Intramolecular 5-endo-trig aminomercuration of β-hydroxy-γ- alkenylamines: Efficient route to a pyrrolidine ring and its application for the synthesis of (+)-castanospermine and analogues

Article abstract of DOI:10.1021/jo0601617

The intramolecular aminomercuration reaction of sugar-derived β-hydroxy-γ-alkenylamines 8a-c undergoes 5-endo-trig cyclization in high yield. The sugar-substituted pyrrolidines thus obtained were elaborated to the synthesis of polyhydroxylated indolizidin

Full text of DOI:10.1021/jo0601617

cyclized piperidine ring skeleton in minor amounts (eq 1).8
However, only a single report is known on the mercury(II)-
mediated 5-endo-trig cyclization of γ-alkenylamine leading to
the formation of a pyrrolidine ring.8a,9 Although the intramo-
lecular exo-trig nucleophilic addition reaction to a double bond
for rings smaller than a five-membered ring is favored over the
endo-trig,10 we have recently demonstrated that the aryl- and
sugar-substituted γ-alkenylamines led to the formation of the
pyrrolidine ring via 5-endo-trig cyclization in the presence of
mercury(II) salt in high yield (eq 2).11 Inspired with this
observation and as a part of our continuing interest in the
synthesis of azasugars,12 we have further investigated the
intramolecular aminomercuration reaction with D-glucose de-
rived â-hydroxy-γ-alkenylamines and noticed that 5-endo-trig
cyclization is indeed a prominent process. The sugar-substituted
pyrrolidine compounds thus obtained in high yield, are found
to be the adequate precursors in the synthesis of azasugars.
Intramolecular 5-endo-Trig Aminomercuration of
â-Hydroxy-γ-alkenylamines: Efficient Route to a
Pyrrolidine Ring and Its Application for the
Synthesis of (+)-Castanospermine and Analogues†
Narayan S. Karanjule, Shankar D. Markad,
Vaishali S. Shinde, and Dilip D. Dhavale*
Department of Chemistry, Garware Research Centre,
UniVersity of Pune, Pune-411 007, India
ddd@chem.unipune.ernet.in
ReceiVed January 24, 2006
The intramolecular aminomercuration reaction of sugar-
derived â-hydroxy-γ-alkenylamines 8a-c undergoes 5-endo-
trig cyclization in high yield. The sugar-substituted pyrro-
lidines thus obtained were elaborated to the synthesis of poly-
hydroxylated indolizidine alkaloids, namely, castanospermine
1a, 1-epi-castanospermine 1b, and 8a-epi-castanospermine
1c, having promising glycosidase inhibitory activities.
Among azasugars, (+)-castanospermine 1a (Figure 1) was
isolated from the seeds of the Australian legume Castanosper-
mum australe,13a as well as from the dried pod of Alexa
leiopetala,13b known to have a significant glycosidase inhibitory
activity.14 In the search for a structure-activity relationship, a
number of natural and unnatural analogues of 1a, with variation
in the number/position and stereochemistry of the hydroxyl
The common occurrence of the pyrrolidine ring in natural
products as well as its use as a chiral auxiliary1 and ligand in
asymmetric synthesis2 led to the development of a number of
inter- and intramolecular pathways for its construction.3 In
particular, intramolecular methodologies mainly involve either
C-N bond formation,4 including rhodium/copper carbenoid
N-H insertion,5 or metal-assisted C-C bond formation of
aminoalkenes.6 Among intramolecular metal-catalyzed hydro-
amination,7 one of the most attractive methods is the stereo-
selective amido- and aminomercuration reactions of δ-alkenyl-
amines that affords a 2-substituted pyrrolidine ring through
preferable 5-exo-trig cyclization in addition to the 6-endo-trig
(6) (a) Coldham, I.; Hufton, R. Tetrahedron Lett. 1995, 36, 2157-2160.
(b) Pedrosa, R.; Andres, C.; Duque-Soladana, J. P.; Mendiguchia, P. Eur.
J. Org. Chem. 2000, 3727-3730. (c) Bustos, F.; Gorgojo, J. M.; Suero, R.;
Aurrecoechea, J. M. Tetrahedron 2002, 58, 6837-6842.
(7) (a) Bajracharya, G. B.; Huo, Z.; Yamamoto, Y. J. Org. Chem. 2005,
70, 4883-4886. (b) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L.
L. Org. Lett. 2005, 7, 1959-1962. (c) Kim, J. Y.; Livinghouse, T. Org.
Lett. 2005, 7, 1737-1739.
(8) For amido- and aminomercuration, see: (a) Perie, J. J.; Laval, J. P.;
Roussel, J.; Lattes, A. Tetrahedron 1972, 28, 675-699. (b) Gasc, M. B.;
Lattes, A.; Perie, J. J. Tetrahedron 1983, 39, 703-731. (c) Stipa, P.; Finet,
J. P.; Le Moigne, F.; Tordo, P. J. Org. Chem. 1993, 58, 4465-4468. (d)
Arnone, A.; Bravo, P.; Donadelli, A.; Resnati, G. J. Chem. Soc., Chem.
Commun. 1993, 984-985. (e) Le Moigne, F.; Tordo, P. J. Org. Chem. 1994,
59, 3365-3367. (f) Pecanha, E. P.; Verli, H.; Rodrigues, C. R.; Barreiro,
E. J.; Fraga, C. A. M. Tetrahedron Lett. 2002, 43, 1607-1611. (g)
Chikkanna, D.; Han, H. Synlett 2004, 2311-2314.
(9) The 5-endo-trig radical- and iodo-cyclization of γ-alkenylamines are
known to give a pyrrolidine ring, see: (a) Chatgilialoglu, C.; Ferreri, C.;
Guerra, M.; Timokhin, V.; Froudakis, G.; Gimisis, T. J. Am. Chem. Soc.
2002, 124, 10765-10772. (b) Knight, D. W.; Redfern, A. L.; Gilmore, J.
J. Chem. Soc., Perkin Trans. 1 2001, 2874-2883. (c) Lee, W. S.; Jang, K.
C.; Kim, J. H.; Park, K. H. Chem. Commun. 1999, 251-252.
(10) (a) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476-482. (b) Baldwin,
J. E.; Thomas, R. C.; Kruce, L. I.; Silberman, L. J. Org. Chem. 1977, 42,
3846-3852.
† Dedicated to Prof. N. S. Narasimhan.
(1) (a) Whitesell, J. K. Chem. ReV. 1989, 89, 1581-1590. (b) White, J.
D.; Xu, Q.; Lee, C.-S.; Valeriote, F. A. Org. Biomol. Chem. 2004, 2, 2092-
2102.
(2) (a) Fache, F.; Schultz, E.; Tommasino, M. L.; Lemaire, M. Chem.
ReV. 2000, 100, 2159-2232. (b) Hoang, L.; Bahmanyar, S.; Houk, K. N.;
List, B. J. Am. Chem. Soc. 2003, 125, 16-17. (c) Chiral Reagents for
Asymmetric Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 2003. (d)
Rogers, C. J.; Dickerson, T. J.; Brogan, A. P.; Janda, K. D. J. Org. Chem.
2005, 70, 3705-3708.
(3) (a) Pichon, M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927-
964 and references therein. (b) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel,
P. J. J. Org. Chem. 1999, 64, 1979-1985. (c) Besev, M.; Engman, L. Org.
Lett. 2002, 4, 3023-3025.
(4) (a) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1995, 60, 3221-
3235. (b) Craig, D.; Jones, P. S.; Rowlands, G. J. Synlett 1997, 1423-
1428. (c) Miura, K.; Hondo, T.; Nakagawa, T.; Takahashi, T.; Hosomi, A.
Org. Lett. 2000, 2, 385-388.
(5) Davis, F. A.; Wu, Y.; Xu, H.; Zhang, J. Org. Lett. 2004, 6, 4523-
4525.
(11) Dhavale, D. D.; Jachak, S. M. Molecules 2005, 10, 893-900.
(12) (a) Patil, N. T.; Tilekar, J. N.; Dhavale, D. D. J. Org. Chem. 2001,
66, 1065-1074. (b) Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.;
PrakashaReddy, J. J. Org. Chem. 2004, 69, 4760-4766. (c) Karanjule, N.
S.; Markad, S. D.; Sharma, T.; Sabharwal, S. G.; Puranik, V. G.; Dhavale,
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therein.
10.1021/jo0601617 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/18/2006
J. Org. Chem. 2006, 71, 4667-4670
4667

SCHEME 1. 1,3-Addition of Vinylmagnesium Bromidea
FIGURE 1. Castanospermine and analogues.
groups at each carbon atom in the indolizidine ring skeleton,
have been synthesized12c,15 and evaluated for the glycosidase
inhibition in the treatment of various diseases such as diabetes,16
cancer,17 and multiple scelerosis,18 as well as viral infections
including AIDS, hepatitis C, and HSV-1.19 As a result of the
highly oxygenated framework in 1a-c, the chiron approach is
the obvious choice for their synthesis.20 In fact, the D-glucose
type of hidden symmetry in 1 could be easily recognized in the
trihydroxylated architect of the piperidine ring, wherein the C-6,
7, and 8 of 1 match with that of the C-2, 3, and 4 of D-glucose
as far as the position and stereochemical aspects are concerned.
However, the building of a pyrrolidine ring, with stereochemi-
cally well-defined hydroxylated carbon center C-1 of 1, requires
an asymmetric pathway. In general, the required carbinol center
is generated first, followed by an intramolecular cyclization, to
get the pyrrolidine ring skeleton. The use of the intramolecular
aminomercuration strategy with D-glucose derived â-hydroxy-
γ-alkenylamines for the formation of pyrrolidine ring and further
elaboration to castanospermine 1a, to the best of our knowledge,
is not known. Our efforts toward the successful implementation
of this methodology for the synthesis of castanospermine 1a,
a Reaction conditions: (a) vinylmagnesium bromide, TMSOTf, THF,
-78 °C, 2 h, 90%; (b) Zn, Cu(OAc)2, AcOH, 80 °C, 1 h; (c) NaHCO3,
CbzCl, MeOH-water (4:1), 3 h; (d) (i) NMO, K2OsO4‚2H2O, acetone-
water (8:1), 12 h; (ii) NaIO4, acetone-water (9:1), 6 h.
1-epi-castanospermine 1b, and 8a-epi-castanospermine 1c are
reported herein.
A 1,3-addition reaction of vinylmagnesium bromide (3.0 eq.)
to nitrone 2 in THF at 0 °C afforded a diastereomeric mixture
of D-gluco- and L-ido-N-allylamines 3a and 3b, respectively,
in the ratio of 55:45 (Scheme 1). The diastereoselectivity in
favor of D-gluco isomer was achieved using TMSOTf (1 equiv)
at -78 °C in dry THF, which gave 3a/3b in the ratio 87/13.21
The spectral and analytical data is found to be identical with
that reported.22 The N-O bond reductive cleavage in 3a using
zinc in acetic acid-water afforded N-benzylamino sugar 4a,22a
which on treatment with benzylchloroformate afforded N-Cbz
protected allylamine 5a.23 Dihydroxylation of 5a (potassium
osmate, NMO), followed by a reaction with NaIO4, afforded
R-amino aldehyde 6a. The similar reaction sequence with
hydroxylamine 3b afforded corresponding 4b, 5b, and R-amino
aldehyde 6b in good yields.24 No epimerization at C-5 in 6a,b
was noticed under NaIO4-mediated oxidative cleavage of the
diol.
(13) (a) Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.;
Pryce, R. J.; Arnold, E.; Clardy, J. Phytochemistry 1981, 20, 811-814. (b)
Nash, R. J.; Fellows, L. E.; Dring, J. V.; Stirotn, C. H.; Carter, D.; Hegarty,
M. P.; Bell, E. A. Phytochemistry 1988, 27, 1403-1406.
(14) (a) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley-Interscience: New
York, 1987; Vol. 5. Howard, A. S.; Michael, J. P. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1986; Vol. 28, Chapter 3. (b) Michael,
J. P. Nat. Prod. Rep. 1990, 9, 485-523.
(15) (a) Svansson, L.; Johnston, B. D.; Gu, J.-H.; Patrik, B.; Pinto, B.
M. J. Am. Chem. Soc. 2000, 122, 10769-10775. (b) Izquiedro, I.; Plaza,
M. T.; Robles, R.; Mota, A. J. Tetrahedron: Asymmetry 1998, 9, 1015-
1027. (c) Kefalas, P.; Grierson, D. S. Tetrahedron Lett. 1993, 34, 3555-
3558. (d) Burgess, K.; Chaplin, D. A.; Henderson, I.; Pan, Y. T.; Elbein,
A. D. J. Org. Chem. 1992, 57, 1103-1109. (e) Furneaux, R. H.; Mason, J.
M.; Tyler, P. C. Tetrahedron Lett. 1995, 36, 3055-3058.
In the next step (Scheme 2), the reaction of vinylmagnesium
bromide with D-gluco-configurated-R-amino aldehyde 6a at -50
°C afforded a diastereomeric mixture of anti/syn products in
1
the ratio 3:1, as is evident from the H NMR spectrum of the
crude product.25 Our attempts to alter the diastereoselectivity
as well as to separate the diastereomers by flash chromatography
were unsuccessful,26 therefore, the mixture was directly treated
with 40% KOH in MeOH for 10 min at 90 °C, which afforded
easily separable carbamates 7a and 7b in the ratio of 3:1. The
(16) Nojima, H.; Kimura, I.; Chen, F.-J.; Sugihara, Y.; Haruno, M.; Kato,
A.; Asano, N. J. Nat. Prod. 1998, 61, 397-400.
(17) Pili, R.; Chang, J.; Partis, R. A.; Mueller, R. A.; Chrest, F. J.;
Passaniti, A. Cancer Res. 1995, 55, 2920-2926.
(18) Walter, S.; Fassbender, K.; Gulbins, E.; Liu, Y.; Rieschel, M.;
Herten, M.; Bertsch, T.; Engelhardt, B. J. Neuroimmunol. 2002, 132, 1-10.
(19) (a) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.;
Namgoong, S. K.; Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W. Proc.
Natl. Acad. Sci. U.S.A. 1988, 85, 9229-9233. (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. U.S.A. 1987, 84, 8120-
8124. (c) Sunkara, P. S.; Bowling, T. L.; Liu, P. S.; Sjoerdsma, A. Biochem.
Biophys. Res. Commun. 1987, 148, 206-210. (d) Whitby, K.; Taylor, D.;
Patel, D.; Ahmed, P.; Tyms, A. S. AntiViral Chem. Chemother. 2004, 15,
141-151. (e) Bridges, C. G.; Ahmed, S. P.; Kang, M. S.; Nash, R. J.; Porter,
E. A.; Tyms, A. S. Glycobiology 1995, 5, 249-253.
(20) For selected syntheses of 1a, 1b, and 1c, see: (a) Denmark, S. E.;
Martinborough, E. A. J. Am. Chem. Soc. 1999, 121, 3046-3056. (b) Cronin,
L.; Murphy, P. V. Org. Lett. 2005, 7, 2691-2693 and references therein.
(c) Bartnicka, E.; Zamojski, A. Tetrahedron 1999, 55, 2061-2076. (d)
Leeper, F. J.; Howard, S. Tetrahedron Lett. 1995, 36, 2333-2338. (e)
Somfai, P.; Marchand, P.; Torsell, S.; Lindstrom, U. M. Tetrahedron 2003,
59, 1293-1299. (f) Zho, Z.; Song, L.; Marino, P. S. Tetrahedron 2005,
61, 8888-8894. (g) Zhao, H.; Hans, S.; Cheng, X.; Mootoo, D. R. J. Org.
Chem. 2001, 66, 1761-1767. (h) Hamana, H.; Ikota, N.; Ganem, B. J. Org.
Chem. 1987, 52, 5492-5494. (i) Zhao, H.; Mootoo, D. R. J. Org. Chem.
1996, 61, 6762-6763. (j) Zhao, H.; Hans, S.; Cheng, X.; Mootoo, D. R. J.
Org. Chem. 2001, 65, 1761-1767.
(21) 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 2, in the presence of TMSOTf (1 equiv)
at -78 °C in THF, which afforded a good diastereoselectivity in the favor
of the D-gluco isomer (∼de 75%), see: (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.
(22) Pedro Merino et al. reported the reaction of vinylmagnesium bromide
with nitrone 2 using Et2AlCl as a Lewis acid in which 3a and 3b were
obtained in the ratio of 77:23, see: (a) Merino, P.; Anoro, S.; Franco, S.;
Gascon, J. M.; Martin, V.; Merchan, F.; Revuelta, J.; Tejero, T.; Tunon, V.
Synth. Commun. 2000, 2989-3021. (b) Merino, P.; Anoro, S.; Castillo, E.;
Merchan, F. L.; Tejero, T. Tetrahedron: Asymmetry 1996, 7, 1887-1890.
For reviews on the 1,3-addition of organometallic reagents to nitrones,
see: (c) Lombardo, M.; Trombini, C. Curr. Org. Chem. 2002, 6, 695-713
and references therein.
(23) The 1H and 13C NMR spectra of compounds 5a,b and 6a,b, 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; Jackman, L. M., Sternhell, S., Eds.;
Pergamon: Elmsford, NY, 1978; p 361.
4668 J. Org. Chem., Vol. 71, No. 12, 2006

SCHEME 2. 5-endo-Trig Cyclization of 8a-ca
FIGURE 2. The Felkin-Anh models of 6a and 6b.
In the 1H NMR spectrum of 7c, the H-5 appeared as a doublet
of doublets at δ 4.12, with a large coupling constant (J5,6 ) 7.7
Hz), indicating the cis relation of H-5 with H-6. This established
the 5R,6S absolute configurations.
The observed stereoselectivity in the addition of the Grignard
reagent to 6a and 6b could be explained in terms of the Felkin-
Anh-like transition states (TSs). As shown in Figure 2, TS I/II
and III/IV were considered for 6a and 6b, respectively, in which
the more electronegative CsN group is placed at a right angle
to the CdO bond.28 In the case of 6a, the re-face attack along
the Burgi-Dunitz trajectory in TS I is favored over the si-face
attack in TS II, as a result of the presence of the sugar ring,
leading to the formation of the anti isomer 7a as the major and
the syn isomer 7b as the minor product. In 6b, the nucleophilic
re-face attack in TS III is restricted due to the presence of the
sugar ring and the C-3 benzyloxy substituent, while the si-face
attack of the Grignard reagent in TS IV, which is free from
any steric hindrance, provided the anti isomer 7c as the only
product.
In the subsequent step, carbamates 7a-c were individually
treated with 40% KOH at 90 °C for 48 h, and the corresponding
â-hydroxy-γ-alkenylamines 8a-c were isolated in good yields
(Scheme 2). This one-pot two-step reaction probably involves
the hydrolysis of carbamate to give in situ formation of carbamic
acid, which undergoes decaboxylation to give the product.
Having sugar-substituted â-hydroxy-γ-alkenylamine 8a-c in
hand, we have examined the intramolecular aminomercuration
using mercury(II) salts. Thus, the reaction of 8a and 8c with
mercury(II) acetate in THF-water at room temperature, fol-
lowed by the reductive demercuration with NaBH4, afforded
exclusively 5-endo-trig-cyclized product 9a and 9c in 74 and
73% yield. Similarly, 8b afforded a sugar-substituted pyrrolidine
ring compound that was found to be relatively unstable over
silica gel column, therefore, it was directly subjected to
O-benzylation to afford dibenzylated pyrrolidine 9b. Thus, the
reaction was found to be compatible in the presence of
â-hydroxyl functionality in 9a-c. In fact, the presence of the
â-hydroxyl group enhances the rate of aminomercuration by
6-fold as compared to that of the unsubstituted sugar γ-alkenyl-
amine and aromatic γ-alkenylamine.11
a Reaction conditions: (a) (i) vinylmagnesium bromide, THF, -50 °C,
1 h; (ii) 40% KOH, MeOH, 90 °C, 10 min; (b) 40% KOH, MeOH, 90 °C,
48 h; (c) Hg(OAc)2, THF-H2O (1:1), NaBH4, 3 h; (d) NaH, BnBr, TBAI,
THF, 0 °C to room temperature, 6 h.
1H NMR data of carbamates 7a and 7b allowed us to establish
the absolute configurations at the newly generated C6 carbinol
stereocenter, wherein the coupling constant between H-5 and
H-6 is decisive. Thus, in 7a, the H-5 appeared at δ 4.20 as a
triplet with a high coupling constant. J5,6 ) 7.8 Hz, while in
7b, the H-5 showed a narrow triplet at δ 4.25 with a small
coupling constant, J5,6 ) 4.4 Hz. The large value of J5,6 (7.8
Hz) in 7a and the small value of J5,6 (4.4 Hz) in 7b indicated
the cis and trans relative orientation of H-5 and H-6. Therefore,
absolute configurations 5S,6R and 5S,6S were assigned for 7a
and 7b, respectively. Similarly, the reaction of vinylmagnesium
bromide with L-ido-configurated-R-amino aldehyde 6b at -50
°C afforded only a single anti-diastereomer that on treatment
with 40% KOH at 90 °C for 10 min afforded carbamate 7c.27
(24) The reaction of D-glucose-derived nitrone 2 with C-2 metalated
thiazole followed by N-O bond cleavage, unmasking the thiazole func-
tionality with MeOTf in acetonitrile then NaBH4 in MeOH, and treatment
with HgCl2 in acetonitrile-water is known to give D-glucose-substituted
N-benzyl-protected R-amino aldehydes; see: (a) Dondoni, A.; Franco, S.;
Junquera, F.; Merchan, F. L.; Merino, P.; Tejero, T.; Bertolasi, V. Chem.s
Eur. J. 1995, 1, 505-520. (b) Dondoni, A.; Junquera, F.; Merchan, F. L.;
Merino, P.; Scherrmann, M.-C.; Tejero, T. J. Org. Chem. 1997, 62, 5484-
5496.
(25) Our results were found to be identical with that reported by J. Jurczak
and co-workers in which the addition of vinylmagnesium bromide to
-N(Bn)Cbz diprotected L-alaninal afforded syn/anti products in the ratio
23:77; see: (a) Gryko, D.; Urbanczyk-Lipkowska, Z.; Jurczak, J. Tetra-
hedron: Asymmetry 1997, 8, 4059-4067. For a review on R-amino
aldehydes, see: (b) Jurczak, J.; Golebiowski, A. Chem. ReV. 1989, 89, 149-
164.
(26) The reaction of 6a with vinylmagnesium bromide (3.0 equiv) in
THF at 0 °C marginally altered the selectivity, giving anti/syn products in
the ratio of 2:1. An additional increase in the temperature did not improve
the selectivity but lowers the combined yield (62%). Changing of the solvent
to diethyl ether or toluene did not change the selectivity. Use of vinyllithium
(3.0 equiv) in THF or in Et2O at -50 °C afforded a 1:1 mixture of the
anti/syn products in low yield. Performing the reaction at 0 °C also led to
the same ratio, with a low combined yield (55%).
The pyrrolidine derivatives 9a-c were found to be the true
intermediates for the synthesis of the target molecules. Thus,
hydrogenolysis of N- and O-benzyl groups in 9a, followed by
selective amine protection, afforded a N-Cbz-protected com-
(28) 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, 1108-1117.
(27) The reaction at 0 °C also afforded a single diastereomer.
J. Org. Chem, Vol. 71, No. 12, 2006 4669

SCHEME 3. Synthesis of 1a-ca
3-O-Benzyl-1,2-O-isopropylidene-5,7,8-trideoxy-5,8-(N-ben-
zylamino)-6(R)-hydroxy-R-D-glycero-D-gluco-oct-1,4-furanose (9a).
Purification using column chromatography (n-hexane/ethyl acetate
) 8/2) afforded 9a (0.58 g, 74%) as a thick liquid: Rf 0.52 (n-
hexane/ethyl acetate ) 3/2); [R]D ) -17.0 (c 0.7, CHCl3); IR (neat)
1
3550-3150 cm-1; H NMR (300 MHz, CDCl3) δ 1.31 (s, 3H),
1.45 (s, 3H), 1.62-1.78 (m, 1H), 1.86-2.06 (m, 1H), 2.10 (br s,
exchanges with D2O, 1H), 2.52 (q, J ) 9.6 Hz, 1H), 2.80-3.00
(m, 2H), 3.45 (d, J ) 13.2 Hz, 1H), 3.96 (d, J ) 13.2 Hz, 1H),
4.01 (d, J ) 3.3 Hz, 1H), 4.10 (dd, J ) 5.8, 3.6 Hz, 1H), 4.39 (d,
J ) 11.2 Hz, 1H), 4.44 (dt, J ) 5.8, 2.4 Hz, 1H), 4.64 (d, J ) 3.9
Hz, 1H), 4.66 (d, J ) 11.2 Hz, 1H), 5.90 (d, J ) 3.9 Hz, 1H),
7.15-7.40 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ 26.4, 26.9,
32.2, 52.3, 60.1, 71.1, 71.6, 74.0, 81.3, 81.5, 82.7, 104.7, 111.6,
126.8, 127.7 (s), 128.2 (s), 128.5, 128.6 (s), 136.5. Anal. Calcd for
C25H31NO5: C, 70.57; H, 7.34. Found: C, 70.64; H, 7.46.
a Reaction conditions: (a) (i) HCOONH4, 10% Pd/C, MeOH, 80 °C, 1
h; (ii) NaHCO3, CbzCl, MeOH-H2O (9:1), 3 h; (b) (i) TFA-H2O (3:2),
2.5 h; (ii) 10% Pd/C, MeOH, 80 psi, 12 h.
pound 10a (Scheme 3). Finally, deprotection of the 1,2-
acetonoide functionality using TFA-water followed by hydro-
genation afforded 1-epi-castenospermine 1b [R]D ) +7.0 (c 0.5,
MeOH) [lit20b [R]D ) +6.2 (c 0.15, MeOH)]. The same
sequence of reactions with 9b and 9c gave (+)-castenospermine
1a [R]D ) +78.9 (c 0.30, H2O) [lit20b [R]D ) +78.6 (c 0.25,
H2O)], and 8a-epi-castanospermine 1c [R]D ) +30.0 (c 0.4,
MeOH) [lit20c [R]D ) +28.0 (c 0.3, MeOH)], respectively. The
N-Cbz-protected compounds 10b,c and target molecules 1a-c
were characterized by spectral and analytical techniques, and
the data for target molecules was found to be in agreement with
that of what was reported.20
In the above sequence, the overall yield of (+)-castanosper-
mine 1a was affected due to the fact that the Grignard reaction
of 6a afforded the required diastereomer 7b in a minor amount.
Disappointed with these results, we thought of an alternative
pathway to epimerize the C-6 hydroxyl group in 9a (eq 3). Thus,
pyrrolidine 9a was treated under Swern oxidation reaction
conditions, which afforded the R-amino ketone 11 in 85% yield.
The NaBH4 reduction of 11 in MeOH-water at -60 °C,
followed by hydrogenolysis and selective amine protection, gave
the required pyrrolidine 10b as the major product (10a/10b )
1:10), which was converted to (+)-castanospermine 1a. The
formation of 10b in major amount could be explained based
on the preferred re-face hydride attack at the carbonyl carbon,
as the si-face is sterically hindered due to the presence of the
C-5-N-Bn group.
3-O-Benzyl-1,2-O-isopropylidene-5,7,8-trideoxy-5,8-(N-ben-
zylamino)-6(S)-O-benzyl-R-L-glycero-D-gluco-oct-1,4-furanose (9b).
Sodium hydride (0.11 g, 2.7 mmol, 60% suspension) in THF (5.0
mL) was cooled to 0 °C, and the crude aminomercuration product
(0.78 g, 0.84 mmol), prepared from 8b in THF (5.0 mL), was added
and stirred for 30 min. Benzyl bromide (0.37 g, 2.2 mmol) in THF
(2.0 mL) and TBAI (0.1 g) was added and stirred for 6 h. Water
(5.0 mL) was added, and the mixture was extracted with diethyl
ether (20 mL × 3). The usual work up was performed, and
purification by column chromatography (n-hexane/ethyl acetate )
9/1) afforded 9b (0.48 g, 66%, overall) as a thick liquid: Rf 0.62
(n-hexane/ethyl acetate ) 3/1); [R]D ) +4.0 (c 0.5, CHCl3); IR
1
(neat) 1612 cm-1; H NMR (300 MHz, CDCl3) δ 1.35 (s, 3H),
1.51 (s, 3H), 1.64-1.86 (m, 2H), 2.30-2.50 (m, 1H), 3.00-3.18
(m, 1H), 3.22-3.50 (m, 2H), 3.98-4.25 (m, 3H), 4.38 (d, J )
12.0 Hz, 1H), 4.50-4.72 (m, 5H), 5.95 (d, J ) 3.9 Hz, 1H), 7.10-
7.45 (m, 15H); 13C NMR (75 MHz, CDCl3) δ 26.5, 26.8, 30.0,
52.0, 60.4, 66.0, 71.1, 72.2, 79.7, 81.3, 82.9, 104.5, 111.5, 126.5,
127.1, 127.6, 127.7, 127.8 (s), 127.9 (s), 128.0 (s), 128.3 (s), 137.2,
138.9, 140.6. Anal. Calcd for C32H37NO5: C, 74.54; H, 7.23.
Found: C, 74.65; H, 7.31.
3-O-Benzyl-1,2-O-isopropylidene-5,7,8-trideoxy-5,8-(N-ben-
zylamino)-6(R)-hydroxy-â-L-glycero-L-ido-oct-1,4-furanose (9c).
Purification by column chromatography (n-hexane/ethyl acetate )
8/2) afforded 9c (0.56 g, 73%) as a thick liquid: Rf 0.52 (n-hexane/
ethyl acetate ) 6/4); [R]D ) -80.0 (c 0.7, CHCl3); IR (neat) 3600-
1
3200, 1623 cm-1; H NMR (300 MHz, CDCl3) δ 1.35 (s, 3H),
1.53 (s, 3H), 1.64 (dd, J ) 13.2, 6.3 Hz, 1H), 1.86-2.03 (m, 1H),
2.11 (br s, exchanges with D2O, 1H), 2.47 (ddd, J ) 11.0, 9.1, 6.3
Hz, 1H), 2.78-2.94 (m, 2H), 3.40 (d, J ) 12.9 Hz, 1H), 4.12 (d,
J ) 3.3 Hz, 1H), 4.13-4.20 (m, 1H), 4.27 (dd, J ) 8.0, 3.3 Hz,
1H), 4.37 (d, J ) 12.4 Hz, 1H), 4.51 (d, J ) 11.3 Hz, 1H), 4.69
(d, J ) 3.9 Hz, 1H), 4.75 (d, J ) 11.5 Hz, 1H), 6.02 (d, J ) 3.9
Hz, 1H), 7.15-7.42 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 26.3,
26.8, 32.9, 52.2, 59.6, 71.7, 72.8, 74.4, 80.9, 83.3, 84.1, 105.0,
111.3, 126.6, 127.9 (s), 128.0 (s), 128.2, 128.6 (s), 129.0 (s), 136.4,
139.3. Anal. Calcd for C25H31NO5: C, 70.57; H, 7.34. Found: C,
70.69; H, 7.42.
Acknowledgment. We are grateful to Prof. M. S. Wadia
for helpful discussions. 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, procedure for the 1,3-addition reaction of vinylmagnesium
bromide with nitrone 2 using TMSOTf, experimental procedures
and spectral and analytical data for compounds 5a,b, 6a,b, 7a-c,
8a-c, 10a-c, 11, and 1a-c, and copies of 1H and 13C NMR spectra
of compounds 7a-c, 8a-c, 9a-c, 10a-c, 11, and 1a-c. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO0601617
In conclusion, the 1,3-addition reaction of D-glucose-derived
nitrone 2 with vinylmagnesium bromide, followed by N-O
bond reductive cleavage, N-protection, and dihydroxylation
followed by oxidative cleavage afforded R-amino aldehydes
6a,b in high yield. The utility of 6a,b was demonstrated in the
synthesis of castanospermine 1a and its analogues 1b and 1c
using the intramolecular aminomercuration strategy.
Experimental Section
General Procedure for Aminomercuration. To a stirred
solution of 8 (0.78 g, 1.83 mmol) in THF-water (1:1, 12 mL) was
added Hg(OAc)2 (1.16 g, 3.6 mmol), and the reaction mixture was
stirred at room temperature for 3 h. Sodium borohydride (0.266 g,
7.2 mmol) was added over a period of 10 min. THF was removed
under reduced pressure, and the residue was extracted with
chloroform (15 mL × 3).
4670 J. Org. Chem., Vol. 71, No. 12, 2006