Influence of N-substituted lactams on acyclic free radical based hydrogen transfer

Article abstract of DOI:10.1016/S0040-4039(01)01213-8

anti Relative stereochemistry is achieved in the hydrogen-transfer reaction of a lactam adjacent to the carbon-centered radical. The sense of diastereoselectivity is reversed using N-substituted lactams, and optimal results favoring syn reduced products are obtained with an α-methylbenzyl group and a Boc group.

Full text of DOI:10.1016/S0040-4039(01)01213-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6041–6044
Influence of N-substituted lactams on acyclic free radical based
hydrogen transfer
Yvan Guindona,b,* and Mohammed Bencheqrouna
aInstitut de recherches cliniques de Montre´al (IRCM), Bio-organic Chemistry Laboratory, 110, avenue des Pins Ouest, Montre´al,
Que´bec, Canada H2W 1R7
bDepartment of Chemistry and Department of Pharmacology, Universite´ de Montre´al, C.P. 6128, succursale Centre-Ville,
Montre´al, Que´bec, Canada H3C 3J7
Received 15 May 2001; accepted 5 July 2001
Abstract—anti Relative stereochemistry is achieved in the hydrogen-transfer reaction of a lactam adjacent to the carbon-centered
radical. The sense of diastereoselectivity is reversed using N-substituted lactams, and optimal results favoring syn reduced
products are obtained with an a-methylbenzyl group and a Boc group. © 2001 Elsevier Science Ltd. All rights reserved.
Carbon-centered free radicals on acyclic molecules1
lization of the low-energy SOMO radical through
hyperconjugation3 (see the anti-predictive transition
state A, Fig. 1).
have started to receive considerable attention from
organic chemists since it was found that significant
diastereocontrol or enantiocontrol could be achieved in
reactions involving these chemical intermediates. Our
group has been particularly interested in the use of
carbon-centered free radicals flanked by an ester and a
stereogenic center bearing a heteroatom such as an
oxygen or a fluorine.2 Hydrogen-transfer reactions of
such radicals have given high anti diastereoselectivity,
particularly when the oxygen heteroatom is embedded
in a ring.2b,c The increase of anti diastereoselectivity
observed in the latter case is known as ‘the exocyclic
effect’.2b,c Scheme 1 shows a hydrogen-transfer reaction
involving tributyltin hydride (Bu3SnH) that gives an
anti:syn ratio of 11:1 when a tetrahydrofuran ring is
present adjacent to the carbon-centered radical. This
result betters significantly the 1.1:1 ratio achieved with
the acyclic counterpart. For the cyclic analogs, a
The present study addresses two questions: (1) whether
a nitrogen can be used as a heteroatom to replace the
oxygen on the stereogenic center adjacent to the car-
bon-centered radical in order to give anti relative stere-
ochemistry in hydrogen-transfer reactions as depicted
by transition state B (R=H, Fig. 1); (2) whether the
presence of a substituent (R group) on the nitrogen can
reverse the radical facial preference of the hydrogen-
transfer reaction to give the syn product. As seen in
Fig. 1, the presence of an R group on the nitrogen may
render more difficult the attack of Bu3SnH from the
bottom face of the radical and raise the energy of
anti-predictive transition state B. As a consequence, a
less energy demanding attack from the top face of the
decrease in diastereoselectivity is noted when
X
(Scheme 1) is an electron withdrawing group. In this
scenario, the carbamate offers better diastereoselectivity
than the carbonate, but the lactone gives the best result
of the three, the anti:syn ratios being 3:1, 1:1, and 7:1,
respectively. The results shown in Scheme 1 were ratio-
nalized using arguments such as minimization of allylic
1,3-strain, minimization of the dipole effect, and stabi-
Keywords: N-substituted lactams; hydrogen transfer; free radical;
diastereoselectivity.
* Corresponding author. Fax: (514) 987-5789; e-mail: guindoy@
ircm.qc.ca
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01213-8

6042
Y. Guindon, M. Bencheqroun / Tetrahedron Letters 42 (2001) 6041–6044
HSnBu3
H
HSnBu3
H
H
H
H
H
X
H
H
H
Y
CO2Me
H
Me
O
CO2Et
H
Me
Me
C
OMe
H
O
Me
N
CO2Me
N
R
O
N
O
O
H
HSnBu3
A anti-predictive
HSnBu3
R
B anti-predictive
C syn-predictive
D syn-predictive
Figure 1. Proposed transition states for the hydrogen transfer step.
radical may be favored as shown in syn-predictive
transition state C.
chromatography, and the free-radical hydrogen-transfer
reactions were then performed using the diastereoiso-
meric mixture.
Lactam 2a was chosen for the realization of the first
part of this study. The idea behind this choice of
substrate was that the presence of a carbonyl adjacent
to the NH could impede the putative hydrogen bond
between the NH and the carbonyl of the ester4 (see syn
competitive transition state D) that would otherwise
complicate the interpretation of the results. The lactam
was prepared by NaBH4/HCl reduction of succinimide
in EtOH to give the 5-ethoxy-2-pyrrolidinone 1a in
nearly quantitative yield.5 The desired diastereoisomeric
bromoester mixture 2a6 was obtained via a Mukaiyama
reaction using bromo silyl ketene acetal7 and v-carbinol
lactam 1a.
As seen in Table 1, entry 1, the reaction of lactam 2a
with Bu3SnH in the presence of Et3B gave a result that
was, in terms of preferred anti diastereoselectivity, simi-
lar to that obtained with the lactone (Scheme 1). This
suggested that the NH could indeed replace the oxygen
as the heteroatom on the stereogenic center even with
the dipole effect between the CꢀN bond and the ester
being less pronounced than in the case of the CꢀO bond
(Fig. 1).
The introduction of an alkyl group on the nitrogen, in
all cases, resulted in a reversal of diastereoselectivity
from the anti isomer preference to a syn isomer prefer-
ence (cf. entry 1 with entries 2–7). Ratios ranging from
1:3 to 1:8 were obtained for the Et, iPr, and Bn
substrates (entries 2–4). Interestingly, an impressive
ratio >20:1 in favor of the syn product was obtained for
N-(a-methylbenzyl) substrate 1e (entry 5). The latter
result can be accounted for by the sp2 character of the
CꢀN bond of the amide, which can impose a barrier of
rotation (allylic 1,3-strain) that increases the rotamer
population wherein the hydrogen on the stereogenic
A series of N-(substituted) lactams bearing different R
groups was used for the second part of the study. The
lactams were prepared via a general approach involving
the reaction of different lithium aluminum amides with
g-butyrolactone8 to afford corresponding hydroxy
amides which were then converted to v-carbinol lac-
tams 1b–1e using Swern oxidation conditions followed
by treatment with HCl in EtOH (Scheme 2). The
desired bromoesters 2b–2e were obtained via
Mukaiyama reactions with the appropriate v-carbinol
lactams 1b–1e. The N-(Ac) 2f and N-(Boc) 2g deriva-
tives of lactam 2a were prepared using acetic anhydride
and di-tert-butyl dicarbonate, respectively.9 The resul-
tant diastereomeric bromides were purified by flash
Table 1. Radical-mediated reduction of lactams
O
O
O
R
R
R
Bu3SnHa
toluene
Et3B
N
N
N
+
CO2Me
Br
CO2Me
CO2Me
Me
a
b
Me
anti
Me
syn
O
O
O
OEt
O
O
N
H
N
R
O
1a, R=H
Entry Lactam
anti:syn
Yield (%)c
c
CO2Me
Br
1b, R=Et
1c, R= iPr
1d, R=Bn
N
R
Product
Ratiob
Me
1e, R=R-(+)-Ph(Me)CH
2a, R=H, 90%
1
2
3
4
5
6
7
2a, R=H
2b, R=Et
2c, R=iPr
2d, R=Bn
1e, R=(R)-Ph(Me)CH- 11:12
2f, R=Ac
3:4
5:6
7:8
9:10
7:1
1:3
1:7
1:8
1:\20
1:5
1:\20
91
73
71
91
2b, R=Et, 95%
2c, R= iPr, 83%
2d, R=Bn, 62%
2e, R=R-(+)-Ph(Me)CH, 32%
2f, R=Ac, 72%
d
e
75
2g, R=Boc, 83%
13:14
15:16
78d
99d
2g, R=Boc
Scheme 2. Reagents and conditions: (a) (i) NaBH4, EtOH; (ii)
HCl 2N (pH 2), EtOH; (b) (i) LiAlH4, Et2O, then RNH2 in
Et2O, 16 h; (ii) (COCl)2, DMSO, Et3N; (iii) HCl 2N (pH 2),
EtOH; (c) TiCl4, Me(Br)CꢁC(OMe)OTMS, CH2Cl2, −78°C;
(d) (Ac)2O, Et3N, DMAP, CH2Cl2, 25°C, 6 h; (e) (Boc)2O,
Et3N, DMAP, CH2Cl2, 25°C, 8 h.
a Conditions: To a cold solution (−78°C) of lactam (0.1 M) in toluene
were added 2 equiv. of Bu3SnH and 0.2 equiv. of Et3B.
b
Ratios of crude mixture products were determined by 1H NMR.
c
Isolated yields of reduced products.
d
The reaction was performed in Cl2Cl2.

Y. Guindon, M. Bencheqroun / Tetrahedron Letters 42 (2001) 6041–6044
6043
center of the a-methylbenzyl group is planar to the
carbonyl of the amide. This conformation forces the
two substituents (methyl and benzyl) to be quasi
orthogonal to the heterocycle making even more
difficult the bottom face trajectory of the Bu3SnH (Fig.
2).
the same as the minor reduced lactam 4 (entry 1),
corroborated that the reduction of N-(Boc) bromo
lactam 2f had in fact led to the formation of the syn
product.
In conclusion, the present study indicates that a nitro-
gen can replace an oxygen as the heteroatom in the
hydrogen-transfer paradigm studied herein to give
access to the anti product. Alternatively, the sense of
diastereoselectivity can be reversed by adding sub-
stituents on the nitrogen, while the use of a-methylben-
zyl and Boc groups in such reactions can provide
optimal results favoring syn isomers.
The reduction of N-(Acyl) bromo lactams was also
considered in this study. As seen in entry 6, the N-(Ac)
substrate gave a 5:1 ratio in favor of the syn product,
while an excellent ratio >20:1 was obtained for the
N-(Boc) derivative. Our rationale for the latter result is
that the two carbonyls take on a synperiplanar or
synclinal10 conformation that positions the tert-butyl
group in the trajectory of the bottom face Bu3SnH
attack (Fig. 2). The conformational arguments consid-
ered herein have been shown to be applicable to early
transition states, which are normally invoked when
free-radical intermediates are involved.11 Of additional
interest is that the mild basic treatment of the N-(Boc)
reduced lactam 16 [MeONa, MeOH, 0°C, 10 min, 80%]
led exclusively to an acyclic b-N-(Boc)-amino ester,12
which belongs to a family of compounds with a large
range of biological activity.
Acknowledgements
This work was supported financially by NSERC. We
thank Dr. Brigitte Gue´rin and Ms. LaVonne Dlouhy
for their assistance in the preparation of this
manuscript.
References
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published results.2 The NMR assignments were verified
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benzylated syn product 10 (Fig. 3) and were further
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Figure 3. X-Ray crystallographic structure of 10.

6044
Y. Guindon, M. Bencheqroun / Tetrahedron Letters 42 (2001) 6041–6044
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1H), 1.83 (s, 3H); 13C NMR: 177.80, 170.50, 63.50, 60.50,
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