Synthesis of pentahydroxy indolizidine alkaloids using ring closing metathesis: Attempts to find the correct structure of uniflorine A

Article abstract of DOI:10.1021/jo060823s

Ring closing metathesis of D-glucose derived diene-substrate containing nitrogen functionality followed by asymmetric dihydroxylation afforded sugar substituted dihydroxylated pyrrolidines 8a-c which on 1,2-acetonide deprotection and reductive amination a

Full text of DOI:10.1021/jo060823s

Synthesis of Pentahydroxy Indolizidine Alkaloids
Using Ring Closing Metathesis: Attempts To
Find the Correct Structure of Uniflorine A
Narayan S. Karanjule, Shankar D. Markad, and
Dilip D. Dhavale*
Garware Research Centre, Department of Chemistry,
UniVersity of Pune, Pune-411 007, India
ddd@chem.unipune.ernet.in
ReceiVed April 19, 2006
FIGURE 1. Indolizidine alkaloids.
of synthetic and naturally isolated product. In another report,
Mariano and co-workers8b have reported a photochemical ring
rearrangement reaction for the synthesis of castanospermine 1
and pentahydroxy indolizidine alkaloids 2d8 and 2e which also
showed deviation in the spectral data from that of the isolated
uniflorine A. As a part of our continuing interest in the synthesis
Ring closing metathesis of D-glucose derived diene-substrate
containing nitrogen functionality followed by asymmetric
dihydroxylation afforded sugar substituted dihydroxylated
pyrrolidines 8a-c which on 1,2-acetonide deprotection and
reductive amination afforded putative uniflorine A 2a and
its analogues 2b-c, respectively.
(2) For the application of the ring closing metathesis reaction to the
synthesis of azasugars, see the following: (a) Ovaa, H.; Stragies, R.; Van
der Marel, G. A.; Van Boom, J. H.; Blechert, S. Chem. Commun. 2000,
1501-1502. (b) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36,
1621-1624. (c) Overkleeft, H. S.; Pandit, U. K. Teterahedron Lett. 1996,
37, 547-550. (d) Verhelst, S. H. L.; Martinez, B. P.; Timmer, S. M.; Lodder,
G.; Van der Marel, G. A.; Overkleeft, H. S.; Van Boom, J. H. J. Org. Chem.
2003, 68, 9598-9603. (e) Huwe, C. M.; Blechert, S. Synthesis 1997, 61-
67. (f) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem. Soc. 1998,
120, 7359-7360. (g) Lindstrom, U. M.; Somfai, P. Tetrahedron Lett. 1998,
39, 7173-7176. (h) Ovaa, H.; Stragies, R.; Van Der Marel, G. A.; Van
Boom, J. H.; Blechert, S. Chem. Commun. 2000, 1501-1502. (i) Voigtmann,
U.; Blechert, S. Org. Lett. 2000, 2, 3971-3974. (j) Subramanian, T.; Lin,
C. C. Tetrahedron Lett. 2001, 42, 4079-4082. (k) Klitze, C. F.; Pilli, R.
A. Tetrahedron Lett. 2001, 42, 5605-5608. (l) Chandra, K. L.; Chan-
drasekhar, M.; Singh, V. K. J. Org. Chem. 2002, 67, 4630-4633. (m)
Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774-7780. (n)
Buschmann, N.; Ru¨ckert, A.; Blechert, S. J. Org. Chem. 2002, 67, 4325-
4329. (o) Lee, H. K.; Chun, J. S.; Pak, C. S. J. Org. Chem. 2003, 68, 2471-
2474.
(3) (a) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., ed.; Wiley-Interscience: New
York, 1987; Vol. 5. (b) Howard, A. S.; Michael, J. P. In The Alkaloids;
Brossi, A., Ed.; Academic Press: New York, 2001; Vol. 55, pp 91-258.
(c) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603-626.
(4) For selected syntheses see the following: (a) Tyler, P. C.; Winchester,
B. G. In Iminosugars as Glycosidase Inhibitors; Stuetz, A., Ed.; Wiley-
VCH Verlag GmbH: Weinheim, Germany, 1999; pp 125-156. (b) Michael,
J. P. Nat. Prod. Rep. 2004, 21, 625-649. (c) Somfai, P.; Marchand, P.;
Torsell, S.; Lindstrom, U. M. Tetrahedron 2003, 59, 1293-1299. (d) Zhao,
H.; Mootoo, D. R. J. Org. Chem. 1996, 61, 6762-6763. (e) Denmark, S.
E.; Herbert, B. J. Org. Chem. 2000, 65, 2887-2896.
(5) (a) Nojima, H.; Kimura, I.; Chen, F.-J.; Sugihara, Y.; Haruno, M.;
Kato, A.; Asano, N. J. Nat. Prod. 1998, 61, 397-400. (b) Pili, R.; Chang,
J.; Partis, R. A.; Mueller, R. A.; Chrest, F. J.; Passaniti, A. Cancer Res.
1995, 55, 2920-2926. (c) Walter, S.; Fassbender, K.; Gulbins, E.; Liu, Y.;
Rieschel, M.; Herten, M.; Bertsch, T.; Engelhardt, B. J. Neuroimmunol.
2002, 132, 1-2.
(6) (a) Matsumura, T.; Kasai, M.; Hayashi, T.; Arisawa, M.; Momose,
Y.; Arai, I.; Amagaya, S.; Komatsu, Y. Pharm. Biol. 2000, 38, 302-307.
(b) Arisawa, M.; Hayashi, T.; Momose, Y. Food Style 21 2001, 5, 69-73.
(c) Momose, Y. Japanese Kokai Tokkyo Koho 2000, 7 pp (JP2000072770,
CAN 32: 203147).
(7) Davis, A. S.; Pyne, S, G.; Skelton, B. W.; White, A. H. J. Org. Chem.
2004, 69, 3139-3143.
(8) (a) Bell, A. A.; Pickering, L.; Watson, A. A.; Nash, R. J.; Griffiths,
R. C.; Jones, M. G.; Fleet, G. W. J. Tetrahedron Lett. 1996, 37, 8561-
8564. (b) Zhao, Z.; Song, L.; Mariano, P. Tetrahedron. 2005, 61, 8888-
8894.
Ring closing metathesis (RCM) of diene-substrate containing
nitrogen functionality followed by asymmetric dihydroxylation
has found wide applicability in the synthesis of nitrogen
heterocycles, alkaloids, peptides, and peptidomimetics.1 The
utility of this approach with sugar substrates wherein the
presence of the hydroxylated carbon framework and feasibility
to manipulate the functional groups into the required diene-
functionality, containing a nitrogen atom, give an easy access
toward the synthesis of azasugars.2 Among azasugars, castano-
spermine 1 (Figure 1) has attracted considerable attention
because of its promising glycosidase inhibitory activity.3 In the
last two decades, a number of castanospermine analogues, with
variation of position and number of hydroxyl groups have been
synthesized4 and evaluated for glycosidase inhibition in the
treatment of various diseases such as diabetes, cancer, and
multiple scelerosis as well as viral infections including AIDS,
hepatitis C, and HSV-1.5 In this respect, M. Arisawa and co-
workers have recently isolated uniflorine A 2a, from leaves of
the tree Eugenia uniflora L,6a which was found to be a promising
inhibitor of maltase and sucrase, with IC50 values of 12 and 3.1
µM, respectively.
In 2004, Pyne and co-workers7 have reported the first total
synthesis of uniflorine A wherein the pentahydroxy indolizidine
ring structure 2a was confirmed by the X-ray crystallographic
data of its peracetyl derivative; however, the authors have
noticed a considerable difference in the 1H and 13C NMR data
(1) For recent reviews, see (a) Nakamura, I.; Yamamoto, Y. Chem. ReV.
2004, 104, 2127-2198. (b) Deiters, A.; Martin, S. F. Chem. ReV. 2004,
104, 2199-2238. (c) Schuster, M.; Blechert, S. Angew. Chem. 1997, 109,
2124-2145. (d) Fuerstner, A. Top. Organomet. Chem. 1998, 1, 37-72.
(e) Armstrong, S. J. Chem. Soc., Perkin Trans. 1 1998, 371-388. (f) Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (g) Phillips, A. J.;
Abell, A. D. Aldrichimica Acta 1999, 32, 75-89. (h) Fuerstner, A. Angew.
Chem. 2000, 112, 3140-7172; Angew. Chem., Int. Ed. 2000, 39, 3012-
3043. (i) Larry, Y. Chem. ReV. 2000, 100, 2963-3008.
10.1021/jo060823s CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/14/2006
J. Org. Chem. 2006, 71, 6273-6276
6273

SCHEME 1. Dihydroxylation of 7a and 7ba
of iminosugars,9 we have now studied the RCM of dienes 6a
and 6b to provide sugar substituted dihydropyrrolidine ring
systems 7a and 7b, respectively, that could be elaborated to
provide 1,2,6,7,8-pentahydroxylated indolizidine alkaloids to
decide whether the naturally isolated product was one of these
isomers. Our visualization relies on the fact that the trihydroxy-
lated piperidine ring skeleton of naturally isolated and synthetic
uniflorine A is identical. We assume that the same piperidine
ring skeleton could be obtained from D-glucose derived nitrone
3 by the π-facial stereoselective 1,3-addition of vinylmagnesium
bromide. This will give an access for the bicyclic skeleton with
different stereochemistry at the ring junction while syn/anti
dihydroxylation in the pyrrolidine ring will afford the dihy-
droxylated pyrrolidines, and all the isomers, if obtained, could
be converted to the compounds with structures analogous to
uniflorine A. Although there are few reports for the synthesis
of pentahydroxy indolizidine alkaloids,10 only a single report
describes the synthesis of 2a,7 whereas the synthesis of 2b and
2c has not been reported so far.
Reaction of vinylmagnesium bromide (3.0 equiv) with nitrone
3, in the presence of TMSOTf (1 equiv) at -78 °C, afforded a
mixture of D-gluco- and L-ido- configurated N-benzylhydroxy-
lamines 4a and 4b in the ratio of 87:13 reported earlier by us
(Scheme 1).11,12 The individual treatment of 4a/4b with zinc in
acetic acid-water afforded N-O bond reductive cleavage
products 5a/5b that on reaction with allyl bromide and potassium
carbonate in dry DMF afforded corresponding N-allyl amino-
sugars 6a and 6b in good yield. The RCM of 6a and 6b using
Grubbs catalyst (1st generation) afforded sugar substituted
dihydropyrrolidine 7a and 7b in high yield, respectively.13
Osmylation of 7a under homogeneous reaction conditions using
potassium osmate and NMO in acetone-water was unsuccess-
ful; however, the dihydroxylation in biphasic reaction condition
using potassium osmate, potassium ferricyanate, methane sul-
fonamide, and potassium carbonate in t-BuOH-H2O at 0 °C
afforded a single R-dihydroxylated product 8a in good yield
a Reaction conditions: (a) vinylmagnesium bromide, TMSOTf, THF, -
78 °C, 2 h, 90%; (b) Zn, Cu(OAc)2, AcOH, 80 °C, 1 h; (c) K2CO3, allyl
bromide, DMF, rt, 12 h; (d) Grubb’s catalyst (1st generation), CH2Cl2, rt,
12 h. (e) K3Fe(CN)6, K2CO3, K2OsO4‚2H2O, MeSO2NH2, t-BuOH/H2O (1:
1), 0 °C, 12 h; (f) Ac2O, DMAP, pyridine, 0 to 25 °C, 6 h; (g) NaOMe, 0
°C, 2 h.
TABLE 1. Dihydroxylation of 7a and 7b
no.
ligand
substrate
product
dra
% yieldb
1
2
3
4
5
6
no ligand
7a
7a
7a
7b
7b
7b
8a
8a
8a
8b/8c
8b/8c
8b/8c
100:0c
100:0c
100:0c
10:90
20:80
0:100c
60
64
61
60
59
62
(DHQ)2PHAL
(DHQD)2PHAL
no ligand
(DHQ)2PHAL
(DHQD)2PHAL
a Determined by 1H NMR of the crude product. b After purification. c No
corresponding peak for minor isomer was observed.
(9) (a) Patil, N. T.; Tilekar, J. N.; Dhavale, D. D. J. Org. Chem. 2001,
66, 1065-1074. (b) Karanjule, N. S.; Markad, S. D.; Sharma, T.; Sabharwal,
S. G.; Puranik, V. G.; Dhavale, D. D. J. Org. Chem. 2005, 70, 1356-
1363. (b) Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.; PrakashaReddy,
J. J. Org. Chem. 2004, 69, 4760-4766 and references therein.
(10) (a) Chen, Y.; Vogel, P. J. Org. Chem. 1994, 59, 2487-2496. (b)
Izquierdo, I.; Plaza, M. T.; Robles, R.; Mota, A. Tetrahedron: Asymmetry
1998, 9, 1015-1027. (c) Picasso, S.; Chen, Y.; Vogel, P. Carbohydr. Lett.
1994, 1, 1-8. (d) Chen, Y.; Vogel, P. Tetrahedron Lett. 1992, 33, 4917-
4920.
(11) These results are consistent with our earlier studies on the 1,3-
addition of methyl-and allyl-magnesium bromide as well as silyl ketene
acetal of ethyl acetate to nitrone 3, in the presence of TMSOTf (1 equiv)
at -78 °C in THF, that afforded a good diastereoselectivity in the favor of
D-gluco isomer (∼de 75%). (a) Saha, N. N.; Desai, V. N.; Dhavale, D. D.
Tetrahedron 2001, 57, 39-46. (b) Dhavale, D. D.; Jachak, S. M.; Karche,
N. P.; Trombini, C. Synlett 2004, 1549-1552. (c) Dhavale, D. D.; Desai,
V. N.; Sindkhedkar, M.; Mali, R. S.; Castellari, C.; Trombini, C.
Tetrahedron: Asymmetry 1997, 8, 1475-1486.
(12) Pedro Merino et al. reported the reaction of vinylmagnesium bromide
with nitrone 3 using Et2AlCl as a Lewis acid in which 4a and 4b were
obtained in the ratio 77:23. Merino, P.; Anoro, S.; Franco, S.; Gascon, J.
M.; Martin, V.; Merchan, F. L.; Revuelta, J.; Tejero, T.; Tunon, V. Synth.
Commun. 2000, 2989-3021.
(13) For the application of the ring closing metathesis reaction to the
synthesis of 2,5-dihydropyrrolidines from dienes see (a) Huwe, C. M.;
Velder, J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 2376-
2378. (b) Fuerstner, A.; Fursterner, A.; Picquet, M.; Bruneau, C.; Dixneuf,
P. H. Chem Commun. 1998, 1315-1316. (c) Fuerstner, A.; Ackermann, L.
Chem. Commun. 1999, 95-96. (d) Bujard, M.; Briot, A.; Gouverneur, V.;
Mioskowski, C. Tetrahedron Lett. 1999, 40, 8795-8788. (e) Fuerstner, A.;
Liebl, M.; Hill, A. F.; Wilton-Ely, J. D. E. T. Chem. Commun. 1999, 601-
602. (f) Hunt, J. C. A.; Laurent, P.; Moody, C. J. Chem. Commun. 2000,
1771-1772.
(Table 1, entry 1)14 which was further characterized as its
diacetate derivative 9a. Asymmetric dihydroxylation of 7a using
either AD-mix-R or AD-mix-â afforded 8a as the only isolable
diastereomer in good yield (entries 2, 3). Osmylation of 7b under
similar reaction conditions afforded an inseparable mixture of
1
diols 8b and 8c in the ratio 1:9 as evident from the H NMR
analysis of the crude reaction mixture (entry 4). An inseparable
mixture of diols 8b,c was subjected to acetylation and purified
to give diacetyl derivatives 9b and 9c that on individual
treatment with sodium methoxide (catalytic) in methanol
afforded pure diols 8b and 8c, respectively. Dihydroxylation
of 7b using AD-mix-R afforded 8b and 8c in the ratio 2:8 (entry
5), while AD-mix-â gave 8c as a single isolable diastereomer
in good yield (entry 6). Our attempts for epoxidation of 7a,b
using m-CPBA as well as 1,2-syn/anti dihydroxylation under
Woodward-Prevost conditions were unsuccessful.15
The absolute configuration at the newly generated C6 and
C7 stereo centers in 9a-c was assigned on the basis of 1H NMR
studies and coupling constant information obtained by decou-
pling experiments. Thus, the appearance of a doublet of doublet
(14) For reviews on dihydroxylation see (a) Masaya, S.; Yoshihiko, I.
Chem. ReV. 1992, 92, 857-871. (b) Corey, E. J.; Noe, M. C.; Sarshar S. J.
Am. Chem. Soc. 1993, 115, 3828-3829. (c) Kolb, H. C.; Van Nieuwenhe,
M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483-2547.
6274 J. Org. Chem., Vol. 71, No. 16, 2006

SCHEME 2. Synthesis of Indolizidines 2a-ca
FIGURE 2. NOE experiments.
a Reaction conditions: (a) (i) HCOONH4, 10% Pd/C, MeOH, 80 °C, 1
h; (ii) CbzCl, NaHCO3, MeOH/H2O (5:1), 2 h; (b) (i) TFA-H2O (3:2), 25
°C, 2.5 h; (ii) 10% Pd/C, MeOH, 80 psi, 12 h; (c) Ac2O, DMAP, pyridine,
0 °C to rt,12 h.
FIGURE 3. Explanation for observed stereoselectivity.
for H-6 in 9a (J6,7 ) 4.2; J5,6 ) 1.2 Hz) and 9b (J6,7 ) 5.8; J5,6
) 2.7 Hz) with a small coupling constant value with H-5
indicated anti relationship of H-6 and H-5 in 9a/9b, while
appearance of triplet for H-6 in 9c (J ) 5.2 Hz) showed syn
relationship of H-6 with both H-5 and H-7. This observation
was supported by 1D NOESY experiments (Figure 2), wherein
irradiation of the H-6 in 9a and 9b showed nOe with the H-7
while in 9c, nOe was observed with both the H-7 and H-5 thus
establishing the relative stereochemistry (6S, 7R) for 9a/9c and
(6R, 7S) for 9b.16 The stereochemical outcome of the reaction
could be explained by the fact that in 7a the addition of bulky
osmium reagent from the R-face of the molecule is preferred
over the â-face attack, since the â-face attack is sterically
hindered by furanose ring and C3-OBn functionality. In 7b
the â-face attack is hindered by C3-OBn and pseudoaxial H-5
(Figure 3).17
In the subsequent step, treatment of 8a (D-gluco-configuration
at C-5) with ammonium formate and 10% Pd/C in dry methanol
at reflux afforded amino alcohol which was directly subjected
to selective amine protection using benzyl chloroformate in the
presence of NaHCO3 in methanol-water to give N-Cbz
protected triol 10a (Scheme 2).
In the final step, cleavage of 1,2-acetonide functionality in
10a using TFA-H2O (3:2) followed by cyclic reductive amina-
tion (H2, 10% Pd/C) afforded 2a as a white solid. The spectral
and analytical data of 2a was found to be in consonance with
that of the synthetically reported uniflorine A7 and is different
from that of the natural product6a [mp 171-173 °C, lit.7 mp
170-172° C; [R]25D ) -5.2 (c 0.40, H2O), lit.7 [R]25D ) -6.0
(c 5.0, H2O); lit.6a [R]D ) -4.4 (c 1.2, H2O)]. Treatment of 2a
with acetic anhydride in pyiridine afforded per-acetate derivative
11a which showed identical spectral and analytical data with
that reported7 [mp 141-142 °C, lit.7 mp 142 °C; [R]25D ) -17
(c 0.90, CHCl3), lit.7 [R]25D ) -15 (c 1.56, CHCl3)]. A similar
reaction sequence, individually, with 8b,c (L-ido-configuration
at C-5) afforded 2(S)-hydroxy-8a-epi-castanospermine 2b, 2(R)-
hydroxy-1,8a-di-epi-castanospermine 2c and corresponding pen-
taacetate derivatives 11b,c. The target molecules 2b,c, N-Cbz
protected triols 10b,c, and pentaacetates 11b,c were character-
ized by spectral and analytical techniques, and the data was
found to be in agreement with the structures. The spectral
properties of 2b,c were different from those of the natural
product.
In conclusion, RCM methodology with aminosugar derived
diene coupled with the substrate directed asymmetric dihy-
droxylation gave an easy access to the synthesis of three
analogues of pentahydroxy indolizidine alkaloids 2a-c. The 1H
and 13C NMR data of known 2a and newly synthesized 2b,c
were found to be different from that of the naturally isolated
uniflorine A. Our results are helpful for further study to
determine the correct structure of natural uniflorine A.
Experimental Section
3-O-Benzyl-1,2-O-isopropylidene-5,6,7,8-tetra-deoxy-5,8-(N-
benzylamino)-r-D-gluco-6-eno-octa-1,4-furanose (7a). The com-
pound 6a (1.4 g, 3.2 mmol) was dissolved in dry CH2Cl2 (20 mL);
benzylidene-bis-tricyclohexylphosphine-dichlororuthenium (0.26 g,
0.32 mmol) was added, and the reaction mixture was stirred at room
temperature for 12 h. Solvent was removed in vacuo to give oil
which on purification by column chromatography (n-hexane/ethyl
acetate ) 90/10) afforded 7a (1.10 g, 82%) as a thick liquid: Rf )
0.63 (n-hexane/ethyl acetate ) 8/2); [R]25D ) -3.3 (c 0.60, CHCl3).
IR (Neat): 1607, 1454 cm-1. 1H NMR (300 MHz, CDCl3): δ 1.36
(s, 3H), 1.64 (s, 3H), 3.25 (bd, J ) 15.0 Hz, 1H), 3.62 (d, J ) 14.1
Hz, 1H), 3.76 (bd, J ) 15.0 Hz, 1H), 4.03 (dd, J ) 7.5, 3.0 Hz,
1H), 4.10 (d, J ) 14.1 Hz, 1H), 4.14 (d, J ) 3.0 Hz, 1H), 4.17-
4.26 (m, 1H), 4.45 (d, J ) 11.7 Hz, 1H), 4.67 (d, J ) 4.2 Hz, 1H),
5.69 (d, J ) 11.7 Hz, 1H), 5.82 (bdd, J ) 6.3, 1.8 Hz, 1H), 5.97
(d, J ) 4.2 Hz, 1H), 5.95-6.20 (m, 1H), 7.20-7.40 (m, 10H). 13
C
NMR (75 MHz, CDCl3): δ 26.2, 26.7, 60.2, 61.0, 68.8, 71.3, 81.3,
82.0, 84.5, 104.8, 111.5, 126.7, 126.8, 127.5(s), 127.6, 127.8(s),
128.1(s), 128.2(s), 128.4(s), 129.8, 137.2. Anal. Calcd for C25H29-
NO4: C, 73.68; H, 7.17. Found: C, 73.60; H, 7.25.
(15) (a) Woodward, R. B.; Brutcher, F. V., Jr. J. Am. Chem. Soc. 1958,
80, 209. (b) Brimble, M. A.; Nairn, M. R. J. Org. Chem. 1996, 61, 4801-
4805.
(16) In this experiment, weak nOe was also observed between the H-6
and the H-5 in 9a and 9b. Similar observation was also noticed in pyrrolidine
derivatives; see Kim, J. H.; Curtis-Long, M. J.; Seo, W. D.; Ryu, Y. B.;
Yang, M. S.; Park K. H. J. Org. Chem. 2005, 70, 4082-4087.
(17) Mukai, C.; Sugimoto, Y.-i.; Miyazawa, K.; Yamaguchi, S.; Hanaoka,
M. J. Org. Chem. 1998, 63, 6281-6287.
3-O-Benzyl-1,2-O-isopropylidene-5,6,7,8-tetra-deoxy-5,8-(N-
benzylamino)-â-L-ido-6-eno-octa-1,4-furanose (7b). The reaction
of 6b (2.1 g, 4.8 mmol) with benzylidene-bis-tricyclohexylphos-
phine-dichlororuthenium (0.39 g, 0.48 mmol) in dry CH2Cl2 (25
mL) was performed under the same reaction conditions described
for synthesis of 7a. Purification by column chromatography (n-
hexane/ethyl acetate ) 90/10) afforded 7b (1.65 g, 84%) as a thick
J. Org. Chem, Vol. 71, No. 16, 2006 6275

liquid: Rf ) 0.56 (n-hexane/ethyl acetate ) 8/2); [R]25 ) -51.2
1H NMR (300 MHz, CDCl3): δ 1.34 (s, 3H), 1.54 (s, 3H), 1.98 (s,
3H), 2.08 (s, 3H), 2.77 (dd, J ) 10.5, 2.0 Hz, 1H), 2.98 (dd, J )
10.5, 5.4 Hz, 1H), 3.34 (dd, J ) 7.7, 5.2 Hz, 1H), 3.56 (d, J )
13.0 Hz, 1H), 3.88 (d, J ) 3.0 Hz, 1H), 4.39 (d, J ) 13.0 Hz, 1H),
4.45 (d, J ) 11.0 Hz, 1H), 4.45-4.55 (m, 1H), 4.60 (d, J ) 3.9
Hz, 1H), 4.61 (d, J ) 11.0 Hz, 1H), 5.17 (bdd, J ) 12.0, 5.4 Hz,
1H), 5.51 (t, J ) 5.2 Hz, 1H), 5.99 (d, J ) 3.9 Hz, 1H), 7.18-7.40
(m, 10H). 13C NMR (75 MHz, CDCl3): δ 20.6, 20.7, 26.3, 26.7,
55.1, 59.1, 62.9, 70.3, 71.8, 72.9, 81.1, 81.8, 83.2, 104.7, 111.4,
126.9, 127.8(s), 128.0, 128.1(s), 128.5(s), 129.3, 137.0, 138.4, 170
0.0, 170.1. Anal. Calcd for C29H35NO8: C, 66.27; H, 6.71. Found:
C, 66.38; H, 6.79.
D
(c 0.63, CHCl3). IR (Neat): 1606, 1452 cm-1. 1H NMR (300 MHz,
CDCl3): δ 1.38 (s, 3H), 1.56 (s, 3H), 3.32 (bd, J ) 15.2 Hz, 1H),
3.55-3.78 (m, 2H), 3.97 (d, J ) 2.1 Hz, 1H), 4.60-4.27 (m, 2H),
4.47 (d, J ) 13.2 Hz, 1H), 4.51 (d, J ) 11.7 Hz, 1H), 4.68 (d, J )
3.9 Hz, 1H), 4.75 (d, J ) 11.7 Hz, 1H), 5.41 (bd, J ) 6.0 Hz, 1H),
5.80 (bd, J ) 6.0 Hz, 1H), 6.05 (d, J ) 3.9 Hz, 1H), 7.20-7.52
(m, 10H). 13C NMR (75 MHz, CDCl3): δ 26.3, 26.7, 59.7, 60.4,
69.6, 71.5, 81.4, 82.6, 85.0, 105.1, 111.3, 126.6, 125.3, 127.9(s),
128.0, 128.1(s), 128.4(s), 128.8(s), 129.3, 137.1, 140.1. Anal. Calcd
for C25H29NO4: C, 73.68; H, 7.17. Found: C, 73.82; H, 7.32.
3-O-Benzyl-1,2-O-isopropylidene-5,8-dideoxy-5,8-(N-benzyl-
amino)-6(S),7(R)-Dihydroxy-r-D-erythro-D-gluco-oct-1,4-furanose
(8a). K3Fe(CN)6 (1.94 g, 5.8 mmol) and K2CO3 (0.80 g, 5.8 mmol)
were dissolved in water (6 mL) and tert-butyl alcohol (2 mL), and
then the mixture was cooled to 0 °C. Methanesulfonamide (0.18 g,
1.9 mmol), catalytic potasium osmate, and alkene 7a (0.8 g, 1.9
mmol) dissolved in tert-butyl alcohol (4 mL) were added, and the
mixture was stirred at 0 °C for 10 h. Sodium sulfite (2 g) was added,
and the mixture was stirred at room temperature for 1 h. All volatiles
were removed in vacuo, and residue was extracted with ethyl acetate
(3 × 20 mL). The combined organic layer was washed with 2 N
KOH (5 mL) followed by water (10 mL) and dried over Na2SO4,
filtered, and evaporated in vacuo to give oil. Purification by column
chromatography (n-hexane/ethyl acetate ) 60/40) gave 8a (0.52
g, 60%) as a thick liquid: Rf ) 0.44 (n-hexane/ethyl acetate )
1/1); [R]25D ) -7.4 (c 0.27, CHCl3). IR (Neat): 3550-3200, 1632,
1458 cm-1. 1H NMR (300 MHz, CDCl3): δ 1.36 (s, 3H), 1.51 (s,
3H), 1.60-2.10 (bs, 2H, exchanges with D2O), 2.56 (dd, J ) 10.8,
2.0 Hz, 1H), 3.18 (dd, J ) 10.8, 4.8 Hz, 1H), 3.18-3.30 (m, 1H),
3.62 (d, J ) 13.2 Hz, 1H), 3.94 (d, J ) 13.2 Hz, 1H), 3.97 (d, J )
3.0 Hz, 1H), 4.12-4.32 (m, 3H), 4.45 (d, J ) 11.4 Hz, 1H), 4.67
(d, J ) 3.9 Hz, 1H), 4.70 (d, J ) 11.4 Hz, 1H), 5.94 (d, J ) 3.9
Hz, 1H), 7.20-7.42 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ
26.3, 26.8, 58.0, 60.5, 66.8, 70.7, 71.7, 73.9, 81.4, 81.7, 82.5, 104.5,
111.8, 127.0, 128.0(s), 128.3(s), 128.6(s), 128.7(s) 136.5, 139.1.
Anal. Calcd for C25H31NO6: C, 68.01; H, 7.08. Found: C, 68.15;
H, 7.20.
(1S,2R,6S,7R,8R,8aR)-1,2,6,7,8-Pentahydroxy-indolizidine (2a).
Compound 10a (0.30 g, 0.76 mmol) in TFA-H2O (6.0 mL, 2:1)
was stirred at 25 °C for 2.5 h. Trifluroacetic acid was coevaporated
with benzene to furnish thick liquid. To a solution of above product
in methanol (10.0 mL) was added 10% Pd/C (0.05 g) and the
solution was hydrogenated at 80 psi for 12 h. The catalyst was
filtered and washed with methanol, and the filtrate was concentrated
to afford thick liquid. Purification by column chromatography
(chloroform/methanol ) 50/50) afforded 2a (0.14 g, 91%) as a
white solid: mp 171-173 °C (lit.6a 174-178 °C); Rf ) 0.44
(MeOH); [R]25 ) -5.2 (c 0.40, H2O) [lit.6a [R]D ) -4.4 (c 1.2,
D
H2O)]. IR (Nujol): 3600-3200 cm-1. 1H NMR (300 MHz, D2O):
δ 2.18-2.41 (m, 2H), 2.35 (dd, J ) 10.5, 6.3 Hz, 1H), 3.14 (dd, J
) 10.8, 5.3 Hz, 1H), 3.32 (t, J ) 9.3 Hz, 1H), 3.38 (t, J ) 9.3 Hz,
1H), 3.40 (dd, J ) 10.5, 6.6 Hz, 1H), 3.58 (ddd, J ) 10.8, 9.6, 5.1
Hz, 1H), 3.95 (t, J ) 7.6 Hz, 1H), 4.24 (q, J ) 6.6 Hz, 1H). 13C
NMR (75 MHz, D2O): δ 54.6, 58.5, 68.0, 69.6, 69.8, 73.2, 73.3,
78.3. Anal. Calcd for C8H15NO5: C, 46.82; H, 7.37. Found: C,
46.84; H, 7.49.
(1R,2S,6S,7R,8R,8aS)-1,2,6,7,8-Pentahydroxy-indolizidine (2b).
The reaction of 10b (0.07 g, 0.16 mmol) with TFA-H2O (2 mL,
2:1) followed by 10% Pd/C (0.02 g) in methanol (4 mL) is
performed under similar reaction conditions as described for 2a.
Purification by column chromatography (chloroform/methanol )
40/60) afforded 2b (0.03 g, 83%) as a thick liquid: Rf ) 0.25
(methanol); [R]25D ) +217.0 (c 0.35, H2O). IR (neat): 3600-3200
1
3-O-Benzyl-1,2-O-isopropylidene-6(R),7(S)-diacetoxy-5,8-
dideoxy-5,8-(N-benzylimino)-r-L-erythro-L-ido-oct-1,4-fura-
nose (9b) and 3-O-Benzyl-1,2-O-isopropylidene-6(S),7(R)-di-
acetoxy-5,8-dideoxy-5,8-(N-benzylimino)-R-D-erythro-L-ido-oct-
1,4-furanose (9c). The reaction of K3Fe(CN)6 (3.9 g, 11.6 mmol),
K2CO3 (1.6 g, 11.6 mmol), methanesulfonamide (0.36 g, 3.8 mmol),
and catalytic potasium osmate with alkene 7a (1.6 g, 3.8 mmol)
was performed under similar reaction conditions as described for
8a followed by purification by column chromatography (n-hexane/
ethyl acetate ) 60/40) which gave a mixture of 8b,c (1.1 g, 62%)
as a thick liquid. The mixture (1.0 g, 2.26 mmol) was dissolved in
pyridine (2.93 g, 36.2 mmol) and cooled to 0 °C. Acetic anhydride
(8.2 g, 81.3 mmol) and catalytic DMAP were added, and the
mixture was stirred at room temperature for 6 h. The usual workup
followed by separation by column chromatography (n-hexane/ethyl
acetate ) 90/10) afforded diacetate 9b (0.12 g, 10%) as a thick
liquid: Rf ) 0.61 (n-hexane/ethyl acetate 3/1); [R]25D ) -19.0 (c
cm-1. H NMR (300 MHz, D2O): δ 2.67 (dd, J ) 11.3, 3.6 Hz,
1H), 2.90-3.07 (m, 2H), 3.21 (dd, J ) 12.6, 2.0 Hz, 1H), 3.68
(dd, J ) 11.3, 6.3 Hz, 1H), 3.95 (bs, 1H), 4.02 (t, J ) 3.0 Hz, 1H),
4.05 (bd, J ) 3.0 Hz, 1H), 4.17 (dd, J ) 9.4, 6.4 Hz, 1H), 4.29 (dt,
J ) 6.4, 4.7 Hz, 1H). 13C NMR (75 MHz, D2O): δ 54.1, 60.1,
64.6, 66.6, 67.4, 68.5, 68.6(s). Anal. Calcd for C8H15NO5: C, 46.82;
H, 7.37. Found: C, 46.989; H, 7.48.
(1S,2R,6S,7R,8R,8aS)-1,2,6,7,8-Pentahydroxy-indolizidine (2c).
The reaction of 10c (0.16 g, 0.40 mmol) with TFA-H2O (3 mL,
2:1) followed by 10% Pd/C (0.03 g) in methanol (5 mL) is
performed under similar reaction conditions as described for 2a.
Purification by column chromatography (chloroform/methanol )
20/80) afforded 2c (0.07 g, 84%) as a thick liquid: Rf ) 0.20
(methanol); [R]25D ) -12.0 (c 0.50, H2O). IR (neat): 3600-3200
1
cm-1. H NMR (300 MHz, D2O): δ 3.20 (dd, J ) 12.4, 3.0 Hz,
1H), 3.25 (dd, J ) 13.5, 2.7 Hz, 1H), 3.31-3.48 (m, 3H), 3.80-
3.90 (m, 1H), 4.01 (t, J ) 4.9 Hz, 1H), 4.25 (t, J ) 4.9 Hz, 1H),
4.50-4.58 (m, 2H). 13C NMR (75 MHz, D2O): δ 54.6, 58.9, 63.9,
67.9, 68.8, 69.2, 69.6, 71.1. Anal. Calcd for C8H15NO5: C, 46.82;
H, 7.37. Found: C, 46.96; H, 7.44.
1
0.52, CHCl3). IR (Neat): 1750, 1615 cm-1. H NMR (300 MHz,
CDCl3): δ 1.29 (s, 3H), 1.50 (s, 3H), 1.88 (s, 3H), 1.98 (s, 3H),
2.54 (t, J ) 9.0 Hz, 1H), 3.11 (d, J ) 9.0, 8.5 Hz, 1H), 3.39 (dd,
J ) 8.3, 2.2 Hz, 1H), 3.57 (d, J ) 13.2 Hz, 1H), 4.01 (d, J ) 3.3
Hz, 1H), 4.17 (dd, J ) 8.3, 3.3 Hz, 1H), 4.26 (d, J ) 13.2 Hz,
1H), 4.46 (d, J ) 11.8 Hz, 1H), 4.60 (d, J ) 3.9 Hz, 1H), 4.67 (d,
J ) 11.8 Hz, 1H), 5.21 (dt, J ) 9.4, 5.8 Hz, 1H), 5.33 (dd, J )
5.8, 2.7 Hz, 1H), 5.97 (d, J ) 3.9 Hz, 1H), 7.18-7.40 (m, 10H).
13C NMR (75 MHz, CDCl3): δ 20.5, 20.6, 26.2, 26.7, 54.2, 59.9,
66.3, 70.1, 71.5, 73.2, 77.2, 81.2, 82.6, 105.1, 111.6, 127.1, 127.3-
(s), 127.7, 128.2, 128.4(s), 129.1, 137.3, 139.0, 169.6, 169.7. Anal.
Calcd for C29H35NO8: C, 66.27; H, 6.71. Found: C, 66.42; H, 6.87.
Further elution with (n-hexane/ethyl acetate ) 90/10) afforded 9c
(0.88 g, 73%) as a thick liquid: Rf ) 0.58 (n-hexane/ethyl acetate
Acknowledgment. We are grateful to Prof. M. S. Wadia
for helpful discussion. We are thankful to CSIR, New Delhi,
for the Senior Research Fellowships to N.S.K. and S.D.M. and
for the financial assistance (Project No. 01(1906)/03/EMR-II).
Supporting Information Available: General experimental
methods, experimental procedures, analytical data for 6a,b, 8b,c,
1
9a, 10a-c, and 11a-c and copies of H and 13C NMR spectra of
compounds 6a,b, 7a,b, 8a-c, 9a-c, 10a-c, 11a-c, and 2a-c.
This material is available free of charge via the Internet at
http://pubs.acs.org.
3/1); [R]25D ) -28.5 (c 0.35, CHCl3). IR (Neat): 1743, 1606 cm-1
.
JO060823S
6276 J. Org. Chem., Vol. 71, No. 16, 2006