Diastereoselective aziridination of chiral α-carbonyl enoates

Article abstract of DOI:10.1021/jo025670x

Nosyloxycarbamates very efficiently aziridinate optically active α-carbonyl enoates with high levels of diastereoselectivity under mild conditions and in a straight-forward process.

Full text of DOI:10.1021/jo025670x

dines from the same starting materials was then reported
by the same authors.9
Continuing our studies, we report here the aziridina-
tion of optically active R-carbonyl enoates derived from
the commercially available alcohols (R*OH) Helmchen’s
auxiliary10 (1a ) and (-)-8-phenylmenthol (1b).
Dia ster eoselective Azir id in a tion of Ch ir a l
r-Ca r bon yl En oa tes1
Stefania Fioravanti,* Alberto Morreale,
Lucio Pellacani,* and Paolo A. Tardella*
Dipartimento di Chimica, Universita` “La Sapienza”,
P.le Aldo Moro 2, I-00185 Roma, Italy
lucio.pellacani@uniroma1.it
Received March 1, 2002
Abstr a ct: Nosyloxycarbamates very efficiently aziridinate
optically active R-carbonyl enoates with high levels of
diastereoselectivity under mild conditions and in a straight-
forward process.
All substrates were easily prepared; aziridination
reactions were carried out in dichloromethane at 0 °C.
Calcium oxide and ethyl or tert-butyl nosyloxycarbamate
were added to the solution of the enoates 2-4. The
expected aziridines 5-10 were obtained after flash
chromatography on silica gel, in the yields displayed in
the Table 1.
No significant differences in reactivities were observed
using both carbamates, and all reactions proceeded in
high yields. Moreover, the aziridinations took place with
a very high asymmetric induction using both chiral
auxiliaries, as shown by 1H and 13C NMR and HPLC
analyses.11
Aziridines receive continuous and increasing interest
in organic synthesis2 as they can possess both biological
and pharmacological activities.3 Nevertheless, despite
their importance, the dearth of single-step preparation
methods of aziridines limits their applicative use.
Direct aziridination of alkenes by carbamates has
proved to be a useful reaction.4 We have proposed the
use of ethyl nosyloxycarbamate (NsONHCO2Et, Ns )
4-nitrobenzenesulfonyl) in the presence of inorganic bases
to obtain aziridines starting from different kinds of
substituted alkenes.5
Substrates 2a and 3a were already reported to undergo
asymmetric conjugate nucleophilic addition from the less
hindered prochiral si-face to give 5-alkyl-substituted
derivatives with a high level of diastereoselection.12 On
the basis of these results, we suggest the configuration
(S,S) for the major diastereomers of aziridines 5a -8a .
We also observed a very good diastereoselectivity using
(-)-8-phenylmenthol as the chiral auxiliary. On the other
hand, it has been reported that R,â-unsaturated esters
derived from (-)-8-phenylmenthol gave other conjugate
additions with a low asymmetric induction.13
In conclusion, we believe that this method offers
considerable advantages for the development of a direct
diastereoselective synthesis of chiral substituted aziri-
dines in high yields under very mild conditions and with
operational simplicity.
Recently, we reported a simple and efficient synthesis
of N-protected aziridines, starting from 1,1-dicarbonyl-
substituted olefins using either ethyl or tert-butyl nosy-
loxycarbamate in the presence of calcium oxide.6 More-
over, the stereoselective amination of analogous substrates
by conjugate addition of hydroxylamino reagents in the
presence of Evans’ catalyst7 has been recently reported.8
A variation of this procedure in two steps giving aziri-
* Phone: +39 06 49913673. Fax: +39 06 490631.
(1) Presented in part at the 12th European Symposium on Organic
Chemistry (ESOC 12), Groningen, The Netherlands, J uly 13-18, 2001.
Abstract P2-105.
(2) For reviews, see: (a) Tanner, D. Angew. Chem. 1994, 6, 625-
646; Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619. (b) Osborn, H.
M. I.; Sweeney, J . Tetrahedron: Asymmetry 1997, 8, 1693-1715. (c)
Stamm, H. J . Prakt. Chem. 1999, 4, 319-331. (d) Atkinson, R. S.
Tetrahedron 1999, 55, 1519-1559. (e) Dodd, R. H. Molecules 2000, 5,
293-298. (f) McCoull, W.; Davis, F. A. Synthesis 2000, 10, 1347-1365.
(3) (a) Armstrong, R. W.; Tellew, J . E.; Moran, E. J . Tetrahedron
Lett. 1996, 37, 447-450. (b) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima,
S. Tetrahedron Lett. 1996, 37, 3471-3474. (c) Ngo, E. O.; Nutter, L.
M.; Sura, T.; Gutierrez, P. L. Chem. Res. Toxicol. 1998, 11, 360-368.
(d) Skelly, J . V.; Sanderson M. R.; Suter, D. A.; Baumann, U.; Read,
M. A.; Gregory, D. S. J .; Bennett, M.; Hobbs, S. M.; Neidle, S. J . Med.
Chem. 1999, 42, 4325-4330. (e) Dvorakova, K.; Payne, C. M.; Tome,
M. E.; Briehl, M. M.; McClure, T.; Dorr, R. T. Biochem. Pharmacol.
2000, 60, 749-758. (f) Brown, F. Vaccine 2000, 20, 322-327.
(4) Lwowski, W.; Maricich, T. J . J . Am. Chem. Soc. 1965, 87, 3630-
3637.
Exp er im en ta l Section
Gen er a l. GC analyses were performed on a capillary column
(methyl silicone, 12.5 m × 0.2 mm). GC MS was performed using
a quadrupole mass spectrometer on a capillary column (phenyl
methyl silicone, 30 m × 0.25 mm). IR spectra were recorded on
(9) Cardillo, G.; Gentilucci, L.; Gianotti, M.; Perciaccante, G.;
Tolomelli, A. J . Org. Chem. 2001, 25, 8657-8660.
(10) Helmchen, G.; Wegner, G. Tetrahedron Lett. 1985, 26, 6051-
6054.
(11) A further test using simple (-)-menthol as the chiral auxiliary
gave a very low induction, as nearly equimolar mixtures of both
diastereomeric aziridines were obtained.
(12) (a) Urban, E.; Knu¨hl, G.; Helmchen, G. Tetrahedron Lett. 1995,
36, 7229-7232. (b) Urban, E.; Riehs, G.; Knu¨hl, G. Tetrahedron 1995,
51, 11149-11164.
(13) Kotsuki, H.; Arimura, K.; Ohishi, T.; Maruzasa, R. J . Org.
Chem. 1999, 64, 3770-3773.
(5) (a) Barani, M.; Fioravanti, S.; Loreto, M. A.; Pellacani, L.;
Tardella, P. A. Tetrahedron 1994, 50, 3829-3834. (b) Fioravanti, S.;
Pellacani, L.; Tabanella, S.; Tardella, P. A. Tetrahedron 1998, 54,
14105-14112.
(6) Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A.
Synthesis 2001, 1975-1978.
(7) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.; Tedrow,
J . S. J . Am. Chem. Soc. 2000, 122, 9134-9142.
(8) Cardillo, G.; Gentilucci, L.; Gianotti, M.; Kim, H.; Perciaccante,
G.; Tolomelli, A. Tetrahedron: Asymmetry 2001, 12, 2395-2398.
10.1021/jo025670x CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/16/2002
4972
J . Org. Chem. 2002, 67, 4972-4974

TABLE 1. Azir id in a tion of Op tica lly Active r-Ca r bon yl En oa tes by Nosyloxyca r ba m a tes
1
a FTIR spectrophotometer in CCl4 as the solvent. H NMR and
13C NMR spectra were recorded at 200 or 300 and 50 or 75 MHz,
respectively. CDCl3 was used as the solvent and CHCl3 as the
internal standard. ESI MS analyses were performed using a
triple-quadrupole mass spectrometer equipped with an ESI
source and a syringe pump. The experiments were conducted
in the positive ion mode. HPLC analyses were performed with
an instrument equipped with a differential refractometer, using
an analytical column (3.9 × 300 mm, 80:20 hexane/ethyl acetate,
flow rate 1.3 mL/min). Eluents were HPLC grade. Optical
rotations were recorded at the sodium D line with a polarimeter
at room temperature. NaH (55/65% suspension in mineral oil)
was washed twice with pentane and dried under nitrogen.
Anhydrous THF and toluene were used as such. Substrates 2a ,
2b, and 3a were easily prepared following reported proce-
dures.12,14
Syn th esis of 4b. According to a reported procedure,15 8-phe-
nylmenthyl 2-methyl-3-oxobutanoate16 (0.68 g, 2.0 mmol) was
added slowly to a stirred suspension of NaH (0.07 g, 3.0 mmol)
(14) Pan, L. R.; Tokoroyama, T. Tetrahedron Lett. 1992, 33, 1469-
1472.
(15) Reich, H. J .; Renga, J . M.; Reich, I. L. J . Am. Chem. Soc. 1975,
97, 5434-5447.
(16) Zhang, Q.; Mohan, R. M.; Cook, L.; Kazanis, S.; Peisach, D.;
Foxman, B. M.; Snider, B. B. J . Org. Chem. 1993, 58, 7640-7651.
J . Org. Chem, Vol. 67, No. 14, 2002 4973

in 40 mL of anhydrous THF at 0 °C. After 1 h, a solution of
PhSeCl (0.38 g, 2.0 mmol) in 5 mL of anhydrous THF was added
dropwise. After 30 min, the solution was diluted with diethyl
ether, washed with saturated NaHCO3 and saturated NaCl, and
dried over Na2SO4. The solvents were evaporated under reduced
pressure. The crude mixture was dissolved in 20 mL of CH2Cl2
and stirred with 40% H2O2 (0.6 mL, 8 mmol) for 3 h at 0 °C.
Then, the mixture was washed with saturated NaHCO3 and
saturated NaCl and dried over Na2SO4. After solvent evapora-
tion, 4b was obtained (0.63 g, yield 96%) and used without
further purification: [R]D -21.46 (c 4.8, CHCl3); IR 1715, 1630
7.05-7.20 (m, 1 H), 7.21-7.38 (m, 4 H); 13C NMR δ 19.3, 21.7,
26.4, 27.0, 27.5, 27.9, 31.4, 33.1, 34.3, 40.1, 41.5, 49.6, 50.1, 50.4,
76.5, 82.8, 125.1, 125.6, 127.7, 150.7, 156.0, 163.2, 200.1; ESI
MS m/z 456 (M+ + 1). Anal. Calcd for C27H37NO5: C, 71.18; H,
8.19; N, 3.07. Found: C, 71.14; H, 8.11; N, 3.03.
7a : mp 167-168 °C (pentane/CHCl3); [R]D -22.1 (c 2.9,
CHCl3); IR 1750, 1736, 1721 cm-1; 1H NMR δ 0.52 (s, 3 H), 0.69
(s, 3 H), 0.83 (s, 3 H), 0.98-2.45 (m, 11 H), 1.25 (t, J ) 7.2 Hz,
3 H), 2.02 (s, 3 H), 2.29 (s, 3 H), 3.81 (d, J ) 7.2 Hz, 1 H), 3.89-
3.92 (m, 1 H), 4.18 (q, J ) 7.2 Hz, 2 H), 5.35 (d, J ) 7.2 Hz, 1
H), 5.64-5.73 (br, 1 H), 6.85 (s, 1 H), 7.10-7.53 (m, 6 H); 13C
NMR δ 11.2, 14.1, 17.3, 20.5, 21.0, 21.3, 22.1, 28.0, 32.0, 38.5,
45.2, 46.8, 47.2, 48.4, 50.3, 62.8, 67.0, 82.9, 128.0, 128.7, 129.6,
1
cm-1; H NMR δ 0.64-2.18 (m, 8 H), 0.93 (d, J ) 6.6 Hz, 3 H),
1.26 (s, 3 H), 1.32 (s, 3 H), 2.38 (s, 3 H), 4.83-5.08 (m, 1 H),
5.74 (d, J ) 1.5 Hz, 1 H), 6.15 (d, J ) 1.5 Hz, 1 H), 7.06-7.50
(m, 5 H); 13C NMR δ 21.7, 24.3, 26.4, 28.5, 31.2, 31.9, 34.8, 39.7,
45.4, 54.2, 75.3, 125.2, 125.7, 128.0, 133.6, 140.9, 151.5, 163.5,
196.6; GC MS m/z 328 (M+, <1), 120 (10), 119 (100), 118 (26),
91 (23), 43 (10). Anal. Calcd for C21H28O3: C, 76.79; H, 8.59.
Found: C, 77.01; H, 8.47.
132.7, 136.3, 138.2, 158.1, 164.8, 196.9; ESI MS m/z 623 (M+
1). Anal. Calcd for C34H42N2O7S: C, 65.57; H, 6.80; N, 4.50; S,
5.15. Found: C, 65.63; H, 6.85; N, 4.52; S, 5.22.
+
8a : mp 206-207 °C (pentane/CHCl3); [R]D -27.1 (c 2.1,
CHCl3); IR 1740, 1718, 1708 cm-1; 1H NMR δ 0.52 (s, 3 H), 0.72
(s, 3 H), 0.84 (s, 3 H), 0.98-2.45 (m, 11 H), 1.41 (s, 9 H), 2.02 (s,
3 H), 2.24 (s, 3 H), 3.51-3.64 (m, 1 H), 3.84 (d, J ) 7.2 Hz, 1 H),
5.29 (d, J ) 7.2 Hz, 1 H), 5.63-5.85 (br, 1 H), 6.82 (s, 1 H), 7.10-
7.62 (m, 6 H); 13C NMR δ 11.2, 17.2, 20.7, 21.0, 21.2, 21.3, 27.7,
28.1, 31.6, 37.9, 44.8, 47.2, 47.7, 48.2, 50.3, 66.5, 82.0, 82.5, 128.0,
128.5, 129.4, 132.4, 136.7, 138.1, 156.5, 165.2, 197.0; ESI MS
m/z 651 (M+ + 1). Anal. Calcd for C36H46N2O7S: C, 66.44; H,
7.12; N, 4.30; S, 4.93. Found: C, 66.49; H, 7.15; N, 4.38; S, 5.02.
Typ ica l Exp er im en ta l P r oced u r e of Azir id in a tion . To a
stirred solution of the substrate (2.0 mmol) in 5 mL of CH2Cl2
were added batchwise CaO (6.0 mmol) and NsONHCO2R (3.0
mmol) at 0 °C. The reaction was monitored by TLC until
completion (see Table 1), and then the crude mixture was diluted
with 10 mL of CH2Cl2 and filtered. After solvent evaporation
under reduced pressure, the residue was purified by flash
chromatography on silica gel (70:30 hexane/ethyl acetate).
5a : mp 133-134 °C (pentane/CHCl3); [R]D +72.3 (c 4.8,
CHCl3); IR 1767, 1733, 1723 cm-1; 1H NMR δ 0.52 (s, 3 H), 0.79
(s, 3 H), 0.84 (s, 3 H), 0.94-2.58 (m, 9 H), 1.22 (t, J ) 7.2 Hz, 3
H), 1.97 (s, 3 H), 2.29 (s, 3 H), 3.76 (d, J ) 7.2 Hz, 1 H), 4.11-
4.31 (m, 2 H), 4.29-4.36 (m, 1 H), 5.28 (d, J ) 7.2 Hz, 1 H),
5.56-5.64 (br, 1 H), 6.82 (s, 1 H), 7.02-7.52 (m, 6 H); 13C NMR
δ 11.1, 13.9, 14.2, 19.2, 20.6, 21.0, 27.9, 31.6, 32.7, 47.2, 48.2,
50.1, 50.7, 51.9, 62.9, 67.0, 81.8, 128.1, 129.5, 132.5, 136.6, 138.0,
157.7, 162.6, 200.5; ESI MS m/z 609 (M+ + 1). Anal. Calcd for
9b: bp 169-170 °C (7 mmHg); [R]D +27.4 (c 4.6, CHCl3); IR
1
1747, 1735, 1723 cm-1; H NMR δ 0.75-1.11 (m, 4 H), 0.84 (d,
J ) 6.5 Hz, 3 H), 1.18 (s, 3 H), 1.24 (t, J ) 7.3 Hz, 3 H), 1.30 (s,
3 H), 1.38-1.48 (m, 1 H), 1.55-1.66 (m, 2 H), 1.82-1.87 (m, 1
H, CH), 2.08 (d, J ) 1.3 Hz, 1 H), 2.11 (d, J ) 1.3 Hz, 1 H), 2.30
(s, 3 H), 4.04-4.19 (m, 2 H), 4.94 (dt, J d ) 4.5 Hz, J t ) 10.7 Hz,
1 H), 7.10-7.15 (m, 1 H), 7.22-7.27 (m, 4 H); 13C NMR δ 14.1,
21.6, 25.6, 26.6, 27.4, 28.3, 31.3, 34.2, 36.3, 39.7, 41.3, 49.5, 50.1,
62.9, 77.3, 125.3, 128.0, 151.2, 158.9, 164.9, 199.0; GC MS m/z
415 (M+, 12), 201 (70), 157 (14), 156 (23), 129 (100), 128 (32),
119 (42), 111 (59), 110 (10), 105 (48), 91 (37), 84 (21), 83 (21), 55
(10), 43 (13), 41 (13). Anal. Calcd for C24H33NO5: C, 69.37; H,
8.00; N, 3.37. Found: C, 69.41; H, 8.07; N, 3.40.
C
33H40N2O7S: C, 65.11; H, 6.62; N, 4.60; S, 5.27. Found: C,
65.18; H, 6.69; N, 4.62; S, 5.32.
6a : mp 164-165 °C (pentane/CHCl3); [R]D +100.8 (c 4.9,
1
CHCl3); IR 1766, 1720 cm-1; H NMR δ 0.53 (s, 3 H), 0.79 (s, 3
H), 0.82 (s, 3 H), 1.00-2.58 (m, 9 H), 1.42 (s, 9 H), 1.98 (s, 3 H,),
2.29 (s, 3 H), 3.79 (d, J ) 7.2 Hz, 1 H), 4.22-4.31 (m, 1 H), 5.28
(d, J ) 7.2 Hz, 1 H), 5.52-5.68 (br, 1 H), 6.83 (s, 1 H), 7.26-
7.55 (m, 6 H); 13C NMR δ 10.9, 13.9, 19.1, 20.7, 21.1, 27.7, 28.0,
31.6, 32.9, 47.2, 48.2, 50.1, 51.1, 52.1, 67.0, 81.8, 82.0, 128.2,
129.5, 132.5, 136.8, 137.9, 156.3, 162.9, 200.9; ESI MS m/z 637
(M+ + 1). Anal. Calcd for C35H44N2O7S: C, 66.01; H, 6.96; N,
4.40; S, 5.03. Found: C, 66.12; H, 6.98; N, 4.46; S, 5.10.
10b: bp 193-194 °C (7 mmHg); [R]D +15.7 (c 4.2, CHCl3); IR
1736, 1722 cm-1; 1H NMR δ 0.72-1.75 (m, 6 H), 0.85 (d, J ) 6.6
Hz, 3 H), 1.24 (s, 3 H), 1.34 (s, 3 H), 1.46 (s, 9 H), 1.87-2.08 (m,
2 H), 2.24 (d, J ) 2.2 Hz, 1 H), 2.26 (d, J ) 2.2 Hz, 1 H), 2.34 (s,
3 H), 4.95 (dt, J d ) 4.4 Hz, J t ) 11.0 Hz, 1 H), 7.10-7.20 (m, 1
H), 7.24-7.31 (m, 4 H); 13C NMR δ 21.6, 26.3, 26.8, 27.2, 27.9,
28.6, 31.3, 34.3, 37.0, 40.0, 41.3, 49.6, 50.2, 77.6, 82.4, 125.3,
125.5, 128.1, 150.8, 157.5, 165.3, 199.2; GC MS m/z 342 (M+
-
5b: viscous oil; [R]D -44.8 (c 5.2, CHCl3); IR 1769, 1738 cm-1
;
101, <1), 128 (88), 120 (10), 119 (100), 118 (55), 109 (57), 91
(33), 41 (10). Anal. Calcd for C26H37NO5: C, 70.40; H, 8.41; N,
3.16. Found: C, 70.33; H, 8.34; N, 3.11.
1H NMR δ 0.85 (d, J ) 6.3 Hz, 3 H), 0.95-1.78 (m, 15 H), 1.84-
2.55 (m, 4 H), 2.20-2.38 (m, 2 H), 3.01-3.08 (m, 1 H), 3.95-
4.42 (m, 2 H), 4.95 (dt, J d ) 4.5 Hz, J t ) 10.5 Hz, 1 H), 7.09-
7.20 (m, 1 H), 7.25-7.36 (m, 4 H); 13C NMR δ 14.2, 19.6, 21.7,
26.6, 26.9, 29.7, 31.4, 32.9, 34.4, 40.0, 41.5, 49.8, 49.9, 63.2, 76.6,
125.1, 125.5, 127.8, 150.9, 157.4, 162.7, 200.1; ESI MS m/z 428
(M+ + 1). Anal. Calcd for C25H33NO5: C, 70.23; H, 7.78; N, 3.26.
Found: C, 70.34; H, 7.56; N, 3.30.
Ack n ow led gm en t . This research was carried
out within the framework of the National Project
“Stereoselezione in Sintesi Organica. Metodologie e
Applicazioni”, supported by the Italian Ministero
dell’Istruzione dell’Universita` e della Ricerca (MIUR)
and by the Universita` di Roma “La Sapienza”.
6b: mp 58-59 °C (pentane); [R]D -10.6 (c 5.1, CHCl3); IR 1762,
1
1724 cm-1; H NMR δ 0.84 (d, J ) 6.6 Hz, 3 H), 0.97-1.81 (m,
12 H), 1.42 (s, 9 H), 1.83-2.28 (m, 4 H), 2.27-2.46 (m, 2 H),
3.05-3.23 (m, 1 H), 4.94 (dt, J d ) 4.5 Hz, J t ) 10.5 Hz, 1 H),
J O025670X
4974 J . Org. Chem., Vol. 67, No. 14, 2002