A concise stereoselective synthesis of (+)-1-deoxy-6-epi-castanospermine

Article abstract of DOI:10.1016/j.tetlet.2016.02.080

A concise stereoselective synthesis of (+)-1-deoxy-6-epi-castanospermine has been developed through stereoselective approach from the chiral precursor R-Glycidol. The key steps in the synthesis involve Grignard reaction through Weinreb amide, followed by Sharpless dihydroxylation and stereoselective reduction of imine assigned the required stereochemical feature of indolizidine azasugar (+)-1-deoxy-6-epi-castanospermine.

Full text of DOI:10.1016/j.tetlet.2016.02.080

Accepted Manuscript
A concise stereoselective synthesis of (+)-1-deoxy-6-epi-castanospermine
Vikas S. Gajare, Sandip R. Khobare, Rajender Datrika, K. Srinivasa Reddy,
Nagaraju Rajana, B. Kishore Babu, B. Venkateswara Rao, U.K. Syam Kumar
PII:
S0040-4039(16)30189-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.080
TETL 47355
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 December 2015
18 February 2016
19 February 2016
Please cite this article as: Gajare, V.S., Khobare, S.R., Datrika, R., Srinivasa Reddy, K., Rajana, N., Kishore Babu,
B., Venkateswara Rao, B., Syam Kumar, U.K., A concise stereoselective synthesis of (+)-1-deoxy-6-epi-
castanospermine, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.080
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1
Tetrahedron Letters
A concise stereoselective synthesis of (+)-1-deoxy-6-epi-castanospermine
aTechnology Development Center, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Miyapur, Hyderabad 500049, India.
bIntegrated Product Development Organization, Dr. Reddys Laboratories, Innovation Plaza, Bachupally, Telangana, 500072, India.
cAU College of engineering (A), Andhra University, Visakhapatanum 530003, India
Fax: +914044658705
E-mail: vikassadashivg@drreddys.com
Received: The date will be inserted once the manuscript is accepted.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise stereoselective synthesis of (+)-1-deoxy-6-epi-castanospermine have been
developed through stereoselective approach from the chiral precursor R-Glycidol. The
key steps in the synthesis involves Grignard reaction through Weinreb amide, followed by
Sharpless dihydroxylation and stereoselective reduction of imine assigned the required
stereochemical feature of indolizidine azasugar (+)-1-deoxy 6-epi-castanospermine.
Available online
Keywords:
Asymmetric synthesis
Azasugar
2009 Elsevier Ltd. All rights reserved.
Wittig reaction
Sharpless dihydroxylation
Polyhydroxy Indolizidine
Indolizidine alkaloids possessing azabicyclic structure are
widely spread in nature and embrace a wide range of
structural and stereochemical feature. Polyhydroxy
indolizidine alkaloids (+) Castanospermine (1), (+)
Swainosonine (2), (+) Letigenosine (3) etc. are the
important natural azasugar found in many plant and shown
racemic synthesis of 1-deoxy-6-epi-Castanospermine are
reported by John et al from the hetero-Diels–Alder adduct
of diethyl 2-nitrosoacrylate.11 Herewith we disclosed the
novel and concise stereoselective approach toward the
synthesis of (+)-1-deoxy-6-epi-Castanospermine (5) starting
from (R)-glycidol.
wide
range
of
biological
activity
(figure1).
OH
OH
Castonospermine (1) was first isolated from the seeds of
Castanospermum austral1 and shown potent glycosidase
inhibitory activity,2 the rigid bicyclic structure of this
molecule are suggested for their potent biological activity.3
As the study progress Castanospermine (1), 1-deoxy
Castanospermine (4) and their stereoisomers are evaluated
in various form of biological activity includes antiviral,4
anticancer,5 antidiabetics, antiobesity6 etc. Among those
isomers (-)-1-deoxy-6-epi-castanospermine (6) found
lysosomal α-mannosidase inhibitory activity in competitive
way.7 Though this compound has shown excellent
biological activity, there are only few synthesis reported in
literature for chirally pure 1-deoxy-6-epi-Castanospermine.
The placement of four different stereo center in continuous
manner make these synthesis challenging.
H
HO
OH
H
H
OH
N
OH
OH
N
OH
N
OH
1
2
3
OH
OH
OH
HO
OH
HO
OH
H
HO
OH
H
H
N
N
N
4
5
6
Richardson et al has reported the synthesis of (-)-1-deoxy-6-
epi-castanospermine (6) from derivative of β-D-
fructopyranoside.8 Meyers et al synthesized (+)-1-deoxy-6-
epi-castanospermine (5) from 1,3-cyclohexane dione and
(S)-Phenyl glycinol.9 Young-Ger Suh and coworker’s
Figure1. Naturally occurring and synthetic analogue of
polyhydroxy indolizidine.
The retro synthetic design for the asymmetric synthesis of
(+)-1-deoxy-6-epi-Castanospermine (5) is depicted in
Scheme 1. The 1-deoxy-6-epi-Castanospermine (5) could
reported the synthesis of
6
from N-acyl-α-
alkoxyvinylpyrrolidines via aza-Claisen rearrangemt.10 The

Tetrahedron Letters
2
be obtained by Mitsunobu cyclization of 1-deoxy
OH
a
O
homonojiromycin derivative (19). The compound 19 could
be synthesized from 15 by global deprotection and in situ
reductive amination reaction. The dihydroxylated
compound 15 could be easily obtained from 14 by Sharpless
dihydroxylation. The trans α, β unsaturated ketone could be
obtained from 14 via Weinreb amide and Grignard reaction.
The protected trans α, β unsaturated ester 12 could be
obtained form 9 by selective oxidation, Wittig reaction and
protection of N-Cbz and free allylic hydroxyl group. N-Cbz
glycidine 9 could be obtained as per literature procedure
from R-Glycidol (7) and ammonia followed by N-Cbz
protection.
OH
H2N
OH
7
8
OH
OH
b
H
N
H
N
O
OH
Cbz
Cbz
9
10
OH
H
c
N
O
Cbz
O
11
OH
OH
O
O
O
N
HO
OH
H
HO
OH
d
N
N
Cbz
Cbz
O
OH
N
N
H
O
O
12
13
19
5
Scheme 2. (a) (i) Aq. Ammonia, 0 °C, 24h (ii) CbzCl, THF-
Water, NaHCO3, 0 °C, 70% (two step) (b) (i) TCCA/TEMPO,
EA, 5 °C, (ii) Ph3PCH=CHCOOEt, DCM, RT, 3h, 50% (Two
step) (c) Acetone-2,2’DMP, Cat. BF3.Et2O, RT, 1 h, 86% (d)
HCl.NH(OCH3)CH3, i-PrMgCl, -20 to -15 °C, 1h, 83%.
O
OH
N
Cbz
OBn
OH
15
O
O
O
The next reaction which was needed Grignard substrate, 3-
benzyloxy-1-bromopropanol was prepared starting from
1,3-propane diol as per literature protocol.15 The 3-
benzyloxy Magnesium bromide was prepared freshly from
3-benzyloxy-1-bromopropanol with Mg in dry THF at
ambient temperature. When the Grignard reaction of 3-
benzyloxy Magnesium bromide attempted on 13 in THF,
the reaction rate was too slow. Even the excess mol euiv of
Grignard substrate or at elevated temperature failed to
achieve the satisfactory yield, conversion was less than
20%. When reaction solvent switched to diethyl ether at 0
°C to 30 °C, the reaction was completed in 1h and the
required product 14 was isolated with 81% yield. The
required stereochemistry in dihydroxylation was achieved
by Sharpless dihydroxylation reaction with AD-mix-α at 0
°C to afford 15 with 75% yield.16 The reaction was highly
stereoselective and the other isomer was observed very less
(98% de) which was separated by column chromatography.
To construct the piperidine skeleton we followed the
cascade approach for deprotection and cyclization as per the
literature procedure. The deprotection of acetonide by using
catalytic p-TSA in methanol, followed by N-Cbz
deprotection, cyclization and reductive amination using
H2/Pd/C17 or H2/Pd(OH)2/C18 along with aqueous HCl. But
in our study this cascade approach was failed to get desired
product and end up with mixtures of isomers, therefore we
proceed in stepwise approach. In first the acetonide was
deprotected with catalytic p-TSA in methanol and after the
usual work up the crude 16 was taken for next conversion.
In next, the deprotection of N-Cbz, cyclization and
reductive amination was carried out in Pd(OH)2/C and 2M
HCl under hydrogen atmosphere, but we end up imine 18
with 75% yield. When we increased the concentration of
HCl, the substrate was degraded and end up with a complex
mixture. Our different attempt to reduce the imine 18,
which include Pd(OH)2 or Pd/C in neutral and basic
condition ruled out to give the required product 19. So
finally the crude imine 18 was reduced with sodium
cyanoborohydride in methanol and acetic acid which gave
the required product 19, the stereochemistry was confirmed
N
Cbz
N
Cbz
O
OBn
O
O
14
12
OH
H
O
N
OH
OH
Cbz
7
9
Scheme 1. Retro synthetic analysis
The synthesis of (+)-1-deoxy-6-epi-Castonaspermine (5)
began using commercially viable enantiomerically pure (R)-
glycidol (7). Thus reaction of (R)-glycidol and ammonia
carried out at 0 °C for 24 h to form 2-amino glycidine 8
which was in situ protected with CbzCl in presence of
sodium bicarbonate to provide 9.12 The trans α, β-
unsaturated ester 11 was obtained by selective oxidation13a
and wittig reaction as per our previous reported protocol
with 50% yield.13 The acetonide protection of amide and
allylic hydroxy of 11 was carried out in acetone-2,2’ DMP
mixture by using catalytic BF3.Et2O with 86% yield of 12.
The Weinreb amide 13 was synthesized from α, β-
unsaturated ester 12 using Bourdox reaction condition at -
20 to -15 °C with 83% yield.14 (Scheme 2).

Tetrahedron Letters
3
at the final compound . The compound 19 was purified by
acidic resin and immediately converted to the final product
using the Mitsunobu’s approach by intramolecular
cyclization of secondary amine and primary hydroxyl.19 The
reaction was carried out with triphenyl phosphine and DIED
at 0 °C for 3h and the required product (+)-1-deoxy-6-epi-
castanospermine (5) was isolated as a thick oil with 43%
yield from crude 18 (Scheme 3). The spectral data of the
isolated product 5 was comparable with the literature
22
value,20 [α]D = +22.5° (c 0.05, MeOH), lit8 [α]D = +23°
(MeOH) and enantiomer of 5 lit10 [α]D = -25.2° (c 0.25,
MeOH).
23
Figure2. NOE effect of indolizidine 5
In conclusion, a new synthetic stereoselective approach for
the construction of polyhydroxylated indolizidine, 1-deoxy-
6-epi-castanospermine have been developed from readily
accessible starting materials in moderate to good yields. The
azabicyclic imino sugar synthesis involves many in situ
conversion includes Sharpless dihydroxylation, Grignard
reaction and asymmetric imine reduction. This synthetic
approach can be useful to synthesize other polyhydroxy
alkaloid analogues.
O
O
N
O
a
N
N
Cbz
Cbz
OBn
O
O
13
14
O
OH
c
b
N
Cbz
OBn
OH
O
15
Acknowledgments
OH
OH OH
H
N
HO
OH
d
The authors would like to thank Dr. Vilas Dahanukar and
Dr. H. Ramamohan of Dr. Reddy’s Laboratories for useful
discussions. We also thank the analytical department, Dr.
Reddy’s Laboratories, for providing the analytical support.
Cbz
OBn
OBn
OH
O
N
16
17
OH
OH
HO
OH
Note: DRL-IPD communication No.: IPDO IPM-00493
HO
OH
e
OH
OH
N
H
References and notes
N
18
19
1.
2.
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Phytochemistry 1990, 29, 107.
OH
HO
OH
H
f
N
5
Scheme3. (a) (i) 1-((3-bromopropoxy)methyl)benzene, Mg,
Dry THF, (ii) Diethyl ether, 0 to 30 °C, 1h, 81%. (b) AD mix α,
Ke3Fe(CN)6, MeSO2NH2, K2CO3, NaHCO3, OsO4, t-BuOH-
Water, 0 °C, 18 h, 75%. (c) p-TSA, MeOH, RT, 16 h, (d) H2,
Pd(OH)2/C, methanol, RT, 8 h then 2N HCl, RT, 12 h, 75%
(two steps) (e) NaBH3CN, acetic acid, methanol, RT, 30 h (f)
PPh3, DIED, Pyridine 0 °C, 3 h, 43% (two steps).
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The configuration and relative stereochemistry of the final
indolizidine structure 5 was further confirmed by APT,
HSQC, and COSY-NOESY tool. The strong NOE effect
between H8a and H7, H8a and H1β indicate H7 and H8a are
same side of the plane. Also NOE between H7 and H6
specify H6 and H7 are on the same side of the ring.
Irradiation to H8a didn’t enhance the intensity of H8, this
indicate H8 and H8a both are on the opposite side of the rin.
The trans diaxial relation between H7 and H8 are revealed
by the coupling constant J7,8 value (9.3 Hz) while the small
value of J6,7 (3.4 Hz) suggested the cis axial-equatorial
orientation. (Figure2).
5.
6.
7.
8.
9.
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Tetrahedron Letters
4
Yan, X.; Haibin, M.; Mao,, Y.; Feng-Ling, Q.; Weihong, T. J. Am.
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20. Spectral data of 5:
1H NMR (400 MHz, D2O): δ ppm 1.53 (m, 1H, H1β), 1.81 (m, 2H,
H2α and H2β), 2.01 (m, 1H, H1α), 2.10 (m, 1H, H8a), 2.25 (q, J = 9.3
Hz, 1H, H3β), 2.39 (dd, J = 1.4 and 12.7 Hz, 1H, H5β), 3.0 (m, 1H,
H5α), 3.10 (dd, J = 2.4 and 12.7 Hz, 1H, H3α), 3.46 (dd, J = 3.4 and
9.3 Hz, 1H, H7), 3.53 (t, J = 9.3 Hz, 1H, H8), 4.01 (brs, 1H, H6). 13C
NMR (100 MHz, D2O): δ ppm 21.8, 28.1, 53.8, 55.8, 68.4, 69.7, 73.4,
75.8. IR (neat) cm-1: 3020, 2400, 1423, 1215. HRMS (ESI): Calcd for
C8H16NO3 (M+H)+ 174.1130, found 174.1128. [α]D22 = +22.5 ° (c 0.05,
MeOH).
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Supplementary Material
Supplementary data associated with this article can be
found, in the online version, at http://
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Tetrahedron Letters
5
Highlights:
 The stereoselective imine reduction was
achieved by using sodium
cyanoborohydride.
 Mitsunobu cyclization selectively with
primary hydroxy.
 Describe in situ reaction include acetonide
deprotection, N-Cbz deprotection
debenzylation, cyclization.