[2,3]-Wittig rearrangement approach to iminosugar C-glycosides: 5-epi-ethylfagomine, 2-epi-5-deoxyadenophorine and formal synthesis of indolizidine 167B and 209D

Article abstract of DOI:10.1016/j.tetlet.2011.08.084

A new strategy for the synthesis of 1,2-dideoxy iminosugar C-glycosides and indolizidines involving highly stereoselective [2,3]-Wittig rearrangement from Garner aldehyde has been developed. This rearrangement yielded an optically pure, highly functionali

Full text of DOI:10.1016/j.tetlet.2011.08.084

Tetrahedron Letters 52 (2011) 5921–5925
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[2,3]-Wittig rearrangement approach to iminosugar C-glycosides:
5-epi-ethylfagomine, 2-epi-5-deoxyadenophorine and formal synthesis of
indolizidine 167B and 209D
B. Chandrasekhar a, J. Prasada Rao a, B. Venkateswara Rao a, , P. Naresh b
⇑
a Organic Division III, Indian Institute of Chemical Technology, Hyderabad, India
b Centre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new strategy for the synthesis of 1,2-dideoxy iminosugar C-glycosides and indolizidines involving
highly stereoselective [2,3]-Wittig rearrangement from Garner aldehyde has been developed. This rear-
rangement yielded an optically pure, highly functionalized key intermediate, which has been further
utilized for the synthesis of 5-epi-ethylfagomine, 2-epi-5-deoxyadenophorine, and 5-hydroxymethyl
indolizidine.
Received 27 April 2011
Revised 10 August 2011
Accepted 14 August 2011
Available online 25 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
[2,3]-Wittig rearrangement of allylic ethers has been demon-
strated to be a versatile synthetic tool in organic synthesis. For
instance, chiral allylic ethers when subjected to Wittig rearrange-
ment conditions give homo allylic alcohol with high optical induc-
tion and complete E-selectivity of the newly formed alkene.
Because of the high stereoselective transposition of the oxygen
and olefin, this reaction has been well utilized in natural product
synthesis.1 In continuation of our efforts in the synthesis of chiral
piperidines and iminosugars,2 herein we describe the synthesis of
some chiral 2,6-dialkylated piperidine skeletons such as 5-epi-eth-
ylfagomine, 2-epi-5-deoxyadenophorine, indolizidine 167B and
indolizidine 209D using stereoselective [2,3]-Wittig rearrange-
ment. Chiral allylic ethers such as I on [2,3]-Wittig rearrangement
should afford the enantiomerically enriched homoallylic alcohol II
with properly oriented trans double bond by 1,4-chiral transfer.1a
This homoallylic alcohol will serve as a general starting material
for the synthesis of iminosugar C- glycosides3 III and 5-substituted
indolizidines IV (Scheme 1).
these natural substances and their analogues became an important
area of work.5 These iminosugars display a wide range of glycosi-
dase inhibitory activities by mimicking the glycosyl oxocarbonium
intermediate.6 Several studies suggested that these compounds are
valuable therapeutic agents against a wide range of diseases.7
N-Alkylated iminosugars such as zevesca 3 and miglitol 4 are pres-
ently commercialized as drugs and various iminosugars are
currently in clinical trials for the treatment of diabetes, cancer, vir-
al infections, lysosomal storage disorder etc.8,9 Iminosugar C-glyco-
sides are a new class of iminosugars in which the oxygen atom of
the N,O-acetal function is replaced by a methylene group to form a
stable C–C bond at C-1. These iminosugars have shown advantages
in terms of potency and selectivity compared to simpler iminoald-
itols and N-substituted iminosugars.10 A comparative study con-
ducted by Martin and co-workers, on N-alkylated and C-alkylated
iminosugars, revealed that the latter compounds showed advan-
tage in the field of antiviral agents by selective inhibition of carbo-
hydrate-processing enzymes.11
Polyhydroxy piperidine derivatives are a major class of imino-
sugars or azasugars. These compounds are pyranose mimics in
which the ring oxygen is replaced by nitrogen. Nojirimycin (NJ) 1
is the first glucose mimic isolated from the fermentation broths
of Streptomyces and later it was isolated from plants and microor-
ganisms. Reduction of nojirimycin 1 will lead to deoxynojirimycin
(DNJ) 2 and later this was also isolated from plant sources and bac-
terial cultures. After the discovery of DNJ 2, more than twenty five
additional analogues of NJ 1 were identified from the plants and
microorganisms.4 Hence the synthesis and biological studies of
1,2-Dideoxy iminosugars such as fagomine 5 isolated from Fag-
opyrum esculeutum showed remarkable biological properties.12
Some of the isomers of fagomine were also isolated and their gly-
cosidase inhibition was studied.13 Several N-alkylated derivatives
of fagomines were synthesized and they were found to have activ-
ities, such as antifungal and antibacterial.14 Two new 1,2-dideoxy
iminosugar C-glycosides having ethyl substitution at C1-position
such as ethyl fagomine 6 and 5-deoxyadenophorine 7 were
isolated from Adenophora spp.15 Ethyl fagomine 6 in which intro-
duction of ethyl group at C-1-a-position of fagomine showed addi-
tional inhibition toward bovine liver
a-galactosidase. Later several
a
-1-C-substituted derivatives of fagomines were synthesized by
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B. Venkateswara
Martin and co-workers screened for their inhibitory effects.16 5-
Deoxyadenophorine 7 showed enhanced inhibitory activity toward
Rao).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.084

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B. Chandrasekhar et al. / Tetrahedron Letters 52 (2011) 5921–5925
dihydroxylation
RI
O
OH
*
RI
R
R
HO
*
OH
NHP
[2,3]-Wittig
Rearrangement
* N *
NHP
RI
R
II
cyclization
H
I
Iminosugar-C-glycosides III
If RI= vinyl
R= alkyl
RI= Ph, vinyl
P= Protective group
acrylation
RCM
*
*
R
Reduction
Double cyclization
R
N
NHP
O
O
5-substituted indolizidines
IV
Scheme 1. [2,3]-Wittig rearrangement and its applications.
OH
OH
OH
OH
HO
HO
OH
6
OH
HO
OH
6
OH
6
3
3
4
4
5
3
4
3
4
2
1
2
1
2
1
2
1
OH
5
5
6 OH
5
N
OH
OH
N
H
N
H
N
R
H
1
R= H, 2
6
5
R= C4H9, 3
R= CH2OCH2CH2OH, 4
OH
OH
OH
OH
4
OH
HO
7
OH
OH
OH
OH
OH
3
4
4
4
2
5
6
3
2
5
6
3
2
5
6
3
1
2
5
6
OH
OH
8
8
8
N
H
N
H
N
H
N
H
1
7
7
1
1
8
7
9
10
Figure 1. Polyhydroxylated piperidines.
O
OR
c
Ph
OH
H
NBoc
a
O
O
d
NBoc
b
O
NBoc
14
R= H, 12
R= Bn,13
11
O
Ph
Ph
TBDPSO
c
OH
TBDPSO
NHBoc
16
NHBoc
15
Scheme 2. [2,3]-WR on benzyl ether. Reagents and conditions: (a) vinyl magnesium bromide, THF, À78 °C, 3 h, 80%; (b) BnBr, NaH, THF, 0 °C to rt, 92%; (c) n-BuLi (3 equiv),
THF, À78 °C to 0 °C, 1 h, 70%; (d) (i) 80% aq AcOH, MeOH, 0 °C-rt, 12 h, 83%; (ii) TBDPSCl, imidazole, CH2Cl2, 0 °C to rt, 12 h, 98%.
a
-galactosidase and inhibition to b-galactosidase as compared to
adenophorine 8.15 Lebreton and co-workers, published the first
total synthesis of 5-deoxyadenophorine 7 and its 1-O- -gluco-
posed to n-BuLi at various temperatures and concentrations, it
failed to generate the expected [2,3]-WR product 14, and every
time only the starting material was recovered. The failure of this
reaction may be due to the presence of oxazolidine ring, which
might exert some strain and also prevent the participation of N-
Boc group in chelation to stabilize the carbanion.20 Therefore, we
proposed to prepare an alternative substrate for [2,3]-WR. Thus,
deprotection of N,O-acetonide group in 13 with aq. AcOH followed
by protection of alcohol with TBDPSCl and imidazole in CH2Cl2
gave 15. Treatment of the compound 15 with n-BuLi at À78 °C
for 1 h indeed gave the rearranged product 16 with excellent stere-
oselectivity (Scheme 2).
a
-D
pyranosyl derivative and also reported the synthesis and biological
evaluation of several racemic 5-deoxyadenophorine analogues
(Fig. 1).17
Our synthesis of iminosugar C-glycosides 9 and 10 starts from
L-serine derived Garner aldehyde 11.18 Vinyl magnesium bromide
addition to Garner aldehyde 11 at À78 °C gave anti adduct 12 as a
major isomer.19 In order to determine the feasibility of [2,3]-WR,
we chose benzyl ether 13 as a model system. Alcohol 12 was con-
verted to benzyl ether 13 using BnBr, NaH. When olefin 13 was ex-

B. Chandrasekhar et al. / Tetrahedron Letters 52 (2011) 5921–5925
5923
tBuO
H
H
C5H11
C2H5
N
N
OLi
N
Li
28
29
TBDPSO
H
Figure 3. Alkylated indolizidines.
H
O
G
19 was treated with n-BuLi in THF to give the desired product 20
in 65% yield. Regioselective reduction of the terminal double bond
in 20 with CoCl3.6H2O/NaBH4 followed by acetylation led to com-
pound 21.21 Having the olefin 21 in hand, we then explored the
critical dihydroxylation to install the chiral centers at C3 and C4.
Our initial experiment with OsO4 gave 1:1 separable diastereomers
(22:23) in 90% yield.22 When the olefin was subjected to Sharpless
G= Ph or Vinyl
Figure 2. Transition state model for [2,3]-WR.
The trans geometry and absolute configuration of the new chiral
center in 16 can be readily predicted based on the five-membered
transition state (TS) of Wittig rearrangement where 1,4-chirality
transfer occurs (Fig. 2).1a The envelope transition state is sterically
more favorable and CH-NBoc group preferentially adopts the exo-
orientation and this will lead to the formation of E-isomer. The
absolute configuration was also predictable by observing the G-
group which prefers the equatorial position during 1,4-chirality
transfer.
This method was extended for the preparation of ethyl substi-
tuted polyhydroxy piperidines, such as 2-epi-5-deoxy adenopho-
rine 9 and 5-epi-ethyl fagomine 10 (Scheme 3). Allylation on 12
with allylbromide, sodium hydride gave compound 17. When trea-
ted with n-BuLi in THF at various temperatures (0, À40, and
À78 °C), compound 17 failed to give the desired product 18 and
a considerable amount of starting material was recovered. This fur-
ther confirmed the negative effect of oxazolidine ring on the course
of the reaction. Isopropylidene deprotection in 17 followed by sily-
lation with TBDPSCl gave compound 19. The diolefinic compound
asymmetric dihydroxylation (SAD) conditions23 with ADmix-
a for
an extended period of time, no dihydroxy compound was formed
and a considerable amount of starting material was recovered.
When the reaction was conducted with modified SAD conditions,
that is, a premixed ADmix-a and K2OsO4.2H2O in t-BuOH:H2O, it
gave a 4:1 separable diastereomeric mixture of dihydroxy com-
pounds 22 and 23 in 88% yield.24 Diol functionality in the major
isomer 22 was subjected to 2,2-DMP in presence of PTSA to give
acetonide derivative which on ester hydrolysis with K2CO3 in
MeOH gave free alcohol 24. Treatment of 24 with MsCl and Et3N
gave a mesyl derivative, which on further reaction with KOtBu in
THF gave a cyclized product 25 in 70% yield. Global deprotection
of compound 25 with TFA:H2O provided the desired 2-epi-5-deoxy
adenophorine 925 in 75% yield. Similarly, the minor diastereomer
23 obtained in dihydroxylation was also converted into piperidine
derivative 5-epi-ethylfagomine 1025 (33.6% overall yield from 23)
via intermediates 26 and 27 using a similar reaction sequence car-
ried out for the preparation of compound 9.
O
b
a
O
NBoc
OH
12
O
NBoc
17
18
c
OTBDPS
d
O
OTBDPS
e
b
TBDPSO
NHBoc
21
OAc
h
NHBoc
OH
NHBoc
19
20
OH
TBDPSO
OH
O
TBDPSO
O
HO
HO
g
f
f
O
N
H
9
TBDPSO
OH OAc
BocHN
BocHN
OH
O
N
22
Boc
24
25
+
OH
TBDPSO
OH
O
N
O
TBDPSO
HO
HO
h
g
O
OH OAc
23
N
H
BocHN
TBDPSO
BocHN
OH
O
Boc
10
26
27
Scheme 3. Synthesis of 2-epi-5-deoxyadenophorine and 5-epi-ethyl fagomine. Reagents and conditions: (a) allyl bromide, NaH, THF, 0 °C to rt, 8 h, 90%; b) n-BuLi (3 equiv),
THF, À78 °C to 0 °C, 1 h, 65%; (c) i) 80% aq AcOH, MeOH, 0 °C to rt, 12 h, 85%; (ii) TBDPSCl, imidazole, CH2Cl2, 0 °C to rt, 12 h, 95%; (d) (i) CoCl3. 6H2O/NaBH4, EtOH 0 °C, 1 h,
80%; (ii) Ac2O, Et3N, CH2Cl2, rt, 3 h, 94%; (e) Admix-
a, K2OsO4Á2H2O, in t-BuOH: H2O (1:1), 0 °C, 24 h, 88%; (f) (i) 2,2-DMP, PTSA, acetone, rt, 3 h, 91%; (ii) K2CO3, MeOH, rt, 2 h,
85%; (g) (i) MsCl, Et3N, CH2Cl2, 0 °C, 1 h; (ii) KOtBu, THF, 0 °C to rt, 24 h, 70% (over 2 steps); (h) TFA:H2O (9:1), 12 h, 75%.

5924
B. Chandrasekhar et al. / Tetrahedron Letters 52 (2011) 5921–5925
TBDPSO
a
TBDPSO
b
TBDPSO
c
20
O
O
NHBoc
OH
NHBoc
30
NHBoc
32
31
O
OH
O
d
Ref 30
H
H
R
HO
N
N
33
R= C2H5, (+)-167B, 28
R= n-C5H11, (+)-209D, 29
Scheme 4. Synthesis of 5-hydroxymethyl indolizidine. Reagents and conditions: (a) Acryloyl chloride, Et3N, CH2Cl2, rt, 3 h, 90%; (b) Grubbs’ I generation catalyst, CH2Cl2, rt,
24 h, 80%; (c) (i) H2, Pd/C, ethylacetate, rt, 24 h, 90%; (ii) LiAlH4, THF, rt, 1 h, 80%; (d) (i) MsCl, Et3N, CH2Cl2, 0 °C, 1 h; (ii) TBAF, THF, rt, 3 h; (iii) TFA: CH2Cl2, 4 h, then Et3N 1 h,
60% (over 3 steps).
Indolizidine alkaloids are widely distributed in nature in both
plant and animal sources with a wide range of biological activi-
ties.26 Among these alkaloids, monosubstituted indolizidine alka-
loids, such as indolizidine 167B 28 and indolizidine 209D 29
with substitution at C5 position have been attractive synthetic tar-
gets over the past 20 years and several methods were developed
for their synthesis (Fig. 3). Among these some of them are starting
from already existing heterocyclic rings such as pyrrolidine or
piperidine.27 Metal (Cu, Pd, Rh, Sn, Ti) catalyzed approaches are
well exploited for the synthesis of indolizidine 167B and 209D.28
Carbocation mediated intra molecular Schmidt reaction has been
well studied to construct the above indolizidines.29 In this regard
Baskaran and co-workers reported a convergent approach for these
indolizidines from an advanced common intermediate 5-hydroxy
methyl indolizidine 33.30
In our approach, the synthesis of 28 and 29 started from our key
intermediate 20. The allylic alcohol 20 on acylation with acryloyl
chloride afforded 30 in 90% yield. Treatment of the acrylate 30 with
Grubbs 1st generation catalyst furnished the lactone ring 31. The
subsequent catalytic hydrogenation of 31 gave the reduced lac-
tone, which on reduction with LiAlH4 in THF afforded the desired
diol 32. Mesylation of 32 using MsCl, Et3N gave a dimesyl deriva-
tive. The crude dimesylate on desilylation and Boc deprotection
followed by cyclization using Et3N afforded 5-hydroxy methyl ind-
olizidine 33. The compound 33 was previously used as a common
intermediate for the synthesis of indolizidines 167B 28 and 209D
29. The spectral and physical data of 33 were identical with the re-
ported values (Scheme 4).30
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In conclusion we have developed a straightforward stereoselec-
tive approach to 2,6-disubstituted piperidines 9, 10, and 33 by
using [2,3]-WR which efficiently furnished the required highly
functionalized and appropriately substituted valuable building
block 20. Here, we also observed the importance of lateral chela-
tion for the Wittig rearrangement to proceed. This methodology
further can be exploited to generate a broad array of analogues
to study the structure-activity relationship for highly potent glyco-
sidase inhibitors. Further application of this methodology to more
complex systems is in progress.
Acknowledgments
The authors B.C, J.P.R and P.N thank CSIR, New Delhi, for re-
search fellowship. We also thank Dr. J. S. Yadav for his support
and encouragement. DST (SR/S1/OC-14/2007)-New Delhi for finan-
cial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.084.
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Tetrahedron: Asymmetry 2004, 15, 3393; Kim, G.; Lee, E. Tetrahedron:
Asymmetry 2001, 12, 2073; (g) Peroche, S.; Remuson, R.; Gelas-Mialhe, Y.;
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25. The NOE experiments further confirmed the given structures 9 and 10. The 1
H
NMR spectrum of compound 9 showed the following coupling constants, J(Ha-
Hb) = 9.5 Hz, J(Hb-Hc) = 9.5 Hz, J(Hc-Hd) = 11.8 Hz, J(Hd-Hf) = 11.8 Hz which clearly
indicates the axial orientation of these protons. This was further confirmed by
observing the strong nOe between Hb-Hd, CH2-Hb, Hc-Hf, and Hc-Ha. In the case
of compound 10, the coupling constants of J(Ha-Hb), J(Hb-Hc), J(Hc-Hd) are less than
6 Hz. The Hd proton gave a brt (ꢀ14.0 Hz) indicating two strong couplings, one
with He(geminal) and other with Hf (axial). This was further confirmed by the
observed strong nOe between (Hf-Ha) and absence of any nOe between Hc-Ha,
and Hc-Hf.
29. (a) Kapat, A.; Nyfeler, E.; Giuffredi, G. T.; Renaud, P. J. Am. Chem. Soc. 2009, 131,
17746; (b) Varga, T. R.; Nemes, P.; Mucsi, Z.; Scheiber, P. Tetrahedron Lett. 2007,
48, 1159; (c) Pearson, W. H.; Walavalkar, R. Tetrahedron 2001, 57, 5081.
30. (a) Reddy, P. G.; Varghese, B.; Baskaran, S. Org. Lett. 2003, 5, 583; (b) Reddy, P.
G.; Baskaran, S. J. Org. Chem. 2004, 69, 3093; (c) Reddy, P. G.; Sankar, M. G.;
Baskaran, S. Tetrahedron Lett. 2005, 46, 4559.
OH
H
d
H
c
H
H
d
b
H
H
e
OH
b
N
H
HO
H
e
H
HO
HO
HO
H
N
C
CH3
H
H
a
H
f
c
H
CH3
Ha
H
f
10
9