Tris(oxazoline)/copper-catalyzed coupling of alkynes with nitrones: A highly enantioselective access to β-lactams

Article abstract of DOI:10.1016/j.tet.2012.04.049

Chiral tris(oxazoline)/Cu(I) complexes are demonstrated as a type of efficient catalysts for the asymmetric Kinugasa reaction of terminal alkynes with C-arylnitrones, providing a highly enantio- and diastereoselective access to optically active β-lactams.

Full text of DOI:10.1016/j.tet.2012.04.049

Tetrahedron 68 (2012) 5042e5045
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Tris(oxazoline)/copper-catalyzed coupling of alkynes with nitrones: a highly
enantioselective access to b-lactams
,
b,
*
Jiang-Hua Chen a, Sai-Hu Liao b, Xiu-Li Sun b, Qi Shen a , Yong Tang
*
a Key Laboratory of Organic Synthesis, Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Suzhou University, Suzhou 215123, PR China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Lu, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral tris(oxazoline)/Cu(I) complexes are demonstrated as a type of efficient catalysts for the asym-
metric Kinugasa reaction of terminal alkynes with C-arylnitrones, providing a highly enantio- and dia-
stereoselective access to optically active b-lactams.
Received 19 February 2012
Received in revised form 2 April 2012
Accepted 12 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 21 April 2012
Keywords:
Asymmetric catalysis
Kinugasa reaction
Trisoxazolines
b-Lactams
Copper
1. Introduction
to the intramolecular reaction by using planar-chiral ligand
phosphaferrocene-oxazoline 3 instead.7b In 2003, our group dem-
onstrated that a Cu(II) catalytic system in combination with tri-
s(oxazoline) (TOX) 4 as a ligand is also effective for the Kinugasa
reaction even under an air atmosphere and without rigorously dry
conditions, and this ‘sidearm’ modification of BOX ligands provided
up to 85% ee and up to 97:3 dr.8 In this reaction, catalytically active
Cu(I) species are supposed to be generated in situ upon the re-
duction of Cu(II) by phenylacetylene. Basak and co-workers dis-
Chiral b-lactam is a key structure of many biologically active
molecules,1 such as penicillin, cephalosporin, thienamycin, and also
a type of useful and extensively employed synthetic intermediates2
in modern organic synthesis, enabling them as one of the best
known four-membered heteocycles. Among the approaches for
their asymmetric synthesis,3,4 the enantioselective catalytic Kinu-
gasa reaction4 of alkynes with nitrones has attracted much atten-
tion and significantly advanced in the last decade, due to the readily
available starting material and high functional group tolerance.
Inspired by the pioneering work of Kinugasa and Hashimoto,5
Miura and co-workers reported the first asymmetric catalytic ver-
sion of the Kinugasa reaction in 1995 and obtained up to 57% ee in
covered
Kinugasa reaction, and up to 15% ee was observed in the synthesis
of exomethylene
-lactams.9 Recently, Guiry and co-workers ap-
L-proline can also be used as a ligand in the Cu(I)-mediated
b
plied HETPHOX ligands 5aec in the Kinugasa reaction, and ach-
ieved a moderate level of enantioselectivity (up to 55% ee).10 In
a book chapter, Evans and co-workers disclosed a highly stereo-
selective copper-catalyzed coupling reaction of alkynes with
nitrones using IndaBOX ligand 6a, and up to 97:3 dr and up to 98%
ee were obtained with a preference for the C-alkylnitrones.11
IndaBOX ligands 6b was also employed by Saito, Otani and co-
workers in a recent report.12 Therefore, only a quite limited num-
ber of highly enantioselective Kinugasa reactions have appeared so
far, and there remains a substantial space for the improvement of
both the yield and stereoselectivity. In fact, although high enan-
tioselectivity has been achieved with certain type of substrates, to
develop a highly efficient and enantioselective catalytic Kinugasa
reaction is still a challenging task.
the coupling of phenylacetylene and
a,N-diphenylnitrone, using
bis(oxazoline) (BOX) 1aec/CuI (Fig. 1) as the catalyst.6 The first
completely enantioselective Kinugasa reaction was reported in
2002 by Fu and co-workers, in which good to high enantiose-
lectivities (up to 93% ee) and high cis-selectivities (up to >95:5 dr)
were obtained with C2-symmetric bis(azaferrocene) 2/CuCl as the
catalyst,7a and later they successfully extended this catalytic system
* Corresponding authors. Tel.: þ86 0512 65880306 (Q.S.); tel.: þ86 21 5492 5156;
fax: þ86 21 5492 5078 (Y.T.); e-mail addresses: qshen@suda.edu.cn (Q. Shen),
tangy@sioc.ac.cn (Y. Tang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.049

J.-H. Chen et al. / Tetrahedron 68 (2012) 5042e5045
5043
efficient copper salt, providing 90% ee and 90:10 dr (entry 9). The
corresponding Cu(II) salt Cu(OTf)2 was more active but the ster-
eoselectivity was slightly lower (entry 6). It is noteworthy that in
Saito’s work CuOTf was found inactive in the IndaBOX-mediated
reaction.12 With respect to both the yield and stereoselectivity,
salt CuOTf$Tol was employed as the copper source for the sub-
sequent elaboration of the ligands.
To examine the influence of the sidearm group (R), a series of
chiral oxazoline moieties was introduced into the IndaBOX scaffold
(Fig. 2). As revealed in Table 2, tert-butyl substituted TOX 10c
proved to be the ligand of choice, giving a fast time (14 h) together
with high cis- and enantioselectivity (90/10 cis/trans, 95% ee, entry
2). Compared with trisoxazoline/Cu(I) complex, the reaction with
the parental bisoxazoline ligand 11 was much slower (44 h, entry 6)
and less enantioselective. It is worth noting that the improvement
of the enantioselectivity from 88% ee to 95% ee at 0 ꢀC requires an
additional energy difference of ca. 0.4 kcal/mol to be created be-
tween the two diastereomeric isomers of the transition state,
which lead to the two opposite enantiomers (R and S) of the
product.14
Fig. 1. Typical chiral ligands for asymmetric Kinugasa reactions.
2. Results and discussion
In our previous study, we have demonstrated that the in-
troduction of an additional oxazoline ‘sidearm’ can not only ac-
celerate the Kinugasa reaction but also improve the
stereoselectivity.8,13 In the following years, much effort has been
devoted to this subject to further improve the performance of this
system. We wish to report here a novel TOX/copper catalyst, with
which a highly enantio- and diastereoselective coupling reaction of
alkynes with C-arylnitrones was realized.
Pseudo C3-symmetric IndaTOX 10a, which was recently de-
veloped in our group and has shown excellent enantioselectivity in
the Nazarov reaction,13j was chosen as a typical TOX ligand for the
reaction optimization. The effect of the copper source was first
examined under the standard reaction conditions established in
our previous study, using acetonitrile as the solvent and dicyclo-
hexylamine as the base.8 As revealed in Table 1, Cu(ClO4)2$6H2O
was efficient for the coupling reaction of phenylacetylene 7a and
Fig. 2. Ligands designed based on a ‘sidearm’ strategy.
Table 2
Effect of the sidearm groupa
CuOTf⋅Tol (10 mol%)
Ligand (12 mol%)
Ph
O
Ph
Ph
Ph
Ph
H
O
nitrone 8a, and cis
b-lactam 9a was obtained in 88% ee as the
N
predominant diastereoisomer (entry 1). Other Cu(II) salts, such as
Cu(OAc)2, CuSO4, and CuBr2 were less active and selective (entries
2e4), while Cu(BF4)2 and Cu(OTf)2 delivered the desired product
with a similar level of stereoselectivity to Cu(ClO4)2$6H2O (entries
5e6 vs entry 1). To our delight, CuOTf$Tol was found as the most
+
N
CH3CN (4 mL)
Cy2NH (1 equiv)
0 °C
Ph
9a
7a
8a
Entry
Ligand
Time (h)
% Yieldb
cis/transc
% eed
1
2
3
4
5
6
10b
10c
10d
10e
10f
11
17
14
36
14
38
44
69
67
69
68
71
69
92/8
92
95
92
91
88
88
Table 1
90/10
89/11
84/16
91/9
The influence of the copper sourcea
93/7
a
b
c
Ligand (0.5 mmol scale, 12 mol %), CuOTf$Tol (10 mol %), N2.
Total isolated yield of cis and trans-isomers.
Determined by 1H NMR.
d
ee’s of cis isomers, determined by chiral HPLC.
Entry
Copper source
Time (h)
% Yieldb
cis/transc
% eed
1
2
3
4
5
6
7
8
9
Cu(ClO4)2$6H2O
Cu(OAc)2
CuSO4
18
66
66
42
42
27
26
26
39
65
59
51
65
64
63
69
70
68
90/10
94/6
88
66
65
69
87
88
63
65
90
Under the optimized reaction conditions, a range of alkynes and
C-arylnitrones were examined, and the results are summarized in
Table 3. Various -lactams were obtained generally in good yields
and high cis- and enantio-selectivities. The electronic nature of the
C-aryl groups (R2) showed little influence on the high enantiose-
lectivity (entries 1e7). N-PMP protected nitrones are also appro-
90/10
90/10
88/12
87/13
92/8
b
CuBr2
Cu(BF4)2
Cu(OTf)2
CuI
CuBr
CuOTf$Tol
87/13
90/10
priate substrates (entries 8e11) nitrone with
substituent exhibited the highest reactivity, furnishing the desired
-lactam product in 98% yield in 6 h (entry 13). The current reaction
a para ester
a
TOX 10a (0.5 mmol scale, 12 mol %), Cu salts (10 mol %), N2.
Total isolated yield of cis and trans-isomers.
Determined by 1H NMR.
b
b
c
also showed a good tolerance of different functionalities, such as
halide, ether, ester, CF3, and heterocycles (entry 13e18). Thus, the
d
ee’s of cis isomers, determined by chiral HPLC.

5044
J.-H. Chen et al. / Tetrahedron 68 (2012) 5042e5045
Table 3
4.2. Typical procedure for the synthesis of chiral ligands
Substrate scope of the TOX/Cu-catalyzed Kinugasa reactiona
To a solution of Inda-bisoxazoline (0.65 g, 1.9 mmol) in dried
THF (30 mL) was added dropwise t-BuLi (2 mL, 1.3 M in THF,
2.6 mmol) within 15e20 min at ꢁ78 ꢀC. The resulting yellow so-
lution was stirred for 1 h at the same temperature, then a solution
of 2-chloromethyl oxazoline or benzyl bromide (2.8 mmol) in THF
(10 mL) was added dropwise at ꢁ78 ꢀC over 20 min. The mixture
was slowly warmed to room temperature and kept stirring for
a further 36 h. The solvent was removed and the residue was di-
luted with CH2Cl2 (100 mL), then washed with H2O (20 mL). The
aqueous layer was extracted with CH2Cl2 (2ꢂ20 mL), and the
combined organic phases were dried over Na2SO4, filtered, and
concentrated. The residue was purified by flash chromatography
(petroleum ether/acetone¼10/1) to afford the desired product. The
syntheses and characterizations of ligands 10aec have been
reported before.13j,15
Entry
R
R1
R2
% Yieldb,c (cis/trans) % eed
67(92/8)
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
p-BrC6H4
PMP
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
PMP
PMP
PMP
PMP
p-MeC6H4
p-EtO2CC6H4 C6H5
p-BrC6H4
C6H5
C6H5
C6H5
C6H5
95
92
92
96
93
93
92
98
94
92
92
93
88
91
93
92
98.5
93
p-MeC6H4 76(94/6)
p-MeOC6H4 71(95/5)
p-FC6H4
p-ClC6H4
p-CF3C6H4 70(92/8)
p-NO2C6H4 73(94/6)
70(94/6)
67(92/8)
C6H5
73(95/5)
9
p-CF3C6H4 61(94/6)
p-BrC6H4
PMP
10
11
12
13
14
15
16
17
18
19e
20
21
67(94/6)
61(95/5)
61(91/9)
98(89/11)
74(93/7)
75(70/30)
34(86/14)
72(95/5)
C6H5
4.2.1. (3aS,3a0S,8aR,8a0R)-2,20-(1-((S)-4-Benzyl-4,5-dihydrooxazol-
2-yl)propane-2,2-diyl)bis(8,8a-dihydro-3aH-indeno [1,2-d] oxazole)
C6H5
(10d). White solid, 56% yield; ½a D20
ꢃ
ꢁ200.0 (c 0.715, CHCl3); 1H NMR
a
-furyl
C6H5
C6H5
(300 MHz, CDCl3):
d 7.50e7.46 (m, 2H), 7.28e7.16 (m, 9H), 7.06 (d,
J¼6.9 Hz, 2H), 5.57 (d, J¼2.7 Hz, 1H), 5.54 (d, J¼2.7 Hz, 1H),
5.32e5.27 (m, 2H), 4.06e4.02 (m, 1H), 3.47e3.25 (m, 4H), 3.02 (dd,
J¼18.0 Hz, 7.8 Hz, 2H), 2.98 (s, 2H), 2.78 (dd, J¼13.8, 5.1 Hz,1H), 2.32
(dd, J¼13.8, 8.7 Hz, 1H), 1.49 (s, 3H); 13C NMR (400 MHz, CDCl3):
p-MeC6H4
C6H5
1-Cyclo-hexenyl C6H5
n-Pentyl C6H5
PMP
C6H5
p-CF3C6H4 55(90/10)
C6H5
C6H5
C6H5
80
>99
71(97/3)
74(97/3)
96
73
a
d
167.5, 167.0, 163.8, 141.6, 141.5, 140.1, 139.5, 137.8, 129.1, 129.0,
TOX 10C (0.5 mmol scale, 12 mol %), CuOTf$Tol (10 mol %), N2.
Total isolated yield of cis and trans-isomers.
b
c
128.6, 128.4, 128.2, 128.1, 127.2, 127.0, 126.2, 125.6, 125.5, 125.4,
125.0, 124.8, 83.4, 83.3, 76.4, 76.3, 76.2, 70.8, 66.8, 41.1, 40.6, 39.5,
39.4, 34.5, 20.8; IR (neat): 3025, 2923, 2853, 1649, 1458, 1227, 1162,
1095, 1019, 986, 857, 750, 702 cmꢁ1; LRMS-ESI (m/z): 518.2
(MþHþ); HRMS-ESI (m/z): calcd for C33H32N3Oþ3 , 518.2453; found,
518.2438.
cis/trans ratios were determined by 1H NMR.
d
e
ee’s of cis isomers, determined by chiral HPLC.
Recrystallized from hexane/EtOAc/CH2Cl2, with cis 9a.
introduction of an additional oxazoline moiety not only increased
the performance of the parental IndaBOX ligand in the Kinugasa
reaction of alkynes with C-arylnitrones, but also altered the sub-
strate scope. To our knowledge, the diastereo- and enantio-
selectivities observed in this TOX/Cu-catalytic system are among
the best results in the asymmetric catalytic Kinugasa reaction.4 The
current substrate scope of our system is also a good complement to
the Evans’ BOX/Cu system.11 Moreover, the enantiomeric purity of
cis product 9a can be readily increased to >99% ee through a single
recrystallization (entry 19). Alkynes also worked well to give the
desired product with moderate to high ees (entries 21e22).
4.2.2. (3aS,3a0S,8aR,8a0R)-2,20-(1-((S)-4-Phenyl-4,5-dihydrooxaz-ol-
2-yl)propane-2,2-diyl)bis(8,8a-dihydro-3aH-indeno[1,2-d]oxazole)
(10e). White solid, 71% yield; ½a D20
ꢃ
ꢁ226.5 (c 0.65, CHCl3); 1H NMR
(300 MHz, CDCl3):
d 7.52e7.47 (m, 2H), 7.30e7.18 (m, 9H), 7.09 (d,
J¼6.9 Hz, 2H), 5.58 (d, J¼7.8 Hz, 1H), 5.55 (d, J¼7.8 Hz, 1H),
5.34e5.27 (m, 2H), 4.86 (t, J¼9.2 Hz, 1H), 3.64e3.55 (m, 2H),
3.67e3.26 (m, 2H), 3.07e2.97 (m, 4H), 1.55 (s, 3H); 13C NMR
(400 MHz, CDCl3):
d 167.4, 167.0, 164.7, 142.1, 141.7, 141.5, 140.1,
139.5, 128.4, 128.3, 128.2, 127.3, 127.2, 127.0, 126.4, 125.5, 125.0,
124.9, 83.4, 76.4, 76.3, 73.8, 69.2, 40.7, 39.6, 39.4, 34.6, 20.9; IR
(neat): 3025, 2922, 2852, 1649, 1479, 1427, 1347, 1277, 1227, 1161,
1097, 988, 856, 750, 700 cmꢁ1; LRMS-ESI (m/z): 504.2 (MþHþ);
HRMS-ESI (m/z): calcd for C32H30N3Oþ3 , 504.2275; found, 504.2282.
3. Conclusions
In summary, TOX 10c was identified as an efficient ligand for the
copper-catalyzed Kinugasa reaction of alkynes with C-arylnitrones.
Both high diastereo- and enantioselectivity (up to 97:3 dr and 98.5%
ee) have been achieved, providing an attractive approach for the
synthesis of enantiomerically enriched
study and further extension of the current reaction is underway.
4.2.3. (3aS,3a0S,8aR,8a0R)-2,20-(1-((4S,5S)-4,5-Diphenyl-4,5-
dihydrooxazol-2-yl)propane-2,2-diyl)bis(8,8a-dihydro-3aH-indeno
[1,2-d]oxazole) (10f). White solid, 88% yield; ½a D20
ꢁ82.5 (c 0.36,
ꢃ
b-lactams. Mechanistic
CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.53e7.49 (m, 2H), 7.29e7.18
(m, 6H), 6.97e6.96 (m, 6H), 6.75e6.69 (m, 4H), 5.59 (d, J¼7.8 Hz,
1H), 5.54 (d, J¼7.5 Hz, 1H), 5.35e5.27 (m, 3H), 4.74 (d, J¼9.9 Hz, 1H),
4. Experimental section
4.1. General
3.33e2.92 (m, 6H), 1.70 (s, 3H); 13C NMR (300 MHz, CDCl3):
d 167.5,
167.1, 164.9, 141.8, 141.5, 140.2, 139.6, 137.4, 136.2, 128.2, 127.5, 127.4,
127.3, 127.0, 126.9, 126.6, 126.0, 125.5, 125.1, 125.0, 85.0, 83.4, 76.4,
73.1, 40.8, 39.6, 39.3, 35.2, 21.3; IR (neat): 3035, 2971, 2917, 1650,
1453, 1347, 1180, 1095, 993, 855, 753, 695 cmꢁ1; LRMS-ESI (m/z):
580.2 (MþHþ); HRMS-ESI (m/z): calcd for C38H34N3Oþ3 , 580.2585;
found, 580.2595.
Commercial solvents were dried and purified by standard pro-
cedures, as specified in ‘Purification of Laboratory Chemicals’.
Various alkyl amines were purchased from commercial suppliers
and were distilled over potassium hydroxide pellets under N2 at-
mosphere. Low- and high-resolution mass spectra were recorded
by EI or ESI method. Optical rotations were determined at 589 nm
4.2.4. (3aS,3a0S,8aR,8a0R)-2,20-(1-Phenylpropane-2,2-diyl)bis(8,8a-
dihydro-3aH-indeno[1,2-d]oxazole) (11). White solid, 87% yield;
(sodium
polarimeter.
D
line) by using
a
PerkineElmer-341 MC digital
½
a 2D0
ꢃ
ꢁ279.7 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.52e7.50
(m, 1H), 7.38 (d, J¼7.2 Hz, 1H), 7.34e7.23 (m, 6H), 7.01e6.97 (m, 1H),

J.-H. Chen et al. / Tetrahedron 68 (2012) 5042e5045
5045
6.84 (t, J¼6.4 Hz, 2H), 6.74e6.73 (m, 2H), 5.55 (d, J¼3.6 Hz, 1H), 5.53
(d, J¼2.4 Hz, 1H), 5.33e5.26 (m, 2H), 3.34 (dd, J¼18 Hz, 7.2 Hz, 2H),
3.23e3.11 (m, 3H), 3.03e2.98 (m, 1H), 1.24 (s, 3H); 13C NMR
(Grant No. 2009CB825300), The Chinese Academy of Sciences, and
The Science and Technology Commission of Shanghai Municipality.
(100 MHz, CDCl3):
d 168.1, 167.9, 141.6, 141.6, 139.6, 139.5, 135.8,
Supplementary data
129.9, 128.2, 128.2, 127.5, 127.3, 127.2, 126.2, 125.6, 125.5, 125.0,
124.9, 83.4, 82.9, 76.4, 76.2, 42.8, 41.4, 39.5, 39.2, 20.4; IR (neat):
3051, 2988, 2957, 2938, 2921, 1649, 1493, 1481, 1451, 1431, 1369,
1352, 1285, 1248, 1225, 1179, 1165, 1087, 1063, 1028, 1015, 991, 949,
939, 857, 838, 761, 741, 711, 701, 615, 598, 552 cmꢁ1; LRMS-ESI (m/
z): 435.2 (MþHþ); HRMS-ESI calcd for C29H27N2O2þ: 435.2067,
found, 435.2062.
1H NMR 13C NMR for new compounds, and HPLC spectra for
9aet. Supplementary data related to this article can be found online
at doi:10.1016/j.tet.2012.04.049.
References and notes
4.3. General procedures for the coupling reaction of alkynes
with nitrones
1. (a) Chemistry and Biology of b-Lactams Antibiotics; Morin, R. B., Gorman, M., Eds.;
Academic: New York, NY, 1982; (b) . ; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Eds. ; Pergamon: New York, NY, 1996; Vol. 1B; (Chapters 1.18e1.20).
2. (a) Ojima, I. Acc. Chem. Res. 1995, 28, 383; (b) Ojima, I.; Delaloge, F. Chem. Soc.
Rev. 1997, 26, 377; (c) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Pure
Appl. Chem. 2000, 72, 1763; (d) Synthesis of b-Lactam Antibiotics; Bruggink, A.,
A mixture of CuOTf$Tol (26 mg, 0.05 mmol) and (S)-Inda tri-
soxazoline 10c (29 mg, 0.06 mmol) in CH3CN (4 mL) was stirred
under N2 at room temperature for 2 h. The solution was cooled to
Ed.; Kluwer: Dordrecht, 2001.
3. For reviews on chiral precursor approaches, see: (a) Georg, G. I.; Ravikumar, V.
T. In The Organic Chemistry of -Lactams; Georg, G. I., Ed.; VCH: New York, NY,
0 ꢀC, and then Cy2NH (100
mL, 0.5 mmol) was added. After 10 min,
b
alkyne (0.75 mmol) was added, followed by the addition of nitrone
(0.5 mmol) after half an hour. After the reaction was completed
(monitored by TLC), the mixture was passed through a short silica
gel column (CH2Cl2 as the eluent). The filtrate was concentrated,
and the residue was purified by flash chromatography (PE/CH2Cl2)
to afford the product. The diastereoselectivity was determined by
1H NMR spectroscopic analysis of the crude product. The de-
termination of enantioselective excess of the cis-isomer was per-
formed by chiral HPLC analysis with a Daicel Chiralcel AD-H/OD-H
column (254 nm, eluent: hexane/iPrOH¼80/20, flow rate: 0.7 mL/
min).
1993; p 295; (b) Ghosez, L.; Marchand-Brynaert, S. In; Trost, B., Fleming, I., Eds.
Comprehensive Organic Synthesis; Pergamon: Oxford, 1991; Vol. 5, p 85; (c) Hart,
D. J.; Ha, D.-C. Chem. Rev. 1989, 89, 1447 for reviews related to asymmetric
catalytic methods, see; (d) Magriotis, P. A. Angew. Chem., Int. Ed. 2001, 40, 4377;
(e) France, S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37,
592 for direct asymmetric catalytic GilmaneSpeeter reaction, see; (f) Gilman,
H.; Speeter, M. J. Am. Chem. Soc. 1943, 65, 2255; (g) Fujieda, H.; Kanai, M.;
Kambara, T.; Iida, A.; Tomioka, K. J. Am. Chem. Soc. 1997, 119, 2060; (h) Tomioka,
K.; Fujieda, H.; Hayashi, S.; Hussein, M. A.; Kambara, T.; Nomura, Y.; Kanai, M.;
Koga, K. Chem. Commun. 1999, 715; (i) Kambara, T.; Hussein, M. A.; Fujieda, H.;
Iida, A.; Tomioka, K. Tetrahedron Lett. 1998, 39, 9055 for direct asymmetric
catalytic Staudinger reaction, see; (j) Staudinger, H. Justus Liebigs Ann. Chem.
1907, 356, 51; (k) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III;
Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831; (l) Wack, H.; Drury, W. J., III; Taggi,
A. E.; Ferraris, D.; Lectka, T. Org. Lett. 1999, 1, 1985; (m) Hodous, B. L.; Fu, G. C. J.
Am. Chem. Soc. 2002, 124, 1578 for rhodium-catalyzed carbonylation of an
aziridine, see; (n) Calet, S.; Urso, F.; Alper, H. J. Am. Chem. Soc. 1989, 111, 931 for
4.3.1. (3S,4S)-4-(4-Fluorophenyl)-1,3-diphenylazetidin-2-one
(9d). Table 3, entry 4, 70% yield (solid, 25 h); ½a D20
ꢃ
þ2.1 (c 0.85,
rhodium-catalyzed intramolecular insertion of a
a-diazo amide into a CeH
i
bond, see; (o) McCarthy, N.; McKervey, M. A.; Ye, T.; McCann, M.; Murphy, E.;
Doyle, M. P. Tetrahedron Lett. 1992, 33, 5983; (p) Doyle, M. P.; Protopopova, M.
N.; Winchester, W. R.; Daniel, K. L. Tetrahedron Lett. 1992, 33, 7819; (q) Doyle,
M. P.; Kalinin, A. V. Synlett 1995, 1075; (r) Watanabe, N.; Anada, M.; Hashimoto,
S.-i.; Ikegami, S. Synlett 1994, 1031; (s) Anada, M.; Watanabe, N.; Hashimoto, S.-
i. Chem. Commun. 1998, 1517; (t) Anada, M.; Hashimoto, S.-i. Tetrahedron Lett.
1998, 39, 9063.
CHCl3); ee is determined by HPLC analysis (Chiralcel OD-H, PrOH/
hexane¼20/80, 0.7 mL/min, 254 nm; tR (minor)¼21.74 min, tR
(major)¼8.85 min), 96% ee; 1H NMR (400 MHz, CDCl3):
d 7.40 (d,
J¼1.2 Hz, 2H), 7.38e7.26 (m, 2H), 7.12e7.01 (m, 8H), 6.81e6.77 (m,
2H), 5.44 (d, J¼6.0 Hz, 1H), 4.99 (d, J¼6.0 Hz, 1H). 13C NMR
(400 MHz, CDCl3):
d 165.4, 163.4, 161.0, 137.5, 131.9, 130.2, 130.2,
4. Reviews: (a) Marco-Contelles, J. Angew. Chem., Int. Ed. 2004, 43, 2198; (b) Pal, R.;
Ghosh, S. C.; Chandra, K.; Basak, A. Synlett 2007, 2321; (c) Stanley, L. M.; Sibi, M.
129.1, 129.0, 128.8, 128.7, 128.2, 127.3, 124.2, 117.1, 115.4, 115.2, 60.3,
59.6; IR (neat): 1744, 1597, 1496, 1456, 1416, 1377, 1265, 1225, 1157,
829, 733, 692 cmꢁ1; LRMS-EI (m/z): 317 (Mþ); HRMS-EI calcd for
C21H16NOFþ: 317.1216; found: 317.1219.
ꢀ
ꢀ
P. Chem. Rev. 2008, 108, 2887; (d) Aranda, M. T.; Perez-Faginas, P.; Gonzalez-
Muniz, R. Curr. Org. Synth. 2009, 6, 325.
~
5. Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem. Commun. 1972, 466.
6. Miura, M.; Enna, M.; Okura, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999.
7. (a) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572; (b) Shintani, R.; Fu,
G. C. Angew. Chem., Int. Ed. 2003, 42, 4082.
4.3.2. (3S,4S)-1-(4-Methoxyphenyl)-3-(p-tolyl)-4-(4(tri-
8. (a) Ye, M.-C.; Zhou, J.; Huang, Z.-Z.; Tang, Y. Chem. Commun. 2003, 2554; (b) Ye,
fluoromethyl)phenyl)azetidin-2-one (9r). Table 3, entry 18, 55%
M.-C.; Zhou, J.; Tang, Y. J. Org. Chem. 2006, 71, 3576.
9. Basak, A.; Ghosh, S. C. Synlett 2004, 1637.
yield (solid, 60 h); ½a D20
ꢃ
ꢁ6.0 (c 2.25, CHCl3); ee is determined by
10. Coyne, A. G.; Mueller-Bunz, H.; Guiry, P. J. Tetrahedron: Asymmetry 2007, 18, 199.
11. Evans, D. A.; Kleinbeck, F.; Ruping, M. In Asymmetric Synthesis e The Essentials;
i
HPLC analysis (Chiralcel AD-H, PrOH/hexane¼20/80, 0.7 mL/min,
254 nm; tR (minor)¼27.34 min, tR (major)¼13.64 min), 93% ee; 1H
€
Christmann, M., Brase, S., Eds.; Wiley-VCH: Weinheim, 2007; p 72.
12. Saito, T.; Kikuchi, T.; Tanabe, H.; Yahiro, J.; Otani, T. Tetrahedron Lett. 2009, 50,
4969.
NMR (400 MHz, CDCl3):
d
7.38 (d, J¼8.0 Hz, 2H), 7.32e7.30 (m, 2H),
7.17 (d, J¼8.0 Hz, 2H), 6.90e6.82 (m, 6H), 5.44 (d, J¼6.0 Hz,1H), 5.00
13. For other applications of the sidearm strategy, see: (a) Zhou, J.; Tang, Y. J. Am.
Chem. Soc. 2002, 124, 9030; (b) Zhou, J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org.
Chem. 2004, 69, 1309; (c) Zhou, J.; Ye, M.-C.; Tang, Y. J. Comb. Chem. 2004, 6, 301;
(d) Zhou, J.; Tang, Y. Chem. Commun. 2004, 432; (e) Huang, Z.-Z.; Kang, Y.-B.;
Zhou, J.; Ye, M.-C.; Tang, Y. Org. Lett. 2004, 6, 1677; (f) Zhou, J.; Tang, Y. Org.
Biomol. Chem. 2004, 2, 429; (g) Ye, M.-C.; Li, B.; Zhou, J.; Sun, X.-L.; Tang, Y. J.
Org. Chem. 2005, 70, 6108; (h) Kang, Y.-B.; Sun, X.-L.; Tang, Y. Angew. Chem., Int.
Ed. 2007, 46, 3918; (i) Xu, Z.-H.; Zhu, S.-N.; Sun, X.-L.; Tang, Y.; Dai, L.-X. Chem.
Commun. 2007, 1960; (j) Cao, P.; Deng, C.; Zhou, Y.-Y.; Sun, X.-L.; Zheng, J.-C.;
Xie, Z.-W.; Tang, Y. Angew. Chem., Int. Ed. 2010, 49, 4463; (k) Zhou, Y.-Y.; Sun, X.-
L.; Zhu, B.-H.; Zheng, J.-C.; Zhou, J.-L.; Tang, Y. Synlett 2011, 935; (l) Zhou, J.;
Tang, Y. Chem. Soc. Rev. 2005, 34, 664.
(d, J¼6.0 Hz, 1H), 3.77 (s, 3H), 2.18 (s, 3H); 13C NMR (400 MHz,
CDCl3):
d 164.9, 156.2, 139.0, 137.2, 130.9, 129.0, 128.6, 128.4, 127.5,
125.2, 125.1, 118.3, 114.4, 60.2, 59.8, 55.4, 21.0; IR (neat): 2963, 1411,
1259, 1081, 1013, 866, 793, 701 cmꢁ1; LRMS-EI (m/z): 411 (Mþ);
HRMS-EI calcd. For C24H20NO2Fþ3 : 411.1446; found: 411.1449.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 20821002 and
20932008), the Major State Basic Research Development Program
14. Walsh, P. J.; Kozlowsk, M. C. Fundamentals of Asymmetric Catalysis; University
Science Books: Sausalito, California, 2008; P5.
15. Cao, C.-L.; Zhou, Y.-Y.; Sun, X.-L.; Tang, Y. Tetrahedron 2008, 64, 10676.