of Lewis acids, electron-withdrawing nitrogen substituents,
and an aromatic group on the imine carbon.5
Scheme 2
In this article we would like to report the first successful
methylene transfer to the aliphatic unactivated aldimines
derived from N,N-dibenzylamino aldehydes using a sulfur
ylide to form R-amino aziridines stereoselectively in high
yields.
The starting N,N-dibenzylamino aldehydes 1 were prepared
from the corresponding R-amino acids through benzylation,
reduction, and oxidation.6 The final step is the Swern
oxidation of N,N-dibenzylamino alcohol, and the reaction
occurs almost quantitatively to provide the R-amino aldehyde
without losing any optical integrity. The R-amino aldehydes
and p-anisidine (p-methoxyaniline) were stirred in methylene
chloride in the presence of molecular sieves to give the
corresponding imines in high yields.7 The N,N-dibenzyl
R-amino aldimines were subjected to the coupling reaction
with dimethylsulfonium methylide prepared from trimeth-
ylsulfonium iodide and n-BuLi. The coupling reactions
proceeded smoothly to give the corresponding aziridines in
high yields (Scheme 2).8 We already reported the stereo-
selective addition reactions to R-N,N-dibenzylamino alde-
hydes 1 and expected this sulfonium ylide addition would
show the same stereoselectivity where the nucleophiles
approach from the re face of the imines by a Felkin-Ahn
transition state.2 While we were preparing this manuscript
Concello´n et al. reported stereoselective preparation of
R-N,N-dibenzylaminoaziridines by highly stereoselective
* We obtained 69% of 3ae aziridine and 19% of methylthio-
methyl addition product to the N-PMP aldimine.
reduction of R-aminoalkyl chloromethyl ketimines prepared
from N,N-dibenzylamino acid esters.9 Though the reaction
pathways are different, nucleophiles (sulfur ylide or hydride)
attack the aldimines or ketimine carbon from the same side
selectively to provide the major product that has opposite
stereochemistry at the C-2 position in the aziridine ring. We
also prepared the corresponding aziridine from the reaction
of cyclohexanecarboxaldehyde in 70%. We found that the
compound data of the minor product obtained from the
reaction of R-N,N-dibenzylphenylalaninal aldimine with
dimethylsulfonium methylide and those of the major product
obtained from the reduction of the corresponding ketimine
were in good agreement.
The above results show that the sulfonium ylide addition
reactions to the R-N,N-dibenzylamino aldimines and hydride
reduction of the R-N,N-dibenzylaminoalkyl chloromethyl
ketimines predominantly take place on the re face of the
CdN double bonds and that the two methodologies can be
complementary for the stereoselective synthesis of function-
alized chiral aziridines.
(5) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.;
Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433-1436.
(6) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1141.
(7) Fujisawa, T.; Hayakawa, R.; Shimizu, M. Tetrahedron Lett. 1992,
33, 7903-7906.
(8) Representative Procedure. Preparation of N-PMP-aziridine from
N,N-dibenzylphenylalaninal. A mixture of the amino aldehyde (139 mg,
0.42 mmol), p-anisidine (57 mg, 0.47 mmol), and 1.0 g of 4 Å MS in 3 mL
of methylene chloride was stirred for 12 h at room temperature. The solvent
was evaporated, and the residue was dissolved in 3 mL of THF. A
suspension of Me3SI (172 mg, 0.85 mmol) in 3 mL of THF was cooled to
-30 °C and treated with n-BuLi (1.6 M, 0.48 mL, 0.77 mmol). The mixture
was stirred for 1 h and cooled to -78 °C. To the sulfonium ylide solution
was added the cooled solution of the N-PMP-imine in 3 mL of THF slowly
at -78 °C. The mixture was slowly warmed to room temperature and stirred
overnight. The reaction was quenched with water, and the aqueous layer
was extracted with ether (5 mL × 5). The combined extract was dried over
K2CO3, and the solvent was evaporated to give a crude product as brown
oil, which was chromatographed on silica gel with 5% EtOAc/hexane to
give 130 mg (69%) of the major product and 35 mg (19%) of the minor
product as oil. Major product (3aa): (-)-(2R,1′S)-2-[1′-(dibenzylamino)-
2′-(phenyl)ethyl]-1-(p-methoxyphenyl)aziridine; [R]28D +53.2 (c, 1.0, CHCl3)
1H NMR (CDCl3, 200 MHz) 7.33-7.08 (m, 15H), 6.85 (d, J ) 9.1 Hz,
2H), 6.75 (d, J ) 9.0 Hz, 2H), 3.88 (d, J ) 13.9 Hz, 2H), 3.74 (s, 3H),
3.70 (d, J ) 13.9 Hz, 2H), 3.18 (d, J ) 7.6 Hz, 2H), 2.84 (q, J ) 7.2 Hz,
1H), 2.27-2.20 (m, 2H), 2.13 (d, J ) 7.1 Hz, 1H); 13C NMR (CDCl3, 50
MHz) 154.8, 147.7, 139.4, 139.3, 129.4, 128.1, 127.8, 127.7, 126.4, 125.7,
121.0, 113.9, 60.9, 55.2, 53.6, 40.2, 36.4, 34.3; MS(EI) 448 (M+), 357,
313, 300, 253, 148, 91. Minor product (3ba): (-)-(2S,1′S)-2-[1′-(diben-
Acknowledgment. M.T.R. and W.K.L. would like to
thank the Alexander von Humboldt Foundation and Korea
Research Foundation (KRF-99-013-000-348) for support.
zylamino)-2′-(phenyl)ethyl]-1-(p-methoxyphenyl)aziridine; Rf 0.40 (Hex/
Supporting Information Available: Experimental pro-
cedure from cyclohexanecarboxaldehyde and compound data
shown in Scheme 2. This material is available free of charge
1
EA 15%); [R]27 -80.2 (c 0.82, CHCl3); H NMR (CDCl3, 500 MHz) δ
D
7.29-7.03 (15H, m), 7.00 (2H, d, J ) 8.7 Hz), 6.80 (2H, d, J ) 8.7 Hz),
4.02 (2H, d, J ) 13.9 Hz), 3.87 (2H, d, J ) 13.8 Hz), 3.76 (3H, s), 3.00-
2.92 (2H, m), 2.78 (1H, dd, J ) 5.3, 12.0 Hz), 2.32 (1H, m), 1.81 (1H, d,
J ) 6.5 Hz), 1.77 (1H, d, J ) 3.1 Hz); 13C NMR (CDCl3, 125 MHz) 154.91,
148.37, 139.92, 139.85, 129.44, 128.61, 128.08, 128.05, 126.67, 125.85,
121.45, 114.25, 61.44, 55.54, 53.97, 39.692, 35.25, 31.88; HRMS calcd
for C31H32N2O 448.251464, found 448.251862. We proved the enantiomeric
purity of the products by making the enantiomers of 3aa and 3ba starting
from D-phenylalanine and analyzed them with chiral HPLC.
OL0164029
(9) Concello´n, J. M.; Bernad, P. L.; Riego, E.; Garc´ıa-Granda, S.; Force´n-
Acebal, AÄ . J. Org. Chem. 2001, 66, 2764-2768.
3120
Org. Lett., Vol. 3, No. 20, 2001