An efficient route to chiral, non-racemic 3-alkyl-3-arylpyrrolidines. Improved stereoselectivity in alkylation of bicyclic lactams and the effect of leaving groups

Article abstract of DOI:10.1016/S0040-4039(00)01471-4

Chiral 3-alkyl-3-arylpyrrolidines were prepared from the substituted bicyclic lactams. Stereoselectivity in the alkylation of bicyclic lactams was improved by using an alkyl triflate or tosylate as the electrophile. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01471-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8193–8197
An efficient route to chiral, non-racemic
3-alkyl-3-arylpyrrolidines. Improved stereoselectivity
in alkylation of bicyclic lactams and the effect of
leaving groups
Kozo Oda† and A. I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 10 August 2000; revised 1 September 2000; accepted 5 September 2000
Abstract
Chiral 3-alkyl-3-arylpyrrolidines were prepared from the substituted bicyclic lactams. Stereoselectivity
in the alkylation of bicyclic lactams was improved by using an alkyl triflate or tosylate as the electrophile.
© 2000 Published by Elsevier Science Ltd.
Keywords: alkyl triflates; diastereoselective alkylation; aminal reduction.
3-Alkyl-3-arylpyrrolidines are valuable constituents of a variety of natural products and
medicinally important compounds.1,2 For example, physostigmine1 and MDL103,8962b are
representative of this class possessing these heterocycles.
O
MeNHCO2
N
N
N
N
H
N
N
OMe
OMe
O
F
(-)-physostigmine
MeO
MeO
MDL103,896
OMe
To date only a few enantioselective synthesis of the 3-alkyl-3-arylpyrrolidines have been
reported. Thus, 2-alkyl-2-arylmalonate was desymmetrized by hydrolysis with pig liver esterase,
which resulted in half esters that were converted into chiral 3-alkyl-3-arylpyrrolidines by Fadel
et al.3 However, the optical purity of the materials was only 71–97% ee due to the variable
* Corresponding author.
†
On leave from Sankyo Co. Ltd, Medicinal Chemistry Research Laboratories, Tokyo, Japan.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01471-4

8194
enantioselectivity of the enzymatic hydrolysis. On the other hand, direct alkylation of enolates
of chiral 2-pyrrolidinones has been reported and has led to some chiral 3-substituted 2-pyrrolidi-
nones.4,5 Utilizing this approach, Royer et al.5 produced chiral 3,3-dialkylpyrrolidinone deriva-
tives from 1-(2-hydroxy-1-phenylethyl)-1,5-dyhydropyrrol-2-one, which was prepared from
R-phenylglycinol and 2,5-dimethoxy-2,5-dihydrofuran. Despite the high diastereoselectivity, the
yield in the second alkylation step was modest. This method has not yet been applied to the
synthesis of 3-alkyl-3-arylpyrrolidines.
We have described the synthesis of chiral 3,3-dialkylsubstituted pyrrolidines 4 by successive
alkylation of the bicyclic lactam 1, followed by removal of the chiral auxiliary in 3 to
pyrrolidines 4 (Scheme 1).6 This process occurs in good overall yields, however, the diastereosel-
ectivity in the alkylation of 1 has been erratic and, at times unsatisfactory. In order to extend
the above procedure to 3-alkyl-3-arylpyrrolidines 4 (R1=alkyl, R2=aryl), the process required
alkylation of angular hydrogen bicyclic lactam 1 to be substituted by both an alkyl and an aryl
group.
Ph
O
Ph
O
Ph
1) LDA, R1X
2) LDA, R2X
R2
R1
R2
R1
H2, Pd/C
LiAlH4
HN
R2
R1
N
H
N
H
HO
N
O
O
1
2
3
4
Scheme 1. Synthesis of chiral 3,3-disubstituted pyrrolidines
The angular hydrogen bicyclic lactam 1 was prepared in good overall yield, from its
succinimide derivative, which in turn, was prepared from S-phenylglycinol and succinic acid or
anhydride.6 The requisite aryl substituted bicyclic lactams 8a–c were prepared from the
corresponding 2-arylsuccinic acids 5a–c.7 Condensation of S-phenylglycinol and 5a–c furnished
the succinimide derivatives 6, which were regioselectively reduced8 and cyclized via the interme-
diate N-acyliminium species9 7 to afford the bicyclic lactams 8a–c (overall yields of 5–8 were
38–62%, Scheme 2).
Ph
O
Ph
O
1) DIBALH
toluene, -78°C
Ph
O
HO2C
HO2C
Ar
S-Phenylglycinol
220°C
HO
N
H
HO
N
Ar
Ar
N
Ar
2) cat.HCl
CH2Cl2, rt
O
O
5a Ar = p-MeO(C6H4)-
5b Ar = m-MeO(C6H4)-
5c Ar = m,p-(MeO)2(C6H3)-
7a~c
6a~c
8a~c
Scheme 2. Preparation of aryl substituted bicyclic lactam
Alkylation of bicyclic lactams (e.g. 8a–c) has been shown to occur predominantly from the
endo (concave) face, and the basis of this stereochemical result has been discussed.6a There is still
some question regarding the major factor responsible for predominant endo alkylation. It is
possible that, in addition to others, the steric repulsion between the angular substituent and
approaching electrophile may be one of the more important factors determining endo selectivity.
Since the alkylation of angular hydrogen lactams leads to generally lower diastereoselectivity
than that of angular alkyl lactams,6a we felt the present case may shed some light on this issue.

8195
Alkylation of bicyclic lactam 8a with iodomethane and LHMDS in tetrahydrofuran at −78°C
gave an endo/exo ratio of 86:14 for 9a and 10a, respectively, in 94% yield (Table 1, entry 1).
Furthermore, the alkylation with allyl bromide proceeded to give an endo/exo ratio of 82:18 for
1
11a and 12a, respectively, in 81% yield (Table 1, entry 5). These ratios were determined by H
NMR and are assumed to be accurate to 3%. The protons at the C-7 methylene in the major
isomer 9a appear separately at 2.25 and 2.94 ppm as a dd. On the other hand, these protons in
the minor isomer 10a appear much closer at 2.60 and 2.63 ppm. The stereochemistry of the
major isomers was initially confirmed by converting them into compounds known in the
literature. Due to the modest 6:1 ratio observed for 9a:10a, a detailed study was initiated to try
to improve the stereoselectivity.
Table 1
Alkylation of bicyclic lactam 8
Ph
O
Ph
O
Ph
O
base, R1X
Ar
R1
Ar
N
H
N
H
N
H
+
Ar
7
7
R1
THF, -78°C
O
O
O
9 R1=Me or 11 R1=Allyl
10 R1=Me or 12 R1=Allyl
8a~c
Entry
Substrate
Base
R1X
Reaction time
Yield (%)
endo/exo (9/10 or 11/12)
1
2
3
4
5
6
7
8
8a
8a
8b
8c
8a
8a
8b
8c
LHMDS
LHMDSa
LHMDSa
LHMDSa
KHMDS
KHMDS
KHMDS
KHMDS
MeI
1 h
94
99
98
96
99
90
98
97
86/14
95/5
96/4
96 /4
83/17
90/10
91/9
MeOTf
MeOTf
MeOTf
AllylBr
AllylOTs
AllylOTs
AllylOTs
20 min
20 min
20 min
15 min
30 min
1 h
30 min
91/9
a The reaction was allowed to warm to −60°C for 20 min and was then recooled to −78°C prior to addition of
the electrophile.
Addition of HMPA or increasing the reaction temperature in the alkylation of 8 had little or
no effect on the stereoselectivity. The metal cation of the base employed during the alkylation
(NaHMDS or KHMDS) also had no effect. Since the nature of the leaving group in the
electrophile had received only little attention in the past,10 this was, therefore, examined.
Interestingly, the ratio of 9a:10a increased considerably to 95:5 when methyl triflate was
substituted for methyl iodide (Table 1, entry 2). Alkylation of the related lactams, 8b and 8c,
with methyl triflate showed similar improvements in stereoselectivities. Improvements were also
observed in the allylation of the lactams. Although the stereoselectivity is slightly lower than
that of methylation, the best result was again obtained using the sulfonate derivative, i.e. allyl
tosylate (Table 1, entries 6–8). An attempt to utilize allyl triflate was not practical due to the
instability of the latter.
In contrast to the above, alkylation using ethyl triflate gave lower selectivity (endo/exo=
81:19, 93% yield). It appears, as of now, that the more bulk present in the electrophile, the more
sensitive it will be to potentially existing steric bias on bicyclo[3.3.0] system. The fact that
triflates and tosylates are usually poor electrophiles in ether solvents, resulting in a lower rate of
alkylation of 8, could be responsible for the increased selectivity in facial alkylation.10b

8196
A representative number of bicyclic lactams (e.g. 9, 11) were converted into 3,3-disubstituted
pyrrolidinone derivatives 13 in good yield by reductive ring opening with triethylsilane and
titanium(IV) chloride at 0°C.11 The minor diastereomer (4–9%) was readily eliminated by
column chromatography at this stage to obtain pure pyrrolidinone 13. Removal of chiral
auxiliary was accomplished by an elimination–hydrolysis procedure. Thus, alcohol 13 was
converted into the corresponding chloride with carbon tetrachloride and triphenylphosphine,
followed by elimination of hydrogen chloride with DBU. Acid hydrolysis of the enamine
(N-styryl pyrrolidinone) afforded optically pure 3,3-disubstituted pyrrolidinones 14 in high
overall yield (Scheme 3, Table 2). Reduction of 14 with lithium aluminium hydride furnished the
3,3-disubstituted pyrrolidines 15 in quantitative yields.
Ph
O
Ph
Ph
O
O
Et3SiH, TiCl4
CH2Cl2, 0°C
1) PPh3, CCl4, CH2Cl2, reflux
Ar
N
H
HO
Ar
R1
Ar
R1
N
N
R1
2) DBU, Toluene, reflux
3) dil,HCl, MeOH, rt
O
13
9 or 11
O
O
Ar
R1
LiAlH4
BnBr or MeI
Ar
R1
Ar
R1
R2
14
HN
HN
N
THF, reflux
NaH, DMF
0°C
15
16
14
Scheme 3. Conversion of bicyclic lactams into pyrrolidines and pyrrolidinones
Table 2
Lactam
13 yield (%)
14
15 [h]D
Ar
R1
Puritya
Yield (%)
[h]D
9a
9b
11b
11c
p-MeO(C6H5)
Me
Me
Allyl
Allyl
95
\99
91
93
98
90
99
97
93
−69.4
−79.4
89.0
+11.1
+11.8
+5.9
m-MeO(C6H5)
m-MeO(C6H5)
m,p-(MeO)2(C6H4)
80b
\99
\99
81.0
+3.1
16
Reported3,12 [h]D (% ee)
Ar
R1
R2
[h]D
p-MeO(C6H5)
m-MeO(C6H5)
m-MeO(C6H5)
Me
Me
Allyl
Allyl
Bn
Me
Bn
Bn
−9.3
−8 (97)
−79.9
−21 (86)
−8.5 (71)
−91.0
−21.4
−10.8
m,p-(MeO)2(C6H4)
a Percent content of major isomer (9 or 11) in the mixture of 9 and 10, or 11 and 12. Pure 9b and 11c were obtained
by recrystallization.
b Yield after recrystallization.

8197
To further address the absolute stereochemistry at C-3 of the pyrrolidines, the known
corresponding lactams were accessed. Treatment of 14 with methyl iodide or benzyl bromide,
and sodium hydride gave N-methyl or N-benzyl lactams 16, whose optical rotation had been
reported.3,12 The sign of [h]D was in agreement with the absolute configuration reported and was
also consistent with the predicted entry of the electrophile to the bicyclic lactams. It is
noteworthy that N-methyl lactam 16 (Ar=m-MeO(C6H5), R1=Me, R2=Me) is identical to the
synthetic intermediate for (−)-physostigmine prepared by Takano et al.12
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