A highly efficient and stereoselective synthesis of polyhydroxylated pyrrolidines via regioselective asymmetric aminohydroxylation (RAA) and intramolecular amidomercuration reactions

Article abstract of DOI:10.1055/s-2003-40347

A new synthetic strategy, which allows a complete stereochemical control of all four chiral centers of two important polyhydroxylated pyrrolidines 8 and 9, is described. The corner-stone of the present strategy is a successful implementation of the regios

Full text of DOI:10.1055/s-2003-40347

LETTER
1279
A Highly Efficient and Stereoselective Synthesis of Polyhydroxylated
Pyrrolidines via Regioselective Asymmetric Aminohydroxylation (RAA) and
Intramolecular Amidomercuration Reactions
Synthesis of
P
a
olyhydroxy
t
lated P
w
yrrolidine
s
inder Singh, Dinesh Chikkanna, Om V. Singh, Hyunsoo Han*
Department of Chemistry, The University of Texas at San Antonio, 6900 N. Loop 1604 West, San Antonio, TX 78249, USA
Fax +1(210)4584958; E-mail: hhan@utsa.edu
Received 18 April 2003
Dedicated to Professor Ray Lemieux for his many contributions to organic and carbohydrate chemistry.
Glycosidases catalyze cleavage of the glycosidic bonds in
Abstract: A new synthetic strategy, which allows a complete
carbohydrates and related molecules through cationic in-
stereochemical control of all four chiral centers of two important
polyhydroxylated pyrrolidines 8 and 9, is described. The corner-
stone of the present strategy is a successful implementation of the
termediates.6 Certain polyhydroxylated pyrrolidines such
as I and II, which closely resemble charge and shape of
regioselective asymmetric aminohydroxylation (RAA) reaction of those intermediates under physiological conditions, have
been shown to be potent inhibitors against glycosidases.7
In addition, I and II (Figure 1) can serve as convenient in-
the designed achiral olefin 1 and the intramolecular stereoselective
amidomercuration reaction of the d-alkenylamide 4, which were
used for the introduction of the vicinal amino alcohol functionality
termediates for the synthesis of more complex nitrogen
and for the construction of the five membered ring in the targets
containing glycosidase inhibitors III (i.e., alexines and
respectively.
casuarines8) and IV (i.e., hyacinthacines9). Moreover, C2-
Key words: carbohydrate, glycosidase inhibitor, polyhydroxylated
symmetrical derivatives of I have been utilized as chiral
pyrrolidine, regioselective asymmetric aminohydroxylation reac-
ligands and catalysts for a variety of chemical transforma-
tion, intramolecular amidomercuration reaction
tions.10 Accordingly, a considerable amount of research
effort has been put forth for the asymmetric synthesis of
I11,12 and II.11,13 However, to the best of our knowledge,
Glycosidases are believed to be involved in numerous im-
all reported synthetic methodologies required chiral mate-
portant biological processes including intestinal diges-
rials at some point of synthesis, and some syntheses need
tion, catabolism and post-translational modification of
rather lengthy routes. A truly asymmetric methodology,
glycoproteins and glycolipids, and carbohydrate recogni-
which is general, flexible, and divergent in terms of
tion.1 Glycosidases are also implicated in many serious
stereochemical manipulation and derivatization, lacks in
diseases such as diabetes,2 metastatic cancer,3 malaria,4
the literature.
and viral infection.5 Therefore, glycosidase inhibitors can
Any useful methodology for the synthesis of I and II
should deal with the stereoselective introduction of the
vicinal amino alcohol functionality as well as the stereo-
selective construction of the 5-membered ring containing
a nitrogen atom. It was reasoned that the former could be
derived from the RAA reaction of an appropriate olefin,14
and the latter could form from the mercury(II)-mediated
cyclization reaction of a d-alkenylamide followed by the
oxidative demercuration reaction.15 Herein, we report a
successful implementation of this strategy to the complete
asymmetric synthesis of the polyhydroxylated pyrrol-
idines 8 and 9 as a respective representative of I and II.
not only have potential to control the above biological
processes at will, but also provide a basis for the develop-
ment of therapeutically useful agents for the treatment of
those diseases.
H
N
H
N
Me
OH
HO
HO
OH
HO
OH
HO
I
II
H (or OH)
H (or OH)
OH
Me
Scheme 1 depicts our asymmetric synthesis of the polyhy-
droxylated pyrrolidines 8 and 9 starting from the achiral
a,b-unsaturated ester 1. The RAA reaction of 1 employing
(DHQD)2PHAL ligand and N-bromoacetamide as a nitro-
gen source and oxidant produced the syn-aminoalcohol 2
with an excellent regio- (>20:1) and enantioselectivity
(>99%). The 4-(p-methoxy)phenoxy (PMP) group of 1
plays dual role in our synthesis: its aryl-aryl stacking in-
teraction with the aryl groups of the RAA catalyst can in-
crease regio- and enantioselectivity of the RAA reaction
of 1 (role as a catalyst binder),16 and it can also act as a
convenient alcohol protection group (role as a protection
N
N
H (or OH)m
HO
HO
HO
OH
HO
OH
IV
III
Figure 1
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1279,1282,ftx,en;S05003ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1280
S. Singh et al.
LETTER
group).17 Protection of the hydroxyl group of 2 by p-meth- considering equilibrium among the chair conformers 4-I,
oxybenzyl (PMB) chloride and sodium hydride gave the 4-II, 4-III, and 4-IV of 4 (Figure 2). When subjected to
ester 3. Partial reduction of the ester 3 by a slow addition the (kinetic) amidomercurization conditions,15b–d the con-
of DIBAL at –78 °C, and reaction of the resulting alde- formers 4-I and 4-III should cyclize to the trans-isomer,
hyde with vinylmagneium bromide at –50 °C generated whereas the conformers 4-II and 4-IV should lead to the
the d-alkenylamide 4 in a 5:1 diastereoselectivity.
cis-isomer. Then, stereochemistry of the amidomercura-
tion reaction of 4 should reflect relative stability of these
conformers under the reaction conditions, and thus the
trans-isomer formed as a predominant product from the
most stable conformer 4-I, in which the a-(p-methoxy-
phenoxy)methyl group occupies an equatorial position
and steric interactions between the substituents are least.
Oxidative-demercuration reaction of 5 was effected by
slowly adding O2 and NaBH4 to 5 in DMF, and gave the
diol 6 as a major product with a small amount of the re-
duction product 7. Deprotection of the PMP group of 6
by CAN and subsequent exhaustive acidic hydrolysis of
the resulting triol furnished the C2-symmetric polyhy-
droxylated pyrrolidine 8 as an HCl salt.18
O
Ac
NH
O
OEt
a
PMPO
O
OEt
OEt
2
3
OH
OMe
1
b
Ac
Ac
NH
NH
O
c
PMPO
PMPO
OH
4
OPMB
OPMB
d
Ac
N
PMPO
PMBO
Ac
Ac
O
H
N
N
H
H
Hg(II)
PMPO
PMBO
HgOAc
e
PMPO
PMBO
HgBr
PMPO
PMBO
OH
N
OH
OH
OH
H
OH
5
6
Cis-isomer
Hg(II)
O
4-IV
g
f
.
PMPO
PMBO
HCl
H
N
Ac
N
O
N
PMPO
PMBO
H
HO
R
g
H
N
H
PMPO
PMBO
H
H
H
HO
OH
HO
OH
H
OH
H
4-II
4-I
8: R = -OH
9: R = -H
7
Hg(II)
Scheme 1 Reagents and conditions: (a) K2OsO4·2H2O (5 mol%),
(DHQD)2PHAL (6 mol%), LiOH, N-bromoacetamide, t-BuOH–H2O
2:1, 4 °C, 8 h, 70%; (b) NaH, PMBCl, DMF, 0 °C, 10 h, 78%; (c) (i)
DIBAL, CH2Cl2, –78 °C, 3 h, 90%, (ii) vinylmagnesium bromide,
THF, –50°C, 1 h then r.t. 1 h, 74%; (d) Hg(OAc)2, then NaHCO3 and
KBr; (e) O2, NaBH4, DMF, 44% for two steps; (f) NaBH4, DMF, 80%
for two steps; (g) (i) CAN, CH3CN–H2O 4:1, 4 °C, 10 min, (ii) 6 N
HCl, reflux, 12 h, 86% for two steps (for 8) and 89% for two steps
(for 9).
O
PMPO
PMBO
Ac
N
Hg(II)
N
H
H
PMPO
HgOAc
HO
PMBO
OH
H
H
4-III
Trans-isomer
Figure 2
When exposed to Hg(OAc)2 in THF, 4 smoothly under-
went an intramolecular cyclization to give the organomer-
curic acetate, which upon addition of KBr transformed to
the organomercuric bromide 5. In the amidomercuration
reaction of 4, the trans-isomer (between the 2- and 5-sub-
situents) formed predominantly in a >15:1 ratio. This as
well as the structure and stereochemistry of 5 were estab-
lished by converting the crude 5 to 8 and comparing with
the literature data (see below). Although the exact cause
for the preferential formation of the trans-isomer remains
to be investigated further, the stereochemical outcome of
the amidomercuration reaction of 4 can be rationalized by
The organomercuric bromide 5 was also used as an inter-
mediate for the synthesis of the other polyhydroxylated
pyrrolidine target 9. In the absence of oxygen, 5 under-
went the reductive demercuration with NaBH4 to give 7.
Deprotection of the PMP group followed by acidic hy-
drolysis converted 7 to the final product 9.18
In summary, the polyhydroxylated pyrrolidines 8 and 9
were synthesized from the common starting olefin 1 in a
highly efficient and stereoselective fashion through the
RAA and intramolecular amidomercuration-oxidative de-
mercuration reactions. Currently, we are in the final stage
Synlett 2003, No. 9, 1279–1282 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Synthesis of Polyhydroxylated Pyrrolidines
1281
(10) (a) Shi, M.; Satoh, Y.; Makihara, T.; Masaki, Y.
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Financial support from National Institute of Health (GM 08194) and
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S. Singh et al.
LETTER
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Synlett 2003, No. 9, 1279–1282 ISSN 1234-567-89 © Thieme Stuttgart · New York