the solvent gave a yellow residue. The residue was purified
Figure 3. Solid state structure of compound 17.
4. Experimental
4.1. General methods
All reactions were carried out in oven-dried apparatus using
dry solvents under anhydrous conditions. Commercial grade
solvents were distilled and dried according to literature
Ph
Ph
OTs
2,2-DMP
OTs O
O
OTs O
O
HO
HO
OBn
OBn
TsCl (1 Equiv), Py
Ac2O, Py
BF3.Et2O, Et3SiH
CH2Cl2, 1 h
78%
PTSA (cat.)
2
°
°
-5 to 0 C, 2 h
0
C to rt
acetone
rt, 5 h
O
O
OAc
19
O
O
OH
2 h, 87%
62%
OAc
20
80%
Ph
Ph
18
OTs
N3
NH2
Lindlar's catalyst
H2 (1 atm)
OBn
OBn
OBn
OBn
OBn
OBn
O
O
O
O
O
O
TsCl, Py
NaN3, DMF
°
0 °C to rt
3 h
86%
MeOH, rt, 4 h
91%
110 C, 24 h
88%
OAc
21
OAc
22
OAc
23
NHTs
NHTs
NHTs
Ts
N
OBn
OBn
OBn
O
O
HO
MsO
MsO
FeCl3 6H2O
MsCl, Py
NaOMe, MeOH
CH2Cl2, rt, 30 min
80%
0 °C to rt
3 h
91%
0 °C to rt, 1h
HO
OBn
OBn
OBn
OBn
88%
BnO
O
OAc
OAc
OAc
27
25
26
24
Scheme 5. Synthesis of 2,4-aziridino-epoxide 27.
NHTs
OH
NHTs
NTs
OMs
O
O
O
O
O
10% Pd/C, H2
MsCl, Py
NaOMe, MeOH
0 °C to rt, 1 h
88%
24
MeOH, rt, 24 h
0 °C to rt
3 h
91%
O
OH
OMs
O
83%
OAc
28
OAc
29
30
Scheme 6. Synthesis of 1,5-aziridino-epoxide 30.

10166
D. Sureshkumar et al. / Tetrahedron 62 (2006) 10162–10170
over silica gel (230–400 mesh) using 10–20% EtOAc in hex-
ane solvent as eluent to afford pure compound 8 (1.28 g,
86%) as a colorless liquid. Rf ¼0.80 (EtOAc/hexanes, 3:7);
[a]2D5 +16.00 (c 1.0, CHCl3); IR (neat): 3281, 1328, 1160,
in dry THF (10 mL), NaH (0.08 g, 3.18 mmol) was slowly
added at 0 ꢀC. The mixture was stirred at 20 ꢀC for 12 h,
and then slowly water (1 mL) was added drop wise at 0 ꢀC
to quench the excess of NaH. The reaction mixture was di-
luted with water and extracted with Et2O (3ꢂ10 mL). The
combined organic layers were dried (Na2SO4) and evapo-
rated to afford after flash chromatography (silica gel; EtOAc/
hexanes, 80:20) the bis-aziridine 11 (0.59 g, 88%) as a color-
less solid. Rf ¼0.80 (EtOAc/hexanes, 1:1); mp: 121 ꢀC; [a]D27
+38.00 (c 1.0, CHCl3); IR (neat): 1596, 1328, 1160, 1090,
1092, 814, 738, 699, 667 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 7.71 (d, J¼8.1 Hz, 2H), 7.32–7.26 (m, 3H),
7.17–7.13 (m, 4H), 4.87 (d, J¼9.3 Hz, 1H), 4.29 (s, 2H),
4.05 (s, 1H), 3.69–3.62 (m, 1H), 3.39–3.29 (m, 2H), 2.35
(s, 3H), 1.30 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 143.2, 138.1, 137.7, 129.4, 128.2, 127.6, 127.5, 127.1,
109.1, 76.7, 72.9, 70.5, 52.2, 26.9, 21.5; HRMS m/z calcd
for C37H44N2O8S2 [M+Na+]: 731.2437; found: 731.2462.
675 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 7.73 (d,
J¼8.4 Hz, 2H), 7.35–7.17 (m, 7H), 4.39 (s, 2H), 3.67–3.57
(m, 2H), 3.08–2.99 (m, 1H), 2.89–2.84 (m, 1H), 2.41 (s,
3H); 13C NMR (75 MHz, CDCl3): d 144.6, 137.5, 134.4,
129.6, 128.3, 127.9, 127.8, 127.6, 72.9, 66.4, 41.9, 39.3,
21.6; HRMS m/z calcd for C34H36N2O6S2 [M+Na+]:
655.1912; found: 655.1914.
4.1.2. (2S,3R,4R,5S)-1,6-Bis(benzyloxy)-2,5-bis(tosyl-
amino)hexane-3,4-diol 9. To a solution of 8 (1 g,
1.41 mmol) in CH2Cl2 (20 mL) at room temperature was
added FeCl3$6H2O11 (1.33 g, 4.94 mmol). The resulting yel-
low to amber colored suspension was stirred for 30 min and
quenched by the addition of saturated aqueous NaHCO3.
The aqueous layer was extracted three times with CH2Cl2,
and the combined organics were washed with brine, dried
over Na2SO4, and concentratedunderreduced pressure. Flash
chromatography of the resulting oil on silica gel (230–400
mesh) and elute with 20% EtOAc/hexanes yielded amino
diol 9 (0.811 g, 86%). Rf ¼0.15 (EtOAc/hexanes, 3:7); [a]D25
ꢁ23.00 (c 1.0, CHCl3); IR (neat): 3469, 3278, 1317, 1160,
4.1.5. (2S,3R)-2-((Benzyloxy)methyl)-3-((2R,3S)-3-
((benzyloxy)methyl)oxiran-2-yl)oxirane 12. Bis-epoxide
12 (0.267 g, 85%) was synthesized from the dimesylate 4
(0.50 g, 0.97 mmol) as a colorless liquid by using the proce-
dure described for compound 11 (see Section 4). Rf ¼0.80
(EtOAc/hexanes, 1:1); [a]2D7 +68.00 (c 1.0, CHCl3); IR
1
(neat): 1454, 1274, 1099, 892, 748, 700 cmꢁ1; H NMR
(300 MHz, CDCl3): d 7.39–7.21 (m, 5H), 4.55 (dd,
J¼15.3, 12.0 Hz, 2H), 3.72 (dd, J¼11.7, 3.0 Hz, 1H), 3.49
(dd, J¼11.7, 5.1 Hz, 1H), 3.17–3.15 (m, 1H), 2.89 (s, 1H);
13C NMR (75 MHz, CDCl3): d 137.6, 128.3, 127.6, 127.5,
73.1, 68.9, 54.4, 53.4; HRMS m/z calcd for C20H22O4
[M+Na+]: 349.1416; found: 349.1424.
1
813, 659 cmꢁ1; H NMR (300 MHz, CDCl3): d 7.71 (d,
J¼8.1 Hz, 2H), 7.34–7.24 (m, 3H), 7.21–7.15 (m, 4H), 4.31
(dd, J¼28.50, 12.0 Hz, 2H), 3.85 (s, 1H), 3.66 (t, J¼4.2 Hz,
1H), 3.37 (dd, J¼9.9, 4.5 Hz, 1H), 3.28 (dd, J¼9.9, 5.4 Hz,
1H), 2.54 (br s, 1H), 2.37 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 143.3, 137.8, 137.3, 129.5, 128.3, 127.7, 127.6,
126.9, 73.1, 70.9, 70.2, 53.4, 21.4; HRMS m/z calcd for
C34H40N2O8S2 [M+Na+]: 691.2124; found: 691.2124.
4.1.6. (S)-2-((4R,5R)-5-((S)-1-(Tosylamino)ethyl)-2,2-di-
methyl-1,3-dioxolan-4-yl)-N-tosyl ethanamine 13. A solu-
tion of ditosylate 8 (0.50 g, 0.71 mmol) in MeOH (10 mL)
was treated with H2 over 10% Pd/C (0.05 mg) at atmo-
spheric pressure for 12 h. The mixture was filtered through
Celite and the solvent was evaporated in vacuo. The crude
residue was purified by chromatography on silica gel
(230–400 mesh) using 30–50% EtOAc in hexane solvent
as eluent to afford pure compound 13 (0.336 g, 90%) as a col-
orless liquid. Rf ¼0.20 (EtOAc/hexanes, 7:3); [a]2D5 ꢁ42.00
(c 1.0, CHCl3); IR (neat): 3472, 3281, 1324, 1158, 816,
4.1.3. (2R,3S,4S,5R)-1,6-Bis(benzyloxy)-3,4-bis((methyl-
sulfonyl)methyl)-N2,N5-ditosylhexane-2,5-diamine 10.
To a solution of diol 9 (0.80 g, 1.19 mmol) in dry CH2Cl2
(10 mL), pyridine (0.3 mL, 3.65 mmol) followed by mesyl
chloride (0.24 mL, 2.98 mmol) were slowly added at 0 ꢀC.
The mixture was stirred at 20 ꢀC for 3 h. The reaction
mixture was diluted with Et2O followed by washing with
cold HCl (1 N). The aqueous layer was extracted with
Et2O (3ꢂ10 mL). The combined organic layers were dried
(Na2SO4) and evaporated to afford after flash chromato-
graphy (silica gel; EtOAc/hexanes, 80:20) dimesylate 10
(0.923 g, 91%) as a colorless liquid. Rf ¼0.50 (EtOAc/
hexanes, 1:1); [a]2D5 +18.00 (c 1.0, CHCl3); IR (neat): 3280,
658 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 7.78 (d, J¼
8.1 Hz, 2H), 7.34 (d, J¼8.1 Hz, 2H), 5.36 (d, J¼9.3 Hz,
1H), 4.17 (s, 1H), 3.64 (dd, J¼11.4, 2.7 Hz, 1H), 3.46–
3.42 (m, 1H), 3.17–3.14 (m, 1H), 2.43 (s, 3H), 1.39 (s,
3H); 13C NMR (75 MHz, CDCl3): d 143.9, 137.4, 129.9,
126.9, 109.7, 79.1, 63.9, 51.4, 26.9, 21.5; HRMS m/z calcd
for C23H32N2O8S2 [M+Na+]: 551.1498; found: 551.1501.
1
1454, 1334, 1162, 1091, 815, 738, 667 cmꢁ1; H NMR
(300 MHz, CDCl3): d 7.64 (d, J¼8.1 Hz, 2H), 7.30–7.26
(m, 3H), 7.19 (d, J¼8.1 Hz, 2H), 7.13–7.09 (m, 2H), 5.13
(d, J¼9.9 Hz, 1H), 5.06 (d, J¼6.0 Hz, 1H), 4.31 (d,
J¼11.7 Hz, 1H), 4.20 (d, J¼11.7 Hz, 1H), 4.02–3.95
(m, 1H), 3.43 (dd, J¼10.5, 2.1 Hz, 1H), 3.24 (s, 3H),
2.87 (dd, J¼10.5, 3.9 Hz, 1H), 2.39 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 143.8, 137.2, 136.9, 129.9, 128.5,
127.9, 127.8, 126.9, 76.7, 73.2, 67.2, 53.7, 39.2, 21.5;
HRMS m/z calcd for C36H44N2O12S4 [M+Na+]: 847.1675;
found: 847.1695.
4.1.7. (1S)-1-((4S,5S)-2,2-Dimethyl-5-(1S)-1-[(4-methyl-
phenyl)sulfonyl]oxy-2-[(methylsulfonyl)oxy]ethyl-1,3-di-
oxolan-4-yl)-2-[(methylsulfonyl)oxy]ethyl 4-methyl-1-
benzenesulfonate 14. The dimesylate 14 (0.358 g, 92%)
was synthesized from the diol 13 (0.30 g, 0.57 mmol) as
a colorless liquid by using the procedure described for com-
pound 10 (see Section 4). Rf ¼0.20 (EtOAc/hexanes, 1:1);
[a]2D5 ꢁ28 (c 1.0, CHCl3); IR (neat): 3278, 1451, 1336,
1171, 1094, 821, 744, 668 cmꢁ1 1H NMR (300 MHz,
;
4.1.4. (2R,3R)-2-((Benzyloxy)methyl)-3-((2R,3R)-3-
((benzyloxy)methyl)-1-tosylaziridin-2-yl)-1-tosylaziri-
dine 11. To a solution of dimesylate 10 (0.90 g, 1.09 mmol)
CDCl3): d 7.78 (d, J¼8.1 Hz, 2H), 7.35 (d, J¼8.1 Hz, 2H),
5.08 (d, J¼9.6 Hz, 1H), 4.07–3.97 (m, 3H), 3.82–3.76 (m,
1H), 2.84 (s, 3H), 2.44 (s, 3H), 1.37 (s, 3H); 13C NMR

D. Sureshkumar et al. / Tetrahedron 62 (2006) 10162–10170
10167
(75 MHz, CDCl3): d 144.1, 137.5, 129.9, 127.0, 110.1, 75.1,
67.3, 50.7, 37.2, 26.8, 21.5; HRMS m/z calcd for
C25H36N2O12S4 [M+Na+]: 707.1049; found: 707.1062.
3.82 (t, J¼10.5 Hz, 1H), 3.61 (dd, J¼9.3, 1.5 Hz, 1H), 3.47
(t, J¼10.5 Hz, 1H), 2.21 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 145.4, 137.3, 136.8, 132.5, 129.9, 129.1, 128.8,
128.2, 127.9, 127.8, 126.2, 126.0, 101.3, 100.4, 77.3, 74.9,
71.0, 68.6, 67.2, 59.7, 21.5; HRMS m/z calcd for
C27H28O8S [M+Na+]: 535.1403; found: 535.1416.
4.1.8. (S)-2-((4R,5R)-2,2-Dimethyl-5-((S)-1-tosylaziridin-
2-yl)-1,3-dioxolan-4-yl)-1-tosyl aziridine 15. The bis-azir-
idine 15 (0.22 g, 87%) was synthesized from the dimesylate
14 (0.35 g, 0.51 mmol) as a colorless solid by using the pro-
cedure described earlier for compound 11 (see Section 4).
Rf ¼0.30 (EtOAc/hexanes, 2:8); mp: 68 ꢀC; [a]D27 ꢁ34.00
(c 1.0, CHCl3); IR (neat): 1930, 1596, 1325, 1162,
4.1.12. (2R,3S,4R,5R)-5-Acetoxy-1,6-bis(benzyloxy)-3,4-
dihydroxy-2-yl-4-methylbenzene sulfonate 20. To a solu-
tion of monotosylate 18 (2.5 g, 4.88 mmol) in dry pyridine
(20 mL), Ac2O (0.51 mL, 5.34 mmol) was slowly added at
0 ꢀC. The reaction mixture was stirred at 20 ꢀC for 2 h and
it was diluted with Et2O followed by washing with cold
HCl (1 N). The aqueous layer was extracted with Et2O
(3ꢂ10 mL). The combined organic layers were dried
(Na2SO4) and the solvent was evaporated to afford crude
acetate 19 (silica gel; EtOAc/hexanes, 80:20) as a colorless
liquid, which was used in the next step without purification.
To a crude solution of 19 in dry CH2Cl2 (40 mL) at 0 ꢀC was
added Et3SiH (1.3 mL, 7.94 mmol) followed by BF3$Et2O
(1.5 mL, 11.6 mmol). After stirring the reaction mixture at
0 ꢀC for 1 h, it was quenched with saturated NaHCO3 solu-
tion (15 mL) and extracted with CH2Cl2 (2ꢂ20 mL). The
organic layer was dried over anhydrous Na2SO4 and concen-
trated under reduced pressure to yield the product, which
was purified by flash chromatography to give pure diol 20
(1.85 g, 68% overall yield). Rf ¼0.20 (EtOAc/hexanes,
3:7); [a]2D5 ꢁ104.00 (c 1.0, CHCl3); IR (neat): 3462, 1740,
678 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 7.81 (d,
J¼8.1 Hz, 2H), 7.35 (d, J¼8.1 Hz, 2H), 3.83 (dd, J¼2.7,
1.5 Hz, 1H), 2.77–2.73 (m, 1H), 2.60 (d, J¼7.2 Hz, 1H),
2.45 (s, 3H), 2.38 (d, J¼4.2 Hz, 1H), 1.25 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 144.9, 134.6, 129.8, 128.0,
110.4, 75.9, 37.8, 30.9, 26.6, 21.6; HRMS m/z calcd for
C23H28N2O6S2 [M+Na+]: 515.1287; found: 515.1304.
4.1.9. (1R)-2-Hydroxy-1-((4S,5S)-5-(1R)-2-hydroxy-1-
[(methylsulfonyl)oxy]ethyl-2,2-dimethyl-1,3-dioxolan-
4-yl)ethyl methanesulfonate 16. The diol 16 (0.175 g,
86%) was synthesized from the dimesylate 5 (0.30 g,
0.54 mmol) as a colorless liquid by using the procedure de-
scribed earlier for compound 13. Rf ¼0.20 (EtOAc/hexanes,
1:1); [a]2D5 +84.00 (c 1.0, CHCl3); IR (neat): 3472, 1317,
1158, 814, 658 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d 4.81–4.79 (m, 1H), 4.37 (dd, J¼3.9, 1.5 Hz, 1H), 4.03
(dd, J¼12.9, 3.3 Hz, 1H), 3.89 (dd, J¼12.9, 6.0 Hz, 1H),
3.19 (s, 3H), 1.44 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 111.3, 82.0, 61.4, 38.7, 26.9; HRMS m/z calcd for
C11H22O10S2 [M+Na+]: 401.0552; found: 401.0546.
1374, 1236, 1092, 736, 696 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 7.75 (d, J¼8.1 Hz, 2H), 7.36–7.18 (m, 12H),
5.00 (q, J¼4.2 Hz, 1H), 4.70 (q, J¼3.9 Hz, 1H), 4.57 (dd,
J¼22.2, 12.0 Hz, 2H), 4.41 (s, 2H), 3.98 (d, J¼8.4 Hz,
1H), 3.83 (d, J¼7.8 Hz, 1H), 3.75 (d, J¼4.5 Hz, 2H),
3.69 (dd, J¼6.0, 4.2 Hz, 2H), 2.38 (s, 3H), 2.07 (s, 3H);
13C NMR (75 MHz, CDCl3): d 170.9, 144.9, 137.7,
137.5, 133.4, 129.7, 128.4, 128.3, 127.9, 127.7, 127.6,
79.3, 73.4, 71.8, 68.7, 68.4, 68.1, 67.7, 21.6, 21.1; HRMS
m/z calcd for C29H34O9S [M+Na+]: 581.1821; found:
581.1833.
4.1.10. (4R,5R)-2,2-Dimethyl-4,5-di((S)-oxiran-2-yl)-1,3-
dioxolane 17. The bis-epoxide 17 (0.063 g, 85%) was syn-
thesized from the diol 16 (0.15 g, 0.40 mmol) as colorless
crystals by using the procedure described for compound 11
(see Section 4). Rf ¼0.70 (EtOAc/hexanes, 3:7); mp: 74 ꢀC;
[a]2D7 ꢁ19.00 (c 1.0, CHCl3); IR (neat): 1460, 1360, 1276,
1
1096, 890, 752, 712 cmꢁ1; H NMR (300 MHz, CDCl3):
d 3.86 (dd, J¼3.3, 1.5 Hz, 1H), 3.10–3.06 (m, 1H), 2.85
(dd, J¼5.4, 4.2 Hz, 1H), 2.75 (dd, J¼5.4, 2.4 Hz, 1H), 1.42
(s, 3H); 13C NMR (75 MHz, CDCl3): d 110.7, 77.9, 51.1,
43.8, 26.6; HRMS m/z calcd for C9H14O4 [M+Na+]:
209.0790; found: 209.0798.
4.1.13. (R)-1-((4S,5R)-5-((S)-1-Azido-2-(benzyloxy)-
ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(benzyloxy)-
ethyl acetate 22. The diol 20 (1.8 g, 3.23 mmol) was
dissolved in dry acetone (15 mL) and then treated with
2,2-dimethoxypropane (1.2 mL, 9.68 mmol) followed by a
solution of pTSA in dry acetone (4 mL). The resultant mix-
ture was allowed to stir for 5 h at room temperature. The
mixture was then diluted with EtOAc (15 mL), washed
with a saturated solution of NaHCO3 (2ꢂ5 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pres-
sure to yield a crude product, which was purified by flash
chromatography to give pure acetonide 21 (1.53 g, 80%
yield). A suspension of acetonide 21 (1.5 g, 2.54 mmol)
and sodium azide (0.198 g, 3.05 mmol) in dry DMF (30 mL)
was stirred at 110 ꢀC for 24 h. After evaporation of DMF,
15 mL of water was added to the residue, which was then
extracted with CH2Cl2. The organic extract was dried
(Na2SO4) and evaporated to give a syrupy liquid, which
was purified by flash column chromatography to give pure
azide 22 (1.05 g, 88%). Rf ¼0.80 (EtOAc/hexanes, 2:8);
[a]2D5 +53.00 (c 1.0, CHCl3); IR (neat): 2105, 1743, 1454,
4.1.11. (2R,4S,5R)-4-((2R,4R,5R)-5-Hydroxy-2-phenyl-
1,3-dioxan-4-yl)-2-phenyl-1,3-dioxan-5-yl-4-methylbenz-
enesulfonate 18. To a solution of diol 2 (3 g, 8.38 mmol)
in dry pyridine (30 mL), tosyl chloride (1.75 g, 9.22 mmol)
was slowly added at ꢁ5 ꢀC. Then the reaction mixture was
stirred for 2 h at 20 ꢀC. The reaction mixture was diluted
with Et2O followed by washing with cold HCl (1 N). The
aqueouslayer was extracted with Et2O (3ꢂ10 mL). The com-
bined organiclayers were dried (Na2SO4)and the solventwas
evaporated to afford after flash chromatography (silica gel;
EtOAc/hexanes, 80:20) monotosylate 18 (2.66 g, 62%) as
a colorless liquid. Rf ¼0.20 (EtOAc/hexanes, 4:6); [a]D25
ꢁ22.00 (c 1.0, CHCl3); IR (neat): 3464, 1338, 1154, 821,
660 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 7.73 (d,
J¼8.1 Hz, 2H), 7.45–7.31 (m, 10H), 7.09 (d, J¼8.1 Hz,
2H), 5.48 (s, 1H), 4.96 (s, 1H), 4.82 (m, 1H), 4.41 (dd,
J¼11.1, 5.4 Hz, 1H), 4.26–4.16 (m, 2H), 4.03 (m, 1H),
1371, 1232, 1097, 738, 698 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 7.37–7.23 (m, 10H), 5.17–5.12 (m, 1H), 4.55

10168
D. Sureshkumar et al. / Tetrahedron 62 (2006) 10162–10170
(d, J¼5.1 Hz, 2H), 4.51 (d, J¼3.0 Hz, 2H), 4.29 (dd, J¼7.8,
5.2 Hz, 1H), 4.10 (dd, J¼7.8, 2.7 Hz, 1H), 3.81–3.61 (m,
4H), 3.53–3.48 (m, 1H), 2.05 (s, 3H), 1.45 (s, 3H), 1.35 (s,
3H); 13C NMR (75 MHz, CDCl3): d 170.1, 137.6, 137.5,
128.4, 128.3, 127.7, 127.6, 127.5, 110.4, 77.8, 76.1, 73.3,
73.2, 69.9, 68.4, 60.7, 26.9, 26.7, 20.9; HRMS m/z calcd
for C25H31N3O6 [M+Na+]: 492.2111; found: 492.2104.
136.8, 129.8, 128.5, 128.4, 128.2, 128.1, 127.9, 127.8,
126.9, 79.6, 73.8, 73.3, 70.3, 68.4, 67.4, 52.6, 39.1, 38.2,
21.6, 20.8; HRMS m/z calcd for C31H39NO12S3 [M+Na+]:
736.1532; found: 736.1533.
4.1.17. (2R,3S)-2-((Benzyloxy)methyl)-3-((2S,3S)-3-
((benzyloxy)methyl)oxiran-2-yl)-1-tosyl aziridine 27. To
a solution of dimesylate 26 (0.50 g, 0.70 mmol) in dry
MeOH (10 mL), NaOMe (0.151 g, 2.8 mmol) was slowly
added at 0 ꢀC. The mixture was stirred at 20 ꢀC for 1 h,
and then MeOH was evaporated under reduced pressure.
The reaction mixture was diluted with water and extracted
with Et2O (3ꢂ10 mL). The combined organic extract was
dried (Na2SO4) and evaporated to afford after flash chroma-
tography (silica gel; EtOAc/hexanes, 80:20) the aziridino-
epoxide 27 (0.296 g, 88%) as a colorless liquid. Rf ¼0.80
(EtOAc/hexanes, 3:7); [a]2D5 +20.00 (c 1.0, CH2Cl2); IR
4.1.14. (R)-2-(Benzyloxy)-1-((4S,5R)-5-((S)-2-(benzyl-
oxy)-1-(tosylamino)ethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)ethyl acetate 24. The tosylate 24 (0.993 g, 78% overall
yield) was synthesized from the azide 22 (1 g, 2.13 mmol)
as a colorless liquid by using the procedure described for
compound 8. Rf ¼0.40 (EtOAc/hexanes, 3:7); [a]2D5 ꢁ30.00
(c 1.0, CHCl3); IR (neat): 3295, 1743, 1454, 1371, 1332,
1232, 1160, 1091, 815, 738, 698, 665 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): d 7.69 (d, J¼8.1 Hz, 2H), 7.32–7.25
(m, 10H), 7.17 (d, J¼8.1 Hz, 2H), 5.20–5.15 (m, 1H), 4.98
(d, J¼9.3 Hz, 1H), 4.52 (dd, J¼18.6, 12.0 Hz, 2H), 4.32
(s, 2H), 4.25 (dd, J¼8.1, 1.5 Hz, 1H), 3.86 (dd, J¼8.1,
6.0 Hz, 1H), 3.65 (dd, J¼11.4, 3.6 Hz, 2H), 3.48 (dd,
J¼11.4, 6.0 Hz, 1H), 3.40 (dd, J¼9.3, 5.1 Hz, 1H), 3.33
(dd, J¼17.1, 9.0 Hz, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 1.35
(s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 170.1, 143.2, 137.9, 137.7, 137.6, 129.5, 128.3, 128.2,
127.6, 127.5, 127.4, 127.3, 126.9, 109.6, 76.6, 75.9, 72.9,
72.8, 72.1, 69.9, 68.7, 52.6, 26.9, 26.7, 21.4, 20.9; HRMS
m/z calcd for C32H39NO8S [M+Na+]: 620.2294; found:
620.2267.
1
(neat): 1361, 1336, 1176, 1162, 923, 721 cmꢁ1; H NMR
(300 MHz, CDCl3): d 7.82 (d, J¼8.1 Hz, 2H), 7.33–7.18
(m, 12H), 4.50 (s, 2H), 4.43 (d, J¼2.4 Hz, 2H), 3.70 (d,
J¼1.8 Hz, 1H), 3.68 (s, 1H), 3.65 (d, J¼2.7 Hz, 1H), 3.44
(dd, J¼11.7, 4.8 Hz, 1H), 3.17 (dd, J¼11.7, 6.0 Hz, 1H),
3.07–3.04 (m, 1H), 2.99 (dd, J¼7.2, 2.1 Hz, 1H), 2.91 (dd,
J¼7.2, 4.5 Hz, 1H), 2.41 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 144.8, 137.6, 134.5, 129.7, 128.4, 128.3, 128.0,
127.8, 127.7, 127.6, 73.3, 73.0, 68.6, 66.7, 55.2, 50.7,
42.9, 41.8, 21.6; HRMS m/z calcd for C27H29NO5S
[M+Na+]: 502.1664; found: 502.1664.
4.1.18. (R)-2-Hydroxy-1-((4S,5R)-5-((S)-2-hydroxy-1-(to-
sylamino)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl
acetate 28. The diol 28 (0.29 g, 83%) was synthesized from
the tosylate 24 (0.50 g, 0.84 mmol) as a colorless liquid
by using the hydrogenolysis procedure described earlier
for compound 13. Rf ¼0.40 (EtOAc/hexanes, 3:7); [a]D25
ꢁ16.00 (c 1.0, CHCl3); IR (neat): 3523, 3297, 1739, 1598,
4.1.15. (2R,3S,4R,5S)-1,6-Bis(benzyloxy)-3,4-dihydroxy-
5-(tosylamino)hexan-2-yl acetate 25. Diol 25 (0.672 g,
80%) was synthesized from acetonide 24 (0.90 g,
1.51 mmol) as a colorless liquid by using the procedure
described for compound 9. Rf ¼0.20 (EtOAc/hexanes, 4:8);
[a]2D5 +21.00 (c 1.0, CHCl3); IR (neat): 3502, 3272, 1733,
1
1
1454, 1240, 1160, 1093, 815, 738, 698 cmꢁ1; H NMR
1454, 1367, 1243, 1176, 1093, 983, 815, 665 cmꢁ1; H
(300 MHz, CDCl3): d 7.70 (d, J¼8.1 Hz, 2H), 7.33–7.17
(m, 12H), 5.47 (d, J¼6.9 Hz, 1H), 5.02–4.97 (m, 1H), 4.52
(d, J¼3.6 Hz, 2H), 4.33 (s, 2H), 3.80–3.71 (m, 4H), 3.46
(d, J¼7.2 Hz, 2H), 3.34–3.29 (m, 3H), 2.37 (s, 3H), 2.04
(s, 3H); 13C NMR (75 MHz, CDCl3): d 170.6, 143.4,
137.6, 137.2, 136.9, 129.6, 128.4, 128.3, 127.8, 127.7,
127.6, 127.1, 73.3, 73.2, 72.2, 69.6, 68.7, 68.6, 68.5, 55.7,
21.5, 20.9; HRMS m/z calcd for C29H35NO8S [M+Na+]:
580.1981; found: 580.1993.
NMR (300 MHz, CDCl3): d 7.71 (d, J¼8.1 Hz, 2H), 7.32
(d, J¼8.1 Hz, 2H), 5.17 (d, J¼8.1 Hz, 1H), 4.28 (dd,
J¼9.9, 2.4 Hz, 1H), 3.99–3.88 (m, 5H), 3.72–3.68 (m,
2H), 2.43 (s, 3H), 2.12 (s, 3H), 1.34 (s, 3H), 1.27 (s, 3H);
13C NMR (75 MHz, CDCl3): d 171.6, 143.9, 137.3, 129.8,
127.0, 109.7, 78.1, 74.9, 71.9, 68.8, 66.1, 51.9, 26.8, 21.6,
21.5, 20.7; HRMS m/z calcd for C18H27NO8S [M+Na+]:
440.1355; found: 440.1362.
4.1.19. (1R)-2-Hydroxy-1-[(4S,5R)-5-((1S)-2-hydroxy-1-
[(4-methylphenyl)sulfonyl]amino ethyl)-2,2-dimethyl-
1,3-dioxolan-4-yl]ethyl acetate 29. The dimesylate 29
(0.312 g, 91%) was synthesized from the diol 28 (0.25 g,
0.60 mmol) as a colorless liquid by using the procedure de-
scribed earlier for compound 10. Rf ¼0.80 (EtOAc/hexanes,
3:7); [a]2D5 ꢁ18.00 (c 1.0, CHCl3); IR (neat): 3303, 1749,
4.1.16. (2R,3S,4R,5S)-1,6-Bis(benzyloxy)-3,4-dimethane-
sulfono-5-(tosylamino)hexan-2-yl acetate 26. The dimesy-
late 26 (0.70 g, 91%) was synthesized from the diol 25
(0.60 g, 1.08 mmol) as a colorless liquid by using the proce-
dure described for compound 10. Rf ¼0.40 (EtOAc/hexanes,
3:7); [a]2D5 +29.00 (c 1.0, CHCl3); IR (neat): 3280, 1749,
1596, 1454, 1353, 1228, 1178, 1093, 954, 738, 700,
1596, 1355, 1226, 1089, 970, 815 cmꢁ1
;
1H NMR
667 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 7.66 (d,
(300 MHz, CDCl3): d 7.78 (d, J¼8.1 Hz, 2H), 7.34 (d, J¼
8.1 Hz, 2H), 5.04 (d, J¼9.6 Hz, 1H), 4.86–4.81 (m, 1H),
4.56 (dd, J¼12.6, 2.1 Hz, 1H), 4.23 (dd, J¼7.8, 1.2 Hz,
1H), 4.11–3.84 (m, 5H), 3.14 (s, 3H), 2.90 (s, 3H), 2.44 (s,
3H), 2.12 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 170.3, 144.1, 137.5, 129.9, 127.1,
110.9, 79.0, 73.9, 67.4, 63.0, 51.9, 38.8, 37.2, 26.8, 26.6,
21.5, 20.7; HRMS m/z calcd for C20H31NO12S3 [M+Na+]:
596.0906; found: 596.0922.
J¼8.1 Hz, 2H), 7.30–7.24 (m, 8H), 7.21 (d, J¼8.1 Hz,
2H), 7.08–7.04 (m, 2H), 5.49 (dd, J¼7.8, 2.4 Hz, 1H),
5.33–5.26 (m, 2H), 5.18 (d, J¼9.9 Hz, 1H), 4.55 (dd,
J¼13.8, 11.4 Hz, 2H), 4.07 (d, J¼11.4 Hz, 1H), 3.95–3.88
(m, 2H), 3.84 (dd, J¼10.2, 5.4 Hz, 1H), 3.69–3.62 (m,
1H), 3.23 (s, 3H), 3.09 (s, 3H), 2.95 (dd, J¼9.9, 3.0 Hz,
1H), 2.67 (dd, J¼9.9, 4.8 Hz, 1H), 2.41 (s, 3H), 1.96 (s,
3H); 13C NMR (75 MHz, CDCl3): d 175.2, 143.9, 137.3,

D. Sureshkumar et al. / Tetrahedron 62 (2006) 10162–10170
10169
5. (a) Szczepina, M. G.; Johnston, B. D.; Yuan, Y.; Svensson, B.;
Pinto, B. M. J. Am. Chem. Soc. 2004, 126, 12458–12469; (b)
Fuzier, M.; Merrer, Y. L.; Depezay, J. C. Tetrahedron Lett.
1995, 36, 6443–6446.
6. (a) Paulsen, H.; Todt, K. Chem. Ber. 1967, 100, 512–520; (b)
Farr, R. A.; Holland, A. K.; Huber, E. W.; Peet, N. P.;
Weintraub, P. M. Tetrahedron 1994, 50, 1033–1044; (c)
Lohray, B. B.; Jayamma, Y.; Chatterjee, M. J. Org. Chem.
4.1.20. (S)-2-((4R,5S)-2,2-Dimethyl-5-((R)-oxiran-2-yl)-
1,3-dioxolan-4-yl)-1-tosylaziridine 30. Dimesylate 29
was subjected to cyclization using the procedure described
earlier for compound 27 to furnish aziridino-epoxide 30
(0.163 g, 80% overall yield). Rf ¼0.60 (EtOAc/hexanes,
3:7); [a]2D5 ꢁ59.00 (c 1.0, CH2Cl2); IR (neat): 1939, 1598,
1325, 1163, 668 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d 7.84 (d, J¼8.1 Hz, 2H), 7.35 (d, J¼8.1 Hz, 2H), 4.02
(dd, J¼7.8, 3.9 Hz, 1H), 3.35 (t, J¼7.8 Hz, 1H), 2.99–2.95
(m, 1H), 2.91–2.85 (m, 1H), 2.81 (dd, J¼8.7, 5.1 Hz, 1H),
2.66 (d, J¼7.5 Hz, 1H), 2.47–2.45 (m, 1H), 2.46 (s, 3H),
2.41 (d, J¼4.8 Hz, 1H), 1.37 (s, 3H), 1.32 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 144.7, 134.5, 129.7, 128.3,
110.8, 79.3, 76.6, 51.4, 45.9, 39.7, 30.4, 26.9, 26.4, 21.6;
HRMS m/z calcd for C16H21NO5S [M+Na+]: 362.1038;
found: 362.1040.
´
1995, 60, 5958–5960; (d) Morıs-Varas, F.; Qian, X.; Wong,
C. H. J. Am. Chem. Soc. 1996, 118, 7647–7652; (e) Qian,
´
X. H.; Morıs-Varas, F.; Fitzgerald, M. C.; Wong, C. H.
Bioorg. Med. Chem. 1996, 4, 2055–2069; (f) Merrer, Y. L.;
Poitout, L.; Depezay, J. C.; Dosbaa, I.; Geoffry, S.; Foglietti,
M. J. Bioorg. Med. Chem. 1997, 5, 519–533; (g) Andreana,
P. R.; Sanders, T.; Janczuk, A.; Warrick, J. I.; Wang, P. G.
Tetrahedron Lett. 2002, 43, 6525–6528; (h) Joseph, C. C.;
Regeling, H.; Zwanenburg, B.; Chittenden, G. J. F. Tetrahedron
2002, 58, 6907–6911; (i) Tilekar, J. N.; Patil, N. T.; Jadhav,
H. S.; Dhavale, D. D. Tetrahedron 2003, 59, 1873–1876; (j)
Painter, G. F.; Elridge, P. J.; Falshaw, A. Bioorg. Med. Chem.
2004, 12, 225–232.
Acknowledgements
We thank CSIR, New Delhi for senior research fellowships to
S.M. and D.S., and DST, New Delhi for CCD X-ray facility
and J. C. Bose National Fellowship to S.C.
7. (a) Merrer, L. Y.; Fuzier, M.; Dosbaa, I.; Foglietti, M. J.;
Depezay, J. C. Tetrahedron 1997, 53, 16731–16746; (b)
Arcelli, A.; Cere, V.; Peri, F.; Pollicino, S.; Ricci, A.
Tetrahedron: Asymmetry 2002, 13, 191–196; (c) Arcelli, A.;
Cere, V.; Peri, F.; Pollicino, S.; Ricci, A. Tetrahedron
2001, 57, 3439–3444; (d) Cere, V.; Mantovani, G.; Peri, F.;
Pollicino, S.; Ricci, A. Tetrahedron 2000, 56, 1225–1231;
(e) Halila, S.; Benazza, M.; Demailly, G. Tetrahedron
Lett. 2001, 42, 3307–3310; (f) Kuszmann, J.; Sohar, P.
Carbohydr. Res. 1977, 56, 105–115; (g) Dureault, A.;
Tranchepain, I.; Depezay, J. C. J. Org. Chem. 1989, 54,
5324–5330.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.08.035.
References and notes
8. Kim, C. U.; McGee, L. R.; Krawczyk, S. H.; Harwood, E.;
Harada, Y.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.;
Cherrington, J. M.; Xiong, S. F.; Griffin, L.; Cundy, D. C.;
Lee, A.; Yu, B.; Gulnik, S.; Erickson, J. W. J. Med. Chem.
1996, 39, 3431–3434.
9. (a) Baggett, N.; Stribblehill, P. J. Chem. Soc., Perkin Trans. 1
1997, 1123–1126; (b) Winn, C. L.; Goodman, J. M.
Tetrahedron Lett. 2001, 42, 7091–7093.
1. (a) Chandrasekar, M.; Chandra, K. L.; Singh, V. K. J. Org.
Chem. 2003, 68, 4039–4045; (b) Chakraborty, T. K.;
Srinivasu, P.; Kiran Kumar, S.; Kunwar, A. C. J. Org. Chem.
2002, 67, 2093–2100; (c) Lohray, B. B.; Baskaran, S.;
Rao, B. S.; Reddy, B. Y.; Rao, I. N. Tetrahedron Lett. 1999,
40, 4855–4856; (d) Babjak, M.; Kapitan, P.; Gracza, T.
Tetrahedron Lett. 2002, 43, 6983–6985; (e) Poitout, L.;
Merrer, Y. L.; Depezay, J. C. Tetrahedron Lett. 1994, 35,
3293–3296.
2. (a) Chandrasekar, M.; Chandra, K. L.; Singh, V. K.
Tetrahedron Lett. 2002, 43, 2773–2775; (b) Chandrasekar,
M.; Raina, S.; Singh, V. K. Tetrahedron Lett. 2000, 41,
4969–4971; (c) Raina, S.; Singh, V. K. Tetrahedron 1996,
52, 4479–4484.
3. (a) Merrer, Y. L.; Dureault, A.; Gravier, C.; Languin, D. M.;
Depezay, J. C. Tetrahedron Lett. 1985, 26, 319–322; (b)
Dureault, C.; Greck, C.; Depezay, J. C. Tetrahedron Lett.
1986, 27, 4157–4160; (c) Merrer, Y. L.; Dureault, A.; Greck,
C.; Languin, D. M.; Gravier, C.; Depezay, J. C. Heterocycles
1987, 25, 541–548.
4. (a) Wang, C. J. J.; Wuonola, M. A. Org. Prep. Proced. Int. 1992,
24, 585–621; (b) Angle, S. R.; Breitenbucher, J. G. Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, The Netherlands, 1995; Vol. 16, pp 453–502; (c)
Leclercq, S.; Daloze, D.; Braekman, J. C. Org. Prep. Proced.
Int. 1996, 28, 501–543; (d) Nadin, A. Contemp. Org. Synth.
1997, 4, 387–414; (e) Bailey, P. D.; Millwood, P. A.; Smith,
P. D. Chem. Commun. 1998, 633–640; (f) Laschat, S.;
Dickner, T. Synthesis 2000, 1781–1813.
10. Crystal data for compound 3: structure was solved by direct
methods (SIR92). Refinement was by full-matrix least-squares
procedures on F2 by using SHELXL-97. Crystal system:
triclinic, space group: P21/c, cell parameters: a¼11.256(4),
b¼9.278(4), c¼12.614(5) A, a¼90.00ꢀ, b¼112.461(6)ꢀ,
˚
3
g¼90.00 , V¼1217.41 A , Z¼2, rcalcd¼1.40 g cmꢁ3, F(000)¼
ꢀ
˚
340, m¼0.272 mmꢁ1, l¼0.71073 A. Total number l.s. para-
˚
meters¼309. R1¼0.053 for 4240 Fo>4s(Fo) and 0.071 for all
8862 data. wR2¼0.104, GOF¼1.035, restrained GOF¼1.035
for all data. (CCDC no. 612123).
11. (a) Aravind, A.; Baskaran, S. Tetrahedron Lett. 2005, 46,
743–745; (b) Aravind, A.; Subhendu, K.; Pratap, V.;
Baskaran, S. Tetrahedron Lett. 2005, 46, 2965–2968; (c)
Debenham, S. D.; Toone, E. J. Tetrahedron: Asymmetry
2000, 11, 385–387.
12. Sen, S. E.; Roach, S. L.; Boggs, J. K.; Ewing, G. L.; Magrath, J.
J. Org. Chem. 1997, 62, 6684–6686.
13. Crystal data for compound 11: structure was solved by direct
methods (SIR92). Refinement was by full-matrix least-squares
procedures on F2 by using SHELXL-97. Crystal system:
triclinic, space group: P21, cell parameters: a¼22.752(3),
b¼7.383(7), c¼22.459(2) A, a¼90.00ꢀ, b¼118.819(3)ꢀ,
˚

10170
D. Sureshkumar et al. / Tetrahedron 62 (2006) 10162–10170
3
g¼90.00 , V¼3305.49 A , Z¼4, rcalcd¼1.27 g cmꢁ3, F(000)¼
b¼11.272(9), c¼8.406(9) A, a¼90.00ꢀ, b¼105.842(2)ꢀ,
ꢀ
˚
˚
1336, m¼0.207 mmꢁ1, l¼0.71073 A. Total number l.s. para-
g¼90.00 , V¼495.35 A , Z¼2, rcalcd¼1.25 g cmꢁ3, F(000)¼
3
ꢀ
˚
˚
meters¼399. R1¼0.049 for 5710 Fo>4s(Fo) and 0.060 for
all 11973 data. wR2¼0.107, GOF¼1.134, restrained
GOF¼1.134 for all data. (CCDC no. 292270).
200, m¼0.098 mmꢁ1, l¼0.71073 A. Total number l.s. para-
˚
meters¼120. R1¼0.045 for 1673 Fo>4s(Fo) and 0.060 for all
3523 data. wR2¼0.085, GOF¼1.079, restrained GOF¼1.079
for all data. (CCDC no. 292059). Crystallographic data (ex-
cluding structure factors) for the structures in this paper
have been deposited to the Cambridge Crystallographic
Data Centre as supplementary publication. Copies of these
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk or
via www.ccdc.cam.ac.uk/conts/retrieving.html.
14. Lohray, B. B.; Vidya, B.; Chatterjee, M.; Jayamma, Y.;
Prasuna, G. Res. Chem. Intermed. 1999, 25, 887–901.
15. Muhlman, A.; Classon, B.; Hallberg, A.; Samuelsson, B.
J. Med. Chem. 2001, 44, 3402–3406.
16. Crystal data for compound 17: structure was solved by direct
methods (SIR92). Refinement was by full-matrix least-squares
procedures on F2 by using SHELXL-97. Crystal system:
triclinic, space group: P21, cell parameters: a¼5.434(6),