Synthesis of aziridine-2,2-dicarboxylates via 1,4-addition of N,O-(bistrimethylsilyl)hydroxylamine to α,β-unsaturated malonates

Full text of DOI:10.1021/jo015907+

J . Org. Chem. 2001, 66, 8657-8660
8657
jugate addition of N,O-bis(trimethylsilyl)hydroxylamine
(TMSNHOTMS) to alkylidene malonates, to give adducts
2 followed by cyclization (Scheme 1).
Syn th esis of Azir id in e-2,2-d ica r boxyla tes
via 1,4-Ad d ition of
N,O-(Bistr im eth ylsilyl)h yd r oxyla m in e to
r,â-Un sa tu r a ted Ma lon a tes
The procedure, exemplified by the reactions outlined
in Scheme 1, affords aziridine 4 in good yields. The
overall process shows that TMSNHOTMS behaves as a
nitrenoidic polisynthon “(-)NH(+)”, reacting as an equiva-
lent of “HN(-)-OTMS” during the nucleophilic addition
to give adduct 2, and like “HN(+)” electrophilic synthon
during the cyclization to aziridine with the displacement
of the (-)OTMS group.8
Giuliana Cardillo,* Luca Gentilucci, Massimo Gianotti,
Rossana Perciaccante, and Alessandra Tolomelli
Dipartimento di Chimica “G. Ciamician” and C.S.F.M.,
Universita` di Bologna, Via Selmi 2, 40126 Bologna
cardillo@ciam.unibo.it
Received J uly 10, 2001
Resu lts a n d Discu ssion
In tr od u ction
Conjugate addition is an important bond-forming
strategy utilized in organic synthesis. In this field, one
of the most straightforward routes for the carbon-
nitrogen bond formation is the 1,4-addition of nitrogen
nucleophiles to electrophilic olefines.9 Recently Reetz and
co-workers10 reported the enhanced reactivity of substi-
tuted alkylidene malonates toward nucleophilic attack
of silylated hydroxylamine simply by stirring the com-
ponents in CH2Cl2 for 18 h at room temperature and in
the absence of catalyst. Under these simple conditions
we carried out the 1,4-addition of N,O-bis(trimethylsilyl)-
hydroxylamine to a variety of dimethyl malonate olefines.
The electrophilic substrates 1a -e have been prepared
by condensation of dimethyl malonate with aliphatic and
aromatic aldehydes in the presence of TiCl4 and pyridine
in THF.11 After workup in water and extraction with
organic solvent, the R,â-unsaturated products were iso-
lated and purified by distillation or chromatography on
silica gel, in yields ranging from 50% to 75% (Scheme 2).
The subsequent 1,4-addition of N,O-bis(trimethylsilyl)-
hydroxylamine to the olefins 1 was performed in CH2Cl2
with a 2:1 ratio of nucleophile in respect to electrophile.
Compound 2 was obtained exclusively in good yield, with
removal of the N-silyl protection during workup from the
disilylated intermediate (Scheme 3). The results of the
addition reaction of the silylated hydroxylamine to
compounds 1a -e are reported in Table 1.
Aziridines1 are important heterocyclic compounds
present in unusual natural products that display strong
biological activity. Azinomycines A and B, for instance,
isolated from the fermentation broth of Streptomyces
griseofuscus, and (+)-FR900482 from the culture broth
of Streptomyces sandaensis are potent antitumor antibi-
otics that exhibit exceptional activity against various
types of mammalian solid tumors. Mitomycin C is an
aziridine-containing antibiotic, produced by Streptomyces
caespitosus, whose antineoplastic activity is associated
with the high reactivity of the strained aziridine ring.2
Recently novel types of peptidic cysteine protease inhibi-
tors containing aziridine-2,3-dicarboxylic acid have been
designed and synthesized.3 Moreover the synthesis has
been reported of a new peptidelike structure containing
an aziridine ring, to introduce a rigid core inside an
oligopeptide frame.4
One of the most important features in aziridine chem-
istry is their use as starting material for further trans-
formations. Aziridines are indeed useful intermediates
in organic synthesis affording, through SN2 ring-opening
reactions, substituted R- or â-amino acids,5 and through
ring expansion of the amido derivatives, oxazolines as a
protected form of hydroxyamino compounds. Recently
we have utilized chiral aziridines in the synthesis of
antibiotic Lysobactin fragments,6 containing hydroxyami-
no acids in syn and anti configurations. In this context
we reported a new synthesis of chiral trans aziridines in
two steps, addition of O-benzylhydroxylamine to unsat-
urated imides and cyclization through the formation
of an intermediate enolate.7 We wish now to report
the synthesis of aziridine-2,2-dicarboxylates via the con-
In an alternative way the conjugate addition reaction
was carried out in 30 min in CH2Cl2 at -40 °C in the
presence of 3% of Yb(OTf)3. In the presence of a greater
amount of catalyst or when the temperature exceeds 0
°C, decomposition of the adduct takes place, affording the
silyl oxime and dimethylmalonate.
During the step of trimethylsilyl deprotection by treat-
ment of 2 with TBAF (1.1 equiv) in THF at room
temperature, the isoxazolidin-5-one12 3 was isolated
(Scheme 4). The attack of fluoride on silicon indeed
induces the formation of tetrabutylammonium hydroxy-
* Tel. +39 051 2099570. Fax +39 051 2099456.
(1) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619.
(b) McCoull, W.; Davis, F. A. Synthesis 2000, 1347-1365.
(2) (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) Remers, W. A.; Iyengar,
B. C. Antitumor Antibiotics. In Cancer Chemotherapeutic Agents; Foye,
W. O., Ed.; American Chemical Society: Washington, DC, 1995; pp
584-592.
(8) Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J . 2000, 6, 1281-
1286.
(3) Schirmeister, T. Biopolymers 1999, 51, 87-97.
(9) (a) Perlmutter, P. Conjugate Addition Reaction in Organic
Synthesis; Pergamon Press: Oxford, 1992. (b) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033-8061. (c) Leonard, J .; Diez-Barra, E.;
Merino, S. Eur. J . Org. Chem. 1998, 2951-2061. (d) Davies, S. G.;
Ichihara, O. J . Synth. Org. Chem. J pn. 1997, 55, 26-34.
(10) Reetz, M. T.; Rohring, D.; Harms, K.; Frenking, G. Tetrahedron
Lett. 1994, 35, 8765-8768.
(11) (a) Cope, A. C.; Hofmann, C. M.; Wuckoff, C.; Hardenbergh, E.
J . Am. Chem. Soc. 1941, 63, 3452-3456. Lehnert, W. Synthesis 1974,
667-669. (b) Lehnert W. Tetrahedron 1973, 29, 635-638. (c) Lehnert
W. Tetrahedron 1972, 28, 663-666.
(4) Filigheddu, S. N.; Taddei, M. Tetrahedron Lett. 1998, 39, 3857-
3860.
(5) (a) J uaristi, E.; Quintana, D.; Escalante, J . Aldrichimica Acta
1994, 27, 3-11. (b) Konopelski, J . P.; Filonova, L. K.; Olmstead, M.
M. J . Am. Chem. Soc. 1997, 119, 4305-4306.
(6) Armaroli, S.; Cardillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli,
A. Org. Lett. 2000, 2, 1105-1107.
(7) (a) Cardillo, G.; Casolari, S.; Gentilucci, L.; Tomasini, C. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1848-1849. (b) Bongini, A.; Cardillo,
G.; Gentilucci, L.; Tomasini, C. J . Org. Chem. 1997, 62, 9148-9153.
10.1021/jo015907+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/17/2001

8658 J . Org. Chem., Vol. 66, No. 25, 2001
Notes
Sch em e 1
Sch em e 4
Sch em e 5
Sch em e 2
Ta ble 2
Sch em e 3
Ta ble 1
a
Calculated on isolated product, after flash chromatography on
silica gel.
matography on silica gel. On the other hand, compound
3 may be easily obtained by refluxing the R,â-unsaturated
derivative 1 and N,O-bis(trimethylsilyl)hydroxylamine in
methanol.13
The most interesting features of the silylated adducts
2a -d is the conversion to iridine-2,2-dimethyl ester 4.
Compound 2 can be considered a precursor of aziridine
because, close to an easily enolizable position, it presents
a nitrogen carrying a O-SiMe3 function, which was
already observed by Ricci et al.14 to be a good leaving
group (Scheme 5). In this work we developed a new mild
method to prepare aziridine-2,2-dicarboxylate simply by
treatment of adduct 2 with a catalytic amount of potas-
sium tertbutoxide15 (0.25 equiv) in CH2Cl2 at room
temperature for 4 h. The Me3SiOK formed acts as base
to complete the cyclization. When a larger amount of base
was added, a mixture of byproducts was observed. The
results obtained in the cyclization reaction are reported
in Table 2.
a
Calculated on isolated product, after flash chromatography on
silica gel.
All substrates (2a -d ) gave good results and easy
formation of aziridines 4a -d . On the contrary, any
attempt to convert 2e to the corresponding aziridine
lamino salt, which easily promotes the transesterifica-
tion.
The reaction was performed successfully on derivatives
2a , 2c, and 2e, giving the corresponding isooxazolidin-
5-ones in 40-60% yield after purification by flash chro-
(13) Keen, S. P.; Weinreb, S. M. Tetrahedron Lett. 2000, 41, 4307-
4310.
(14) (a) Casarini, A.; Dembech, P.; Lazzari, D.; Marini, E.; Reginato,
G.; Ricci, A.; Seconi, G. J . Org. Chem. 1993, 58, 5620-5623. (b)
Bernardi, P.; Dembech, P.; Fabbri, G.; Ricci, A.; Seconi, G. J . Org.
Chem. 1999, 64, 641-643.
(15) Seko, S.; Tani, N. Tetrahedron Lett. 1998, 39, 8117-8120.
(16) W.; Hansen, T.; J orgensen, K. A. Chem. Commun. 2001, 347-
348.
(12) (a) Baldwin, J . E.; Harwood, L. M.; Lombard, M. J . Tetrahedron
1984, 21, 4363-4370. (b) Baldwin, S. W.; Aube`, J . Tetrahedron Lett.
1987, 28, 179-182. (c) Ishikawa, T.; Nagai, K.; Kudoh, T.; Saito, S.
Synlett 1995, 1171-1173. (d) Sibi, M. P.; Liu, M. Org. Lett. 2000, 2,
3393-3396.

Notes
J . Org. Chem., Vol. 66, No. 25, 2001 8659
1a : IR (film) 2959, 2866, 1734, 1437 cm-1; 1H NMR (CDCl3) δ
1.08 (d, 6H, J ) 6.6 Hz), 2.60-2.73 (m, 1H), 3.76 (s, 3H), 3.80
(s, 3H), 6.85 (d, 1H, J ) 10.8 Hz); 13C NMR (CDCl3) δ 21.7, 29.5,
52.1, 52.2, 125.7, 155.7, 164.3; MS m/z 186 (2), 171 (5), 155 (11),
122 (100), 111 (6), 94 (18), 67 (19), 59 (14). Anal. Calcd: C, 58.05;
H, 7.58. Found: C, 58.03; H, 7.59.
Sch em e 6
1b: IR (film) 2959, 2853, 1739, 1440, 1241 cm-1 1H NMR
;
(CDCl3) δ 0.95 (t, 3H, J ) 7.5 Hz), 1.52 (sext, 2H, J ) 7.5 Hz),
2.28 (q, 2H, J ) 7.5 Hz), 3.78 (s, 3H), 3.83 (s, 3H), 7.04 (t, 1H,
J ) 7.5 Hz); 13C NMR (CDCl3) δ 13.5, 21.5, 31.6, 51.9, 52.0, 127.8,
149.9, 164.0, 165.6; MS m/z 186 (2), 155 (21), 122 (100), 113 (53),
94 (33), 59 (28). Anal. Calcd: C, 58.05; H, 7.58. Found: C, 58.07;
H, 7.61.
1c: IR (film) 2965, 2866, 1746, 1646, 1434 cm-1 1H NMR
;
(CDCl3) δ 0.88 (d, 6H, J ) 6.6 Hz), 1.20-1.41 (m, 8H), 1.42-
1.55 (m, 2H), 2.29 (q, 2H, J ) 4.6 Hz), 3.78 (s, 3H), 3.83 (s, 3H),
7.04 (t, 1H, J ) 4.9 Hz); 13C NMR (CDCl3) δ 22.2, 28.0, 38.5,
52.0, 52.1, 128.4, 149.1, 164.1, 165.7; MS m/z 200 (2), 169 (14),
158 (13), 136 (58), 126 (100), 113 (33), 98 (47), 68 (40), 59 (24).
Anal. Calcd: C, 59.98; H, 8.05. Found: C, 59.95; H, 8.08.
1d : IR (film) 2926, 2952, 1739, 1646, 1428 cm-1 1H NMR
;
failed, although different conditions and several bases
were tested to induce cyclization. In contrast, the decom-
position prevails to give the corresponding phenyl O-silyl
oxime and malonate.
(CDCl3) δ 0.94 (t, 3H, J ) 6.9 Hz), 1.77-1.86 (m, 1H), 2.19 (dd,
2H, J ) 6.9, 7.8 Hz), 3.79 (s, 3H), 3.83 (s, 3H), 7.06 (t, 1H, J )
7.8 Hz); 13C NMR (CDCl3) δ 13.9, 22.5, 28.1, 28.8, 29.0, 29.7,
31.5, 52.0, 52.1, 127.7, 150.3, 164.1, 165.6; MS m/z 201 (3), 186
(11), 169 (30), 141 (100), 126 (45), 112 (38), 99 (69), 68 (60), 55
(34). Anal. Calcd: C, 64.44; H, 9.15. Found: C, 64.41; H, 9.18.
The nitrogen group protection of aziridine 4a was
performed by treatment with benzoyl chloride in CH2Cl2
in the presence of TEA and DMAP. The benzamide 5a ,
obtained in quantitative yield, was analyzed by 1H NMR
and showed a methyl ester resonance at 4.0 ppm and
another one shielded at 3.5 ppm. The amide 5a is a very
stable molecule whose regioselective hydrolysis of the
more shielded methyl ester was achieved by treatment
with 1 equiv of KOH in methanol for 4 days at room
temperature. In the similar way the partial hydrolysis
of 4a was performed by treatment of the unprotected
aziridine in methanol for 12 h in the presence of 1 equiv
of KOH (Scheme 6). The reaction furnished a 1:1 mixture
of monocarboxylic acids.
In conclusion, in this work we have reported the
synthesis of aziridine-2,2-dicarboxylates, which are a new
class of unusual amino acids that can be utilized in the
synthesis of biologically active polipeptides. The design
of receptor-selective peptide containing unusual amino
acids and peptidomimetic ligands with highly potent and
specific biological properties has become indeed one of
the most important areas in bioorganic and medicinal
chemistry.
1e: IR (film) 2998, 2946, 1732, 1620, 1427 cm-1 1H NMR
;
(CDCl3) 3.86 (s, 6H), 7.38-7.45 (m, 5H), 7.79 (s, 1H); 13C NMR
(CDCl3) δ 52.7, 125.4, 128.8, 129.3, 130.6, 132.6, 142.8, 164.3,
167.0; MS m/z 220 (56), 189 (54), 160 (83), 129 (39), 121 (100),
102 (72), 91 (22), 59 (27). Anal. Calcd: C, 65.45; H, 5.49. Found:
C, 65.46; H, 5.47.
Gen er a l P r oced u r e for th e 1,4-Ad d ition of N,O-Bis-
(tr im eth ylsilyl)h yd r oxyla m in e to 1. A stirred solution of 1
(2 mmol) in CH2Cl2 (10 mL) at -40 °C under inert atmosphere
was treated with Yb(Otf)3 (0.04 mmol, 21 mg). After 10 min N,O-
bis(trimethylsilyl)hydroxylamine was added in one portion (4
mmol, 0.85 mL). The reaction was monitored by TLC and
quenched with HCl 0.1 M (1 mL) after 30 min. The organic layer
was diluted with 20 mL of CH2Cl2, washed with water, and dried
over Na2SO4, and solvent was removed under reduced pressure.
Compound 2 was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate, 1:1 as eluant).
2a : IR (film) 3277, 2959, 1739, 1441 cm-1; 1H NMR (CDCl3) δ
0.13 (s, 9H), 0.97 (d, 3H, J ) 6.6 Hz), 1.03 (d, 3H, J ) 6.6 Hz),
1.57-1.74 (m, 1H), 3.34 (dd, 1H, J ) 4.2, 7.7 Hz), 3.61 (d, 1H, J
) 4.2 Hz), 3.73 (s, 3H), 3.77 (s, 3H), 6.01-6.18 (bs, 1H); 13C NMR
(CDCl3) δ -1.0, 19.7, 20.3, 29.2, 50.8, 52.1, 52.2, 68.3, 169.1,
169.6. Anal. Calcd: C, 49.46; H, 8.65; N, 4.81. Found: C, 49.48;
H, 8.62; N, 4.79.
2b: IR (film) 3250, 2939, 1733, 1434, 1242 cm-1 1H NMR
;
(CDCl3) δ 0.11 (s, 9H), 0.92 (t, 3H, J ) 6.6 Hz), 1.26-1.58 (m,
4H), 3.36-3.47 (bm, 1H), 3.74 (s, 3H), 3.76 (s, 3H), 3.80 (d, 1H,
J ) 4.8 Hz), 5.66-5.80 (bs, 1H); 13C NMR (CDCl3) δ -0.9, 14.0,
20.0, 31.9, 52.0, 52.2, 62.1, 169.1. Anal. Calcd: C, 49.46; H, 8.65;
N, 4.81. Found: C, 49.45; H, 8.63; N, 4.82.
Ack n ow led gm en t. We thank MURST (Cofin 2000
and 60%) and the University of Bologna (funds for
selected topics) for financial support. We thank C.I.N-
.M.P.I.S. (Consorzio Interuniversitario Nazionale Metod-
ologie e Processi Innovativi di Sintesi) for the fellowship
to Dott.ssa. Perciaccante.
2c: IR (film) 3283, 2959, 1745, 1447, 1241 cm-1 1H NMR
;
(CDCl3) δ 0.12 (s, 9H), 0.91 (d, 3H, J ) 6.6 Hz), 0.92 (d, 3H, J )
6.6 Hz), 1.17 (ddd, 1H, J ) 4.2, 9.1, 13.7 Hz), 1.38 (ddd, 1H, J )
4.6, 9.1, 13.7 Hz), 1.73-1.87 (m, 1H), 3.50 (dt, 1H, J ) 4.5, 9.1
Hz), 3.74 (s, 3H), 3.76 (s, 3H), 3.82 (d, 1H, J ) 4.5 Hz), 5.50-
5.90 (bs, 1H); 13C NMR (CDCl3) δ -0.9, 21.9, 23.3, 25.2, 38.9,
52.0, 52.2, 60.3, 169.0, 169.1. Anal. Calcd: C, 51.12; H, 8.91; N,
4.59. Found: C, 51.11; H, 8.93; N, 4.61.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Syn th esis of 1. To a chilled
solution (0 °C) of TiCl4 (20 mmol, 2.2. mL) in THF (15 mL) under
nitrogen atmosphere were added dimethylmalonate (10 mmol,
1.14 mL) and aldehyde (10 mmol). After 40 min of stirring,
pyridine (40 mmol, 3.23 mL) was added, and the reaction
mixture was allowed to stir overnight, slowly warming to room
temperature. The reaction was then quenched with a saturated
solution of NaHCO3 (2 mL), and after removal of THF under
reduced pressure, the residue was extracted twice with ethyl
acetate. The organic layers were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. Compound
1 was isolated by flash chromatography on silica gel (cyclohex-
ane/ethyl acetate, 9/1) or distilled from the crude reaction
mixture by bulb to bulb distillation.
2d : IR (film) 3462, 3277, 2959, 1739, 1427 cm-1 1H NMR
;
(CDCl3) δ 0.11 (s, 9H), 0.88 (t, 3H, J ) 6.8 Hz), 1.22-1.35 (m,
8H), 1.36-1.46 (m, 2H), 3.38-3.43 (m, 1H), 3.74 (s, 3H), 3.76
(s, 3H), 3.79 (d, 1H, J ) 4.8 Hz), 5.71-5.79 (bs, 1H); 13C NMR
(CDCl3) δ -0.9, 14.1, 22.6, 26.8, 29.2, 29.5, 29.7, 31.8, 52.0, 52.3,
62.3, 169.1. Anal. Calcd: C, 55.30; H, 9.57; N, 4.03. Found: C,
55.32; H, 9.60; N, 4.05.
;
2e: IR (film) 3277, 3032, 2959, 1746, 1434 cm-1 1H NMR
(CDCl3) δ 0.04 (s, 9H), 3.52 (s, 3H), 3.76 (s, 3H), 3.99 (d, 1H, J
) 8.6 Hz), 4.66 (d, 1H, J ) 8.6 Hz), 5.87-5.98 (bs, 1H), 7.25-
7.31 (m, 5H); 13C NMR (CDCl3) δ -1.1, 52.3, 52.5, 54.7, 65.8,

8660 J . Org. Chem., Vol. 66, No. 25, 2001
Notes
127.9, 128.1, 128.2, 137.4, 167.6, 168.4. Anal. Calcd: C, 55.36;
H, 7.12; N, 4.30. Found: C, 55.38; H, 7.13; N, 4.26.
200(93), 156(26), 140(67), 112(76), 96(100). Anal. Calcd: C, 55.80;
H, 7.96; N, 6.51. Found: C, 55.82; H, 7.95; N, 6.50.
4d : IR (film) 3291, 2952, 2846, 1733, 1448 cm-1 1H NMR
;
Gen er a l P r oced u r e for th e Rin g Closu r e of 2 to Isox-
a zolid in -5-on e 3. Adduct 2 (1 mmol) was dissolved in dry THF
(5 mL) under nitrogen atmosphere, and tetrabutylammonium
fluoride (1.1 mmol, 0.287 g) was added in one portion at 0 °C.
The reaction was vigorously stirred for 1 h and then quenched
with water. After THF was removed under reduced pressure,
the residue was diluted with Et2O and washed twice with water.
The organic layers were dried over Na2SO4, and solvent was
removed under reduced pressure. Isoxazolidin-5-one 3 was
isolated by flash chromatography on silica gel (cyclohexane/Et2O,
7/3 as eluant).
(CDCl3) δ 0.81-0.92 (m, 3H), 1.12-1.37 (m, 10H), 1.38-1.40 (m,
2H), 1.98 (d, 1H, J ) 9.6 Hz), 2.51-2.59 (m, 1H), 3.79 (s, 6H);
13C NMR (CDCl3) δ 14.1, 22.7, 27.2, 29.2, 29.3, 30.5, 31.7, 45.0,
45.3, 52.8, 53.6, 167.1, 170.0; MS m/z 257 (2), 198(26), 173 (59),
138 (16), 114 (100), 69(23). Anal. Calcd: C, 60.68; H, 9.01; N,
5.44. Found: C, 60.64; H, 8.98; N, 5.47.
Syn th esis of N-Ben zoyl-a zir id in e 5a . Benzoyl chloride (1.1.
mmol, 0.127 mL) in CH2Cl2 (5 mL) was added dropwise to a
stirred solution of aziridine 4a (1 mmol) and TEA (1.2 mmol,
0.167 mL) in CH2Cl2 (5 mL). The reaction was left stirring for 2
h and then quenched with water. After diluting with 20 mL of
CH2Cl2 and washing with water, the organic layer was dried
over Na2SO4, and solvent was removed under reduced pressure.
Compound 5a was obtained in 97% yield after flash chromatog-
raphy on silica gel as a white solid (cyclohexane/Et2O, 8/2)
3a : IR (film) 3244, 2964, 1786, 1741, 1438, 1270, 1164 cm-1
;
1H NMR (CDCl3) δ 0.98 (d, 3H, J ) 6.6 Hz), 1.02 (d, 3H, J ) 6.6
Hz), 1.80-1.93 (m, 1H), 3.52 (d, 1H, J ) 6.3 Hz), 3.82-3.84(m,
1H), 3.83 (s, 3H); 13C NMR (CDCl3) δ 18.6, 18.8, 31.0, 51.5, 53.3,
68.5, 167.1, 173.0; MS m/z 187 (2), 144 (100), 128 (11), 112 (41),
111 (44), 101 (31), 59 (44). Anal. Calcd: C, 51.33; H, 7.00; N,
7.48. Found: C, 51.35; H, 6.99; N, 7.49.
5a : mp 81-84 °C; IR (film) 3059, 2972, 1739, 1693, 1428, 1242
1
cm-1; H NMR (CDCl3) δ 1.10 (d, 3H, J ) 6.6 Hz), 1.23 (d, 3H,
3c: IR (film) 3231, 2952, 2926, 1786, 1733, 1448 cm-1; 1H NMR
(CDCl3) δ 0.96 (d, 3H, J ) 6.6 Hz), 0.97 (d, 3H, J ) 6.6 Hz),
1.40-1.69 (m, 2H),1.70-1.81 (m, 1H), 3.41 (d, 1H, J ) 6.6 Hz),
3.85 (s, 3H), 4.05-4.28 (m, 1H); 13C NMR (CDCl3) δ_22.3, 22.7,
25.1, 41.2, 53.4, 53.7, 61.5, 166.7, 173.0; MS m/z 201 (2), 169
(11), 144 (41), 116 (64), 101 (100), 69 (59), 59 (72). Anal. Calcd:
C, 53.72; H, 7.51; N, 6.96. Found: C, 53.69; H, 7.52; N, 6.96.
J ) 6.3 Hz), 1.30-1.41 (m, 1H), 3.14 (d, 1H, J ) 9.6 Hz), 3.34
(s, 3H), 3.94 (s, 3H), 7.38-7.60 (m, 3H), 8.10-8.14 (m, 2H); 13
C
NMR (CDCl3) δ 18.8, 20.8, 29.7, 52.7, 52.9, 53.0, 128.3, 128.6,
130.0, 132.9, 165.0, 165.3, 175.6; MS m/z 305 (6), 290 (11), 200
(13), 105 (100), 77 (33). Anal. Calcd: C, 62.94; H, 6.27; N, 4.59.
Found: C, 62.92; H, 6.26; N, 4.59.
3e: IR (film) 3244, 3025, 2946, 1786, 1733, 1282, 1143 cm-1
;
P a r tia l Hyd r olysis of Azir id in e 5a . To a stirred solution
of aziridine 5a (0.5 mmol, 150 mg) in MeOH (5 mL) at room
temperature was added KOH (1 equiv, 2 mL of 0.25 M solution
in MeOH) in one portion. The mixture was left stirring at room
temperature for 4 days and quenched with diluted HCl, and then
solvent was removed under reduced pressure. The residue was
diluted with EtOAc and washed twice with water. The organic
layer was dried over Na2SO4, and solvent was removed under
reduced pressure to give aziridine 6a in 81% yield.
1H NMR (CDCl3) δ 3.85 (s, 3H), 3.91 (d, 1H, J ) 8.4 Hz), 5.28
(dd, 1H, J ) 8.4, 8.8 Hz), 7.38-7.49 (m, 6H); 13C NMR (CDCl3)
δ 53.5, 54.4, 65.7, 126.6, 129.2, 130.6, 166.1, 172.2; MS m/z 221
(1), 177 (71), 162 (6), 146 (100), 119 (36), 104 (41), 91 (24). Anal.
Calcd: C, 59.73; H, 5.01; N, 6.33. Found: C, 59.75; H, 5.01; N,
6.34.
Gen er a l P r oced u r e for th e Rin g Closu r e of 2 to Azir i-
d in e 4. To a stirred solution of 2 (1 mmol) in dry CH2Cl2 at room
temperature under nitrogen atmosphere was added tBuOK (0.25
mmol, 0.25 mL, solution 1 M in THF) in one portion. After 4 h
of stirring, the reaction was quenched with water, extracted
twice with CH2Cl2, and dried over Na2SO4, and solvent was
removed under reduced pressure. Aziridine 4 was isolated by
flash chromatography on silica gel (cyclohexane/diethyl ether,
7:3 as eluant).
6a : IR (film) 3131, 2965, 1752, 1706, 1283 cm-1 1H NMR
;
(CDCl3) δ 1.09 (d, 3H, J ) 6.6 Hz), 1.21 (d, 3H, J ) 6.6 Hz),
1.31-1.51 (m, 1H), 3.07 (d, 1H, J ) 9.02 Hz), 3.94 (s, 3H), 6.51-
6.82 (bs, 1H), 7.35-7.51 (m, 3H), 8.04-8.11 (m, 2H); 13C NMR
(CDCl3) δ 18.6, 20.6, 29.7, 52.6, 52.9, 53.2, 128.2, 128.5, 132.7,
133.6, 165.6, 167.3, 175.8; MS m/z 291 (2), 248 (7), 142 (4), 105
(100), 77 (24). Anal. Calcd: C, 61.85; H, 5.88; N, 4.81. Found:
C, 61.88; H, 5.86; N, 4.82.
4a : IR (film) 3297, 2959, 2859, 1739, 1441 cm-1 1H NMR
;
(CDCl3) δ 0.88-1.28 (m, 7H), 1.98 (d, 1H, J ) 9.6 Hz), 2.28-
2.37 (m, 1H), 3.82 (s, 6H); 13C NMR (CDCl3) δ 19.2, 20.7, 30.2,
45.9, 51.4, 52.5, 53.4, 166.3, 169.8; MS m/z 201 (7), 186 (6), 169
(1), 142 (100), 132 (36), 100 (19), 82 (94), 55 (52). Anal. Calcd:
C, 53.72; H, 7.51; N, 6.96. Found: C, 53.70; H, 7.53; N, 6.97.
P a r tia l Hyd r olysis of Azir id in e 4a . To a stirred solution
of aziridine 4a (0.5 mmol, 100 mg) in MeOH (5 mL) at room
temperature was added KOH (1 equiv, 2 mL of 0.25 M solution
in MeOH) in one portion. The mixture was left stirring at room
temperature for 12 h and quenched with diluted HCl, and then
solvent was removed under reduced pressure. The residue was
diluted with EtOAc and washed twice with water. The organic
layer was dried over Na2SO4, and solvent was removed under
reduced pressure to give aziridine 7a in 78% yield as a white
solid.
4b: IR (film) 3277, 2965, 2906, 1733, 1441 cm-1 1H NMR
;
(CDCl3) δ 0.95 (t, 3H, J ) 7.1 Hz), 1.49-1.57 (m, 4H), 2.02 (bd,
1H, J ) 9.0 Hz), 2.52-2.68 (m, 1H), 3.81 (s, 3H), 3.82 (s, 3H);
13C NMR (CDCl3) δ 13.8, 20.5, 29.7, 32.1, 44.8, 52.8, 53.4, 164.9,
166.7; MS m/z 201 (3), 186 (11), 169 (30), 141 (100), 126 (45),
112 (38), 99 (69), 68 (60), 55 (34). Anal. Calcd: C, 53.72; H, 7.51;
N, 6.96. Found: C, 53.73; H, 7.52; N, 6.94.
7a : mp 114-116 °C; IR (film) 3423, 2972, 1746, 1640, 1361
1
cm-1; H NMR (CDCl3) δ 0.96 (d, 3H, J ) 6.8 Hz), 1.15 (d, 3H,
4c: IR (film) 3291, 2952, 2873, 1726, 1434 cm-1 1H NMR
;
J ) 6.6 Hz), 1.40-1.60 (m, 1H), 2.44 (d, 1H, J ) 9.4 Hz), 3.92
(s, 3H), 5.35-5.81 (bs, 1H); 13C NMR (CDCl3) δ 19.4, 20.9, 29.2,
52.9, 53.4, 54.3, 170.1, 170.7. Anal. Calcd: C, 51.33; H, 7.00; N,
7.48. Found: C, 51.28; H, 6.98; N, 7.50.
(CDCl3) δ 0.96 (d, 3H, J ) 6.6 Hz), 0.98 (d, 3H, J ) 6.6 Hz),
0.98-1.20 (m, 1H), 1.52 (ddd, 1H, J ) 4.2, 6.9, 13.8 Hz), 1.77-
1.88 (m, 1H), 2.03 (bd, 1H, J ) 9.6 Hz), 2.62 (dt, 1H, J ) 4.2,
9.6 Hz), 3.81 (s, 3H), 3.82 (s, 3H); 13C NMR (CDCl3) δ 22.3, 22.5,
27.1, 38.6, 43.7, 44.9, 52.8, 53.4, 166.8, 169.8; MS m/z 215(1),
J O015907+