Hg(II) reagent-controlled stereoselective synthesis of 2,5-cis- and 2,5-trans-polyhydroxylated pyrrolidines

Article abstract of DOI:10.1055/s-2004-832804

Stereoselectivity in the intramolecular amidomercuration reaction of 11, which could form 2,5-cis- and 2,5-trans-polyhydroxylated pyrrolidines, was found to be dependent on the nature of the Hg(II) salts used as well as on the stereochemistry and protection state of the hydroxyl group at the allylic carbon. Thus, the amidomercuration reaction of 11 with Hg(CF₃CO ₂)₂ led to the predominant formation of the 2,5-cis-polyhydroxylated pyrrolidine 16, while use of Hg(CF₃SO ₃)₂ generated the corresponding 2,5-trans isomer 17. Isomers 16 and 17 were further elaborated to stereoselectively synthesize 2,5-dideoxy 2,5-imino-D-altritol and 2,5-dideoxy 2,5-imino-D-galactitol (for 20 and 21), which are known to be potent D-galactosidase inhibitors.

Full text of DOI:10.1055/s-2004-832804

LETTER
2311
Hg(II) Reagent-Controlled Stereoselective Synthesis of 2,5-cis- and
2,5-trans-Polyhydroxylated Pyrrolidines
S
ynthesis of 2,5-
c
i
i
s
-
and
n
2,5-trans-Po
e
sted Pyrro
h
lidines Chikkanna, 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 July 2004
ous works from this laboratory on the regioselective
asymmetric aminohydroxylation reaction (RAA) of ole-
fins,3 intramolecular amidomercuration reaction of d-
alkenylcarbamates followed by oxidative demercuration
Abstract: Stereoselectivity in the intramolecular amidomercura-
tion reaction of 11, which could form 2,5-cis- and 2,5-trans-polyhy-
droxylated pyrrolidines, was found to be dependent on the nature of
the Hg(II) salts used as well as on the stereochemistry and protec-
tion state of the hydroxyl group at the allylic carbon. Thus, the ami- reaction could provide a general and efficient route to
domercuration reaction of 11 with Hg(CF3CO2)2 led to the
predominant formation of the 2,5-cis-polyhydroxylated pyrrolidine
16, while use of Hg(CF3SO3)2 generated the corresponding 2,5-
the construction of substituted pyrrolidine rings,4 little re-
trans isomer 17. Isomers 16 and 17 were further elaborated to ste-
reoselectively synthesize 2,5-dideoxy 2,5-imino-D-altritol and 2,5-
these compounds (Scheme 1). Even though the intramo-
lecular amidomercuration reaction has long been used for
search work has been done to the application of this reac-
tion on a system like II, that could give rise to the direct
asymmetric formation of polyhydroxylated pyrrolidine
rings (II to III in Scheme 1).5
dideoxy 2,5-imino-D-galactitol (for 20 and 21), which are known to
be potent D-galactosidase inhibitors.
Key words: carbohydrate, glycosidase inhibitor, polyhydroxylated
pyrrolidine, regioselective asymmetric aminohydroxylation reac-
tion, intramolecular amidomercuration reaction
Boc
O
NH
RAA
PMPO
*
PMPO
OH
OEt
OH
OBn
I
II
Naturally occurring polyhydroxylated pyrrolidines and
pyrrolizidines such as (2R,3R,4R,5R)-bis(hydroxymeth-
yl)dihydroxypyrrolidine (1: DMDP), hyacinthacines (2
and 3), australine (4), alexine (5), and casuarine (6) have
displayed potent glycosidase inhibitory activities, and
have also been shown to have some potential as antiviral
and antiretroviral agents (Figure 1).1 In addition to such
profound biological activities, their intriguing structures
have made them a subject of intense synthetic scrutiny in
recent years.2
i) HgX2
ii) [O]
Boc
HO
HO
N
N
PMPO
OH
2
5
OHn= 0, 1, 2
BnO
OH
III
HO
IV
Scheme 1 A unified strategy for the asymmetric synthesis of poly-
hydroxylated pyrrolidines and pyrrolidizines.
A plausible general strategy for the asymmetric total syn-
thesis of these compounds would involve the asymmetric
synthesis and further elaboration of DMDP and its stereo-
isomers. It was thought that, in connection with the previ-
Furthermore, since all intramolecular amidomercuration
reactions of d-alkenylcarbamates/amides reported up to
date led to the predominant formation of trans-2,5-substi-
tuted pyrrolidine rings, developing a Hg(II)-mediated
methodology for the stereoselective formation of cis-2,5-
substituted pyrrolidine rings would greatly expand the
synthetic scope of the intramolecular amidomercuration
reactions. Herein, we demonstrate that the stereochemical
outcome of the intramolecular amidomercuration reac-
tions of II is dependent upon several factors such as the
stereochemistry and protection state of the hydroxyl
group at the allylic carbon (the carbon with an asterisk in
Scheme 1) as well as the nature of the counterion in the
mercury(II) salt used. Also reported is the complete
stereoselective synthesis of two potent D-galactosidase in-
hibitors, namely 2,5-dideoxy 2,5-imino-D-galactitol and
2,5-dideoxy 2,5-imino-D-altritol via the methodology de-
veloped here.
HO
OH
HO
HO
5
N
NH
N
HO
HO
HO
2
H
H
OH
HO
HO
HO
1, DMDP
2, Hyacinthacine A1
3, Hyacinthacine B1
HO
HO
HO
N
N
N
OH
HO
HO
HO
H
H
H
HO
OH
HO
OH
HO
OH
4, Australine
5, Alexine
6, Casuarine
Figure 1 Potent polyhydroxylated pyrrolidine and pyrrolizidine
inhibitors of glycosidases.
The requisite d-alkenylcarbamates 10–13 were prepared
starting from the readily available a,b-unsaturated ester I6
(Scheme 2). The RAA reaction of I using the
SYNLETT 2004, No. 13, pp 2311–2314
Advanced online publication: 03.09.2004
DOI: 10.1055/s-2004-832804; Art ID: S05804ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
4

2312
D. Chikkanna, H. Han
LETTER
O
Table 1 Amidomercuration Reactions of 10 and 12
Ac
OEt
NH
O
Boc
N
Boc
N
a
O
10
or
PMPO
OEt
OEt
+
PMPO
HgBr
PMPO
BnO
HgBr
5
2
7
OH
OMe
12
I
OR
BnO
OR
15
14
b
Entry
1
R
Reaction conditionsa
Hg(CF3SO3)2
Yield (%) 14:15
Ac
Boc
NH
O
NH
O
c
PMPO
Ab
Bb
Ab
A
B
65
>15:1
>15:1
>15:1
>15:1
>15:1
>15:1
NRc
PMPO
-H
-H
-Ac
-H
-H
-Ac
-H
-H
-H
-H
-H
-H
OEt
8
OBn
OBn
9
2
60
d
3
78
Boc
Boc
4
Hg(CF3CO2)2
92
NH
NH
e
PMPO
PMPO
OR
f
OR
f
5
86
OBn
10: R = H-
12: R = Ac-
OBn
11: R = H-
13: R = Ac-
6
A
A
B
75
7
Hg(CH3SO3)2
Hg(CH3CO2)2
HgF2
NRc
79
Scheme 2 Asymmetric synthesis of the substrates 10–13 for the in-
tramolecular amidomercuration reactions. 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, BnCl,
DMF, 0 °C, 10 h, 78%; (c) (i) (Boc)2O, DMAP, THF, reflux, 4 h; (ii)
H2NNH2, MeOH, 4 h, 85%; (d) (i) DIBAL, CH2Cl2, –78 °C, 3 h, 90%;
(ii) vinylmagnesium bromide, THF, –50 °C, 1 h then r.t. 1 h, 60%; (e)
(i) PPh3, DIAD, p-nitrobenzoic acid, THF; (ii) K2CO3, MeOH, 55%;
(f) Ac2O, DMAP (cat.), Et3N, CH2Cl2, quantitative for 12 and 13.
8
>15:1
NRc
9
A
B
NRc
82
10
11
12
>15:1
NRc
A
B
NRc
90d
>15:1
a Condition A: –78 °C in THF then NaHCO3, KBr. Condition B: at
ambient temperature in THF then NaHCO3, KBr.
b Two equivalents of K2CO3 were added to prevent the Boc-deprotec-
tion.
(DHQD)2PHAL as a ligand and N-bromoacetamide as a
nitrogen source/oxidant afforded the syn-aminoalcohol 7
with an excellent regio-(>20:1) and enantioselectivity
(>99% ee and 70% yield after one recrystallization from c NR: no reaction.
d Isolated as mercuric fluoride.
ethyl acetate). Protection of the hydroxyl group with ben-
zylchloride and sodium hydride in DMF gave the benzyl
ether 8.7 The N-acetyl group of 8 was converted to the N-
Boc group to give the carbamate 9 by reacting with di-
tert-butyl dicarbonate in the presence of catalytic DMAP
followed by the cleavage of the N-acetyl group through
hydrazinolysis.8 Partial reduction of the ester 9 by slow
addition of DIBAL at –78 °C and subsequent reaction of
the resulting aldehyde with vinylmagnesium bromide
generated the d-alkenylcarbamate 10 in a 4:1 S:R
diastereoselectivity. Stereochemistry of the hydroxy
group in 10 was inverted by Mitsunobu reaction employ-
ing triphenylphosphine and diisopropyl azadicarboxylate
in the presence of p-nitrobenzoic acid.9 Transesterifica-
tion of the resulting benzoate furnished the diastereomeric
d-alkenylcarbamate 11. The alcohols 10 and 11 were con-
verted into the corresponding acetates 12 and 13 by treat-
ment with acetic anhydride, triethylamine, and a catalytic
amount of DMAP. Compounds 10–13 were used to study
the effects of stereochemistry and protection state of the
allylic hydroxyl group on the stereoselectivity of their
intramolecular amidomercuration reactions.
as the corresponding acetate did not change the stereo-
chemical outcome (Table 1, entry 1 vs. 3 as well as entry
4 vs. 6). Relatively less reactive Hg(II) reagents such as
methansulfonate, acetate, and fluoride salts required
ambient temperature for the amidomercuration reactions
(entries 7–12). When mercuric triflate was used, two
equivalents of potassium carbonate were also needed to
prevent deprotection of the Boc-group (entries 1–3).
Given the present data as well as the previous literature re-
sults, it was anticipated that the intramolecular amidomer-
curation reaction of 11 and 13 should also occur with
predominant 2,5-trans selectivity. To gain further insight
into this possibility, the intramolecular amidomercuration
reaction of the d-alkenylcarbamates 11 and 13 was as-
sessed under similar conditions (Table 2). Interestingly, in
this case the reaction was found to be largely dependent
on the nature of Hg(II) reagent, temperature, and/or
protection state of the allylic alcohol functionality. Thus,
mercuric triflate, mercuric acetate, and mercuric fluoride
showed 2,5-trans selectivity, whereas mercuric tri-
fluoroacetate, and mercuric methansulfonate exhibited
2,5-cis selectivity. Treatment of 11 with mercuric triflate
at –78 °C followed by the addition of potassium bromide
to the reaction mixture led to a mixture of the 2,5-cis- and
2,5-trans-pyrrolidines 16 and 17 in 1:6 ratio (entry 1).
In general, regardless of the nature of the Hg(II) reagent
and of the reaction temperature, the intramolecular ami-
domercuration reactions of 10 proceeded with predomi-
nant 2,5-trans selectivity in accordance with the previous
observations (Table 1).4,5 Protection of the allylic alcohol
Synlett 2004, No. 13, 2311–2314 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,5-cis- and 2,5-trans-Polyhydroxylated Pyrrolidines
2313
Table 2 Amidomercuration Reactions of 11 and 13
Boc
N
Boc
N
a
Boc
N
Boc
N
PMPO
OTEMP
PMPO
HgBr
11
or
+
PMPO
BnO
HgBr
PMPO
BnO
HgBr
BnO
OH 18
BnO
OH
13
17
OR
OR
b
16
17
Boc
N
.
HCl
H
N
Entry
1
R
Reaction conditionsa
Yield (%) 16:17
c
HO
OH
PMPO
OH
-H
-H
Hg(CF3SO3)2
Ab
Bb
Ab
A
95
1:6
1:6
2:3
20
OH
HO
BnO
OH
19
2
87
Boc
N
.
HCl
H
3
-Ac
-H
-H
-Ac
-H
-H
-H
-H
-H
-H
73
N
PMPO
HgBr
HO
OH
4
Hg(CF3CO2)2
82
15:1
3:1
BnO
OH
HO
OH
16
21
5
B
85
Scheme 3 Stereoselective synthesis of the potent galactosidase in-
hibitors 20 and 21. Reagents and conditions: (a) O2, TEMPO (10
equiv), NaBH4, DMF, 15 min, 75%; (b) Zn, HOAc–THF–H20 3:1:1,
80 °C, 1 h, 85%; (c) (i) CAN, MeCN–H2O 4:1, 4 °C, 10 min; (ii) 3 N
HCl, EtOAc, 30 min; (iii) Pd/C, H2, 24 h, 78% for three steps.
6
A
69
3:2
7
Hg(CH3SO3)2
Hg(CH3CO2)2
HgF2
A
NRc
83
NRc
2:1
8
B
9
A
NRc
79
NRc
1:2
tritol (20) and 2,5-dideoxy-2,5-imino-D-galactitol (21),
which were known to be potent D-galactosidase inhibitors
(Scheme 3).10 Oxidative–demercuration reaction of 17
with NaBH4–TEMPO–O2 furnished the TEMPO adduct
18,11 which was converted to the diol 19 by treatment of
Zn/HOAc. Deprotection of PMP, Boc, and benzyl groups
by CAN,12 3 N HCl, and hydrogenation, respectively,
converted 19 to 20. Similarly, 21 was obtained from 16.
The spectral data (1H NMR and 13C NMR) of 20 and 21
were found to be consistent with those reported in the
literature.10b,13
10
11
12
B
A
NRc
93d
NRc
1:3
Bd
a Condition A: –78 °C in THF then NaHCO3, KBr. Condition B: at
ambient temperature in THF then NaHCO3, KBr.
b Two equivalents of K2CO3 were added to prevent the Boc-deprotec-
tion.
c NR: no reaction.
d Isolated as mercuric fluoride.
Similar results were obtained at ambient temperature (en-
try 2). However, to our pleasant surprise, reaction of 11
with mercuric trifluoroacetate at –78 °C generated the
2,5-cis-pyrrolidine 16 with a high selectivity (15:1, entry
4). The selectivity decreased to 3:1 at room temperature
(entry 5). To the best of our knowledge, 2,5-cis selectivity
has not been previously observed in the intramolecular
amidomercuration reaction of d-alkenylcarbamates/
amides. Regardless of the Hg(II) reagent used, protection
of the hydroxyl group as its acetate resulted in a loss of se-
lectivity (entries 3 and 6). As before, mercuric acetate,
mercuric methanesulfonate, and mercuric fluoride failed
to react at –78 °C (entries 7, 9 and 11), but at room tem-
perature they led to pyrrolidine formation with low selec-
tivities (entries 8, 10 and 12). Although the exact cause for
the stereodivergence in the intramolecular amidomercura-
tion reaction of 11 and 13 remains to be investigated fur-
ther, the present results indicate that steric factor and
directing effect by the allylic hydroxyl group are inter-
playing. Nonetheless, it is shown that a judicious selection
of the Hg(II) reagent and reaction temperature in the in-
tramolecular amidomercuration reaction of 11 enables the
stereoselective formation of 2,5-cis- and 2,5-trans-poly-
hydroxylated pyrolidines, 16 and 17.
Acknowledgment
Financial support from National Institute of Health (GM 08194) and
The Welch Foundation (AX-1534) is gratefully acknowledged.
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Synlett 2004, No. 13, 2311–2314 © Thieme Stuttgart · New York

2314
D. Chikkanna, H. Han
LETTER
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(13) Compound 14: [a]D +20.0 (c 1.0, CHCl3). 1H NMR (500
MHz, CDCl3): d = 7.35–7.25 (5 H, m), 6.82–6.75 (4 H, m),
4.77–4.64 (1 H, m), 4.60–4.55 (2 H, m), 4.25 and 3.84 (1 H,
br s), 4.20–4.02 (5 H, m), 3.75 (3 H, s), 2.30 and 2.11 (1 H,
m,) 1.59 and 1.30 (1 H, t, J = 10.5 Hz), 1.44 and 1.40 (9 H,
s). 13C NMR (125 MHz, CDCl3): d = 154.0, 153.9, 152.8,
137.4, 128.6, 128.2, 127.8, 115.9, 114.6, 81.3, 80.9, 73.4,
71.6, 65.4, 56.7, 55.6, 55.3, 30.3, 28.4, minor peaks due to
rotational isomer(s): 81.0, 80.4, 73.7, 71.6, 70.8, 65.4, 64.1,
58.9, 54.6. Compound 16: [a]D +50.0 (c 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3): d = 7.35–7.28 (5 H, m), 6.93 (2 H,
d, J = 9.0 Hz), 6.83 (2 H, d, J = 9.0 Hz), 4.71 (1 H, d,
J = 11.5 Hz), 4.67 (1 H, d, J = 11.5 Hz), 4.25–4.12 (6 H, m),
3.78–3.70 (1 H, m), 3.77 (3 H, s), 2.25 (1 H, dd, J = 11.5 and
6.0 Hz), 2.17 (1 H, dd, J = 11.5 and 4.5 Hz), 1.48 (9 H, s).
13C NMR (125 MHz, CDCl3): d = 155.1, 154.5, 151.9, 137.3,
128.5, 128.1, 127.9, 116.2, 114.7, 81.2, 77.1, 72.6, 70.9,
66.7, 60.1, 59.1, 55.7, 34.0, 28.5. Compound 17: [a]D +19.0
(c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): d = 7.40–7.20
(5 H, m), 6.85–6.70 (4 H, m), 4.72 (1 H, d, J = 11.5 Hz), 4.51
(1 H, d, J = 11.5 Hz), 4.50–4.35 (2 H, m), 4.25–4.10 (3 H,
m), 4.00 (1 H, br s), 3.71 (3 H, s), 1.91 (1 H, d, J = 12.0 Hz),
1.48 (1 H, d, J = 12.0 Hz), 1.32 (9 H, s). 13C NMR (75 MHz,
CDCl3): d = 154.8, 154.1, 152.0, 137.3, 128.5, 128.0, 127.7,
116.8, 114.6, 81.6, 75.9, 75.8, 71.4, 65.5, 65.4, 58.3, 55.6,
35.0, 28.4.
Synlett 2004, No. 13, 2311–2314 © Thieme Stuttgart · New York