Diversity oriented concise asymmetric synthesis of azasugars: A facile access to l-2,3-trans-3,4-cis-dihydroxyproline and (3S,5S)-3,4,5-trihydroxypiperidine

Article abstract of DOI:10.1016/j.tetlet.2015.10.013

Diversity oriented concise asymmetric syntheses of l-2,3-trans-3,4-cis-dihydroxyproline and (3S,5S)-3,4,5-trihydroxypiperidine have been developed from (R)-glycidol. The key step of the synthesis is Sharpless asymmetric dihydroxylation on enantiomerically pure TBDMS protected allylic alcohol 14 which generates the triol intermediate 15 in excellent de. The (2R,3R,4S)-2,3-dihydroxypentanoate derivative 15 was subsequently converted to natural pyrrolidine azasugar 1 and non-natural piperidine azasugar 4 under cascade reaction conditions in good yields.

Full text of DOI:10.1016/j.tetlet.2015.10.013

Tetrahedron Letters 56 (2015) 6659–6663
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diversity oriented concise asymmetric synthesis of azasugars:
a facile access to L-2,3-trans-3,4-cis-dihydroxyproline and
(3S,5S)-3,4,5-trihydroxypiperidine
Vikas S. Gajare a,c, Sandip R. Khobare a, Rajender Datrika a, K. Srinivas Reddy a, Nagaraju Rajana a,
Sarvesh Kumar b, B. Venkateswara Rao c, U. K. Syam Kumar b,
⇑
a Technology Development Center, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Miyapur, Telangana 500049, India
b Integrated Product Development Organization, Dr. Reddy’s Laboratories Ltd, Innovation Plaza, Bachupally, Telangana 500072, India
c AU College of Engineering (A), Andhra University, Visakhapatanum 530003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Diversity oriented concise asymmetric syntheses of L-2,3-trans-3,4-cis-dihydroxyproline and (3S,5S)-
Received 22 August 2015
Revised 30 September 2015
Accepted 4 October 2015
Available online 9 October 2015
3,4,5-trihydroxypiperidine have been developed from (R)-glycidol. The key step of the synthesis is
Sharpless asymmetric dihydroxylation on enantiomerically pure TBDMS protected allylic alcohol 14
which generates the triol intermediate 15 in excellent de. The (2R,3R,4S)-2,3-dihydroxypentanoate
derivative 15 was subsequently converted to natural pyrrolidine azasugar 1 and non-natural piperidine
azasugar 4 under cascade reaction conditions in good yields.
Keywords:
Diastereoselective synthesis
Azasugar
Ó 2015 Elsevier Ltd. All rights reserved.
Wittig reaction
Sharpless dihydroxylation
Pyrrolidine and piperidine
Substituted pyrrolidine and piperidine azasugars are important
class of biologically active molecules as many of these compounds
exhibit promising chemotherapeutic potential in the treatment of
various diseases such as viral infections, cancer, AIDS, and dia-
betes.1 Nojirimycin2a (3) and deoxynojirimycin2b (3a) have been
found to be potent glycosidase inhibitors (Fig. 1). Minor
structural or functional modifications on these carbohydrate
mimetics can impart remarkable changes to their potency and
specificity of inhibition.3 Polyhydroxylated pyrrolidines and
piperidines are found to be potent anti-HIV,4 anti-neoplastic and
anticancer agents.5 They are also present in active molecules for
the treatment of diabetes and viral infections.6 Due to the remark-
able biological importance of these classes of azasugars, their con-
cise, efficient, and enantioselective synthesis are highly desirable.
On the onset of our studies, the motive was to develop efficient
routes for the synthesis of natural product 2,3-trans-3,4-cis-dihy-
droxy proline (DHP) 1 and (3S,5S)-3,4,5-trihydroxy piperidine 4.
The natural product 1 was isolated from the marine mussel Mytilus
edulis and it was structurally identified as a constituent of the sixth
residue in the repeating decapeptide sequence of the adhesive
protein Mefp1.7 Fleet and Son had demonstrated the synthesis of
2,3-trans-3,4-cis-dihydroxy proline (1) from -gluconolactone in
D
1988 before its identification from natural sources.8 Subsequently,
different synthetic approaches are reported in the literature for the
synthesis of 1. Most of these synthetic protocols for the deceptively
simple looking azasugars relay upon carbohydrate or chiral
aminoacids as starting material for achieving stereochemical
requirement of polyhydroxy frame work.9 Azasugars 5–7 (Fig. 1)
had been isolated from Eupatorium fortunei TURZ by Kusano and
co-workers.10 The plant extract of Eupatorium fortunei TURZ was
traditionally used in folk medicines as diuretic, antipyretic,
emmanagogue and also as antidiabetic agent.
Results and discussion
Ganem and co-workers, reported the synthesis of 3,4,5-trihy-
droxy piperidines 5, 7, and 8 starting from D-hexose before their
isolation from natural sources.11 Other synthetic approaches for
these chirally pure azasugars reportedly use Grubbs metathesis12
and photo-induced electron transfer reaction13 as key steps. As a
part of our efforts to develop new methodologies for the synthesis
of biologically active natural products,14 herein we disclose a
diversity oriented and concise asymmetric approach to access
⇑
Corresponding author. Fax: +91 4023045439/5438.
E-mail address: syam_kmr@yahoo.com (U.K. Syam Kumar).
http://dx.doi.org/10.1016/j.tetlet.2015.10.013
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

6660
V. S. Gajare et al. / Tetrahedron Letters 56 (2015) 6659–6663
OH
followed by the Boc protection in methanol in the presence of cat-
OH
HO
OH
HO
OH
HO
R
OH
OH
alytic amount of TEA (0.1 equiv) afforded N-Boc amino diol 11 as a
single enantiomer. The selective oxidation of primary hydroxyl
group in 11 to the corresponding aldehyde 12 by keeping the
unprotected secondary alcohol intact was attempted next. Various
oxidation conditions including TCCA/TEMPO,16 NaOCl/TEMPO,17
NCS/TEMPO18 etc., were screened. Good yield along with high site
selectivity was observed when the oxidation was carried out with
TEMPO/TCCA in ethyl acetate. The aldehyde 12 was found to be
unstable, hence we decided to use it directly for Wittig olefination
reaction without further purification. Thus, the exposure of 12 to
Wittig olefination reaction with ethyl-2-(triphenylphosphoranyli-
dene)acetate in DCM furnished the required product after column
chromatographic purification in 49% isolated yield. Wittig olefina-
tion reaction furnished trans-alkene as the major product which
was confirmed by coupling constant value in 1H NMR spectrum
(J = 15.6 Hz). The minor product cis olefin presumably underwent
intramolecular cyclization to the corresponding furanone either
during the reaction or during the column chromatography, how-
ever, the furanone couldn’t be characterized, as it was heavily con-
taminated with triphenylphospine oxide.19 The attempted
Sharpless asymmetric dihydroxylation reaction on allylic hydroxyl
HO
OH
OH
OH
N
H
N
H
2
N
H
N
H
4
O
3
3a
R = OH
R = H
1
OH
OH
OH
OH
HO
OH
HO
OH
HO
OH
HO
OH
N
H
N
H
N
H
N
H
5
6
7
8
Figure 1.
natural product 2,3-trans-3,4-cis-dihydroxy proline 1 and non-
natural product (3S,5S)-3,4,5-trihydroxy piperidine 4 with high
diastereoselectivity. Our synthetic design was surmised to access
both the pyrrolidine and piperidine based natural azasugars 1
and 4 from simple and commercially accessible R-glycidol chiral
entity.
The retrosynthetic design for the stereoselective synthesis of 1
and 4 is described in Scheme 1. 2,3-trans-3,4-cis-Dihydroxyproline
(1) could be obtained from N-Boc amino ester intermediate 16 by
the global deprotection of N-Boc and O-TBDMS groups followed
by the base induced cyclization. Intermediate 16 could be obtained
by the selective tosylation of active hydroxyl group of diol 15,
which in turn could be accessed from allyl hydroxyl ester interme-
diate 14 under Sharpless asymmetric dihydroxylation conditions.
ester intermediate 13 with AD-mix-a did not afford the required
product. Reasoning that the chelation of unprotected allylic hydro-
xyl group with ‘Os reactive species’ during the course of dihydrox-
ylation might be the possible cause (Fig. 2) for the failure of
Sharpless asymmetric hydroxylation reaction,20 the free hydroxyl
group in 13 was protected as TBDMS ether. The TBDMS protected
intermediate 14 was subsequently subjected to Sharpless asym-
metric dihydroxylation reaction21 using AD-mix-
required product 15 in 65% yield as single diastereomer
a to furnish the
The trans a,b-unsaturated ester 14 could be obtained by the selec-
a
tive oxidation of primary hydroxyl group followed by Wittig olefi-
nation on aminodiol intermediate 11. The aminodiol intermediate
11 in turn could be synthesized from R-glycidol by following the
literature report.15 On the other hand, the azasugar (3S,5S)-3,4,5-
trihydroxy piperidine (4) could be synthesized from the aminote-
trol derivative 21. The reduction of ester functionality in 15 fol-
lowed by the selective tosylation of the primary hydroxyl group
could afford the aminotetrol derivative 21.
The synthesis of natural product 2,3-trans-3,4-cis-dihydroxy
proline 1 and (3S,5S)-3,4,5-trihydroxy piperidine 4 was initiated
with commercially available enantiomerically pure (R)-glycidol
(9). Exposure of glycidol 9 to aqueous ammonia at 0 °C for 24 h
(Scheme 2). The structure of 15 was established by NOESY and
COSY NMR studies, and the stereochemical configuration is
assigned based on the literature precedence on similar substrates
obtained via Sharpless asymmetric dihydroxylation reaction.22
The bulky TBDMS protected hydroxyl group plays critical role for
the facial selectivity during the Sharpless asymmetric dihydroxyla-
tion reaction (Fig. 2) as it controls the rotational isomer
population.23
Dihydroxy intermediate 15 was subsequently subjected to
selective tosylation of the secondary alcohol
a to the ester in the
presence of TsCl/TEA in DCM solvent. The reaction was sluggish
at 0–5 °C and the desired product 16 was formed only in 30% yield
even after prolonged maintenance of the reaction mixture for
about 72 h. However, when the reaction was conducted at
25–30 °C, better conversion was observed and 16 was isolated in
63% yield along with around 20% of unreacted starting material.
Under these reaction conditions, tosylation was found to be highly
regioselective, probably due to proximity of C2 hydroxyl with ester
group which increase its acidity and thus favouring the selective
monotosylation.24 Also the C2 hydroxyl group is far away from
the bulky OTBDMS, which also make the tosyl protection on C2
highly regioselective with respect to C3. The global deprotection
of N-Boc and O-TBDMS groups in hydroxyl intermediate 16 was
performed with a solution of HCl in 1,4-dioxane (4 M) at ambient
temperature. Under these acidic conditions, the global deprotected
compound 17 underwent in situ lactonisation to afford 18. Being
an HCl salt, the lactone 18 was found to be highly hygroscopic
and attempted isolation of this intermediate 18 was not successful.
Therefore, 18 was subsequently subjected to barium hydroxide
treatment which resulted in a cascade reaction involving the
neutralization of HCl salt, ring opening of the lactone, and further
heteroannulation to the required natural product 2,3-trans-3,4-
cis-dihydroxy proline 1 as a barium salt.25 The pH of the reaction
mixture was adjusted to 5 with acetic acid and the resulting reac-
tion mixture was purified over IR 120 acidic resin to afford 126 as
OH
HO
OH
HO
OH
OH
N
H
1
N
H
O
4
TsO
TBDMSO
BocHN
TBDMSO
OH
OEt
BocHN
OTs
O
OH
16
OH
21
TBDMSO
BocHN
OH
OEt
OH
15
O
OTBDMS
OH
O
BocHN
OEt
OH
BocHN
OH
O
14
11
Scheme 1. Retro synthetic analysis.
9

V. S. Gajare et al. / Tetrahedron Letters 56 (2015) 6659–6663
6661
Minimal torsional strain,
increase the rotational
isomer populations
Possibilty of
complexation with Os
reactive species
Restricted rotation due to increased torsional
strain, minimize the rotational isomer population
OH
O
OR
O
O
BocHN
BocHN
OEt
OEt
MeO
MeO
O
O
O
Os
O
Os
O
O
N
N
O
N
N
N
N
N
N
O
O
MeO
O
MeO
O
N
N
N
N
Possibilty of multiple side reaction
and low conversions, either due to
chelation with reactive Osmium
species, or basic nature of the
reaction conditions
No binding with allylic hydroxyl group
and bulky protection further direct the
Sharpless Assymetric Dihydroxylation
Figure 2.
TBDMSO
BocHN
OH
OH
TBDMSO
BocHN
OH
OH
O
a
a
BocHN
OH
OH
OH
OEt
H2N
OH
11
OH
20
OH
15
O
9
10
OH
OH
TBDMSO
BocHN
OH
OH OH
b
BocHN
OEt
c
O
BocHN
b
OTs
ClHH2N
OTs
O
13
OH
OH
12
OTBDMS
21
OH
TBDMSO
BocHN
22
d
c
BocHN
OEt
OEt
OH
N
HO
OH
O
OH
15
O
14
H.HCl
Scheme 2. (a) (i) aq ammonia, 0 °C, 24 h; (ii) (Boc)2O, MeOH, TEA (cat.), rt, 71% (two
step); (b) (i) TCCA/TEMPO, ethyl acetate, 5 °C; (ii) Ph3P = CHCOOEt, DCM, 30 °C, 3 h,
49% (two steps); (c) TBDMSCl, imidazole, DCM, rt, 16 h, 91%; (d) K3Fe(CN)6, MeSO2-
4
Scheme 4. (a) NaBH4, THF/MeOH, 0 °C to rt, 2 h, 85%; (b) TsCl/NMI, DCM, 0 °C, 3 h,
NH2, K2CO3, OsO4, AD mix
a
, 0 °C to RT, 65%.
71%; (c) (i) HCl in EtOAc, rt 3 h; (ii) DIPEA, water, rt, 30 h; (iii) 6 N HCl in methanol,
73%.
TBDMSO
BocHN
OTs
TBDMSO
BocHN
OH
H2O); Mp 244.8 °C, [Lit.8
[a
]
D
+7.5° (c 0.16, H2O), Mp
20
a
OEt
O
3
c
OEt
4
c
2
c
247 °C]. The overall yield of the synthesis of 2,3-trans-3,4-cis-dihy-
droxy proline 1 is 16.5% starting from enantiomerically pure
(R)-glycidol (9).
O
OH
16
OH
O
15
O
OH OTs
After the successful synthesis of the natural product 1, we
focused our attention toward the enantio pure synthesis of
(3S,5S)-3,4,5-trihydroxy piperidine 4 (pure single diastereomer)
(Scheme 4). Thus ethyl-2,3-dihydroxypentanoate derivative 15
was subjected to ester reduction using sodium borohydride in a
mixture of methanol and THF to provide tert-butyl ((2S,3R,4S)-2-
((tert-butyldimethylsilyl)oxy)-3,4,5-trihydroxypentyl)carbamate
20 in 85% isolated yield. The regioselective tosylation of the pri-
mary hydroxyl group in the presence of secondary alcohol was
accomplished in 71% isolated yield using TsCl in the presence of
ClH3N
HO
b
OEt
ClHH2N
HO
18
OTs
O
OH
17
OH OTs
OH
Ba2
H2N
O
Ba+2
O
N
H
OH
19
O
2
2
O
1a
HO
OH
N-methyl imidazole as
a
mild base.27 No di-tosylation was
c
OH
observed under these reaction conditions. The monotosyl interme-
diate 21 was found to be less stable and it decomposed rapidly on
heating. However, we were successful in the isolation and charac-
terization of monotosyl intermediate 21. In the next sequence of
reaction for the synthesis of (3S,5S)-3,4,5-trihydroxy piperidine 4,
the global deprotection of N-Boc and O-TBDMS groups in 21 was
carried out with a solution of hydrochloric acid in ethyl acetate
to yield (2S,3S,4S)-5-amino-2,3,4-trihydroxypentyl-4-methylben-
zenesulfonate 22 as a highly hygroscopic hydrochloride salt.
Subsequent neutralization of 22 was expected to result in
N
H
O
1
Scheme 3. (a) TsCl, TEA, DCM, 0 °C to RT, 16 h, 63%; (b) (i) 1,4-dioxane:HCl, rt, 2 h
(ii) 0.1 N Ba(OH)2, (pH = 9), rt, 3 h, (c) IR 120 resin, 77%.
white solid in 77% overall yield (Scheme 3). The spectral data of the
natural product 2,3-trans-3,4-cis-dihydroxy proline 1 is in agree-
22
ment with the literature reported values. [
a
]
+7.99° (c 0.3,
D

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V. S. Gajare et al. / Tetrahedron Letters 56 (2015) 6659–6663
(3S,5S)-3,4,5-trihydroxy piperidine 428 in diastereomerically pure
form via an intramolecular SN2 process. Different base and solvent
combinations, for example, CaCO3 in methanol, TEA in acetonitrile,
N-methyl morpholine in toluene, etc., were screened for the
cyclization of 22. Under these conditions, the reaction was found
to be very sluggish at room temperature and a substantial amount
of unreacted starting material was observed even after prolonged
reaction time. On the contrary, a complex mixture of products
was observed at higher reaction temperatures. Finally, the use of
Hunig’s base (N,N-diisopropylethylamine) in water at ambient
temperature resulted in complete consumption of the starting
material. The crude (3S,5S)-3,4,5-trihydroxy piperidine 4 was
purified on acidic IR 120 resin to afford the enantiopure (3S,5S)-
3,4,5-trihydroxy piperidine as a free base, which was subsequently
converted to hydrochloride salt 4 by using 6 N HCl in methanol in
73% yield starting from 21 (Scheme 4). The spectral data of our
7. Taylor, S. W.; Waite, J. H.; Ross, M. M.; Shabanowitz, J.; Hunt, D. F. J. Am. Chem.
Soc. 1994, 116, 10803.
8. Fleet, G. W. J.; Son, J. C. Tetrahedron 1988, 44, 2637.
9. (a) Nobuo, Ikota Chem. Pharm. Bull. 1993, 41, 1717; (b) Zanardi, F.; Battistini, L.;
Nespi, M.; Rassu, G.; Spanu, P.; Cornia, M.; Casiraghi, G. Tetrahedron: Asymmetry
1996, 1167; (c) Claudette, A.; Weir; Carol, M. T. J. Org. Chem. 1999, 5, 1554; (d)
Fujii, M.; Miura, T.; Kajimoto, T.; Ida, Y. Synlett 2000, 1046; (e) Carol, M. T.;
William, D. B.; Claudette, A. W.; Jae, H. P. J. Org. Chem. 2002, 13, 4466; (f)
Stephen, G. D.; Emma, M. F.; James, A. L.; Paul, M. R.; James, E. T. J. Org. Chem.
2014, 79, 9686; (g) Chirke, S. S.; Rajender, A.; Lakshmi, J. K.; Venkateswara Rao,
B. Tetrahedron Lett. 2015, 55, 1218.
10. Sekioka, T.; Shibano, M.; Kusano, G. Nat. Med. 1995, 49, 332.
11. Bernotas, R. C.; Papandreou, G.; Urbach, J.; Ganem, B. Tetrahedron Lett. 1990, 31,
3393.
12. (a) Michael, G.; Inge, L.; Robert, M.; Bryan, W. Bioorg. Med. Chem. 2010, 11,
1857; (b) Hidekazu, O.; Yukiko, M.; Hiroki, T. J. Org. Chem. 2005, 70,
5207.
13. (a) Pandey, G.; Kapur, M.; Khan, M. I.; Gaikwad, S. M. Org. Biomol. Chem. 2003, 1,
3321; (b) Pandey, G.; Bharadwaj, K. C.; Khan, M. I.; Shashidhara, K. S.; Puranik,
V. G. Org. Biomol. Chem. 2008, 6, 2587.
14. (a) Vikas, S. G.; Sandip, R. K.; Malavika, B.; Nagaraju, R.; Venkateswara, B. R.;
Syam Kumar, U. K. Tetrahedron Lett. 2015, 56, 374; (b) Sandip, R. K.; Vikas, S. G.;
Nagaraju, R.; Rajender, D.; Srinivasa, K. R.; Syam Kumar, U. K.; Siddaiah, V.
Tetrahedron Lett. 2015, 56, 2207; (c) Srinivasan, A. K.; Shyamapada, B.; Syam
Kumar, U. K. Org. Biomol. Chem. 2014, 12, 6105; (d) Suresh Babu, M.;
Ramamohan, M.; Raghunadh, A.; Raghavendra Rao, K.; Dahanukar, Vilas H.;
Pratap, T. V.; Syam Kumar, U. K.; Dubey, P. K. Tetrahedron Lett. 2014, 55, 4739;
(e) Raghunadh, A.; Suresh Babu, M.; Ramamohan, M.; Raghavendra Rao, K.;
Krishna, T.; Gangadhara Chary, R.; Rao, V. L.; Syam Kumar, U. K. Tetrahedron
Lett. 2014, 55, 2986; (f) Sandip, R. K.; Vikas, S. G.; Subbarao, J.; Syam Kumar, U.
K.; Murthy, Y. L. N. Tetrahedron Lett. 2013, 54, 2909; (g) Shankar, R.; More,
Satish S.; Madhubabu, M. V.; Vembu, N.; Syam Kumar, U. K. Synlett 2012, 1013;
(h) Raghunadh, A.; Suresh Babu, M.; Anil Kumar, N.; Santosh, G.; Rao, V. L.;
Syam Kumar, U. K. Synthesis 2012, 44, 283; (i) Shankar, R.; Manoj, B. W.;
Madhubabu, M. V.; Vembu, N.; Syam Kumar, U. K. Synlett 2011, 844; (j) Manoj,
B. W.; Shankar, R.; Syam Kumar, U. K.; Gill, C. H. Synlett 2011, 84; (k)
Shanmugapriya, D.; Shankar, R.; Satyanarayana, G.; Vilas, H. D.; Syam Kumar,
U. K.; Vembu, N. Synlett 2008, 2945–2950.
(3S,5S)-3,4,5-trihydroxy piperidine are identical to the literature
27
reported values. [
a]
+15.5° (c 0.3, MeOH): Mp 191.1 °C [Lit.11
D
[a] +16° (c 0.5, MeOH), Mp 191–192 °C].
D
In conclusion,
a versatile asymmetric strategy for the
construction of -2,3-trans-3,4-cis-dihydroxyproline 1 and (3S,5S)-
L
3,4,5-trihydroxypiperidine (pure single diastereomer) 4 has been
developed from chirally pure glycidol for the first time in the
literature. The synthesis involves multiple cascade reactions, site
selective oxidation and regioselective protection as well as
intramolecular heteroannulation. It is quite obvious that other
densely functionalized piperidine and pyrrolidine azasugars can
be synthesized by following synthetic methodology described here
with excellent stereo chemical controls.
15. Breuning, M.; David, H.; Melanie, S.; Gessner, H.; Carsten, S. Chem. Eur. J. 2009,
46, 12764.
Acknowledgements
16. Luca, L. D.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041.
17. Castejon, P.; Moyano, A.; Pericas, M. A.; Riera, A. Chem. Eur. J. 1996, 2, 1001.
18. Cadoni, R.; Porcheddu, A.; Giacomelli, G.; De Luca, L. Org. Lett. 2012, 14, 5014.
19. (a) Matsumoto, K.; Koyachi, K.; Shindo, M. Tetrahedron 2013, 69, 1043; (b)
Gockel, B.; Goh, S. S.; Puttock, E.; Baars, H.; Chaubet, G.; Anderson, E. A. Org.
Lett. 2014, 16, 4480.
20. Iwashima, M.; Kinsho, T.; Smith, B. M., III Tetrahedron Lett. 1995, 36, 2199.
21. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.
S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M. J. Org. Chem. 1992, 57, 2768.
22. (a) He, L.; Byun, Hoe-Sup; Bittman, R. J. Org. Chem. 2000, 66, 7618; (b) Barros,
M. T.; Barros, M. T.; Janurio-Charmier, O.; Mayock, C. D.; Pires, M. Tetrahedron
Lett. 1996, 52, 7861.
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 Ltd
for providing support.
DRL-IPD Communication No.: IPDO-IPM-00464.
Supplementary data
23. (a) Saito, S.; Morikawa, Y.; Moriwake, T. J. Org. Chem. 1990, 55, 5424;
(b) Saito, S.; Hirohara, Y.; Narahara, O.; Moriwake, T. J. Am. Chem. Soc. 1989,
111, 4533.
24. (a) Fleming, P. R.; Sharpless, B. J. Org. Chem. 1991, 56, 2869; (b) Denis, J.; Correa,
A. J.; Greene, A. E. J. Org. Chem. 1990, 55, 1957.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
013.
25. Bols, M.; Lundt, I. Acta Chem. Scand. 1992, 46, 298.
26. Synthesis of (2S,3R,4S)-3,4-dihydroxypyrrolidine-2-carboxylic acid (1): A solution
of 16 (300 mg, 0.534 mmol) in 1,4-dioxane HCl (3 mL, 4 molar solution) was
stirred for 3 h at ambient temperature. After completion of the reaction,
solvents were evaporated under vacuum and the residue was diluted with
water (9.0 mL). Reaction mixture was maintained at pH 9.0 for 4 h by drop
wise addition of 0.1 N Ba(OH)2 solution. The reaction mass was acidified with
acetic acid to pH ꢀ 5 and purified with acidic resin IR 120 (H+). Product was
eluted in 5% aqueous ammonia. Product fraction was evaporated to get solid
which was further purified with ethanol to afford 60.5 mg (77% yield) of the
desired product (1). 1H NMR (400 MHz, D2O): d ppm 3.28 (dd, J = 12.3, 3.9 Hz,
C5HA, 1H), 3.52 (dd, J = 12.3, 4.9 Hz, C5HB, 1H), 3.97 (d, J = 4.9 Hz, C2H, 1H),
4.32–4.37 (m, C3H and C4H, 2H); 13C NMR (100 MHz, D2O,
trimethylsilylpropionic acid sodium salt used as internal reference): d ppm
51.2, 67.1, 72.8, 76.9, 174.9. IR (KBr) cmÀ1: 3402, 3245, 2714, 2567, 1650, 1613,
1438, 1344, 1255, 1137. HRMS (ESI): Calcd for C5H10NO4 (M+H)+ 148.0610,
References and notes
1. (a) Lairson, L. L.; Withers, S. G. Chem. Commun. 2004, 2243; (b) Kim, C. U.;
Williams, H.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.;
Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119,
681.
2. (a) Inouye, S. E.; Tsuruoka, Y.; Ito, T.; Niida, T. Tetrahedron 1968, 24, 2125; (b)
Yagi, M.; Kouno, T.; Aoyagi, Y.; Murai, H. Nippon Nogeikagaku Kaishi 1976, 50,
571.
3. Daher, A.; Fleet, G.; Namgoong, S. K.; Winchester, B. Biochem. J. 1989, 258, 613.
4. Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms, A. S.; Petursson, S.;
Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.; Son, J. C.; Wilson, F.; Witty, D.
R.; Jacob, G. S.; Rademacher, T. W. FEBS Lett. 1988, 237, 128.
5. (a) Fiaux, H.; Popowycz, F.; Favre, S.; Schütz, C.; Vogel, P.; Gerber-Lemaire, S.;
Jullierat-Jeanneret, L. J. Med. Chem. 2005, 48, 4237; (b) Bello, C.; Dal Bello, G.;
Cea, M.; Garuti, A.; Rocco, I.; Cirmena, G.; Moran, E.; Nahimana, A.; Duchosal,
M. A.; Fruscione, F.; Pronzato, P.; Grossi, F.; Patrone, F.; Ballestrero, A.; Dupuis,
M.; Sordat, B.; Nencioni, A.; Vogel, P. Bioorg. Med. Chem. 2010, 18, 3320; (c)
Bello, C.; Dal Bello, G.; Cea, M.; Nahimana, A.; Garuti, A.; Aubry, D.; Garuti, A.;
Motta, G.; Moran, E.; Fruscione, F.; Pronzato, P.; Grossi, F.; Patrone, F.;
Ballestrero, A.; Dupuis, M.; Sordat, B.; Zimmermann, K.; Loretan, J.;
Wartmann, M.; Duchosal, M. A.; Nencioni, A.; Vogel Bioorg. Med. Chem. 2011,
19, 7720; (d) Gross, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer Res.
1995, 1, 935; (e) Nishimura, Y. Curr. Top. Med. Chem. 2003, 3, 575.
6. (a) Somsak, L.; Nagya, V.; Hadady, Z.; Docsa, T.; Gergely, P. Curr. Pharm. Des.
2003, 9, 1177; (b) Greimel, P.; Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M. Curr. Top.
Med. Chem. 2003, 3, 513.
found 148.0614. [
H2O), Mp 247 °C].
a] a]
22 +7.99° (c 0.3, H2O), Mp 244.8 °C. [lit8: [ 20 +7.5° (c 0.16,
D D
27. Karjalainen, O. K.; Koskinen, A. M. Org. Biomol. Chem. 2011, 9, 1231.
28. Synthesis of (3S,5S)-piperidine-3,4,5-triol hydrochloride (4): A solution of 21
(500 mg, 0.96 mmol) in ethyl acetate containing HCl (10 mL) was stirred at
ambient temperature for 3 h. Solvent was evaporated under vacuum and the
residue was diluted with water (5 ml). N,N-Diisopropyl ethyl amine (621 mg,
4.82 mmol) was added to the reaction mixture and stirred for 30 h at ambient
temperature. Solvent was evaporated under vacuum and the residue was
diluted with water (5 mL). The mixture was acidified with acetic acid to pH ꢀ 5
and purified using acidic resin IR 125 (H+). Product eluted in 5% aqueous
ammonia. Product fraction was evaporated under vacuum to get free amine.
The free amine was further diluted with methanol and treated with 6 M HCl,

V. S. Gajare et al. / Tetrahedron Letters 56 (2015) 6659–6663
6663
stirred, and concentrated under vacuum to obtain the hydrochloride salt,
which was further purified with ethanol to afford 120 mg (73% yield) of the
desired product. 1H NMR (400 MHz, D2O): d ppm 2.92 (dd, J = 12.7, 8.3 Hz, 1H
[H2ax]), 3.17–3.20 (m, 1H, [H6ax]), 3.25 (dd, J = 13.2, 5.9 Hz, 1H, [H6eq]), 3.37
(dd, J = 12.7, 2.4 Hz, 1H [H2eq]), 3.75 (dt, J = 7.8, 2.4, 1H, [H4]), 4.05–4.10 (m,
1H [H3]), 4.21–4.23 (m, 1H, [H5]); 13C NMR (100 MHz, D2O): d ppm 45.5, 46.0,
64.7, 65.0, 70.8. IR (KBr) cmÀ1: 3345, 3298, 3081, 2922, 2903, 2855, 1610, 1440,
1406, 1368. HRMS (ESI): Calcd for C5H12NO3 (M+H)+ 134.0817, found
27
134.0811. [
a
]
+15.5° (c 0.3, MeOH), Mp 191.1 °C. [lit11
[a
]
+16° (c 0.5,
D
D
MeOH), Mp 191–192 °C].