A short and efficient synthesis of 1-deoxy-castanospermine and 1-deoxy-8a-epi-castanospermine

Article abstract of DOI:10.1016/S0040-4039(00)02103-1

A new route for the synthesis of 1-deoxy-castanospermine 2 and 1-deoxy-8a-epi-castanospermine 3 has been developed via a sequential triple reductive amination process of a suitably protected D-gluco-oct-5-ulo-1,8-dialdose, which was easily prepared by three carbon homologation of readily available α-D-xyclo-pentodialdose using an appropriate Grignard reagent followed by oxidation.

Full text of DOI:10.1016/S0040-4039(00)02103-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 747–749
A short and efficient synthesis of 1-deoxy-castanospermine and
1-deoxy-8a-epi-castanospermine
Nitin T. Patil, Jayant N. Tilekar and Dilip D. Dhavale*
Department of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
Received 25 August 2000; revised 9 November 2000; accepted 15 November 2000
Abstract—A new route for the synthesis of 1-deoxy-castanospermine 2 and 1-deoxy-8a-epi-castanospermine 3 has been developed
via a sequential triple reductive amination process of a suitably protected D-gluco-oct-5-ulo-1,8-dialdose, which was easily
prepared by three carbon homologation of readily available a-D-xylo-pentodialdose using an appropriate Grignard reagent
followed by oxidation. © 2001 Elsevier Science Ltd. All rights reserved.
The synthesis of polyhydroxylated indolizidine alka-
loids such as castanospermine 1 and 1-deoxy-cas-
tanospermine 2 is a fascinating area of research.1,2 Due
to their promising glycosidase inhibitory activity, these
compounds are potential chemotherapeutic agents for
the treatment of diabetes, obesity, cancer and AIDS.3
Amongst various stereoisomers of castanospermine, the
structural assignment of 1-deoxy-8a-epi-castanosper-
mine 3 was in doubt.4,5 As a part of our continuing
efforts in the synthesis of polyhydroxylated piperidine
alkaloids,6 we are now reporting the synthesis of 1-
deoxy-castanospermine 2 and 1-deoxy-8a-epi-castano-
spermine 3. As per our visualisation (Scheme 1), the
synthesis of 2 or 3 involves the sequential triple reduc-
tive amination of a suitably protected D-gluco-oct-5-
ulo-1,8-dialdose. The addition of the requisite three
carbon Grignard reagent to the readily available a-D-
xylo-pentodialdose 4 followed by oxidation would give
an easy access to D-gluco-oct-5-ulo-1,8-dialdose.
The reaction of a-D-xylo-pentodialdose6a 4 with the
Grignard reagent prepared from magnesium and 2-(2-
bromoethyl)-1,3-dioxolane in THF, afforded
a
diastereomeric mixture of the C5-carbinols which was
Scheme 1.
Keywords: alkaloids; indolizidine; enzyme inhibitors; Grignard reaction.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02103-1

748
N. T. Patil et al. / Tetrahedron Letters 42 (2001) 747–749
Scheme 2. Reagents and conditions: i, Mg, 2-(2-bromoethyl)-1,3-dioxolane (1.2 equiv.), Et2O, −78°C to rt, 6 h, 90%. ii, DMSO,
(COCl)2, Et3N, CH2Cl2, −78°C to rt, 4 h, 92%. iii, 80% aq. acetic acid, 70°C, 2 h, 80%. iv, Ph2CHNH2 (1.1 equiv.), AcOH (1.1
equiv.), NaCNBH3 (2.5 equiv.), MeOH, −78°C to rt, 12 h, 95%. v, 10% Pd/C, H2, MeOH, 80 Psi, 20 h. vi, CbzCl (1.1 equiv.),
NaHCO3, EtOH–H2O (8:2), 2 h, 85%. vii, TFA–H2O (3:2), rt, 2 h. viii, 10% Pd/C, H2, MeOH, 80 Psi, 90%.
directly subjected to Swern oxidation to give 5† in 92%
yield (Scheme 2). Selective deprotection of the acetal
functionality (80% AcOH) afforded 1,2-O-isopropyli-
dene-3-O-benzyl-D-gluco-oct-5-ulo-1,8-dialdose 6.7
Treatment of 6 with aminodiphenylmethane, in the
presence of sodium cyanoborohydride and acetic acid
in methanol gave an inseparable diastereomeric mixture
of 7a and 7b in the ratio of 45:55. In the subsequent
step, hydrogenolysis gave a mixture of the amino alco-
hols which was directly reacted with CbzCl in ethanol
and 5,6,7,8-tetradeoxy-5,8-(N-benzoxycarbonylimino)-
1,2-O-isopropylidene-a-D-gluco-oct-1,4-furanose 8a and
its C5-epimer b-L-ido-oct-1,4-furanose 8b were isolated
by chromatographic purification in 38% and 47% yield,
respectively.8 The specific rotation† of 8a was found to
be in agreement with that reported2b however, 8b was
independently characterised by spectral and analytical
data.† Treatment of 8a with TFA–H2O followed by
hydrogenation gave 1-deoxy-castanospermine 2.
Analogously, reaction of 8b with TFA–H2O followed
by hydrogenation afforded 1-deoxy-8a-epi castanosper-
mine 3 in good yield. The rotation, spectral and analyt-
ical data† for 2 and 3 were found to be in good
agreement with those reported.9
† Selected physical data for 5: thick liquid, [h]D=−69.30 (c 0.92,
CHCl3); wmax (Nujol) 1718 cm−1 lH (CDCl3, 300 MHz): 1.32 (3H, s,
CH3), 1.47 (3H, s, CH3), 1.85–2.03 (2H, m, CH2), 2.70–2.85 (2H, m,
CH2), 3.70–3.98 (4H, m, CH2), 4.27 (1H, d, J 3.6 Hz, H-2), 4.46 (1H,
d, J 11.7 Hz, OCH2Ph), 4.57 (1H, d, J 11.7 Hz, OCH2Ph), 4.59 (1H,
d, J 3.7 Hz, H-3), 4.67 (1H, d, J 3.7 Hz, H-4), 4.88 (1H, t, J 4.5 Hz,
H-8), 6.06 (1H, d, J 3.6 Hz, H-1), 7.18–7.40 (5H, m, ArH). lc
(CDCl3, 75 MHz): 26.2, 26.7, 26.8, 34.5, 64.8, 72.3, 81.7, 83.6, 85.3,
103.3, 105.8, 112.2, 127.6, 127.9, 128.4, 136.8, 207.5. Anal. Calcd for
C20H26O7: C, 63.48; H, 6.93. Found C, 63.70; H, 6.70. For 8a: thick
liquid; [h]D=+29.00 (c 0.56, CHCl3); wmax (Neat) 3366, 1675 cm−1; lH
(CDCl3, 300 MHz): 1.31 (3H, s, CH3), 1.49 (3H, s, CH3), 1.84–2.05
(3H, m, H-6/H-7), 2.09–2.15 (1H, m, H-6/H-7), 3.38–3.45 (2H, m,
N-CH2), 3.80 (1H, dd, J=10.2, 1.8 Hz, H-4), 4.02 (1H, d, J 1.8 Hz,
H-3), 4.14 (1H, dt, J 10.2, 6.2 Hz, H-5), 5.26 (1H, bs, exchanges with
D2O, OH), 4.59 (1H, d, J 3.7 Hz, H-2), 5.14 (2H, ABq, J 12.5 Hz,
OCH2Ph), 5.90 (1H, d, J 3.7 Hz, H-1), 7.26–7.38 (5H, m, ArH). lc
(CDCl3, 75 MHz): 23.0, 26.1, 27.1, 28.2, 48.8, 59.9, 68.1, 73.9, 81.0,
85.0, 105.2, 112.3, 128.0, 128.4, 129.1, 136.0, 157.1. Anal. Calcd for
The coupling constant J8,8a is important in the determi-
nation of the configuration at C8a while, the conforma-
tion of 3 could be determined by the coupling constant
values between H5, H6, H7, and H8. The initial geome-
try in the precursor 8b ensures that, in the product 3 the
substituents at C6, C7 and C7, C8 should be trans. The
comparison of 1H NMR spectra of 2 and 3 revealed the
downfield shift of all the protons in 3 with respect to
the corresponding protons in 2 (Table 1). This is indica-
tive of equatorial orientation of these protons in 3 as
against axial as noted for 2. In this case of 3 H6
appeared as a broad singlet at l 4.55 while H7 and H8
were found to be accidentally equivalent and showed
broad singlet at l 4.42. This indicated that J6,7 and J8,8a
are small values (WHꢀ5 Hz) suggestive of the equato-
rial orientation of these protons. The small value of
J8,8a along with the axial orientation of C8-OH, sug-
gests that the C8a substituent is equatorial with the
C8a(S) configuration accounting for the structure of
1-deoxy-8a-epi-castanospermine 3. This observation is
C
19H25NO6: C, 62.79; H, 6.93. Found: C, 62.68; H, 6.81. For 8b:
thick liquid; [h]D=−72.27 (c 0.44, CHCl3); wmax (Neat) 3390, 1693
cm−1; lH (300 MHz): 1.30 (3H, s, CH3), 1.48 (3H, s, CH3), 1.82–1.94
(2H, m, H-6/H-7), 1.96–2.20 (2H, m, H-6/H-7), 3.42–3.58 (2H, m,
NCH2), 4.0 (1H, t, J=3.0 Hz, H-4), 4.13 (1H, d, J=2.9 Hz, H-3),
4.26–4.34 (1H, m, H-5), 4.48 (1H, d, J=3.6 Hz, H-2), 5.13 (2H, ABq,
J=12.3 Hz, OCH2Ph), 5.87 (1H, d, J=3.6 Hz, H-1), 7.24–7.42 (5H,
m, ArH). lc (75 MHz): 23.6, 26.1, 26.7, 29.7, 47.2, 55.5, 67.5, 75.7,
84.0, 85.0, 104.5, 111.2, 127.8, 128.0, 128.4, 136.3, 158.7. Anal. Calcd
for C19H25NO6: C, 62.79; H, 6.93. Found C, 62.80; H, 6.79. For 2
mp: 176–178°C (reported 178–181°C)2b, [h]D=+50.10 (c 0.7, MeOH)
[reported +50.6 (c 0.2, MeOH)].2b For 3: semisolid; [h]D=+23.0 (c
0.72, MeOH) [reported +22.5 (c 1.13, MeOH)5a–b]; wmax (KBr) 3360–
3250 cm−1 (broad band); lH (300 MHz, pyridine-d5+D2O): 1.72–2.00
(3H, m, H-1/H-2), 2.22–2.40 (1H, m, H-1/H-2), 2.84–3.00 (1H, m,
H-3), 3.44 (1H, bd, J=12.3 Hz, H-5), 3.49–3.67 (2H, m, H-8a and
H-3), 3.69 (1H, bd, J=12.3 Hz, H-5), 4.42 (2H, bs, H-7 and H-8),
4.55 (1H, bs, H-6). lc (125 MHz, pyridine-d5): 21.1, 24.5, 54.7, 55.5,
64.6, 70.5, 70.7, 70.9. Anal. Calcd for C8H15NO3: C, 55.47; H, 8.73.
Found C, 55.80; H, 9.02.

N. T. Patil et al. / Tetrahedron Letters 42 (2001) 747–749
Table 1. Comparison of H NMR spectra of 2 and 3
749
1
H5a
H5e
H6
H7
H8
H8a
2
3
2.30 (t)
3.43 (dd)
4.33 (ddd)
3.91 (t)
3.86 (t)
2.94 (dt) J8a,1a=8.6 Hz J8a,1e=2.0
Hz
3.49–3.67 (m, 2H)
J5a,5e=J5a,6a=10.5 Hz
J
5e,6a=5.2 Hz
3.69 (bd)
5a,5e=12.3 Hz
J6,7=8.6 Hz
J
7,8=8.6 Hz
J
8,8a=8.6 Hz
3.44 (bd) J5a,5e=12.3
Hz
4.55 (bs, 1H)
4.42 (bs, 2H)
J
further supported by the observed two doublets at l
3.44 and 3.69 (J5e,5a=12.3 Hz) for the protons H5a and
H5e wherein, the absence of J5a,6e and J5e,6e is sugges-
tive of the fact that H6 is equatorial and bisecting the
H5 protons. Based on those data the conformation
assigned for 3 was C8 while that of 2 was C5 as shown
in 3a and 2a, respectively.
R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asym-
metry 2000, 11, 1645.
4. Martin and co-workers claimed the synthesis of 3 however,
the subsequent paper from the same group stated that the
compound reported was not 3 but its diastereomer namely
1-deoxy-8-epi-castanospermine. (a) Martin, S. F.; Chen,
H.; Yang, C-P. J. Org. Chem. 1993, 58, 2867. (b) Martin,
S. F.; Chen, H.; Lynch, V. M. J. Org. Chem. 1995, 60, 276.
5. The other report by Denis and Chan also described the
synthesis of 3. Nevertheless, in their paper, the characteri-
sation of structure for 1-deoxy-8a-epi-castanospermine,
5
8
In conclusion, we have demonstrated an efficient
method for the synthesis of 1-deoxy-castanospermine 2
and 1-deoxy-8a-epi-castanospermine 3. The easy
availability of the chiral starting materials, mild reac-
tion conditions and good yields make the route attrac-
tive and indicate that it could operate on a gram scale.
1
based on H NMR analysis, was doubtful (a) Denis, Y. S.;
Chan, T.-H. J. Org. Chem. 1992, 57, 3078. Only recently
they have revised their stereochemical assignment for 3 (b)
Denis, Y. S.; Chan, T.-H. Can. J. Chem. 2000, 78, 776
6. (a) Desai, V. N.; Saha, N. N.; Dhavale, D. D. J. Chem.
Soc., Chem. Commun. 1999, 1719; (b) Dhavale, D. D.;
Saha, N. N.; Desai, V. N. J. Org. Chem. 1997, 62, 7482; (c)
Dhavale, D. D.; Desai, V. N.; Sindkhedkar, M. D.; Mali,
R. S.; Castellari, C.; Trombini, C. Tetrahedron: Asymmetry
1997, 8, 1475.
Acknowledgements
We gratefully acknowledge the financial support from
BRNS, Mumbai. NTP is thankful to CSIR, New Delhi
for JRF.
7. At this stage, compound 6 was reacted with TFA–H2O to
cleave the acetal as well as the 1,2-acetonide groups and
the product obtained was subjected to one pot triple
reductive amination to get indolizidine ring skeleton. This
process, however, gave complex mixture of products.
8. The assignment of stereochemistry at C5 was made by
References
1. (a) For a review, see: Burgess, K.; Henderson, I. Tetra-
hedron 1992, 48, 4045. (b) Denmark S. E.; Herbert B. J.
Org. Chem. 2000, 65, 2887 and references cited therein.
2. (a) Yoda, H.; Nakajima, T.; Takabe, K. Synlett 1997, 911;
(b) Hendry, D.; Hough, L.; Richardson, A. C. Tetrahedron
1988, 44, 6143; (c) Martin, S. F.; Chen, H.-J.; Yang, C.-P.
J. Org. Chem. 1993, 58, 2867; (d) Izquierdo, I.; Plaza, M.
T.; Robles, R.; Rodriguez, C.; Ramirez, A.; Mota, A. J.
Eur. J. Org. Chem. 1999, 64, 1269.
1
comparison of H NMR data of 8a and 8b and confirmed
by conversion of 8a to known compound 2.
9. Although, our rotation value and 13C NMR data of 3
match with that reported by Denis and Chan,5a,b there is a
1
discrepancy in the H NMR data probably due to solvent
shift. Denis and Chan reported the 1H NMR of 3 in
methanol-d4. It may be noted that methanol-d4 itself shows
two signals at l 3.31 and 4.80, which obscure the signals
due to compound 3. In addition, exchange of HC-OH
protons of 3, with methanol-d4, also gives signal at l 4.84
due to HDO.
3. (a) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical
and Biological Perspectives; Pelletier, S. W., Ed.; Wiley:
New York, 1987; Vol. 5, pp. 1–54; (b) Asano, N.; Nash,
.
.