1,3-Dipolar cycloaddition reaction of D-glucose-derived nitrone with allyl alcohol: Synthesis of 2-hydroxy-1-deoxycastanospermine analogues

Article abstract of DOI:10.1021/jo048176x

(Chemical Equation Presented) The synthesis and evaluation of glycosidase inhibitory activity of polyhydroxylated indolizidine alkaloids namely 2-hydroxy-1-deoxycastanospermine 3a,b and 2-hydroxy-1-deoxy-8a-epi- castanospermine 3c,d is reported. The key s

Full text of DOI:10.1021/jo048176x

1,3-Dipolar Cycloaddition Reaction of D-Glucose-Derived Nitrone
with Allyl Alcohol: Synthesis of
2-Hydroxy-1-deoxycastanospermine Analogues
Narayan S. Karanjule,† Shankar D. Markad,† Tarun Sharma,‡ Sushma G. Sabharwal,‡
Vedavati G. Puranik,§ and Dilip D. Dhavale*,†
Department of Chemistry, Garware Research Centre, and Division of Biochemistry, Department of
Chemistry, University of Pune, Pune-411 007, India, and Centre for Material Characterization,
National Chemical Laboratory, Pune-411 008, India
ddd@chem.unipune.ernet.in
Received October 15, 2004
The synthesis and evaluation of glycosidase inhibitory activity of polyhydroxylated indolizidine
alkaloids namely 2-hydroxy-1-deoxycastanospermine 3a,b and 2-hydroxy-1-deoxy-8a-epi-castano-
spermine 3c,d is reported. The key step involves the intermolecular 1,3-dipolar cycloaddition of
allyl alcohol to D-glucose-derived nitrone 4, followed by tosylation, that afforded four diastereomeric
sugar-substituted isoxazolidines 5a-d with the desired regioselectivity. The one-pot conversion of
5a-d to pyrrolidines 8a-d by hydrogenolysis, removal of 1,2-acetonoide functionality, and
hydrogenation afforded corresponding target molecules 3a-d.
Introduction
cancer,6 and viral infections, including AIDS.7 As a part
of our continuing interest in the synthesis of azasugars,8
we have now studied the intermolecular 1,3-DC reaction
of D-glucose-derived nitrone 4 with allyl alcohol, as a key
step, in the formation of sugar-substituted isoxazolidines
that are elaborated in the synthesis of 2-hydroxy-1-
deoxycastanospermine analogues 3a,d.9
The 1,3-dipolar cycloaddition (DC) of nitrone with
olefin, leading to the formation of isoxazolidine, followed
by N-O bond reductive cleavage is a useful strategy in
the synthesis of amino compoundssthe key intermedi-
ates to nitrogen heterocycles.1 Among nitrones, the sugar-
derived nitrones represent versatile substrates as they
provide a polyhydroxylated carbon framework with mul-
tiple avenues of chirality as well as an access for amino
group transformation required for the synthesis of poly-
hydroxylated piperidine, pyrrolidine, pyrrolizidine, in-
dolizidine, and quinolizidine alkaloids.2 This class of
compounds, commonly known as azasugars, namely
nojirimycin 1 and castanospermine 2 (Figure 1), have
attracted considerable attention because of their promis-
ing glycosidase inhibitory activity.3 In the search for a
structure-activity relationship, a number of natural and
unnatural derivatives of castanospermine have been
synthesized4 and evaluated for glycosidase inhibition in
the treatment of various diseases such as diabetes,5
(1) For reviews on the 1,3-dipolar cycloaddition of nitrones, see: (a)
Osborn, H. M.; Gemmell, N.; Harwood, L. M. J. Chem Soc., Perkin
Trans. 1 2002, 2419-2438. (b) Frederickson, M. Teterahedron 1997,
53, 403-425. (c) Confalone, P. N.; Huie, E. M. Org. React. 1988, 36,
1-173. (d) Torseel, K. B. G. Nitrile Oxides, Nitrones and Nitronates
in Organic synthesis; Feuer H., Ed.; VCH: Weinheim, Germany, 1988.
(e) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779-2831. (f)
Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 8, 863-910. (g)
Adams, J. P.; Box, D. S. J. Chem. Soc., Perkin Trans. 1 1999, 749-
764. (h) Karlsson, S.; Hogberg, H. E. Org. Prep. Proced. Int. 2001, 33,
103-172. (i) Koumbis, A. E.; Gallos, J. K. Curr. Org. Chem. 2003, 7,
585-628. (j) Padwa, A.; Pearson, W. H. J. Nat. Prod. 2004, 67, 1074-
1074. (k) Padwa, A.; Pearson, W. H. Org. Process Res. Dev. 2004, 8,
293-293. (l) Padwa, A.; Pearson, W. H. J. Am. Chem. Soc. 2002, 124,
12633-12634. (m) Cycloadditon Reactions in Organic synthesis; Car-
ruthers, W., Ed.; Tetrahedron organic chemistry series; Pergamon
Press: New York, 1990; Vol. 8, pp 269-314. (n) Advances in Cycload-
dition; Curran, D. P., Ed.; JAI Press: London, UK, 1988, Vol. 1; 1990,
Vol. 2; 1993, Vol. 3. (o) Gothelf, K. V. In Cycloaddition reactions in
organic synthesis; Kobayashi, S., Jorgensen, K. A., Eds.; Wiley-VCH:,
Weinheim, Germany, 2002; Chapter 6, pp 211-247. (p) Kanemasa, S.
In Cycloaddition reactions in Organic synthesis; Kobayashi, S., Jor-
gensen, K. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002; Chapter
7, pp 249-300.
† Department of Chemistry, Garware Research Centre, University
of Pune.
‡ Division of Biochemistry, Department of Chemistry, University of
Pune.
§ Centre for Material Characterization, National Chemical Labora-
tory.
10.1021/jo048176x CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/26/2005
1356
J. Org. Chem. 2005, 70, 1356-1363

2-Hydroxy-1-deoxycastanospermine Analogues
hydrogenation (one-pot hydrogenolysis and reductive
aminocyclization). The N-O bond reductive cleavage of
tosyloxylated isoxazolidine 5 and concomitant nucleo-
philic displacement of the -O-tosyl group, by in situ
generated secondary amino functionality, will give an
access to 8. Thus, the isoxazolidine 5 is the key inter-
mediate that could be derived from the 1,3-DC of D-
glucose-derived nitrone 4 with the allyl alcohol followed
by tosylation. Our visualization relies on the fact that
the 1,3-DC of nitrones with the allyl alcohol occur with
perfect regioselectivity, wherein the oxygen of the 1,3-
dipole attacks the more highly substituted carbon of the
double bond to produce the corresponding cycloadduct in
excellent yield.10 We assume that the same regioselec-
tivity would be obtained with the sugar nitrone 4 and as
far as the regioselectivity is perfect, the π-facial stereo-
selectivity will not be a serious problem as the Re face
cycloaddition will provide D-gluco-configurated isoxazo-
lidines while the Si facial selectivity will afford L-ido-
configurated isoxazolidines and all the stereomers, if
obtained, could be converted to 2-hydroxy-1-deoxycastano-
spermine 3a,b and 2-hydroxy-1-deoxy-8a-epi-castano-
spermine 3c,d, respectively. Although a few reports are
available on the use of 1,3-DC of the nitrones with allyl
alcohol,11 the application of this strategy with nitrone 4
toward the synthesis of castanospermine analogues, to
the best of our knowledge, is not known. Our efforts in
the successful implementation of this methodology for the
synthesis of 2-hydroxy-1-deoxycastanospermine ana-
logues 3a-d are reported herein.
FIGURE 1. Azasugars and analogues.
SCHEME 1. Retrosynthetic Analysis
Regioselective 1,3-Dipolar Cycloaddition of Ni-
trone 4 with Allyl Alcohol. The requisite Z-nitrone 4
was prepared from the D-glucose as reported earlier by
us.8a The 1,3-DC of 4 with the allyl alcohol in acetone at
30 °C for 7 days was sluggish; however, refluxing for 48
h afforded an inseparable mixture of isoxazolidines in
Results and Discussion
Retrosynthetic Analysis. As shown in the retrosyn-
thetic analysis (Scheme 1), the requisite bicyclic ring
skeleton of the 2-hydroxy-1-deoxycastanospermine could
be built up by 1,2-acetonoide cleavage of 8 followed by
(2) For the synthetic applications of nitrones to azasugars, see: (a)
Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa,
K. Angew. Chem. 2004, 43, 1559-1562. (b) Nagasawa, K.; Hashimoto,
Y. Chem. Rec. 2003, 3, 201-211. (c) Torrente, S.; Noya, B.; Branchadell,
V.; Alonso, R. J. Org. Chem. 2003, 68, 4772-4783. (d) Marco-Contelles,
J.; Opazo, E. J. Carbohydr. Chem. 2002, 21, 201-218. (e) Cravotto,
G.; Giovenzana, G. B.; Pilati, T.; Sisti, M.; Palmisano, G. J. Org. Chem.
2001, 66, 8447-8453. (f) Silva, A. M. G.; Tome, A. C.; Neves, M. G. P.
M. S.; Silva, A. M. S.; Cavaleiro, J. A. S.; Perrone, D.; Dondoni, A.
Tetrahedron Lett. 2002, 43, 603-605. (g) Gebarowski, P.; Sas, W. Chem.
Commun. 2001, 915-916.
(3) For nojirimycin, see: (a) Hughes, A. B.; Rudge, A. J. Nat. Prod.
Rep. 1994, 11, 135-162. (b) Sears, P.; Wong, C, H. J. Chem. Soc., Chem.
Commun. 1998, 1161-1170. (c) Butters, T. D.; Van den Brock, L. A.
G. M.; Fleet, G. W. J.; Krulle, T. M.; Wormald, M. R.; Dwek, R. A.;
Platt, F. M. Tetrahedron: Asymmetry 2000, 11, 113-124. For castano-
spermine, see: (d) 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.
(e) Michael, J. P. Nat. Prod. Rep. 1990, 9, 485-523.
(4) (a) Zho, H.; Hans, S.; Cheng, X.; Mootoo, D. R. J. Org. Chem.
2001, 66, 1761-1767. (b) Svansson, L.; Johnston, B. D.; Gu, J.-H.;
Patrik, B.; Pinto, B. M. J. Am. Chem. Soc. 2000, 122, 10769-10775.
(c) Izquiedro, I.; Plaza, M. T.; Robles, R.; Mota, A. J. Tetrahedron:
Asymmetry 1998, 9, 1015-1027. (d) Kang, S. H.; Kim J. S. J. Chem.
Soc., Chem. Commun. 1998, 1353-1354. (e) Kefalas, P.; Grierson, D.
S. Tetrahedron Lett. 1993, 34, 3555-3558. (f) Ina, H.; Kibayashi, C.
J. Org. Chem. 1993, 58, 52-61. (g) Burgess, K.; Chaplin, D. A,;
Henderson, I.; Pan, Y. T.; Elbein, A. D. J. Org. Chem. 1992, 57, 1103-
1109. (h) Furneaux, R. H.; Mason, J. M.; Tyler, P. C. Tetrahedron Lett.
1995, 36, 3055-3058.
(6) Humphries, M. J.; Matsumoto, K.; White, S. L.; Olden, K. Cancer
Res. 1986, 46, 5215-5222.
(7) (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.
1987, 84, 8120-8124. (c) Sunkara, P. S.; Bowling, T. L.; Liu, P. S.;
Sjoerdsma, A. Biochem. Biophys. Res. Commun. 1987, 148, 206-210.
(8) (a) Dhavale, D. D.; Desai, V. N.; Sindkhedkar, M.; Mali, R. S.;
Castellari, C.; Trombini, C. Tetrahedron: Asymmetry. 1997, 8, 1475-
1486. (b) Patil, N. T.; Tilekar, J. N.; Dhavale, D. D. J. Org. Chem. 2001,
66, 1065-1074. (c) Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.;
PrakashReddy, J. J. Org. Chem. 2004, 69, 4760-4766. (d) Dhavale,
D. D.; Jachak, S. M.; Karche, N. P.; Trombini, C. Synlett 2004, 1549-
1552 and references therein.
(9) The synthesis of 2-hydroxy-1-deoxy castanospermine 3a and 3b
has been reported wherein the assignment of absolute configuration
at C-2 is not given. The authors have reported only the 13C NMR
values: Compernolle, F.; Joly, G.; Peeters, K.; Toppet, S.; Hoomaert,
G. Tetrahedron 1997, 53, 12739-12754. The compounds 3c,d are not
reported so far.
(10) (a) Kanemasa, S.; Uemura, T.; Wada, E. Tetrahedron Lett. 1992,
33, 7889-7892. (b) Kanemasa, S.; Nishiuchi, M.; Kamimura, A.; Hori,
K. J. Am. Chem. Soc. 1994, 116, 2324-2339. (c) Murahashi, S.; Imada,
Y.; Kohno, M.; Kawakami, T. Synlett 1993, 395-396. (d) Tamura, O.;
Yamaguchi, T.; Noe, K.; Sakamoto, M. Tetrahedron Lett. 1993, 34,
4009-4010. (e) Tamura, O.; Yamaguchi, T.; Okabe, T.; Sakamoto, M.
Synlett 1994, 620-622.
(11) (a) Merino, P.; Tejero, T.; Laguna, M.; Cerrada, E.; Moreno, A.;
Lopez, J. A. Org. Bio. Chem. 2003, 1, 2336-2342. (b) Kumar, K. R. R.;
Mallesha, H.; Rangappa, K. S. Synth. Commun. 2003, 33, 1545-1555.
(c) Ding, X.; Taniguchi, K.; Ukaji, Y.; Inomata, K. Chem. Lett. 2001,
30, 468-469. (d) Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Org. Lett. 2001, 3, 953-955.
(5) (a) Truscheit, E.; Frommer, W.; Junge, B.; Muller, L.; Schmidt,
D. D.; Wingender, W. Angew. Chem. 1981, 20, 744-761. (b) Furneaux,
R. H.; Gainsford, G. J.; Mason, J. M.; Tyler, P. C.; Hartley, O.;
Winchester, B. G. Tetrahedron 1997, 53, 245-268.
J. Org. Chem, Vol. 70, No. 4, 2005 1357

Karanjule et al.
SCHEME 2a
a Reaction conditions: (a) (i) allyl alcohol, acetone, 70 °C, 48 h, 95% (ii) TsCl, pyridine, 0 to 25 °C, 2 h, 87% (syn:anti 76:24).
95% yield (after chromatographic purification) which on
further treatment with p-toluenesulfonyl chloride in
pyridine followed by careful separation of the crude
mixture by flash chromatography afforded tosyloxylated
isoxazolidines 5a-d in 49%, 07%, 17%, and 14% yield,
respectively (87% combined yield), with complete regio-
selectivity (Scheme 2). Our attempts to improve the
stereoselectivity at the prochiral C-5 nitrone carbon
under various reaction conditions such as change of
solvent, temperature, stoichiometry of reactants, and
different Lewis acids were unsuccessful.12 Thus, the 1,3-
DC of 4 with the allyl alcohol and subsequent tosylation
afforded a mixture of the syn and anti isomers in the ratio
3:1 in which the products 5a and 5b were formed by the
addition of the allyl alcohol to the Re face while 5c and
5d were formed by the addition of the allyl alcohol to the
Si face of the nitrone 4.13
Assignment of the Relative Stereochemistry at
C-5 and C-7 in Isoxalidines 5a-d. Fortunately, the
O-tosylated isoxazolidines 5a and 5d were obtained as
crystalline solids. The single-crystal X-ray analysis of 5a
FIGURE 2. ORTEP drawing of compound 5a.
(Figure 2) and 5d (Figure 3) established the absolute
configurations at newly generated C5 and C7 stereo-
centers as (5R,7S) and (5S,7S), defining these as D-gluco
and L-ido derivatives, respectively. However, the stereo-
chemical assignments in 5b and 5c were derived from
the correlation study. For this, 5a-d were individually
subjected to N-O bond reductive cleavage with use of
Zn-acetic acid, which afforded corresponding pyrrolidines
6a-d in good yields (Scheme 3). This one-pot two-step
reaction of 5 probably involves in situ generation of
â-amino alcohol that concomitantly undergoes nucleo-
philic displacement of the -O-tosyl group leading to the
formation of the 7-hydroxy-pyrrolidine-ring skeleton. At
this stage, we thought of oxidizing the C7 hydroxyl group,
in 6a-d, to the corresponding keto functionality, which
is expected to give only two C5 epimeric 7-keto products.
This will enable us to get the absolute configuration at
C5 in 6, and from X-ray data correlation of 5a and 5d
one can assign the relative stereochemistry at C7 in 6.
(12) The cycloaddition reaction in benzene and toluene at reflux had
little effect on stereoselectivity and the use of dichloromethane and
acetonitrile at reflux did not afford the products. The same reaction,
in the absence of solvent, was complete in 4 h affording only three
isoxazolidines 5a:5c:5d in the ratio 3.2:1.2:1.0. The 1,3-DC with Lewis
FIGURE 3. ORTEP drawing of compound 5d.
acids such as Cu(OTf)2 or TBDMSOTf (0.5 and 1.0 equiv), either in
acetone or in dichloromethane at the elevated temperature, furnished
a complex mixture of products, probably due to the cleavage of the
Thus, individual Swern oxidation of 6a and 6b afforded
D-gluco-configurated 7-keto compound 7a as a thick oil
1,2-acetonoide group, thus precluding the use of Lewis acids in the
1,3-DC reaction of sugar nitrone.
(Scheme 3) while 6c and 6d gave L-ido-configurated
7-keto product 7b as a colorless solid in good yields.14 The
absolute configuration at C5 in 6a and 6d was estab-
lished as (5R) and (5S) from the corresponding X-ray
(13) The isomers 5a and 5c are often referred as exo while 5b and
5d are called endo.1a,f However since exo and endo are more correctly
used for bicyclic systems, we have dropped this terminology as
suggested by one of the referees. We are thankful to the referee for
his comments.
1358 J. Org. Chem., Vol. 70, No. 4, 2005

2-Hydroxy-1-deoxycastanospermine Analogues
SCHEME 3a Determination of Absolute
Stereochemistry
SCHEME 4a Synthesis of 3a-d
a Reaction conditions: (a) Zn, Cu(OAc)2, AcOH, 70 °C, 1 h; (b)
DMSO, (COCl)2, (Et)3N, -78 to 25 °C, 3 h.
a Reaction conditions: (a) (i) HCOONH4, Pd/C, MeOH, 80 °C, 1
h; (ii) CbzCl, NaHCO3, MeOH, 0 to 25 °C, 2 h; (b) (i) TFA-H2O
(3:2), 25 °C, 2 h; (ii) H2, Pd/C, MeOH, 80 psi, 25 °C, 12 h; (c) Ac2O,
pyridine, DMAP, 0 to 25 °C, 12 h.
structure of 5a and 5d; therefore, the same absolute
configuration (5R) and (5S) was assigned in 6b and 6c,
respectively. The absolute configuration at C7 in 6a and
6d was noticed to be (7S) and as the 6a/6b and 6c/6d
were found to be C7-epimeric alcohols, the C7-configu-
ration in 6b and 6c was therefore assigned as (7R). As
6b and 6c were derived from 5b and 5c, respectively,
the same relative stereochemistry (5R,7R) and (5S,7R)
was assigned to the corresponding precursor isoxazo-
lidines 5b and 5c.
Synthesis of 2-Hydroxy-1-deoxycastanospermine
Analogues 3a-d. Treatment of 5a with ammonium
formate and 10% Pd/C followed by selective amine
protection, with benzyl chloroformate, afforded N-Cbz
protected diol 8a in 70% yield (Scheme 4). This one-pot
three-step hydrogenation reaction resulted in N-O bond
cleavage, intramolecular aminocyclization to form the
pyrrolidine ring skeleton, and the removal of N- and
O-benzyl groups. Subsequently, deprotection of 1,2-
acetonoide functionality in 8a with TFA-water followed
by hydrogenation (H2, 10% Pd/C) afforded 2-(S)-hydroxy-
1-deoxycastenospermine 3a. The same sequence of reac-
tions with 5b, 5c, and 5d gave 2-(R)-hydroxy-1-deoxy-
castenospermine 3b, 2(R)-hydroxy-1-deoxy-8a-epi-casteno-
spermine 3c, and 2(S)-hydroxy-1-deoxy-8a-epi-casteno-
spermine 3d, respectively. The N-Cbz protected diols
8a-d and target molecules 3a-d were characterized by
spectral and analytical techniques and the data were
found to be in agreement with the structures. The
individual reactions of 3a-d with Ac2O in pyridine
afforded corresponding acetyl derivatives 9a-d, which
were characterized by spectral and analytical methods.
are given in Table 1. In case of 3a, the appearance of
two triplets for H7 and H8 at δ 3.23 and 3.14 (J ) 9.3
Hz), one doublet of doublet of doublet for H6 at δ 3.51 (J
) 11.0, 9.3, and 5.4 Hz) and a triplet for H5a at δ 2.25 (J
) 11.0 Hz) clearly indicated the trans-diaxial relationship
between the H5a, H6, H7, H8, and H8a. The large
coupling constants of these protons require axial orienta-
8
tion and indicated the C5 conformation (A) (Figure 4)
for 3a. Similarly, in the case of 3b, the appearance of
two triplets at δ 3.20 and 3.39 (J ) 9.3 Hz) corresponding
to H7 and H8 indicated the trans-diaxial orientation of
H6a, H7, and H8. In addition, the H5a resonated as
triplet at δ 2.29 with a large coupling constant (J5a,5e
)
J5a,6a ) 11.0 Hz) that requires trans-diaxial disposition
of H6a and H5a. The axial arrangements of these protons
8
thus indicated C5 conformation (A) for 3b.
The 1H NMR spectra of 3c,d were found to be different
wherein H6, H7, and H8 protons were deshielded as
compared to the corresponding protons in 3a and 3b. This
downfield shift indicated the equatorial orientation of
these protons as opposed to the axial orientation in 3a,b.
The initial geometry in the precursor 5c,d ensures that,
in the product 3c,d, the substituents at C6, C7, and C8
should be trans. The low values for the coupling constants
between H6, H7, and H8 in 3c (5.6 Hz) and 3d (WH
)
3.0 Hz) supported the fact that these protons are equato-
rial. This suggested the 5C8 conformation (B) for both the
bicyclic indolizidines 3c,d. The doublet of doublet for H-8
at δ 3.69 (J ) 5.6, 3.6 Hz) in 3c and narrow multiplet at
δ 3.73-3.85 (WH ) 3.0 Hz) in 3d indicated that the C8a
substituent is equatorial with (8aS) absolute configura-
tion. From an empirical calculation of the energy differ-
ence between the two conformations 5C8 and 8C5, (B) and
(C), respectively, it is evident that in the 8C5 conformation
(C) the 1,3-diaxial interactions between C5-Ha and
C8a-C1 and between C7-H and C8a-C1 destabilize this
Conformational Assignments of 3a-d. We have
recently reported that the 1-deoxycastanospermine and
1-deoxy-8a-epi-castanospermine exist in 8C5 and 5C8
conformations, respectively.8b The conformational aspects
1
of 3a-d were studied by using H NMR data wherein
the assignment of signals and coupling constants infor-
mation were obtained from decoupling experiments and
(14) The formation of keto product 7a obtained separately from 6a/
6b was found to be identical on the basis of super imposable IR and
other spectral and analytical data. Similarly, the keto product 7b
derived from 6c/6d was found to be identical on the basis of mp, mixed
mp, and super imposable IR and other spectral and analytical data.
5
conformation. On the contrary, in the C8 conformation
(B), both the 1,3-diaxial interactions are absent and, in
addition, the conformation 5C8 is stabilized by the intra-
J. Org. Chem, Vol. 70, No. 4, 2005 1359

Karanjule et al.
H8a
TABLE 1. 1H-1H Coupling Constant Values of Compounds 3a-d
H2
H5a
H5e
3.12 (dd)
(J5e,6a ) 5.4 Hz
H6
H7
3.23 (t)
(J7,6
J7,8 ) 9.3 Hz)
H8
3.14 (t)
3a δ 4.34-4.44 (m) 2.25 (t)
3.51 (ddd)
2.54 (ddd)
(J8a,1a ) 7.3 Hz,
J8a,1b ) 6.4 Hz)
(J5a,5e
)
(J6a,5a ) 11.0 Hz,
J6a, 5e ) 5.4 Hz,
J6, 7 ) 9.3 Hz)
)
(J8,7 ) J8,8a
)
J5a,6a ) 11.0 Hz)
9.3 Hz)
3b δ 4.38-4.48 (m) 2.29 (t)
(J5a,5e
J5a,6a ) 11.0 Hz)
3.24 (dd)
(J5e,6a ) 5.0 Hz)
3.61 (ddd)
3.20 (t)
(J7,6
J7,8 ) 9.3 Hz)
3.35 (t)
(J8,7 ) J 8,8a
9.3 Hz)
2.45 (ddd)
(J8a,1a ) 8.4 Hz,
J8a, 1b ) 6.3 Hz)
)
(J6a,5a ) 11.0 Hz,
J6a,5e ) 5.0 Hz,
J6,7 ) 9.3 Hz)
)
)
3c δ 4.47-4.58 (m) 2.72 (dd)
2.65(dd)
(J5e,6e ) 3.3 Hz)
3.82 (dt) (J6e,5a
)
3. 74 (t)
(J7,6
J7,8 ) 5.6 Hz)
3.69 (dd)
(J8,7 ) 5.6 Hz,
J8,8a ) 3.6 Hz)
3.04 (ddd)
(J5a,6e ) 5.6 Hz,
J5a,5e ) 12.2 Hz)
2.9-3.05 (narrow 3.08-3.25 (m)
J6,7 ) 5.6 Hz,
)
(J8a,1a ) 6.0 Hz,
J8a,1b ) 12.0 Hz)
3.08-3.25 (m)
J6e,5e ) 3.3 Hz)
3d δ 4.45-4.50
(narrow
3.74-3.85 (narrow multiplet) (WH ) 3.0 Hz)
multiplet)
multiplet)
Conclusions
In summary, the 1,3-DC of D-glucose-derived nitrone
4 with allyl alcohol followed by tosylation afforded
tosyloxylated isoxazolidines 5a-d with complete regio-
selectivity in high yield. The utility 5a-d was demon-
strated in the synthesis of 2-hydroxy-1-deoxycastano-
spermine analogues 3a-d. The conformational study of
3a-d indicated that the C2-OH functionality has no
effect on conformational preference as 3a/3b attains 8C5
while 3c/d have 5C8 conformations analogous to 1-deoxy-
castanospermine and 1-deoxy-8a-epi-castanospermine,
respectively. The glycosidase inhibitory study showed
that compound 3b is more potent toward â-glucosidase.
FIGURE 4. Conformations of 3a-d.
TABLE 2. IC50 Values for Compounds 3a-da
IC50 (mM)
enzyme
3a
NI
16.53
20.00
28.56
3.71
3b
3c
3d
4.6
4.26
NI
10.97
7.94
R-galactosidase (almond)
â-galactosidase (bovine)
R-mannosidase (Jack bean)
R-glucosidase (yeast)
9.76
6.45
36.23
NI
3.93
ND
4.28
8.48
4.59
Experimental Section
1,2-O-Isopropylidene-3-O-benzyl-4R-[(3′R,5′S)-N-ben-
zyl-5′-tosyloxymethyl-3′-isoxazolidinyl]-r-L-threo-1,4-fura-
nose (5a), 1,2-O-Isopropylidene-3-O-benzyl-4R-[(3′R,5′R)-
N-benzyl-5′-tosyloxymethyl-3′-isoxazolidinyl]-r-L-threo-
1,4-furanose (5b), 1,2-O-Isopropylidene-3-O-benzyl-4R-
[(3′S,5′R)-N-benzyl-5′-tosyloxymethyl-3′-isoxazolidinyl]-
r-L-threo-1,4-furanose (5c), and 1,2-O-Isopropylidene-3-
O-benzyl-4R-[(3′S,5′S)-N-benzyl-5′-tosyloxymethyl-3′-
isoxazolidinyl]-r-L-threo-1,4-furanose (5d). Nitrone 4 (2.0
g, 5.2 mmol), allyl alcohol (3.5 g, 52.0 mmol), and acetone (10
mL) were refluxed at 70 °C for 48 h. The solvent was removed
under reduced pressure and purification by column chroma-
tography with n-hexane/ethyl acetate 70/30 afforded the
mixture of cycloadducts as a thick liquid (2.2 g, 95%). To a
mixture of cycloadducts (2.0 g, 4.5 mmol) in dry pyridine (5
mL) cooled at 0 °C was added p-toluenesulfonyl chloride (1.03
g, 5.4 mmol), then the mixture was stirred at room tempera-
ture for 4 h. Quenching with cold water followed by the usual
workup and extraction with ethyl acetate (3 × 30 mL) afforded
a thick oil. Separation by flash column chromatography and
elution first with n-hexane/ethyl acetate (95/5) gave 5a (1.31
g, 49%) as a white solid; mp 119-120 °C; Rf 0.57 (n-hexane/
ethyl acetate ) 6/4); [R] D +8.0 (c 0.25, CHCl3); IR (Nujol) 1595,
â-glucosidase (almond)
2.96
a NI ) inhibition not observed under assay conditions. ND )
not determined. Data are the average of three sets of assay
performed.
molecular hydrogen bonding in a six-membered transi-
tion state as shown in Figure 4.15 It may be noted that
conversion of conformation (C) to (B) should give the
N-C3 bond axial; however, this bond would attain the
more stable equatorial geometry due to the nitrogen lone
pair flipping that further assists in releasing the 1,3-
diaxial interaction of the N-C3 bond with C6 and C8-
OH.
Glycosidase Inhibitory Study. The castanospermine
2 is a potent but nonselective inhibitor of many glyco-
hydrolases including the intestinal disaccharidases.16 The
castanospermine analogues 3a-d thus obtained were
tested for inhibitory activity against glycosidases, namely
a-galactosidase (E.C. 3.2.1.22), â-galactosidase (E.C.
3.2.1.23), R-mannosidase (E.C. 3.2.1.24), R-glucosidase
(E.C. 3.2.1.20), and â-glucosidase (E.C. 3.2.1.21). All the
compounds showed inhibition in micromolar ranges and
the results obtained are summarized in Table 2. The
inhibitory profile of 3a-d also corroborates the nonselec-
tive nature of inhibition as in the case of castanospermine
2.
1
1495, 1358 cm-1; H NMR (300 MHz, CDCl3) δ 1.28 (s, 3H),
1.44 (s, 3H), 2.11-2.24 (m, 1H), 2.46 (s, 3H), 2.60 (dt, J ) 13.3,
8.4 Hz, 1H), 3.68-3.80 (m, 1H), 3.76 (d, J ) 13.5 Hz, 1H), 3.94
(d, J ) 13.5 Hz, 1H), 4.00-4.12 (m, 3H), 4.15 (dd, J ) 10.2,
3.9 Hz, 1H), 4.33 (d, J ) 12.0 Hz, 1H), 4.44-4.58 (m, 1H), 4.55
(d, J ) 12.0 Hz, 1H), 4.58 (d, J ) 3.9 Hz, 1H), 5.87 (d, J ) 3.9
Hz, 1H), 7.20-7.42 (m, 12H), 7.81 (d, J ) 8.0 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 21.6, 26.2, 26.7, 33.5, 60.7, 62.4, 70.2,
71.7, 74.3, 81.2, 81.7, 82.0, 104.8, 111.7, 127.4, 127.5, 127.8,
128.0 (s), 128.3 (s), 128.4(s), 128.9 (s), 129.8 (s), 132.6, 137.0,
137.3, 144.8. Anal. Calcd for C32H37NO8S: C, 64.52; H, 6.26.
Found: C, 64.68; H, 6.38. Further elution with n-hexane/ethyl
acetate (95/5) afforded 5b (0.19 g, 7%) as a thick liquid; Rf 0.54
(15) Such types of 5C8 conformations for other isomers of castano-
spermine are also known, see: Hendry D.; Hough, L.; Richardson, A.
C. Tetrahedron 1988, 44, 6153-6168.
(16) Rhinehart, B. L.; Robinson, K. M.; King, C. H.; Liu, P. S.
Biochem. Pharmacol. 1990, 39, 1537-1543.
1360 J. Org. Chem., Vol. 70, No. 4, 2005

2-Hydroxy-1-deoxycastanospermine Analogues
(n-hexane/ethyl acetate ) 6/4); [R]D +6.6 (c 0.30, CHCl3); IR
137.1, 138.7. Anal. Calcd for C25H31NO5: C, 70.57; H, 7.34.
Found: C, 70.62; H, 7.39.
1
(Neat) 1590, 1445, 1355 cm-1; H NMR (300 MHz, CDCl3) δ
1.28 (s, 3H), 1.44 (s, 3H), 2.37 (ddd, J ) 12.9, 8.7, 8.4 Hz, 1H),
2.43 (s, 3H), 2.55 (ddd, J ) 12.9, 8.8, 1.7 Hz, 1H), 3.71-3.82
(m, 1H), 3.81 (d, J ) 13.7 Hz, 1H), 3.89 (d, J ) 13.7 Hz, 1H),
4.0-4.17 (m, 4H), 4.30 (d, J ) 11.5 Hz, 1H), 4.25-4.37 (m,
1H), 4.52 (d, J ) 11.5 Hz, 1H), 4.56 (d, J ) 3.9 Hz, 1H), 5.86
(d, J ) 3.9 Hz, 1H), 7.15-7.34 (m, 12H), 7.75 (d, J ) 8.5 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ 21.7, 26.2, 26.8, 32.2, 62.3,
62.8, 68.9, 71.9, 77.2, 79.0, 81.6, 82.1, 104.9, 111.9, 127.8 (s),
128.0 (s), 128.4 (s), 128.5(s), 129.6 (s), 129.9 (s), 132.4, 137.1,
145.1. Anal. Calcd for C32H37NO8S: C, 64.52; H, 6.26. Found:
C, 64.70; H, 6.42. Next elution with n-hexane/ethyl acetate
(90/10) afforded 5c (0.47 g, 17%) as a thick liquid; Rf 0.50 (n-
hexane/ethyl acetate ) 6/4); [R]D -10.6 (c 1.5, CHCl3); IR
5,6,8-Trideoxy-5,8-(N-benzylimino)-1,2-O-isopropyl-
idene-3-O-benzyl-7(R)-hydroxy-r-L-glycero-D-gluco-oct-
1,4-furanose (6b). Purification by column chromatography
(n-hexane/ethyl acetate ) 70/30) afforded 6b (0.30 g, 84%) as
a white solid; mp 93-94 °C; Rf 0.60 (ethyl acetate); [R]D -40.0
(c 0.25, CHCl3); IR (Nujol) 3550-3200, 1612, 1454 cm-1 1H
;
NMR (300 MHz, CDCl3 + D2O) δ 1.35 (s, 3H), 1.44 (s, 3H),
2.19-2.38 (m, 2H), 2.39 (dd, J ) 10.2, 3.6 Hz, 1H), 3.01 (d, J
) 10.2 Hz, 1H), 3.08-3.12 (m, 1H), 3.60 (d, J ) 13.2 Hz, 1H),
3.87 (d, J ) 3.3 Hz, 1H), 3.94 (d, J ) 13.2 Hz, 1H), 4.12-4.20
(m, 1H), 4.25 (t, J ) 3.3 Hz, 1H), 4.46 (d, J ) 12.0 Hz, 1H),
4.62 (d, J ) 3.9 Hz, 1H), 4.69 (d, J ) 12.0 Hz, 1H), 6.00 (d, J
) 3.9 Hz, 1H), 7.20-7.32 (m, 10H); 13CNMR (75 MHz, CDCl3)
δ 26.4, 26.9, 36.2, 58.8, 61.0, 61.8, 70.6, 71.5, 81.5, 82.3 (s),
104.7, 111.8, 127.0, 127.3 (s), 127.8, 128.3 (s), 128.4 (s), 128.8
(s), 137.3, 138.8. Anal. Calcd for C25H31NO5: C, 70.57; H, 7.34.
Found: C, 70.71; H, 7.30.
1
(Neat) 1588, 1450, 1360 cm-1; H NMR (300 MHz, CDCl3) δ
1.32 (s, 3H), 1.47 (s, 3H), 2.33 (ddd, J ) 9.3, 5.1, 1.8 Hz, 1H),
2.45 (s, 3H), 2.59 (ddd, J ) 9.3, 9.0, 1.8 Hz, 1H), 3.75-3.78
(m, 1H), 3.78 (d, J ) 13.5 Hz, 1H), 3.91 (d, J ) 13.5 Hz, 1H),
4.16 (d, J ) 3.0 Hz, 1H), 4.10-4.17 (m, 3H), 4.29-4.38 (m,
1H), 4.32 (d, J ) 11.7 Hz, 1H), 4.55 (d, J ) 11.7 Hz, 1H), 4.59
(d, J ) 3.9 Hz, 1H), 5.90 (d, J ) 3.9 Hz, 1H), 7.20-7.38 (m,
12H), 7.81 (d, J ) 8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
21.6, 26.1, 26.7, 32.1, 62.5, 62.7, 69.5, 71.7, 76.2, 79.5, 81.5,
81.9, 104.8, 111.6, 127.2, 127.5 (s), 127.8, 127.9(s), 128.2 (s),
128.4 (s), 128.9 (s), 129.8 (s), 132.5, 137.2, 137.2, 144.9. Anal.
Calcd for C32H37NO8S: C, 64.52; H, 6.26. Found: C, 64.60; H,
6.48. Further elution with n-hexane/ethyl acetate (85/15)
afforded 5d (0.37 g, 14%) as a white solid; mp 133-134 °C; Rf
0.42 (n-hexane/ethyl acetate ) 6/4); [R]D -110.0 (c 1.0, CHCl3);
IR (Nujol) 1598, 1454, 1365 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.36 (s, 3H), 1.53 (s, 3H), 1.93 (dt, J ) 12.3, 8.7 Hz, 1H),
2.04-2.15 (m, 1H), 2.46 (s, 3H), 3.24 (dd, apparent quartet J
) 8.7 Hz, 1H), 3.67 (d, J ) 14.4 Hz, 1H), 3.90 (d, J ) 3.0 Hz,
1H), 3.96 (d, J ) 4.5 Hz, 2H), 4.09-4.19 (m, 1H), 4.22 (dd, J
) 8.7, 3.0 Hz, 1H), 4.47 (d, J ) 11.7 Hz, 1H), 4.53 (d, J ) 14.4
Hz, 1H), 4.65 (d, J ) 3.9 Hz, 1H), 4.74 (d, J ) 11.7 Hz, 1H),
6.01 (d, J ) 3.9 Hz, 1H), 7.20-7.54 (m, 12H), 7.80 (d, J ) 8.1
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 21.5, 26.2, 26.6, 34.0,
61.8, 63.8, 69.6, 71.6, 73.1, 80.9, 81.6, 82.5, 104.4, 111.7, 126.8,
127.9 (s), 128.0 (s), 128.3 (s), 128.3, 128.7 (s), 129.0 (s), 129.8
(s), 132.6, 136.6, 137.9, 144.8. Anal. Calcd for C32H37NO8S: C,
64.52; H, 6.26. Found: C, 64.78; H, 6.50.
General Procedure for the Conversion of 5 to 6. Zinc
dust (0.30 g, 4.6 mmol) was added to a solution of copper(II)
acetate (0.01 g, 0.007 mmol) in glacial acetic acid (1 mL) under
nitrogen atmosphere and the mixture was stirred at room
temperature for 10 min until the color disappeared. Compound
5 (0.50 g, 0.93 mmol) in glacial acetic acid (0.7 mL) and water
(0.3 mL) was successively added and the reaction mixture was
heated at 70 °C for 1 h. On cooling to room temperature,
sodium salt of EDTA (0.1 g) was added and the mixture was
stirred for 10 min and then made alkaline to pH 10 by addition
of 3 N NaOH. The resulting solution was extracted with
chloroform (3 × 10 mL) and the combined organic layer was
evaporated under reduced pressure.
5,6,8-Trideoxy-5,8-(N-benzylimino)-1,2-O-isopropyl-
idene-7(R)-hydroxy-â-L-glycero-L-ido-oct-1,4- furanose (6c).
Purification by column chromatography (n-hexane/ethyl ace-
tate ) 60/40) afforded 6c (0.28 g, 79%) as a thick liquid; Rf
0.34 (ethyl acetate); [R]D -80.0 (c 0.27, CHCl3); IR (neat) 3550-
1
3200, 1618, 1450 cm-1; H NMR (300 MHz, CDCl3) δ 1.34 (s,
3H), 1.55 (s, 3H), 1.60-1.82 (m, 2H), 2.38 (dd, J ) 10.7, 4.6
Hz, 1H), 2.66 (br s, exchanges with D2O, 1H), 3.29 (dd, J )
10.7, 5.8 Hz, 1H), 3.44 (ddd, apparent quartet, J ) 8.5 Hz,
1H), 3.60 (d, J ) 13.2 Hz, 1H), 3.88 (d, J ) 3.0 Hz, 1H), 4.28-
4.42 (m, 2H), 4.46 (d, J ) 11.5 Hz, 1H), 4.54 (d, J ) 13.2 Hz,
1H), 4.61 (d, J ) 3.9 Hz, 1H), 4.69 (d, J ) 11.7 Hz, 1H), 6.03
(d, J ) 3.9 Hz, 1H), 7.20-7.41 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 26.3, 26.6, 37.2, 59.1, 61.0, 61.5, 69.0, 71.7, 80.8, 83.1,
83.5, 105.4, 111.6, 127.3, 127.8 (s), 128.0, 128.2 (s), 128.4 (s),
129.8 (s), 137.0. Anal. Calcd for C25H31NO5: C, 70.57; H, 7.34.
Found: C, 70.82; H, 7.52.
5,6,8-Trideoxy-5,8-(N-benzylimino)-1,2-O-isopropyl-
idene-7(S)-hydroxy-â-D-glycero-L-ido-oct-1,4- furanose (6d).
Purification by column chromatography (n-hexane/ethyl ace-
tate ) 65/35) afforded 6d (0.29 g, 82%) as a thick liquid; Rf
0.44 (ethyl acetate); [R]D -48.5 (c 0.70, CHCl3); IR (Neat)
3600-3200, 1628, 1454 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.37 (s, 3H), 1.40-1.55 (m, 1H), 1.57 (s, 3H), 2.23-2.38 (m,
2H), 2.47 (br s, exchanges with D2O, 1H), 2.88 (d, J ) 10.2
Hz, 1H), 2.98 (ddd, apparent quartet, J ) 8.5 Hz, 1H), 3.37
(d, J ) 13.5 Hz, 1H), 3.96 (d, J ) 3.0 Hz, 1H), 4.08-4.18 (m,
1H), 4.34 (dd, J ) 8.7, 3.0 Hz, 1H), 4.48 (d, J ) 11.7 Hz, 1H),
4.58 (d, J ) 13.5 Hz, 1H), 4.63 (d, J ) 3.9 Hz, 1H), 4.72 (d, J
) 11.7 Hz, 1H), 6.05 (d, J ) 3.9 Hz, 1H), 7.15-7.50 (m, 10H);
13C NMR (75 MHz, CDCl3) δ 26.3, 26.7, 38.3, 58.7, 60.9, 62.4,
69.9, 71.7, 80.9, 83.6, 85.5, 105.5, 111.5, 126.7, 127.9 (s), 128.0
(s), 128.5 (s), 129.2 (s), 137.0, 138.9. Anal. Calcd for C25H31-
NO5: C, 70.57; H, 7.34. Found: C, 70.67; H, 7.42.
5,6,8-Trideoxy-5,8-(N-benzylimino)-1,2-O-isopropyl-
idene-r-D-gluco-oct-1,4-furan-7-ulose (7a). To a solution of
oxalyl chloride (0.033 g, 0.26 mmol) in CH2Cl2 (1 mL) at -78
°C was added DMSO (0.04 g, 0.51 mmol) and the mixture was
stirred for 15 min, a solution of alcohol 6a/6b (0.1 g, 0.23 mmol)
in CH2Cl2 (1 mL) was added, and the mixture was stirred at
-78 °C for an additional 1 h. Triethylamine (0.12 g, 1.1 mmol)
was added, and the mixture was allowed to warm to room
temerature. The usual workup followed by purification by
column chromatography (n-hexane/ethyl acetate ) 90/10)
afforded 7a (0.07 g, 70%) as a thick liquid; Rf 0.70 (n-hexane/
ethyl acetate ) 5/5); [R]D -26.6 (c 0.30, CHCl3); IR (Neat) 1749,
1654 cm-1;1H NMR (300 MHz, CDCl3) δ 1.35 (s, 3H), 1.55 (s,
3H), 2.58 (dd, J ) 19.0, 7.5 Hz, 1H), 2.80 (dd, J ) 19.0, 7.0
Hz, 1H), 2.83 (d, J ) 17.4 Hz, 1H), 3.31 (d, J ) 17.4 Hz, 1H),
3.51-3.58 (m, 1H), 3.52 (d, J ) 13.8 Hz, 1H), 4.04 (d, J ) 3.3
Hz, 1H), 4.08 (d, J ) 13.8 Hz, 1H), 4.47 (d, J ) 11.8 Hz, 1H),
4.47-4.52 (m, 1H), 4.67 (d, J ) 3.8 Hz, 1H), 4.73 (d, J ) 11.8
Hz, 1H), 5.97 (d, J ) 3.8 Hz, 1H), 7.20-7.50 (m, 10 H); 13C
5,6,8-Trideoxy-5,8-(N-benzylimino)-1,2-O-isopropyl-
idene-3-O-benzyl-7(S)-hydroxy-r-D-glycero-D-gluco-oct-
1,4-furanose (6a). Purification by column chromatography (n-
hexane/ethyl acetate ) 70/30) afforded 6a (0.29 g, 81%) as a
thick oil; Rf 0.58 (ethyl acetate); [R]D -17.8 (c 0.41, CHCl3);
1
IR (Neat) 3540-3200, 1632, 1458 cm-1; H NMR (300 MHz,
CDCl3 + D2O) δ 1.38 (s, 3H), 1.55 (s, 3H), 2.00-2.12 (m, 1H),
2.30 (dt, J ) 13.5, 6.3 Hz, 1H), 2.50 (dd, J ) 10.5, 3.9 Hz, 1H),
3.14 (d, J ) 10.5, 5.4 Hz, 1H), 3.57 (ddd, apparent quartet J
) 6.6, 6.3 Hz, 1H), 3.71 (d, J ) 13.2 Hz, 1H), 4.01 (d, J ) 3.3
Hz, 1H), 4.03 (d, J ) 13.2 Hz, 1H), 4.16 (dd, J ) 6.0, 3.3 Hz,
1H), 4.36-4.44 (m, 1H), 4.45 (d, J ) 12.0 Hz, 1H), 4.65 (d, J
) 3.3 Hz, 1H), 4.68 (d, J ) 12.0 Hz, 1H), 5.94 (d, J ) 3.3 Hz,
1H), 7.21-7.42 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 26.2,
26.7, 38.0, 59.7, 60.6, 61.1, 70.6, 71.4, 81.6, 82.0, 82.2, 104.6,
111.5, 127.0, 127.6 (s), 127.9, 128.3 (s), 128.4 (s), 128.7 (s),
J. Org. Chem, Vol. 70, No. 4, 2005 1361

Karanjule et al.
NMR (75 MHz, CDCl3) δ 26.2, 26.8, 40.3, 58.6, 59.6, 60.6, 71.6,
79.6, 81.7, 82.6, 104.7, 111.6, 127.3, 127.6 (s), 128.0, 128.4 (s),
128.6 (s), 137.0, 137.9, 214.6. Anal. Calcd for C25H29NO5: C,
70.90; H, 6.90. Found: C, 71.01; H, 6.72.
furanose (8c). Purification by column chromatography (n-
hexane/ethyl acetate ) 70/30) afforded 8c (0.135 g, 73%) as a
thick liquid; Rf 0.54 (ethyl acetate); [R]D -58.0 (c 0.275, CHCl3);
1
IR (Neat) 3570-3230, 1678, 1438, 1354 cm-1; H NMR (300
MHz, CDCl3) δ 1.37 (s, 3H), 1.54 (s, 3H), 2.17-2.25 (m, 2H),
3.00 (br s, exchanges with D2O, 2H), 3.57 (dd, J ) 11.5, 4.6
Hz, 1H), 3.76 (br d, J ) 11.5 Hz, 1H), 4.00-4.12 (m, 1H), 4.41
(d, J ) 3.0 Hz, 1H), 4.47-4.57 (m, 2H), 4.58-4.70 (m, 1H),
5.20 (ABq, J ) 12.4 Hz, 2H), 5.96 (d, J ) 3.9 Hz, 1H), 7.26-
7.44 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 26.0, 26.7, 29.3,
54.9, 55.0, 67.6, 69.6, 75.2, 83.4, 85.0, 104.5, 111.3, 127.8 (s),
128.0, 128.4 (s), 136.1, 157.6. Anal. Calcd for C19H25NO7: C,
60.15; H, 6.64. Found: C, 60.41; H, 6.60.
5,6,8-Trideoxy-5,8-(N-benzylimino)-1,2-O-isopropyl-
idene-â-L-ido-oct-1,4-furan-7-ulose (7b). The reaction of
oxalyl chloride (0.026 g, 0.20 mmol), DMSO (0.032 g, 0.41
mmol), alcohol 6c/6d (0.08 g, 0.18 mmol), and triethylamine
(0.09 g, 0.9 mmol) in CH2Cl2 (2 mL) was performed under the
same conditions as mentioned for 7a. Purification by column
chromatography (n-hexane/ethyl acetate ) 90/10) afforded 7b
(0.058 g, 74%) as a white solid; mp 129-130 °C; Rf 0.64 (n-
hexane/ethyl acetate ) 1/1); [R]D -123.0 (c 0.32, CHCl3); IR
(Nujol) 1745, 1650 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.38 (s,
3H), 1.57 (s, 3H), 2.15 (dd, J ) 18.0, 10.5 Hz, 1H), 2.41 (dd, J
) 18.0, 6.6 Hz, 1H), 2.72 (d, J ) 18.0 Hz, 1H), 3.28 (d, J )
18.0 Hz, 1H), 3.35-3.47 (m, 1H), 3.46 (d, J ) 13.2 Hz, 1H),
3.92 (d, J ) 2.7 Hz, 1H), 4.37 (dd, J ) 7.8, 2.7 Hz, 1H), 4.46
(d, J ) 11.7 Hz, 1H), 4.65 (d, J ) 3.9 Hz, 1H), 4.69 (d, J )
13.2 Hz, 1H), 4.73 (d, J ) 11.7 Hz, 1H), 6.07 (d, J ) 3.9 Hz,
1H), 7.20-7.48 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ 26.4,
26.8, 40.6, 59.3, 60.5, 61.8, 71.8, 80.6, 83.4, 84.5, 105.6, 111.8,
127.1, 128.0 (s), 128.4 (s), 128.7 (s), 129.0, 136.8, 138.3, 212.6.
Anal. Calcd for C25H29NO5: C, 70.90; H, 6.89. Found: C, 70.98;
H, 7.04.
General Procedure for the Conversion of 5 to 8. A
solution of compound 5 (0.30 g, 0.50 mmol), 10% Pd/C (0.075
g), and ammonium formate (0.19 g, 3.0 mmol) in methanol (4
mL) was refluxed for 1 h. The reaction mixture was filtered
through Celite and the filtrate was evaporated to give a thick
oil. To a solution of amino alcohol (0.12 g, 0.50 mmol) in
methanol-water (10 mL, 9:1) cooled to 0 °C was added
benzylchloroformate (0.1 g, 0.60 mmol) and sodium bicarbonate
(0.126 g, 1.5 mmol) and the solution was stirred for 2.5 h.
Methanol was evaporated under reduced pressure and the
aqueous layer was extracted with chloroform (3 × 15 mL).
After the usual workup the chloroform layer was evaporated
under reduced pressure.
5,6,8-Trideoxy-5,8-(N-benzoxycarbonylimino)-1,2-O-
isopropylidene-7(S)-hydroxy-â-D-glycero-L-ido-oct-1,4-
furanose (8d). Purification by column chromatography (n-
hexane/ethyl acetate ) 60/40) afforded 8d (0.145 g, 76%) as a
white solid; mp 168-169 °C; Rf 0.39 (ethyl acetate); [R]D -96.0
(c 0.50, CHCl3); IR (Nujol) 3550-3200, 1674, 1421, 1346 cm-1
;
1H NMR (300 MHz, CDCl3 + D2O) δ 1.33 (s, 3H), 1.50 (s, 3H),
2.00 (d, J ) 14.1 Hz, 1H), 2.45 (ddd, J ) 14.0, 9.6, 5.8 Hz,
1H), 3.44 (d, J ) 12.3 Hz, 1H), 3.85 (dd, J ) 12.3, 6.3 Hz, 1H),
4.23 (d, J ) 2.0 Hz, 1H), 4.29 (d, J ) 2.0 Hz, 1H), 4.32-4.42
(m, 2H), 4.54 (d, J ) 3.3 Hz, 1H), 5.18 (ABq, J ) 12.3 Hz, 2H),
5.95 (d, J ) 3.3 Hz, 1H), 7.20-7.40 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 26.2, 26.9, 41.4, 55.6, 57.4, 68.0, 70.0, 74.9, 83.6, 84.8,
104.3, 112.1, 128.0 (s), 128.3, 128.5 (s), 135.8, 157.5. Anal.
Calcd for C19H25NO7: C, 60.15; H, 6.64. Found: C, 60.32; H,
6.78.
General Procedure for the Conversion of 8 to 3. A
solution of 8 (0.10 g, 0.26 mmol) in TFA-H2O (3 mL, 2:1) was
stirred at 25 °C for 2.5 h. Trifluroacetic acid was coevaporated
with benzene to furnish a thick liquid. To a solution of the
above product in methanol (5 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.
(2S,6S,7R,8R,8aR)-2,6,7,8-Tetrahydroxyindolizidine (3a).
Purification by column chromatography (chloroform/methanol
) 80/20) afforded 3a (0.04 g, 80%) as a white solid; mp 205-
207 °C dec; Rf 0.40 (chloroform/methanol 1/1); [R]D +44.4 (c
0.21, MeOH); IR (Nujol) 3676-3250 cm-1; 1H NMR (300 MHz,
D2O) δ 1.79 (ddd, J ) 14.0, 10.5, 7.3 Hz, 1H), 1.88 (ddd, J )
14.0, 6.4, 1.8 Hz, 1H), 2.25 (t, J ) 11.0 Hz, 1H), 2.28 (dd, J )
10.5, 5.0 Hz, 1H), 2.54 (ddd, J ) 9.3, 7.3, 6.4 Hz, 1H), 3.12
(dd, J ) 11.0, 5.4 Hz, 1H), 3.14 (t, J ) 9.3 Hz, 1H), 3.23 (t, J
) 9.3 Hz, 1H), 3.40 (dd, J ) 10.5, 6.9 Hz, 1H), 3.51 (ddd, J )
11.0, 9.3, 5.4 Hz, 1H), 4.34-4.44 (m, 1H); 13C NMR (75 MHz,
D2O) δ 37.7, 54.0, 60.7, 65.0, 68.4, 69.4, 73.3, 77.7. Anal. Calcd
for C8H15NO4: C, 50.75; H, 7.98. Found: C, 50.89; H, 8.04.
5,6,8-Trideoxy-5,8-(N-benzoxycarbonylimino)-1,2-O-
isopropylidene-7(S)-hydroxy-r-D-glycero-D-gluco-oct-1,4-
furanose (8a). Purification by column chromatography (n-
hexane/ethyl acetate ) 80/20) gave 8a (0.137 g, 72% overall)
as a white solid; mp 115-116 °C; Rf 0.62 (ethyl acetate); [R]D
+64.0 (c 0.25, CHCl3); IR (Nujol) 3600-3250, 1670, 1427 cm-1
;
1H NMR (300 MHz, CDCl3 + D2O) δ 1.38 (s, 3H), 1.47 (s, 3H),
2.21 (ddd, J ) 13.8, 7.8, 6.0 Hz, 1H), 2.35 (dt, J ) 13.8, 4.8
Hz, 1H), 3.50 (dd, J ) 11.9, 5.1 Hz, 1H), 3.69 (dd, J ) 11.9,
2.7 Hz, 1H), 3.76 (dd, J ) 9.9, 2.1 Hz, 1H), 4.07 (d, J ) 2.1 Hz,
1H), 4.33 (ddd, J ) 9.9, 7.8, 6.0 Hz, 1H), 4.47-4.58 (m, 1H),
4.62 (d, J ) 3.6 Hz, 1H), 5.17 (ABq, J ) 12.3 Hz, 2H), 5.91 (d,
J ) 3.6 Hz, 1H), 7.32-7.42 (m, 5H); 13C NMR (75 MHz, CDCl3)
δ 25.9, 26.7, 38.3, 53.8, 54.4, 67.8, 69.5, 73.7, 83.0, 84.9, 104.5,
111.4, 128.0 (s), 128.3, 128.6 (s), 135.8, 157.1. Anal. Calcd for
C19H25NO7: C, 60.15; H, 6.64. Found: C, 60.30; H, 6.82.
(2R,6S,7R,8R,8aR)-2,6,7,8-Tetrahydroxyindolizidine
(3b). Purification by column chromatography (chloroform/
methanol ) 75/25) afforded 3b (0.04 g, 80%) as a thick liquid;
Rf 0.33 (chloroform/methanol 1/1); [R]D +40.0 (c 0.60, MeOH);
1
5,6,8-Trideoxy-5,8-(N-benzoxycarbonylimino)-1,2-O-
isopropylidene-7(R)-hydroxy-r-L-glycero-D-gluco-oct-1,4-
furanose (8b). Purification by column chromatography (n-
hexane/ethyl acetate ) 80/20) afforded 8b (0.143 g, 75%) as a
thick liquid; Rf 0.67 (ethyl acetate); [R]D +40.0 (c 0.40, CHCl3);
IR (Neat) 3429-3230 cm-1; H NMR (300 MHz, D2O) δ 1.45
(ddd, J ) 12.9, 8.4, 2.7 Hz, 1H), 2.29 (t, J ) 11.0 Hz, 1H), 2.45
(ddd, J ) 9.3, 8.4, 6.3 Hz, 1H), 2.51 (ddd, J ) 12.9, 6.3, 1.4
Hz, 1H), 2.74 (dd, J ) 11.5, 6.3 Hz, 1H), 3.03 (br d, J ) 11.5
Hz, 1H), 3.20 (t, J ) 9.3 Hz, 1H), 3.24 (dd, J ) 11.0, 5.0 Hz,
1H), 3.35 (t, J ) 9.3 Hz, 1H), 3.61 (ddd, J ) 10.9, 9.3, 5.0 Hz,
1H), 4.38-4.48 (m, 1H); 13C NMR (75 MHz, D2O) δ 37.9, 54.6,
61.4, 66.4, 69.0, 69.9, 74.2, 78.0. Anal. Calcd for C8H15NO4: C,
50.75; H, 7.98. Found: C, 50.82; H, 8.12.
1
IR (Neat) 3600-3200, 1674, 1421, 1346 cm-1; H NMR (300
MHz, CDCl3 + D2O) δ 1.26 (s, 3H), 1.50 (s, 3H), 2.14 (ddd, J
) 13.9, 8.4, 4.7 Hz, 1H), 2.36 (d, J ) 13.9 Hz, 1H), 3.49 (d, J
) 12.3 Hz, 1H), 3.67 (dd, J ) 12.3, 3.9 Hz, 1H), 4.12 (d, J )
2.1 Hz, 1H), 4.23 (dd, J ) 9.9, 8.4 Hz, 1H), 4.42 (dd, J ) 9.9,
2.1 Hz, 1H), 4.54 (dd, J ) 4.7, 3.9 Hz, 1H), 4.62 (d, J ) 3.9 Hz,
1H), 5.16 (s, 2H), 5.91 (d, J ) 3.9 Hz, 1H), 7.25-7.44 (m, 5H);
13C NMR (75 MHz, CDCl3) δ 26.2, 26.6, 36.7, 54.8, 55.6, 67.6,
70.5, 73.6, 81.9, 85.1, 104.3, 111.5, 127.9 (s), 128.2, 128.5 (s),
135.9, 156.7. Anal. Calcd for C19H25NO7: C, 60.15; H, 6.64.
Found: C, 60.24; H, 6.78.
(2R,6S,7R,8R,8aS)-2,6,7,8-Tetrahydroxy-indolizidine
(3c). Purification by column chromatography (chloroform/
methanol ) 50/50) afforded 3c (0.04 g, 80%) as a thick liquid;
Rf 0.39 (methanol); [R]D -32.0 (c 0.37, MeOH); IR (Neat) 3450-
3200 cm-1 1H NMR (300 MHz, D2O) δ 1.66 (ddd, J ) 13.7,
;
6.0, 1.4 Hz, 1H), 2.16 (ddd, J ) 13.7, 12.0, 8.2 Hz, 1H), 2.35
(dd, J ) 11.5, 5.5 Hz, 1H), 2.65 (dd, J ) 12.2, 3.3 Hz, 1H),
2.72 (dd, J ) 12.2, 5.6 Hz, 1H), 3.04 (ddd, J ) 12.0, 6.0, 3.6
Hz, 1H), 3.34 (dd, J ) 11.5, 7.1 Hz, 1H), 3.69 (dd, J ) 5.6, 3.6
5,6,8-Trideoxy-5,8-(N-benzoxycarbonylimino)-1,2-O-
isopropylidene-7(R)-hydroxy-â-L-glycero-L-ido-oct-1,4-
1362 J. Org. Chem., Vol. 70, No. 4, 2005

2-Hydroxy-1-deoxycastanospermine Analogues
Hz, 1H), 3.74 (t, J ) 5.6 Hz, 1H), 3.82 (dt, J ) 5.6, 3.3 Hz,
1H), 4.47-4.58 (m, 1H); 13C NMR (75 MHz, D2O) δ 33.3, 52.8,
60.6, 62.0, 68.2, 69.2, 69.6, 70.5. Anal. Calcd for C8H15NO4: C,
50.75; H, 7.98. Found: C, 50.92; H, 8.16.
4.3 Hz, 1H), 2.64 (dd, J ) 13.2, 2.5 Hz, 1H), 2.79 (ddd, J )
8.0, 5.5, 2.0 Hz, 1H), 3.23 (br d, J ) 13.2 Hz, 1H), 3.71 (dd, J
) 10.5, 6.7 Hz, 1H), 4.94 (dd, J ) 5.0, 3.2 Hz, 1H), 5.00-5.08
(m, 2H), 4.15-4.24 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 20.9
(s), 21.1, 21.3, 33.1, 51.9, 58.7, 60.5, 67.0, 67.3, 67.7, 71.2, 168.5,
170.1 (s), 170.6. Anal. Calcd for C16H23NO8: C, 53.78; H, 6.49.
Found: C, 54.00; H, 6.62.
(2S,6S,7R,8R,8aS)-2,6,7,8-Tetraacetoxyindolizidine (9d).
Purification by column chromatography (n-hexane/ethyl ace-
tate ) 70/30) afforded 9d (0.047 g, 85%) as a thick liquid; Rf
0.28 (n-hexane/ethyl acetate 1/1); [R]D -5.3 (c 0.75, CHCl3);
IR (Neat) 1726 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.75 (ddd,
J ) 13.2, 11.7, 5.4 Hz, 1H), 2.07 (s, 3H), 2.12 (s, 3H), 2.19 (s,
3H), 2.21 (s, 3H), 2.29 (ddd, J ) 13.2, 8.4, 5.7 Hz, 1H), 2.45-
2.56 (m, 3H), 3.18 (d, J ) 11.1 Hz, 1H), 3.20 (dd, J ) 13.5, 1.5
Hz, 1H), 4.91 (d, J ) 1.5 Hz, 1H), 4.99 (t, J ) 1.8 Hz, 1H),
5.03 (t, J ) 2.7 Hz, 1H), 5.17 (dd, J ) 13.5, 6.0 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 20.8, 20.8, 21.1, 21.2, 32.8, 51.9, 60.0,
60.1, 67.1, 67.2, 67.8, 71.3, 168.4, 170.0, 170.1, 171.0. Anal.
Calcd for C16H23NO8: C, 53.78; H, 6.49. Found: C, 53.82; H,
6.59.
(2S,6S,7R,8R,8aS)-2,6,7,8-Tetrahydroxyindolizidine (3d).
Purification by column chromatography (chloroform/methanol
) 30/70) afforded 3d (0.039 g, 79%) as a thick liquid; Rf 0.18
(methanol); [R]D +35.5 (c 0.45, MeOH); IR (Neat) 3435-3220
1
cm-1; H NMR (300 MHz, D2O) δ 1.34 (dt, J ) 14.2, 4.8 Hz,
1H), 2.33 (dt, J ) 14.2, 7.5 Hz, 1H), 2.90-3.06 (m, 2H), 3.08-
3.25 (m, 3H), 3.74-3.85 (narrow m, 3H), 4.45-4.50 (m, 1H);
13C NMR (75 MHz, D2O) δ 33.1, 53.0, 61.4, 63.2, 67.3, 68.0(s),
68.8. Anal. Calcd for C8H15NO4: C, 50.75; H, 7.98. Found: C,
50.86; H, 8.08.
General Procedure for 3 to 9. To an ice-cooled solution
of 3 (0.03 g, 0.15 mmol) in dry pyridine (0.4 g, 4.4 mmol) was
added acetic anhydride (1.0 g, 10.0 mmol) and DMAP (0.0019
g, 0.015 mmol) and the mixture was stirred for 12 h at room
temperature. The reaction was decomposed with cold water
(2 mL) and extracted with chloroform (3 × 5 mL). The usual
work up afforded a thick oil.
(2S,6S,7R,8R,8aR)-2,6,7,8-Tetraacetoxyindolizidine (9a).
Purification by column chromatography (n-hexane/ethyl ace-
tate ) 80/20) afforded tetraacetate 9a (0.045 g, 80%) as a white
solid; mp 105-106 °C; Rf 0.25 (n-hexane/ethyl acetate ) 7/3);
[R]D +17.1 (c 1.05, CHCl3); IR (Nujol) 1732 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.88-2.20 (m, 2H), 2.04 (s, 12H), 2.24 (t, J )
10.5 Hz, 1H), 2.32 (dd, J ) 10.0, 4.5 Hz, 1H), 2.53 (dt, J ) 9.3,
6.3 Hz, 1H), 3.30 (dd, J ) 10.5, 5.1 Hz, 1H), 3.60 (dd, J ) 10.0,
6.9 Hz, 1H), 4.84 (t, J ) 9.3 Hz, 1H), 5.01 (ddd, J ) 15.0, 9.9,
5.4 Hz, 1H), 5.09 (t, J ) 9.3 Hz, 1H), 5.13-5.22 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 20.7 (s), 20.8, 21.0, 36.5, 51.9, 59.3,
63.2, 70.3, 72.6, 73.4, 74.3, 169.8, 170.0, 170.3, 170.5. Anal.
Calcd for C16H23NO8: C, 53.78; H, 6.49. Found: C, 53.90; H,
6.61.
(2R,6S,7R,8R,8aR)-2,6,7,8-Tetraacetoxyindolizidine (9b).
Purification by column chromatography (n-hexane/ethyl ace-
tate ) 80/20) afforded 9b (0.045 g, 80%) as a thick liquid; Rf
0.29 (n-hexane/ethyl acetate ) 7/3); [R]D +13.3 (c 0.45, CHCl3);
IR (Neat) 1738 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.71 (ddd,
J ) 13.8, 9.6, 3.8 Hz, 1H), 2.02 (s, 6H), 2.03 (s, 3H), 2.06 (s,
3H), 2.11 (t, J ) 10.5 Hz, 1H), 2.27 (ddd, J ) 9.3, 7.8, 6.6 Hz,
1H), 2.43 (ddd, J ) 13.8, 7.8, 6.6 Hz, 1H), 2.56 (dd, J ) 11.0,
6.3 Hz, 1H), 3.12 (d, J ) 11.0 Hz, 1H), 3.33 (dd, J ) 10.5, 4.6
Hz, 1H), 4.98 (t, J ) 9.3 Hz, 1H), 5.09 (t, J ) 9.3 Hz, 1H),
5.05-5.18 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 20.7 (s), 20.8,
21.1, 36.4, 52.1, 59.4, 64.6, 70.3, 72.5, 73.4, 74.6, 169.9, 170.0,
170.4, 171.4. Anal. Calcd for C16H23NO8: C, 53.78; H, 6.49.
Found: C, 53.87; H, 6.52.
Procedure for Inhibition Assay. Inhibition potencies of
the castanospermine analogues 3a-d were determined by
measuring the residual hydrolytic activities of the glycosidases.
The substrates (Purchased from Sigma Chemicals Co. USA.)
p-nitrophenyl-R-D-glucopyranoside, p-nitrophenyl-â-D-glucopy-
ranoside, p-nitrophenyl-â-D-galactopyranoside, and p-nitro-
phenyl-R-D-galactopyranoside, of 2 mM concentration, were
prepared in 0.025 M citrate buffer with pH 6.0, and p-nitro-
phenyl-R-D-mannopyranoside, of 2 mM concentration, was
prepared in 0.025 M citrate buffer with pH 4.0. The test
compound (of various concentrations of 0.5 µM to 1 mM) was
preincubated with the enzyme, buffered at its optimal pH, for
1 h at 25 °C. The enzyme reaction was initiated by the addition
of 100 µL of substrate. Controls were run simultaneously in
the absence of test compound. The reaction was terminated
at the end of 10 min by the addition of 0.05 M borate buffer
(pH 9.8) and absorbance of the liberated p-nitrophenol was
measured at 405 nm with a Shimadzu Spectrophotometer UV-
1601. One unit of glycosidase activity is defined as the amount
of enzyme that hydrolyzed 1 µmol of p-nitrophenyl pyranoside
per minute at 25 °C.
Acknowledgment. We are grateful to Prof. M. S.
Wadia for helpful discussions. We are thankful to CSIR,
New Delhi (No. 01(1906)/03/EMR-II) for the financial
support and UGC, New Delhi for the grant to purchase
the high-field (300 MHz) NMR facility.
(2R,6S,7R,8R,8aS)-2,6,7,8-Tetraacetoxyindolizidine (9c).
Purification by column chromatography (n-hexane/ethyl ace-
tate ) 70/30) afforded 9c (0.048 g, 86%) as a thick liquid; Rf
0.56 (ethyl acetate); [R]D +5.7 (c 0.70, CHCl3); IR (Neat) 1730
Supporting Information Available: General experimen-
tal methods, crystallographic data for 5a and 5d, and copies
1
of H and 13C NMR spectra of compounds 3a-d, 5a-d, 6a-
d, 7a,b, 8a-d, and 9a-d. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.81 (ddd, J ) 13.7, 5.5,
1.1 Hz, 1H), 2.05 (ddd, J ) 13. 7, 11.2, 8.0 Hz, 1H), 2.07 (s,
3H), 2.15 (s, 3H), 2.16 (s, 3H), 2.19 (s, 3H), 2.21 (dd, J ) 10.5,
JO048176X
J. Org. Chem, Vol. 70, No. 4, 2005 1363