A new stereoselective approach to aminocyclohexitols using a Grignard addition on to an N-benzyl sugar imine and RCM

Article abstract of DOI:10.1016/j.tetasy.2011.07.015

A new stereoselective approach for the synthesis of cyclohexitols using a Grignard addition on to an N-benzyl sugar imine and RCM from d-glucose has been described; the glycosidase inhibitory activity of these amino cyclohexitols has also been studied.

Full text of DOI:10.1016/j.tetasy.2011.07.015

Tetrahedron: Asymmetry 22 (2011) 1342–1346
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A new stereoselective approach to aminocyclohexitols using a Grignard
addition on to an N-benzyl sugar imine and RCM
Maddimsetti Venkateswara Rao a, Bandari Chandrasekhar a, Batchu Venkateswara Rao a,
,
⇑
Jasti Lakshmi Swarnalatha b
a Organic Division-III, Indian Institute of Chemical Technology, Hyderabad 500607, India
b Bio-Transformations Laboratory, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2011
Accepted 15 July 2011
A new stereoselective approach for the synthesis of cyclohexitols using a Grignard addition on to an
N-benzyl sugar imine and RCM from -glucose has been described; the glycosidase inhibitory activity
of these amino cyclohexitols has also been studied.
D
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
NH2
HO
NH2
NH2
HO
HO
HO
HO
The development of inhibitors for glycosidases is an important
challenge toward the treatment of diseases, such as diabetes, can-
cer, viral infections, lysosomal disorders1 and so on. Recently amino
cyclohexitols have drawn considerable attention as potent glycosi-
dase inhibitors. Some of the naturally occurring and biologically ac-
tive amino cyclohexitols include valiolamine 1, validamine 2, and
valienamine 3. Voglibose 4 (Fig. 1), which is a derivative of valiol-
OH
OH
HO
OH
OH
OH
valiolamine 1
OH
OH
OH
validamine 2
valienamine 3
amine shows excellent inhibitor activity against
a
-glycosidases2
and is used as a drug in the treatment of diabetes.3 Therefore, the
synthesis and biological evaluation of analogues of valiolamine is
an important area of research.4 The key structural feature that ap-
pears in most of these compounds is the presence of amino and
hydroxymethyl units at the 1- and 3-positions on a polyhydroxy
cyclohexane moiety. In the context of glycosidase inhibition, these
compounds can be considered as structural analogs of monosac-
charides containing a basic nitrogen function at the anomeric cen-
ter. In particular, the amino group mimics the protonated form of
NH2
NH2
OH
HN
OH
HO
HO
OH
HO
OH
OH
OH
OH
OH
OH
OH
OH
voglibose 4
6
5
Figure 1.
the leaving group oxygen atom in the
a- and b-orientation in the
transition state of glycosidase catalyzed reactions.5 However, gly-
cosidase inhibition of aminocyclitols as a function of the various
structural and stereochemical features still remains to be fully
understood. Hence, the synthesis of new analogs can provide not
only a better understanding of glycosidase function but also lead
to inhibitors with improved therapeutic activity.
sugars. Recently, we developed an approach for the synthesis of
bicyclic imino sugars using a stereoselective Grignard addition
onto sugar imines and RCM.6 Herein, we report the application of
the above strategy for the synthesis of two new aminocarbapyra-
noses 5 and 6, which are structural analogs of valiolamine 1. Our
synthesis started from aldehyde 7, which can be prepared from
commercially available D
-glucose using a known procedure.7 Con-
2. Results and discussions
densation of aldehyde 7 with benzylamine in the presence of 4 Å
molecular sieves afforded chiral imine 8, which was used as such
for the next step without any purification. Treatment of imine 8
with allyl magnesium bromide in THF at 0 °C gave syn-amino olefin
9 as the exclusive isomer (Scheme 1). The stereochemistry of the
newly generated stereogenic center was confirmed at a later stage
Over the last few years, our group has been involved in the
development of new synthetic strategies for carbasugars and imino
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.015

M. V. Rao et al. / Tetrahedron: Asymmetry 22 (2011) 1342–1346
1343
by 1H NMR chemical shifts and coupling constants and also by NOE
Hg2
HO
Ha
OH
Hg1
experiments. The formation of the syn-isomer is in accordance
with our earlier observation, wherein the ring oxygen, the chelates
with the Grignard reagent directs the nucleophile to undergo addi-
tion with high stereoselectivity8 (Fig. 2). The amino functionality in
compound 9 was protected as its Cbz derivative by treating it with
benzyloxy carbonyl chloride in the presence of NaHCO3 in MeOH to
afford compound 10 in 92% yield. Next, 1,2-isopropylidene group
in compound 10 was removed using TFA–H2O to give hemiacetal
11. Hemiacetal 11 was treated with NaIO4 in CH2Cl2–H2O to give
the aldehyde, which was reduced to diol 12 with NaBH4 in metha-
nol in 74% yield. The N-Cbz protecting group was advantageously
utilized for the selective protection of the secondary hydroxyl
group of 12. Thus, treatment of compound 12 with NaH in THF
Hf
NH2
OH
NH2
OH
Hd
OH
HO
He
HO
OH
HO
OH
Hc
Hb
5
Figure 3.
3. Glycosidase inhibitory study
9
gave oxazolidinone 13. Reduction of 13 with Na/liquid NH3 fur-
nished compound 14. This diene 14, upon reaction with Grubbs’
second generation catalyst10 in toluene at reflux afforded the
aminocyclitol 15. Isopropylidenation of 15 with 2,2-DMP in the
presence of PTSA (catalyst) at room temperature gave 16.
The inhibitory activities of compounds 5 and 6 were tested
against a few enzymes, and the results are shown in Table 1. The
glycosidase inhibitory activity against
a-glucosidase (yeast), b-glu-
cosidase (almonds), -galactosidase (green coffee beans) and
a
b-galactosidase (Kluyveromyces lactis) for compounds 5 and 6 were
studied and the IC50 values are summarized in Table 1. The residual
hydrolytic activities of the glycosidases were measured spectromet-
rically on the corresponding chromogenic nitrophenyl glycosides as
substrates in an aqueous phosphate buffer at pH 6.8. All enzymes
and substrates were purchased from Sigma–Aldrich Co., USA. The
assays were performed with a fixed concentration of the substrate
(1.6 mM) in a phosphate buffer and the enzyme concentration was
O
O
ref.6
a
O
D-glucose
O
BnO
7
BnN
100 ll (1 mg/ml) in 20 ml of substrate solution. The substrate and
BnHN
O
compounds were preincubated for 1 min and the reaction was
started by the addition of the enzyme. The reaction for the enzyme
activity was followed for 5 min at 405 nm. Compound 5 was found
O
b
O
O
O
O
to show moderate inhibition of a-glucosidase and a-galactosidase
BnO
BnO
at concentrations of 0.82 and 1.2 mM respectively, whereas it
showed no inhibition of b-glucosidase and b-galactosidase. On the
other hand, compound 6 showed no inhibition of b-glucosidase,
9
8
Scheme 1. Reagents and conditions: (a) BnNH2, 4 Å molecular sieves, CH2Cl2, 0 °C,
4 h; (b) allyl magnesium bromide, ether, 0 °C, overnight, 92%.
a-galactosidase, and b-galactosidase, but exhibited inhibition of
a-glucosidase at a concentration of 1.02 mM.
R
Br
Mg
R
Table 1
Br
Mg
Glycosidase inhibitory activity, IC50 values in mM
BnN
Enzymes
-Glucosidase
b-Glucosidase
-Galactosidase
5
6
O
O
a
0.82 mM
NI⁄
1.02 mM
NI⁄
H
NBn
O
H
O
O
a
1.2 mM
NI⁄
NI⁄
NI⁄
O
b-Galactosidaes
BnO
H
BnO
H
NI: no inhibition at 2 mM concentration.
Figure 2.
4. Conclusion
In conclusion, we have developed an efficient synthetic strategy
for the preparation of two new aminocarbapyranoses using a Grig-
nard reaction on a chiral imine, ring closing metathesis and dihydr-
oxylation as key steps; their glycosidase inhibition was also
studied. The extension of this approach for the preparation of other
aminocyclitols is currently in progress in our laboratory.
The stereoselective dihydroxylation of 16 with osmium tetraox-
ide in the presence of NMO in acetone/water (3:1) gave the dihy-
droxylated compound 17 as the exclusive isomer.11,12 Global
deprotection of isopropylidene and the oxazolidine rings in com-
pound 17 with 6 M HCl in methanol at reflux12 afforded amino car-
basugar 5. Reduction of the olefin in compound 15 with H2, Pd/C in
methanol followed by deprotection of the oxazolidine ring with
6 M HCl in methanol at reflux gave 6 in 75% yield (Scheme 2).
The new two amino carbasugars 5 and 6 were confirmed by using
1D NOE and coupling constants. The coupling constant JHa-
Hb = 10.0 Hz in compound 5 confirms the axial orientation of the
Ha and Hb protons. The strong NOE between Hc–Hb, Hc–Hd and
Hc–He further confirmed the structure of compound 5 (Fig. 3).
5. Experimental
5.1. General
TLC was performed on Merck Kiesel gel 60; F254 plates (layer
thickness 0.25 mm). Column chromatography was performed on

1344
M. V. Rao et al. / Tetrahedron: Asymmetry 22 (2011) 1342–1346
CbzBnN
CbzBnN
O
O
OH
OH
c
b
O
a
9
O
BnO
11
BnO
d
10
O
O
CbzBnN
RN
HN
OH
O
g
f
O
OH
OH
OH
OBn
OR
OH
12
R= Bn, 13
R= H, 14
15
e
j
O
O
HN
NH2
HN
NH2
O
OH
O
h
i
OH
HO
HO
O
OH
O
OH
O
OH
O
OH
OH
17
OH
6
16
5
Scheme 2. Reagents and conditions: (a) CbzCl, NaHCO3, MeOH, rt, 4 h, 92%; (b) TFA/H2O (2:1), rt, 3 h, 74%; (c) NaIO4, MeOH–H2O, 6 h, then NaBH4, MeOH, rt, 1 h, 74%; (d)
NaH, THF, 0 °C, 20 min, 92%; (e) Na, liquid NH3, THF, ꢂ78 °C, 20 min, 64%; (f) Grubbs’ second generation catalyst, toluene, reflux, 4 h, 61%; (g) 2,2-DMP, PTSA, CH2Cl2, 0 °C, 1 h,
71%; (h) OsO4, NMO, acetone/H2O (3:1), 0 °C, 24 h, 94%; (i) 6 M HCl, MeOH, reflux, 12 h, 73%; (j) 10% Pd/C, MeOH, 1 h, then 6 M HCl, MeOH, H2, reflux, 12 h, 75%.
silica gel (60–120 mesh) using ethyl acetate and hexane mixture as
eluents. Melting points were determined on a Fisher John’s melting
point apparatus. IR spectra were recorded on a Perkin–Elmer RX-1
FT-IR system. 1H NMR and 13C NMR spectra were recorded using
Bruker Avance-300 MHz, Varian-400, and 500 MHz spectrometers.
1H NMR data are expressed as chemical shifts in ppm followed by
multiplicity (s—singlet; d—doublet; t—triplet; q—quartet; m—mul-
tiplet), number of proton (s) and coupling constant (s) J (Hz). 13C
NMR chemical shifts are expressed in ppm. Optical rotations were
measured with a JASCO digital polarimeter. Accurate mass mea-
surement was performed on Q STAR mass spectrometer (Applied
Biosystems, USA). Compounds were analyzed by using proton 1D
NMR techniques. Here the conformations are fixed by considering
the observed coupling constants and NOEs.
5.94–5.72 (m, 3H), 5.39 (d, 1H, J = 11.3 Hz), 5.26 (d, 1H,
J = 17.9 Hz), 5.07–4.98 (m, 2H), 4.70 (d, 1H, J = 11.1 Hz), 4.60–
4.52 (m, 2H), 4.14 (d, 1H, J = 8.6 Hz), 3.8 (d, 1H, J = 12.6 Hz), 3.7
(d, 1H, J = 12.6 Hz), 2.78 (m, 1H), 2.47 (m, 1H), 2.27 (m, 1H), 1.60
(s, 3H), 1.36 (s, 3H); 13C NMR (CDCl3, 300 MHz) d 140.6, 138.5,
135.4, 134.6, 128.2, 128.07, 128.04, 127.0, 126.7, 126.5, 117.5,
116.8, 112.5, 103.3, 85.3, 82.6, 81.8, 66.9, 55.7, 50.5, 33.1, 26.7,
26.6; ESIMS m/z: 436 [M+H]+; HRMS (ESI) calcd for C27H33NO4
[M+H]+ 436.2487, found 436.2484.
5.1.2. Benzyl benzyl ((S)-1-(3aR,5R,6R,6aR)-6-(benzyloxy)-2,2-
dimethyl-6-vinyl-tetra hydrofuro[2,3-d][1,3]dioxol-5-yl)but-3-
enyl)carbamate 10
To a stirred solution of 9 (5 g, 11.46 mmol) in dry methanol
(50 mL) was added sodium bicarbonate (2.88 g, 34.39 mmol) fol-
lowed by CbzCl (3.23 mL, 22.92 mmol) at 0 °C. The reaction mix-
ture was stirred at rt for 4 h. Methanol was evaporated under
reduced pressure and reaction mixture was diluted with water
(50 mL) and extracted with ethyl acetate (2 ꢀ 100 mL). The com-
bined organic layers were dried over Na2SO4, concentrated, and
purified by column chromatography (hexane/ethyl acetate 9:1) to
5.1.1. (S)-N-Benzyl-1-((3aR,5R,6R,6aR)-6-(benzyloxy)-2,2-
dimethl-6-vinyl-tetra hydrofuro[2,3-d][1,3]dioxol-5yl)but-3en-
1-amine 9
To a solution of aldehyde 7 (4.0 g, 13.11 mmol) in dry CH2Cl2
(40 mL) and molecular sieves 4 Å (0.8 g) was added benzylamine
(1.43 mL, 13.11 mmol) at room temperature and kept at 0 °C for
4 h. The reaction mixture was filtered and concentrated to give
crude imine 8, which was used as such for the next step. To a solu-
tion of allyl magnesium bromide prepared from Mg (3.07 g,
128.12 mmol) and allyl bromide (10.86 mL, 128.12 mmol) in ether
(40 mL), was added chiral imine 8 (5.05 g,12.81 mmol) in ether
(50 mL) at 0 °C. After stirring overnight at room temperature, the
reaction mixture was poured into saturated aqueous NH4Cl
(150 mL) and extracted with ethylacetate (3 ꢀ 150 mL). The com-
bined organic layers were washed with water, brine, then dried
over Na2SO4, concentrated under reduced pressure and purified
by column chromatography (hexane/ethyl acetate 8:2) to afford
the corresponding amino olefin 9 as a yellow oil (5.15 g, 92% for
give compound 10 (6.0 g, 91.8%) as
¼ þ20:6 (c 2.29, CHCl3); IR mmax 3432, 3065, 3030, 2985,
2929, 1697, 1455, 1378, 1247, 1219, 1108, 1043, 738, 698 cmꢂ1
a
colorless syrup.
½ ꢁ
a 3D0
;
1H NMR (CDCl3, 300 MHz)⁄ d 7.39–7.10 (m, 14H), 6.95 (br s, 1H),
5.96–5.13 (m, 5H), 5.12–4.77 (m, 3H), 4.75–4.17 (m, 7H), 4.01
(m, 1H), 2.66–2.03 (m, 2H), 1.40–1.25 (br s, 6H); 13C NMR (CDCl3,
300 MHz)⁄ d 157.4, 157.2, 138.9, 138.7, 138.4, 138.2, 138.1,
137.7, 136.9, 136.4, 134.9, 134.4, 134.2, 134.0, 133.8, 133.4,
129.6, 128.0, 127.8, 127.5, 127.4, 127.3, 127.1, 126.9, 126.7,
126.4, 126.2, 118.5, 118.2, 116.8, 116.3, 112.4, 103.2, 103.1, 85.7,
85.4, 82.2, 82.0, 81.1, 80.1, 80.0, 77.2, 66.9, 66.8, 66.7, 58.5, 55.7,
55.2, 46.1, 45.8, 33.1, 31.8, 31.7, 26.5; ESIMS m/z: 570 [M+H]+.
two steps). ½a 3D0
ꢁ
¼ þ47:1 (c 1.46, CHCl3); IR mmax 3448, 3066,
HRMS (ESI) calcd for C
35H39NO6 [M+Na]+ 592.2675, found
3028, 2985, 2926, 1637, 1494, 1455, 1377, 1215, 1166, 1102,
592.2694. ⁄1H and 13C NMR showed a doubling of the signals due
to a rotameric mixture.
1030, 737 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 7.34–7.13 (m, 10H),
;

M. V. Rao et al. / Tetrahedron: Asymmetry 22 (2011) 1342–1346
1345
5.1.3. Benzyl benzyl ((S)-1-(2R,3S,4R)-3-(benzyloxy)-4,5-
dihydroxy-3-vinyltetra hydrofuran-2,-yl)but-3-enyl)-
carbamate 11
NMR (CDCl3, 300 MHz) 7.39–7.09 (m, 10H), 5.75–5.59 (m, 1H),
5.52–5.39 (dd, 1H, J = 10.5, 11.3 Hz), 5.27–5.09 (m, 4H), 4.72 (1H,
J = 15.1 Hz), 4.54–4.43 (m, 3H), 3.99 (d, 1H, J = 15.1 Hz), 3.93–
3.75 (m, 2H), 3.71–3.63 (m, 1H), 2.47–2.35 (m, 1H), 2.33–2.21
(m, 1H), 1.93–1.72 (br s, 1H); 13C NMR (CDCl3, 300 MHz) d 157.5,
138.2, 135.2, 132.4, 131.5, 128.5, 128.4, 128.3, 127.8, 127.5,
126.8, 120.6, 119.6, 80.5, 76.0, 64.8, 61.0, 53.6, 45.8, 36.2; ESIMS
m/z: 394 [M+H]+. HRMS (ESI) calcd for C24H27NO4 [M+Na]+
416.1837, found 416.1833.
To compound 10 (5.9 g, 10.35 mmol) TFA/H2O (2:1, 40 ml) was
added at 0 °C then the reaction mixture was warmed to room tem-
perature and stirred for 3 h. The solvents were removed by three
co-evaporations with toluene (3 ꢀ 30 mL), and the residual prod-
uct was dissolved in water and neutralized with saturated NaHCO3
and then extracted with ethyl acetate (2 ꢀ 100 mL). The combined
organic layer was dried over Na2SO4, concentrated under reduced
pressure and the crude product was purified by column chroma-
tography (hexane/ethyl acetate 1:1) to give the lactol 11 (4.1 g,
5.1.6. (4S,5R)-4-Allyl-5-((S)-1,2-hydroxybut-3en-2-yl)-
oxazolidin-2-one 14
74.8%) as a syrup. ½a D30
ꢁ
¼ þ32:9 (c 0.77, CHCl3); IR
m
max, 3411,
To a solution of sodium (2.45 g, 106.87 mmol) in liquid NH3
(50 mL) at ꢂ78 °C was added compound 13 (1.4 g, 3.56 mmol) dis-
solved in dry THF (25 mL). After the addition the acetone/dry ice
bath was replaced by a CCl4/dry ice bath and stirred for 20 min
and again cooled to ꢂ78 °C. The blue solution was stirred for
30 min and solid NH4OAc (2 g) was added, after which the reaction
mixture was brought to room temperature. After evaporation of
the ammonia, the residue was partitioned between ethyl acetate
(100 mL) and H2O (100 mL). The aqueous layer was separated
and extracted with ethyl acetate (2 ꢀ 100 mL) and the combined
organic layers were washed with saturated NaCl, dried over anhy-
drous Na2SO4, concentrated under reduced pressure, and purified
by column chromatography (hexane/ethyl acetate = 2:8) to afford
3065, 3030, 2941, 1675, 1452, 1419, 1310, 1246, 1092, 1037,
737, 698 cmꢂ1 1H NMR (CDCl3, 300 MHz)⁄ d 7.51–6.99 (m, 15H),
;
6.20–3.62 (m, 17H), 3.08–2.05 (m, 3H); 13C NMR (CDCl3, 300 MHz)⁄
d 157.7, 138.8, 137.9, 137.6, 136.5, 136.2, 134.2, 134.1, 133.2,
133.0, 132.6, 129.6, 128.3, 128.1, 127.8, 127.6, 127.5, 127.4,
127.3, 127.0, 126.8, 126.5, 119.4, 119.0, 116.9, 116.7, 102.4,
102.2, 95.7, 95.4, 85.6, 85.5, 81.7, 80.0, 78.7, 77.2, 78.3, 78.3,
72.9, 67.0, 66.8, 56.1, 46.2, 32.4, 32.2, 31.8; ESIMS m/z: 530
[M+H]+; HRMS (ESI) calcd for C32H35NO6 [M+Na]+ 552.2362, found
552.2386. ⁄1H and 13C NMR showed a doubling of the signals due to
a rotameric mixture.
5.1.4. Benzyl benzyl ((4S,5R,6S)-6-(benzyloxy)-5-hydroxy-6-
(hydroxymethyl)octa-1,7-dien-4-yl)carbamate 12
compound 14 (0.49 g, 64.6%) as a colorless oil. ½a D30
¼ ꢂ37:5
ꢁ
(c 0.48, MeOH); IR mmax, 3415, 2927, 1738, 1648, 1409, 1246, 1066,
To a solution of lactol 11 (4.0 g, 7.54 mmol) in methanol (40 mL)
was added NaIO4 (12.86 g, 60.37 mmol) in H2O (40 mL) at 0 °C. The
reaction mixture was stirred at rt for 4 h. Methanol was removed
under reduced pressure. The reaction mixture was extracted with
CH2Cl2 (2 ꢀ 100 mL). The combined organic layers were washed
with aq NaHCO3 (50 mL), dried and concentrated to give the crude
aldehyde, which was used as such for the next reaction without
any purification. To a solution of the aldehyde in dry methanol
(25 mL) was added NaBH4 (0.38 g, 10.54 mmol) at 0 °C and stirred
for 1 h. The reaction mixture was quenched by adding satd NH4Cl
after which MeOH was removed under reduced pressure and ex-
tracted with ethyl acetate (2 ꢀ 100 mL). The organic layer was
dried over Na2SO4, concentrated, and purified by column chroma-
tography (hexane/ethyl acetate 1:1) to afford diol 12 (2.8 g, 74% for
1020, 764 cmꢂ1 1H NMR (CD3OD, 300 MHz) d 5.90–5.74 (m, 2H),
;
5.52 (d, 1H, J = 16.9 Hz), 5.34 (d, 1H, J = 11.1 Hz), 5.24–5.12 (m,
1H), 4.41 (d, 1H, J = 4.5 Hz), 3.81 (dd, 1H, J = 4.5, 10.9 Hz), 3.68 (d,
1H, J = 11.5 Hz), 3.45 (d, 1H, J = 11.5 Hz), 2.46–2.35 (m, 1H), 2.32–
2.20 (m, 1H); 13C NMR (CD3OD, 300 MHz) d 161.3, 136.5, 134.0,
119.3, 118.2, 81.9, 76.8, 66.4, 53.7, 41.3; ESIMS m/z: 214 [M+H]+.
HRMS (ESI) calcd for
236.0887.
C
10H15NO4 [M+Na]+ 236.0898, found
5.1.7. (3aS,7S,7aR)-7-Hydroxy-7-(hydroxymethyl)-3a,4,7,7a-
tetrahydrobenzo[d] oxazol-2(3H)-one 15
To diene 14 (0.45 g, 2.11 mmol) in dry toluene (80 mL), Grubbs’
II generation catalyst (0.179 g, 0.211 mmol) was added and the
resulting purple solution turned brown after 10 min. The reaction
mixture was refluxed for 4 h, concentrated under reduced pres-
sure, and the residue was purified by column chromatography
(hexane/ethyl acetate: 2:8) to give compound 15 as a light brown
2 steps) as a thick liquid. ½a D30
ꢁ
¼ þ245:7 (c 1.52, CHCl3), IR mmax
,
3373, 3065, 3031, 2926, 1739, 1668, 1447, 1238, 1076, 736,
700 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 7.44–7.22 (m, 10H), 7.20–
;
7.09 (m, 3H), 6.89–6.78 (m, 2H), 6.02–5.79 (m, 2H), 5.40–5.17
(m, 3H), 5.08 (d, 1H, J = 12.2 Hz), 4.94–4.61 (m, 5H), 4.54 (d, 1H,
J = 10.5 Hz), 4.02–3.90 (m, 2H), 3.83–3.70 (m, 2H), 3.35–3.23 (br
s, 1H), 2.80–2.66 (m, 1H), 2.27–2.14 (br s, 1H), 1.94–1.82 (br s,
1H); 13C NMR (CDCl3, 300 MHz) d 157.9, 138.5, 136.9, 136.2,
135.3, 134.6, 128.8, 128.4, 128.2, 128.1, 128.0, 127.7, 127.5,
117.3, 116.2, 82.2, 72.6, 67.6, 65.4, 63.2, 60.1, 54.0, 34.3; ESIMS
m/z: 502 [M+H]+; HRMS (ESI) calcd for C31H35NO5 [M+Na]+
524.2412, found 524.2428.
oil (0.24 g, 61.5%). ½a D30
ꢁ
¼ þ101:8 (c 0.77, MeOH); IR
m
;
max, 3416,
1H NMR
d 5.98–5.93 (m, 1H), 5.63 (dd, 1H, J = 2.1,
2925, 1947, 1746, 1632, 1388, 1230, 1038, 764 cmꢂ1
(D2O, 500 MHz)
10.4 Hz), 4.36 (d, 1H, J = 12.6 Hz), 4.08–4.04 (m, 1H), 3.85 (dd,
2H, J = 12.2, 6.1 Hz), 2.64–2.57 (m, 1H), 2.31–2.23 (m, 1H); 13C
NMR (D2O, 300 MHz) d 164.6, 131.4, 130.7, 89.6, 76.1, 65.9, 55.8,
32.5; ESIMS m/z: 208 [M+Na]+. HRMS (ESI) calcd for C8H11NO4
[M+Na]+ 208.0585, found 208.0578.
5.1.8. (3aS,40S,7aR)-20,20-Dimethyl-3,3a,4,7a-tetrahydro-2H-
spiro[benzo[d]oxazole-7,40-[1,3]dioxolan]-2-one 16
5.1.5. (4S,5R)-4-Allyl-3-benzyl-5-((S)-2-(benzyloxy)-
1-hydroxybut-3en-2-yl) oxazolidin-2-one 13
To a solution of compound 15 (0.21 g, 1.13 mmol) in CH2Cl2
(3 mL) was added 2,2-dimethoxy propane (0.41 mL, 3.40 mmol)
and PTSA (catalyst) and then stirred for 1 h at room temperature.
After evaporation of the solvents, water was added (2 mL) and ex-
tracted with ethyl acetate (2 ꢀ 10 mL). The combined organic lay-
ers were washed with brine (10 mL) dried over Na2SO4 and
concentrated in vacuo. Purification by column chromatography
(hexane/ethyl acetate, 8:2) afforded 16 as a white solid (0.18 g,
To a solution of 12 (2.1 g, 4.19 mmol) in dry THF (20 mL) was
added sodium hydride [0.501 g (60% w/w in wax), 23.11 mmol]
at room temperature and the mixture was stirred under nitrogen
atmosphere for 20 min. The reaction mixture was quenched by
adding saturated aqueous NH4Cl and extracted with ethyl acetate
(100 mL). The organic layer was dried over anhydrous Na2SO4, con-
centrated under reduced pressure and purified through column
chromatography (hexane/ethyl acetate 4:6) to afford oxazolidine
71.1%). Mp 148 °C ½a D30
ꢁ
¼ þ68:0 (c 1.3, CHCl3); IR
mmax, 3286,
13 (1.53 g, 92.8%) as a liquid. ½a D30
ꢁ
¼ ꢂ6:1 (c 2.0, CHCl3); IR mmax
2922, 2853, 1745, 1375, 1223, 1170, 1061 cmꢂ1 1H NMR (CDCl3,
;
3431, 3030, 2930, 1732, 1442, 1243, 1063, 738, 701 cmꢂ1
;
1H
300 MHz) 5.86 (br s, 1H), 5.80–5.73 (m, 1H), 5.69–5.64 (m, 1H),

1346
M. V. Rao et al. / Tetrahedron: Asymmetry 22 (2011) 1342–1346
4.34 (d, 1H, J = 8.6 Hz), 4.30 (d, 1H, J = 12.4 Hz), 3.84 (d, 1H,
J = 8.6 Hz), 3.49 (m, 1H), 2.50 (m, 1H), 2.23 (m, 1H), 1.49 (S, 3H),
1.45 (S, 3H); 13C NMR (CDCl3, 300 MHz) d 159.8, 131.9, 125.9,
110.6, 83.6, 81.2, 67.6, 54.7, 30.4, 26.7, 26.0; ESIMS m/z 226
[M+H]+; HRMS (ESI) calcd for C11H15NO4 [M+Na]+ 248.0898, found
248.0905.
compound 6 as a white semi solid (0.021 g, 75%). ½a D30
¼ þ47:3 (c
ꢁ
0.2, H2O), IR
619 cmꢂ1
mmax, 3382, 2957, 2361, 2123, 1624, 1095, 1059,
;
1H NMR (D2O, 300 MHz) d 3.74 (d, 1H, J = 12.2 Hz),
3.62 (d, 1H, J = 12.2 Hz), 3.60 (d, 1H, J = 10.0 Hz), 3.29–3.17 (m,
1H), 2.09–1.90 (m, 2H), 1.76–1.26 (m, 4H); 13C NMR (CDCl3,
300 MHz) d 76.2, 75.5, 62.3, 52.9, 31.6, 28.1, 19.0; ESIMS m/z:
162 [M+H]+; HRMS (ESI) calcd for C7H15NO3 [M+H]+ 162.1130,
found 162.1123.
5.1.9. (3aS,40R,5S,6S,7aR)-5,6-Dihydroxy-20,20-dimethylhexa-
hydro-2H-spiro[benzo[d]oxazole-7,40-[1,3]dioxolan]-2-one 17
To a stirred solution of compound 16 (0.08 g, 0.35 mmol) in ace-
tone/H2O (3:1, 4 mL) was added NMO monohydrate (72 mg,
0.53 mmol) followed by OsO4 (9 mg, 0.035 mmol) at 0 °C and stir-
red at room temperature for 24 h. After the addition of Na2SO3
(0.049 g, 0.39 mmol), acetone was removed under reduced pres-
sure and the reaction mixture was diluted with water and ex-
tracted with dichloromethane (3 ꢀ 10 mL). The combined organic
layers were dried over Na2SO4, concentrated under reduced pres-
sure, purified by column chromatography (hexane/ethyl acetate,
2:8) to give compound 17 as a white solid (0.086 g, 94.5%). Mp
Acknowledgments
M.V.R, B.C., and J.L.S. thank the CSIR, New Delhi, for a research
fellowship. We also thank Dr. J. S. Yadav for his support and
encouragement. We also thank DST (SR/S1/OC-14/2007), New
Delhi, for financial support.
References
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234 °C; ½a 3D0
ꢁ
¼ ꢂ6:8 (c 0.5, MeOH); IR
m
max, 3384, 3251, 2993,
2903, 1751, 1378, 1248, 1224, 1058, 944 cmꢂ1
;
1H NMR (CD3OD,
300 MHz) d 4.30 (d, 1H, J = 9.1 Hz), 4.11–4.07 (m, 1H), 4.05 (d,
1H, J = 9.1 Hz), 3.90 (d, 1H, J = 12.1 Hz), 3.79–3.67 (m, 1H), 3.66
(d, 1H, J = 3.0 Hz), 2.08 (td, 1H, J = 3.3, 12.8 Hz), 1.57 (dt, 1H,
J = 2.6 Hz), 1.33 (s, 6H); 13C NMR (CDCl3, 300 MHz) d 163.0,
110.0, 86.3, 85.6, 74.6, 71.2, 64.4, 54.1, 33.5, 26.65, 26.6; ESIMS
m/z: 282 [M+Na]+. HRMS (ESI) calcd for C11H17NO6 [M+Na]+
282.0953, found 282.0941.
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5.1.10. (1R,2S,3S,4S,6S)-6-Amino-2-(hydroxymethyl)-
cyclohexane-1,2,3,4-tetraol 5
To a solution of compound 17 (0.055 g, 0.21 mmol) in MeOH,
was added 6 M HCl (2 mL) at 0 °C, and then stirred at reflux for
12 h. Next the solution was concentrated under reduced pressure
and purified by column chromatography using Dowex 50w X 8–
400 to afford compound 5 as a white semi-solid (0.03 g, 73.1%),
½
a 3D0
ꢁ
¼ þ27:2 (c 0.2, H2O), IR
mmax,3424, 2922, 2852, 1630, 1571,
1462, 570 cmꢂ1 1H NMR (D2O, 300 MHz) d 4.21–4.07 (m, 1H,
;
Hd), 3.96–3.82 (s, 2H, Hg1, Hg2), 3.70 (d, 1H, JHc-Hd = 3.0 Hz, Hc),
3.38 (d, 1H, JHa-Hb = 10.0 Hz, Hb), 3.31–3.17 (m, 1H, Ha), 2.07 (td,
1H, J = 4.1, 13.9 Hz, Hf), 1.59 (dt, 1H, J = 2.2, 13.2 Hz, He); 13C
NMR (CDCl3, 200 MHz) d 77.5, 76.7, 75.7, 67.7, 62.1, 49.1, 32.8;
ESIMS m/z: 194 [M+H]+. HRMS (ESI) calcd for C7H15NO5 [M+H]+
194.1028, found 194.1022.
5.1.11. (1S,2R,3S)-3-Amino-1-(hydroxymethyl) cyclohexane-1,2-
diol 6
To a solution of compound 14 (0.04 g, 0.17 mmol) in MeOH was
added 10% Pd/C (cat) and stirred under an H2 atmosphere for 1 h.
The reaction mixture was filtered through Celite and concentrated
under reduced pressure, after which the crude reaction mixture
was dissolved in MeOH. Next, 6 M HCl (1 mL) was added at 0 °C,
and the reaction mixture was refluxed for 12 h. The reaction mix-
ture was concentrated under reduced pressure and purified by col-
umn chromatography using Dowex 50w X 8–400 to afford the