Catalytic Asymmetric Aziridination of a,b-Unsaturated Aldehydes
FULL PAPER
1H); 13C NMR (100 MHz, CDCl3): d=195.8, 160.2, 135.5, 135.2, 129.9,
128.7, 128.64, 128.58, 128.4, 127.1, 68.8, 50.2, 35.2, 34.2 ppm; HRMS
(ESI): m/z: calcd for C18H17NO3Na: 318.1101 [M+Na]+; found: 318.1099;
[a]2D5 =+49.7 (c=1.0 in CHCl3) for an enantiomerically enriched sample
of 92% ee; the enantiomeric excess was determined by HPLC analysis in
comparison with authentic racemic material (ODH column, n-hexane/
comparison with authentic racemic material (ODH column, n-hexane/
iPrOH 95:5, 0.5 mLminÀ1): tR (major enantiomer)=22.1, tR (minor enan-
tiomer)=23.6 min.
One-pot synthesis of b-amino acid ester derivatives 16: A mixture of al-
dehyde 1 (1.0 mmol), 2 (1.2 mmol), NaOAc (3.0 mmol), and catalyst 10
(5–20 mol%) in CHCl3 (4.0 mL) was stirred at room temperation for the
time shown in the Table 8. Then, alcohol (3 equiv) and 2-(perfluoro-
phenyl)-6,7-dihydro-5H-pyrrolo[2,1-c,1,2,4]triazol-2-ium tetrafluoroborate
(3 mol%) were added to the reaction mixture. The resulting solution was
stirred for 16 h at room temperature. After that, the solvent was evapo-
rated and product 16 was purified by flash column chromatography.
iPrOH 95:5, 1.0 mLminÀ1
, 210 nm): tR (major enantiomer)=21.5, tR
(minor enantiomer)=25.0 min.
General procedure for the aziridination reaction between 4-methyl-N-
(tosyloxy)benzenesulfonamide 2 f and a,b-disubstituted enals 1: a,b-Dis-
ubstituted enal 1aa–ee (1.0 equiv, 0.25 mmol), 4-methyl-N-(tosyloxy)ben-
zenesulfonamide 2 f (1.2 equiv, 0.30 mmol), and NaOAc (0.375 mmol,
1.5 equiv) were added to a stirred solution of catalyst 10 (20 mol%) in
toluene (0.5 mL) at room temperature and the resulting reaction mixture
was vigorously stirred for the reported time. Next, the reaction was di-
rectly loaded upon a silica-gel column and immediate chromatography
(pentane/EtOAc 10:1) furnished the aziridine product 3nn–rr.
(R)-Methyl 3-{[(benzyloxy)carbonyl]amino}hexanoate (16b): Colorless
oil; 1H NMR (400 MHz, CDCl3): d=7.37–7.31 (m, 5H), 5.18 (d, J=
8.8 Hz, 1H), 5.09 (s, 2H), 4.02–3.96 (m, 1H), 3.66 (s, 3H), 2.54 (t, J=
6.4 Hz, 2H), 1.53–1.47 (m, 2H), 1.40–1.35 (m, 2H), 0.91 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=172.2, 156.0, 136.7, 128.6,
128.2, 127.1, 66.7, 51.8, 48.0, 39.0, 36.7, 19.5, 13.9 ppm; HRMS (ESI): m/
z: calcd for C15H21NO4Na: 302.1363 [M+Na]+; found: 302.1371; [a]D25 =+
7.5 (c=1.0 in CHCl3) for an enantiomerically enriched sample of
93% ee; the enantiomeric excess was determined by HPLC analysis in
comparison with authentic racemic material (Ad-column, n-hexane/
ACHTUNGTRENNUNG(2S,3R)-2-Ethyl-3-propyl-1-tosylaziridine-2-carbaldehyde (3nn): Color-
less oil. 1H NMR (400 MHz, CDCl3): d=9.47 (s, 1H), 7.83 (d, J=8.0 Hz,
2H), 7.36 (d, J=7.6 Hz, 2H), 3.53 (dd, J=5.6, 2.4 Hz, 1H) 2.45 (s, 3H),
2.07–1.97 (m, 1H), 1.59–1.50 (m, 1H), 1.48–1.30 (m, 4H), 1.01 (t, J=
7.2 Hz, 3H), 0.90 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=195.1, 144.7, 136.6, 129.8, 127.7, 62.7, 52.0, 29.4, 21.8, 20.8, 19.5, 13.7,
10.5 ppm; HRMS (ESI): m/z: calcd for C15H21NO3SNa: 318.1134
[M+Na]+; found: 318.1126; [a]D25 =+4.9 (c=1.0 in CHCl3) for an enan-
tiomerically enriched sample of 99% ee; the enantiomeric excess was de-
termined by HPLC analysis in comparison with the authentic racemic
material (ODH-column, n-hexane/iPrOH 98:2, 0.5 mLminÀ1, 250 nm): tR
(major enantiomer)=20.1, tR (minor enantiomer)=21.6 min.
iPrOH 95:5, 1.0 mLminÀ1
, 210 nm): tR (minor enantiomer)=13.2, tR
(major enantiomer)=15.0 min.
Preparation of (R)-ethyl 3-aminohexanoate (17a): 10% (w/w) of Pd/C
(10%) was added to a stirred solution of ester 16a (15 mg, 0.05 mmol) in
MeOH (1 mL). The reaction was stirred under 90 atm. of hydrogen over-
night. Then the crude reaction mixture was filtered through a plug of
Celite. The solvent was removed under reduced pressure to afford the
pure product 17a (8 mg, quant.).
Procedure for the epoxidation of a-substituted enal (1u): 2-Benzylacry-
laldehyde (1u) (0.25 mmol, 1 equiv) and H2O2 (0.3 mmol, 1.2 equiv) were
added to a stirred solution of catalyst 10 (20 mol%) in toluene (0.5 mL).
The reaction mixture was vigorously stirred at room temperature for
24 h. The crude reaction mixture was passed through a silica gel column
(pentane/EtOAc 10:1) to give the pure product 15 (24 mg, yield: 59%).
Compound 15: Rf =0.52 (pentane/EtOAc 6:1).
(S)-2-Benzyloxirane-2-carbaldehyde (15): Colorless oil; 1H NMR
(400 MHz, CDCl3): d=8.97 (s, 1H), 7.34–7.24 (m, 5H), 3.26 (d, J=
15.2 Hz, 1H), 3.21 (t, J=15.2 Hz, 1H), 3.03 (d, J=4.8 Hz 1H), 2.88 ppm
(d, J=4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): 198.7, 135.0, 130.1,
128.6, 127.1, 61.5, 49.0, 33.2 ppm; HRMS (ESI): m/z: calcd for
C10H10O2Na: 185.0570 [M+Na]+; found: 185.0573; [a]2D5 =À23.9 (c=1.0
in CHCl3) for an enantiomerically enriched sample of 86% ee. The enan-
tiomeric excess was determined by HPLC analysis in comparison with
authentic racemic material (OJ-column, iso-hexane/iPrOH 98:2,
0.5 mLminÀ1, 210 nm): tR (major enantiomer)=50.5, tR (minor enantio-
mer)=58.2 min.
1
(R)-Ethyl 3-aminohexanoate (17a): H NMR (400 MHz, CDCl3): d=4.10
(q, J=7.2 Hz, 2H), 3.11–3.15 (m, 1H), 2.41 (dd, J=4.0, 15.6 Hz, 1H),
2.19 (dd, J=8.8, 15.6 Hz, 1H), 1.53 (br s, 2H), 1.29–1.37 (m, 4H), 1.21 (t,
J=7.2 Hz, 3H), 0.90 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=172.6, 60.2, 47.9, 42.6, 39.7, 19.1, 14.2, 13.9 ppm; [a]2D5 =+10.9
(c=0.5 in H2O) (lit. (S)-17a: [a]2D5 =À10.7 (c=2.1 in H2O)).[39]
General procedure for the oxidation/esterification of aziridine 3: Activat-
ed manganese dioxide (2.4 mmol, 209 mg, 17 equiv) was added to a
stirred solution of aldehyde 3 (0.14 mmol, 1 equiv) and sodium cyanide
(15 mg, 0.3 mmol, 2 equiv) in methanol (0.73 mL) at 08C.[48] After stirring
the mixture at 08C for 40 min, the reaction mixture was diluted with
ethyl acetate and filtered through a pad of Celite. The filtrated was con-
centrated in vacuo. The residue was diluted with ether, washed with satu-
rated aqueous ammonium chloride and brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified by silica gel
column chromatography (pentane/ethyl acetate 4:1) to give the corre-
sponding ester 18.
AHCTUNGTERG(NNUN 2S,3S)-1-Benzyl 2,3-dimethyl aziridine-1,2,3-tricarboxylate (18k): Color-
Preparation of (3R)-benzyloxycarbonylamino-hexanoic acid ethyl ester
(16a): Compound 3a (25 mg, 0.1 mmol, 1.00 equiv) was added to a solu-
tion of 3-benzyl-4,5-dimethylthiazolium chloride[36] (3 mg, 0.01 mmol,
10% equiv) in CH2Cl2 (0.5 mL) at room temperature. EtOH (18 mL,
0.3 mmol, 3.0 equiv) and DIPEA (4 mL, 0.02 mmol, 20 mol%) were
added to this suspension. The resulting solution was warmed to 308C and
stirred for 15 h. The reaction mixture was treated with sat. aq. NH4Cl
(1 mL) and extracted with EtOAc (3ꢃ5 mL). The combined organic ex-
tracts were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash chromatogra-
phy (hexane/EtOAc 3:1) to afford ester 16a (19 mg, 63%). Compound
16a: Rf =0.45 (pentane/EtOAc 3:1).
less oil; 1H NMR (400 MHz, CDCl3): d=7.38 (m, 5H), 5.18 (m, 2H),
3.76 (s, 6H), 3.45 (s, 2H), 2.19 ppm (s, 1H); 13C NMR (100 MHz, CDCl3):
d=166.8, 158.4, 135.2, 128.8, 128.7, 128.7, 69.1, 53.2, 40.3 ppm; HRMS
(ESI): m/z: calcd for C14H15O6N: 316.0792 [M+Na]+; found: 316.0794;
[a]2D5 =+5.3 (c=0.2 in CHCl3).
Typical procedure for the opening of aziridine 3 by NaOMe: NaOMe
(0.78 mmol, 2.1 equiv) in MeOH (1 mL) was added to aldehyde 3b
(79 mg, 0.37 mmol, 1 equiv) and the reaction mixture was stirred for 16 h
at room temperature. Then, the reaction was quenched by adding H2O
slowly. The mixture was extracted with ethyl acetate (3ꢃ10 mL). The
combined organic fractions were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (pentane/ethyl acetate 3:1) to
give diester 19b in 35% yield (36 mg). Compound 19b: Rf =0.17 (pen-
tane/EtOAc 3:1).
(R)-Ethyl 3-(benzyloxycarbonylamino)hexanoate (16a): Colorless oil;
1H NMR (400 MHz, CDCl3): d=7.29–7.37 (m, 5H), 5.17 (br s, 1H), 5.09
(s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.98–4.02 (m, 1H), 2.51–2.59 (m, 2H),
1.42–1.53 (m, 2H), 1.29–1.38 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 0.91 ppm
(t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=156.0, 136.8, 129.0,
128.7, 128.6, 128.2, 66.7, 60.7, 48.1, 39.2, 36.8, 19.5, 14.3, 13.9 ppm; HRMS
(ESI): m/z: calcd for C16H23O4N: 316.1519 [M+Na]+; found: 316.1524;
[a]2D5 =+18.1 (c=1.0 in CHCl3) for an enantiomerically enriched sample
of 94% ee. The enantiomeric excess was determined by HPLC analysis in
tert-Butyl (2R,3R)-2-hydroxy-1,1-dimethoxyheptan-3-ylcarbamate (19b):
1
Colorless oil; H NMR (400 MHz, CDCl3): d=4.73 (brd, J=8.4 Hz, 1H),
4.28 (d, J=6.0 Hz, 1H), 3.77 (brs, 1H), 3.67 (s, 1H), 3.45 (s, 3H), 3.41 (s,
3H), 2.47 (s, 1H), 1.44 (s, 9H), 1.44–1.35 (m, 4H), 0.92 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=156.1, 104.3, 79.4, 73.5,
Chem. Eur. J. 2011, 17, 7904 – 7917
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7915