Intermolecular Michael addition of substituted amines to a sugar-derived α,β-unsaturated ester: Synthesis of 1-deoxy-D-gluco- and -L-ido-homonojirimycin, 1-deoxy-castanospermine and 1-deoxy-8a-epi-castanospermine

Article abstract of DOI:10.1021/jo0010476

The synthesis of polyhydroxylated piperidine alkaloids, namely, 1-deoxy-D-gluco-homonojirimycin 3a, 1-deoxy-L-ido-homonojirimycin 3b, and indolizidine alkaloids 1-deoxy-castanospermine 5a and 1-deoxy-8a-epi-castanospermine 5b, has been achieved. The key step involved is the intermolecular Michael addition of benzylamine to α,β-unsaturated ester 1, derived from D-glucose, which afforded diastereomeric mixture of β-amino esters 6a and 6b with D-gluco- and L-ido- configuration at C5, respectively. Attempts were made to increase and/or alter the diastereoselectivity at the newly generated stereocenter. The high stereoselectivity, in favor of L-ido-isomer 6b, was achieved under kinetically controlled conditions by using lithium N-benzyl amide as a Michael donor. The β-amino esters 6a and 6b represent common intermediates to target molecules. Thus, LAH reduction of 6a and 6b, individually, gave β-amino alcohol 7a and 7b. Sequential hydrogenolysis, selective protection of the amino group, followed by hydrolysis of the 1,2-acetonide functionality, and hydrogenation gave 3a and 3b, respectively. On the other hand, the β-amino ester 6a was converted to γ-amino ester 13a by Arndt-Eistert synthesis, which on hydrogenolysis and treatment with sodium acetate gave γ-lactam 14a. The LAH reduction afforded pyrrolidene. The N-protection-hydrolysis-hydrogenation cascade successfully executed, and 1-deoxy-castanospermine 5a was obtained in good yield. The same sequence of reactions was applied to β-amino ester 6b, which afforded 1-deoxy-8a-epi-castanospermine 5b.

Full text of DOI:10.1021/jo0010476

VOLUME 66, NUMBER 4
FEBRUARY 23, 2001
© Copyright 2001 by the American Chemical Society
Articles
In ter m olecu la r Mich a el Ad d ition of Su bstitu ted Am in es to a
Su ga r -Der ived r,â-Un sa tu r a ted Ester : Syn th esis of
1-Deoxy-D-glu co- a n d -L-id o-h om on ojir im ycin ,
1-Deoxy-ca sta n osp er m in e a n d 1-Deoxy-8a -epi-ca sta n osp er m in e
Nitin T. Patil, J ayant N. Tilekar, and Dilip D. Dhavale*
Department of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
ddd@chem.unipune.ernet.in
Received J uly 12, 2000
The synthesis of polyhydroxylated piperidine alkaloids, namely, 1-deoxy-D-gluco-homonojirimycin
3a , 1-deoxy-L-ido-homonojirimycin 3b, and indolizidine alkaloids 1-deoxy-castanospermine 5a and
1-deoxy-8a-epi-castanospermine 5b, has been achieved. The key step involved is the intermolecular
Michael addition of benzylamine to R,â-unsaturated ester 1, derived from D-glucose, which afforded
diastereomeric mixture of â-amino esters 6a and 6b with D-gluco- and L-ido- configuration at C5,
respectively. Attempts were made to increase and/or alter the diastereoselectivity at the newly
generated stereocenter. The high stereoselectivity, in favor of L-ido-isomer 6b, was achieved under
kinetically controlled conditions by using lithium N-benzyl amide as a Michael donor. The â-amino
esters 6a and 6b represent common intermediates to target molecules. Thus, LAH reduction of 6a
and 6b, individually, gave â-amino alcohol 7a and 7b. Sequential hydrogenolysis, selective protection
of the amino group, followed by hydrolysis of the 1,2-acetonide functionality, and hydrogenation
gave 3a and 3b, respectively. On the other hand, the â-amino ester 6a was converted to γ-amino
ester 13a by Arndt-Eistert synthesis, which on hydrogenolysis and treatment with sodium acetate
gave γ-lactam 14a . The LAH reduction afforded pyrrolidene. The N-protection-hydrolysis-
hydrogenation cascade successfully executed, and 1-deoxy-castanospermine 5a was obtained in good
yield. The same sequence of reactions was applied to â-amino ester 6b, which afforded 1-deoxy-
8a-epi-castanospermine 5b.
In tr od u ction
study is available with chiral Michael acceptors,2a-d and
to our knowledge the readily accessible R,â-unsaturated
Among the strategies available for the asymmetric
synthesis of â-amino esters, one of the most attractive is
the stereoselective intra-1 or inter-2 molecular Michael
addition of an ammonia equivalent to an R,â-unsaturated
ester. In general, these routes make use of chiral amines
and achiral R,â-unsaturated esters. However, a limited
(1) (a) Saito, S.; Matsumoto, S.; Sato S.; Inaba M.; Moriwake, T.
Heterocycles 1986, 24, 2785. (b) Shishido, K.; Sukegawa, Y.; Fukumoto,
K. J . Chem. Soc., Perkin Trans. 1 1987, 993. (c) Wakabayashi, T.; Saito,
M. Tetrahedron Lett. 1977, 93. (d) Schneider, C., Borner, C. Synlett
1998, 652. (e) Banwell, M. G.; Bui, C. T.; Pham, H. T. T.; Simpson, G.
W. J . Chem. Soc., Perkin Trans. 1 1996, 967. (f) Bunce, R. A.; Peeples,
C. J .; J ones, P. B. J . Org. Chem. 1992, 57, 1727. (g) Hirama, M.;
Shigemoto, T.; Yamazaki, Y.; Ito, S. J . Am. Chem. Soc. 1985, 107, 1797.
* FAX: 91-20-5653899.
10.1021/jo0010476 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/23/2001

1066 J . Org. Chem., Vol. 66, No. 4, 2001
Patil et al.
Sch em e 1
F igu r e 1.
ester 1, derived from D-glucose, has been exploited only
by our group.3a In this context, we recently reported a
highly diastereoselective intramolecular conjugate addi-
tion strategy for the synthesis of 1-deoxy-L-ido-homonojir-
imycin (3b)3a utilizing intermediate 1. This class of
compounds, in particular nojirimycin (3c) and castano-
spermine (5c) (Figure 1), has attracted considerable
attention because of their promising glycosidase inhibi-
tory activity.4 In the search for structure-activity rela-
tionships, a number of natural and unnatural derivatives
of nojirimycin5 and castanospermine6 have been synthe-
sized and evaluated for glycosidase inhibition in the
treatment of various diseases such as diabetes,7 cancer,8
and viral infections, including AIDS.9 As a part of our
continuing interest in the synthesis of nojirimycin ana-
logues,3 we are now describing an altogether different
strategy for the synthesis of homonojirimycin analogues
3a ,b, 1-deoxy-castanospermine (5a ), and 1-deoxy-8a-epi-
castanospermine (5b) (Figure 1). Although, a few reports
are available for the synthesis of 5a ,10 only a single
asymmetric pathway for the synthesis of 5b has been
reported.11,12
As shown in the retrosynthetic analysis (Scheme 1),
(2) (a) Merino, P.; Franco S., Merchan F. L.; Tejero, T. Tetrahedron
Asymmetry 1998, 9, 3945. (b) Matsunaga, H.; Sakamaki, T.; Nagaoka,
H.; Yamada, Y. Tetrahedron Lett. 1983, 24, 3009. (c) Fronza, Z.;
Fuganti, C.; Grasselli, P.; Marinoni, G. Tetrahedron Lett. 1979, 3883.
(d) Bernardi, A.; Capelli, A. M.; Gennari, C.; Scolastico, C. Tetrahe-
dron: Asymmetry 1990, 1, 21. (e) Davies, S. G.; Ichihara, O.; Walters,
I. A. S. Synlett 1993, 461. (f) Costello, J . F.; Davies, S. G.; Ichihara, O.
Tetrahedron: Asymmetry 1994, 5, 1999. (g) Davies, S. G.; Garrido, N.
M.; Ichihara O.; Walters, I. A. S. J . Chem Soc., Chem. Commun. 1993,
1153. (h) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J . J . Chem. Soc.,
Perkin Trans. 1 1994, 2385. (i) Davies S. G.; Fenwick, D. R. J . Chem.
Soc., Chem. Commun. 1995, 1109. (j) Hawkins, J . M.; Lewis, T. A. J .
Org. Chem. 1992, 57, 2114. (k) Angelo, J .; Maddaluno, J . J . Am. Chem.
Soc. 1986, 108, 8112. (l) Ma, D.; Zhang, J . J . Chem. Soc., Perkin Trans.
1 1999, 1589. (m) Perlmutter, P.; Tabone, M. Tetrahedron Lett. 1988,
29, 949. (n) J enner, G. Tetrahedron Lett. 1995, 36, 233.
(3) (a) Desai, V. N.; Saha, N. N.; Dhavale, D. D. J . Chem. Soc., Chem.
Commun. 1999, 1719. (b) Dhavale, D. D.; Saha, N. N.; Desai, V. N. J .
Org. Chem. 1997, 62, 7482. (c) Dhavale, D. D.; Desai, V. N.; Sindkhed-
kar, M. D.; Mali, R. S.; Castellari, C.; Trombini, C. Tetrahedron:
Asymmetry. 1997, 8, 1475. (d) Saha, N. N.; Desai V. N.; Dhavale, D.
D. Tetrahedron 2001, 57, 39.
(4) For nojirimycin, see: (a) Hughes, A. B.; Rudge, A. J . Nat. Prod.
Rep. 1994, 11, 135. (b) Sears, P.; Wong, C.-H. J . Chem. Soc., Chem.
Commun. 1998. 1161. (c) 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. For castanospermine,
see: (d) Elbein, A. D.; Molyneux, R. J . In Alkloids: Chemical and
Biological Prespectives; Pelletier, S. W.; Ed.; Wiley: New York, 1987;
Vol. 5, Chapter 1, p 1.(e) Howard, A. S.; Michael, J . P. Alkoloids (N.Y.)
1986, 28, 183. (f) Michael, J . P. Nat. Prod. Rep. 1990, 485.
the key intermediate in our approach, common to both
types of target molecules, is the sugar-based â-amino
(6) (a) Burgess, K.; Henderson, I. Tetrahedron 1992, 48, 4045. (b)
Izquierdo, I.; Plaza, M. T.; Robles, R.; Mota, A. J . Tetrahedron:
Asymmetry 1998, 9, 1015. (c) J irousek, M. R.; Cheung, A. W-H.;
Babine, R. E.; Sass, P. M.; Schow, S. R.; Wick, M. M. Tetrahedron Lett.
1993, 34, 3671. (d) Marek, D.; Wadouachi, A.; Uzan, R.; Beaupere, D.;
Nowogrocki, G.; Laplace, G. Tetrahedron Lett. 1996, 37, 49. (e) Zhao,
H.; Mootoo, D. R. J . Org. Chem. 1996, 61, 6762. (f) Maggini, M.; Prato,
M.; Ranelli, M.; Scorrano, G. Tetrahedron Lett. 1992, 33, 6537. (g)
Kang, S. H.; Kim J . S. J . Chem. Soc., Chem. Commun., 1998, 1353.
(h) Kefalas, P.; Grierson, D. S. Tetrahedron Lett. 1993, 34, 3555. (i)
Ina, H.; Kibayashi, C. J . Org. Chem. 1993, 58, 52. (j) Furneaux, R. H.;
Mason, J . M.; Tyler, P. C. Tetrahedron Lett. 1994, 35, 3143. (k)
Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547. (l)
Mulzer, J .; Dehmlow, H J . Org. Chem. 1992, 57, 3194. (m) Burgess,
K.; Chaplin, D. A.; Henderson, I.; Pan, Y. T.; Elbein, A. D. J . Org. Chem.
1992, 57, 1103. (n) Kim, N.-S.; Choi, J .-R.; Cha, J . K. J . Org. Chem.
1993, 58, 7096. (o) Furneaux, R. H.; Masson, J . M.; Tyler P. C.
Tetrahedron Lett. 1995, 36, 3055.
(7) (a) Truscheit, E.; Frommer, W.; J unge, B.; Muller, L.; Schmidt,
D. D.; Wingender, W. Angew. Chem., Int. Ed. Engl. 1981, 20, 744. (b)
Furneaux, R. H.; Gainsford, G. J .; Mason, J . M.; Tyler, P. C.; Hartley,
O.; Winchester, B. G. Tetrahedron 1997, 57, 245.
(5) (a) Aoyagi, S.; Fujimaki, S.; Kibayashi, C. J . Chem. Soc., Chem.
Commun. 1990, 1457 (b) Wong, C.-H.; Provencher, L.; Porco, J . A.;
J ung, S.-H.; Wang, Y.-F.; Chen, L.; Wang, R.; Steensma, D. H. J . Org.
Chem. 1995, 60, 1492. (c) Rassu, G.; Pinna, L.; Spanu, P.; Culeddu,
N.; Casiraghi, G.; Fava, G. G.; Ferrari, M. B.; Pelosi, G. Tetrahedron
1992, 48, 727. (d) Herdeis, C.; Schiffer, T. Tetrahedron 1996, 52, 14745.
(e) Compernolle, F.; J oly, G.; Peeters, K.; Toppet, S.; Hoornaert, G.;
Kilonda, A.; Bila, B. Tetrahedron 1997, 53, 12739. (f) Szolcsanyi, P.;
Gracza, T.; Koman, M.; Pronayova, N.; Liptaj, T. J . Chem. Soc., Chem.
Commun. 2000, 471.
(8) (a) Humphries, M. J .; Matsumoto, K.; White, S. L. Cancer Res.
1986, 46, 5215. (b) Humphries, M. J .; Matsumoto, K.; White, S. L.;
Olden, K. Cancer Res. 1986, 46, 5215
(9) (a) Karples, 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. 1998, 85, 9229. (b) Walker, B. D.;
Kowalski, M.; Goh, W. C.; Kozarsky, K.; Krieger, M.; Rosen, C.;
Rohrschneider, L.; Haseltine, W. A.; Sodroski, J . Proc. Natl. Acad. Sci.
1987, 84, 8120. (c) Sunkara, P. S.; Bowling, T. L.; Liu, P. S.; Sjoerdsma,
A. Biochem. Biophys. Res. Commun. 1987, 148, 206

Synthesis of Polyhydroxylated Piperidine Alkaloids
J . Org. Chem., Vol. 66, No. 4, 2001 1067
Ta ble 1. In ter m olecu la r Con ju ga te Ad d ition Rea ction of Am in es to Su ga r -Der ived r,â-Un sa tu r a ted Ester s 1a -d .
reaction conditions
entry
substrate
amine (equiv)
solvent
temp (°C)
time
product
6a and 6b
yielda (%)
ratio
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1a
1a
1a
1a
1b
1b
1a +1b
1a +1b
1a +1b
1a +1b
1a +1b
1c+1d
1c+1d
PhCH2NH2 (2.5)
PhCH2NH2 (2.5)
PhCH2NH2 (2.5)
PhCH2NH2 (2.5)
PhCH2NH2 (2.5)
PhCH2NH2 (1.1)
PhCH2NH2 (2.5)
PhCH2NH2 (2.5)
Ph2CHNH2 (2.5)
Ph2CHNH2 (2.5)
PhCH2NHLi (1.1)
Ph2CHNHLi (1.1)
Ph2CHNHLi (2.5)
PhCH2NH2 (2.5)
PhCH2NH2 (1.1)
25
25
25
25
-10
25
25
25
25
25
-40
-40 to 25
-40 to 25
25
12 h
3 d
3 d
3 d
4 d
12 h
1.5 d
4 d
4 d
4 d
90
80
82
78
70b
65b
75
76
30/70
25/75
28/72
30/70
30/70
24/76
25/75
25/75
THF
CH2Cl2
MeOH
6a and 6b
6a and 6b
6a and 6b
6a and 6b
6a and 6b
6a and 6b
6a and 6b
no reaction
no reaction
6b
CH2Cl2
THF
THF
THF
THF
2 h
85
0/100
20/80
15 h
15 h
15 h
12 h
6c or 6d c
6c or 6d
6e and 6f
6e and 6f
6g
30d
30d
90
25
59b
14
16
17
18
1c+1d
1d
1c+1d
PhCH2NH2 (2.5)
PhCH2NH2 (2.5)
PhCH2NH2 (1.1)
-5
25
25
4 d
12 h
20 h
6g
62
0/100
20/80
20/80
6e and 6f
6e and 6f
6g
6e and 6f
6g
6e and 6f
6g
complex mixture
no reaction
90
THF
55b
15
19
20
1c+1d
1c+1d
PhCH2NH2 (1.1)
PhCH2NH2 (1.1)
CH2Cl2
MeOH
ΤΗF
25
25
18 h
20 h
56b
13
20/80
20/80
55b
14
21
22
1d
1d
PhCH2NHLi (1.1)
Ph2CHNH2 (2.5)
-40
25
2 h
4 d
a
b
Yields refer to the isolated yields after chromatography. Starting recovered ∼20%. c Relative stereochemistry was not assigned.
Starting recovered ∼50%. e Relative stereochemistry was tentatively assigned. f Stereochemistry was assigned by chemical co-relation.
d
ester 6 that could be derived from the stereoselective
Resu lts a n d Discu ssion
intermolecular Michael addition of substituted amines
to R,â-unsaturated ester 1, derived from D-glucose. An
attractive feature of this strategy lies in its inherent
flexibility. The stereoselectivity at the prochiral â-carbon
atom could be controlled either by making use of differ-
entially protected sugar derived R,â-unsaturated esters
derived from D-glucose or by appropriately substituted
amines. Our efforts in the successful implementation of
this methodology for the formation of homoazasugars
3a ,b and indolizidine alkaloids 5a ,b are reported herein.
Ster eoselective Mich a el Ad d ition of Su bstitu ted
Am in es to Su ga r -Der ived R,â-Un sa tu r a ted Ester s.
The present synthetic route starts with R,â-unsaturated
esters 1a +1b, prepared as we have previously reported.3a
Having both the Z and the E isomers in hand, the
conjugate addition reaction with a variety of substituted
amines was studied (eq 1). As shown in Table 1, the
(10) (a) Yoda, H.; Nakajima, T.; Takabe, K. Synlett 1997, 911. (b)
Hendry, D.; Hough, L.; Richardson, A. C. Tetrahedron 1988, 44, 6143.
(c) Martin, S. F.; Chen, H.-J .; Yang, C.-P. J . Org. Chem. 1993, 58, 2867.
(d) Izquierdo, I.; Plaza, M. T.; Robles, R.; Rodriguez, C.; Ramirez, A.;
Mota, A. J . Eur. J . Org. Chem. 1999, 64, 1269.
(11) (a) Denis, Y. S.; Chan, T-H. J . Org. Chem. 1992, 57, 3078. In
this paper, Denis and Chan reported the synthesis of 5b and three
other stereoisomers of 1-deoxy-castanospermine wherein the stereo-
chemical assignment using 1H NMR was erroneous. Only recently they
have revised the stereochemistry and corrected their assignment,
see: Denis, Y. S.; Chan T-H. Can. J . Chem. 2000, 78, 776. We are
thankful to one of the referees for providing this reference.
(12) A report by Martin et al. also claimed the first synthesis of
1-deoxy-8a-epi-castanospermine 5b. However, a subsequent paper from
the same group stated that the compound reported was not 5b but its
diastereomer, namely, 1-deoxy-8-epi-castanospermine, see: (a) Martin,
S. F.; Chen, H.; Yang C-P. J . Org. Chem. 1993, 58, 2867. (b) Martin,
S. F.; Chen, H.; Lynch, V. M. J . Org. Chem. 1995, 60, 276.
(13) Since only one diastereomer, either 6c or 6d , was in hand, we
were not able to assign the configuration at C5 on the basis of 1H NMR
data.
Michael addition of N-benzylamine with 1a (Z-isomer),
at 25 °C for 12 h in the absence of solvent, afforded 6a
(D-gluco) and 6b (L-ido) in a 3:7 ratio (entry 1). To
improve the stereoselectivity at the prochiral C5 center,
various reaction conditions (e.g., change of solvent, tem-
perature and stoichiometry of reactants, etc.) were tried.
Changing the solvent had no effect on the stereoselec-
tivity (entries 2-4). The reaction at -10 °C for 4 days
was sluggish and afforded 6a and 6b in poor yield with
no significant change in the stereoselectivity (entry 5).
(14) We have also performed the 1,4 addition reaction of N-
benzylamine and diphenylmethylamine, in the absence and in the
presence of solvent with D-glucose-derived R,â-unsaturated ester A.
The reactions in methanol (rt, 5 days or reflux, 12 h) did not give
product.
(15) (a) Prakash, K. R. C.; Rao, S. P. Tetrahedron Lett. 1991, 32,
7473. (b) Tulshian, D.; Doll, R. J .; Stansberry, M. F.; McPhail, A. T. J .
Org. Chem. 1991, 56, 6819.

1068 J . Org. Chem., Vol. 66, No. 4, 2001
Patil et al.
Sch em e 2a
Change in the stoichiometry of the reactants (i.e., de-
creasing the amine-ester ratio) lowered the combined
yield with marginal increase of the diastereomer 6b
(entry 6). To understand the effect of double bond
geometry on the stereoselectivity, the reactions were also
performed with 1b (E-isomer). Under identical reaction
conditions as above, no appreciable change was observed
in the stereoselectivity (entries 7 and 8), but the reactions
were sluggish as compared to 1a (Z-isomer). These
findings led us to make use of the mixture of 1a and 1b
for further studies.2b
The effect of size of the amino substituent was studied
in the above reaction using diphenylmethylamine. The
reaction of diphenylmethylamine with a mixture of 1a
and 1b at 25 °C was found to be very slow, and a large
amount of the starting material (88%) was recovered,
even after 4 days (entry 9). The use of THF as the solvent
in the above reaction failed to give the product (entry 10).
This study thus precluded the use of other bulky amino
derivatives as Michael donors. Subsequently, we thought
of using lithium N-benzylamide as more nucleophilic
Michael donor. The reaction of lithium N-benzylamide
(1.1 equiv) with a mixture of 1a and 1b in THF at -40
°C for 2 h afforded 6b (L-ido isomer) as the only isolable
diastereomer in 85% yield (entry 11). On the other hand,
lithium diphenylmethyl amide (1.1 equiv) at -40 to 25
°C for 15 h gave either 6c or 6d (eq 1) in 30% yield13
along with the starting material (entry 12). Use of a high
molar ratio of lithium diphenylmethyl amide (2.5 equiv)
did not provide an appreciable change in the course of
the reaction (entry 13).
a
(a) LiAlH4, THF, rt, 2 h; (b) HCOONH4, MeOH, 10%Pd/C,
reflux, 2 h; (c) CbzCl, NaHCO3, EtOH-H2O (1:1), 4 h; (d) TFA-
H2O (3:2), rt, 2 h; (e) 10%Pd/C, H2, MeOH, 45 psi.
N-benzylamides 6e and 6f as a major products and the
intermolecular Michael addition product 6g as the minor
product (entry 15). Performing the same reaction at -5
°C for 4 days afforded 6g (L-ido-isomer) as the only
isolable product in 62% yield (entry 16). Using 1d as a
substrate, the above reaction led to identical results
(compare entries 17 and 14). Changing the solvent was
less effective (entries 18-20). Using lithium N-benzyl-
amide with 1c/1d (at -40 °C) led to a complex mixture
of products (entry 21). The reaction of 1c/1d with
diphenylmethylamine did not proceed at 25 °C, even after
4 days (entry 22).
Assign m en t of th e Rela tive Ster eoch em istr y a t
C5 of th e â-Αm in o Ester s 6a , 6b, a n d 6g. It was
difficult to assign the relative stereochemistry at C5 in
6a and 6b at this stage, so the stereochemical assign-
ments were then made in the subsequent stage. The
reduction of the ester functionality in 6a and 6b, sepa-
rately, with LAH in THF afforded the â-amino alcohols
7a and 7b in 87% and 84% yield, respectively (Scheme
2). The comparative 1H NMR data of the C5-epimeric pair
7a and 7b turned out to be informative. It is known that
for a given C5-epimeric pair, derived from D-gluco-
furanose, the J 4,5 in the L-ido isomer (threo-relationship)
is consistently larger than that of the corresponding
D-gluco isomer (erythro-relationship).18 The higher value
of J 4,5 observed in the diastereomer 7b (9.5 Hz), as
compared to 7a (6.9 Hz) indicated the L-ido configuration
for 7b and the D-gluco configuration for 7a . This assign-
ment was further supported by a comparison of the
chemical shifts of H3 in both the isomers. The chemical
shift of H3 is reported to be diagnostic such that, in the
L-ido-isomer, it is significantly upfield (δ ∼3.6) as com-
pared to that in the D-gluco (δ ∼4.0).18 In 7b, H3 appeared
upfield at δ 3.86 as compared to 7a at 4.03 δ, further
supporting the D-gluco- and L-ido- configuration at C5
to 7a and 7b, respectively. This fixed the configurations
at C5 in 6a and 6b as 5R and 5S, respectively. This
assignment was confirmed by the conversion of 6a and
6b to compounds of known configuration (vide infra). The
configuration at C5 in 6g was assigned by chemical
correlation as follows. The hydrogenolysis of 6b (L-ido-
isomer) and 6g, separately, using 10% Pd/C and am-
monium formate in methanol (eq 2) followed by N-Cbz
In an attempt to alter the stereochemistry at C5, we
changed the Michael acceptor14 by replacing the bulky
-OBn group at C3 in 1a /1b with an -OH group. For this,
ethyl 1,2-O-isopropylidine-5,6-dideoxy-hept-5-eno-fura-
nuranate (1c/1d ) was prepared as per the literature
procedure.15 The reaction of 1,2-O-isopropylidene-R-D-
xylo-pentodialdose with Ph3PdCHCOOEt in acetonitrile
under reflux for 15 min afforded an inseparable mixture
of 1c and 1d (Z:E ) 55:45).16 The same Wittig reaction
in acetonitrile (reflux for 2 h) yielded 1d (E-isomer) and
its lactone (by cyclization of Z-isomer 1c)17 in 42% and
40% yield, respectively. The conjugate addition reactions
with 1c/1d were then studied. The reaction of N-benzyl-
amine (2.5 equiv) with a mixture of 1c and 1d at 25 °C
for 15 h afforded an inseparable diastereomeric mixture
of amides 6e and 6f (eq 1) in 90% yield (entry 14),
wherein an intermolecular Michael addition and ami-
nolysis of ester functionality had occurred simulta-
neously. Use of 1.1 equiv of N-benzylamine with a
mixture of 1c and 1d at 25 °C for 12 h afforded the
(16) The reaction of 1,2-O-isopropylidene-R-D-xylo-pentodialdose
with Ph3PdCHCOOEt in acetonitrile at reflux is reported to yield 1d
(E-isomer) as a major product in 86% yield after 2 h (ref 14b). However,
we have noticed that the reaction is complete after 15 min.
(17) The analytical and spectral data of lactone B was consistent
with the reported data, see: Baskaran, S.; Trivedi, G. K. Ind. J . Chem.
1994, 33B, 562.
(18) Cornia, M.; Casiraghi, G. Tetrahedron 1989, 45, 2869.

Synthesis of Polyhydroxylated Piperidine Alkaloids
J . Org. Chem., Vol. 66, No. 4, 2001 1069
protection afforded identical six-membered δ-lactones
that were characterized by analytical and spectral meth-
ods.19 Since 6b and 6g afforded the same δ-lactone and
as 6b had 5S configuration, the same stereochemistry
was therefore assigned to compound 6g (5S).
Exp la n a tion for th e Obser ved Ster eoselectivity
in th e Mich a el Ad d ition . The observed stereoselectivity
in the conjugate addition to 1a -d could be rationalized
in terms of Felkin-Anh like transition states.20 As shown
in Figure 2, four transition states I, II, III, and IV were
considered for 1a -d . In conformations I and II, the more
electronegative C-O group of the furanose ring, whereas
in III and IV the largest C3-benzyloxy substituent were
placed at right angles to the CdC bond. In the Felkin-
Anh like model it is known that, the nucleophile should
attack from the side opposite to the group perpendicular
to the CdC. In the case of 1a ,b , the re face attack in
conformer I (to give D-gluco-isomer) and si face attack in
conformer II (to give L-ido-isomer) is hindered by the C3-
benzyloxy group. Therefore, we considered conformers III
and IV. We presumed that the conformer III has the
preference over IV due to the favorable alkene-arene
π-stacking effect2k wherein the si face attack of the
lithium N-benzylamide (or N-benzylamine), by chelation
with furanose ring oxygen, explains the formation of
L-ido-isomer. In the C3-hydroxy compounds 1c,d , the
alkene-arene π-stacking stabilization effect is absent;
therefore, we believe that the furanose C-O bond will
adopt the perpendicular position21 favoring the conform-
ers I and II. The nucleophilic attack along the Burg-
Dunitz trajectory to I or II would then lead to the product
formation, as there is no hindrance in the absence of
benzyl group. Although conformer I is free from steric
interactions, the conformation II is likely to be more
stabilized through hydrogen bonding of C3-OH with the
carbonyl group of carboethoxy functionality (particularly
in case of 1c). The si face attack of N-benzylamine, which
is free from steric hindrance, provides the L-ido-isomer
in excess.
F igu r e 2. Felkin-Anh like transition states for 1a -d .
alcohol 8a , and selective protection of the amino group
with CbzCl gave 9a (90% yield in the two steps).
Deprotection of the 1,2-acetonide functionality in 9a with
TFA-water followed by hydrogenation afforded 1-deoxy-
D-gluco-homonojirimycin (3a ) in 90% yield. The same
sequence of reactions with 6b gave 1-deoxy-L-ido-
homonojirimycin (3b) (72% from 6b). Compounds 8a ,b,
9a ,b, 3a and 3b were characterized by spectral and
analytical techniques. The data were found to be in
agreement with the corresponding compounds that we
have reported earlier.3d
Syn th esis of 1-Deoxy-ca sta n osp er m in e 5a a n d
1-Deoxy-8a -epi-ca sta n osp er m in e 5b. The positions
and the configurations of the hydroxyl groups (at C2, C3,
and C4) in 6a and 6b were noticed to be identical with
those in castanospermine 5c (at C6, C7, and C8). It was
obvious that elaboration of 6a , with D-gluco-configuration
at C5, would lead to 1-deoxy-castanospermine (5a ) and
elaboration of 6b, with L-ido-configuration at C5, would
give 1-deoxy-8a-epi-castanospermine (5b).
Syn th esis of 1-Deoxy-D-glu co-h om on ojir im ycin
a n d 1-Deoxy-L-id o-h om on ojir im ycin 3a a n d 3b. The
utility of 6a and 6b was initially demonstrated in the
formation of the corresponding iminosugars 3a and 3b.
As shown in Scheme 2, reduction of the ester group in
6a with LAH in THF afforded alcohol 7a in 87% yield.
Hydrogenolysis of 7a gave the debenzylated amino
The protection of amino group in 6a with CbzCl
afforded 10a in 95% yield22 (Scheme 3). Hydrolysis of the
ester functionality in 10a with LiOH in aqueous metha-
nol gave the acid 11a in 96% yield. In the next step,
conversion of 11a to mixed anhydride followed by reaction
with diazomethane in ether gave R-diazo ketone 12a in
69% yield. Wolff rearrangement23 of 12a using silver
benzoate and Et3N in methanol afforded the γ-amino
(19) Spectral data for lactone: IR (neat) 3358, 1727 (broad band);
1H NMR (CDCl3, 300 MHz) 1.31 (s, 3H), 1.48 (s, 3H), 1.52-1.80 (bs,
1H, exchanges with D2O), 2.68 (dd, J ) 17.1, 6.6 Hz, 1H), 2.82 (dd, J
) 17.1, 5.1 Hz, 1H), 4.10-4.18 (m, 2H), 4.28-4.39 (m, 1H), 4.53 (d, J
) 3.5 Hz, 1H), 5.10 (ABq, J ) 12.3 Hz, 2H), 5.93 (d, J ) 3.5 Hz, 1H),
7.20-7.40 (m, 5H). Anal. Calcd for C18H21NO7: C, 59.49; H, 5.83. Found
C, 59.65; H, 5.98.
(20) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2201. (c) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2205. (d) Anh, N. T. Top. Curr. Chem. 1980, 88, 145.
(21) As per Houck’s explanation, the most electronegative group
adopts the perpendicular position (C-O bond in our case) and such
conformation is stabilized through the mixing of the CdC π* orbital
with the lowest energy σ* orbital of a most electronegative substituent,
see: Houck, K. N.; Paddon-Row: N. M.; Rondon, N. G.; Wu, Y. D.;
Brown, F. K.; Spellmeyer, C. D.; Metz, J . T.; Li, Y. L.; Loncharich, R.
J . Science 1986, 231, 1108.
(22) The 1H and 13C NMR spectra of compounds 10a , 11a , 12a , 13a
and 10b, 11b, 12b, 13b, in which a N-Cbz group is present, showed
doubling of signals. This was due to isomerization by restricted rotation
around CdN, see: Applications of NMR Spectroscopy in Organic
Chemistry; J ackman, L. M., Sternhell, S., Eds.; Pergamon Press:
Elmsford, NY, 1978; p 361. An analogous observation was also noticed
by others (ref 11a).

1070 J . Org. Chem., Vol. 66, No. 4, 2001
Patil et al.
Sch em e 3a
F igu r e 3.
data as well as the optical rotation for 5a were consistent
with that reported.10 Synthesis of 5a thus confirmed our
assignment of the relative stereochemistry for compounds
6a and 6b as D-gluco-and L-ido-isomers, respectively.
The reaction sequence was repeated for 6b as above
(Scheme 3). The corresponding C5-epimeric compounds
10b, 11b, 12b, 13b, and 14b were isolated and charac-
terized by spectral and analytical data.22 Subsequently,
the lactam functionality in 14b was reduced with LAH
in THF to provide pyrrolidine 15b, which was converted
to the N-Cbz protected pyrrolidine compound 16b. Com-
parison of the 1H NMR spectra of C5-epimeric compounds
16a and 16b led to an interesting observation. In general,
the relative configuration at C5, for such types of
epimeric compounds, is revealed by J 4,5, and it is known
that, for the given C5-epimeric pair, the J 4,5 is larger for
L-ido-isomer than for the corresponding D-gluco-isomer18
(vide supra). However, in the case of 16a (D-gluco) the
observed J 4,5 (10.2 Hz) is larger than the J 4,5 (3.0 Hz) in
16b. This finding is opposite to that reported and could
be attributed to the possible hydrogen bonding between
C3-OH and carbonyl oxygen of N-Cbz group by rotation
about the C4-C5 bond (Figure 3). In this situation the
molecule is held in such a way that, for the hydrogen
bonded D-gluco isomer 16a , the dihedral angle between
H4 and H5 is ∼180° and that for L-ido isomer 16b is ∼60°
thus resulting in the observed coupling constants. We
confirmed the assignment by converting 16a into the
known compound 5a .
a
(a) CbzCl, NaHCO3, EtOH-H2O (9:1), rt, 4 h; (b) LiOH,
MeOH-H2O (4:1), rt, 4 h; (c) EtOCOCl, NEt3, THF, 0 °C, 30 min;
(d) CH2N2, Et2O, 0 to 25 °C, 1.5 h; (e) PhCOOAg, NEt3, MeOH, rt,
1.5 h; (f) 10%Pd/C, H2, MeOH; (g) CH3COONa, MeOH, reflux, 4
h; (h) LiAlH4, THF, reflux, 20 h; (i) CbzCl, NaHCO3, EtOH, rt,
1.5 h; (j) TFA-H2O (3:2), rt, 2 h; (k) 10%Pd/C, H2, MeOH.
ester 13a in 85% yield. Next, 13a was subjected to
hydrogenolysis24 (10% Pd/C in methanol). The product
obtained was refluxed with sodium acetate in methanol
to give the γ-lactam 14a in 80% yield.25 The reduction of
the lactam functionality in 14a with LAH in THF gave
the pyrrolidine 15a , which on reaction with CbzCl gave
16a . The observed rotation value of 16a was consistent
Targeting the synthesis of 1-deoxy- 8a-epi-castanosper-
mine (5b), compound 16b was reacted with TFA/H2O to
cleave the 1,2-O-isopropylidene functionality, and the
product obtained was subjected to hydrogenation. The
crude product was purified by chromatography to get 5b
as a semisolid. The rotation and 13C NMR11,27 data of 5b
was also in accordance with the reported data. However,
with the reported value.10b The H and 13C NMR spectra
1
1
our H NMR data differed from that reported.28 We have
were also found to be in good agreement with the
structure.26 In subsequent steps, opening of the 1,2-
acetonide group followed by hydrogenation and purifica-
tion by chromatography afforded 1-deoxy-castanosper-
mine (5a ) as a white solid. The physical and the spectral
independently characterized the compound 5b . The
comparison of H NMR data of 5a and 5b is given in
1
Figure 4. In 1-deoxy-castanospermine 5a , the appearance
of two triplets at 3.91 and 3.86 δ (J ) 8.6 Hz), one doublet
of doublet at 3.43 δ (J ) 10.5 and 5.2 Hz), and a triplet
at 2.30 δ (J ) 10.5 Hz) clearly indicated the trans-diaxial
relationship between the H5a, H6, H7, H8, and H8a. The
(23) Tilekar, J . N.; Patil, N. T.; Dhavale, D. D. Synthesis 2000, 3,
395. J efford, C. W.; Tang, Q.; Zaslona, A. J . Am. Chem. Soc. 1991,
113, 3513.
8
large coupling constants indicated the C5 conformation
(24) The IR spectrum of the hydrogenolysis product showed two
carbonyl frequencies, one at 1735 and the other at 1661 cm-1 indicating
the presence of open chain N- and O-debenzylated γ-amino ester and
pyrrolidone 14a .
(25) At this stage, we have made another attempt to convert 13a
into 5a . Thus, opening of the 1,2-acetonide group in 13a followed by
hydrogenolysis using 10% Pd/C should give the required ring skeleton.
However, this approach failed in our hands and led to a complex
mixture of products.
(26) In case of compounds 16a ,b, the isomerization by rotation about
the formal CdN appears to be sufficiently rapid resulting into an
averaged, well resolved spectra. We could not correlate our 1H NMR
spectrum, recorded at 298 °K, with the reported one for 16a that was
recorded at 328 °K.
(27) 13C NMR data: (125 MHz, pyridine-d5) 21.1, 24.5, 54.7, 55.5,
64.6, 70.5, 70.7, 70.9. Reported:11a (methanol-d4) 22.4, 25.9, 56.4, 56.8,
66.6, 71.6, 71.8, 71.9.
(28) 1H NMR data of compound 5b: 1H NMR (300 MHz, pyridine-
d5 + D2O)1.72-2.00 (m, 3H), 2.22-2.40 (m, 1H), 2.84-3.00 (m, 1H),
3.44 (bd, J ) 12.3 Hz, 1H), 3.49-3.67 (m, 2H), 3.69 (bd, J ) 12.3 Hz,
1H), 4.42 (bs, 2H), 4.55 (bs, 1H). Reported:11 (methanol-d4) 2.33-2.50
(m, 4H), 3.24 (q, J ) 9.4 Hz, 1H), 3.49 (dd, J ) 2.0, 12.4 Hz, 1H), 3.62
(t, J ) 6.2 Hz, 1H), 3.78 (dd, J ) 2.6, 12.4 Hz, 1H), 4.32-4.49 (m, 3H),
4.85 (m, 1H). It may be noted that methanol-d4 itself shows two signals
at 3.31 and δ 4.80, which would obscure the signals due to compound
5b. In addition, exchange of -OH protons of 5b with CD3OD would
give HDO, which also shows the signal at δ 4.80.

Synthesis of Polyhydroxylated Piperidine Alkaloids
J . Org. Chem., Vol. 66, No. 4, 2001 1071
Con clu sion
In summary, the intermolecular Michael addition of
amines to D-glucose-derived R,â-unsaturated ester 1
afforded â-amino ester 6a (D-gluco-isomer) as a minor and
6b (L-ido-isomer) as a major product. The high stereo-
selectivity in favor of L-ido-isomer was achieved under
kinetically controlled conditions using lithium-N-benzyl-
amide. The utility of sugar â-amino esters 6a and 6b was
successfully demonstrated in the synthesis of 1-deoxy-
D-gluco-homonojirimycin (3a ), 1-deoxy-L-ido-homonojiri-
mycin (3b), and indolizidine alkaloids 1-deoxy-castano-
spermine (5a ) and 1-deoxy-8a-epi-castanospermine (5b).
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were recorded with a
Thomas-Hoover melting point apparatus and are uncorrected.
IR spectra were recorded with FTIR as a thin film or in Nujol
mull or with KBr pelletes and are expressed in cm-1. 1H (300,
500 MHz) and 13C (75, 125 MHz) NMR spectra were recorded
in CDCl3 as a solvent unless otherwise stated. Chemical shifts
were reported in δ unit (ppm) with reference to TMS as an
internal standard. Elemental analyses were carried out with
a C,H-analyzer. Optical rotations were measured using a
polarimeter at 25 °C. Thin-layer chromatography was per-
formed on precoated plates (0.25 mm, silica gel 60 F254). Flash
chromatography was performed on silica gel (200-400 mesh),
and column chromatography was carried out with silica gel
(100-200 mesh). Whenever required, the reactions were
carried out in oven-dried glassware under dry N2. Diazo-
methane and silver benzoate were prepared as per the
literature procedure. N-Benzylamine and diphenylmethyl-
amines were distilled before use. Diethyl ether, THF, ethyl
acetate, dichloromethane, n-hexane, and methanol were puri-
fied and dried before use. Petroleum ether that was used is a
distillation fraction between 40 and 60 °C. N-Benzylamine,
n-BuLi (1.6 M solution in hexane), LAH, CbzCl, 10% Pd/C were
purchased from Aldrich and/or Fluka. After work up the
organic layer was washed with brine, dried over anhydrous
sodium sulfate, and evaporated at reduced pressure. Ethyl 3-O-
benzyl-5,6-dideoxy-1,2-O-isopropylidene-R-D-xylo-5-eno-hepto-
furanuranoate 1a,b and ethyl 5,6-dideoxy-1,2-O-isopropylidene-
R-D-xylo-5-eno-heptofuranuranoate 1c,d were prepared as per
literature procedure.14 For the experimental detail of the
compounds 3a ,b, 8a ,b, 9a ,b, see ref 3d.
1
F igu r e 4. The comparison of H NMR data of 5a and 5b.
for 5a . However, in the 1H NMR spectra of 5b, the
downfield shift of all the protons, with respect to the
corresponding protons in 5a , indicated the equatorial
orientation of these protons as opposed to the axial
orientation in 5a . The coupling constant J 8,8a is important
for the determination of the configuration at C8a, while
the conformation of 5b would be determined by the
coupling constant values between H5, H6, H7, and H8.
The initial geometry in the precursor 16b ensures that
in the product 5b the substituents at C6, C7 and C7, C8
should be trans. The low values for the coupling constants
(WH ≈ 6.0 Hz) for H6, H7, and H8 indicated that the
protons at these carbons are equatorial.29 This suggested
5
the C8 conformation for the bicyclic indolizidine 5b. The
small value of WH ≈ 6 Hz for H8, along with the axial
orientation of C8-OH, indicated that the C8a substituent
is equatorial with the 8aS configuration. This observation
was supported by two broad doublets at 3.69 and 3.44 δ
(J 5e,5a ) 12.3 Hz) corresponding to the protons H5a and
H5e. The small WH ≈5 Hz suggested that H6 is equatorial
and bisecting the H5 protons (dihedral angle ∼55°) thus
confirming the 5C8 conformation. From an empirical
calculation of the energy difference between the two
Gen er a l P r oced u r e for In ter m olecu la r Ad d ition of
Am in es to R,â-Un sa tu r a ted Ester 1. In a two-neck round-
bottom flask, compound 1 (1.00 mmol) and amine (1.10 or 2.50
mmol) were mixed together in the presence or absence of the
solvent under dry N2. The reaction mixture was stirred at
appropriate temperature and time (Table 1). After completion
of the reaction, the solvent (if used) was evaporated under
reduced pressure (if used), and the residue thus obtained was
purified by column/flash chromatography.
8
5
conformations C5 and C8 (Figure 4) it is evident that in
the C5 conformation the 1,3-diaxial interaction between
8
C5-Ha and C8a-C1 and between C7-H and C8a-C1
destabilize this conformation. On the contrary, in the
conformation 5C8, both of the 1,3-diaxial interactions
(between H and C1-alkyl substituent) are absent and, in
addition, the conformation 5C8 is stabilized by the in-
tramolecular hydrogen bonding in the six-member tran-
sition state as shown in Figure 4.30 This explains the
Eth yl-3-O-ben zyl-5-(N-ben zyla m in o)-5,6-d id eoxy-1,2-O-
isop r op ylid en e-R-D-glu co-h ep tofu r a n u r on a te (6a ) a n d
E t h yl-3-O-b en zyl-5-(N-b en zyla m in o)-5,6-d id eoxy-1,2-O-
isop r op ylid en e-â-L-id o-h ep tofu r a n u r on a te (6b). A solu-
tion of 1a ,b (1.00 g, 2.87 mmol) and N-benzylamine (0.76 g,
7.18 mmol) was stirred at room temperature under N2. After
24 h the reaction mixture was directly loaded on a flash
chromatography column. Elution first with petroleum ether/
ethyl acetate 98/2 afforded â-amino ester 6a (0.35 g, 27%) as
5
preferential orientation of 5b in C8 conformation, which
is in agreement with the observed spectra. It may be
noted that conversion of 8C5 to 5C8 should give N-C3 bond
axial, but as a result of nitrogen flipping, this bond would
have the more stable equatorial geometry as shown in
Figure 4.
a thick liquid: Rf ) 0.47 (n-hexane/ethyl acetate 6/4); [R]D
)
-42.16 (c 0.44, CHCl3); IR (neat) 3330, 1730; 1H NMR (300
MHz) 1.27 (t, J ) 7.2 Hz, 3H), 1.33 (s, 3H), 1.50 (s, 3H), 1.66
(bs, 1H, exchanges with D2O), 2.61 (dd, J ) 6.7, 15.7 Hz, 1H),
2.83 (dd, J ) 4.2, 15.7 Hz, 1H), 3.55 (ddd, J ) 4.2, 6.7, 8.8 Hz
1H), 3.75 (d, J ) 12.8 Hz, 1H), 3.87 (d, J ) 12.8 Hz, 1H), 4.12
(d, J ) 3.0 Hz, 1H), 4.15 (q, J ) 7.2 Hz, 2H), 4.20 (dd, J ) 3.0,
8.8 Hz, 1H), 4.56 (d, J ) 11.6 Hz, 1H), 4.62 (d, J ) 3.7 Hz,
1H), 4.70 (d, J ) 11.6 Hz, 1H), 5.92 (d, J ) 3.7 Hz, 1H), 7.15-
(29) In the 1H NMR spectrum of 5b, recorded with a 500 MHz
instrument, the chemical shifts for H7 and H8 were equivalent. In
13C NMR the C6, C7, and C8 carbons appeared in the close vicinity (δ
70.5, 70.7, and 70.9) indicating nearly identical electronic environment
for these carbons.
(30) Such type of 5C8 conformations for other isomers of castano-
spermine are also known, see: Hendry D.; Hough, L.; Richardson, A.
C. Tetrahedron 1988, 44, 6153.

1072 J . Org. Chem., Vol. 66, No. 4, 2001
Patil et al.
7.35 (m, 10H); 13C NMR (75 MHz) 14.2, 26.3, 26.8, 35.7, 51.2,
52.5, 60.2, 72.0, 81.6, 81.7, 82.0, 104.7, 111.5, 126.8, 127.7,
127.8, 128.0, 128.2, 128.4, 137.4, 140.5, 172.3. Anal. Calcd for
(10 mL) was added at 0 °C, stirred for 10 min, and quenched
with a saturated solution of NH4Cl (2 mL). The solution was
filtered, and the residue was washed with ethyl acetate (3 mL
× 3). The organic layer was evaporated and purified by column
chromatography (CHCl3/MeOH 98/2) to gave 7a (0.4 g, 87%)
as a thick liquid: Rf ) 0.77 (CHCl3/MeOH 9/1); [R]D ) -30.38
C
26H33NO6: C, 68.55; H, 7.30. Found: C, 68.79; H, 7.55.
Further elution with petroleum ether/ethyl acetate 95/5 gave
6b (0.82 g, 63%) as a pale yellow solid: mp 70-72 °C; Rf )
1
0.36 (n-hexane/ethyl acetate 6/4); [R]D ) -26.25 (c 0.32,
(c 0.65, CHCl3); IR (Nujol) 3750-3340 (broad); H NMR (300
1
CHCl3); IR (Nujol) 3337, 1731; H NMR (300 MHz) 1.25 (t, J
MHz) 1.33 (s, 3H), 1.50 (s, 3H), 1.77-1.83 (m, 2H), 2.85-2.90
(bs, 2H, exchanges with D2O), 3.32-3.40 (m, 1H), 3.79 (d, J )
12.3 Hz, 1H), 3.75-3.90 (m, 2H), 3.94 (d, J ) 12.3 Hz, 1H),
4.03 (d, J ) 3.3 Hz, 1H), 4.20 (dd, J ) 3.3, 6.9 Hz, 1H), 4.48
(d, J ) 11.5 Hz, 1H), 4.64 (d, J ) 3.8 Hz, 1H), 4.69 (d, J )
11.5 Hz, 1H), 5.95 (d, J ) 3.8 Hz, 1H), 7.15-7.35 (m, 10H);
13C NMR (75 MHz) 26.2, 26.8, 31.9, 51.8, 56.9, 62.5, 71.8, 81.4,
81.6, 82.2, 104.7, 111.5, 127.1, 127.5, 128.0, 128.2, 128.5, 128.7,
136.8, 139.8. Anal. Calcd for C24H31NO5: C, 69.71; H 7.56.
Found: C, 69.59; H, 7.40.
) 7.1 Hz, 3H), 1.35 (s, 3H), 1.51 (s, 3H), 1.80 (bs, 1H, exchanges
with D2O), 2.33 (dd, J ) 6.7, 14.8 Hz, 1H), 2.45 (dd, J ) 4.6,
14.8 Hz, 1H), 3.55 (ddd, J ) 4.6, 6.7, 8.8 Hz, 1H), 3.86 (ABq,
J ) 12.7 Hz, 2H), 3.97 (d, J ) 3.1 Hz, 1H), 4.12 (q, J ) 7.1 Hz,
2H), 4.26 (dd, J ) 3.1, 8.8 Hz, 1H), 4.47 (d, J ) 11.8 Hz, 1H),
4.67 (d, J ) 3.9 Hz, 1H), 4.72 (d, J ) 11.8 Hz, 1H), 5.97 (d, J
) 3.9 Hz, 1H), 7.22-7.45 (m, 10H); 13C NMR (75 MHz) 14.0,
26.1, 26.6, 36.3, 51.4, 53.6, 60.2, 71.2, 81.5, 81.6, 82.1, 104.7,
111.4, 126.6, 127.7, 127.8, 128.0, 128.1, 128.3, 136.9, 140.4,
171.5. Anal. Calcd for C26H33NO6: C, 68.55; H, 7.30. Found:
C, 68.72; H, 7.40.
Gen er a l P r oced u r e Usin g Lith iu m N-Ben zyl Am id e or
Lith iu m N-Dip h en ylm eth yl Am id e. To a stirred solution
of amine (0.69 mmol) in dry THF (3 mL) at -10 °C under dry
N2 was added n-BuLi (1.6 M in hexane, 0.43 mL, 0.69 mmol),
and the mixture was stirred at the same temperature for 10
min. The reaction mixture was cooled to -40 °C, and a solution
of 1a -d (0.574 mmol) in dry THF (2 mL) was added over a
period of 10 min. The mixture was stirred for 2 h at the same
temperature, quenched with saturated solution of aqueous
NH4Cl, diluted with water, and extracted with ethyl acetate
(5 mL × 3). Work up and purification by column chromatog-
raphy afforded the Michael addition product.
3-O-Ben zyl-5,6-d id eoxy-5-N-(b en zyla m in o)-1,2-O-iso-
p r op ylid en e-â-L-id o- h ep to-1,4-fu r a n ose (7b). The reaction
of 6b (0.5 g, 1.10 mmol) with LAH (0.20 g, 5.49 mmol) was
performed under the same conditions as reported for 6a . Flash
chromatography (CHCl3/MeOH 96/4) afforded 7b (0.95 g, 84%)
as a thick liquid: Rf ) 0.48 (CHCl3/MeOH 9/1); [R]D ) -32.65
1
(c 0.65, CHCl3); IR (neat) 3250-3600 (broad); H NMR (300
MHz, CDCl3 + D2O) 1.33 (s, 3H), 1.50 (s, 3H), 1.38-1.65 (m,
2H), 3.38 (m, 1H), 3.69-3.82 (m, 2H), 3.86 (d, J ) 3.1 Hz, 1H),
3.89 (ABq, J ) 12.1 Hz, 2H), 4.24 (dd, J ) 3.1, 9.5 Hz, 1H),
4.41 (d, J ) 11.7 Hz, 1H), 4.66 (d, J ) 3.8 Hz, 1H), 4.70 (d, J
) 11.7 Hz, 1H), 5.96 (d, J ) 3.8 Hz, 1H), 7.21-7.39 (m, 10H);
13C NMR (75 MHz) 26.2, 26.8, 29.5, 50.8, 56.8, 62.3, 71.8, 81.4,
81.7, 81.9, 104.8, 111.7, 127.1, 128.1, 128.2, 128.5, 128.6, 136.9,
139.7. Anal. Calcd for C24H31NO5: C, 69.71; H, 7.56. Found:
C, 69.70; H, 7.40.
E t h yl-5-N -(b e n zyla m in o)-5,6-d id e oxy-1,2-O-isop r o-
pyliden e-â-L-ido-h eptofu r an u r on ate (6g) an d 5,6-Dideoxy-
1,2-O-isop r op ylid en e-5-(N-b en zyla m in o)-â-L-id o-h ep t o-
fu r a n u r o-(N-ben zyl)-a m id e (6f). A solution of 1c-d (0.50
g, 1.94 mmol) and N-benzylamine (3.64 g, 2.12 mmol) was
stirred at 25 °C, in the absence of solvent, under dry N2. After
12 h the reaction mixture was directly loaded on a flash column
chromatography. Elution first with petroleum ether/ethyl
acetate 95/5 afforded â-amino ester 6g (0.10 gm, 14%) as a
thick liquid: Rf ) 0.55 (n-hexane/ethyl acetate 1/1); [R]D ) +5.8
Eth yl 3-O-Ben zyl-5-(N-ben zyl-N-ben zoxyca r bon yla m i-
n o)-5,6-d id eoxy-1,2-O-isop r op ylid en e-R-D-glu co-h ep t o-
fu r a n u r on a te (10a ). To a stirred solution of 6a (1.00 g, 2.19
mmol) and sodium bicarbonate (0.75 g, 8.93 mmol) in ethanol-
water (2 mL, 1:1) was added benzyloxycarbonyl chloride (0.45
g, 2.64 mmol) at 0 °C. The mixture was stirred at 30 °C for 3
h. Water (5 mL) was added, and reaction mixture was
extracted with chloroform (10 mL × 3). Workup and purifica-
tion by column chromatography (petroleum ether/ethyl acetate
95/5) gave 10a (1.37 g, 97%) as a thick liquid: Rf ) 0.48 (n-
hexane/ethyl acetate 6/4); [R]D ) -32.97 (c 2.2, CHCl3); IR
(neat) 1730, 1695; 1H NMR (500 MHz) 1.00-1.40 (m, 9H),
2.52-2.93 (m, 2H), 3.50-4.00 (m, 3H), 4.20-4.95 (m, 7H), 5.0-
5.30 (m, 2H), 5.82 (bs, 1H), 7.10-7.50 (m, 15H). Anal. Calcd
for C34H39NO8: C, 69.25; H, 6.67. Found: C, 69.35; H, 6.78.
1
(c 1.0, CHCl3); IR (Nujol) 3150-3300 (broad band), 1718; H
NMR (300 MHz, CDCl3 + D2O) 1.27 (t, J ) 7.1 Hz, 1H), 1.30
(s, 3H), 1.45 (s, 3H), 2.72 (dd, J ) 7.5, 15.4 Hz, 1H), 2.80 (dd,
J ) 4.7, 15.4 Hz, 1H), 3.58 (ddd, J ) 1.4, 4.7, 7.5 Hz, 1H),
3.70 (d, J ) 12.3 Hz, 1H), 3.91 (d, J ) 12.3 Hz, 1H), 4.14 (dd,
J ) 1.4, 2.9 Hz, 1H), 4.17 (q, J ) 7.1 Hz, 2H), 4.27 (d, J ) 2.9
Hz, 1H), 4.46 (d, J ) 3.5 Hz, 1H), 5.89 (d, J ) 3.5 Hz, 1H),
7.25-7.36 (m, 5H); 13C NMR (125 MHz) 14.1, 26.3, 26.9, 36.2,
50.4, 54.1, 60.9, 77.4, 78.7, 85.8, 104.9, 111.6, 127.7, 128.5,
128.7, 137.8, 171.4. Anal. Calcd for C19H27NO6: C, 62.45; H,
7.45. Found: C, 62.35; H, 7.40.
Eth yl 3-O-Ben zyl-5-(N-ben zyl-N-ben zoxyca r bon yla m i-
n o)-5,6-d id eoxy-1,2-O-isop r op ylid en e-â-L-id o-h ep tofu r a -
n u r on a te (10b). The reaction of 6b (2.00 g, 4.39 mmol) with
benzyloxycarbonyl chloride (0.90 g, 5.28 mmol) under the same
conditions reported for 6a gave 10b (2.74 g, 97%) as a thick
liquid: Rf ) 0.45 (n-hexane/ethyl acetate 7/3); [R]D ) -19.6 (c
Further elution with petroleum ether/ethyl acetate 9/1
afforded a diastereomeric mixture of 6e and 6f in the ratio
20:80 (0.49 g, 59%) as a thick liquid: Rf ) 0.2 (n-hexane/ethyl
acetate 6/4); IR (neat) 3200-3300, 1644; for major isomer 6f:
1H NMR (300 MHz) 1.29 (s, 3H), 1.38 (s, 3H), 2.49 (dd, J )
14.2, 8.7 Hz, 1H), 2.77 (dd, J ) 14.2, 4.3 Hz, 1H), 3.63-3.70
(m, 1H), 3.75 (d, J ) 12.5 Hz, 1H), 3.90 (d, J ) 12.5 Hz, 1H),
4.09 (t, J ) 2.5 Hz, 1H), 4.28 (d, J ) 2.5 Hz, 1H), 4.35 (dd, J
) 5.3, 14.6 Hz, 1H, becomes doublet with J ) 14.6 on D2O
exchange), 4.46 (d, J ) 3.6 Hz, 1H), 4.51 (dd, J ) 14.6, 6.1 Hz,
1H, becomes doublet with J ) 14.6 on D2O exchange), 5.88 (d,
J ) 3.6 Hz, 1H), 6.4 (bs, 1H), 7.22-7.34 (m, 12H); 13C NMR
(125 MHz,) 26.1, 26.8, 38.9, 43.7, 50.6, 54.5, 77.2, 78.7, 85.8,
104.7, 111.5, 127.5, 127.8, 128.3, 128.6, 128.7, 137.8, 138.3,
170.2. Anal. Calcd for C24H30N2O5: C, 69.71; H, 7.56. Found:
C, 69.67; H, 7.76. The 1H and 13C NMR spectra showed
additional peaks (20%) corresponding to D-gluco isomer 6e.
3-O-Ben zyl-5,6-d id eoxy-5-(N-b en zyla m in o)-1,2-O-iso-
p r op ylid en e-R-D-glu co-h ep to-1,4-fu r a n ose (7a ). To an ice-
cooled suspension of LAH (0.20 g, 5.49 mmol) in dry THF (5
mL) was added a solution of 6a (0.5 g, 1.1 mmol) in dry THF
(5 mL) over a period of 10 min. The reaction mixture was
warmed to room temperature and stirred for 2 h. Ethyl acetate
1
1, CHCl3); IR (neat) 1734, 1699; H NMR (500 MHz), 1.06 (t,
J ) 7 Hz, 3H), 1.28,1.31,1.42 (each s, 6H), 2.55, 2.90 (each m,
1H), 3.62-3.92 (m, 3H), 4.25-4.75 (m, 8H), 5.05-5.30(m, 2H),
5.76, 5.86 (each s, 1H), 7.10-7.50 (m, 15H). Anal. Calcd for
C34H39NO8: C, 69.25; H, 6.67. Found C, 69.30; H, 6.70.
Eth yl 3-O-Ben zyl-5-(N-ben zyl-N-ben zoxyca r bon yla m i-
n o)-5,6-d id eoxy-1,2-O-isop r op ylid en e-R-D-glu co-h ep t o-
fu r a n u r on ic a cid (11a ). To an ice-cooled solution of 10a (1.00
g, 1.69 mmol) in methanol/water (20 mL, 4/1) was added
lithium hydroxide monohydrate (0.43 g, 10.24 mmol) at 0 °C.
The mixture was brought to 25 °C and the pH of the solution
was adjusted to 7 by addition of 0.5 M H3PO4, the solvent was
evaporated, and residue thus obtained was extracted with
chloroform (10 mL × 3). Purification by column chromatog-
raphy (chloroform/methanol 98/2) afforded 11a (0.95 g, 96%)
as a thick liquid: Rf ) 0.62 (chloroform/methanol 9/1); [R]D
)
-33.89 (c 0.72, CHCl3); IR (neat) 1735, 1695; 1H NMR (500
MHz, CDCl3 + D2O) 1.26, 1.30, 1.38 (each s, 6H), 2.60-3.00
(m, 2H), 3.59-3.79 (bs, 1H), 4.20-4.40 (m, 2H), 4.45-4.58 (m,

Synthesis of Polyhydroxylated Piperidine Alkaloids
J . Org. Chem., Vol. 66, No. 4, 2001 1073
5H), 5.02-5.32 (m, 2H), 5.85 (bs, 1H), 7.07-7.29 (m, 15H).
Anal. Calcd for C32H35NO8: C, 68.43; H, 6.28. Found: C, 68.40;
H, 6.29.
-50.87 (c 3.0, CHCl3); IR (neat) 1736, 1695; 1H NMR (500
MHz) 1.25, 1.32 (each singlet, 6H), 1.90-2.42 (m, 4H), 3.52-
3.56 (two singlets, 3H), 3.90-5.10 (m, 8H), 5.12-5.32 (m, 2H),
5.84 (bs, 1H), 7.10-7.30 (m, 15H); 13C NMR (125 MHz) 26.1,
26.6, 30.8, 31.0, 51.3, 67.3, 69.7, 71.8, 80.8, 81.4, 81.8, 104.7,
111.4, 127.2, 127.6, 127.9, 128.0, 128.4, 136.1, 137.2, 138.5,
172.1, 173.0. 13C NMR showed additional signals correspond-
ing to other isomer. Anal. Calcd for C34H39NO8: C, 69.25; H,
6.67. Found: C, 69.36; H, 6.60.
Met h yl 3-O-Ben zyl-5-(N-b en zyl-N-b en zoxyca r b on yl-
a m in o)-5,6,7-tr id eoxy-1,2-O-isop r op ylid en e-â-L-id o-octo-
1,4-fu r a n u r on a te (13b). The reaction of 12b (0.8 g, 1.37
mmol) for 12a gave 13b (0.69 g, 85%) as a white solid: mp
Eth yl 3-O-Ben zyl-5-(N-ben zyl-N-ben zoxyca r bon yla m i-
n o)-5,6-d id eoxy-1,2-O-isop r op ylid en e-â-L-id o-h ep tofu r a -
n u r on ic a cid (11b). The reaction of 10b (2.00 g, 3.39 mmol)
with lithium hydroxide monohydrate (0.86 g, 20.49 mmol)
under the same conditions reported for 10a gave 11b (1.9 g,
96%) as a thick liquid: Rf ) 0.6 (chloroform/methanol 9/1);
[R]D ) -25.75 (c 0.8, CHCl3); IR (neat) 3500-3600 (broad
band), 1739, 1702; 1H NMR (500 MHz, CDCl3 + D2O) 1.28,
1.30, 1.44 (each singlet, 6H), 2.09 (dd, J ) 15.0, 4.5 Hz) and
2.20 (dd, J ) 13.0, 3.5 Hz) (each dd, 1H), 2.57-2.70, 2.87-
2.98 (each m, 1H), 3.70, 3.83 (each bs, 1H), 4.30-4.52 (m, 3H),
4.55-4.75 (m, 4H), 5.13, 5.23 (each s, 2H), 5.77, 5.88 (each bs,
1H), 7.10-7.45 (m, 15H); 13C NMR (125 MHz) for major isomer
26.4, 26.8, 34.5, 55.5, 67.1, 71.3, 77.0, 78.9, 80.9, 81.1, 104.7,
111.8, 126.9, 127.6, 127.7, 127.8, 128.0, 128.3, 128.4, 136.4,
136.8, 138.2, 156.1, 176.0. 13C NMR showed additional signals
corresponding to other isomer. Anal. Calcd for C32H35NO8: C,
68.43 H, 6.28. Found: C, 68.33; H, 6.30.
5,6,8-Tr id eoxy-1,2-O-isop r op ylid en e-3-O-b en zyl-5-(N-
ben zyl-N-ben zoxy ca r b on yl a m in o)-8-d ia zo-R-D-glu co-
octo-1,4-fu r a n -7-u lose (12a ). A solution of 11a (0.80 g, 1.42
mmol) in THF (10 mL) was cooled to 0 °C under dry N2.
Triethylamine (0.16 gm, 1.57 mmol) and ethylchloroformate
(0.17 mL, 1.57 mmol) were added one after another. After 15
min, the suspension was allowed to warm to 25 °C and filtered
through Celite. To the filtrate was added a freshly prepared
solution of diazomethane in diethyl ether [(prepared from
N-nitrosomethyl urea (1.02 g, 7.12 mmol) and KOH (2 g)]
dropwise over a period of 30 min. The mixture was stirred for
1.5 h, during which the reaction slowly attained room tem-
perature. The solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography
(petroleum ether/ethyl acetate 9/1) to give 12a (0.52 g, 62%)
102-103 °C; Rf ) 0.34 (n-hexane/ethyl acetate 7/3); [R]D
)
-20.5 (c 0.4, CHCl3); IR (Nujol) 1740, 1695; 1H NMR (500
MHz) 1.28,1.30 (each s, 6H), 1.34-1.48 (m, 2H), 1.97-2.18 (m,
2H), 3.48 (s, 1.8H), 3.52 (s, 1.2H), 3.78 (m, 0.4H), 3.85 (m,
0.6H), 4.20-4.40 (bm, 1H), 4.40-4.55 (m, 2H), 4.58-4.78 (m,
3H), 5.14 (s, 1.2H), 5.19(s, 0.8H), 5.85 (s, 0.4H), 5.92 (s, 0.6H),
7.20-7.50 (m, 2H). 13C NMR showed additional signals cor-
responding to other isomer. Anal. Calcd for C34H39NO8: C,
69.25; H, 6.67. Found: C, 69.45; H, 6.75.
5,6,7-Tr ideoxy-5,8-im in o-1,2-O-isopr opyliden e-R-D-glu co-
oct-1,4-fu r a n -8-u lose (14a ). A mixture of 13a (0.4 g, 0.68
mmol) and 10% Pd/C (0.05 g) in methanol (10 mL) was
hydrogenolysed at 80 psi for 12h. The catalyst was filtered
through Celite and washed with methanol. To the filtrate,
anhydrous sodium acetate (0.06 g, 0.23 mmol) was added, and
the mixture was refluxed for 6,h. The pH of the solution was
adjusted to 8 by addition of 1 N NaOH. Methanol was removed,
and the solution was extracted with chloroform (5 mL × 5).
The chloroform layer was dried and evaporated to give a
gummy solid ,which was purified by column chromatography
(chloroform/methanol 4/1) to give 14a (0.13 g, 80%) as a yellow
solid: mp 152-153 °C; Rf ) 0.56 (chloroform/methanol 98/2);
1
[R]D ) -3.04 (c 0.46, CHCl3); IR (Nujol) 3147, 1661; H NMR
as thick liquid: Rf ) 0.35 (n-hexane/ethyl acetate 7/3); [R]D
)
(300 MHz, DMSO-d6) 1.23 (s, 3H), 1.38 (s, 3H), 1.64-1.80 (m,
1H), 2.02-2.22 (m, 3H), 3.67-3.76 (m, 1H), 3.78 (dd, J ) 8.4,
2.3 Hz, 1H), 4.02 (bd, J ) 2.3 Hz, 1H becomes doublet with J
) 2.3 Hz on D2O exchange), 4.40 (d, J ) 3.6 Hz, 1H), 5.40 (d,
J ) 4.9 Hz, 1H, disappears on D2O exchange), 5.85 (d, J ) 3.6
Hz, 1H), 7.57 (bs, 1H, disappears on D2O exchange); 13C NMR
(125 MHz, DMSO-d6) 24.6, 26.8, 27.3, 30.5, 53.3, 74.4, 83.6,
85.9, 105.4, 112.6, 180.9. Anal. Calcd for C11H17NO5: C, 54.31;
H, 7.04. Found: C, 54.55; H, 7.14.
-12.2 (c 4.0, CHCl3); IR (neat) 2106, 1696, 1642; 1H NMR (500
MHz) 1.26, 1.40, 1.43 (each s, 6H), 2.52-3.10 (m, 2H), 3.74,
3.76 (each bs, 1H), 4.15-4.92 (m, 8H), 5.10-5.32 (m, 2H), 5.84
(d, J ) 3.2 Hz, 1H), 7.10-7.50 (m, 15H); 13C NMR (125 MHz)
26.2, 26.6, 41.2, 52.7, 54.7, 67.2, 67.7, 71.6, 80.5, 81.4, 82.0,
104.7, 111.6, 127.1, 127.7, 127.9, 128.4, 136.4, 137.1, 138.4,
155.9, 158.0, 191.7. 13C NMR shows additional signals. Anal.
Calcd for C33H35N3O7: C, 67.68; H, 6.02. Found: C, 67.78; H,
6.32.
5,6,7-Tr id eoxy 5,8-im in o-1,2-O-isop r op ylid en e-â-L-id o-
oct-1,4-fu r a n -8-u lose (14b). A solution of 13b (0.60 g, 1.02
mmol) in methanol (10 mL) hydrogenated in the presence of
10% Pd/C under the same conditions reported for 13a gave
14b (0.20 g, 80%) as a white solid: mp 168-170 °C; Rf ) 0.5
(chloroform/methanol 4/1); [R]D ) -104.35 (c 0.40, MeOH); IR
5,6,8-Tr id eoxy-1,2-O-isop r op ylid en e-3-O-b en zyl-5-(N-
ben zyl-N-ben zoxy ca r bon yl a m in o)-8-d ia zo-â-L-id o-octo-
1,4-fu r a n -7-u lose (12b). The reaction of 11b (1.60 g, 2.85
mmol) with ethylchloroformate (0.34 g, 3.14 mmol) and then
with diazomethane [(prepared from N-nitrosomethyl urea (2.04
g, 14.24 mmol) and KOH (4 g)] under the same conditions
reported for 11a gave 12b (1.08 g, 65%) as a yellow solid: mp
98-99 °C; Rf ) 0.26 (n-hexane/ethyl acetate 7/3); [R]D ) -26.00
(c 0.5, CHCl3); IR (Nujol) 2106, 1697, 1640; 1H NMR (500 MHz)
1.43, 1.31, 1.33, 1.29 (each s, 6H), 2.00-2.15 (m, 1H), 2.40-
2.98 (m, 1H), 3.75, 3.8 (each bs, 1H), 4.25-4.50 (m, 3H), 4.52-
4.75 (m, 4H), 4.80 (bs, 1H), 5.11, 5.23 (each ABq, J ) 12.6 Hz,
1H), 5.82, 5.88 (each d, J ) 2.5 Hz, 1H), 7.10-7.50 (m, 15H);
13C NMR (125 MHz) 26.3, 26.7, 40.5, 54.7, 66.9, 67.5, 70.9,
71.2, 79.1, 80.9, 81.6, 104.6, 111.7, 127.0, 127.4, 127.7, 127.9,
128.0, 128.2, 128.4, 136.5, 136.8, 138.2, 155.9, 191.7. 13C NMR
showed additional peaks corresponding to other isomer. Anal.
Calcd for C33H35N3O7: C, 67.68 H, 6.02. Found: C, 67.91; H,
6.25.
1
(Nujol) 3321 (broad band), 1681; H NMR (300 MHz, DMSO-
d6) 1.23 (s, 3H), 1.38 (s, 3H), 1.62-1.78 (m, 1H), 2.02-2.20
(m, 3H), 3.63-3.80 (m, 2H), 4.02-4.06 (m, 1H, became bd, J
) 2.3 Hz on D2O exchange), 4.42 (d, J ) 3.6 Hz, 1H), 5.40 (d,
J ) 4.9 Hz, 1H disappear on D2O exchange), 5.85 (d, J ) 3.6
Hz, 1H), 7.58 (s, 1H, exchanges with D2O); 13C NMR (125 MHz,
DMSO-d6) 23.0, 25.1, 25.8, 29.5, 54.2, 74.5, 83.6, 85.7, 105.0,
111.5, 180.0. Anal. Calcd for C11H17NO5: C, 54.31; H, 7.04.
Found: C, 54.25; H, 7.12.
5,6,7,8-Tetr a d eoxy-5,8-(N-ben zoxyca r bon ylim in o)-1,2-
O-isop r op ylid en e-R-D-glu co-oct-1,4-fu r a n ose (16a ). To an
ice-cooled suspension of LAH (0.93 g, 2.45 mmol) in dry THF
(4 mL) was added a solution of 14a (0.12 g, 0.49 mmol) in dry
THF (6 mL) over a period of 10 min. The mixture was refluxed
for 18 h. Ethyl acetate (10 mL) was added at 0 °C and stirred
for 10 min. The reaction was quenched with a saturated
aqueous solution of NH4Cl (2 mL) and filtered, and the residue
was rinsed with ethyl acetate (5 mL). Work up gave 15a as
thick liquid. To a stirred solution of 15a in ethanol/water (2
mL, 1/1) were added sodium bicarbonate (0.17 g, 1.97 mmol)
and benzyloxycarbonyl chloride (0.10 g, 0.59 mmol) at 0 °C.
The mixture was stirred at 25 °C for 2 h. Workup followed
with extraction with chloroform (5 mL × 3). The chloroform
layer was dried and evaporated to afford a thick liquid that
Met h yl 3-O-Ben zyl-5-(N-b en zyl-N-b en zoxyca r b on yl-
a m in o)-5,6,7-t r id eoxy-1,2-O-isop r op ylid en e-R-D-glu co-
octo-1,4-fu r a n u r on a te (13a ). To
a solution of R-diazo
ketone 12a (0.5 g, 0.85 mmol) in anhydrous MeOH (12 mL)
was added dropwise a solution of silver benzoate (0.06 g, 0.27
mmol) in triethylamine (1 mL) under dry N2. The mixture was
stirred at 25 °C for 1.5 h. The solvent was evaporated, and
the residue was purified by column chromatography (petro-
leum ether/ethyl acetate 95/5) to give 13a (0.42 g, 83%) as a
thick liquid: Rf ) 0.46 (n-hexane/ethyl acetate 7/3); [R]D
)

1074 J . Org. Chem., Vol. 66, No. 4, 2001
Patil et al.
was purified by column chromatography (petroleum ether/
ethyl acetate 92/8) to give 16a (0.13 g, 74%) as a thick liquid:
Rf ) 5.5 (n-hexane/ethyl acetate 6/4); [R]D ) +29.00 (c 0.56,
CHCl3) [reported +28.30 (c,1.1, CHCl3)];10b IR (neat) 3366,
[reported +50.6 (c 0.2, MeOH)];10b IR (KBr pellet) 3380, 3270
1
(broad band); H NMR (300 MHz, pyridine-d5 + D2O) 1.39-
1.58 (m, 1H), 1.64-1.82 (m, 2H), 1.93-2.06 (m, 1H), 2.10-
2.24 (m, 2H), 2.30 (t, J ) 10.5 Hz, 1H), 2.94 (dt, J ) 8.6, 2.0
Hz, 1H), 3.43 (dd, J ) 5.2, 10.5 Hz, 1H), 3.86 (t, J ) 8.6 Hz,
1H), 3.91 (t, J ) 8.6 Hz, 1H), 4.33 (ddd, J ) 10.5, 8.6, 5.2 Hz,
1H); 13C NMR (125 MHz, pyridine-d5) 21.9, 28.6, 53.2, 56.9,
68.3, 71.5, 75.9, 80.9. Anal. Calcd for C8H15NO3: C, 55.47; H,
8.73. Found: C, 55.77; H, 8.98.
1
1675; H NMR (300 MHz) 1.31 (s, CH3), 1.49 (s, CH3), 1.84-
2.05 (m, 3H), 2.09-2.15 (m, 1H), 3.38-3.45 (m, 2H), 3.80 (dd,
J ) 10.2, 1.8 Hz, 1H), 4.02 (d, J ) 1.8 Hz, 1H), 4.14 (, J )
10.2, 6.2 Hz, 1H), 5.26 (bs, 1H, exchanges with D2O), 4.59 (d,
J ) 3.7 Hz, 1H), 5.14 (ABq, J ) 12.5 Hz, 2H), 5.90 (d, J ) 3.7
Hz, 1H), 7.26-7.38 (m, 5H), 13C NMR (75 MHz) 23.0, 26.1,
27.1, 28.2, 48.8, 59.9, 68.1, 73.9, 81.0, 85.0, 105.2, 112.3, 128.0,
128.4, 129.1, 136.0, 157.1. Anal. Calcd for C19H25NO6: C, 62.79;
H, 6.93. Found: C, 62.68; H, 6.81.
5,6,7,8-Tetr a d eoxy-5,8-(N-ben zoxyca r bon ylim in o)-1,2-
O-isop r op ylid en e-â-L-id o-oct-1,4-fu r a n ose (16b). The reac-
tion of 14b (0.20 g, 0.82 mmol) with LAH (0.16 g, 4.1 mmol)
under the same conditions reported for 14a gave 15b as a thick
liquid that on treatment with benzyloxycarbonyl chloride (0.16
g, 0.94 mmol) under the same conditions reported for 15a gave
16b (0.22 g, 74%) as a thick liquid: Rf ) 0.42 (n-hexane/ethyl
acetate 6/4); [R]D ) -72.27 (c 0.44, CHCl3); IR (neat) 3390,
1693; 1H NMR (300 MHz) 1.30 (s, 3H), 1.48 (s, 3H), 1.82-1.94
(m, 2H), 1.96-2.20 (m, 2H), 3.42-3.58 (m, 2H), 4.0 (t, J ) 3.0
Hz, 1H), 4.13 (d, J ) 2.9 Hz 1H), 4.26-4.34 (m, 1H), 4.48 (d,
J ) 3.6 Hz, 1H), 5.13 (ABq, J ) 12.3 Hz, 2H), 5.87 (d, J ) 3.6
Hz 1H), 7.24-7.42 (m, 5H); 13C NMR (75 MHz) 23.6, 26.1, 26.7,
29.7, 47.2, 55.5, 67.5, 75.7, 84.0, 85.0, 104.5, 111.2, 127.8, 128.0,
128.4, 136.3, 158.7. Anal. Calcd for C19H25NO6: C, 62.79; H,
6.93. Found: C, 62.80; H, 6.79.
(6S,7R,8R,8a R)-6,7,8-Tr ih yd r oxy-in d olizid in e (5a ). A
solution of 16a (0.10 g, 0.28 mmol) in TFA/H2O (2 mL, 3/2)
was stirred at 25 °C for 2 h. Trifluroacetic acid was coevapo-
rated with benzene to furnish a thick liquid, which was directly
used in the next reaction. A solution of the above product in
methanol (5 mL) was added 10% Pd/C (0.01 g), and the solution
was hydrogenated at 80 psi for 16 h. The catalyst was filtered
and washed with methanol and the filtrate concentrated to
get a sticky solid which was purified by column chromatog-
raphy (chloroform/methanol 9/1) to give 5a (0.04 g, 90%) as a
white solid: mp 176-178 °C (reported 178-181 °C)10b; Rf )
0.45 (chloroform/methanol 9/1) [R]D ) +50.10 (c 0.7, MeOH)
(6S,7R,8R,8a S)-6,7,8-Tr ih yd r oxy-in d olizid in e (5b). The
reaction of 16b (0.16 g, 0.44 mmol) with TFA/H2O (2 mL, 3/2)
under the same conditions reported for 16a gave the corre-
sponding hemiacetal as a thick liquid, which on hydrogenation
with 10% Pd/C (0.02 g) in methanol under the same conditions
reported for 16a gave 5b as a thick liquid. Column chroma-
tography using chloroform/methanol 8/2 as an eluent gave
(0.065 g, 87%) as a semisolid: Rf ) 0.2 (chloroform/methanol
1/1); [R]D ) +23.0 (c 0.72, MeOH) [reported +22.5 (c 1.13,
1
MeOH)11]; IR (KBr pellet) 3360-3250 (broad band); H NMR
(300 MHz, pyridine-d5 + D2O) 1.72-2.00 (m, 3H), 2.22-2.40
(m, 1H), 2.84-3.00 (m, 1H), 3.44 (bd, J ) 12.3 Hz, 1H), 3.49-
3.67 (m, 2H), 3.69 (bd, J ) 12.3 Hz, 1H), 4.42 (bs, 2H), 4.55
(bs, 1H); 13C NMR (125 MHz, pyridine-d5) 21.1, 24.5, 54.7, 55.5,
64.6, 70.5, 70.7, 70.9. Anal. Calcd for C8H15NO3: C, 55.47; H,
8.73. Found: C, 55.80; H, 9.02.
Ack n ow led gm en t. We are grateful to BRNS, Mum-
bai for the financial support (98/37/11/BRNS). N.T.P.
is thankful to BRNS, Mumbai (in part) and CSIR, New
Delhi for a fellowship. We are indebted to Prof. M. S.
Wadia and Prof. N. S. Narasimhan for the discussion.
We gratefully acknowledge UGC, New Delhi, for the
grant to procure the high field NMR facility (300 MHz)
and TIFR (Mumbai) for the 500 MHz NMR facility.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 3a ,b, 5a ,b, 6a ,b, 6g, 7a ,b, 10a ,b, 14a ,b,
and 16a ,b. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0010476