Asymmetric dihydroxylation of D-glucose derived α,β-unsaturated ester: Synthesis of azepane and nojirimycin analogues

Article abstract of DOI:10.1021/jo049509t

The asymmetric dihydroxylation of a D-glucose derived α,β- unsaturated ester 3 afforded syn vicinal diols in good to high diastereoselectivity. The conversion of these vicinal diols to the corresponding cyclic sulfate, regio-, stereoselective nucleophilic

Full text of DOI:10.1021/jo049509t

Asym m etr ic Dih yd r oxyla tion of D-Glu cose Der ived
r,â-Un sa tu r a ted Ester : Syn th esis of Azep a n e a n d Nojir im ycin
An a logu es
Dilip D. Dhavale,*,† Shankar D. Markad,† Narayan S. Karanjule,† and J . PrakashaReddy‡
Department of Chemistry, Garware Research Centre, University of Pune, Pune-411 007, India, and
Division of Organic Chemistry, National Chemical Laboratory, Pune-411 008, India
ddd@chem.unipune.ernet.in
Received March 25, 2004
The asymmetric dihydroxylation of a D-glucose derived R,â-unsaturated ester 3 afforded syn vicinal
diols in good to high diastereoselectivity. The conversion of these vicinal diols to the corresponding
cyclic sulfate, regio-, stereoselective nucleophilic ring opening by sodium azide, and LAH reduction
afforded amino heptitols 7a ,b that were converted to azepane 1c,d and nojirimycin analogues 2c,d .
In tr od u ction
Among the strategies available for the dihydroxylation
of olefins,1 one of the most attractive is the asymmetric
dihydroxylation with osmium tetroxide in combination
with cinchona alkaloids.2 Furthermore, the formation of
cyclic sulfite or sulfate from diols, followed by regio- and
stereoselective nucleophilic ring opening of the latter,
makes this approach extremely versatile for organic
synthesis.3 This strategy has been widely exploited in the
synthesis of many natural products. However, only
limited applications are known for azasugars.4 In recent
years, attention has been increasingly focused on the
structure-activity relationship of azasugars, particular
in seven-membered hydroxy and tetraoxy azepanes 1a ,b5
and six-membered piperidine alkaloids, namely nojiri-
mycin 2a and 1-deoxynojirimycin 2b (Figure 1).4 These
compounds have become important synthetic targets
because of their promising glycosidase inhibitory activity
in the treatment of various diseases such as diabetes,
cancer, and viral infections, including AIDS.4,6 In addi-
F IGURE 1. Azepane and nojirimycin anlogues.
tion, azepanes are also potentially useful as DNA minor
groove binding ligands (MGBL).5d The hydroxyl groups
in azepanes adopt different conformations due to the
flexibility of the seven-membered ring (compared with
five- or six-membered rings) thereby increasing the
probability of forming hydrogen bonds with nitrogen
base, thus showing the ability to point into the minor
(4) (a) Inouye, S.; Tsuruoka, T.; Ito, T.; Niida, T. Tetrahedron 1968,
24, 2125-2144. (b) Iida, H.; Yamazaki, N.; Kibayashi, C. J . Org. Chem.
1987, 52, 3337-3342. (c) Aoyagi, S.; Fujimaki, S.; Yamazaki, N.;
Kibayashi, C. J . Org. Chem. 1991, 56, 815-819. (d) Kajimoto, T.; Liu,
K. K. C.; Pederson, R. L.; Zhong, Z.; Ichikawa, Y., J r.; Porco, J . A.;
Wong, C. H. J . Am. Chem. Soc. 1991, 113, 6187-6196. (e) Fairbanks,
A. J .; Carpentor, N. C.; Fleet, G. W. J .; Ramsden, N. G.; Cenci de Bello,
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48, 3365-3376. (f) Grandel, R.; Kazmaier, U. Tetrahedron Lett. 1997,
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De Rensis, F.; Ruccioni, L. Tetrahedron 1997, 53, 3409-3416. (h) Xu,
Y.; Zhou, W. J . Chem. Soc., Perkin Trans. 1 1997, 1, 741-746. (i) Asano,
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R. J .; Fleet, G. W. J . J . Nat. Prod. 1998, 61, 625-628. (j) Uriel, C.;
Santoyo-Gonzalez, F. Synlett 1999, 5993-5995. (k) Godin, G.; Compain,
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Bols, M.; Lillelund, V. H.; J ensen, H. H.; Liang, X. Chem. Rev. 2002,
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† University of Pune.
‡ National Chemical Laboratory.
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1999, 121, 11229-11230. (b) Costas, M.; Adrianne, K.; Chen, T. K.;
J o, D. H.; Que, L. J . Am. Chem. Soc. 2001, 123, 6722-6723. (c)
Salvadori, P.; Pini, D.; Petri, A. J . Am. Chem. Soc. 1997, 119, 6929-
6930. (d) Bergstad, K.; J onsson, S. Y.; Backvall, J . E. J . Am. Chem.
Soc. 1999, 121, 10424-10425. (e) Ahrgren, L.; Sutin, L. Org. Process
Res. Dev. 1997, 1, 425-427.
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Corey, E. J .; Noe, M. C.; Sarshar S. J . Am. Chem. Soc. 1993, 115, 3828-
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10.1021/jo049509t CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/09/2004
4760
J . Org. Chem. 2004, 69, 4760-4766

Synthesis of Azepane and Nojirimycin Analogues
SCHEME 1. Retr osyn th etic An a lysis
groove of DNA. The high water solubility, allowing them
to circumvent the problem of poor bioavailability seen
in many other MGBL’s, is an additional advantage of
these compounds. The development of new azasugars
thus opened a dynamic research field at the interface
between glycobiology and synthetic organic chemistry.
During the course of our investigations in the area of
nojirimycin, castanospermine, and azepane analogues,7
we thought of synthesizing altogether different one-
carbon ring homologues of 1-deoxynojirimycin namely
azepanes 1c and 1d , with -CH2OH functionality at C5,
as well as piperidine alkaloids 1-deoxy-D-altronojirimycin
2c, a recently reported natural product from the bark
extract of Angylocalyx pynaertii (Leguminosae),8 and 2d
(1-deoxy-L-nojirimycin),9 the enantiomer of 1-deoxynojiri-
mycin 2b.
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis. As shown in retrosynthetic
analysis (Scheme 1), the key intermediate in our ap-
proach, common to both types of target molecules, is the
6-aminoheptulose 7 that could be derived by applying the
asymmetric dihydroxylation, cyclic sulfate formation, and
nucleophilic azide ring opening protocol to the easily
available D-glucose-derived R,â-unsaturated ester 3. An
attractive feature of this strategy lies in its inherent
flexibility wherein the stereoselectivity of the vicinal diol
formation, at the R,â-unsaturated double bond, could be
controlled by making use of the Sharpless asymmetric
dihydroxylation. Our efforts in the successful implemen-
tation of this method for the formation of azepanes 1c,d
and piperidine alkaloids 2c,d are reported herein.
Asym m etr ic Dih yd r oxyla tion of 3. The required
(E)-ethyl-1,2-O-isopropylidene-3-O-benzyl-5,6-dideoxy-R-
D-xylo-5-enoheptofuranuronate (3) was prepared from
D-glucose as reported earlier.7f The dihydroxylation of 3
with potassium osmate (catalytic), potassium ferricya-
nide, potassium carbonate, and methane sulfonamide in
tert-butyl alcohol-water (1:1) afforded a diastereomeric
mixture of vicinal diols 4a and 4b in the ratio 2:1 (eq 1).
(6) (a) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497-534. (b)
Karpas, A.; Fleet, G. W. J .; Dwek, R. A.; Petursson, S.; Namgoong, S.
K.; Ramsden, N. G.; J acob, G. S.; Rademacher, T. W. Proc. Natl. Acad.
Sci. U.S.A. 1988, 85, 9229-9233. Karpas, A.; Fleet, G. W. J .; Dwek,
R. A.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.; J acob, G. S.;
Rademacher, T. W. FEBS Lett. 1988, 237, 128-132. (c) Fleet, G. W. J .
Chem. Brit. 1989, 287-292. (d) Winchester, B.; Fleet, G. W. J .
Glycobiology 1992, 2, 199-210. (e) Hughes, A. B.; Rudge, A. J . J . Nat.
Prod. Rep. 1994, 11, 135. (f) Merror, Y. L.; Poitout, L.; Deepazy, J .;
Dosbaa, I.; Geoffroy, S.; Foglietti, M. Bioorg. Med. Chem. 1997, 5, 519-
533. (g) Sears, P.; Wong, C. H. J . Chem. Soc., Chem Commun. 1998,
1161. (h) Butters, T. D.; Van den Brock, L. A. G. M.; Fleet, G. W. J .;
Krulle, T. M.; Wormold, M. R.; Dwek, R. A.; Platt, F. M. Tetrahedron:
Asymmetry 2000, 11, 113-124. (i) Stuts, A. E. Iminosugars as
Glycosidase Inhibitors. Nojirimycin and Beyond; Wiley/VCH: Wein-
heim, Germany, 1999.
(7) (a) Dhavale, D. D.; Desai, V. N.; Sindkhedkar, M.; Mali, R. S.;
Castellari, C.; Trombini, C. Tetrahedron: Asymmetry 1997, 8, 1475-
1486. (b) Dhavale, D. D.; Saha, N. N.; Desai, V. N. J . Org. Chem. 1997,
62, 7482-7484. (c) Desai, V. N.; Saha, N. N.; Dhavale, D. D. J . Org.
Chem. 1999, 64, 1715-1719. (d) Desai, V. N.; Saha, N. N.; Dhavale,
D. D. J . Chem. Soc., Chem. Commun. 1999, 1719-1720. (e) Saha, N.
N.; Desai, V. N.; Dhavale, D. D. Tetrahedron 2001, 57, 39-46. (f) Patil,
N. T.; Tilekar, J . N.; Dhavale, D. D. J . Org. Chem. 2001, 66, 1065-
1074. (g) Patil, N. T.; Tilekar, J .; Dhavale, D. Tetrahedron Lett. 2001,
42, 747-749. (h) Dhavale, D. D.; Patil, N. T.; J ohn, S.; Sabharwal, S.
Bioorg. Med. Chem. 2002, 10, 2155-2160. (i) Dhavale, D. D.; Saha, N.
N.; Desai, V. N.; Tilekar, J . N. Arkivoc 2002, 8, 91-105. (j) Tilekar, J .
N.; Patil, N. T.; J adhav, H. S.; Dhavale, D. D. Tetrahedron 2003, 59,
1873-1876. (k) Dhavale, D. D.; Chaudhari, V. D.; Tilekar, J . N.
Tetrahedron Lett. 2003, 44, 7321-7323.
The appreciable difference in Rf value allowed us to
separate the isomers by column chromatography. For-
tunately, 4a was obtained as a colorless solid and the
single-crystal X-ray analysis (Figure 2) established the
absolute configurations at the newly generated stereo-
centers as 5R and 6R. The formation of 4a as a major
product is in accordance with Kishi’s empirical rule,10
wherein the syn-hydroxylation from the side opposite to
the preexisting furanose alkoxy group is preferred, while
the syn-hydroxylation from the same side of the preexist-
ing furanose alkoxy group, which is sterically more
compressed, afforded the minor product 4b with absolute
configurations 5S and 6S. The diastereoselectivity in the
formation of 4a and 4b was improved by using cinchona
alkaloids as chiral ligands. Thus, the use of [(DHQ)2PHAL]
in osmylation afforded 4a with high diastereoselectivity
(de 94%), while the use of [(DHQD)2PHAL] gave 4a :4b
1
in the ratio 32:68 as determined by the H NMR of the
crude mixture (Table 1).
The utility of 4a ,b was initially demonstrated in the
formation of azepane analogues 1c,d , respectively. As
shown in Scheme 2, treatment of diol 4a with thionyl
(8) (a) Asano, K.; Yasuda, K.; Kizu, H.; Kato, A.; Fan, J .; Nash, R.
J .; Fleet, W. J .; Molyneux, R. J . Eur. J . Biochem. 2001, 268, 35-41.
(b) Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A. A.;
Nash, R. J .; Fleet, G. W. J .; Asano, N. J . Nat. Prod. 2002, 65, 1875-
1881.
(9) Although compound 2d is reported in the literature, its NMR
study and conformational aspects are not known. It is reported that
2d possesses moderate to high inhibitory activity against almond â-D-
glucosidase and bovine liver â-D-galactosidase (a) Noritaka, C.; Yuka,
F.; Hiroyuki, I.; Seiichiro, O. Carbohydr. Res. 1992, 237, 185-194. (b)
Schaller, C.; Vogel, P.; J ager, V. Carbohydr. Res. 1998, 314, 25-35.
(10) (a) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron 1984, 40,
2247-2255. (b) Brimacombe, J . S.; Kabir, A. K. M. S. Carbohydr. Res.
1986, 150, 35-51. (c) J arosz, S. Carbohydr. Res. 1988, 183, 209-215.
J . Org. Chem, Vol. 69, No. 14, 2004 4761

Dhavale et al.
SCHEME 3. Syn th esis of 2c,d a
a
Reaction conditions: (a) Ac2O, py, DMAP. (b) (i) TFA:H2O
(2:1), 0 °C to room temperature, 2.5 h; (ii) NaIO4, acetone:H2O
(5:1),
0 °C, 1.5 h; (iii) H2, Pd/C, MeOH, 80 psi, 12h; (iv)
MeOH:HCl (9:1), 80 °C, 6 h. (c) NH3, rt, 15 min.
sulfate 5a in 86% yield. The regioselective ring opening
of cyclic sulfate 5a with sodium azide, at the R-position
to the carboethoxy group in an SN2 fashion, followed by
acid hydrolysis provided the azido ester 6a in high yield.
Reduction of the azido ester 6a with LAH afforded an
amino alcohol that was directly subjected to hydrogenoly-
sis with ammonium formate in the presence of 10% Pd/C
followed by reaction with benzyl chloroformate to give
N-Cbz-protected amino alcohol 7a . The compound 7a was
reacted with TFA-water to cleave the 1,2-acetonide
functionality, and the product thus obtained was sub-
jected to hydrogenation with 10% Pd/C in methanol-HCl
(9:1) to give 1,6-dideoxy-1,6-imino-(2S,3R,4R,5R,6R)-L-
glycero-D-gluco-heptitol 1c as a hydrochloride salt. The
same sequence of reactions with 4b gave the hydrochlo-
ride of 1,6-dideoxy-1,6-imino-(2S,3R,4R,5S,6S)-D-glycero-
L-ido-heptitol 1d . The compounds 5b, 6b, and 7b were
obtained in good yields and were characterized by
spectral and analytical techniques and the data were
found to be in agreement with the structures (Scheme
2).
F IGURE 2. ORTEP drawing of compound 4a .
TABLE 1. Asym m etr ic Dih yd r oxyla tion of 3
entry
ligand
ratio of 4a /4b
yield, %
1
2
3
no ligand
(DHQ)2PHAL
(DHQD)2PHAL
67:33
97:03
32:68
91
88
82
SCHEME 2. Syn th esis of 1c,d a
Although the physical and spectral data of 1c,d were
found to be consistent with the structures, the configu-
rational assignment at each carbon atom in 1c was based
on the X-ray analysis of 4a while in the case of 1d the
configurational assignment was tentatively made on the
expected syn-dihydroxylation from the other face of 3
1
leading to 4b. The H NMR spectrum of 1c and 1d did
not give any supportive information on the conforma-
tional and configurational assignment due to the flex-
ibility in seven-membered ring systems.7j,k As an alter-
native, we thought of converting 4a,b to the corresponding
six-membered piperidine analogues 2c,d wherein the
configurational assignment at each carbon atom will be
clearly evident from the six-membered cyclic structure,
with either 4C1 or 1C4 conformations, and the same
configurational assignments would be applicable to
azepane analogues. For this, the amino alcohols 7a ,b
(obtained from 4a ,b) were found to be the true interme-
diates wherein cleavage of the anomeric carbon atom (C1)
and reductive aminocyclization would afford the corre-
sponding six-carbon azasugars 2c,d . Thus, peracetylation
of 7a with acetic anhydride in pyridine afforded the
peracetylated product 8a (Scheme 3). In the subsequent
a
Reaction conditions: (a) (i) SOCl2, Py, CH2Cl2, 0 °C, 30 min;
(ii) NaIO4, RuCl3‚3H2O, CH3CN:H2O (3:1), 0 °C, 10 min. (b) (i)
NaN3, acetone:water (4:1), 0 to 25 °C, 2 h; (ii) 20% H2SO4, ether:
water (6:1), 25 °C, 6 h. (c) (i) LAH, THF, 0 to 25 °C, 3 h; (ii)
HCOONH4, Pd/C, MeOH, 80 °C, 1 h; (iii) CbzCl, MeOH:H2O
(9:1), 0 to 25 °C, 3.5 h; (d) (i) TFA:H2O (2:1), 0 to 25 °C, 2.5 h; (ii)
H2, Pd/C, MeOH:HCl (9:1), 80 psi, 24 h.
chloride in pyridine afforded the cyclic sulfite that was
further oxidized with sodium metaperiodate and a cata-
lytic amount of ruthenium trichloride to furnish the cyclic
4762 J . Org. Chem., Vol. 69, No. 14, 2004

Synthesis of Azepane and Nojirimycin Analogues
steps, cleavage of the 1,2-acetonide functionality in 8a
by TFA-water, treatment with sodium metaperiodate (to
cleave the anomeric carbon atom), and hydrogenation
with 10% Pd/C in methanol afforded triacetoxy-1-deoxy-
altronojirimycin.11
One-pot removal of O-acetoxy and -formyl groups with
MeOH:HCl (9:1) afforded the hydrochloride salt of 1-deoxy-
altronojirimycin 2c as a sticky solid [R]D +31.0 (c 2.0,
MeOH) [lit.4o [R]589 +33.2 (c 0.5, MeOH)], which on
treatment with methanolic ammonia and purification by
resin column afforded 2c. The rotational value and
spectral data of 2c were found to be in consonance with
that reported.4o Similarly, the reaction of 7b gave 1-deoxy-
L-nojirimycin 2d as a hydrochloride salt. The compounds
5b, 6b, 7b, and 8b were characterized by spectral and
analytical techniques and the data were found to be in
agreement with the structures. The compound 2d ‚HCl
showed the specific rotation value [R]D -46.0 (c 1.26, H2O)
which is identical, but with opposite sign of rotation, to
that reported for the hydrochloride salt of 1-deoxy-D-
nojirimycin 2b [lit.4n [R]D +46.9 (c 0.17, H2O)], indicating
their enantiomeric relationship. Furthermore, treatment
of 2d ‚HCl with methanolic ammonia and purification
with resin column afforded 1-deoxy-L-nojirimycin 2d as
a free base that showed identical analytical data with
that reported.9
F IGURE 3. Conformations of 2c,d .
at each carbon atom of 2c,d provided proofs for the
stereochemistry of azepane analogues 1c,d at four ste-
reocenters.
Con clu sion s
We have demonstrated the utility of D-glucose-derived
R,â-unsaturated ester 3 in the synthesis of new nojiri-
mycin and azepane analogues using an asymmetric
dihydroxylation, cyclic sulfate formation, and nucleophilic
ring-opening protocol. The easy availability of reagents,
high yielding steps, and good regio- and stereoselectivity
in the process would give easy access for the synthesis
of different types of otherwise difficult azasugars required
for structure-activity relationship studies, as a number
of R,â-unsaturated esters could be readily prepared from
the pool of chiral compounds. Another interesting aspect
of the present route is that we have converted D-glucose
to 2d , the enantiomer of 2b, and 2b has been prepared
earlier from D-glucose.4a Thus a single starting compound
D-glucose has been used to synthesize two enantiomers
having several stereocenters.
Con for m a tion a l An a lysis. Azasugars are known to
exist in 4C1 or 1C4 conformations.4 To determine the
conformations of 2c and 2d , we studied the 1H NMR
spectra and the coupling constant information was
obtained by decoupling experiments. In the 1H NMR
spectrum of 2c, the appearance of a doublet of doublets
corresponding to the H1a proton with one large geminal
(J 1a,1e ) 14.1 Hz) and another small vicinal (J 1a,2 ) 2.1
Hz) coupling indicated the axial-equatorial relation with
the H2 proton. The initial geometry in the precursor 8a
ensures that in the product 2c the substituent at C2/C3
should be trans. Therefore, the proton at H3 should be
equatorial. Unfortunately, H2 and H3 appeared as ac-
cidentally equivalent protons. However, the appearance
of H5 as a doublet of triplets (J 4,5 ) 9.6 and J 5,6 ) 4.5
Hz) proves that C4/C5 are diaxial protons. The coupling
constant value between H5 and H4 was evident from the
decoupling experiments and was found to be 9.6 Hz. The
large value of J 4,5 clearly requires the trans-diaxial
relationship of these protons, thus indicating the 4C1
Exp er im en ta l Section
Eth yl 3-O-Ben zyl-1,2-O-isop r op ylid en e-â-L-glycer o-D-
glu co-h ep tofu r a n u r on a te (4a ) a n d Eth yl 3-O-Ben zyl-1,2-
O-isop r op ylid en e-r-D-glycer o-L-id o-h ep t ofu r a n u r on a t e
(4b). To a mixture of K3Fe(CN)6 (8.51 g, 25.86 mmol), K2CO3
(3.57 g, 25.86 mmol), and (DHQD)2PHAL or (DHQ)2PHAL
(0.067 g, 0.0862 mmol, 1 mol %) or without ligand in t-BuOH/
H2O (1:1, 80 mL) at 0 °C was added a catalytic amount of
potassium osmate (0.189 g, 0.516 mmol) followed by meth-
anesulfonamide (0.82 g, 8.62 mmol). After the solution was
stirred for 5 min at 0 °C, the compound 3 (3.0 g, 8.62 mmol)
in t-BuOH/H2O (1:1, 20 mL) was added over a period of 5 min.
The reaction mixture was stirred at 0 °C for 24 h and quenched
with solid sodium sulfite (6 g). The stirring was continued for
another 45 min and the reaction mixture was extracted with
ethyl acetate (5 × 40 mL). The combined organic phase was
washed with 10% KOH and worked up to afford a diastereo-
meric mixture of diols 4a and 4b. Purification by column
chromatography and elution first with n-hexane/ethyl acetate
(9/1) gave 4a as a white solid (2.0 g, 61%). Mp 91-93 °C; Rf
0.60 (n-hexane/ethyl acetate ) 5/5); [R]D -27.2 (c 0.52, CHCl3);
IR (Nujol) 3200-3600 (broad band), 1742, 1456, 1379, 1076,
1
conformation with 5R absolute configuration. In the H
NMR spectrum of 2d the appearance of a triplet corre-
sponding to H3 with J 2,3 ) J 3,4 ) 9.0 Hz indicated the
axial orientation of this proton with H2 and H4. The
triplet corresponding to H4 with J 4,5 ) J 3,4 ) 9.0 Hz
requires a trans-diaxial relationship with H3 and H5.
Thus, the axial-axial relationship of H2/H3, H3/H4, and
1
1024 cm-1; H NMR (300 MHz, CDCl3) δ 1.32 (t, J ) 7.2 Hz,
3H), 1.33 (s, 3H), 1.51 (s, 3H), 2.69 (d, J ) 9.0 Hz, exchanges
with D2O, 1H), 3.15 (d, J ) 4.9 Hz, exchanges with D2O, 1H),
4.15 (d, J ) 3.0 Hz, 1H), 4.23-4.37 (m, 4H), 4.39 (dd, J ) 4.9,
1.4 Hz, 1H), 4.61 (d, J ) 11.7 Hz, 1H), 4.62 (d, J ) 3.9 Hz,
1H), 4.71 (d, J ) 11.7 Hz, 1H), 5.94 (d, J ) 3.9 Hz, 1H), 7.25-
7.35 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.2, 26.3, 26.8,
62.0, 69.8, 71.0, 72.3, 79.1, 81.9, 82.4, 104.9, 111.8, 127.7 (s),
127.9, 128.4 (s), 137.2, 173.1. Anal. Calcd for C19H26O8: C,
59.68; H, 6.85. Found: C, 59.62; H, 6.75. Further elution with
n-hexane/ethyl acetate (8/2) afforded 4b as a thick liquid (1.0
g, 30%). Rf 0.54 (n-hexane/ethyl acetate 5/5); [R]D -16.5 (c 0.48,
1
H4/H5 clearly requires the C4 conformation of 2d with
5S absolute configuration. Thus, the stereochemistry
assigned to 2c,d on the basis of the stereochemistry of
1
7a ,b was confirmed by the H NMR of 2c,d . Because the
formation of 2c,d involves the loss of the corresponding
anomeric carbon of 7a ,b, the configurational assignments
(11) In these particular experiments, triacetylated products were
obtained as a mixture of two compounds one with free C3-OH and
other with C3-OCHO. Our attempts to separate the mixture were
unsuccessful. Therefore, we directly converted the triacetylated prod-
ucts to corresponding hydrochlorides.
CHCl3); IR (neat) 3200-3600 (broad band), 1741, 1624 cm-1
;
1H NMR (300 MHz, CDCl3 + D2O) δ 1.32 (t, J ) 7.2 Hz, 3H),
J . Org. Chem, Vol. 69, No. 14, 2004 4763

Dhavale et al.
1.38 (s, 3H), 1.52 (s, 3H), 4.03 (broad s, 1H), 4.09 (d, J ) 2.4
Hz, 1H), 4.30 (q, J ) 7.2 Hz, 2H), 4.37-4.41 (m, 2H), 4.51 (d,
J ) 12.0 Hz, 1H), 4.71 (d, J ) 3.9, Hz 1H), 4.76 (d, J ) 12.0
Hz, 1H), 6.01 (d, J ) 3.9 Hz, 1H), 7.38 (s, 5H); 13C NMR (75
MHz, CDCl3) δ 14.1, 26.3, 26.7, 61.9, 70.7, 70.9, 71.7, 80.8,
81.5, 82.2, 104.9, 112.0, 127.8 (s), 128.1, 128.5 (s), 136.8, 172.5.
Anal. Cald for C19H26O8: C, 59.68; H, 6.85. Found: C, 59.58;
H, 6.97.
7/3); [R]D -55.8 (c 0.82, CHCl3); IR (neat) 3400-3600 (broad
band), 2114, 1742, 1456, 1377, 1211, 1026, 856 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.32 (t, J ) 7.2 Hz, 3H), 1.33 (s, 3H), 1.49
(s, 3H), 2.79 (d, J ) 7.2 Hz, 1H, exchanges with D2O), 4.12 (d,
J ) 3.3 Hz, 1H), 4.20 (d, J ) 3.0 Hz, 1H), 4.24-4.39 (m, 3H),
4.36 (dt, J ) 7.8, 7.2, 3.3 Hz, 1H, became dd J ) 7.8, 3.3 Hz
on D2O exchange), 5.54 (d, J ) 11.4 Hz, 1H), 4.62 (d, J ) 3.6
Hz, 1H), 4.73 (d, J ) 11.4 Hz, 1H), 5.91 (d, J ) 3.6 Hz, 1H),
7.32-7.37 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.0, 26.2,
26.7, 61.8, 64.0, 70.1, 71.9, 78.6, 81.4, 81.8, 104.8, 111.8, 127.5
(s), 127.9, 128.4 (s), 136.7, 167.7. Anal. Calcd for C19H25N3O7:
C, 56.01; H, 6.18. Found: C, 56.22; H, 6.28.
E t h yl 6-Azid o-6-d eoxy-3-O-b en zyl-1,2-O-isop r op yli-
d en e-â-L-glycer o-L-id o-h ep tofu r a n u r on a te (6b). The reac-
tion of cyclic sulfate 5b (1.78 g, 4.03 mmol) with sodium azide
(1.57 g, 24.17 mmol) followed by hydrolysis with 20% H2SO4
(3 mL) as described in the preparation of 6a , and column
purification (n-hexane/ethyl acetate ) 8.5/1.5), afforded 6b as
a thick liquid (1.46 g of 89%); Rf 0.56 (n-hexane/ethyl acetate
) 7/3); [R]D -40.7 (c 0.59, CHCl3); IR (neat) 3200-3600 (broad
band), 2106, 1743, 1454, 1379, 1179, 1024 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.28 (t, J ) 7.2 Hz, 3H), 1.34 (s, 3H), 1.49 (s,
3H), 3.38 (d, J ) 2.1 Hz, 1H, exchanges with D2O), 3.86 (d, J
) 6.3 Hz, 1H), 4.12 (d, J ) 3.6 Hz, 1H), 4.18-4.28 (m, 3H),
4.35 (dd, J ) 3.9, 3.6 Hz, 1H), 4.48 (d, J ) 11.7 Hz, 1H), 4.66
(d, J ) 3.9 Hz, 1H), 4.72 (d, J ) 11.7 Hz, 1H), 5.98 (d, J ) 3.9
Hz, 1H), 7.33-7.30 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.1,
26.4, 26.9, 61.9, 62.6, 70.8, 74.7, 78.4, 82.2, 82.9, 104.7, 112.1,
127.7 (s), 128.2, 128.5 (s), 136.2, 168.9. Anal. Calcd for
E t h yl 3-O-Ben zyl-5,6-cyclic su lfa t e-1,2-O-isop r op y-
lid en e-â-L-glycer o-D-glu co-h ep tofu r a n u r on a te (5a ). To an
ice-cooled solution of 4a (2.0 g, 5.26 mmol) and pyridine (1.15
g, 14.58 mmol) in dry dichloromethane (20 mL) was added
thionyl chloride (0.53 mL, 7.21 mmol) dropwise over a period
of 10 min. After 20 min at 0 °C, the reaction was quenched
with cold water and extracted with dichloromethane (3 × 30
mL). Usual workup afforded crude cyclic sulfite that was
dissolved in acetonitrile:water (30 mL, 5:1), cooled at 0 °C.
Sodium metaperiodate (1.54 g, 7.21 mmol) followed by RuCl3‚
3H2O (5 mg) were added and the solution was vigorously
stirred for 10 min. The reaction mixture was diluted with
diethyl ether and the organic layer was filtered through a pad
of Celite. The filtered organic layer was washed with water
and sodium bicarbonate solution and worked up to afford a
thick liquid that on purification by column chromatography
(n-hexane/ethyl acetate ) 9/1) gave 5a as a white solid (2.0 g,
86.0%). Mp 99-101 °C; Rf 0.46 (n-hexane/ethyl acetate ) 8/2);
[R]D -79.1 (c 0.86, CHCl3); IR (Nujol) 1747, 1460, 1375, 1221,
1080, 1022 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.26 (t, J ) 7.2
Hz, 3H), 1.32 (3H, s), 1.49 (3H, s), 4.10 (d, J ) 3.3 Hz, 1H),
4.12 (dq, J ) 10.8, 7.2 Hz, 1H), 4.26 (dq, J ) 10.8, 7.2 Hz,
1H), 4.52 (d, J ) 11.4 Hz, 1H), 4.58 (dd, J ) 3.6, 3.3 Hz, 1H),
4.64 (d, J ) 11.4 Hz, 1H), 4.65 (d, J ) 3.6 Hz, 1H), 5.34 (d, J
) 3.9 Hz, 1H), 5.48 (dd, J ) 6.3, 3.9 Hz, 1H), 5.97 (d, J ) 3.6
Hz, 1H), 7.24-7.38 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 13.9,
26.3, 26.9, 63.1, 72.3, 77.6, 78.1, 79.5, 80.9, 81.9, 105.5, 112.6,
127.8 (s), 128.3, 128.6 (s), 136.0, 164.8. Anal. Calcd for
C
19H25N3O7: C, 56.01; H, 6.18. Found: C, 56.18; H, 6.25.
6-(N-Ben zoxyca r bon yla m in o)-6-d eoxy-1,2-O-isop r op y-
lid en e-r-D-glycer o-D-glu co-h ep tofu r a n ose (7a ). To an ice
cooled suspension of LAH (0.486 g, 14.74 mmol) in dry THF
(4 mL) was added azido ester 6a (1.0 g, 2.46 mmol) in dry THF
(10 mL) at 0 °C and the solution was stirred for 10 min. The
reaction mixture was slowly warmed to room temperature and
stirred for an additional 2 h. Reaction was quenched by adding
ethyl acetate (30 mL), followed by an aqueous solution of
ammonium chloride (3 mL). The reaction mixture was filtered
through Celite and the filtrate was concentrated under vacuum.
The solution of crude amino alcohol (0.833 g, 2.46 mmol), 10%
Pd/C (0.200 g), and ammonium formate (1.24 g, 19.66 mmol)
in methanol (10 mL) was refluxed for 1 h. The reaction mixture
was filtered through Celite and the filtrate was evaporated to
give a thick oil. To a cooled solution of amino alcohol (0.565 g,
2.46 mmol) in methanol-water (10 mL, 9:1) was added
benzylchloroformate (0.503 g, 2.92 mmol) and sodium bicar-
bonate (0.500 g, 5.95 mmol) at 0 °C and the solution was
stirred for 2.5 h. Methanol was evaporated under reduced
pressure and the residue was extracted with chloroform (3 ×
20 mL). Usual workup and purification by column chroma-
tography (n-hexane/ethyl acetate ) 1/1) gave 7a as a white
solid (0.47 g, 52.0% overall). Mp 135-137 °C; Rf 0.41 (ethyl
acetate); [R]D +11.7 (c 0.51, CHCl3); IR (Nujol) 3200-3600
C
19H24O10S: C, 51.34; H, 5.44. Found: C, 51.42; H, 5.52.
Eth yl 3-O-Ben zyl-5,6-(cyclic su lfa te)-1,2-O-isop r op y-
lid en e-r-D-glycer o-L-id o-h ep tofu r a n u r on a te (5b). The re-
action of 4b (1.8 g, 4.71 mmol) with pyridine (0.98 mL, 13.03
mmol) and thionyl chloride (0.45 mL, 6.45 mmol) followed by
oxidation with sodium metaperiodate (1.34 g, 6.45 mmol) and
ruthenium trichloride trihydrate (4 mg) as described in the
preparation of 5a and purification by column chromatography
(n-hexane/ethyl acetate ) 8.5/1.5) afforded 5b as a white solid
(1.8 g, 85.0%). Mp 101-103 °C; Rf 0.63 (n-hexane/ethyl acetate
) 7/3); [R]D +23.0 (c 0.69, CHCl3); IR (Nujol) 1749, 1620, 1400,
1
1213, 1080, 1026 cm-1; H NMR (300 MHz, CDCl3) δ 1.23 (t,
J ) 7.2 Hz, 3H), 1.34 (s, 3H), 1.49 (s, 3H), 4.15 (dq, J ) 11.1,
7.2 Hz, 2H), 4.22 (d, J ) 4.8 Hz, 1H), 4.53 (d, J ) 11.7 Hz,
1H), 4.65 (t, J ) 5.4 Hz, 1H), 4.67 (d, J ) 11.7 Hz, 1H), 4.69
(d, J ) 3.9 Hz, 1H), 5.15 (d, J ) 6.3 Hz, 1H), 5.29 (dd, J ) 6.3,
5.8 Hz, 1H), 6.03 (d, J ) 3.9 Hz, 1H), 7.22-7.42 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ 13.9, 26.6, 27.2, 63.3, 71.9, 77.0, 78.1,
81.4, 81.8, 82.3, 105.5, 113.1, 127.5 (s), 128.1, 128.5 (s), 136.3,
164.5. Anal. Calcd for C19H24O10S: C, 51.34; H, 5.44. Found:
C, 51.38; H, 5.50.
(broad band), 1687.6, 1560.3, 1456.2, 1375.2 cm-1 1H NMR
;
(300 MHz, CDCl3 + D2O) δ 1.30 (s, 3H), 1.44 (s, 3H), 3.72 (dd,
J ) 12.3, 4.8 Hz, 1H), 3.92-3.99 (m, 2H), 4.01 (dd, J ) 8.1,
3.9 Hz, 1H), 4.16 (dd, J ) 8.1, 2.4 Hz, 1H), 4.39 (d, J ) 2.4 Hz,
1H), 4.51 (d, J ) 3.6 Hz, 1H), 5.10 (s, 2H), 5.92 (d, J ) 3.6 Hz,
1H), 7.24-7.34 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 26.3,
27.0, 53.4, 61.6, 70.8, 72.6, 77.2, 79.3, 82.0, 105.2, 112.1, 127.8
(s), 128.0, 128.5 (s), 137.1, 162.3. Anal. Calcd for C18H25NO8:
C, 56.39; H, 6.57. Found: C, 56.48; H, 6.74.
Eth yl 6-Azido-6-deoxy-3-O-ben zyl-1,2-O-isopr opyliden e-
r-D-glycer o-D-glu co-h ep tofu r a n u r on a te (6a ). To a stirred
solution of cyclic sulfate 5a (2.0 g, 4.52 mmol) in acetone:water
(25 mL, 4:1) at 0 °C was added sodium azide (1.76 g, 27.15
mmol) and the reaction mixture was allowed to attain room
temperature and then stirred for 2 h. The mixture was
concentrated under reduced pressure and diethyl ether (40 mL)
and water (6 mL) were added. After dropwise addition of 20%
H2SO4 (4 mL) the resulting solution was stirred at room
temperature for 6 h. The solution was neutralized by adding
saturated potassium carbonate solution (10 mL) and the
reaction mixture was extracted with diethyl ether (3 × 30 mL),
which on usual workup and purification by column chroma-
tography with (n-hexane/ethyl acetate ) 8/2) afforded 6a as a
thick liquid (1.5 g, 81.7%). Rf 0.55 (n-hexane/ethyl acetate )
6-(N-Ben zoxyca r bon yla m in o)-6-d eoxy-1,2-O-isop r op y-
lid en e-â-L-glycer o-L-id o-h ep tofu r a n ose (7b). The reaction
of 6b (1.4 g, 3.43 mmol) with LAH (0.68 g, 20.6 mmol) followed
by hydrogenolysis and N-Cbz protection as described for 7a
and purification by column chromatography (n-hexane/ethyl
acetate ) 4/6) afforded 7b as a white solid (0.75 g, 57%). Mp
119-121 °C; Rf 0.50 (ethyl acetate); [R]D -10.6 (c 0.56, CHCl3);
IR (KBr) 3200-3600 (broad band), 1711, 1537, 1227, 1076
1
cm-1; H NMR (300 MHz, CDCl3 + D2O) δ 1.30 (s, 3H), 1.46
4764 J . Org. Chem., Vol. 69, No. 14, 2004

Synthesis of Azepane and Nojirimycin Analogues
(s, 3H), 3 0.72 (dd, J ) 11.4, 4.5 Hz, 1H), 3.77-3.79 (m, 1H),
3.98 (dd, J ) 11.7, 2.7 Hz, 1H), 4.19-4.24 (m, 2H), 4.30 (d, J
) 2.0 Hz, 1H), 4.53 (d, J ) 3.6 Hz, 1H), 5.11 (ABq, J ) 11.0
Hz, 2H), 5.98 (d, J ) 3.9 Hz, 1H), 7.32 (broad s, 5H); 13C NMR
(75 MHz, CDCl3) δ 26.3, 26.9, 53.9, 61.8, 67.2, 72.1, 76.0, 79.6,
85.2, 104.8, 111.9, 128.0 (s), 128.2, 128.4 (s), 135.8, 156.8. Anal.
Calcd for C18H25NO8: C, 56.57; H, 6.18. Found: C, 56.48; H,
6.25.
1,6-Dideoxy-1,6-im in o-(2S,3R,4R,5R,6R)-L-glycer o-D-glu -
co-h ep titol (1c) Hyd r och lor id e. A solution of 7a (0.10 g,
0.269 mmol) in TFA-H2O (3 mL, 2:1) was stirred at 25 °C for
2.5 h. Trifluroacetic acid was coevaporated with benzene to
furnish a thick liquid. To a solution of the above product in
methanolic hydrochloric acid (5 mL, 9:1) was added 10% Pd/C
(0.05 g). The solution was hydrogenated at 80 psi for 24 h.
The catalyst was filtered through Celite and washed with
methanol. The filtrate was concentrated to obtain a semisolid
of 1c (0.045 g, 75%). Rf 0.20 (chloroform/methanol 8/2); [R]D
+15.9 (c 1.26, MeOH); IR (Nujol) 3200-3600 (broad band)
cm-1; 1H NMR (300 MHz, D2O) δ 3.19 (broad dd, J ) 12.6, 7.2
Hz, 1H), 3.26-3.35 (m, 1H), 3.38-3.48 (m, 1H), 3.72 (dd, J )
12.4, 6.0 Hz, 1H), 3.80-3.92 (m, 4H), 4.02 (broad d, J ) 7.2
Hz, 1H); 13C NMR (75 MHz, D2O) δ 45.3, 59.7, 60.2, 67.6, 70.5,
72.3, 75.1. Anal. Calcd for C7H16ClNO5: C, 36.61; H, 7.02.
Found: C, 36.68; H, 7.25.
50.6, 62.2, 67.1, 70.9, 77.5, 83.7, 104.3, 112.4, 128.1 (s), 128.2,
128.5 (s), 136.1, 155.6, 170.2 (s), 170.5 (s). Anal. Calcd for
C24H31NO11: C, 56.58; H, 6.13. Found: C, 56.65; H, 6.20.
1,5-Dideoxy-1,5-im in o-(2R,3S,4R,5R)-D-altr itol (1-Deoxy-
a ltr on ojir im ycin ) Hyd r och lor id e (2c‚HCl) a n d 2c. A
solution of 8a (0.20 g, 0.393 mmol) in TFA-H2O (2:1, 3 mL)
was stirred at 25 °C for 2.5 h. Trifluroacetic acid was
coevaporated with benzene to furnish a thick liquid. To a
cooled solution of hemiacetal (0.162 g, 0.38 mmol) in acetone:
water (10 mL, 5:1) was added sodium metaperiodate (0.099 g,
0.46 mmol). After the reaction was stirred for 1.5 h ethylene
glycol (0.2 mL) was added and the reaction mixture was
concentrated and residue extracted with chloroform (3 × 15
mL). Workup and column purification (n-hexane/ethyl acetate
) 8/2) afforded an aldehyde that was directly subjected to
hydrogenation in methanol (8 mL) and 10% Pd/C (0.10 g)
under 80 psi for 12 h. The catalyst was filtered and washed
with methanol and the filtrate was concentrated to get a
gummy solid that was directly subjected to deacetylation by
MeOH:HCl (3 mL, 9:1) under reflux for 6 h. Then reaction
mixture was cooled to room temperature,and on freeze-drying
afforded a semisolid of 2c as hydrochloride (0.042 g, 54%
overall). Rf 0.24 (chloroform/methanol ) 5/5); [R]D +31.0 (c 2.0,
MeOH) [lit.4o [R]589 +33.2 (c 0.5, MeOH)]; IR (neat) 3200-3600
1
(broad band) cm-1; H NMR (300 MHz, D2O) δ 3.09 (dd, J )
13.5, 2.7 Hz, 1H), 3.19-3.30 (m, 2H), 3.70 (dd, J ) 12.6, 6.7
Hz, 1H), 3.84 (dd, J ) 12.6, 3.6 Hz, 1H), 3.87-3.92 (m, 2H),
3.99-4.24 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 43.8, 55.8,
58.1, 63.5, 66.1, 68.3. Anal. Calcd for C6H14ClNO4: C, 36.10;
H, 7.07. Found: C, 35.95; H, 7.25.
1,6-Did eoxy-1,6-im in o-(2S,3R,4R,5S,6S)-D-glycer o-L-id o-
h ep titol (1d ) Hyd r och lor id e. A solution of 7b (0.10 g, 0.269
mmol) in TFA-H2O (3 mL, 2:1) was stirred at 25 °C for 2.5 h,
and following the procedure described in the synthesis of 1c
afforded 1d as a sticky gum (0.040 g, 80%). Rf 0.18 (chloroform/
methanol 8/2); [R]D -4.8 (c 3.35, MeOH); IR (neat) 3200-3600
(broad band) cm-1; 1H NMR (300 MHz, D2O) δ 3.27-3.36 (m,
2H), 3.56-3.74 (m, 2H), 3.76-3.87 (m, 2H), 3.88-3.96 (m, 1H),
3.98-4.16 (m, 2H); 13C NMR (75 MHz, D2O) δ 45.9, 58.9, 60.5,
67.5, 68.4, 75.1, 75.6. Anal. Calcd for C7H16ClNO5: C, 36.61;
H, 7.02. Found: C, 36.63; H, 7.10.
3,5,7-Tr i-O-acetyl-6-(N-ben zoxycar bon ylam in o)-6-deoxy-
1,2-O-isop r op ylid e n e -r-D -glycer o-D -glu co-h e p t ofu r a -
n ose (8a ). To an ice-cooled solution of 7a (0.50 g, 1.30 mmol)
in dry pyridine (1.5 mL) was added acetic anhydride (2.65 g,
26.11 mmol). After the mixture was stirred for 8 h at room
temperature, ice water was added and extracted with chloro-
form (3 × 15 mL). Usual workup and chromatographic
purification (n-hexane/ethyl acetate ) 9/1) afforded triacetate
8a as a thick liquid (0.524 g, 79%). Rf 0.54 (n-hexane/ethyl
acetate 7/3); [R]D +2.0 (c 1.0, CHCl3); IR (Nujol) 3346, 1747
(broad), 1668 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 3H),
1.55 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 4.10-4.21
(m, 1H), 4.30-4.46 (m, 2H), 4.43 (dd, J ) 9.6 and 2.7 Hz, 1H),
4.49 (d, J ) 3.6 Hz, 1H), 5.10 (d, J ) 12.0 Hz, 1H), 5.17 (dd,
J ) 9.6 and 2.7 Hz, 1H), 5.18 (d, J ) 12.0 Hz, 1H), 5.28 (bd,
J ) 8.7 Hz, 1H, exchanges with D2O), 5.33 (d, J ) 2.7 Hz,
1H), 5.94 (d, J ) 3.6 Hz, 1H), 7.39 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 20.7, 20.8 (s), 26.2, 26.7, 51.8, 62.6, 66.9, 69.6, 74.9,
82.9 (s), 105.1, 112.5, 128.1 (s), 128.5 (s), 136.3, 156.0, 169.6,
169.9, 170.8 (s). Anal. Calcd for C24H31NO11: C, 56.58; H, 6.13.
Found: C, 56.45; H, 6.25.
A solution of 2c‚HCl (0.042 g, 0.21 mmol) in methanol and
25% aqueous ammonia (2:1, 3 mL) was stirred at room
temperature for 15 min. The solvent was evaporated on a
rotary evaporator and the crude mixture was loaded on Dowex
50W × 8 (100-200 mesh) resin. Elution with methanol-25%
aq ammonia (19:1) afforded 2c (0.028 g, 82%) as a semisolid.
Rf 0.30 (chloroform/methanol ) 5/5); [R]D +21.0 (c 0.92, H2O)
[lit.8a [R]D +19.1 (c 0.74, H2O)]; IR (neat) 3200-3600 (broad
band) cm-1; 1H NMR (300 MHz, D2O) δ 2.68 (dd, J ) 14.1, 2.1
Hz, 1H), 2.75 (dt, J ) 9.6, 4.5 Hz, 1H), 2.87 (dd, J ) 13.8, 2.1
Hz, 1H), 3.62 (d, J ) 4.5 Hz, 2H), 3.69 (dd, J ) 9.6, 2.7 Hz,
1H), 3.75-3.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 44.3,
55.6, 60.3, 65.7, 68.8, 70.3. Anal. Calcd for C6H13NO4: C, 44.16;
H, 8.03. Found: C, 44.35; H, 8.25.
1,5-Dideoxy-1,5-im in o-(2R,3S,4S,5S)-L-glu citol (1-Deoxy-
L-n ojir im ycin ) Hyd r och lor id e (2d ‚HCl) a n d 2d . The reac-
tion of 8b (0.19 g, 0.373 mmol) with TFA:H2O (2:1, 3 mL), then
with NaIO4 (0.094 g, 0.44 mmol) and hydrogenolysis in the
presence of 10% Pd/C (0.10 g), followed by deacetylation in
methanolic hydrochloric acid (3 mL, 9:1) with the same
reaction conditions as used for 8a afforded 2d ‚HCl as a
semisolid (0.070 g, 48.6% overall). Rf 0.20 (chloroform/methanol
) 5/5); [R]D -46.0 (c 1.26, H2O); IR (neat) 3200-3600 (broad
band) cm-1 1H NMR (300 MHz, D2O) δ 2.84 (dd, J ) 12.3,
;
12.0 Hz, 1H), 3.08 (ddd, J ) 10.2, 5.2, 3.4 Hz, 1H), 3.38 (dd, J
) 12.3, 5.4 Hz, 1H), 3.41 (t, J ) 9.3 Hz, 1H), 3.47 (dd, J )
10.2, 9.3 Hz, 1H), 3.66 (ddd, J ) 12.0, 9.3, 5.4 Hz, 1H), 3.74
(dd, J ) 12.6, 5.2 Hz, 1H), 3.81 (dd, J ) 12.6, 3.4 Hz, 1H); 13
C
3,5,7-Tr i-O-acetyl-6-(N-ben zoxycar bon ylam in o)-6-deoxy-
1,2-O-isopr opyliden e-â-L-glycer o-L-ido-h eptofu r an ose (8b).
The reaction of 7b (0.55 g, 1.44 mmol) with acetic anhydride
(2.93 g, 28.72 mmol) and dry pyridine (1.6 mL) under the same
conditions used for 7a followed by column chromatography (n-
hexane:ethyl acetate ) 8/2) afforded 8b as a white solid (0.56
g, 77%). Mp 141-143 °C; Rf 0.48 (n-hexane/ethyl acetate )
7/3); [R]D -3.9 (c 1.03, CHCl3); IR (Nujol) 3375, 1738 (broad),
NMR (75 MHz, CDCl3) δ 43.8, 55.8, 58.1, 63.5, 66.1, 68.3. Anal.
Calcd for C6H14ClNO4: C, 36.10; H, 7.07. Found: C, 36.05; H,
7.18.
The reaction of 2d ‚HCl (0.058 g, 0.29 mmol) in methanol
and 25% aqueous ammonia as described for 2c and resin
column purification afforded 2d as a solid (0.045 g, 95%). Mp
192-194 °C (lit.9b mp 193-195 °C); Rf 0.10 (chloroform/
1689, 1524, 1460, 1377 cm-1
;
1H NMR (300 MHz, CDCl3) δ
methanol ) 5/5); [R]D -45.5 (c 0.81, H2O) [lit.9b [R]25 -46°
589
1.34 (s, 3H), 1.53 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 2.13 (s,
3H), 4.10-4.22 (m, 3H), 4.50 (dd, J ) 7.2, 3.3 1H), 4.56 (d, J
) 3.9 Hz, 1H), 5.12 (ABq, J ) 12.0 Hz, 2H), 5.26 (d, J ) 3.3
Hz, 1H), 5.33 (broad s, exchanges with D2O, 1H), 5.36 (dd, J
) 7.2, 3.3 Hz, 1H), 5.94 (d, J ) 3.9 Hz, 1H), 7.32-7.42 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 20.7 (s), 21.0, 26.2, 26.7,
(c 0.3 H2O)]; IR (neat) 3200-3600 (broad band) cm-1; 1H NMR
(300 MHz, D2O) δ 2.46 (dd, J ) 12.0, 11.0 Hz, 1H), 2.56 (ddd,
J ) 9.0, 6.3, 3.0 Hz, 1H), 3.11 (dd, J ) 12.0, 5.4 Hz, 1H), 3.21
(t, J ) 9.0 Hz, 1H), 3.29 (t, J ) 9.0 Hz, 1H), 3.47 (ddd, J )
11.0, 9.0, 5.4 Hz, 1H), 3.60 (dd, J ) 11.7, 6.3 Hz, 1H), 3.79
(dd, J ) 11.7, 3.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 48.3,
J . Org. Chem, Vol. 69, No. 14, 2004 4765

Dhavale et al.
60.3, 60.9, 70.4, 71.0, 78.0. Anal. Calcd for C6H13NO4: C, 44.16;
H, 8.03. Found: C, 44.05; H, 7.95.
New Delhi for the grant to purchase the high-field (300
MHz) NMR facility.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods, crystallographic data for 4a , and copies of 1H and
13C NMR spectra of compounds 1c‚HCl, 1d ‚HCl, 2c‚HCl, 2d ‚
HCl, 2c, 2d , 4a , 4b, 5a , 5b, 6a , 6b, 7a , 7b, 8a , and 8b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. We are grateful to Prof. M. S.
Wadia for helpful discussion. We are thankful to DST
(SP/S1/G23-2000), New Delhi for the financial support.
S.D.M. is thankful to CSIR, New Delhi for the J unior
Research Fellowship. We gratefully acknowledge UGC,
J O049509T
4766 J . Org. Chem., Vol. 69, No. 14, 2004