Intramolecular asymmetric C-H insertion of N-arylalkyl, N-bis(trimethylsilyl)methyldiazoamides mediated by chiral rhodium(II) catalysts. Synthesis of (R)-β-benzyl-γ-aminobutyric acid

Article abstract of DOI:10.1016/j.tetasy.2005.12.020

The enantio- and site-selectivity of the intramolecular C-H insertion reactions of acyclic N-arylalkyl, N-bis(trimethylsilyl)methyl α-diazoacetamides, and α-carboalkoxy-α-diazoacetamides 1a-g, catalyzed by chiral Rh(II) carboxamidates and Rh(II) carboxyla

Full text of DOI:10.1016/j.tetasy.2005.12.020

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 297–307
Intramolecular asymmetric C–H insertion of N-arylalkyl,
N-bis(trimethylsilyl)methyldiazoamides mediated by chiral
rhodium(II) catalysts. Synthesis of
(R)-b-benzyl-c-aminobutyric acid
Andrew G. H. Wee,* Sammy C. Duncan and Gao-jun Fan
Department of Chemistry and Biochemistry, University of Regina, Regina, Saskatchewan, Canada S4S 0A2
Received 25 November 2005; accepted 13 December 2005
Abstract—The enantio- and site-selectivity of the intramolecular C–H insertion reactions of acyclic N-arylalkyl, N-bis(trimethylsil-
yl)methyl a-diazoacetamides, and a-carboalkoxy-a-diazoacetamides 1a–g, catalyzed by chiral Rh(II) carboxamidates and Rh(II)
carboxylates were studied. In general, the reaction showed good to excellent chemoselectivity. Regioselectivity for most of the reac-
tions was high, but was also found to be influenced by the structure of the diazo substrate and the chiral Rh(II) catalyst employed.
The highest enantioselectivity for the reactions catalyzed by chiral Rh(II) carboxamidates was 69% and Rh2(4R-MEOX)4 was found
to be the most effective. For the chiral Rh(II) carboxylate catalyzed reactions, the highest ee obtained was 75% and Rh2(S-PTTL)4 is
the optimal catalyst. The method was applied toward the synthesis of a GABA analogue, (R)-b-benzyl-c-aminobutyric acid.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
yielded c-lactams with ee up to 81% and 91%,
respectively.
The c-lactam moiety is found in many natural and non-
natural, biologically active molecules,1 as well as in
many useful synthetic intermediates. Its widespread
occurrence and use has spurred the interest of synthetic
chemists to develop methods for the synthesis of c-lac-
tam derivatives.2
Furthermore, it is also clear that the efficiency for c-lac-
tam formation is often undermined by the poor regio-
and chemoselectivity of the reaction of the diazoamides
and, consequently, much effort has been directed at care-
fully designing diazoamides wherein one of the N-sub-
stituents of the tertiary diazoamide unit is unreactive
toward the Rh(II)-carbenoid intermediate, with the
aim of promoting C–H insertion at the desired N-substi-
tuent. Several N-protecting groups [e.g., N-(2,4,6-
trimethylbenzyl),2b N-(p-methoxyphenyl),3 N-(p-nitro-
phenyl),4a,b N-tert-butyl4c,d] have been explored and
some have been evaluated in asymmetric C–H insertion
reaction of diazoamides.5
The Rh(II)-catalyzed intramolecular C–H insertion
reaction of diazoamides for the preparation of chiral,
non-racemic c-lactams has not been as extensively inves-
tigated compared to the Rh(II)-catalyzed asymmetric
C–H insertion of diazoacetates to form c-lactones.
However, it has been shown that chiral non-racemic c-
lactams were accessible via Rh(II)-catalyzed intramole-
cular C–H insertion reaction of tertiary diazoamides.
For example, an ee of c-lactams as high as 98% was real-
ized in the Rh(II)-catalyzed C–H insertion of chiral ester
diazoanilides.3a Further, the chiral Rh(II)-catalyzed
reaction of ester diazoanilides4a,b and diazoamides4c,d
We recently reported the intramolecular C–H insertion
of N-[bis(trimethylsilyl)methyl]diazoamides and demon-
strated that the N-[bis(trimethylsilyl)methyl] (N-
BTMSM) group is a practical conformational control
element,6a,b which promoted good to excellent site-
selectivity in the reaction of N-(BTMSM)diazoamides.
Moreover, we have shown7 that the C–H insertion
reaction in 5-N-(BTMSM)diazoamide derivatives of
*
Corresponding author. Tel.: +1 306 585 4767; fax: +1 306 337
2409; e-mail: andrew.wee@uregina.ca
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.020

298
A. G. H. Wee et al. / Tetrahedron: Asymmetry 17 (2006) 297–307
1,3-dioxanes, catalyzed by homochiral Rh(II)-carbox-
amidates, gave bicyclic-c-lactams in high yield and high
enantioselectivity (Eq. 1).
of the crude keto amide gave the diazoamide 3 in 74%
yield. Subsequent deacylation (aq THF, LiOHÆH2O) of
3 furnished 1b (74%). Acylation of 2 (R = Ph(CH2)2)
with ethyl diazomalonyl chloride gave 1e (80%) and
treatment of 2 (R = 4-MeOPh(CH2)2) with methyl diazo-
malonyl chloride afforded 1f (85%).
O
O
BTMSM
BTMSM
N
N
N2
Rh2(4R-MEOX)4
ð1Þ
2.2. Chiral Rhodium(II)-catalyzed reaction of compounds
1 and determination of the enantioselectivity and assign-
ment of C-4 absolute configuration of c-lactams
O
O
CH2Cl2
O
O
(S,S), 90% e.e.
Ph
Ph
The intramolecular C–H insertion reaction of diazo-
amides 1a–g was catalyzed by 2 mol % of chiral Rh(II)
carboxamidates and Rh(II) carboxylates in dry dichlo-
romethane (Eq. 2).
The influence of the N-BTMSM group on the enantio-
selectivity of the C–H insertion reaction in conforma-
tionally flexible N-arylalkyl, N-BTMSM diazoamides
has not yet been reported. Here, we describe the results
of our studies on the reaction of N-BTMSM diazoacet-
amides and a-carboalkoxy diazoacetamides catalyzed
by chiral Rh(II) carboxamidates and Rh(II) carboxy-
lates. It was found that the chemoselectivity of the reac-
tion, in general, ranges from good to excellent.
Regioselectivity, however, was found to be catalyst
dependent and Rh2(4R-MEOX)4 and Rh2(S-PTTL)4
were identified as optimal catalysts herein.
X
R
X
N2
R
X
2 mol%
Rh2L4
R
N
O
N
O
CH2Cl2, reflux
N
O
BTMSM
BTMSM
BTMSM
1
5
4
a; X = H, R = Ph
b; X = H, R = 4-MeOPh
c; X = H, R = CH2Ph
d; X = CO2Me, R = Ph
e; X = CO2Et, R = Ph
f; X = CO2Me, R = 4-MeOPh
g; X = CO2Me, R = CH2Ph
N
BTMSM
6
O
2. Results and discussion
ð2Þ
2.1. Preparation of diazo compounds 1b,e,f
All products were readily separated by flash chromato-
graphy. The N-(BTMSM)-c-lactams 4 were quite non-
polar and were not amenable to HPLC analysis using
various Chiralcelꢁ columns (e.g., OB and OD). There-
fore, the c-lactams 4 were chemically transformed to
the more polar c-lactams 7a–c (Scheme 2).
The N-arylalkyl-N-(BTMSM)diazoamides 1a–g were
used in this study. Diazoamides 1a,c,d,g have previously
been described6a,b with the exception of the diazoamides
1b,e,f. The latter diazoamides were prepared (Scheme 1
and Fig. 1), using our established procedures,6a,b in
good overall yields (74–85%).
Thus, for the c-lactams 4a and c6a,b the N-(BTMSM)
group was oxidatively (CAN)8 converted to the corre-
sponding N-formyl derivative, which was then hydro-
Thus, acylation of the amine 2 (R = 4-MeOPh(CH2)2)
with diketene followed by diazotization (MsN3, DBU)
O
H
R
c
N
a or b
X
R
N
BTMSM
BTMSM = CH(SiMe3)2
N2 BTMSM
2
3; X = Ac, R = 4-MeOPh(CH2)2
1e; X = CO2Et, R = Ph(CH2)2
1f; X = CO2Me, R = 4-MeOPh(CH2)2
O
(CH2)2PhOMe-4
N2HC
1b
N
BTMSM
Scheme 1. Preparation of N-BTMSM diazoamides 1b,e,f. Reagents and conditions: (a) for 3: (i) diketene, cat. DMAP, THF, rt; (ii) MsN3, DBU,
MeCN, rt; 74%, (b) EtO2CC(@N2)COCl (1e, 80%) or MeO2CC(@N2)COCl (1f, 85%), 2,6-lutidine, CH2Cl2, 0 ꢂC, (c) LiOHÆH2O, THF–H2O (1:1
v/v), rt; 74%.
O
X
(CH2)2R
a; X = H, R = Ph, b; X = H, R = 4-MeOPh
c; X = H, R = CH2Ph, d; X = CO2Me, R = Ph
e; X = CO2Et, R = Ph, f; X = CO2Me, R = 4-MeOPh
g; X = CO2Me, R = CH2Ph
N
N2 BTMSM
1
Figure 1. N-BTMSM diazoamides 1a–g.

A. G. H. Wee et al. / Tetrahedron: Asymmetry 17 (2006) 297–307
299
CAN, aq. MeCN;
X
R
a, b, c
R
MeOH, Na2CO3
or KF.H2O, aq. DMSO
O
N
O
N
1) aq. DMSO, NaCl
2) CAN, aq. MeCN;
BTMSM
R'
4
7
d, f, g
MeOH, Na2CO3
a, R = Ph, R' = H
b; R = 4-MeOPh, R' = Me
c; R = CH2Ph, R' = H
or aq. DMSO, NaCl
OMe
Ph
Ph
1) LiAlH4, THF
O
N
N
H
2) PhC(O)Cl
O
Ph
O
8
N
from Rh2(4R-MEOX)4
reaction
9
7c
SiMe3
Scheme 2. Conversion of c-lactams 4 to 7 and 9.
lyzed under basic conditions (Na2CO3) to give 7a3a,9 and
7c, respectively. With 4b, double desilylation was
achieved using potassium fluoride in hot, aqueous
DMSO to furnish a 73% yield of 7b. The ester lactams
4d and g were subjected to Krapcho decarboxylation10
followed by removal of the N-(BTMSM) group (CAN;
Na2CO3) to afford c-lactams 7a (from 4d6a) and 7c
(from 4g6a), respectively. In the case of 4f, decarboxyl-
ation (aq DMSO, NaCl) gave the desired 7b and the
mono-desilylated product 8, and in a ratio of 1:4.3.
primarily 4a with varying amounts of the cycloheptatri-
ene 6.6a,b The corresponding b-lactam 5a was not
detected. The ratio of 4a:6 was found to be dependent
on the chiral Rh(II) carboxamidate catalyst employed.
With
Rh2(5R-MEPY)4,
Rh2(4R-MEOX)4,
and
Rh2(4R-MEAZ)4, 1a reacted with excellent regio- and
high chemoselectivity to afford the c-lactam 4a (entries
1–3). Only a small amount (3–6%) of the cycloaddition
product 6 was formed. It is useful to note that achiral
Rh(II) carboxamidate catalysts, such as Rh2(Cap)4, gave
a 3.3:16b ratio of 4a:6, whereas the chiral Rh(II) carbox-
amidates exhibited a high degree of chemoselectivity
(13–24:1 of 4a:6). However, with Rh2(4S-MACIM)4
and Rh2(4S-MPPIM)4 (entries 4 and 5), 1a yielded a sig-
nificant amount of the cycloaddition product 6 along
with the desired c-lactam 4a. The ratio of 4a:6 was 2–
3.5:1, which was similar to that obtained with the achiral
Rh(II) catalysts.6b The poor chemoselectivity observed
with Rh2(MPPIM)4 and Rh2(MACIM)4 when com-
pared to Rh2(5R-MEPY)4, Rh2(4R-MEOX)4, and
Rh2(4R-MEAZ)4 may be attributed to the steric size
of the catalysts; both Rh2(MPPIM)4 and Rh2(MA-
CIM)4 are bulkier catalysts. It is plausible that the steric
bulk of these catalysts and the steric size of the N-
BTMSM protecting group of the diazoamide result in
an increase in steric congestion within the environment
surrounding the metallocarbenoid centre. Therefore, it
is reasonable to suggest that before the key C–H inser-
tion reaction step, the bulky catalyst could have dissoci-
ated from the carbenoid carbon centre, which would
result in the generation of a very reactive, achiral free
carbene. The free carbene is expected to undergo C–H
insertion and aromatic cycloaddition to form 4a and 6,
respectively.
The sense of induction at the newly formed C-4 in c-lac-
tam 7a was determined by comparison of the specific
rotation of 7a with that of the known3a,9 (S)-4-phenyl-
2-pyrrolidinone ([a]D = +37.5) and (R)-4-phenyl-2-pyr-
rolidinone ([a]D = ꢀ37.5). The sense of induction for
compound 7b was inferred from that of compound 7a.
For compound 7c, the sense of induction at C-4 was
determined via a chemical correlation approach. Thus
c-lactam 7c, derived from the Rh2(4R-MEOX)4-cata-
lyzed reaction of 1c, was reduced with lithium aluminium
hydride to obtain the corresponding 4-benzylpyrrol-
idine, which was immediately treated with benzoyl chlo-
ride under Schotten–Bauman11 conditions to obtain the
known12 benzamide 9 (Scheme 2). The sign of the spe-
23
cific rotation of synthetic 9, ½aꢁD ¼ ꢀ28:6 (c 0.35,
CH2Cl2), was the same as that reported in the literature
for (R)-9 ([a]D = ꢀ57.4 (c 0.76, CH2Cl2)). This indicated
that the C-3 absolute configuration in synthetic 9 was R,
which in turn, indicated that the C-4 absolute configura-
tion was R in 7c as well as in 4c.
The enantioselectivity of the C–H insertion reaction for the
formation of c-lactams 4 was determined via HPLC analy-
sis of compounds 7 using either a Chiralcel OBꢁ (c-lactams
7aand 7c) or ADꢁ (c-lactam7b) column. No attempts were
made at determining the enantiomeric excesses of the b-
lactam products 5 or the cycloheptatriene derivative 6.
The combined results are summarized in Table 1.
Compound 1b (entry 6) was also investigated to deter-
mine whether the presence of an electron-donating
methoxy group on the phenyl ring would promote the
formation of the corresponding cycloheptatriene deriva-
tive over the c-lactam 4b. When 1b was treated with
Rh2(4R-MEOX)4 only the c-lactam 4b was formed in
high yield (83%); neither the b-lactam 5b nor a cyclo-
heptatriene derivative was detected. Compared to the
phenylethyl system 1a (entry 2) the reaction of 1b
2.3. Regio- and chemoselectivity
The reaction of 1a, catalyzed by the chiral Rh(II)
carboxamidate catalysts, proceeded efficiently to give

300
A. G. H. Wee et al. / Tetrahedron: Asymmetry 17 (2006) 297–307
Table 1. Reaction of diazoamide 1a–g catalyzed by homochiral Rh(II) catalysts
a
Entry
Diazoamide
Rh2Lꢂ4
Yield (%)d
Rel. yield (%)
C4 config. of 7
4e:5:e6
ee (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
1c
1d
1d
1d
1d
1d
1d
1e
1e
1e
1f
Rh2(5R-MEPY)4
Rh2(4R-MEOX)4
Rh2(4R-MEAZ)4
Rh2(4S-MACIM)4
Rh2(4S-MPPIM)4
Rh2(4R-MEOX)4
Rh2(5R-MEPY)4
Rh2(4R-MEOX)4
Rh2(S-PTPA)4
87
89
82
86
93
83
90
92
92
87
80
80
77
89
92
87
80
82
73
90
75
93:0:7
95:0:5
96:0:4
67:0:33
78:0:22
100:0:0
100:0
7a, R, 38
7a, R, 43
7a, R, 34
7a, S,i 8
7a, —, 0
7b, R, 69
7c, R,j 32
7c, R,k 43
7a, R, 5
7a, R, 7
7a, R, 65
7a, R, 75
7a, nd, 9
7a, S, 35
nd
b
100:0
9
100:0:0
100:0:0
71:29f,g:0
50:50:g0
100:0:0
100:0:0
100:0:0
100:0:0
55:45:h0
90:10:0
100:0
10
11
12
13
14
15
16
17
18
19
20
21
Rh2(S-PTV)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
c
Rh2(S-DOSP)4
Rh2(4R-MEAZ)4
Rh2(S-PTPA)4
Rh2(S-PTV)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTPA)4
Rh2(S-PTV)4
nd
nd
7b, R, 51
7c, S,l 24
7c, S,l 44
7c, S,m 64
1g
1g
1g
85:15
56:44
Rh2(S-PTTL)4
nd, Not determined.
a All the reactions were conducted in refluxing dry dichloromethane, under argon, using 2 mol % of the chiral Rh(II) catalysts.
b The Rh2(4S-MEOX)4-catalyzed reaction gave the 43% ee of 7a.
c Reaction was conducted in dry toluene at 50 ꢂC (oil bath).
d Isolated yield.
e The C2–C3 trans stereochemistry in compounds 4d–g was assigned based on the H-3 doublet, J3,4 = 9 Hz. The C2–C3 trans stereochemistry in b-
lactam product 5d,e was assigned based on the vicinal coupling constant, J3,4, of 3 Hz.6b
f Compounds 4d and 5d are run very close together during TLC. Careful separation by column chromatography afforded an analytical sample of 5d
for characterization purposes.
g 1H NMR analysis of the crude reaction mixture after prefiltration over a short pad of silica gel to remove the Rh(II) catalyst. Ratio of 4e:5e was
based on the integration of the double doublet centred at d 2.68 due to one of the benzylic protons of 5d and the double doublet at d 3.42 due to H-
5 in 4d.
h 1H NMR analysis of the crude reaction mixture after prefiltration over a short pad of silica gel to remove Rh(II) catalyst. Ratio of 4e:5e was based
on the integration of the double doublet centred at d 2.76 due to one of the benzylic protons of 5e and the double doublet at d 3.40 due to H-5 in
4e.
i Absolute configuration assigned based on comparison of sign of specific rotation to 7a.
j Absolute configuration was inferred from data obtained for 7c derived from 4c (entry 8) via comparison of [a]D.
23
k 7c derived from 4c (entry 8) ½aꢁD ¼ þ4:4 (c 1.30, CH2Cl2).
l Absolute configuration was inferred from data obtained for 7c derived from 4c,g via comparison of [a]D of 7c.
23
m 7c derived from 4g, ½aꢁD ¼ ꢀ3:1 (c 0.80, CH2Cl2).
showed excellent regio- and chemoselectivity. The pres-
ence of an electron-donating p-methoxy group in the
phenyl ring appears to be especially conducive for C–
H insertion at the benzylic position even though cyclo-
addition of the metallocarbenoid to the electron-rich
phenyl moiety is also feasible.
was studied next. Although Rh2(4R-MEAZ)4 is classi-
fied as a Rh(II) carboxamidate, it has been shown to
possess higher reactivity compared to its relatives,13
such as Rh2(5R-MEPY)4 and Rh2(4R-MEOX)4, and is
effective for the decomposition of the ester diazoamides.
We tested Rh2(4R-MEAZ)4 on 1d to examine its effi-
ciency in catalyzing the C–H insertion reaction and to
ascertain the level of asymmetric induction that can be
achieved with this catalyst.
Diazoacetamide 1c is the homologue of 1a; however, the
Rh2(5R-MEPY)4- and Rh2(4R-MEOX)4-catalyzed C–H
insertion reaction of 1c proceeded with high regioselec-
tivity and excellent chemoselectivity to give only 4c
(compare entries 7 and 8–1 and 2). This outcome was
also in accord with the results obtained when achiral
Rh(II) catalysts were used.
With 1d, all the catalysts with the exception of Rh2(S-
PTTL)4 were found to provide excellent regioselectivity
to give only the c-lactam 4d (entries 9, 10, 13, and 14).
Further, in the case of Rh2(4R-MEAZ)4, the presence
of an a-substituent on the metallocarbenoid carbon sup-
pressed the aromatic cycloaddition pathway, which
would have led to the formation of the corresponding
cycloheptatriene compound (compare entries 3 and
The reaction of the a-carbalkoxy substituted diazoacet-
amides 1d–g catalyzed by Rh2(S-PTPA)4, Rh2(S-PTV)4,
Rh2(S-PTTL)4, Rh2(S-DOSP)4, and Rh2(4R-MEAZ)4

A. G. H. Wee et al. / Tetrahedron: Asymmetry 17 (2006) 297–307
301
14). With Rh2(S-PTTL)4, the closely moving c-lactam
2.4. Enantiomeric excess and absolute configuration
of c-lactams 4a–d,f,g
4d and the b-lactam 5d were formed14 in an overall yield
of 80%, and in a ratio of 2.4:1 (entry 11). More surpris-
ingly, when the Rh2(S-PTTL)4-catalyzed reaction of 1d
was repeated in toluene15 (50 ꢂC), the metallocarbenoid
reaction showed no regioselectivity in the C–H insertion
reaction. Although a high overall yield of 4d and 5d was
obtained, the ratio of 4d:5d was 1:1 (entry 12). The
results from 1d prompted us to study the reaction of 1e
catalyzed by Rh2(S-PTPA)4, Rh2(S-PTV)4, and Rh2(S-
PTTL)4 in refluxing dichloromethane to assess whether
a slight change from an O-methyl to an O-ethyl group
in the diazomalonyl unit would affect the regioselectivity
of the reaction.
The highest enantioselectivity observed for the reaction
of 1a was with Rh2(4R-MEOX)4 where a 43% level of
asymmetric induction was realized (entry 2). Both
Rh2(5R-MEPY)4 and Rh2(4R-MEAZ)4 were provided
nearly the same degree of asymmetric induction (entries
1 and 3), but were obviously inferior to Rh2(4R-
MEOX)4. The poorest enantioselectivity was observed
for Rh2(MPPIM)4 and Rh2(MACIM)4 (entries 4 and
5), in which the former catalyst provided a racemic mix-
ture of 7a. However, the reaction of 1b with the optimal
catalyst, Rh2(4R-MEOX)4, gave the best result wherein
a respectable 69% level of asymmetric induction was
realized (entry 6). The lack of asymmetric induction
observed for the Rh2(4S-MACIM)4 and Rh2(4S-MPPIM)4
(entries 4 and 5) lends further support to the notion that
the bulky, chiral Rh(II) catalysts and the carbenoid car-
bon were not closely associated with each other during
the key C–H insertion reaction step leading to the for-
mation of c-lactam 4a.
We found that with Rh2(S-PTPA)4 and Rh2(S-PTV)4
(entries 15 and 16), the reaction of 1e proceeded very
efficiently and with excellent regioselectivity to afford
only the c-lactam 4e. Again, Rh2(S-PTTL)4 behaved
anomalously in this trio of catalysts; a 1.2:1 ratio of
an inseparable mixture of 4e:5e was obtained in high
overall yield. Compared to the results of 1d (entry 11),
it is clear that with Rh2(S-PTTL)4 a small structural
change in the ester O-alkyl group (OMe!OEt) of the
diazomalonyl unit had a detrimental effect on the regio-
selectivity of the reaction (compare entries 11 and 17). It
is also interesting to note that the regioselectivity
obtained in this case is comparable to the result from
the Rh2(S-PTTL)4-catalyzed reaction of 1d in toluene
(compare entries 12 and 17). The reactions of 1f,g
proved to be interesting. As was observed in the reaction
of 1b (entry 6), a p-methoxy substituent on the phenyl
moiety promoted metallocarbenoid insertion exclusively
at the benzylic position. It was surmised that the regio-
selectivity of the C–H insertion reaction in 1d could be
improved upon through the incorporation of a methoxy
group on the phenyl ring. This notion was confirmed
through the Rh2(S-PTTL)4-catalyzed reaction of 1f,
which afforded a 9:1 ratio of 4f:5f (compare entries 11
and 18).
Modest enantioselectivity was obtained for the reaction
of 1c (entries 7 and 8); the ees were comparable to the
enantioselectivity obtained for the Rh2(5R-MEPY)4
and Rh2(4R-MEOX)4-catalyzed reaction of 1a (entries
1 and 2). It has also been documented3a,4d,16 that the
type of solvent has an effect on the stereoselectivity of
Rh(II)-carbenoid mediated reactions. Ether-type sol-
vents were found to be useful in enhancing the enantio-
selectivity of the C–H insertion reaction without
adversely affecting the catalytic efficiency of the Rh(II)
catalyst. Further, a recent study4d showed that ether
type solvents were especially conducive for achieving
high enantioselectivity in the Rh2(4R-MEOX)4-cata-
lyzed reaction of N-(benzyloxyethyl),N-(tert-butyl)-a-
diazoacetamide.
Encouraged by these results, we studied the Rh2(4R-
MEOX)4-catalyzed reaction of 1c in refluxing dry
diethyl ether, tetrahydrofuran (THF), dimethoxyethane
(DME), and 1,4-dioxane to determine whether any
improvement in enantioselectivity of the reaction could
be realized. In general, a high yield (96–99%) of the
product 4c was obtained, but the ees of the reactions
were disappointingly lower than that obtained in dichlo-
romethane (entry 8). Interestingly, the ee for 7c (4c) fell
into two groups; the lower boiling ether and THF gave
lower but very similar ee (ether, 15%; THF, 17%) and
the higher boiling solvents DME and 1,4-dioxane gave
slightly higher ees (DME, 24%; 1,4-dioxane, 23%).17
The reaction of 1g (homologue of 1d) catalyzed by chiral
Rh(II) carboxylates was also interesting in light of the
results obtained for 1d (compare entries 9, 10, and 11
with 19, 20, and 21). With Rh2(S-PTPA)4, 1g gave only
the c-lactam 4g and this outcome was identical to the
result obtained for 1d (compare entries 9 and 19). The
Rh2(S-PTTL)4-catalyzed reaction of 1g afforded a mix-
ture of 4g and 5g as was in the case of 1d (compare
entries 11 and 21). However, the regioselectivity of the
reaction was poor; the ratio of 4g:5g was 1.2:1. Unlike
1d, the Rh2(S-PTV)4-catalyzed reaction of 1g gave a
5.5:1 ratio of 4g:5g (compare entries 10 and 20). The rea-
sons for the decrease in regioselectivity for Rh2(S-
PTTL)4 and especially Rh2(S-PTV)4 accompanying a
very small change in chain length is not well understood
at this time, but may be related to the overall steric inter-
play of the N-substituent in 1d with the chiral carboxyl-
ate ligands in the transition states for C–H insertion.
The data showed that as the size of steric crowding in
the carboxylate ligand (Bn < i-Pr < t-Bu) of the Rh(II)
catalysts increases, there is an increasing tendency for
b-lactam formation.
The sense of induction at the C-4 stereocentre in the c-
lactams 7a,b,c was found to be R when an R-configu-
rated catalyst was used and S when an S-configurated
catalyst was utilized.
In the C–H insertion reaction of 1d catalyzed by chiral
Rh(II) carboxylates and conducted in dichloromethane,
Rh2(S-PTTL)4 exhibited the highest enantioselectivity
of 65% (entry 11). The ee of the reaction was higher
(75%) when toluene was used as the solvent (entry 12).

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A. G. H. Wee et al. / Tetrahedron: Asymmetry 17 (2006) 297–307
Enantiocontrol was, however, very poor for Rh2(S-
PTPA)4, Rh2(S-PTV)4, and Rh2(S-DOSP)4 (entries 9,
10, and 13). The enantioselectivity of the reaction of 1f
with Rh2(S-PTTL)4 depreciated significantly when com-
pared to 1d (entry 11), which indicated that the presence
of the electron-donating methoxy group was disadvan-
tageous for enantiocontrol. The sense of induction at
C-4 in compounds 7a,b for the reactions catalyzed by
the S-configurated Rh(II) carboxylates was R.
compounds of type 10 has been described in four pat-
ents,20 and compounds 10 were claimed to possess sim-
ilar biological activities to those of 11.
The preparation of 10 was readily achieved starting from
4c (43% ee). N-Deprotection of 4c (CAN; Na2CO3,
MeOH) yielded 7c as a solid; recrystallization of 7c from
petroleum ether/ethyl acetate slightly improved its ee to
47% (50% yield of recrystallized 7c). Hydrolysis of 7c
using aqueous 6 M HCl at reflux furnished 10 as its
hydrochloride salt. Subsequent purification of 10ÆHCl
The Rh2(4R-MEAZ)4-catalyzed reaction of 1d provided
a 35% ee of 7a (entry 14). It is useful to note that the
level of induction at C-4 is almost identical to the result
obtained for the Rh2(4R-MEAZ)4-catalyzed reaction of
1a (entry 3). Interestingly, the sense of induction at C-4
for the Rh2(4R-MEAZ)4-catalyzed reaction was oppo-
site to that realized with Rh2(S-PTTL)4 (compare entries
11 and 14) as well as that obtained for 1a (compare
entries 3 and 14).
on Dowex 50 · 2–400 (H+) afforded the amino acid
22
(R)-10 {mp: 169–169.6 ꢂC; ½aꢁD þ 6:25 (c 1.20, MeOH)}.
3. Summary
In summary, we have found that the intramolecular C–
H insertion reaction of the diazoacetamides 1a–c cata-
lyzed by chiral Rh(II) carboxamidates proceeded with
excellent regioselectivity to afford good to high yields
of c-lactams 4. However, the chemoselectivity of the
reaction was found to be catalyst dependent; the hin-
dered Rh(II) carboxamidate catalysts Rh2(4R-MA-
Among the three Rh(II) carboxylate catalysts tested
against 1g, Rh2(S-PTTL)4 provided the highest enantio-
selection at C-4 (64% ee) in the formation of 4g (entry
21). The enantioselectivity achieved in the Rh2(S-
PTPA)4- and Rh2(S-PTV)4-catalyzed reaction were also
substantially higher than that obtained with 1d (com-
pare entries 19 and 20 to entries 9 and 10). The sense
of induction at C-4 in 7c was determined as S for the
S-configurated Rh(II) carboxylate catalysts.
CIM)4
and
Rh2(4R-MPPIM)4
showed
poor
chemoselectivity. The chiral Rh(II) carboxylate cata-
lyzed reaction of the diazoamides 1d–g proceeded with
excellent chemoselectivity, but regioselectivity was influ-
enced by the type of catalyst used. Rh2(S-PTTL)4
showed a consistent pattern for promoting b-lactam
5 formation. Enantioselectivity up to 69% was realized
with the Rh(II) carboxamidates, with Rh2(4R-MEOX)4
as the best catalyst in the group. For the Rh(II) carboxy-
lates, asymmetric induction up to 75% were achieved;
Rh2(S-PTTL)4 was found be the best catalyst, but its
effectiveness is tempered by the poor regioselectivity
obtained for the C–H insertion reaction. The utility of
the N-BTMSM-c-lactams in synthesis was demon-
strated by the facile conversion of (R)-4c to a GABA
analogue, (R)-b-benzyl-c-aminobutyric acid (10, 47%
ee). Studies directed at improving the enantioselectivity
of the reaction of N-BTMSM diazoamides and the use
of the application of the method in natural product
synthesis are ongoing.
2.5. Synthesis of b-benzyl-c-aminobutyric acid 10
The N-BTMSM-c-lactams are useful starting materials
that can be readily transformed into biologically active
compounds. To demonstrate this concept, we synthe-
sized b-benzyl-c-aminobutyric acid 10 from the c-lactam
4c (Scheme 3). It is well documented that b-aryl-c-ami-
nobutyric acid, typified by (R)-(ꢀ)-c-amino-b-(4-chloro-
phenyl)butyric acid 11a [(R)-Balcofen] and (R)-(ꢀ)-c-
amino-b-(phenyl)butyric acid 11b, are clinically impor-
tant agonists that act on GABAB-receptors;18 (R)-balco-
fen being the most potent and selective agonist. These
types of compounds have been shown to possess a range
of physiologically important properties such as anti-
spasticity, anti-epileptic, anti-hypertensive, anti-asth-
matic, and analgesic activities and, therefore, have
potential use in therapeutic applications. As a result,
there is much interest directed at the synthesis of
b-aryl-c-aminobutyric acid.19 In contrast, less attention
has been paid to the synthesis of b-arylmethyl-c-amino-
butyric acid, exemplified by 10, which can be considered
as the b-side chain homologue of 11. The synthesis of
4. Experimental
4.1. General
Only diagnostic absorptions in the infra-red spec-
trum are reported. 1H and 13C NMR spectra were
Ph
Ph
Ph
1) 6M HCl (aq)
N-deprotection
R
O
2)Dowex
HO2C
O
N
N
50x2-400
NH2
H
BTMSM
4c (43 % e.e.)
(from Rh2(R-MEOX)4)
10
7c
Ar
11 a; Ar = 4-ClPh
R
b; Ar = Ph
HO2C
NH2
Scheme 3. Synthesis of (R)-10.

A. G. H. Wee et al. / Tetrahedron: Asymmetry 17 (2006) 297–307
303
recorded in CDCl3, unless stated otherwise, using
either a Bruker 200 MHz QNP or Varian Mercury
300 MHz NMR spectrometer. Tetramethylsilane
(dH = 0.00) and the CDCl3 resonance (dC = 77.0) were
used as internal references. Reaction progress was
monitored by thin-layer chromatography on Merck sil-
ica gel 60F254 precoated (0.25 mm) on aluminium
backed sheets. Air and moisture sensitive reactions
were conducted under a static pressure of argon. All
organic extracts were dried over anhydrous Na2SO4.
Chromatographic purification implies flash chromato-
graphy, which was performed on Merck silica gel 60
(230–400 mesh). Optical rotations were measured, at
the NaD line, on an Optical Activity (AA-5) polarimeter.
HPLC analysis of compounds was performed using a
Waters 600 pump equipped with a Waters 2487 UV
detector (k = 254 nm) and controlled by PC workstation
running the Millenium32ꢁ program; enantiomeric sepa-
ration was achieved using either a Chiralcelꢁ OB or
AD column (1.5 mm · 250 mm) using hexane/2-propa-
nol (90:10 or 95:5 v/v) as eluent, and a flow rate of
1.2 mL/min. Dichloromethane, 1,4-dioxane, dimeth-
oxyethane, and acetonitrile were dried by distillation
from calcium hydride. THF and diethyl ether were dried
by distillation from sodium using sodium benzophenone
ketyl as indicator. Compounds 1a,c,d,g and racemic
4a,c,d,g have been reported6a previously.
(118 mg, 2.75 mmol) in H2O (0.5 mL) was added. The
mixture was stirred at rt and reaction progress was
closely monitored by TLC. After 3 h, the reaction
mixture was evaporated to remove THF, saturated
NH4Cl was added and the aqueous mixture was
extracted thoroughly with CH2Cl2. The combined
CH2Cl2 layers were washed with water, dried (Na2SO4),
filtered, and concentrated. The crude oil was purified by
chromatography to give 1b (220 mg, 74%). IR: mmax
(neat): 3067, 2102, 1697, 1606 cmꢀ1
;
1H NMR
(200 MHz) d = 0.12 (s, 18H, 2 · SiMe3), 1.94 (br s,
1H, (Me3Si)2CH), 2.65–2.90 (m, 2H, CH2), 3.30–3.10
(m, 2H, NCH2), 3.80 (s, 3H, OMe), 4.95 (s, 1H,
CHN2), 6.88 (d, 2H, J = 8.8 Hz, Ph), 7.10 (d, 2H,
J = 8.8 Hz, Ph); 13C NMR (50.3 MHz) d = 0.70, 34.1,
46.0, 46.9, 54.6, 55.2, 114.2, 129.9, 129.7, 158.4; HRMS:
calcd for C17H28N3O2Si2 (Mꢀ15) 362.1720, found
362.1718.
4.3. General procedure for the preparation of a-carbo-
alkoxy-a-diazoacetamides 1e,f
The appropriate secondary amine 2 (R = Ph(CH2)2 or 4-
MeOPh(CH2)2) (1.0 mmol) was dissolved in dry CH2Cl2
(3 mL) under Ar. 2,6-Lutidine (2.0 mmol) was added to
the solution and the mixture was cooled to 0 ꢂC. The
appropriate diazomalonyl chloride (1.5 mmol) in dry
CH2Cl2 (3 mL) was then transferred to the reaction mix-
ture via cannula. The reaction was stirred at 0 ꢂC and
then at rt. After 2 h, it was washed successively with sat-
urated NaHCO3, H2O, and then saturated NaCl. The
organic layer was dried (Na2SO4), the filtered solution
was concentrated in vacuo, and the residue was purified
by flash chromatography.
4.2. N-Bis(trimethylsilyl)methyl-N-[2-(4-methoxyphen-
yl)ethyl]-a-diazoacetamide, 1b
N-(4-Methoxyphenethyl)bis(trimethylsilyl)methylamine
was prepared in 54% yield from the alkylation of 2
(R = H, 637 mg, 3.63 mmol) with 4-methoxyphenethyl
bromide (781 mg, 3.63 mmol) in dry DMF containing
Na2CO3 (270 mg, 2.54 mmol) and NaI (150 mg,
1 mmol). IR: mmax (neat) 1613, 1583 cmꢀ1 1H NMR
;
4.4. N-Bis(trimethylsilyl)methyl-N-phenethyl-a-carbo-
ethoxy-a-diazoacetamide, 1e
(200 MHz) d = 0.0 (s, 18H, 2 · SiMe3), 0.75 (br s, 1H,
NH), 1.32 (s, 1H, (Me3Si)2CH), 2.55–2.90 (m, 4H,
NCH2, CH2Ph), 3.80 (s, 3H, OMe), 6.81 (d, 2H,
J = 8.8 Hz, Ph), 7.12 (d, 2H, J = 8.8 Hz, Ph); 13C
NMR (50.3 MHz) d = 0.70, 35.7, 39.7, 55.2, 55.6,
113.8, 129.6, 132.3.
Yield: 80%; IR: mmax (neat): 3064, 3027, 2123, 1709,
1618 cmꢀ1 1H NMR (200 MHz) d = 0.13 (s, 18H,
;
2 · SiMe3), 1.30 (t, 3H, J = 8.0 Hz, CO2CH2Me),
2.08–2.24 (br s, 1H, (Me3Si)2CH), 2.95 (t, 2H,
J = 8.0 Hz, CH2Ph), 3.48 (t, 3H, J = 8.0 Hz, NCH2),
4.28 (q, 2H, J = 8.0 Hz, CO2CH2Me), 7.10–7.40 (m,
5H, Ph).; 13C NMR (50.3 MHz) d = 0.50, 14.4, 35.1,
45.2, 55.2, 61.3, 126.5, 128.6, 138.1, 158.4, 162.8;
HRMS: calcd for C19H30N3O3Si2 (Mꢀ15) 404.1825,
found 404.1820.
Amine 2 (R = 4-MeOPh(CH2)2, 300 mg, 0.97 mmol)
was treated with diketene (122 mg, 0.12 mL, 1.45 mmol)
in dry THF containing DMAP (24 mg, 0.194 mmol) to
give the crude acetoacetamide (381 mg), which was not
purified but subjected to diazotization with methane-
sulfonyl azide (235 mg, 1.94 mmol) in dry acetonitrile
containing DBU (295 mg, 0.29 mL, 1.94 mmol) to give
3 (330 mg, 81%). IR: mmax (neat): 1721, 1658, 1626 cmꢀ1
;
4.5. N-Bis(trimethylsilyl)methyl-N-[2-(4-methoxyphen-
yl)ethyl]-a-methoxycarbonyl-a-diazoactetanamide, 1f
1H NMR (200 MHz) d = 0.14 (s, 18H, 2 · SiMe3), 2.18
(br s, 1H, (Me3Si)2CH), 2.30 (s, 3H, Me), 2.83 (t, 2H,
J = 8.4 Hz, CH2), 3.40 (t, 2H, J = 8.4 Hz, NCH2), 3.78
(s, 3H, OMe), 6.84 (d, 2H, J = 8.8 Hz, Ph), 7.08 (d, 2H,
J = 8.8 Hz, Ph); 13C NMR (50.3 MHz) d = 0.60, 26.9,
34.0, 45.4, 56.2, 65.9, 113.9, 114.1, 128.5, 129.7, 158.4;
HRMS: calcd for C20H33N3O3Si2 (M+) 419.2060, found
419.2059.
1
Yield: 85%; IR: mmax (neat): 2120, 1713, 1616 cmꢀ1; H
NMR (200 MHz) d = 0.10 (s, 18H, 2 · SiMe3), 2.12
(br s, 1H, (Me3Si)2CH), 2.86 (t, 2H, J = 7.9 Hz, CH2),
3.45 (t, 2H, J = 7.9 Hz, NCH2), 3.80 (s, 6H, CO2Me,
OMe), 6.85 (d, 2H, J = 8.8 Hz, Ph), 7.12 (d, 2H,
J = 8.8 Hz Ph). 13C NMR (50.3 MHz) d = 0.60, 34.2,
45.1, 52.2, 55.2, 55.4, 114.0, 129.6, 130.1, 158.3, 163.3.
HRMS: calcd for C20H33N3O4Si2 (Mꢀ15) 420.1775,
found 420.1774.
Compound 3 (330 mg, 0.79 mmol) was dissolved in 1:1
v/v THF–H2O (16 mL) and a solution of LiOHÆH2O

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A. G. H. Wee et al. / Tetrahedron: Asymmetry 17 (2006) 297–307
4.6. General procedure for chiral rhodium(II)-catalyzed
reactions of diazoamides 1a–g
92%; Rh2(S-PTV)4, 87%; Rh2(S-PTTL)4, 44%; IR: mmax
(neat): 3063, 3031, 1735, 1682 cmꢀ1 1H NMR
;
(200 MHz) d = 0.14 (s, 18H, 2 · SiMe3), 1.27 (t, 3H,
J = 8.0 Hz, CO2CH2Me), 2.96–3.15 (br s, 1H, (Me3-
Si)2CH), 3.42 (dd, 1H, J = 10.0, 8.0 Hz, H-50), 3.60 (d,
1H, J = 10.0 Hz, H-3), 3.78 (dd, 1H, J = 10.0, 8.0 Hz,
H-4), 3.98 (dd, 1H, J = 10.0, 8.0 Hz, H-5), 4.20 (q,
2H, J = 8.0 Hz, CO2 CH2Me), 7.10–7.45 (m, 5H, Ph);
13C NMR d (50.3 MHz): 0.1, 14.1, 41.5, 41.7, 55.3,
61.5, 127.0, 127.5, 128.5, 129.0, 140.3, 167.4, 169.9;
HRMS: calcd for C19H30NO3Si2 (Mꢀ15) 376.1764,
found 376.1753.
The appropriate chiral catalyst (2 mol %) in dry CH2Cl2
(3 mL) was refluxed at 45 ꢂC under argon. A solution of
the appropriate diazo compound in dry CH2Cl2 (2 mL)
was added slowly, via cannula, to the refluxing solution.
The progress of the reaction was monitored by TLC.
After the reaction was complete, the reaction mixture
was cooled to rt and concentrated in vacuo, and the res-
idue purified by flash chromatography.
4.6.1. 1-Bis(trimethylsilyl)methyl-4-phenyl-2-pyrrolidinone,
4a. Yield: Rh2(5R-MEPY)4, 81%; Rh2(4R-MEOX)4,
85%; Rh2(4R-MEAZ)4, 79%; Rh2(4R-MACIM)4, 58%;
Rh2(4R-MPPIM)4, 73%; Mp: 66.8–68.4 ꢂC; IR: mmax
For the Rh2(S-PTTL)4-catalyzed reaction, an insepara-
ble mixture of the c-lactam 4e and the b-lactam 5e was
obtained. IR: mmax (neat): 3063, 3031, 1755, 1734,
1685 cmꢀ1; 1H NMR (b-lactam signals are within square
brackets) (200 MHz) d = 0.14 (s, 18H, 2 · SiMe3), [1.20
(t)] and 1.25 (t) (3H, J = 7.2 Hz, Me)(3H), [2.05 (br s)]
and 3.00–3.10 (br s) (1H, NCH(SiMe3)2), [3.04 (dd,
J = 14.0, 6.2 Hz, PhCH)], [3.40 (dd, J = 14.0, 6.2 Hz,
PhCH)], 3.40 (dd, J = 9.3, 8.2 Hz, H-5), and 3.78 (dd,
J = 9.3, 8.2 Hz, H-50) (2H), [3.59 (d, J = 2.3 Hz)] and
3.61 (d, J = 8.4 Hz) (1H, H-3), 3.90–4.30 (m, 3H, H-4,
OCH2), 7.10–7.40 (m, 5H, PhH).
1
(CDCl3): 3038, 1661, 1604 cmꢀ1; H NMR (200 MHz)
d = 0.10 (d, 18H, 2 · SiMe3), 2.66 (dd, 1H, J = 16.4,
8.8 Hz, H-30), 2.78 (dd, 1H, J = 16.4, 8.8 Hz, H-3),
3.10–3.24 (br s, 1H, (Me3Si)2CH), 3.32–3.60 (m, 1H,
H-4), 3.44 (dd, 1H, J = 15.9, 7.8 Hz, H-50), 3.70 (dd,
1H, J = 15.9, 7.8 Hz, H-5), 7.05–7.45 (m, 5H, Ph).
HRMS: calcd for C17H29NOSi2 (M+) 319.1778, found
319.1783.
4.6.2. 1-Bis(trimethylsilyl)methyl-4-(4-methoxyphenyl)-2-
pyrrolidinone, 4b. Yield: 83%; IR: mmax (neat): 1677,
4.6.6. 1-Bis(trimethylsilyl)methyl-3-methoxycarbonyl-4-
(4-methoxyphenyl)-2-pyrrolidinone, 4f. Yield: 74%;
1613 cmꢀ1 1H NMR (200 MHz) d = 0.01 (s, 18H,
;
IR: mmax (neat): 1742, 1682, 1613 cmꢀ1 1H NMR
;
2 · SiMe3), 2.55 (dd, 1H, J = 16.5, 9.5 Hz, H-30), 2.78
(dd, 1H, J = 16.5, 9.5 Hz, H-3), 3.12–3.25 (br s, 1H,
(Me3Si)2CH), 3.39 (dd, J = 16.0, 7.5 Hz, H-50), 3.49
(ddd, 1H, J = 15.5, 8.7, 8.7 Hz, H-4), 3.72 (dd, 1H,
J = 16.0, 7.6 Hz, H-5), 3.80 (s, 3H, OMe), 6.90 (d, 2H,
J = 8.8 Hz, Ph), 7.16 (d, 2H, J = 8.8 Hz, Ph); 13C
NMR (50.3 MHz) d = 0.0, 36.3, 36.9, 38.7, 55.3, 57.1,
114.2, 127.8, 133.3, 158.6, 172.3; HRMS: calcd for
C18H31NO2Si2 (M+) 349.1993, found 349.1896.
(200 MHz) d = 0.10 (m, 18H, 2 · SiMe3), 3.13–2.94 (br
s, 1H, (Me3Si)2CH), 3.41 (dd, J = 14.6, 8.9 Hz, H-50),
3.58 (d, 1H, J = 8.9 Hz, H-3), 3.58–4.18 (m, 8H, H-4,
H-5, OMe, CO2Me), 6.89 (d, 2H, J = 8.8 Hz, Ph), 7.15
(d, 2H, J = 8.8 Hz, Ph); 13C NMR d (50.3 MHz): 0.0,
37.5, 40.9, 51.7, 52.7, 55.3, 55.4, 113.9, 114.3, 128.1,
128.3, 159.1, 170.1; HRMS: cacld. For C19H30NO4Si2
(Mꢀ15) 392.1713, found 392.1704.
4.6.7. 1-Bis(trimethylsilyl)methyl-3-methoxycarbonyl-4-
benzyl-2-pyrrolidinone, 4g. Yield: Rh2(S-PTPA)4,
73%; Rh2(S-PTV)4, 77%; Rh2(S-PTTL)4, 42%; IR: mmax
4.6.3. 1-Bis(trimethylsilyl)methyl-4-benzyl-2-pyrrolidinone,
4c. Yield: Rh2(5R-MEPY)4, 90%; Rh2(4R-MEOX)4,
92%; IR: mmax (CH2Cl2 film): 3065, 1657 cmꢀ1 1H
;
(neat): 3027, 1742, 1683 cmꢀ1 1H NMR (200 MHz)
;
NMR (200 MHz) d = 0.10 (s, 18H, 2 · SiMe3), 2.19
(dd, 1H, J = 16.1, 5.8 Hz, H-30), 2.40–2.80 (m, 4H,
CH2Ph, H-4, H-3), 3.08 (br s, 1H, (Me3Si)2CH), 3.15
(dd, 1H, J = 9.9, 5.1 Hz, H-50), 3.42 (dd, 1H, J = 9.8,
6.9 Hz, H-5), 7.05–7.40 (m, 5H, Ph). HRMS: calcd for
C17H28NOSi2 (Mꢀ15) 318.1709, found 318.1710.
d = 0.10 (s, 18H, 2 · SiMe3), 2.78 (d, 2H, J = 7.3 Hz,
CH2Ph), 2.94–3.17 (m, 3H, H-50, (Me3Si)2CH, H-4),
3.21 (d, 1H, J = 6.9 Hz, H-3), 3.49 (dd, 1H, J = 9.1,
7.3 Hz, H-5), 3.63 (s, 3H, CO2Me), 7.05–7.40 (m, 5H,
Ph). HRMS: calcd for C20H33NO3Si2 (Mꢀ15)
376.1764, found 376.1765.
4.6.4. 1-Bis(trimethylsilyl)methyl-3-methoxycarbonyl-4-
phenyl-2-pyrrolidinone, 4d. Yield: Rh2(S-PTPA)4,
92%; Rh2(S-PTV)4, 87%; Rh2(S-PTTL)4, 44%; Rh2(S-
DOSP)4, 77%; IR: mmax (neat): 3063, 3030, 1742,
4.6.8. 1-Bis(trimethylsilyl)methyl-3-methoxycarbonyl-4-
phenyl-2-azetidinone, 5d. Yield: 23%; IR: mmax (neat):
1
3029, 1755, 1734 cmꢀ1; H NMR (200 MHz) d = 0.11
(d, 18H, 2 · SiMe3), 2.04 (s, 1H, (Me3Si)2CH), 2.76
(dd, 1H, J = 14, 8.2 Hz H-50), 3.05 (dd, 1H, J = 14,
5.3 Hz, H-5), 3.62 (d, 1H, J = 2.4 Hz, H-3), 3.68 (s,
3H, CO2Me), 4.07 (ddd, 1H, J = 8.4, 6.0, 2.2 Hz, H-4),
7.10–7.40 (m, 5H, Ph); 13C NMR d (50.3 MHz): ꢀ0.5,
0.1, 38.3, 38.6, 52.3, 57.8, 58.7, 127.0, 128.5, 128.6,
128.8, 135.2, 160.8, 162.1; HRMS: calcd for C18H28NO3-
Si2 (Mꢀ15) 362.1607, found 362.1577.
1633 cmꢀ1 1H NMR (200 MHz) d = 0.10 (s, 18H,
;
2 · SiMe3), 2.90–3.12 (br s, 1H, (Me3Si)2CH), 3.42
(dd, 1H, J = 9.8, 7.7 Hz, H-50), 3.50 (d, 1H,
J = 8.8 Hz, H-3), 3.65 (s, 3H, CO2Me), 3.64 (dd, 1H,
J = 9.8, 8.7 Hz, H-5), 3.84 (ddd, 1H, J = 8.8, 8.7,
7.7 Hz, H-4), 7.10–7.45 (m, 5H, Ph). HRMS: calcd for
C18H28NO3Si2 (Mꢀ15) 362.1607, found 362.1598.
4.6.5.
1-Bis(trimethylsilyl)methyl-3-ethoxycarbonyl-4-
4.6.9. 1-Bis(trimethylsilyl)methyl-3-methoxycarbonyl-4-
(4-methoxybenzyl)-2-azetidinone, 5f. Yield: 8%; IR:
phenyl-2-pyrrolidinone, 4e. Yield: Rh2(S-PTPA)4,

A. G. H. Wee et al. / Tetrahedron: Asymmetry 17 (2006) 297–307
305
1
mmax (CDCl3): 1750, 1734 cmꢀ1; H NMR (200 MHz)
d = 0.15 (s, 18H, 2 · SiMe3), 2.10 (s, 1H, (Me3Si)2CH),
2.68 (dd, 1H, J = 7.9, 13.0 Hz, H-50), 3.01 (dd, 1H,
J = 13.0, 5.0 Hz, H-5), 3.60 (d, 1H, J = 2.4 Hz, H-3),
3.69 (s, 3H, OMe), 3.79 (s, 3H, CO2Me), 3.97 (ddd,
1H, J = 8.6, 5.7, 2.4 Hz, H-4), 6.85 (d, 2H, J = 8.8
Hz, Ph), 7.10 (d, 2H, J = 8.8 Hz, Ph); 13C NMR
d (50.3 MHz): ꢀ0.2, 0.0, 37.7, 38.3, 52.3, 55.2, 58.0,
58.7, 114.2, 128.1, 129.7, 158.6, 168.1; HRMS:
calcd for C19H30NO4Si2 (Mꢀ15) 392.1713, found
392.1723.
yielded the N-formyl lactams. For N-formyl-4-phenyl-2-
pyrrolidinone (85%): IR: mmax (neat): 3060, 1744,
1696 cmꢀ1 1H NMR (200 MHz) d = 2.77 (dd, 1H,
;
J = 17.6, 7.5 Hz, H-30), 2.98 (dd, 1H, J = 17.4, 7.5 Hz,
H-3), 3.54–3.75 (m, 2H, H-50, H-4), 4.10–4.28 (m, 1H,
H-5), 7.02–7.50 (m, 5H, Ph), 9.12 (s, 1H, CHO); 13C
NMR (50.3 MHz) d = 36.9, 39.6, 48.7, 126.5, 127.6,
129.0, 140.1, 159.8, 175.8. For N-formyl-4-benzyl-2-pyr-
rolidinone (85%): IR: mmax (neat): 3061, 3027, 1750,
1
1695 cmꢀ1; H NMR d (200 MHz): 2.54–2.89 (m, 2H,
H-4, H-3), 2.72 (d, 2H, J = 8.8 Hz, CH2Ph), 2.73 (dd,
1H, J = 18.5, 7.8 Hz, H-30), 3.38 (dd, 1H, J = 12.6,
5.8 Hz, H-50), 3.78 (dd, 1H, J = 12.6, 5.8 Hz, H-5),
7.05–7.40 (m, 5H, Ph), 9.08 (s, 1H, CHO); 13C NMR
(50.3 MHz) d = 33.2, 38.2, 39.7, 46.9, 126.7, 128.6,
128.7, 138.0, 159.9, 175.8.
4.6.10. 1-Bis(trimethylsilyl)methyl-3-methoxycarbonyl-4-
(2-phenylethyl)-2-azetidinone, 5g. Yield: Rh2(S-PTV)4,
14%; Rh2(S-PTTL)4, 38%; IR: mmax (neat): 3063, 1750,
1734 cmꢀ1 1H NMR (200 MHz) d = 0.11 (d, 18H,
;
2 · SiMe3), 1.68–1.52 (m, 1H, H-50), 2.15 (s, 1H, (Me3-
Si)2CH), 2.03–2.29 (m, 1H, H-5), 2.68 (t, 2H,
J = 8.0 Hz, CH2Ph), 3.41 (d, 1H, J = 2.4 Hz, H-3),
3.71 (s, 3H, CO2Me), 3.82–3.58 (m, 1H, H-4), 7.0–7.40
(m, 5H, Ph); 13C NMR d (50.3 MHz): ꢀ0.2, ꢀ0.1,
31.9, 33.2, 37.8, 52.3, 57.1, 58.9, 126.4, 128.2, 128.6,
140.2, 160.8, 168.4; HRMS: calcd for C19H30NO3Si2
(Mꢀ15) 371.1764, found 371.1742.
Sodium carbonate (1.5 mmol) was added to the N-for-
myl c-lactams (1.0 mmol) in MeOH (3 mL). The mixture
was stirred at room rt for 1 h. The mixture was concen-
trated and the residue was extracted with CH2Cl2
(3 · 5 mL), the combined organic layers were dried, fil-
tered and evaporated. The residue was purified by flash
chromatography to give either 7a or 7c.
4.6.11. 2-Bis(trimethylsilyl)methyl-2,3,4,9a-tetrahydro-
1H-cyclohepta[c]pyridin-1-one,
4.7.1. 4-Phenyl-2-pyrrolidinone, 7a. Yield: 85%; IR:
mmax (CDCl3): 3240, 3029, 1691 cmꢀ1
;
1H NMR
6. Yield:
Rh2(5R-
MEPY)4, 6%; Rh2(4R-MEOX)4, 5%; Rh2(4R-MEAZ)4,
3%; Rh2(4R-MACIM)4, 28%; Rh2(4R-MPPIM)4, 21%;
(200 MHz) d = 2.50 (dd, 1H, J = 16.3, 9.5 Hz, H-30),
2.75 (dd, 1H, J = 16.3, 9.5 Hz, H-3), 3.43 (dd, 1H,
J = 9.5, 6.8 Hz, H-50), 3.57–3.98 (m, 2H, H-4, H-5),
6.80–7.10 (br s, 1H, NH), 7.15–7.60 (m, 5H, Ph). 13C
NMR (50.3 MHz) d = 38.0, 40.2, 49.6, 126.7, 127.1,
128.8, 142.2, 177.9.
IR: mmax (CDCl3): 3026, 1633, 1622 cmꢀ1 1H NMR
;
(200 MHz) d = 0.10 (s, 18H, 2 · SiMe3), 2.40–2.72 (br
s, 3H, H-4, (Me3Si)2CH), 3.20–3.62 (m, 2H, H-3),
4.10–4.30 (br s, 1H, H-10), 5.39 (dd, 1H, J = 5.1,
9.0 Hz, H-6), 5.99–6.04 (br s, 1H, H-5), 6.08–6.27 (m,
1H, H-7), 6.42–6.63 (m, 2H, H-8, H-9); 13C NMR d
(50.3 MHz): 0.1, 30.9, 39.1, 45.5, 47.8, 118.4, 120.3,
122.4, 125.7, 129.8, 130.1, 132.8, 168.4. HRMS: calcd
for C17H29NOSi2 (M+) 319.1788, found 319.1783.
Compound 7a derived from Rh2(4R-MEOX)4-catalyzed
22
reaction product 4a had ½aꢁD ¼ ꢀ12:8 (c 0.60, MeOH);
22
22
lit.:9 (R)-7a, ½aꢁD ¼ ꢀ37:8; (S)-7a, ½aꢁD ¼ þ37:5.
Compound 7a derived from: Rh2(4R-MEPY)4-catalyzed
22
4.7. General procedure for the preparation of 7a and 7c
reaction product 4a had ½aꢁD ¼ ꢀ6:3 (c 1.6, MeOH);
Rh2(4R-MEAZ)4-catalyzed reaction product 4a had
22
To a mixture of either 4d or 4g (1.0 mmol) and NaCl
(3.0 mmol) was added aqueous DMSO (4.0 mL, 3:1 v/v
DMSO/H2O). The mixture was heated at 150 ꢂC (oil
bath) under argon and the progress of the decarboxyl-
ation was monitored by TLC. After 28 h, the reaction
mixture was cooled to rt and excess solid NaCl was
added. The aqueous mixture was extracted with EtOAc
(3 · 5 mL), washed with brine, and dried over Na2SO4.
The residue was purified by flash chromatography to
give 4a or 4c.
½aꢁD ¼ ꢀ9:5 (c 0.50, MeOH); Rh2(4R-MACIM)4-cata-
22
lyzed reaction product 4a had ½aꢁD ¼ þ2:7 (c 0.90,
MeOH); Rh2(4R-MEAZ)4-catalyzed reaction product
22
4d had ½aꢁD ¼ þ16:0 (c 0.63, MeOH); Rh2(S-PTTL)4-
22
catalyzed reaction product 4d had ½aꢁD ¼ ꢀ20:0 (c
0.40, MeOH).
HPLC analysis using Chiralcael OBꢁ column eluting
with hexane/2-propanol, 90:10 v/v: tR (R)-7a = 9.20
min, tR (S)-7a = 12.4 min.
A solution of ceric(IV) ammonium nitrate (6.0 mmol) in
distilled water (4 mL) was added, under argon, to a solu-
tion of the N-BTMSM c-lactam 4a or 4c (1.0 mmol) in
CH3CN (8 mL) at 0 ꢂC. The mixture was stirred at
0 ꢂC for 30 min and at rt for 3 h. Sodium bisulfite was
added to the mixture and the mixture was stirred at
room temperature for an additional 20 min. The crude
product was concentrated and the residue was extracted
with EtOAc (3 · 5 mL). The combined organic layers
were dried, filtered, and the solvent evaporated to give
the crude product. Purification by flash chromatography
4.7.2. 4-Benzyl-2-pyrrolidinone, 7c. Yield: 84%; Mp:
102.5–103.9 ꢂC; IR: mmax (CDCl3): 3220, 3031,
1693 cmꢀ1 1H NMR (200 MHz) d= 2.09 (dd, 1H,
;
J = 16.5, 6.8 Hz, H-30), 2.41 (dd, 1H, J = 16.5, 6.8 Hz,
H-3), 2.62–2.87 (m, 1H, H-4), 2.74 (br s, 2H, CH2Ph),
3.10 (dd, 1H, J = 8.8, 5.8 Hz, H-50), 3.39 (dd, 1H,
J = 8.8, 5.8 Hz, H-5), 6.78–6.99 (br s, 1H, NH), 7.05–
7.40 (m, 5H, Ph). 13C NMR (50.3 MHz) d = 33.2,
36.5, 40.3, 47.4, 126.3, 128.5, 128.6, 139.2, 178.3.
HRMS: calcd for C11H13NO 175.0997, found 175.1002.

306
A. G. H. Wee et al. / Tetrahedron: Asymmetry 17 (2006) 297–307
HPLC analysis using Chiralcael OBꢁ column eluting
with hexane/2-propanol, 90:10 v/v: tR (R)-7c =
11.5 min, tR (S)-7c = 15.8 min.
benzyl-2-oxopyrrolidine 7c (from the Rh2(4R-MEOX)4
catalyzed reaction product 4c) 34.0 mg, 0.19 mmol in
dry THF (3 mL) via cannula. The mixture was stirred
at rt for 15 min and refluxed for 24 h. The reaction
mixture was cooled to 0 ꢂC and 10% aqueous NaOH
was added until all the solid component was dissolved.
To this was added benzoyl chloride (3.0 mol equiv).
The reaction mixture was stirred at rt for about 20 h.
THF was evaporated and solid NaCl was added to
the aqueous layer. It was then extracted with Et2O
(3 · 5 mL) and dried over Na2SO4. The residue was
4.7.3.
7b
1-Methyl-4-(4-methoxyphenyl)-2-pyrrolidinone,
4.7.3.1. From 4b. c-Lactam 4b (35 mg, 0.1 mmol)
and powdered KFÆ2H2O (28 mg, 0.3 mmol) were mixed
in aqueous DMSO (4.0 mL, 10:1 v/v DMSO/H2O). The
mixture was refluxed at 170 ꢂC (oil bath) under argon
and the progress of the reaction was monitored by
TLC. After 4 h, the reaction mixture was cooled to rt,
excess solid NaCl was added, and the mixture was
extracted with EtOAc (3 · 5 mL). The combined organic
layers were washed with brine and dried (Na2SO4). The
solution was filtered, concentrated, and purified by flash
chromatography. Yield of 7b: 73%.
purified by flash chromatography (4:1 CH2Cl2/ace-
22
tone). Yield: 67%; ½aꢁD ¼ ꢀ28:6 (c 0.35, CH2Cl2);
22
lit.12 ½aꢁD ¼ ꢀ57:4 (c 0.76, CH2Cl2); IR: mmax (neat):
3059, 3026, 1628, 1575 cmꢀ1 1H NMR (200 MHz)
;
d = 1.50–1.80 (m, 1H, H-40), 2.19–1.88 (m, 1H, H-4),
2.35–2.89 (m, 3H, H-3, CH2Ph), 3.22 (dd, 1H,
J = 18.0, 8.4 Hz, H-50), 3.30–3.70 (m, 2H, H-20, H-5),
3.70–3.90 (m, IH, H-2), 6.95–7.60 (m, 10H, Ph). 13C
NMR (mixture of amide rotamers) (50.3 MHz) d =
[29.9] 32.0, [38.7] 39.2, [39.5] 41.2, [45.6] 49.1, [51.3]
54.5, 126.2, 127.0, 128.2, 128.4, 128.5, 128.6, 129.7,
136.8, 139.9, 169.7.
4.7.3.2. From 4f. c-Lactam 4f (105 mg, 0.41 mmol)
and powdered NaCl (142 mg, 2.43 mmol) were mixed
in aqueous DMSO (4.0 mL, 10:1 v/v DMSO/H2O).
The mixture was refluxed at 170 ꢂC (oil bath) under
argon and the progress of the reaction was monitored
by TLC. After 19 h, the reaction mixture was cooled
to rt, excess solid NaCl was added and the mixture
was extracted with EtOAc (3 · 5 mL). The combined
organic layers were washed with brine and dried
(Na2SO4). The solution was filtered, concentrated, and
purified by flash chromatography to give the desired
7b (12 mg, 23%) and the mono-desilylated c-lactam 8
(51 mg, 72%).
Compound 7c, derived from Rh2(4R-MEOX)4-cata-
22
lyzed reaction product 4c had ½aꢁD ¼ þ2:3 (c 1.10,
CH2Cl2), gave (R)-9. Compound 7c derived from the
Rh2(4R-MEPY)4-catalyzed
reaction
product
4a
22
had ½aꢁD ¼ þ2:3 (c 1.10, CH2Cl2), and from Rh2-
22
(S-PTTL)4-catalyzed reaction product 4g had ½aꢁD
ꢀ3:1 (c 0.8, CH2Cl2).
¼
4.7.3.3. Compound 7b. IR: mmax (neat): 1688,
4.9. (R)-3-Benzyl-4-aminobutanoic acid, 10
1612 cmꢀ1 1H NMR (200 MHz) d = 2.48 (dd, 1H,
;
J = 16.8, 8.4 Hz, H-30), 2.88 (dd, 1H, J = 16.8, 8.4 Hz,
H-3), 2.98 (s, 3H, NMe), 3.35 (dd, 1H, J = 9.0, 2.5 Hz,
H-50), 3.42–3.61 (m, 1H, H-4), 3.72 (dd, 1H, J = 7.0,
2.6 Hz, H-5), 3.78 (s, 3H, OMe), 6.87 (d, 2H,
J = 8.8 Hz, Ph), 7.14 (d, 2H, J = 8.8 Hz, Ph). 13C
NMR (50.3 MHz) d = 29.5, 35.4, 38.9, 55.3, 56.9,
114.1, 127.7, 137.4, 158.5; HRMS: calcd for
C12H15NO2 (M+) 205.1103, found 205.1102.
A solution of c-lactam (7c, 25 mg, 0.14 mmol) in 6 M
aqueous HCl solution (3 mL) was heated at reflux for
2.5 h. Upon cooling, the green solution was washed once
with EtOAc (3 mL). The aqueous layer was then con-
centrated under reduced pressure. The resulting residue
was applied to ion exchange chromatography (Dowex
50 · 2–400 ion exchange resin, 200–400 mesh) eluted
with water and then 5% ammonium hydroxide solution.
Evaporation of water gave 10 as a white solid (25 mg,
HPLC analysis using Chiralcael ADꢁ column eluting
with hexane/2-propanol, 95:5 v/v: tR (S)-7b = 20.9
min, tR (R)-7b = 23.1 min.
22
91%). Mp: 169–169.6 ꢂC; ½aꢁD ¼ þ6:25 (c 1.2, MeOH);
IR 3416 (br), 1636 cmꢀ1 1H NMR (D2O, 300 MHz)
;
d = 2.19 (dd, 2H, J = 7.4, 1.5 Hz, 2H-2), 2.230–2.38
(m, 1H, H-3), 2.60 (d, 2H, J = 7.2 Hz, PhCH2), 2.84
(dd, 1H, J = 13.0, 5.4 Hz, H-4), 2.92 (dd, 1H,
J = 13.0, 5.4 Hz, H-40), 7.15–7.25 (m, 3H, Ph), 7.25–
7.35 (m, 2H, Ph); 13C NMR (D2O, 75 MHz) d =
36.0, 37.9, 40.1, 43.2, 126.9, 128.9, 129.5, 139.2,
180.6. HRMS: calcd for C11H15NO2 193.1103, found
193.1104.
4.7.4. 4-(4-Methoxyphenyl)-1-(trimethylsilyl)methyl-2-
pyrrolidinone, 8. IR: mmax (neat): 3062, 1684, 1603
cmꢀ1 1H NMR (200 MHz) d = 0.10 (s, 9H, SiMe3),
;
2.53 (dd, 1H, J = 15.6, 8.5 Hz, H-30), 2.79 (dd, 1H,
J = 15.6, 8.5 Hz, H-3), 2.85 (s, 2H, Me3SiCH2), 3.37
(dd, 1H, J = 9.6, 6.0 Hz, H-50), 3.43–3.62 (m, 1H, H-
4), 3.70 (dd, 1H, J = 9.6, 6.0 Hz, H-5), 7.10–7.40 (m,
5H, Ph); 13C NMR (50.3 MHz) d = ꢀ1.7, 34.1, 37.1,
38.2, 57.0, 126.7, 126.8, 128.7, 142.5, 172.7; HRMS:
calcd for C14H20NO2Si (Mꢀ1) 246.1314, found
246.1317.
Acknowledgments
We thank the Natural Sciences and Engineering Re-
search Council, Canada and the University of Regina
for financial support. We thank Marcela Valenzuela
and Professor Michael P. Doyle for initial chiral HPLC
analysis of compound 7b.
4.8. (R)-1-Benzoyl-3-benzylpyrrolidine, 9
LiAlH4 (0.49 mmol) was suspended in dry THF (2 mL)
and cooled to 0 ꢂC under argon. To this was added 4-

A. G. H. Wee et al. / Tetrahedron: Asymmetry 17 (2006) 297–307
307
8. Palomo, C.; Aizpurua, J. M.; Legido, M.; Galarza, R.;
Deya, P. M.; Dunogues, J.; Picard, J.-P.; Ricci, A.; Seconi,
G. Angew. Chem., Int. Ed. Engl. 1996, 35, 1239.
9. Zelle, R. E. Synthesis 1991, 1023.
10. Krapcho, A. P. Synthesis 1982, 805 and 893.
11. Smith, M. B.; March, J. Advanced Organic Chemistry, 5th
ed.; Wiley: New York, NY, 2001; Chapter 10, p 506.
12. Andres, C.; Duque-Saladana, J. P.; Pedrosa, R. J. Org.
Chem. 1999, 64, 4273.
13. Doyle, M. P.; Davies, S. B.; Hu, W. Org. Lett. 2000, 2, 1145.
14. The preferential formation of b-lactams from the reaction
of ester diazoacetamides was observed for Rh2(S-PTPA)4:
Watanabe, N.; Anada, M.; Hashimoto, S.-i.; Ikegami, S.
Synlett 1994, 1031.
15. Solvent effects on regioselectivity, see Ref. 3a.
16. (a) Kitagaki, S.; Matsuda, H.; Watanabe, N.; Hashimoto,
S.-i. Synlett 1997, 1171; (b) Davies, H. M. L.; Saikali, E.;
Young, W. B. J. Org. Chem. 1991, 56, 5696.
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