An efficient stereoselective synthesis of (3S,4R)-4-(hydroxymethyl) pyrrolidin-3-ol from (S)-diethylmalate

Article abstract of DOI:10.1016/j.tetlet.2005.03.077

A concise stereoselective synthesis of an imino sugar, (3S,4R)-4- (hydroxymethyl)pyrrolidin-3-ol from (S)-diethylmalate has been developed in five steps and in overall yield of 28%.

Full text of DOI:10.1016/j.tetlet.2005.03.077

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3327–3330
An efficient stereoselective synthesis of
(3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol from (S)-diethylmalate
Pravin L. Kotian and Pooran Chand*
BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA
Received 16 February 2005; revised 14 March 2005; accepted 15 March 2005
Available online 2 April 2005
Abstract—A concise stereoselective synthesis of an imino sugar, (3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol from (S)-diethylmalate
has been developed in five steps and in overall yield of 28%.
ꢀ 2005 Published by Elsevier Ltd.
Hydroxy pyrrolidines, also known as imino sugars, are
known to have an inhibitory effect on certain en-
zymes1–3 and glial GABA uptake.4 The use of these imi-
no sugars as building blocks for the synthesis of some
compounds having antibacterial activity is well docu-
mented.5,6 The very first aza C-nucleoside incorporating
imino sugar was reported by Sorensen et al.3 Recently,
some highly potent purine nucleoside phosphorylase
(PNP) inhibitors (1a–c, Chart 1) have been reported
based upon imino sugars.7–12 One of these PNP inhibi-
tors, BCX-1777 (1a), is one of our clinical candidates
for T-cell- and B-cell-mediated malignancies. Another
clinical candidate, BCX-4208 (2, Chart 1), has evolved
from the second generation of PNP inhibitors, where
(3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol (3) is the pre-
cursor for its preparation.13,14
O
N
O
N
H
H
N
N
NH
NH
H
HO
N
N
R'
R
1a, R = R' = OH
1b, R = H, R' = OH
1c, R = OH, R' = H
HO
OH
2
H
N
H
N
HO
OH
HO
OH
3
4
Chart 1.
The very first synthesis of 3 was reported by Jaeger and
Biel15 from N-benzylglycinate and ethyl acrylate. This
compound was obtained as a mixture of cis/trans-iso-
mers. The synthesis of the trans-racemic compound
was first reported by Makino and Ichikawa16 starting
from fumaric acid dimethylester. The pure enantiomer
of the trans-isomer, (3R,4R)-4-(hydroxymethyl)pyrroli-
adapted to a practical large-scale preparation of the de-
sired trans-isomer, which was used for the preparation
of kilo quantities of our clinical candidate, BCX-4208.
We are now interested in the preparation of the opti-
cally pure cis-isomer of 4-(hydroxymethyl)pyrrolidin-3-
ol (4), which has been used for the preparation of one
of the isomers of BCX-4208 (2), and it could also be-
come the precursor for other bioactive molecules. A lit-
erature search revealed only one reference for the
preparation of the cis-isomer starting from D-xylose in
12 steps.22 We envisioned the synthesis of this com-
pound from diethylmalate, in which the hydroxyl group
is already present; hydroxymethyl could be introduced
stereoselectively at the active methylene position; and
din-3-ol (3), was prepared by Filichev from glucose
17,18
and xylose involving a 14–15-stepsynthesis.
A
shorter synthesis of this isomer was achieved by Karls-
son and Hogberg19,20 via asymmetric 1,3-dipolar cyclo-
addition using camphor sultam as a chiral auxiliary.
This synthesis was recently modified by us21 and
Keywords: Diethylmalate; Imino sugar.
*
Corresponding author. Tel.: +1 205 444 4627; fax: +1 205 444
4640; e-mail: pchand@biocryst.com
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.03.077

3328
P. L. Kotian, P. Chand / Tetrahedron Letters 46 (2005) 3327–3330
OH
CO2Et
OBOM
OBOM
OH
a
b
EtO2C
EtO2C
CO2Et
OBn
HO
5
OBn
6
7
c
6
HO
OH
BOMO
OBn
OBOM
3
2
4
5
OMs
e
d
MsO
N
N
.
HCl
H
OBn
4
8
9
Scheme 1. Reagents and conditions: (a) LDA, ClCH2OCH2Ph, HMPA, THF, ꢁ78 ꢁC to rt; (b) LiAlH4, Et2O; (c) MsCl, pyridine; (d) BnNH2, 60 ꢁC;
(e) H2, Pd/C (10%), HCl.
the diester groups would give dialcohol on reduction
and the cyclization of dialcohol with amine through
mesylate would result in the desired imino sugar. The
search of the literature showed that diethylmalate has
been used for the introduction of hydroxymethyl
functionality by Kinoshita and co-workers23 for the
preparation of one natural product and the reported
synthesis in this paper has indeed given the isomer we
needed for this work.
0 ꢁC for 1 h to furnish dimesylated product 8 in 62% iso-
lated yield.27 Cyclization of dimesyl derivative 8 was
accomplished in excess of benzylamine at 60 ꢁC, yielding
88% isolated pyrrolidine 9.28 Hydrogenolysis of the benz-
yl derivative 9 was done in the presence of 10% Pd/C in
ethanol at 70 psi using 2.0 equiv of concd HCl, which re-
sulted into quantitative yield of debenzylated product 4
as hydrochloride.29 The structure of 4 was confirmed by
NOE experiments. Since compound 4 is reported in the
literature as p-nitrobenzoate, we decided to convert
hydrochloride into p-nitrobenzoate by first making it
as free base then reacting with an equivalent amount
of p-nitrobenzoic acid.30 Again, the structure was
(S)-Diethylmalate (5) (Scheme 1) was obtained from
commercially available (S)-malic acid as reported in
the literature24 through acid catalyzed esterification with
ethanol. The chemical and the optical purity were com-
pared with literature [1H NMR and optical rotation
confirmed by NOE experiments and the optical purity
25
D
was compared with literature reports ½aꢀ ꢁ12.8 (c
25
D
25
D
25
D
1
½aꢀ ꢁ15.53 (c 12.08, acetone), lit.24 ½aꢀ 15.12 (c 5.65,
0.62, methanol), lit.22 ½aꢀ ꢁ10.2 (c 0.6, methanol). H
acetone)]. (S)-Diethylmalate was subjected to alkylation
under the same conditions as reported by Kinoshita and
co-workers. The alkylation was done with 3.0 equiv of
benzyl chloromethyl ether (BOM–Cl) in THF using
2.2 equiv of freshly prepared LDA as base at ꢁ78 ꢁC.
The reaction resulted into exclusive formation of one
isomer, which was characterized as diethyl (2S,3R)-3-
benzyloxymethyl-2-benzyloxymethoxysuccinate (6).25 The
characterization was based upon Kinoshita and
co-workers report23 (experimental details and 1H
NMR data were obtained from Kinoshita), where this
compound was used for the preparation of a natural
product. The desired compound 6 was isolated in 69%
yield (lit.23 70% in the provided experimental details)
after chromatographic purification. It appears that the
reaction is very stereospecific, since we did not isolate
any product corresponding to other isomer. The only
other product isolated was nonalkylated diethyl (2S)-
2-benzyloxymethoxysuccinate in 16.5% yield. Reduction
of 6 was achieved with 2.0 equiv of LAH in THF at re-
flux temperature and dialcohol 7 was obtained in 76%
yield with complete retention of stereochemistry.26 Since
methanesulfonyloxy groups have been successfully used
for the formation of pyrrolidine ring through the reac-
tion with benzylamine, we chose the same groupfor
our synthesis. Therefore, dialcohol 7 was reacted with
3.0 equiv of methanesulfonyl chloride in pyridine at
NMR, 13C NMR, and mpare comparable to the litera-
ture report.
In conclusion, we have developed a short and efficient
synthesis of (3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol,
which could be a valuable starting material for bioactive
molecules.
References and notes
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183.
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3, 525–540.
30 min. The reaction mixture was heated at reflux for 4 h
and quenched by drop-wise addition of water (3 mL) after
cooling to 0 ꢁC. The reaction mixture was filtered through
a pad of Celite and MgSO4 and the cake washed with
1000 mL ethyl acetate. The filtrate was concentrated under
vacuum and the residue purified by flash column chroma-
tography (275 g silica gel, eluting with 0–25% chloroform–
methanol–ammonium hydroxide [80:18:2] in chloroform)
to furnish 5.56 g (76%) of 7 as an oil; 1H NMR (CDCl3): d
7.41–7.29 (m, 10H), 4.89 (d, J = 7.0 Hz, 1H), 4.77 (d,
J = 7.0 Hz, 1H), 4.72–4.59 (dd, J = 12.0 and 25.0 Hz, 2H),
4.50 (s, 2H), 3.92–3.85 (m, 1H), 3.81–3.78 (d, J = 4.5 Hz,
2H), 3.75 (br s, 1H), 3.67 (d, J = 5.0 Hz, 1H), 3.62 (d,
J = 6.0 Hz, 2H), 3.16 (br s, 1H), 2.76 (br s, 1H), 2.12–2.03
(m, 1H); IR (KBr): 3432, 3014, 2886, 1454, 1365, 1216,
13. Evans, G. B.; Furneaux, R. H.; Tyler, P. C.; Schramm, V.
L. Org. Lett. 2003, 5, 3639–3640.
14. Evans, G. B.; Furneaux, R. H.; Lewandowicz, A.;
Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2003, 46,
5271–5276.
1026 cmꢁ1
;
MS (ES+) 369.41 [(M+Na)+]. Anal.
25
(C20H26O5Æ0.25H2O) C, H. ½aꢀD ꢁ7.5 (c 1.45, acetone).
27. Compound 8: Compound 7 (10.5 g, 30.3 mmol) was added
to
a solution of methanesulfonyl chloride (7 mL,
15. Jaeger, E.; Biel, J. H. J. Org. Chem. 1965, 30, 740–744.
16. Makino, K.; Ichikawa, Y. Tetrahedron Lett. 1998, 39,
8245–8248.
17. Filichev, V. V.; Pederson, E. B. Tetrahedron 2001, 57,
9163–9168.
18. Filichev, V. V.; Brandt, M.; Pederson, E. B. Carbohydr.
Res. 2001, 333, 115–122.
19. Karlsson, S.; Hogberg, H.-E. Tetrahedron: Asymmetry
2001, 12, 1977–1982.
20. Karlsson, S.; Hogberg, H.-E. Org. Lett. 1999, 1, 1667–
1669.
21. Kotian, P. L.; Lin, T.-H.; El-Kattan, Y.; Chand, P. Org.
Proc. Res. Dev. 2005, 2, 193–197.
22. Godskesen, M.; Lundt, I. Tetrahedron Lett. 1998, 39,
5841–5844.
23. Ueki, T.; Morimoto, Y.; Kinoshita, T. Chem. Commun.
2001, 1820–1821.
90.9 mmol) in pyridine (30 mL) at 0 ꢁC over a period of
1 h and allowed to warm to room temperature overnight.
The reaction mixture was concentrated under vacuum
and to the residue added 0.5 N aqueous HCl (100 mL)
and ether (100 mL). The organic layer was separated and
washed with brine (50 mL), dried (MgSO4), filtered, and
concentrated. The residue was purified by flash column
chromatography (400 g silica gel, eluting with 0–50% ethyl
acetate in hexanes) to furnish 9.45 g (62%) of 8 as an oil;
1H NMR (DMSO-d6): d 7.36–7.28 (m, 10H), 4.82 (q,
J = 7.0 Hz, 2H), 4.59 (dd, J = 12.0 and 16.0 Hz, 2H), 4.47
(s, 2H), 4.45–4.37 (m, 2H), 4.31–4.24 (m, 2H), 4.02 (m,
1H), 3.55 (d, J = 5.0 Hz, 2H), 3.16 (s, 6H), 2.14–2.31 (m,
1H); IR (KBr): 3546, 3026, 2940, 2881, 1734, 1455,
1360 cmꢁ1
;
MS (ES+) 525.31 [(M+Na)+]. Anal.
25
(C22H30O9S2) C, H. ½aꢀD ꢁ4.37 (c 1.15, ethanol).
28. Compound 9: A mixture of 8 (8.78 g, 17.5 mmol) and
benzylamine (90 mL) was heated at 60 ꢁC for 16 h. The
reaction mixture was concentrated to remove most of
benzyl amine and to the residue added ethyl acetate
(100 mL) and hexanes (100 mL). The mixture was filtered
to remove solids and the filtrate concentrated. The residue
was purified by flash column chromatography (250 g silica
gel, eluting with 0–50% ethyl acetate in hexanes) to furnish
6.41 g (88%) of 9 as an oil: 1H NMR (CDCl3): d 7.24–7.26
(m, 15H), 4.73 (q, J = 7.0 Hz, 2H), 4.54 (dd, J = 12.0 and
17.0 Hz, 2H), 4.50 (s, 2H), 4.34 (m, 1H), 3.75–3.58 (m,
3H), 3.50 (dd, J = 7.5 and 9.0 Hz, 1H), 2.99 (dd, J = 5.5
and 10.0 Hz, 1H), 2.86 (dd, J = 7.0 and 8.0 Hz, 1H), 2.58
(m, 2H), 2.46 (t, J = 9.0 Hz, 1H); IR (KBr): 3013, 2942,
2864, 2797, 1495, 1454 cmꢁ1; MS (ES+) 418.41 [M+1].
24. Meyers, A. I.; Lawson, J. P.; Walker, D. G.; Linderman,
R. J. J. Org. Chem. 1986, 51, 5111–5123.
25. Compound 6: To
a solution of diisopropylamine
(9.05 mL, 64.6 mmol) in THF (100 mL) was added drop-
wise n-BuLi (1.6 M in hexanes, 36.5 mL, 58.3 mmol) at
0 ꢁC over a period of 10 min under nitrogen atmosphere.
The LDA formed was stirred further at 0 ꢁC for 30 min
and cooled to ꢁ78 ꢁC and to this was added dropwise (S)-
25
diethyl malate (5.04 g, 26.5 mmol, ½aꢀD ꢁ15.53 (c 12.08,
acetone) over a period of 10 min. The reaction mixture
was further stirred at ꢁ78 ꢁC for 30 min and warmed to
ꢁ20 ꢁC and maintained at ꢁ20 ꢁC for 1 h. After cooling to
ꢁ78 ꢁC again, BOM–Cl (11 mL, 79.5 mmol) was added
over a period of 10 min and was stirred at this temperature
for 6 h and at room temperature for 24 h. The reaction
mixture was quenched with glacial acetic acid (7.5 mL) in
ether (10 mL) and poured into 100 mL water. The mixture
was extracted with ether (4 · 100 mL) and the combined
organic layers were washed with brine (100 mL), dried
(MgSO4), filtered, and concentrated to furnish oily
residue. Purification of the crude by flash column chro-
matography (300 g, silica gel) eluting with ethyl acetate in
25
Anal. (C27H31NO3) C, H, N. ½aꢀD ꢁ8.6 (c 1.17, ethanol).
29. Compound 4 as hydrochloride: To a mixture of 9 (1.04 g,
2.5 mmol) and Pd/C (10%, 1 g) in ethanol (25 mL) was
added concd HCl (0.41 mL, 5 mmol) and hydrogenated at
70 psi for 4 days. The reaction mixture was filtered
through Celite to remove catalyst and concentrated under
vacuum to dryness to furnish 0.38 g (100%) of 4 as a
semisolid. An analytical sample was prepared by crystal-
lization from ethanol/ether to furnish 4 as a white solid:
mp94–96 ꢁC; 1H NMR (DMSO-d6): d 9.21 (br s, 2H,
NH2+), 5.39 (d, J = 4.0 Hz, 1H, 3-OH), 4.72 (t, J = 5.0 Hz,
1H, 6-OH), 4.26 (dd, J = 7.5 and 3.5 Hz, 1H, H-3), 3.65–
3.55 (m, 1H, H-6), 3.48–3.38 (m, 1H, H-6), 3.29–3.12 (m,
2H, H-2a, H-5a), 3.04 (d, J = 12.0 Hz, 1H, H-2b), 2.84 (t,
J = 11.0 Hz, 1H, H-5b), 2.29–2.12 (m, 1H, H-4); 13CNMR
(DMSO-d6): d 45.59, 46.35, 53.02, 58.33, 69.03; IR (KBr)
3370, 3012, 2921, 1590, 1398, 1317 cmꢁ1; MS (ES+) 118.72
1
hexanes (0–30%) furnished 7.92 g (69%) of 6 as an oil; H
NMR (DMSO-d6): d 7.37–7.23 (m, 10H), 4.76 (s, 2H), 4.54
(s, 2H), 4.46–4.45 (m, 3H), 4.13–4.01 (m, 4H), 3.74–3.58
(m, 2H), 3.17 (dd, J = 7 and 12 Hz, 1H), 1.16 (t, J = 7 Hz,
3H), 1.15 (t, J = 7 Hz, 3H); IR (KBr) 3019, 2901, 1735,
1455, 1374, 1215, 1040 cm ꢁ1; MS (ES+) 453.39 [100%
25
(M+Na)+]. Anal. (C24H30O7) C, H. ½aꢀD ꢁ38.15 (c 1.28,
acetone).
26. Compound 7: A solution of 623 (9 g, 21.12 mmol) in THF
(20 mL) was added to a mixture of LAH (1.61 g,
42.23 mmol) in THF (20 mL) at 0 ꢁC over a period of
25
[M+1]. Anal. (C5H11NO2ÆHCl) C, H, N. ½aꢀD ꢁ19.8 (c
0.61, methanol).

3330
P. L. Kotian, P. Chand / Tetrahedron Letters 46 (2005) 3327–3330
30. Compound 4 as p-nitrobenzoate: A solution of 4 hydro-
chloride (85 mg, 0.56 mmol) in water (3 mL) was loaded
on a ion exchange resin (IR-120, H+, 8 mL) and washed
with water (80 mL) followed by concd ammonium
hydroxide (50 mL). The relevant fractions were pooled
and concentrated under vacuum to furnish 0.038 g
(0.35 mmol) of free base of 4. The free base was dissolved
in ethanol (1 mL) and to this added an ethanolic solution
of p-nitrobenzoic acid (0.04 N, 8.75 mL, 0.35 mmol) and
concentrated under vacuum to dryness. The residue was
crystallized from ethanol/ether to furnish 0.04 g of p-
nitrobenzoate 4 as a white solid: mp158 ꢁC (lit.22 mp147–
148 ꢁC); 1H NMR (D2O): d 8.14 (d, J = 8.8 Hz, 2H,
aromatic), 7.84 (d, J = 8.8 Hz, 2H, aromatic), 4.45 (t,
J = 3.4 Hz, 1H, H-3), 3.70 (dd, J = 11.3 and 7.4 Hz, 1H,
H-6), 3.61 (dd, J = 11.3 and 7.4 Hz, 1H, H-6), 3.40 (dd,
J = 11.7 and 8.7 Hz, 1H, H-5a), 3.30 (dd, J = 12.7 and
3.5 Hz, 1H, H-2a), 3.24 (d, J = 13.0 Hz, 1H, H-2b), 3.03 (t,
J = 11.5 Hz, 1H, H-5b), 2.41 (m, 1H, H-4); 13C NMR
(D2O): d 45.28, 45.91, 53.77, 58.70, 69.78, 123.83, 129.90,
143.08, 149.24, 173.98; IR (KBr) 3453, 3391, 3291, 2951,
1644, 1589, 1511, 1388 cmꢁ1; MS (ES+) 118.69 [M+1].
25
Anal. (C12H16N2O6) C, H, N. ½aꢀD ꢁ12.8 (c 0.62, meth-
25
anol), lit.22 ½aꢀD ꢁ10.2 (c 0.6, methanol).