Stereoselective strategy for the synthesis of (+)-polyoxamic acid and some polyhydroxylated pyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2013.08.126

An efficient strategy for the synthesis of dihydroxy chiral amino moiety which can be utilized for the synthesis of polyoxamic acid, 1,4-dideoxy-1,4- imino-d-xylitol, and dihydroxy pyrrolidine by using highly diastereoselective nucleophilic addition on ch

Full text of DOI:10.1016/j.tetlet.2013.08.126

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective strategy for the synthesis of (+)-polyoxamic acid and
some polyhydroxylated pyrrolidines
⇑
Macha Lingamurthy, Anugula Rajender, Batchu Venkateswara Rao
Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient strategy for the synthesis of dihydroxy chiral amino moiety which can be utilized for the syn-
Received 20 June 2013
Revised 26 August 2013
Accepted 30 August 2013
Available online xxxx
thesis of polyoxamic acid, 1,4-dideoxy-1,4-imino-
diastereoselective nucleophilic addition on chiral imine has been reported.
Ó 2013 Elsevier Ltd. All rights reserved.
D-xylitol, and dihydroxy pyrrolidine by using highly
Keywords:
Polyoxamic acid
Iminosugars
Glycosidase inhibitors
Stereoselective
Grignard reaction
R
Dihydroxy chiral amino moiety which is shown in Fig. 1 is an
important unit of many biologically active natural compounds
H
N
H
N
CO2H
O
O
OH NH2
N
OH
NH
H2N
O
NH
HO
such as polyoxin J 1a, polyoxin L 1b, polyoxin B 1c, polyoxin
D
O
OH
HO
OH
HO
1d, 1,4-dideoxy-1,4-imino- -xylitol 2, and also dihydroxy alkyl-
D
OH
O
OH
O
2
3
ated pyrrolidine 3. Polyoxamic acid 4, a well known acyclic 3,4-
dihydroxy amino acid moiety, is a structural component of the
above polyoxins.1 These polyoxins are the peptidyl nucleoside
antibiotics and they act against serinepalmitoyl transferase2 to
block the biosynthesis of sphingolipids, phytopathogenic fungus,
and chitin synthetase3 of candida albicans and human fungi patho-
polyoxins
R
OH NH2
1a
(
)
CH3
H
J
HO
OH
L
1b
(
)
OH
O
CH2OH
CO2H
B
1c
( )
4
1d
D (
)
gen.4 1,4-Dideoxy-1,4-imino-
D-xylitol 2 belongs to an important
Figure 1. Some of the representative biologically active compounds.
class of iminosugars (polyhydroxylated pyrrolidines) isolated from
the pteridophyte Arachniodes standishii,5 which is a known glycosi-
dase inhibitor6 and also a weak inhibitor of glycogen phosphory-
lase b.7 It has also been observed that alkyl substituent
iminosugars are showing strong glycosidase inhibitor activity.8
Generally, glycosidases are involved in several important meta-
bolic processes such as digestion, biosynthesis of glycoproteins,
and the lysosomal catabolism of glycoconjugation, therefore glyco-
sidase inhibitors have therapeutic applications for cancer, diabetes,
bacterial, viral infections, and lysosomal storage disorders.9 De-
spite the numerous clinical applications, many reports have been
developed for the synthesis of 2 and 4 compounds.10,11 Compound
3 comes under the class of alkylated dihydroxy pyrrolidine, whose
structural analogues are known for their glycosidase inhibitor
activity.8 So far one synthesis has been reported for 3 in the form
of its enantiomer.12
In continuation our efforts in developing a synthetic approach
toward iminosugars and phytosphingosines using a highly stereo-
selective nucleophilic addition on N-glycosylamine derivatives,13
herein we report an efficient strategy for the generation of dihy-
droxy chiral amino moiety 5 which can be utilized for the synthesis
of (+)-polyoxamic acid 4,11 1,4-dideoxy-1,4-imino- -xylitol 2,10
D
and alkyl substituted dihydroxy pyrrolidine 312 using a highly ster-
eoselective Grignard addition of chiral imine as shown in
Scheme 1.
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail address: drb.venky@gmail.com (B.V. Rao).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.126
Please cite this article in press as: Lingamurthy, M.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.08.126

2
M. Lingamurthy et al. / Tetrahedron Letters xxx (2013) xxx–xxx
OH NH2
M
HO
OH
Cbz
Bn
H
Bn
HN
BnN
MOMO
NHBn
MOMO
TBDPSO
MOMO
TBDPSO
OH
O
MOMO
TBDPSO
H
N
N
4
OH
Chelation controlled
H
OMOM
OMOM
OMOM
6
OH
HO
5
2
H
11
R
H
Nucleophile
(Vinyl unit)
N
6
OH
HO
Scheme 1. Retrosynthetic pathway.
L-(+)DET
3
Figure 2. Chelation-controlled addition of imine 6.
7
Scheme 1. Retrosynthetic pathway.
OMOM
Bn
H
N
MOMO
TBDPSO
i(a), i(b)
i(c)
TBDPSO
OH
OMOM
OH
O
OMOM
O
MOMO
EtO
ii
i
10
OMOM
6
EtO
HO
OEt
OEt
OMOM
OH
OMOM
O
OH
O
9
8
Cbz
7
Bn
HN
OMOM
MOMO
TBDPSO
BnN
MOMO
iii
iii
TBDPSO
ii
TBDPSO
OH
OMOM
OMOM
Cbz
OMOM
10
5
11
Scheme 2. Synthesis of key intermediate 10. Reagents and conditions: (i) MOMCl,
DIPEA, DMAP, DCM, 0 °C to rt, 12 h, 99%; (ii) LAH, THF, 0 °C to rt, 2h, 98%; (iii)
TBDPSCl, n-BULi, THF, 0 °C, 1 h, 99%.
OH NH2
BnN
MOMO
TBDPSO
iv
HO
OH
COOH
OMOM
OH
O
12
4
Scheme 3. Synthesis of (+)-polyoxamic acid 4. Reagents and conditions: (i) (a)
(COCl)2, DMSO, Et3N, DCM, À78 °C, 2 h; (b) BnNH2, DCM, 4 Å molecular sieves,
Na2SO4, À4 °C,4 h; (c) vinylmagnesium bromide, THF, 0 °C to rt, 30 min, 85% (over 3
steps); (ii) CbzCl, NaHCO3, MeOH, 0 °C to rt, 2 h, 90%; (iii) (a) O3, DCM, À78 °C, then
Me2S; (b) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, 0 °C to rt, 2 h, 80% (over 2
steps); (iv) 10% Pd/C, H2, MeOH, rt, 12 h, then 6 M HCl, rt, 6 h, 85%.
Our synthesis commenced from the commercially available
diethyl L-tartarate 7. Treatment of 7 with MOMCl and DIPEA in
DCM gave compound 8 in 99% yield Scheme 2.14a
Reduction of ester functionality in 8 with LiAlH4 in THF afforded
the diol 9 in 98% yield.14a Selective protection of diol 9 in THF using
TBDPSCl and n-BuLi gave alcohol 10 in 99% yield.15 Swern oxida-
tion of primary alcohol 10 gave the desired aldehyde, which on
treatment with BnNH2 in DCM at À4 °C gave the corresponding
imine 6. Grignard addition on crude imine 6 with vinylmagnesium
bromide at 0 °C gave threo isomer 11 diasteroselectively as the sole
product in 85% (from 10). The highly diasteroselective addition
was expected on the basis of the Chelation–Cram model, in which
the nucleophile (vinyl) approaches from the less hindered face of
the conformationally locked imine (Fig. 2).16 Treatment of the sec-
ondary amine in 11 with CbzCl and NaHCO3 in MeOH gave com-
pound 5 in good yield. For the synthesis of polyoxamic acid,
ozonolysis of the terminal olefin in compound 5 at À78 °C afforded
the aldehyde, which underwent Pinnick oxidation to give acid 12 in
80% (over two steps). The compound 12 was subjected to hydrog-
enolysis over catalytic Pd/C in MeOH followed by acid treatment
with 6 M HCl afforded the desired final product (+)-polyoxamic
acid 4. The analytical and spectral data were in good agreement
with the reported values.11n
Cbz
Cbz
BnN
MOMO
TBDPSO
BnN
MOMO
TBDPSO
i
OH
ii
OMOM
5
OMOM
OMOM
13
14
H
N
Cbz
BnN
MOMO
HO
iii
iv
OH
OMOM
OH
HO
OMOM
15
2
Scheme 4. Synthesis of 1,4-dideoxy-1,4-imino-D-xylitol 2. Reagents and condi-
tions: (i) (a) O3, DCM, 30 min, then Me2S, À78 °C; (b) NaBH4, MeOH, 0 °C to rt, 1 h,
85% (over 2 steps); (ii) MOMCl, DIPEA, DCM, DMAP, 0 °C to rt, 12 h, 90%; (iii) TBAF,
THF, rt, 1 h, 87%; (iv) (a) MsCl, Et3N, DCM, DMAP, 30 min; (b) 10% Pd/C, H2, MeOH,
rt, 12 h, then 6 M HCL, rt, 12 h, 80%.
Cbz
H
This approach helps in synthesizing polyoxin J 1a, polyoxin L
1b, polyoxin B 1c, and polyoxin D 1d. Removal of the silyl group
in 5 with TBAF followed by known carbamoylation17 and oxidation
of the olefin will give carbamoyl polyoxamic acid. Coupling of this
acid with appropriately protected thymine polyoxin C, will yield
the above polyoxins based on the reported procedures Scheme 3.17
BnN
MOMO
HO
N
ii
i
5
OMOM
16
OH
HO
3
Scheme 5. Synthesis of dihydroxy pyrrolidine 3. Reagents and conditions: (i) TBAF,
THF, rt, 1 h, 90%; (ii) (a) MsCl, Et3N, DCM, DMAP, 30 min; (b) 10% Pd/C, H2, MeOH, rt,
12 h, then 6 M HCL, rt, 6 h, 80%.
For the synthesis of 1,4-dideoxy-1,4-imino-D-xylitol 2, com-
pound 5 in DCM was subjected to ozonolysis at À78 °C to afford
the aldehyde, which on reduction with NaBH4 in MeOH gave pri-
mary alcohol 13 in 85% yield (for 2 steps). Protection of primary
alcohol in 13 as MOM ether using MOMCl and DIPEA in DCM gave
compound 14 in 90% yield. Cleavage of the silylether group in 14
using TBAF in THF afforded alcohol 15 in good yield. Treatment
of primary alcohol 15 with MsCl and Et3N in DCM gave the mesy-
lated product, which on hydrogenolysis in the presence of catalytic
Pd/C in MeOH and treatment of the crude mixture with 6 M HCl
2 in 80% yield (over 2 steps), whose spectral and analytical data
were in good accordance with the literature values Scheme 4.10a
Then, we turned our attention to synthesize dihydroxy pyrroli-
dine 3. Treatment of compound 5 with TBAF gave alcohol 16 in 90%
yield. For the construction of the pyrrolidine ring, compound 16
was mesylated and the mesylated mixture was subjected to
hydrogenolysis followed by acid treatment with 6 M HCl to afford
gave the desired final compound 1,4-dideoxy-1,4-imino-D-xylitol
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M. Lingamurthy et al. / Tetrahedron Letters xxx (2013) xxx–xxx
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analytical data were in good accordance with the reported ent-3
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In conclusion, we have achieved the synthesis of dihydroxy
chiral amino moiety 5 a versatile intermediate for the synthesis
of (+)-polyoxamic acid 4, 1,4-dideoxy-1,4-imino-D-xylitol 2, and
dihydroxy pyrrolidine 3 using a highly diastereoselctive Grignard
addition on imine 6 as the key step from the commercially avail-
able diethyl L-tartarate as a starting material. Future applications
of this strategy for the synthesis of some molecules containing
polyhydroxy chiral amino units are under progress.
Acknowledgments
M.L.M thanks CSIR-New Delhi and A.R .thanks UGC-New Delhi
for financial support as part of XII Five Year plan programme under
title ORIGIN (CSC-0108). The authors also thank the Director, CSIR-
IICT for the constant support and encouragement.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
08.126.
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Please cite this article in press as: Lingamurthy, M.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.08.126