Concise and highly stereoselective syntheses of D-fagomine and 2-epi-fagomine

Article abstract of DOI:10.1016/j.tetlet.2016.02.046

Highly stereoselective total syntheses of polyhydroxylated piperidines D-fagomine and 2-epi-fagomine have been developed starting from 3,4,6-tri-O-benzyl-D-glucal which is a derivative of D-Glucose. Key steps in the synthesis of these azasugars involved N-Boc-protected amine preparation from oxime followed by stereo specific iodination of alcohol and cascade cyclization triggered by N-Boc deprotection.

Full text of DOI:10.1016/j.tetlet.2016.02.046

Accepted Manuscript
Concise and highly stereoselective syntheses of D-fagomine and 2-epi-fagomine
Kallam Srinivasa Reddy, Rajender Datrika, Sandip R. Khobare, Vikas S. Gajare,
Nagaraju Rajana, H. Rama Mohan, J. Moses Babu, V. Siddaiah, T.V. Pratap
PII:
S0040-4039(16)30155-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.046
TETL 47321
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 December 2015
10 February 2016
12 February 2016
Please cite this article as: Reddy, K.S., Datrika, R., Khobare, S.R., Gajare, V.S., Rajana, N., Rama Mohan, H., Moses
Babu, J., Siddaiah, V., Pratap, T.V., Concise and highly stereoselective syntheses of D-fagomine and 2-epi-
fagomine, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.046
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Tetrahedron Letters
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Concise and highly stereoselective syntheses of D-fagomine and 2-epi-
fagomine
Kallam Srinivasa Reddy a,b, Rajender Datrika a, Sandip R Khobare a, Vikas S Gajare a, Nagaraju Rajana a, H Rama
Mohan a, J Moses Babu a, V. Siddaiah b, T V Pratap a,*
a Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500049, India
Fax +91(40) 44658699; E-mail: tvpratap@drreddys.com
b Department of Organic Chemistry & FDW, Andhra University, Visakhapatnam 530 003, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Highly stereoselective total syntheses of polyhydroxylated piperidines D-fagomine and 2-epi-
fagomine has been developed starting from 3,4,6-tri-O-benzyl-D-glucal which is a derivative of
D-Glucose. Key steps in the synthesis of these azasugars involved N-Boc-protected amine
preparation from oxime followed by stereo specific iodination of alcohol and cascade cyclization
triggered by N-Boc deprotection.
Received in revised form
Accepted
Available online
Keywords:
Polyhydroxylated piperidine
D-fagomine
2015 Elsevier Ltd. All rights reserved.
2-epi-fagomine
Inversion
Double inversion
Polyhydroxyated piperidines are known for their biological
activity as glycosidase inhibitors.1 These compounds are
found to possess effective therapeutic activity against a
wide range of diseases including diabetes,2 viral infection
and tumor metastasis.3 Glycosidases are the enzymes
involved in carrying out several fundamental biological
processes, azasugars that are either agonistic or antagonistic
to these enzymes have thus acquired great significance from
synthesis perspective.
occurrence increasing the availability of its analogues with
different substitution pattern and stereochemistry would
benefit the scientific community to establish the structure
activity relationship. Several syntheses of D-fagomine (1)
and 2-epi-fagomine (2), both from carbohydrate9 and from
non-carbohydrate10 precursors have been reported in the
literature. Yaswanth et al. reported the total synthesis of D-
fagomine and 2-epi-fagomine by intramolecular reductive
amination from 2-deoxy-1-azido sugars.9d Yokoyama et al.
reported the synthesis of D-fagomine by Sharpless
asymmetric
dihydroxylation
and
Pd(II)-catalyzed
D-fagomine (1), is a naturally occurring azasugar that was
first isolated from Japanese buckwheat seeds of Fagopyrum
esculentum austral Moench in 1974,4 and Castanospermum
austral (a member of Leguminosae family).5 The stereo
isomers of this compound were isolated from the leaves and
roots of Xanthocercis zambesiaca.6 This azasugar has an
inhibitory activity against mammalian intestinal α-
glucosidase and β-galactosidase.7
cyclization starting from 3-(t-butoxylcarbonylamino)
propanol.10e Chemo-enzymatic synthesis of D-fagomine
reported by Jesu´s Joglar and Pere Clape´s with FSA-
catalyzed aldol addition of dihydroxyacetone (DHA) to N-
Cbz-3-aminopropanal and reductive amination.10g Kim et
al. reported the synthesis of D-fagomine by stereoselective
intramolecular oxazine formation catalyzed by palladium(0)
and piperidine formation by catalytic hydrogenation of
oxazine.10i The diastereoselective synthesis of D-fagomine
reported by Min et al. from D-lyxose.10j Bates and Shuyi
Ng reported the synthesis of 2-epi-fagomine by gold(I)-
catalysed allene cyclisation.10k These syntheses though
resulted desired product in high yields, the use of complex
reagents, reaction conditions and multistep synthetic
sequences involved in these syntheses invite even simple
and scalable approaches for synthesis of these natural
products.
Figure-1: D-fagomine 1 and 2-epi-fagomine 2
Also, it has potent antihyperglycemic effect on diabetic
mice via potentiation of glucose induced insulin secretion.8
The hyperglycemic condition in mice was caused by
inducing Streptozocin in them. These important biological
properties of D-fagomine clubbed with its structural
similarity with sugars have attracted chemists as an
important synthetic target. Because of its limited natural
Herein we describe our successful effort towards the highly
stereoselective total synthesis of D-fagomine (1) and its
epimer 2-epi-fagomine (2) from a common intermediate 5,
which was derived from 3,4,6-tri-O-benzyl-D-glucal. The
retrosynthetic approach for synthesis 1 and 2 is described in

2
Tetrahedron Letters
Scheme 1. The D-fagomine (1) could be obtained from tert-
butyl ((3R,4S,5S)-3,4,6-tris(benzyloxy)-5-iodohexyl)
carbamate (6) by intramolecular N-alkylation triggered by
N-Boc deprotection. The compound 6 could be obtained
from a common intermediate tert-butyl ((3R,4R,5R)-3,4,6-
tris(benzyloxy)-5-hydroxyhexyl)
carbamate
(5)
by
iodination with inversion of configuration at C5 position.
The compound 5 in turn could be obtained from (4R,5S,6R)-
4,5-bis(benzyloxy)-6-((benzyloxy) methyl) tetrahydro-2H-
pyran-2-ol (4) by oxime formation followed by one pot
reduction of oxime and N-Boc protection. The compound 4
is traced from 3,4,6-tri-O-benzyl-D-glucal (3) which on
catalytic hydration affords compound 4. On the other hand,
the 2-epi-fagomine (2) could be obtained from (2R,3S,4R)-
Scheme 2: (a) PPh3.HBr, THF, water, rt, 4 h, 85%; (b) NH2OH.HCl,
sodium acetate, methanol, water, rt, 3 h, 91%; (c) NaBH4, NiCl2.6H2O,
Boc2O, methanol, 0 °C to rt, 74%.
1,3,4-tris(benzyloxy)-6-((tert-butoxycarbonyl)
amino)
hexan-2-yl methanesulfonate (8) by Boc deprotection
followed by N-alkylation. The compound 8 could be
obtained from tert-butyl ((3R,4R,5R)-3,4,6-tris (benzyloxy)
-5-hydroxyhexyl) carbamate (5) by mesylation with
retention of configuration at C5 position.
The secondary alcohol of intermediate 5 was converted to
iodide 6 using iodine, triphenylphosphine and imidazole15 in
toluene at reflux temperature for 2 h. This reaction proceeds
by activation of triphenylphosphine with iodine, followed
by attack of the alcohol oxygen at phosphorus to generate
an oxyphosphonium intermediate. The oxygen is then
transformed into a leaving group undergo SN2 displacement
by iodide with inversion of configuration at C5 position.
Iodide 6 on treatment with ethanolic HCl lead to
deprotection of the tertiary butoxy carbamate and the amine
got converted to corresponding amine hydrochloride salt.
After distillation of ethanol this intermediate was treated
with K2CO3 in acetonitrile at reflux temperature for 2 h
which triggers the amine to participate in SN2 reaction at C5
with inversion of configuration to afford tri-O-benzyl-D-
fagomine with desired stereochemistry. Latter it was
subjected to debenzylation using catalytic hydrogenation in
presence of Pd/C to furnish the target molecule D-fagomine
1 (Scheme 3). The spectral data of obtained D-fagomine 1
was found to be in accordance with the reported data.
H
N
I
NHBoc
OH NHBoc
a
BnO
BnO
BnO
BnO
BnO
BnO
b
OBn
OBn
OBn
6
5
7
H
N
Scheme 1: Retrosynthetic analysis.
HO
c
Results and discussion
HO
OH
Synthesis of D-fagomine (1) and 2-epi-fagomine (2)
commenced with 3,4,6-tri-O-benzyl-D-glucal 3 a derivative
of D-Glucose.11 The synthesis of key intermediate 5 is
described below (Scheme 2). Thus 3,4,6-tri-O-benzyl-D-
glucal 3 was converted to lactal 4 by catalytic hydration12
with PPh3-HBr in THF-Water mixture at ambient
temperature. Lactal 4 was converted to oxime with
hydroxylamine hydrochloride and sodium acetate in
methanol at ambient temperature.13 The oxime was further
reduced with NaBH4 and NiCl2 in methanol14 and amine
thus obtained reacts with di-tert-butyl dicarbonate in the
same pot to afford the intermediate 5.
1
Scheme-3: (a) I2, PPh3, imidazole, toluene, reflux, 2 h, 79%; (b) (i)
10% EtOH-HCl, rt, 2 h; (ii) K2CO3, acetonitrile, reflux, 4 h, 95%; (c) 10%
Pd/C, conc.HCl, H2, methanol, rt,18 h, 82%.
Subsequently attention was paid on the synthesis of 2-epi-
fagomine 2. The hydroxyl group of intermediate 5 was
converted to a leaving group here in this case a mesylate 8 by
reacting with mesyl chloride, triethylamine and DMAP in
dichloromethane.16 Deprotection of the tertiarybutyl
carbamate followed by reaction with K2CO3 in acetonitrile
lead to intramolecular cyclization17 with net inversion of
configuration at C5 position to afford tri-O-benzyl-2-epi-
fagomine. Latter it was subjected to debenzylation using
catalytic hydrogenation in presence of Pd/C 18 to afford 2-epi-
fagomine 2 (Scheme 4).

H
N
Effenberger, F.; Null, V. Liebigs Ann. Chem. 1992, 1211–1212; (d)
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NHBoc
OMs
NHBoc
a
OH
BnO
BnO
BnO
BnO
BnO
BnO
b
OBn
OBn
OBn
8
9
5
H
N
c
HO
HO
OH
2
Scheme-4: (a) MsCl, DMAP, TEA, DCM, 0 °C to rt, 2 h, 90%; (b) (i)
10% EtOH-HCl, rt, 2 h; (ii) K2CO3, acetonitrile, reflux, 4 h, 92%; (c) 10%
Pd/C, conc.HCl, H2, methanol, rt, 18 h, 76%.
In summary, a highly stereoselective synthesis of D-fagomine
(1) and 2-epi-fagomine (2) has been developed with good
yields. The double inversion of stereochemistry at C5 position
via iodide gave the D-fagomine 1 while single inversion via
mesylate gave the 2-epi-fagomine 2. The route of synthesis
developed for these iminosugars utilize fairly inexpensive
reagents and operationally friendly processes. This strategy
can be utilized for the stereoselective synthesis of other
polyhydroxylated piperidines. The application of this
methodology for the synthesis of other biologically active
complex polyhydroxylated piperidines is currently underway.
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752; (b) Bucher, C.; Gilmour, R. Angew. Chem. Int. Ed. 2010, 49, 8724
– 8728.
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Acknowledgments
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The authors would like to thank Dr. Vilas Dahanukar and Dr.
Rashid Abdul Rahman Khan of Dr. Reddy’s Laboratories for
continued support. We also thank the Analytical Department,
Dr. Reddy’s Laboratories, for providing the analytical support.
DRL-IPD Communication No.: IPDO IPM-00471
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Graphical Abstract (for review)
Graphical Abstract
Concise and highly stereoselective syntheses of
D-fagomine and 2-epi-fagomine.
Leave this area blank for abstract info.
Kallam Srinivasa Reddya,b, Rajender Datrikaa, Sandip R Khobarea, Vikas S Gajarea, Nagaraju Rajanaa, H Rama
Mohana, J Moses Babua , V. Siddaiahb, T V Pratap a*