Asymmetric synthesis of diversely substituted N-hydroxypyrrolidines using cycloadditions with chiral nitrone enolate/ylids

Article abstract of DOI:10.1016/S0040-4039(01)02305-X

A stereoselective synthesis of diversely substituted N-hydroxypyrrolidines is reported, based on the cycloaddition reaction of chiral non-racemic nitrone ylids with a variety of α,β-unsaturated esters.

Full text of DOI:10.1016/S0040-4039(01)02305-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 967–971
Asymmetric synthesis of diversely substituted
N-hydroxypyrrolidines using cycloadditions with chiral nitrone
enolate/ylids
Stephen Hanessian* and Malken Bayrakdarian
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Succ. Centre-Ville, Montre´al, P.Q., Canada H3C 3J7
Received 28 August 2001; accepted 28 November 2001
Abstract—A stereoselective synthesis of diversely substituted N-hydroxypyrrolidines is reported, based on the cycloaddition
reaction of chiral non-racemic nitrone ylids with a variety of a,b-unsaturated esters. © 2002 Elsevier Science Ltd. All rights
reserved.
The pyrrolidine nucleus is found as a common subunit
of many naturally occurring alkaloids,1,2 or an entity in
itself as for example the antifungal antibiotic preussin.3
Several polysubstituted pyrrolidines have shown very
potent activities as enzyme inhibitors,4 as agonists, or
antagonists of receptors.5 Polyhydroxy pyrrolidines,
considered as ‘azasugars’ that mimic carbohydrates, are
known to be inhibitors of glycosidases.6 Beside their
pharmacological activities, several substituted pyrrolidi-
nes and prolines are also used as chiral catalysts7 and
auxiliaries8 in a variety of asymmetric reactions.
pyrrolidines.10 In this communication, we report our
results on the asymmetric synthesis, characterization
and further functionalization of diversely substituted
N-hydroxypyrrolidines resulting from the reaction of
chiral nitrone ylids or their enolate equivalents with a
variety of a,b-unsaturated esters.
Treatment of N,O-bis(tert-butoxycarbonyl) hydroxyl-
amine ethyl glycinate 1 with TFA, followed by
condensation11 with chiral pyruvate esters 3, afforded
the intended nitrones 4–6 as single isomers based on
NOE studies (Scheme 1).
There are numerous methods for the stereocontrolled
synthesis of substituted heterocycles including pyrrolidi-
nes and prolines using a 1,3-dipolar cycloaddition.9 A
lesser exploited reaction is the condensation of nitrone
enolate/ylids derived from glycinate esters with electron
deficient alkenes to give polysubstituted N-hydroxy-
Cycloadditions of cinnamate esters with nitrones 4–6
were carried out in THF at 0°C in the presence of
lithium bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) as catalyst.12 The stereoselectivity of the
cycloaddition reaction was studied by varying the
O
OBoc
N
OH
N
CH2Cl2, NaHCO3, MgSO4
TFA, CH2Cl2
TFA-
EtO2C
N
Me
EtO2C
EtO2C
O
Boc
H
H
1
2
COR*
Me
COR*
OMe
Ph
3
4, R* = A
5, R* = B
6, R* = C
O
O
O
single isomer
Ph
(85-90%, 2 steps)
R* :
A
B
C
Scheme 1.
Keywords: 1,3-dipolar cycloaddition; pyrrolidine scaffold.
* Corresponding author. Tel.: (514) 343-6738; fax: (514) 343-5728; e-mail: stephen.hanessian@umontreal.ca
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02305-X

968
S. Hanessian, M. Bayrakdarian / Tetrahedron Letters 43 (2002) 967–971
Scheme 2 and Table 1. A definite improvement was
observed with benzyl cinnamate and 8-phenylmenthyl
ester nitrone 5 (Table 1, entry 4, 9:1 ratio). With
benzhydryl cinnamate as the dipolarophile (Table 1,
entry 5), cycloaddition led to a single isomer in 85%
yield.13 Similar enhancement in diastereoselectivity has
been previously observed in intramolecular Michael
additions of anions of menthyl and 8-phenylmenthyl
esters of b-diketones to a,b-unsaturated esters.14
Michael-type additions of phosphonamide anions to
benzhydryl and tert-butyl cinnamates exhibit higher
selectivity compared to methyl or benzyl esters.15
nature of the cinnamate ester 7 with each of the
nitrones 4–6. Little or only modest improvement was
observed between methyl and benzyl esters as seen in
OH
Me
COR*
O
N
DBU, LiBr, THF
N
EtO2C
EtO2C
Me
CO2R
Ph
COR*
Ph
CO2R
4-6
7
8
Scheme 2.
Scheme 3 and Table 2 show the generality of the
cycloadditions for benzhydryl acrylate, and for a series
of substituted cinnamates which afforded a single
diastereomer in each case. With the exception of the
cis-cinnamate ester (50%), yields for each N-hydroxy-
pyrrolidine 10 synthesized were excellent. The absolute
configuration of the cycloadducts was proven by
detailed NOE studies of the crude products, and by an
X-ray crystal structure of a derivative.
Table 1.
Entry
R
R*a
Yieldb/ratioc
1
2
3
4
5
6
Me
Bn
Me
Bn
CHPh2
CHPh2
A
A
B
B
B
C
78% (1.6:1)
85% (1.6:1)
70% (3:1)
75% (9:1)
85%, 1 isomer
60% (1:1)
a Scheme 1.
The reactions were also successful in the case of benzyl-
idene nitrone analog 11, which underwent cycloaddi-
tion with menthyl acrylate and 8-phenylmenthyl
acrylate in the presence of LiBr and MTBD16 to give
1:1 and 2:1 mixtures of separable diastereomeric pyrro-
lidines 12, 13 and 14, 15, respectively (Scheme 4).
b Isolated yield after silica gel purification.
c Determined by 1H and 13C spectroscopy of the crude product.
OH
O
Me
CO2R*
N
DBU, LiBr, THF
EtO2C
R1
EtO2C
N
Me
R2
Contrary to cyclizations of azomethine ylids which can
be carried out in the presence of several additives,12 the
reactions of nitrones 4–6 were only successful in the
presence of lithium bromide and a base such as DBU,
regardless of the nature of the solvent used (MeCN,
CH2Cl2, THF, toluene). With LiHMDS in THF at
−78°C, the same diastereoselectivity was observed. No
reaction took place in the presence of additives such as
AgOAc, MgBr2, or CoCl2.12e,f
CO2R*
CO2CHPh2
R2
CO2CHPh2
R1
5
10
9
single isomer
R* = (-)-8-phenylmenthyl
Scheme 3.
Table 2.
Yielda/ b
90%
R1
H
R2
H
H
H
H
75%
85%
Me
F3C
80%
F
H
85%
MeO
50%c
H
a Isolated yield after silica gel purification. b For details see
ref. 13. c 30% of 5 was isolated.
Scheme 4.

S. Hanessian, M. Bayrakdarian / Tetrahedron Letters 43 (2002) 967–971
969
also benefit from a pre-coordination of the cinnamate
ester carbonyl group with the lithium cation. As the
size of the cinnamate ester group decreases from benz-
hydryl to benzyl to methyl, and especially when a
menthyl auxiliary is used, the alternative endo-re face
approach is also possible. We tentatively suggest that
the other minor product in the cycloadditions is the
diastereomer corresponding to the enantiomeric pyrro-
lidine B (Fig. 1).
It is of interest to comment on the stereochemical
outcome of these cycloadditions in which only car-
bonꢀcarbon bond formation was observed. In contrast,
there are numerous examples of isoxazolidine forma-
tion in the cycloaddition of nitrones with unsaturated
compounds.9 In the absence of a chiral auxiliary,
nitrone ethyl ester and methyl cinnamate afforded the
racemic endo-adduct corresponding to 8 as the major if
not exclusive product. The results in Scheme 2 and
Table 1 show that the size of the cinnamate ester and
the nature of the chiral auxiliary have an influence on
the diastereoselectivity. Thus, with methyl or benzyl
cinnamates and menthyl nitrone lithium enolate 4, vir-
tually no selectivity was observed. An enrichment of the
product 8 was observed in going to the 8-phenylmen-
thyl nitrone lithium enolate 5 eventually leading to a
single isomer with benzhydryl cinnamate. Thus, bulky
esters on the dipole and dipolarophile appear to have a
cooperative effect in enhancing the diastereoselectivity
of the cycloaddition reaction.
The cycloaddition of the benzylidene nitrone 11 with
methyl acrylate afforded a 1:1 mixture of two cycload-
ducts which could be separated. Cycloaddition with
menthyl and 8-phenylmenthyl acrylates afforded com-
pounds 12/13 and 14/15 as separable diastereomers in
each case. It follows that these are products arising
from endo- and exo-transition states, respectively,
approaching the si- and re-faces of the nitrone enolate
(Fig. 1 C,D).
We chose to study a number of chemoselective trans-
formations that would differentiate the functional
appendages and offer opportunities for further modifi-
cation in the context of a program aimed at generating
diversity in a proline type scaffold. Hydrogenolysis of
the benzhydryl ester 16 as a prototype, and intramolec-
ular coupling afforded the novel bicyclic lactone 17
whose X-ray crystal structure confirmed the configura-
tional assignment of the cycloaddition products
(Scheme 5). Reduction of the NꢀO bond using molyb-
denum hexacarbonyl20 afforded 18, which was trans-
These results can be accommodated by a concerted
pathway,17 in which the re face of the planar nitrone
lithium enolate is masked by the dimethyl benzyl
group18 of the auxiliary as illustrated in Fig. 1. This
conformation also allows for a preferred syn planar
arrangement of the methine hydrogen on the menthyl
ring with the ester carbonyl.14,19 An endo-si face
approach of the cinnamate ester in an s-cis conforma-
tion exposing its re face would lead to the observed
major isomer A. Such a transition state model could
OH
Me
N
EtO2C
O
re
CO2R*
R
OH
Li
O
O
Me
CO2R*
N
O
Ph
CO2R
EtO2C
Ph
Li
O
O
N
A
O
O
+
EtO
H
O
N
O
R
Ph
CO2R
si
OH
N
O
O
EtO
H
A
O
Me
CO2R*
R
Ph
EtO2C
O
Ph
endo T.S. model
endo T.S. model
Ph
CO2R
-nitrone si face
-cinnamate s-cis/re face
B
-nitrone re/si face
-cinnamate s-cis re/si face
O
R*
OH
N
OH
Li
O
N
O
EtO2C
Ph
EtO2C
Ph
O
N
Li
O
N
+
H
O
EtO
O
CO2R*
CO2R*
R*
si
H
O
C
D
EtO
exo T.S. model
endo T.S. model
-nitrone re face
-acrylate s-cis/si face
-nitrone si face
-acrylate s-cis/re face
Figure 1.

970
S. Hanessian, M. Bayrakdarian / Tetrahedron Letters 43 (2002) 967–971
OH
H
N
O
O
Me
CO2R*
CO2CHPh2
18
Me
CO2R*
EtO2C
N
Mo(CO)6
EtO2C
Me
CO2R*
1. H2, Pd/C
N
EtO2C
MeCN/H2O
90%
2. EDC, DMAP, DMF
70% (2 steps)
CO2CHPh2
16
17
R* = (-)-8-phenylmenthyl
Boc2O, MeCN
Et3N, DMAP
84%
Boc
Boc
Boc
N
Me
N
Me
Me
N
1. H2, Pd/C
EtO2C
EtO2C
HOH2C
CO2R*
O
2. EDC, HOBt, DMAP
Dibal-H, CH2Cl2
CO2R*
CH2OH
O
-78 oC to -50 o
60%
C
CH2Cl2, benzylamine
(50%, 2 steps)
CO2CHPh2
HN
20
HN
19
21
Scheme 5.
formed into the N-Boc derivative 19. Hydrogenolysis
and coupling under standard conditions with a proto-
typical amine gave benzylamide 20 (Scheme 5). Treat-
ment of 20 with Dibal-H21 resulted in the cleavage of
the ethyl and 8-phenylmenthyl esters affording the
amide prototype 21. A focussed library of diversely aryl
substituted amides related to 21 can be easily assem-
bled, since the cycloaddition reaction is possible with a
variety of cinnamate esters.
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The synthesis of polyfunctional, enantiopure N-hydroxy-
pyrrolidines and pyrrolidines reported in this paper
complements our previous results22 utilizing azomethine
ylid chemistry.9,23 The nitrone methodology is versatile
and affords a different set of diastereomers, in addition
to maintaining the N-hydroxy functionality intact.
The polyfunctional pyrrolidine motifs available through
nitrone cycloaddition methodology represent core scaf-
folds with functionally diverse appendages which can
find utility in displaying desirable pharmacophores to
biological targets. The successful implementation of the
method with a variety of aryl substituted cinnamates
shows its potential in parallel array synthesis.
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Acknowledgements
We thank NSERC for financial assistance through the
Medicinal Chemistry Chair Program.
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