Asymmetric Synthesis of trans-b-Lactams on Water
FULL PAPER
According to the generally accepted mechanism[10b] of the
Kinugasa reaction, we postulated a possible intermediate
that could rationalize the observed sense of geometric in-
duction. In the aforementioned Kinugasa reactions by
Tang’s group, copper(II) was reduced in situ into copper(I)
by phenylacetylene.[14b] As shown in Scheme 3, owing to the
Experimental Section
Preparation of chiral secondary diamine ligand L1: To a solution of
(1R,2R)-(+)-1,2-diaminocyclohexane (19.0 mmol, 2.166 g) in MeOH
(30 mL) was added cycloheptanone (38 mmol, 4.5 mL, 2.0 equiv) at 258C
and the mixture was stirred for 30 min. To this mixture was added
MeOH (10 mL) and NaBH4 (41.8 mmol, 1.581 g, 2.2 equiv) and the reac-
tion was monitored by TLC. The residue was diluted with EtOAc
(15 mL) and wished with water (3ꢂ20 mL). The product was isolated by
flash column chromatography on silica gel (EtOAc/MeOH, 8:1 to 4/1) to
give compound L1 (5.248 g, 17.0 mmol, 89% yield) as an oil.
Typical experimental procedure for the Kinugasa reaction of nitrone 2a
with phenylacetylene (1a; Table 2, entry 8): Ligand L1 (12.2 mg,
0.04 mmol) and CuACHTNUTRGNEUNG(OTf)2 (7.2 mg, 0.02 mmol) were stirred together in
water (0.4 mL) at 358C for 30 min. Then, the solution was cooled to
208C and nBu2NH (34 mL, 0.2 mmol) was added. After 10 min, phenyla-
cetylene (1a, 22 mL, 0.2 mmol) was added and, when the color of the re-
sulting mixture had turned light yellow, nitrone 2a (56.6 mg, 0.21 mmol)
was added to the solution and the mixture was stirred for 2 days. The
crude product was directly purified by flash chromatography on silica gel
(petroleum ether/EtOAc, 30:1 to 9:1) to afford compound 3a (90%
yield, trans/cis 99:1, 91% ee) as a white solid. Further purification by
column chromatography afforded compound trans-3a. M.p. 1448C;
[a]2D2 =+9.96 (CHCl3, c=0.552, 91% ee); 1H NMR (400 MHz, CDCl3):
d=7.96 (d, J=8.7 Hz, 2H), 7.55–7.27 (m, 12H), 5.01 (d, J=2.6 Hz, 1H),
4.18–4.44 (m, 3H), 1.35 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=165.98, 165.92, 140.98, 137.02, 134.33, 130.89, 129.45, 129.13,
128.93, 128.09, 127.42, 125.87, 116.71, 65.40, 63.88, 60.89, 14.33 ppm;
HRMS (ESI): m/z calcd for C24H21NO3+Na+: 394.1419 [M+Na]+; found:
394.1416; the ee and d.r. were determined by comparison with authentic
racemates, chiral HPLC (Daicel Chiralcel IA column; n-hexane/2-propa-
Scheme 3. Proposed catalytic model.
nol, 90:10; flow rate: 1.0 mLminÀ1
; l=254 nm): t=23.0 min (trans,
steric hindrance of one cycloheptyl subunit on the diamine
ligand and the amine additive, the [3+2] cycloaddition pro-
ceeded with attack of the copper(I) phenylacetylide on the
Si face of nitrone 2a. Isoxazoline intermediate B was then
transformed into enolate C, which was intercepted with a
proton to generate a mixture of cis- and trans-b-lactam 3a.
The extent of formation of the trans isomer was a result of
isomerization at the C3 position under the basic conditions
of the catalyst that were used. Such a method is attractive as
a facile route to the highly diastereoselective and enantio-
major), 21.4 min (trans, minor).
Experimental procedure for the scale-up reaction: Ligand L1 (244.0 mg,
0.8 mmol) and Cu(OTf)2 (144.0 mg, 0.4 mmol) were stirred together in
AHCTUNGTRENNUNG
water (8 mL) in a round-bottomed flask (25 mL) under a N2 atmosphere
at 358C for 30 min. Then, the solution was cooled to 208C and nBu2NH
(680 mL, 4 mmol) was added. After 10 min, alkyne 1a (440 mL, 4.0 mmol)
was added and, when the color of the resulting mixture had turned light
yellow, nitrone 2c (1.272 g, 4.2 mmol) was added to and the mixture was
stirred for 4 days. The resulting mixture was quenched with an aqueous
solution of NaCl and extracted with CH2Cl2. The combined organic
layers were dried over Na2SO4 and evaporated in vacuo. The crude prod-
uct was purified by flash chromatography on silica gel (petroleum ether/
EtOAc, 30:1 to 9:1) to give compound trans-3c (1.269 g, 3.1 mmol) as a
white solid (78% yield, >19:1 d.r., 95% ee).
ACHTUNGTRENNUNGselective synthesis of trans-lactams.
Procedure for the transformation of cis-3a into trans-3a: Ligand L1
(6.2 mg, 0.02 mmol), CuACTHNUTRGNE(NUG OTf)2 (3.6 mg, 0.01 mmol), and cis-3a (37.1 mg,
Conclusion
0.1 mmol) were mixed with water (0.2 mL) and stirred in a test tube
under a N2 atmosphere at 208C. Then, nBu2NH (17 mL, 0.1 mmol) was
added and the mixture was stirred for 2 days. The reaction mixture was
purified by flash column chromatography on silica gel (petroleum ether/
EtOAc, 30:1 to 9:1) to give compound 3a (33.7 mg, 0.091 mmol) as a
white solid (91% yield, 98:2 d.r., 94% ee). The d.r. was determined by
1H NMR spectroscopy and the ee value was determined by HPLC analy-
sis (Chiral IA column; n-hexane/2-propanol, 90:10; flow rate:
We have successfully developed a highly enantioselective
Kinugasa reaction by using water as the solvent for the first
time. This mild and operationally simple method provides a
one-step route to optically active trans-b-lactams in good
yields, enantioselectivities, and diastereoselectivities (up to
90% yield, >99:1 d.r., and 98% ee). This procedure toler-
ates a relatively wide range of substrates and excellent re-
sults can be obtained for gram-scale reactions “on water”,
which opens up a new pathway to various biologically im-
portant, non-racemic b-lactam derivatives in one pot. This
promising result should enhance the use of water as a reac-
tion medium in enantioselective catalysis.
1.0 mLminÀ1
minor).
;
l=254 nm): t=23.0 min (trans, major), 21.4 min (trans,
Acknowledgements
We appreciate the National Natural Science Foundation of China
(21021001 and 20902060), the Ministry of Education of China
(20110181130014), and the Major State Basic Research and Development
Program (973 Program, 2011CB808600) for financial support.
Chem. Eur. J. 2013, 19, 7561 – 7567
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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