Cremonesi et al.
JOCArticle
(d, J = 15.2, 1H, CH2Ph); 4.29 (q, J = 7.0, 2H, COOCH2CH3);
4.31 (m, 1H, H-3a0); 4.77 (d, J = 15.2, 1H, CH2Ph); 4.81 (s, 1H,
H-4); 4.81 (d, J = 12.6, 1H, CH2Ph(Cbz)); 4.91 (d, J = 12.6, 1H,
CH2Ph(Cbz)); 5.75 (d, J = 8.9, 1H, H-6a0); 7.22-7.38 (m, 15H,
Ph). 13C NMR (DMSO-d6) shows the presence of two rotamers:
δ 13.8 (COOCH2CH3); 44.5 (CH2Ph); 47.8, 48.8 (C-3a0);
49.5, 50.2 (CH2Ph); 61.7 (COOCH2CH3); 65.9, 66.1 (C-4);
66.8 (CH2Ph(Cbz)); 82.1 (C-3); 91.9, 93.2 (C-6a0); 126.1-
135.7 (Ph); 152.5, 152.9 (COOCH2Ph, COOCH2CH3); 159.4
7.10-7.37 (m, 15H, Ph). 13C NMR shows the presence of two
rotamers: δ 45.0, 45.7 (C-40); 49.6, 50.1 (CH2Ph); 57.0, 57.4 (C-
4); 60.4, 61.3 (C-50); 63.3, 63.6 (C-10); 66.8, 67.7 (CH2Ph(Cbz));
77.8, 78.5 (C-3); 126.5-136.0 (Ph); 153.8 (COOCH2Ph), 168.4
(C-2). IR (neat): 1716 (νCO, NCOOCH2Ph), 1763 (νCO, NCO).
MS-FABþ (m/z) 463 [M þ Na]þ, 441 [M þ H]þ. Anal. Calcd for
C27H24N2O4: C, 73.62; H, 5.49; N, 6.36. Found: C, 73.51; H
5.60; N, 6.39.
(3R,4R)-2-Benzyl-7,8-dihydroxy-1-oxo-3-phenyl-2,5-diazasp-
iro[3.4]octane-5-carboxylic Acid Benzyl Ester (12). 4-Methyl-
morpholine N-oxide (NMO) (0.11 g, 0.94 mmol) and OsO4
(2.5% w/w solution in t-BuOH, 20 mol %, 1.58 mL, 0.13 mmol)
were added to a solution of 5a (0.27 g, 0.68 mmol) in an acetone/
water 10:1 mixture (20 mL). The mixture was stirred at room
temperature for 40 h. The solvent was removed under reduced
pressure, and the residue was taken up with AcOEt (10 mL) and
washed with 5% aq HCl and saturated Na2S2O3 solution. The
organic layer was dried (Na2SO4), and the solvent was removed
under reduced pressure. The crude products were purified by
column chromatography (SiO2, n-hexane/AcOEt = 25:75) to
afford a colorless oil (0.26 g, 85%, inseparable mixture of two
diastereoisomers with a ratio = 83:17 determined by NMR). 1H
NMR (DMSO-d6, T = 120 °C): major diastereoisomer δ 3.22
(dd, J = 10.3, 6.9, 1H, H-6); 3.32 (dd, J = 10.3, 7.2, 1H, H-6);
4.20 (d, J = 15.4, 1H, CH2Ph); 4.22 (m, 1H, H-7); 4.35 (t, J =
4.2, 1H, H-8); 4.46 (m, 2H, OH); 4.55 (s, 1H, H-3); 4.75 (d, J =
15.4, 1H, CH2Ph); 4.77 (d, J = 12.4, 1H, CH2Ph(Cbz)); 4.92 (d,
J = 12.4, 1H, CH2Ph(Cbz)); 7.16-7.34 (m, 15H, Ph); minor
diastereoisomer δ 5.07 (s, 1H, H-3).13C NMR shows the pre-
sence of two rotamers: major diastereoisomer δ 45.5, 45.6 (C-6);
51.6, 52.2 (CH2Ph); 66.4, 66.9 (C-3); 67.3, 68.3 (CH2Ph(Cbz));
69.5, 70.1 (C-7); 76.9, 78.1 (C-8); 81.0 (C-4); 127.2-136.8
(Ph); 154.8 (COOCH2Ph); 167.4 (C-1); minor diastereoisomer
δ 45.8 (C-6); 52.9, 53.2 (CH2Ph); 62.5, 63.8 (C-3); 67.1, 68.1
(CH2Ph(Cbz)); 69.0, 69.9 (C-7); 73.6, 74.6 (C-8); 80.4 (C-4);
127.2-136.8 (Ph). IR (Nujol): 1707 (νCO, NCOOCH2Ph), 1750
(νCO, NCO). MS-ESI (m/z): 481 [M þ Na]þ. Anal. Calcd for
C27H26N2O5: C, 70.73; H, 5.72; N, 6.11. Found: C, 70.60; H
5.66; N, 6.25.
(3R,4R)-1-Benzyl-3-formyl-2-oxo-4-phenylazetidin-3-yl(2-oxo-
ethyl)carbamic Acid Benzyl Ester (13). NaIO4 (0.16 g, 0.77
mmol) and OsO4 (2.5% w/w solution in t-BuOH, 5 mol %,
188 μL, 0.015 mmol) were added to a solution of 5a (0.13 g,
0.31 mmol) in an acetone/water 5:1 mixture (6 mL). The mixture
was stirred at room temperature for 46 h. The solvent was
removed under reduced pressure, and the residue was taken
up with CH2Cl2 (10 mL). The organic layer was washed with
brine and dried (Na2SO4), and the solvent was removed under
reduced pressure to afford a colorless amorphous solid (0.14 g,
98%). [R]20D = þ35.1 (c 1.41, CHCl3). 1H NMR (C6D6) shows
the presence of two rotamers: δ major rotamer 3.57 (d, J =
15.0, 1H, CH2CHO); 3.91 (d, J = 18.6, 1H, CH2Ph); 4.32 (d, J =
18.6, 1H, CH2Ph); 4.44 (d, J = 12.2, 1H, CH2Ph(Cbz)); 4.56 (d,
J = 15.0, 1H, CH2CHO); 4.68 (d, J = 12.2, 1H, CH2Ph(Cbz));
5.29 (s, 1H, H-4); 6.60-7.05 (m, 15H, Ph); 8.96 (s, 1H, CHO);
9.90 (s, 1H, CHO); minor rotamer 3.47 (d, J = 15.0, 1H,
CH2CHO); 3.83 (d, J = 18.2, 1H, CH2Ph); 4.40 (d, J = 18.2,
1H, CH2Ph); 4.50 (d, J = 12.1, 1H, CH2Ph(Cbz)); 4.58 (d, J =
15.0, 1H, CH2CHO); 4.60 (d, J = 12.1, 1H, CH2Ph(Cbz)); 4.96
(s, 1H, H-4); 6.60-7.05 (m, 15H, Ph); 9.41 (s, 1H, CHO); 9.93
(s, 1H, CHO). 13C NMR shows the presence of two rotamers:
δ 44.9, 45.2 (CH2Ph); 56.5, 56.8 (CH2CHO); 62.2, 62.7 (C-4);
68.2, 68.7 (CH2Ph(Cbz)); 84.5 (C-3); 127.8-129.3, (Ph); 155.0
(COOCH2Ph); 161.4 (C-2); 193.5, 194.6 (CHO); 195.9, 196.1
(C-2). IR (Nujol): 1654 (νCO, COOCH2CH3); 1714 (νCO
,
NCOOCH2Ph), 1764 (νCO, NCO). MS-FABþ (m/z): 540 [M þ
H]þ. Anal. Calcd for C31H29N3O6: C, 69.00; H, 5.42; N, 7.79.
Found: C, 68.90; H 5.39; N, 7.68.
(3R,3a0S,4S,6a0R)-1-Benzyl-2-oxo-4-phenyl-60,6a0-dihydrosp-
iro[azetidine-3,40-pyrrolo[3,4-d]isoxazole]-30,50(3a0H)-dicarboxylic
Acid 50-Benzyl 30-Ethyl Ester (80). From 50a and ethyl R-nitro-
acetate (17%). [R]20D = þ187.3 (c 0.65, CH2Cl2).
(3S,3a0S,4S,6a0R)-1-Benzyl-2-oxo-4-phenyl-3a0,6a0-dihydros-
piro[azetidine-3,60-pyrrolo[3,4-d]isoxazole]-30,50(40H)-dicarboxylic
Acid 50-Benzyl 30-Ethyl Ester (90). From 50a and ethyl R-nitro-
acetate (12%). [R]20D = -38.1 (c 0.74, CH2Cl2).
(1R,2S,40R,5S,6R)-10-Benzyl-20-oxo-40-phenyl-3H-spiro[3-aza-
bicyclo[3.1.0]hexane]-2,30-azetidine]-3,6-dicarboxylic Acid 3-Benzyl
6-Ethyl Ester (10). (CuOTf)2C6H6 (5.8 mg, 0.011 mmol) was
added to a solution of 5a (0.10 g, 0.23 mmol) in dry CH2Cl2
(1.5 mL) under nitrogen atmosphere. The mixture was heated at
40 °C, and then ethyl diazoacetate (EDA) (0.11 mL, 0.92 mmol)
was dropped in during 7 h. After 24 h, other (CuOTf)2C6H6
(5.8 mg, 0.011 mmol) was added, and a second amount of ethyl
diazoacetate (EDA) (0.11 mL, 0.92 mmol) was dropped in
during 3 h. The mixture was heated at reflux for a total of
48 h. The solvent was then removed under reduced pressure, and
the crude product was purified by means of column chro-
matography (SiO2, toluene/AcOEt = 90/10). The product was
recrystallized from i-Pr2O/n-hexane to afford a colorless solid
(0.09 g, 79%): mp 126-9 °C; [R]20D = -84.5 (c 1.025, CHCl3).
1H NMR (DMSO-d6, T = 120 °C): δ 1.22 (t, J = 7.0, 3H,
COOCH2CH3); 1.82 (t, J = 3.1, 1H, H-6); 2.16 (m, 1H, H-5);
2.50 (dd, J = 7.1, 3.0, 1H, H-1); 3.20 (dd, J = 11.1, 4.0, 1H,
H-4); 3.63 (d, J = 11.1, 1H, H-4); 4.15 (q, J = 7.0, 2H,
COOCH2CH3); 4.32 (d, J = 15.1, 1H, CH2Ph); 4.70 (d, J =
15.1, 1H, CH2Ph); 4.72 (d, J = 12.6, 1H, CH2Ph(Cbz)); 4.87 (d,
J = 12.6, 1H, CH2Ph(Cbz)); 4.89 (s, 1H, H-40); 7.16-7.37 (m,
15H, Ph). 13C NMR shows the presence of two rotamers: δ 14.0
(C-6); 22.0, 22.7 (COOCH2CH3); 30.9, 32.2 (C-5); 45.1
(CH2Ph); 48.9, 49.4 (C-4); 60.5 (COOCH2CH3); 65.7,66.5
(CH2Ph(Cbz)); 68.1, 68.4 (C-40); 78.2, 78.9 (C-2); 126.5-135.9
(Ph); 151.7, 152.8 (COOCH2Ph, COOCH2CH3); 170.9 (C-20).
IR (Nujol): 1717 (νCO, NCOOCH2Ph), 1766 (νCO, NCO). MS-
FABþ (m/z): 533 [M þ Na]þ, 511 [M þ H]þ. Anal. Calcd for
C31H30N2O5: C, 72.92; H, 5.92; N, 5.49. Found: C, 72.76; H
5.92; N, 5.39.
(10R,20R,4R,50S)-1-Benzyl-2-oxo-4-phenyl-30H-spiro[azetidine-
3,20-[6]oxa[3]azabicyclo[3.1.0]hexane]-30-carboxylic Acid Benzyl
Ester (11). A solution of m-chloroperbenzoic acid (m-CPBA)
(0.14 g, 1.06 mmol, purity e77%) in dry CH2Cl2 (4 mL) was
dropped into a solution of 5a (0.15 g, 0.35 mmol) in dry CH2Cl2
(1.5 mL) heated at 40 °C during 4 h under nitrogen atmosphere
for 24 h. The mixture was cooled and washed with 5% aq
NaHCO3. The organic layer was dried (Na2SO4), and the solvent
was removed under reduced pressure. The crude product was
purified by column chromatography (SiO2, toluene/AcOEt =
90:10) to afford a colorless oil (0.12 g, 75%). [R]20D = -166.7 (c
0.72, CHCl3). 1H NMR (DMSO-d6, T = 120 °C): δ 3.50 (d, J =
12.7, 1H, H-40); 3.72 (dd, J = 12.7, 2.4, 1H, H-40); 4.09 (m, 1H,
H-50); 4.22 (d, J = 3.1, 1H, H-10); 4.41 (d, J = 15.1, 1H, CH2Ph);
4.84 (d, J = 15.1, 1H, CH2Ph); 4.84 (d, J = 12.8, 1H, CH2Ph-
(Cbz)); 4.85 (d, J = 12.8, 1H, CH2Ph(Cbz)); 4.91 (s, 1H, H-4);
(CHO). IR (nujol): 1726 (νCO, NCOOCH2Ph), 1769 (νCO
,
NCO). MS-EIþ (m/z): 456 (Mþ). Anal. Calcd for C27H24-
N2O5: C, 71.04; H, 5.30; N, 6.14. Found: C, 71.10; H 5.22; N,
6.24.
2016 J. Org. Chem. Vol. 75, No. 6, 2010