A route to selective functionalization of polyhydroxypyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2011.12.037

A route to selective functionalization of polyhydroxypyrrolidines is described. The method is based on orthogonal protection/deprotection along the process of synthesis of the referred pyrrolidines, which consist in hydroxylation of the double bond of 2-a

Full text of DOI:10.1016/j.tetlet.2011.12.037

Tetrahedron Letters 53 (2012) 1029–1032
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Tetrahedron Letters
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A route to selective functionalization of polyhydroxypyrrolidines
Carlos A. D. Sousa a, Fabio Rizzo-Aguiar a, M. Luísa C. Vale a, Xerardo García-Mera b, Olga Caamaño b,
José E. Rodríguez-Borges a,
⇑
a Centro de Investigação em Química, Department of Chemistry and Biochemistry, Faculty of Science, University of Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal
b Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, E-15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A route to selective functionalization of polyhydroxypyrrolidines is described. The method is based on
orthogonal protection/deprotection along the process of synthesis of the referred pyrrolidines, which con-
sist in hydroxylation of the double bond of 2-azabicyclo[2.2.1]hept-5-enes followed by its oxidative cleav-
age and in situ reduction of the intermediate dialdehyde. The synthesis of a novel N-hydroxypyrrolidine is
also described.
Received 2 November 2011
Revised 5 December 2011
Accepted 9 December 2011
Available online 16 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Polyhydroxypyrrolidines
Orthogonal protection
Selective functionalization
Azasugar
OH
OH
Currently, the synthesis of iminosugars, also called azasugars, is
an important and active field in synthetic organic chemistry.1 Due
to their structural resemblance to sugars and the consequent ability
to act as glycosidase inhibitors,2 these molecules (polyhydroxylated
pyrrolidines/piperidines) often show potential in biological func-
tions mediated by carbohydrates. In fact, these ‘glycomimetics’ have
shown application in the control of diabetes,3 Gaucher’s disease,4
cancer3c,5 and viral infections (including influenza)3c,6 or HIV.7 In
particular, DAB 1 (1), fagomine (2), and (2S,3R,4R)-3,4-dihydroxypr-
oline (3) have been screened as potential inhibitors of HIV replica-
tion.6d,e 1-Deoxynojirimycin (4) has proved to be a powerful
OH
OH
HO
HO
OH
OH
OH
OH
HO
HO
CO2H
N
OH
N
H
N
N
H
H
H
4
3
2
1
OH
OH
N
HO
HO
HO
OH
OH
HO
OH
OH
OH
OH
N
N
N
OR
6
R
R
OTBDPS
8
5
7
inhibitor of a
-glycosidases8; and its N-alkylated form is used to treat
Gaucher’s disease (Migustat (5)).4e Some O-alkylated N-hydroxypi-
peridines (6) have also been described as active against
glycosidases.9
Selective protection of the hydroxyl groups of prolinate 9, pre-
pared from azabicycle 10 (exo isomer) by hydroxylation of the dou-
ble bond and subsequent oxidative cleavage and in situ reduction
of the intermediate dialdehyde,10 using tert-butylchlorodiphenylsi-
lane was attempted (Scheme 1). However, the addition of equimo-
lar amounts of tert-butylchlorodiphenylsilane resulted in a mixture
of monoprotected pyrrolidines 11 and 12 (yield = 45%; ratio 1:3)
and diprotected pyrrolidine 13.11
In this context, we have previously reported the synthesis of
polyhydroxymethylpyrrolidines 7 and 8.10 Herein we describe a
route to the selective functionalization of the hydroxyl groups of
this class of compounds, including novel polyhydroxymethyl
N-hydroxypyrrolidines, whose synthesis is also described.
The absolute configuration of compounds 11 and 12 was
unequivocally determined from crystallographic data of X-ray dif-
fraction of the 3,5-dinitrobenzoylderivative of the isolated major
monosilylated pyrrolidine 12 (Fig. 1).11
Although compounds 11 and 12 can be isolated by column chro-
matography, this method is not effective for the selective protection
of the hydroxyl groups of compound 9, particularly if we aim to
⇑
Corresponding author. Tel.: +351 220402564; fax: +351 220402659.
E-mail address: jrborges@fc.up.pt (J.E. Rodríguez-Borges).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.037

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C. A. D. Sousa et al. / Tetrahedron Letters 53 (2012) 1029–1032
Scheme 1. Reagents and conditions: (i) OsO4/N-methylmorpholine N-oxide, diox-
ane/acetone/H2O, rt, 12 h (90%); (ii) NaIO4/SiO2, CH2Cl2/H2O, 30 min; (iii) NaBH4,
MeOH, 30 min (ii + iii, 84%); (iv) ClSitBuPh2, Et3N, DMAP, CH2Cl2, 12 h, 0 °C [11, 11%;
12, 34%, 13, 15%].
obtain compound 11. On the other hand, disilylated methyl proli-
nate 13 could readily be obtained in an 89% yield by using twice
the equimolar amount of tert-butylchlorodiphenylsilane. Further
application of a selective protection/deprotection methodology to
compound 13, yielded pyrrolidines 14–18 (Scheme 2), thus provid-
ing the possibility of regioselective functionalization at positions 1,
2, 3, and 5 of the (2R,3R,5R)-tris(hydroxymethyl)pyrrolidine.
N-debenzylation of 13 to afford 14 was accomplished by
hydrogenolysis. Reduction of the ester group of 13 with borane di-
methyl sulfide afforded compound 15, whereas treatment of 13
with lithium aluminum hydride led to concomitant desilylation
at position 3, yielding compound 16. The structure of 16 was
unequivocally established by X-ray crystallography of the mono-
hydrated chloride 20 (Fig. 2).12 O-acetylation of 16 followed by
O-desilylation afforded compound 18.
Scheme 2. Reagents and conditions: (i) H2 6 bar, Pd/C 10%, HCl/MeOH, 10 days
(74%); (ii) BH3ÁSMe2 (5 M in Et2O), 75 °C, 48 h (40%); (iii) LiAlH4, Et2O (89%); (iv)
AcCl, Et3N, DMAP, CH2Cl2, 24 h, 0 °C (70%); (v)TBAF/H2O, acetone, 20 h (83%); (vi)
H2/Pd(OH)2 10% in MeOH, 40 h (70%); (vii) MeOH/H2O/HCl/CH2Cl2 (slow
evaporation).
of the hydroxyl group with tert-butylchlorodiphenylsilane, fol-
lowed by N-debenzylation afforded compound 25, which is suit-
able for N-functionalization.
In what concerns N-hydroxypyrrolidines, only a few reports of
multi-step syntheses were found in the literature.14 N-hydroxy-
pyrrolidines can be obtained by
a similar methodology as
The endo stereoisomer of azabicycle 10 (21) was submitted to
the same process of hydroxylation of the double bond described
before, affording compound 22; oxidative cleavage of 22 followed
by in situ reduction of the intermediate dialdehyde afforded azabi-
cycle 23 in a 13% overall yield (Scheme 3).13 Subsequent protection
described above, starting from the exo stereoisomer of the N-hy-
droxy-azabicycle 26 (Scheme 4).15 After protection of the hydroxyl
group of 26 using tert-butylchlorodiphenylsilane, the resulting
bicycle 27 was submitted to di-hydroxylation followed by oxida-
tive cleavage and in situ reduction, affording pyrrolidine 29.
Figure 1. X-ray single crystal structure of the 1,3-dinitrobenzoyl derivative of 12.

C. A. D. Sousa et al. / Tetrahedron Letters 53 (2012) 1029–1032
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starting material with recovery of traces of bicyclic compounds,
pointing to the occurrence of undesired rearrangements similar
to those illustrated in Scheme 3 for compound 22.
All new compounds presented in this work were fully charac-
terized by 1H and 13C NMR and mass spectrometry.
In conclusion, an efficient and straightforward orthogonal pro-
tection/deprotection methodology, allowing selective introduction
of functional groups in polyhydroxymethylpyrrolidines, whose
synthesis revealed to be effective and simple, has been developed.
Acknowledgments
The authors thank to Fundação para a Ciência e Tecnologia
(FCT) for financial support given to Faculdade de Ciências da Uni-
versidade do Porto (project PTDC/QUI/67407/2006) and through
the re-equipment program REDE/1517/RMN/2005 and CONC-
REEQ/275/QUI. C.A.D.S. and F.R.A. thank for Grants SFRH/BD/
31526/2006 and SFRH/BD/45545/2008, respectively.
Supplementary data
Supplementary data (NMR data, NMR spectra and mass spec-
troscopy data for all compounds) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2011.12.037.
Figure 2. X-ray single crystal structure of 20.
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BnOC(NH)CCl3, CF3SO3H, CH2Cl2, 1.5 h, rt (99%); (vi) TBAF/H2O, acetone, 24 h, rt
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