Synthesis of γ-butyrolactams by photoinduced PhSe group transfer radical cyclization and formal synthesis of (±)-isocynometrine with diphenyldiselenide as promoter

Article abstract of DOI:10.1021/jo9017099

(Chemical Equation Presented) We have developed a strategy for constructing nitrogen heterocycles by photoinduced PhSe group transfer radical cyclization. trans-α,β-Disubstituted γ-butyrolactams (2-pyrrolidinones) were prepared in good yields (38-73%) wit

Full text of DOI:10.1021/jo9017099

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Synthesis of γ-Butyrolactams by Photoinduced PhSe Group Transfer
Radical Cyclization and Formal Synthesis of (()-Isocynometrine with
Diphenyldiselenide as Promoter
Dan Yang,*,†,‡ Gao-Yan Lian,† Hai-Feng Yang,† Jin-Di Yu,† Dan-Wei Zhang,*,† and
Xiang Gao†
†Department of Chemistry, Fudan University, Shanghai 200433, China, and ‡Department of Chemistry, The
University of Hong Kong, Pokfulam Road, Hong Kong, China
yangdan@hku.hk; zhangdw@fudan.edu.cn
Received August 6, 2009
We have developed a strategy for constructing nitrogen heterocycles by photoinduced PhSe group
transfer radical cyclization. trans-R,β-Disubstituted γ-butyrolactams (2-pyrrolidinones) were
prepared in good yields (38-73%) with high regioselectivity and stereoselectivity from N-alkenyl
R-PhSe β-keto amides. Reaction outcomes were modulated by the steric effect of the substituents
on the nitrogen atom of the cyclization precursors and the stereoelectronic effect of the substrates.
Diphenyldiselenide, as an additive, was found to promote ring closure. The advantage of this
strategy in natural product synthesis is demonstrated by a formal synthesis of (()-isocynome-
trine.
Introduction
synthesizing cyclic skeletons.5 Previously, we reported Lewis
acid-catalyzed atom/group transfer radical cyclization reac-
tions of unsaturated R-bromo/phenylseleno β-keto esters6
and amides7,8 to yield five-membered-ring carbocycles with
two substituents trans to each other. High enantiomeric
excesses have been achieved by using chiral Mg(ClO4)2/
bis(oxazoline) complexes as catalysts (up to 94% ee for
unsaturated R-bromo β-keto esters,6b and up to 97% ee
for R-PhSe β-keto esters6c). Here we report the PhSe group
transfer radical cyclization of N-alkenyl R-PhSe β-keto
amides and its application in the formal synthesis of
(()-isocynometrine.
γ-Butyrolactams (2-pyrrolidinones) are a class of versatile
core structures found in many natural products (such as iso-
cynometrine1 and Clausenamide2) with interesting biological
activities. They are also excellent precursors for the synthesis of
biologically active pyrrolidine derivatives such as (þ)-R-allokai-
nic acid and its analogue (-)-R-kainic acid.3 Therefore, they
have stimulated great interest in the development of new ways of
synthesizing pyrrolidinone skeletons with diverse structural
features.4
Results and Discussion
PhSe Group Transfer Radical Cyclization of N-Alkenyl
r-PhSe β-Keto Amides. In our previous work, stereoselective
Since the pioneering work of Curran, atom/group transfer
radical cyclization has become an important method for
(2) Clausenamide was isolated from an aqueous extract of leaves of
Chinese folk medicine Clausena lansium and exhibits potent hepatoprotective
and antiamnesiac effects. For the discovery and characterization of Clausen-
amide, see: (a) Yang, M.-H.; Cao, Y.-H; Li, W.-X. Yaoxue Xuebao 1987, 22, 33.
For examples of bioactivities, see: (b) Xu, L; Liu, S.-L; Zhang, J.-T. Chirality
2005, 17, 239. (c) Yu, L.; Liu, G. Zhongguo Yaoxue Zazhi 2000, 35, 446. (d) Liu,
Y.; Shi, C. Z.; Zhang, J. T. Yaoxue Xuebao 1991, 26, 166.
(1) For the discovery of isocynometrine, see: (a) Khuong-Huu, F.;
Monseur, X.; Ratle, G.; Lukacs, G.; Goutarel, R. Tetrahedron Lett. 1973, 14,
1757. For the structure determination of isocynometrine, see: (b) Chiaroni, A.;
Riche, C.; Tchissambou, L.; Khuong-Huu, F. J. Chem. Res., Synop. 1981, 182.
8610 J. Org. Chem. 2009, 74, 8610–8615
Published on Web 10/23/2009
DOI: 10.1021/jo9017099
r
2009 American Chemical Society

Yang et al.
JOCArticle
SCHEME 1
TABLE 1. Effects of Lewis Acid and Temperature on the PhSe Group Transfer Radical Cyclization of 1aa
yieldb (%)
entry
Yb(OTf)3 (equiv)
1
condition
solvent
time (h)
2a
3a
4a
1c
2
3
4
hν
hν
hν
Et2O
Et2O
THF
THF
3.5
3.5
6
40
21
75
81
11
10
28
1
55
44
c
aUnless otherwise indicated, all reactions were carried out with 0.4-0.5 mmol of substrate in 10 mL of solvent. bIsolated yield. 10% substrate
recovered.
PhSe group transfer radical cyclization of C-alkenyl R-PhSe
subjected to photolysis condition. The results are summar-
ized in Table 1.
β-keto amides was achieved in 80% yield with 0.6
equiv of Yb(OTf)3 as catalyst under photolysis condition
at -45 °C in CH2Cl2 (eq 1).8 We expected that the addition
of Yb(OTf)3 might be useful in the PhSe group transfer
radical cyclization of N-alkenyl R-PhSe β-keto amides.
Therefore, after the condensation of N-allyl-N-tert-butyla-
cetamide with ethyl benzoate,9 followed by the introduction
of a phenylseleno group at the R-carbon (Scheme 1),
N-alkenyl R-PhSe β-keto amide 1a was prepared and
Substrate 1a is stable at room temperature without radical
initiator. The reaction of 1a in Et2O was first irradiated with
UV light at room temperature in the presence of 1 equiv of
Yb(OTf)3. After 3.5 h, 10% of the substrate was recovered,
and reduced product 2a (40%), cyclization product 3a
(21%), and cyclopropanation product 4a (11%) were ob-
tained (Table 1, entry 1). In contrast, in the control reaction
without the addition of Lewis acid, 3a was obtained in 75%
yield (entry 2). When the solvent was changed to THF, the
yield of 3a was improved to 81% over an extended reaction
time along with the formation of reduced product 2a (10%;
entry 3).10 These results indicated that Lewis acid Yb(OTf)3
had no positive effect on the cyclization of 1a to yield 3a. In
contrast, when the reaction was carried out in the presence of
1 equiv of Yb(OTf)3 without UV light irradiation, 4a was
obtained in 44% yield with the concomitant formation of
reduced product 2a (28%), and no compound 3a was obtained
(entry 4). Since there is no radical initiation, 4a is believed to be
formed by a Lewis acid-promoted ionic cyclization11 followed
by an intramolecular SN2 substitution reaction to form the
(3) Parsons, A. F. Tetrahedron 1996, 52, 4149 and references cited
therein.
(4) For selected examples of the synthesis of γ-butyrolactams and pyrro-
lidines, see: (a) Lei, A.; Waldkirch, J. P.; He, M.; Zhang, X. Angew. Chem.,
€
Int. Ed. 2002, 41, 4526. (b) Jahn, U.; Muller, M.; Aussieker, S. J. Am. Chem.
Soc. 2000, 122, 5212. (c) Trost, B. M.; Pinkerton, A. B.; Kremzow, D. J. Am.
Chem. Soc. 2000, 122, 12007. (d) Duncan, D.; Livinghouse, T. J. Org. Chem.
2001, 66, 5237. (e) Marino, J. P.; Zou, N. Org. Lett. 2005, 7, 1915.
(f) Iwamoto, K.; Kojima, M.; Chatani, N.; Murai, S. J. Org. Chem. 2001,
66, 169. (g) Nagashima, H.; Isono, Y.; Iwamatsu, S.-I. J. Org. Chem. 2001,
66, 315. (h) Yoon, C. H.; Flanigan, D. L.; Chong, B.-D.; Jung, K. W. J. Org.
Chem. 2002, 67, 6582. (i) Schobert, R.; Bieser, A.; Mullen, G.; Gordon, G.
Tetrahedron Lett. 2005, 46, 5459. (j) Paderes, M. C.; Chemler, S. R. Org. Lett.
2009, 11, 1915. (k) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. J. Org.
Chem. 2008, 73, 5558. (l) Clark, A. J.; Wilson, P. Tetrahedron Lett. 2008, 49,
4848. (m) Jiang, C.; Frontier, A. J. Org. Lett. 2007, 9, 4939. (n) Young, I. S.;
Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953.
(5) For reviews, see: (a) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem.
Rev. 1991, 91, 1237. (b) Curran, D. P. Synthesis 1988, 489. (c) Byers, J. In
Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, Germany; 2001; Vol. 1, Chapter 1.5. (d) Curran, D. P. In Comprehen-
sive Organic Synthesis; Trost, B. M., Flemming, I., Eds.; Pergamon: Oxford, UK,
1991; Vol. 4, Chapter 4.2. (e) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P.
Tetrahedron 2005, 61, 10603.
(6) (a) Yang, D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung, K.-K. J. Am.
Chem. Soc. 2001, 123, 8612. (b) Yang, D.; Gu, S.; Yan, Y.-L.; Zhao, H.-W.;
Zhu, N.-Y. Angew. Chem., Int. Ed. 2002, 41, 3014. (c) Yang, D.; Zheng, B.-F.;
Gao, Q.; Gu, S.; Zhu, N.-Y. Angew. Chem., Int. Ed. 2006, 45, 255.
(7) Yang, D.; Yan, Y.-L.; Law, K.-L.; Zhu, N.-Y. Tetrahedron 2003, 59,
10465.
(8) Yang, D.; Gao, Q.; Lee, O.-Y. Org. Lett. 2002, 4, 1239.
(9) Christoffers, J.; Werner, T.; Unger, S.; Frey, W. Eur. J. Org. Chem.
2003, 425.
(10) Here 2a may come from the abstraction of hydrogen atom from the
solvent. See: (a) Chung, S. K. J. Org. Chem. 1980, 45, 3513. (b) Ashby, E. C.;
Welder, C. O. Tetrahedron Lett. 1995, 36, 7171.
(11) Jackson, W. P.; Ley, S. V.; Morton, J. A. Tetrahedron Lett. 1981, 22,
2601.
J. Org. Chem. Vol. 74, No. 22, 2009 8611

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TABLE 2. PhSe Group Transfer Radical Cyclization of N-Alkenyl R-PhSe β-Keto Amidesa
yield (%)b
entry
substrate
R1
R2
R3
R4
time (h)
2
3
5
1
2
3
1a
1b
1c
1d
1e
1f
H
H
H
CH3
H
H
H
H
CH3
H
H
t-Bu
t-Bu
t-Bu
t-Bu
Bn
6
6
6
7
6
10
20
31
31
30
46
48
81
65
CH3
CH3
H
CH3
CH3
CH3
8
27
41
64 (1.8:1)c
45e
4
5d
6
H
H
H
H
Me
Me
20
36
16e
7f
1f
37e
aUnless otherwise indicated, all reactions were carried out at room temperature with 0.4-0.5 mmol of substrate in 10 mL of THF. bIsolated yield.
e
cRatio of trans:cis isomers. Stereochemistry was determined by NOESY experiment. d11% substrate recovered. Diastereomer ratio could not be
determined because of signal overlap in 1H NMR. fReacted at the THF refluxing temperature.
cyclopropyl ring.6 These results clearly indicated that 3a
was produced via radical cyclization induced by UV light,
whereas Lewis acid Yb(OTf)3 made the cyclization reaction
complicated.
The 3,4-trans relationship of products 3a was determined
by NOESY experiments (Figure 1). The methylene group of
CH2SePh has strong NOE with both Ha and Hd, but no NOE
with Hc, which suggested that the CH2SePh group, Ha, and
Hd are on one face of the pyrrolidine ring, while the benzoyl
group, Hb, and Hc are on the other face. Thus the trans
relationship of the substituents benzoyl group and CH2SePh
group is ascertained. The weak NOE observed between
Ha and Hb is accorded with the above stereochemistry
assignment.
To determine the structures and stereochemistries of
cyclized products 3b, 3c, 3e, and 3f with three stereogenic
centers, oxidative elimination of the PhSe group by hydrogen
peroxide was performed (Scheme 2).13 Only one regioisomer
of the elimination product with a γ-lactam structure was
observed in the 1H NMR spectrum of each reaction mixture.
The 3,4-trans relationship of products 5b, 5c, 5e, and 5f was
assigned by the coupling constants (J = 6-8 Hz) of the
R-protons according to the literature reports.6 The stereo-
chemistries of 3d, 5b, and 5e were further confirmed by
NOESY experiments, and that of 5f was further confirmed
by comparing with the literature report.14
SCHEME 2
FIGURE 1. NOE correlations of compound 3a.
To explore the substrate scope, several N-alkenyl R-PhSe
β-keto amides (1b-f) were prepared as cyclization precur-
sors following the synthetic strategy of 1a12 and subjected to
the optimized radical cyclization conditions (Table 2). trans-
γ-Butyrolactam products (3a-c, 3e, 3f, 5b, and 5c) were
obtained from 1a-c and 1e-f (entries 1-3 and 5-7) through
5-exo cyclization mode. A mixture of trans-3d and cis-3d with
a ratio of 1.8:1 was produced from substrate 1d (entry 4).
Cyclization yield in the range of 68-81% was achieved for
N-tert-butyl R-PhSe β-keto amides 1a-d (entries 1-4), as
compared to 45% for benzyl-substituted substrate 1e (entry
5). Only 16% yield was attained for the methyl-substituted
substrate 1f (entry 6), but the yield can be increased to 37%
when the reaction temperature was raised to that of refluxing
THF (entry 7).
The above results reveal that the substituents on the
nitrogen atom of the tertiary amides and reaction tempera-
ture significantly affect the reaction results.15a Tertiary
amides generally have two rotamers around the C-N bonds.
Among the three substrates 1b (R4 = t-Bu), 1e (R4 = Bn),
and 1f (R4 = Me), which differ only in the substituent on the
amide nitrogen atom, only one rotamer was detected for
substrate 1b, whereas two rotamers were observed with a
ratio of about 5:3 for substrate 1e and a 1:1 ratio for substrate
1f (determined by 1H NMR). This was possibly caused by the
moderate rate for the rotation of the amide C-N bond
(about 105 s-1 at 20 °C)15 and the steric effect of the
(13) Beach, J. W.; Kim, H. O.; Jeong, L. S.; Nampalli, S.; Islam, Q.; Ahn,
S. K.; Babu, R.; Chu, C. K. J. Org. Chem. 1992, 57, 3887.
(14) Xie, X.; Lu, X.; Liu, Y.; Xu, W. J. Org. Chem. 2001, 66, 6545.
(15) (a) Curran, D. P.; Tamine, J. J. Org. Chem. 1991, 56, 2746. (b) Musa,
O. M.; Horner, J. H.; Newcomb, M. J. Org. Chem. 1999, 64, 1022.
(12) For details, see the Supporting Information.
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SCHEME 3
FIGURE 2. Retro-synthetic analysis for (()-isocynometrine.
substituents on the amide group. As shown in Scheme 3, both
rotamers A and B are in equilibrium for 1e and 1f. In the case
of 1b, rotamer A is strongly favored over B due to the large
size of the tert-butyl group. While the radical intermediate
generated from rotamer A can cyclize to give product 3, the
radical intermediate generated from rotamer B cannot cy-
clize directly. As a result, substrate 1b gave the highest yield
of the desired product (3b) (Table 2, cf. entry 2 versus entries
5 and 6). However, raising the reaction temperature will
accelerate the rotation of the amide bond and disturb
the equilibrium between rotamers A and B, thus conse-
quently increase the cyclization yield (Table 2, cf. entry 7
versus entry 6).
Synthesis of the Key Intermediate for (()-Isocynometrine.
Isocynometrine is an imidazole alkaloid isolated from the
Cynometra species, which has been used in Africa as a
traditional folk medicine with antitussive and analgesic
activities. Several total syntheses of this alkaloid have been
reported.14,19 In the retro-synthetic analysis, the cyclized
products 5b, 5e, and 5f are possible intermediates
(Figure 2). As suggested by the above results, the cyclization
of tert-butyl protected amides 1b gave the highest yield, but
unexpectedly, the tert-butyl group of 3b or 5b could not be
removed under acidic condition.20 Thus we decided to
optimize the reaction conditions to improve the yield for
the radical cyclization of N-methyl R-phenylseleno β-keto
amide 5f.
SCHEME 4. Proposed Transition States for Radical Cycliza-
tion
It is known that diphenyldiselenide can be used as an
accelerant in many radical pathways.21 Homolytic cleavage
of the Se-Se bond of diphenyldiselenide under UV or visible
light irradiation is a common method to produce phenylse-
leno radical (PhSe•), which can initiate radical chain reaction
or be involved in radical propagation steps to accelerate the
reaction process. Kinetic study of phenylseleno radical addi-
tion reaction to vinyl monomers indicated that the addition
reaction is reversible. In addition, the recombination of
PhSe• radical is faster (rate constant 7 ꢀ 109 M-1 s-1) than
radical addition of PhSe• to a CdC double bond (rate
constants in the range of 1.4 ꢀ 104 to 2.9 ꢀ 106 M-1 s-1).22
Thus we supposed that a high concentration of diphenyldi-
selenide may build up a persistent phenylseleno radical
concentration to benefit both the initiation of R-centered
radical and the subsequent radical cylization step.
As shown in Table 2, the yield of cyclized product 3f can be
improved by raising the reaction temperature to that of the
reflux THF and moderately extending the reaction time
(Table 2, cf. entry 7 versus entry 6). Further raising the
reaction temperature to that of refluxing toluene did accel-
erate the reaction but gave no improvement to the cyclization
yield of 3f (38% in 12 h; Table 3, entry 1). However, in the
presence of 4 equiv of diphenyldiselenide, the total yield of
cyclized products 3f and 5f was increased to 53% along with
The outcome of regio- and stereocontrol is rationalized in
Scheme 4. Because of dipole repulsion, the two carbonyl
groups of the substrates prefer to be trans to each other. Two
possible transition states (TS1 and TS2) are involved in this
reaction. The steric interaction between the benzoyl group
and the olefinic group will decrease the stability of TS1,
whereas that between the R1 substituent and the benzoyl
group disfavors TS2. The reactions of substrates 3a-c
(where R1 = H) preferentially proceed through TS2 because
of less steric repulsion,16-18 and give trans-disubstituted
5-exo ring closure products. For 1d, where R1 = Me, the
similar size of the methyl group and the methylene group
yielded two diastereomers with a ratio of 1.8:1 through TS2
and TS1, respectively (Table 2, entry 4).
(19) (a) Tchissambou, L.; Benechie, M.; Khuong-Huu, F. Tetrahedron
1982, 38, 2687. (b) Xu, W.; Kong, A.; Lu, X. J. Org. Chem. 2006, 71, 3854.
(20) Earle, M. J.; Fairhurst, R. A.; Heaney, H.; Papageorgiou, G. Synlett
1990, 10, 621.
(16) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions: Concepts, Guidelines, and Synthetic Applications; VCH:
Weinheim, Germany; 1996; Chapter 2, pp 23-115.
(17) For models for predicting and rationalizing the outcomes of radical
cyclization, see: (a) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem.
Soc., Chem. Commun. 1980, 482. (b) Beckwith, A. L. J.; Lawrence, T.; Serelis,
A. K. J. Chem. Soc., Chem. Commun. 1980, 484. (c) Beckwith, A. L. J.;
Schiesser, C. H. Tetrahedron Lett. 1985, 26, 373. (d) Spellmeyer, D. C.; Houk,
K. N. J. Org. Chem. 1987, 52, 959. (e) Broeker, J. L.; Houk, K. N. J. Org.
Chem. 1991, 56, 3651.
(18) For examples of controlled radical cyclization, see: (a) Belvisi, L.;
Gennari, C.; Poli, G.; Scolastico, C.; Salom, B. Tetrahedron: Asymmetry
1993, 4, 273. (b) Myers, A. G.; Condroski, K. R. J. Am. Chem. Soc. 1995, 117,
3057. (c) Takahashi, T.; Tomida, S.; Sakamoto, Y.; Yamada, H. J. Org.
Chem. 1997, 62, 1912.
(21) (a) Renaud P. In Topics in Current Chemistry: Organoselenium Chem-
istry; Wirth T., Ed.; Springer-Verlag: Berlin, Germany, 2000; Vol. 208, pp
95-108. (b) Ogawa, A. In Main Group Metals in Organic Synthesis; Yamamoto,
H., Oshima, K., Eds; Wiley-VCH: Weinheim, Germany, 2004; Vol. 2, Chapter
15.4. (c) Shi, M.; Lu, J.-M. J. Org. Chem. 2006, 71, 1920. (d) Tingoli, M.; Tiecco,
M.; Testaferri, L.; Andrenacci, R.; Balducci, R. J. Org. Chem. 1993, 58, 6097. (e)
Ogawa, A.; Obayashi, R.; Sekiguchi, M.; Masawaki, T.; Kambe, N.; Sonoda, N.
Tetrahedron Lett. 1992, 33, 1329. (f) Ogawa, A.; Obayashi, R.; Ine, H.; Tsuboi,
Y.; Sonoda, N.; Hirao, T. J. Org. Chem. 1998, 63, 881. (g) Ogawa, A.; Yokoyama,
H.; Yokoyama, K.; Masawaki, T.; Kambe, N.; Sonoda, N. J. Org. Chem. 1991, 56,
5721. (h) Tsuchii, K.; Doi, M.; Ogawa, I.; Einaga, Y.; Ogawa, A. Bull. Chem. Soc.
Jpn. 2005, 78, 1534. (i) Clive, D. L. J.; Pham, M. P.; Subedi, R. J. Am. Chem. Soc.
2007, 129, 2713.
(22) Ito, O. J. Am. Chem. Soc. 1983, 105, 850.
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TABLE 3. Optimization of Reaction Conditions for the Cyclization of 1fa
yield (%)b
entry
solvent
temp (°C)
PhSeSePh (equiv)
time (h)
2f
3f
5f
1
2
3
toluene
THF
toluene
xylene
toluene
110
66
110
143
110
12
6
6
6
6
40c
13
38c
44
<1%
9
<1%
<1%
<1%
4
4
4
4
44c
51
53c
47
4
5d
33
66
aUnless otherwise indicated, all reactions were carried out with 0.5 mmol of substrate in 10 mL of solvent. bYield determined by 1H NMR. cIsolated
yield. d0.5 mmol of substrate in 1 mL of solvent.
SCHEME 5. Plausible Mechanism of Radical Cyclization Promoted by PhSeSePh
13% yield of reduced product 2f after refluxing in THF for 6
h (entry 2). Under refluxing condition in toluene, a similar
yield of the cyclized product 3f (53%) was obtained (entry 3).
Upon increasing the reaction temperature to that of reflux-
ing xylene, the yield was slightly decreased (47%, entry 4).
On the basis of these results, we concluded that excessively
high reaction temperatures are ineffective for improving the
yield of cyclization. On the other hand, more reduced
product 2f was obtained from the reaction in toluene
(44%) than that in THF (13%; cf. entry 3 versus entry 2).
Upon increasing the concentration of the reaction mixture
by a factor of 10, the yield of cyclized product 3f was
increased to 66% (entry 5).
also plays the role of a radical trap to the cyclized radical RC to
give the product 3f and regenerate PhSe•, which promotes the
chain propagation of radical ring closure.
We then applied this method to the formal synthesis of the
key intermediate of (()-isocynometrine (Scheme 6). The key
intermediate 5f was prepared from N-methylacetamide in
40% yield in 5 steps. The key step was the PhSe group
transfer radical cyclization promoted by PhSeSePh. A mix-
ture of 3f and the oxidative elimination product 5f was
obtained; after oxidative elimination of the mixture by
H2O2/pyridine, the key intermediate of (()-isocynometrine
was generated.
Conclusion
A plausible mechanism of the radical cyclization reactions
is shown in Scheme 5. Under UV irradiation, diphenyldise-
lenide is homolytically cleaved into phenylseleno radicals.
Then the radical intermediates A and B (RA and RB) are
generated from conformers E-1f and Z-1f, respectively.
Radical A (RA) can cyclize smoothly whereas RB cannot.
In the presence of diphenyldiselenide, RB can transform and
regenerate substrate 1f. But under the radical reaction con-
dition, both RA and RB can abstract the hydrogen atom from
the solvent to produce reduced product 2f.10 The better
hydrogen donor the solvent is (for example, toluene over
THF), the more reduced product 2f is formed (Table 3, cf.
entry 3 versus entry 2). On the other hand, diphenyldiselenide
In summary, trans-R,β-disubstituted γ-butyrolactams
have been efficiently constructed through a PhSe group
transfer radical cyclization reaction, which is characterized
by high stereoselectivity and moderate to good yields. The
size of the substituent on the nitrogen atom (R4 group)
of tertiary amides is positively correlated with the yield of
this reaction, presumably because of the steric effect on
substrates’ conformation. The key intermediate for the
total synthesis of nature product (()-isocynometrine was
obtained in 40% overall yield from N-methylacetamide.
The key step is a photoinduced PhSe group transfer radical
cyclization promoted by diphenyldiselenide.
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JOCArticle
SCHEME 6. Preparation of the Key Intermediate of (()-Isocynometrine
Experimental Section
mixture of 3f and 5f (66 mg, 0.18 mmol) in THF (5 mL) was added
drop of pyridine. Hydrogen peroxide (30% solution,
a
A 320 nm, 125W high-pressure mercury lamp was used as
the UV source. The reactions were carried out in Pyrex glass
flasks.
Typical Procedure for Diphenyldiselenide-Promoted PhSe
Group-Transfer Radical Cyclization Reaction. trans-3-Ben-
40 μL, 0.36 mmol) was then added dropwise to the above mixture
at 0 °C. After stirring overnight, the reaction mixture was concen-
trated on a rotavap to remove the solvent. The residue was dissolved
in dichloromethane, washed with saturated NaHCO3 solution,
water, brine and then dried over anhydrous MgSO4. The crude
product was purified by flash chromatography to give 5f (34 mg,
49% yield in two steps) as a light yellow oil. Analytical TLC (silica
gel 60), EtOAc:n-hexane = 1:2, Rf = 0.36; 1H NMR (400 MHz,
CDCl3) δ 8.09 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H),
7.49 (t, J = 7.8 Hz, 2H), 5.86 (ddd, J = 17.4, 11.2, 2.3 Hz, 1H), 5.15
(d, J = 17.0 Hz, 1H), 5.10 (d, J = 11.2 Hz, 1H), 4.30 (d, J =
6.4 Hz, 1H), 3.71 (t, J= 8.2 Hz, 1H), 3.69-3.61 (m, 1H), 3.23 (dd, J
= 8.2, 6.0 Hz, 1H), 2.89 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 195.5, 169.6, 137.6, 136.6, 133.7, 129.6, 128.6, 116.9, 56.6, 53.2,
39.3, 30.1.
zoyl-1-methyl-4-(1-(phenylseleno)ethyl)pyrrolidin-2-one
(3f).
Compound 1f (294 mg, 0.76 mmol) and PhSeSePh (948 mg,
3.04 mmol) were dissolved in toluene (1.8 mL). The solution was
degassed with N2 for 30 min, warmed up to reflux, and irra-
diated with a 125 W high-pressure mercury lamp for 6 h. The
reaction was monitored by TLC. After concentration and
filtration through a short plug of silica gel, 3f was obtained in
1
66% yield (determined by H NMR). The crude product was
further purified by flash column chromatography to give a
mixture of 3f and 5f as a light yellow oil. 3f (diastereoisomer
ratio = 3:2): Analytical TLC (silica gel 60), EtOAc:n-hexane =
1:2, Rf = 0.45; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 6.8
Hz, 0.4 ꢀ 2H), 8.01 (d, J = 6.8 Hz, 0.6 ꢀ 2H), 7.65-7.24 (m,
8H), 4.49-4.48 (m, 1H), 3.65-3.60 (m, 1H), 3.38-3.27 (m, 3H),
2.87 (s, 0.6 ꢀ 3H), 2.84 (s, 0.4 ꢀ 3H), 1.40-1.38 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 196.1, 196.0, 169.4, 169.2, 136.7,
136.6, 135.1(2), 133.6, 133.5, 129.7, 129.6, 129.4, 129.3,
128.6, 128.2(2), 128.1(2), 55.8, 55.3, 52.3, 51.8, 43.5, 43.2,
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (Project No.
20229201), Science and Technology Commission of Shanghai
Municipality (STCSM), Fudan University, The University of
Hong Kong, and The Research Grants Council of Hong Kong
(Project No. HKU7121/02P). D.-W.Z. thanks Fudan Uni-
versity for the conferment of the Century Star Award.
40.9, 40.8, 30.0, 20.6, 19.9; IR (neat) 2922, 1696, 1676 cm-1
;
LRMS for C20H21NO2Se (EI, 20 eV) m/z 387 (Mþ, 3), 105 (100);
HRMS (EI) for C20H21NO2Se (Mþ): calcd 387.0738, found
387.0735.
Supporting Information Available: Synthetic schemes, char-
acterization data, and NMR spectra of compounds 1a-f, 2a-f,
3a-f, 4a, 5b, 5c, 5e, and 5f. This material is available free of
charge via the Internet at http://pubs.acs.org.
Typical Procedure for Oxidative Elimination of the PhSe Group.
trans-3-Benzoyl-1-methyl-4-vinylpyrrolidin-2-one (5f).14 To the
J. Org. Chem. Vol. 74, No. 22, 2009 8615