Synthetic approaches to imino sugar (2R,3R,4S)-2-(hydroxymethyl)-4- methylpyrrolidine-3,4-diol from naturally occurring sugar and amino acid

Article abstract of DOI:10.1016/j.tetlet.2010.11.068

Imino sugar compound 3 was prepared by two alternative routes starting from ribose and d-serine. From d-serine (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)- 3-methylpyrrolidin-2-one was prepared in five steps in 50% overall yield, which was further converte

Full text of DOI:10.1016/j.tetlet.2010.11.068

Tetrahedron Letters 52 (2011) 365–368
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic approaches to imino sugar (2R,3R,4S)-2-(hydroxymethyl)-4-
methylpyrrolidine-3,4-diol from naturally occurring sugar and amino acid
⇑
Pravin L. Kotian , Ajit Ghosh, Tsu-Hsing Lin, Minwan Wu, V. Satish Kumar, Yarlagadda S. Babu,
Pooran Chand
BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 April 2010
Revised 11 November 2010
Accepted 13 November 2010
Available online 18 November 2010
Imino sugar compound 3 was prepared by two alternative routes starting from ribose and D-serine. From
D-serine (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methylpyrrolidin-2-one was prepared in five
steps in 50% overall yield, which was further converted into (2R,3R,4S)-2-(hydroxymethyl)-4-methylpyr-
rolidine-3,4-diol in three steps in 23% overall yield.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Imino sugar
HCV
1. Introduction
plan to explore imino sugar derivatives as antiviral agents for
HCV, by replacing the ribose moiety of compound 7 with imino
Chiral polyhydroxylated pyrrolidines, also called as imino sug-
ars, are important components of biologically-active molecules.
They are found to be widespread in plants and microorganisms.1
Polyhydroxylated pyrrolidines mimic the structure of natural sug-
ars and are useful intermediates for the synthesis of various prom-
ising bioactive molecules. These have resulted in various analogs
useful as antiviral,2 antidiabetic,3 anticancer,4 and various autoim-
mune disease targets. We have used imino sugars 1 and 2 (Fig. 1),
to synthesize compound 4 (BCX-4208) and 5 (BCX-1777) as potent
inhibitors of human purine nucleoside phosphorylase (PNP). PNP
inhibitors represent a novel class of selective immunosuppressive
agents useful in the treatment of a wide variety of T-cell mediated
disorders. These include psoriasis, rheumatoid arthritis, and other
T-cell proliferative disorders, such as organ transplant rejection
and adult T-cell leukemia.5,6 BCX-4208 and BCX-1777 are currently
in clinical trials as PNP inhibitors for the treatment of psoriasis and
cutaneous T-cell lymphoma (CTCL). We plan to further broaden the
use of this imino sugar in the field of antiviral compounds (HCV).
HCV infection, identified in 1989, is a chronic liver disease. Cur-
rently there are no vaccines available. The current standard of
treatment involves using pegylated interferon combined with
Ribavarin. Since this therapy has poor response rate in genotype
1 patients and involves severe side effects, there is a significant un-
met medical need for safer and more effective HCV agents.11 We
sugar 3.
20-b-C-Methyl-b-
D
-ribofuranosyl adenine 6 and its 9-deaza
derivative 7 (Fig. 2) have shown very good activity against HCV
in replicon assay.7–10 The importance of the 20-b-C-methyl group
in the ribose moiety has been well demonstrated.12 Since we plan
to synthesize compound 8 where ribose moiety of 7 has been re-
placed by aza sugar, a shorter synthesis of imino sugar (3) was very
much desired. Therefore we have developed a practically feasible
short synthesis for imino sugar (3) from naturally occurring
D-serine.
H
N
H
N
H
N
HO
HO
HO
OH
HO OH
HO
O
OH
HO
1
2
3
NH
NH
H
O
N
NH
N
N
NH
N
HO
OH
HO
OH
(BCX-4208)
⇑
Corresponding author. Tel.: +1 (205)444 4628; fax: +1 (205)444 4640.
E-mail addresses: pkotian@biocryst.com (P.L. Kotian), pchand@therachem.org
(P. Chand).
4
5 (BCX-1777)
Figure 1.
Present address: United Chem Resources, LLC, Birmingham, AL, USA.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.068

366
P. L. Kotian et al. / Tetrahedron Letters 52 (2011) 365–368
NH
N
NH
N
H
NH2
NH2
O
NH2
O
N
N
HO
HO
HO
N
N
N
N
N
HO
HO
HO
HO
OH
OH
8
7
6
Figure 2.
to compound 13 as reported previously by Schramm.19 A similar
titanium(IV) chloride mediated addition of methyl magnesium
bromide on monocyclic ketone 13 gave three isomers 14, 15, and
16 in the ratio of 2:1:1. Compound 16 is probably formed by the
enolization of the 4-benzyloxy group followed by 1,2-addition to
the ketone. The stereochemistry of compound 14 was confirmed
by 1H NMR NOE experiments of its derivative. Protection of the ter-
tiary hydroxy group as the benzyloxy group followed by deprotec-
tion of the Boc group on compound 14 gave the key aza sugar 18.
Deprotection of protecting groups on compound 17 by catalytic
hydrogenation under acidic condition gave the imino sugar 3
whose stereochemistry was confirmed by the X-ray crystallogra-
phy (Fig. 1). The nitrogen on imino sugar 3 was selectively pro-
tected as an Fmoc group to furnish compound 19. Protection of
the 3,4-hydroxy group as an acetonide gave compound 20. Finally,
protection of the primary hydroxyl group as TBDMS and deprotec-
tion of Fmoc from the aza sugar gave the protected imino sugar 21.
The drawback with the above method was the loss of stereo
control during the titanium(IV) chloride mediated addition of
methyl magnesium bromide on monocyclic ketone 13. We decided
to explore an alternative route to minimize this loss of stereo con-
2. Results and discussion
The preparation of compounds 1 and 2 has been previously re-
ported.13–15 Sardina16 and Qing17 previously reported the synthesis
of isomers of compound 3 from trans-4-hydroxy-
and co-workers18 reported an approach to make nonmethylated
isomers of compound 3 starting from -tyrosine. We envisioned
two approaches making use of the chiral pool available from
natural sugar and amino acid. Our first approach started from the
known pyrrolidine 9 (Scheme 1), which can be conveniently
prepared in multi-gram quantities from ribonolactone.14a
L-proline. Park
D
Ribonolactone is easily derived from
D
-ribose.14b Schramm and
co-workers19 have reported the synthesis of compound 10 from
compound 9 by a series of selective protection of 4,6 hydroxy
group via tetraisopropyldisiloxane derivative, which was followed
by oxidation of free alcohol on 10 to give the ketone 11.
Titanium(IV) chloride mediated addition of methyl magnesium
bromide on ketone 11 resulted in the selective
a-addition of the
methyl group. This selectivity may be arising from the addition
of the methyl group from the outside of the concave face of the
bicyclic system 11. We thought that opening the bicyclic system
would lead to loss in selectivity. We functionalized compound 10
trol. In our second approach (Scheme 2) starting from D-serine we
Boc
Boc
H
BnO
N
H
O
TBDMSO
O
N
Si
O
N
N
i
vii
Si
O
OBn
vi
ii d
BnO
Si
O
O
Si
12
O
O
O
OH
11
10
9
ii
Boc
Troc
N
Boc
N
Boc
N
BnO
BnO
BnO
BnO
N
iii
+
+
OH
OH
BnO
OH
BnO
O
BnO
BnO
14
13
15
16
iv
2:1:1 in favor of desired product
Boc
N
H
H
BnO
HO
N
N
BnO
ii d
v
BnO
OBn
HO
OH
18
BnO
OBn
17
3
(2R,3R,4S)-2-(Hydroxymethyl)
-4-methylpyrrolidine-3,4-diol
[α] = +44 (c = 0.39, MeOH)
viii
Fmoc
Fmoc
H
TBDMSO
x, xi
HO
N
HO
N
N
ix
O
O
O
O
HO
OH
21
19
20
Scheme 1. Reagents and notes: (i) (a) 10% TFA, (b) Et3N/(Boc)2O, (c) 1,3-dichlorotetraisopropyldisiloxane; (ii) (a) MOMBr, DIPEA, (b) TBAF/THF, MeOH, (c) NaH/BnBr, (d) THF/
TFA/H2O, (e) 2,2,2-trichloro-ethylchloroformate, Et3N, (f) DMSO/TFAA/Et3N; (iii) (a) TiCl4/MeMgBr, (b) Zn-dust/AcOH; (c) (Boc)2O/Et3N, CH2Cl2; (iv) NaH/BnBr DMF; (v) HCl,
Pd/C, MeOH; (vi) CrO3; (vii) (a) MeMgBr, (b) TBAF, (c) NaH, BnBr; (viii) Fmoc Cl, DIPEA; (ix) Me2CO, 2,2-dimethoxypropane, p-TSA; (x) TBDMSCl, imidazole; (xi) 20%
piperidine.

P. L. Kotian et al. / Tetrahedron Letters 52 (2011) 365–368
HO
367
HO
H
CO2H
R
NH2
H
N
H
HO
i
O
CO2Me
HO
ref 20
O
N
Boc
23
22
HO
OH
D-SERINE
24
Single isomer
obtained
93% yield with DMF
1:2 ratio
ii
79% yield without DMF
1:2.5 ratio
H
N
H
HO
O
O
N
O
H
+
HO
N
O
O
O
O
O
HO OH
25
3
26
v
iii
iii
H
N
H
H
N
HO
O
TBDMSO
N
O
iv
O
O
O
O
O
O
28
27
21
Scheme 2. Reagents and notes: (i) HCl, MeOH, base, pH 7; (ii) DMP, DMF, catalytic p-TSA, 70 °C, 16 h; (iii) LAH; (iv) TBDMSiCl, py, imidazole; (v) methanolic HCl.
prepared enantiomerically pure (S)-tert-butyl 4-((1S,2S)-1,2-dihy-
droxy-3-methoxy-2-methyl-3-oxopropyl)-2,2-dimethyloxazolidi-
ne-3-carboxylate compound 23 according to the literature
methods.20 The synthesis of the other enantiomer of compound
23 has been reported by Kauppinen and Koskinen20 starting from
In order to compare the imino sugar from both the routes, imino
sugar 27 was hydrolyzed using methanolic HCl to furnish com-
pound 3. The physical properties of the compounds made by the
two routes were comparable (Fig. 3).22
In conclusion, we have developed methods to synthesize the
L
-serine in 60% overall yield.21 Treatment of compound 23 with
protected imino sugar with the 20-b-C-methyl configuration for
concd HCl gave the corresponding hydroxylated pyrrolidone 24
the first time via two routes, from ribonolactone and D-serine.
Functionalization of compound 21 to the target molecule 8 and
its biological activity will be published in a later publication.
as a white solid in 60% yield [½a D25
ꢀ
+97.6 (c 1.01, H2O), +89.82
(c 1.12, MeOH)]. Treatment of pyrrolidone 24 with DMP and ace-
tone with a catalytic amount of p-TSA gave mixtures of lactam
26 and 25 in 79% yield in 2.5:1 ratio. However, using DMF com-
pound 24 gave a 2:1 ratio of lactams 26 and 25 in 93% yield. Lactam
26 was converted into the corresponding protected imino sugar 28
using LAH. The protecting group on primary hydroxyl of imino lac-
tam 26 was labile and during LAH reduction, imino sugar 27 was
also formed along with imino sugar 28. Similarly, LAH reduction
of lactam 25 followed by the protection of the primary alcohol gave
the fully-protected imino sugar 21.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.068.
References and notes
1. Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645–1680.
2. Durantel, D.; Branza-Nichita, N.; Carrouee-Durantel, S.; Butters, T. D.; Dwek, R.
A.; Zitzmann, N. J. Virol. 2001, 75, 8987–8998.
3. Andersen, B.; Rassov, A.; Westergaard, N.; Lundgren, K. Biochem. J. 1999, 342,
545–550.
4. Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer Res. 1995, 1, 935–
944.
5. Kazmers, I. S.; Mitchell, B. S.; DaDonna, P. E.; Wotring, I. I.; Townsend, L. B.;
Kelly, W. N. Science 1981, 214, 1137–1139.
6. Sircar, J. C.; Gilbertsen, R. B. Drugs Future 1988, 13, 653–668.
7. Eldrup, A. B.; Allerson, C. R.; Bennet, C. F.; Bera, S.; Bhat, B.; Bhat, N.; Bosserman,
M. J.; Brooks, J.; Burlein, C.; Carroll, S. S.; Cook, P. D.; Getty, K. L.; MacCoss, M.;
McMasters, D. R.; Orakash, T. P.; Prhavc, M.; Song, Q.; Tomassini, J. E.; Xia, J. J.
Med. Chem. 2004, 47, 2283.
8. Griffith, R. C.; Lou, L.; Roberts, C. D.; Schmitz, U. Ann. Rep. Med. Chem. 2004, 39,
223.
9. Prakash, T. P.; Prhavc, M.; Eldrup, A. B.; Cook, P. D.; Carroll, S. S.; Olsen, D. B.;
Stahlhut, M. W.; Tomassini, J. E.; MacCoss, M.; Galloway, S. M.; Hilliard, C.;
Bhat, B. J. Med. Chem. 2005, 48, 1199.
10. Olsen, D. B.; Eldrup, A. B.; Bartholomew, L.; Bhat, B.; Bosserman, M. R.; Ceccacci,
A.; Colwell, L. F.; Fay, J. F.; Flores, O. A.; Getty, K. L.; Grobler, J. A.; Lafemina, R. L.;
Market, E. J.; Migliaccio, G.; Prhavc, M.; Stalhurt, M. W.; Tomassini, J. E.;
MacCoss, M.; Hazuda, D. J.; Carroll, S. S. Antimicrob. Agents Chemother. 2004, 48,
3944.
11. Manns, M. P.; Foster, G. R.; Rockstroh, J. K.; Zeuzem, S.; Zoulim, F.; Houghton,
M. Nat. Rev. Drug Disc. 2007, 6, 991–1000.
12. Carroll, S. S.; Olsen, D. B. Infect. Disord.: Drug Targets 2006, 6, 17–29.
13. Yokoyama, M.; Momotake, A. Synthesis 1999, 9, 1541–1554.
Figure 3. ORTEP representation of sugar hydrochloride highlighting the stereo-
chemistry of compound 3 showing the three chiral centers for C2, C3, and C4 atoms.

368
P. L. Kotian et al. / Tetrahedron Letters 52 (2011) 365–368
14. (a) George, W. J. F.; Jong, C. S. Tetrahedron 1988, 44, 2637–2647; (b) Kamath, V.;
Morris, P.; Williams, J. D.; Townsend, L. Org. Synth. 2005, 82, 75.
15. Kotian, P. L.; Lin, T.-H.; El-Kattan, Y.; Chand, P. Org. Proc. Res. Dev. 2005, 9, 193–
197.
16. Blanco, M.-J.; Sardina, F. J. J. Org. Chem. 1996, 61, 4748–4755.
17. Qiu, X.-L.; Qing, F.-L. J. Org. Chem. 2005, 70, 3826–3837.
18. Kim, J. H.; Curtis-Long, M. J.; Seo, W. D.; Ryu, Y. B.; Yang, M. S.; Park, K. H. J. Org.
Chem. 2005, 70, 4082–4087.
3410, 2976, 2941, 2913, 2874, 1722, 1684, 1456, 1396, 1365, 1260, 1175, 1115,
1068, 1034, 979 cmꢁ1; MS (ES+) 356.42 (M+Na). Anal. Calcd for C15H27NO7: C,
54.04; H, 8.16; N, 4.20. Found: C, 54.23; H, 8.25; N, 4.19. ½a D25
ꢀ
+28.22 (c 1.09,
EtOH); ½a 2D5
ꢀ
+15.57 (c 1.02, CHCl3). The optical rotation for the corresponding
enantiomer of compound 23 as reported20 from
L
-serine is ½a 2D5
ꢁ9.2 (c 1,
ꢀ
CHCl3).
22. Compound
3 from ribonolactone route: mp 216–218 °C; Anal. Calcd for
C6H13NO3ꢂHCl: C, 39.24; H, 7.68; N, 7.62. Found: C, 39.11; H, 7.46; N, 7.49. ½a D25
ꢀ
19. Evans, G. B.; Furneaux, R. H.; Lewandowicz, A.; Schramm, V. L.; Tyler, P. C. J.
Med. Chem. 2003, 46, 3412–3423.
+44 (c 0.39, methanol).
Compound 3 from D
-serine: mp 214.0 °C; 1HNMR (300 MHz, MeOD) d 3.91
20. Kauppinen, P. M.; Koskinen, A. M. P. Tetrahedron Lett. 1997, 38, 3103–3106.
(dd, J = 3.3, 11.9, 1H), 3.84 (d, J = 8.9, 1H), 3.77 (dd, J = 5.7, 11.9, 1H), 3.53
(ddd, J = 3.3, 5.7, 9.0, 1H), 3.25 (d, J = 12.1, 1H), 3.15 (d, J = 12.1, 1H), 1.38–
1.31 (m, 3H) 13CNMR (75 MHz, MeOD) d 76.27, 76.18, 64.58, 59.61, 55.29,
21.09; MS (ES+) 148.2 (M+1); Anal. Calcd for C6H13NO3ꢂHCl: C, 39.24; H,
21. Starting from D-serine methyl ester using the procedure as reported in Ref. 20
compound 23 was obtained as a white solid; mp 84–87 °C. 1HNMR (C6D6): d
5.02 (s, 1H), 4.23 (d, J = 9.0 Hz, 1H), 4.12 (dd, J = 9.0 and 9.7 Hz, 1H), 3.96 (dd,
J = 5.8 and 6.4 Hz, 1H), 3.63 (dd, J = 9.2 and 5.8 Hz, 1H), 3.31 (s, 3H), 2.44 (d,
J = 10.6 Hz, 1H), 1.58 (s, 3H), 1.50 (s, 3H), 1.36 (s, 9H), 1.33 (s, 3H); IR (KBr)
7.68; N, 7.63. Found: C, 39.41; H, 7.98; N, 7.55.
methanol).
½ ꢀ +54 (c 0.24,
a 2D5