1,2-dihydrobenzocyclobutene 19. PLC Purification [diethyl
ether–hexane (1:4)] gave compound 19 (0.1 g, 83%), bp
140 ЊC/2 mmHg (lit.,24 105–110 ЊC/0.4 mmHg); δH (300 MHz)
2.04 (6H, s, OCOMe), 6.12 (2H, s, 1-H and 2-H) and 7.22–7.32
(4H, m, ArH).
Diacetate 19 (0.16 g, 0.73 mmol) was subjected to oxidative
cleavage (RuO2–NaIO4) using a similar procedure to that
described for compound 18. Purification of the product by
PLC [diethyl ether–hexane (2:3)] gave meso-dimethyl 2,3-
diacetoxysuccinate 23 (0.15 g, 79%), mp 97–99 ЊC (from
MeOH) (Found: C, 45.6; H, 5.4. C10H14O8 requires C, 45.8; H,
5.4%); δH (500 MHz) 2.19 (6H, s, O2CMe), 3.84 (6H, s, CO2Me)
and 5.67 (2H, s, 2-H, 3-H). Compound 23 was found to be
spectrally and chromatographically indistinguishable from an
authentic sample of meso-dimethyl 2,3-diacetoxysuccinate.
ated off and the resulting crude product was purified by
PLC (EtOAc) to give (10R,11S)-10,11-dihydroxy-2-phenyl-
2,3,5,7,8,8a-hexahydro-1H-5,8a-ethanocyclobuta[c][1,2,4]tri-
azolo[1,2-a]pyridazine-1,3-dione 28 (0.03 g, 66%), mp 171–
172 ЊC (CHCl3–hexane); [α]D ϩ2 (pyridine) (Found: C, 60.9; H,
4.5; N, 13.3. C16H15N3O4 requires C, 61.3; H, 4.8; N, 13.4%);
δH (300 MHz) 2.70 (1H, m, 8-H), 2.87 (1H, m, 8-H), 3.10 (1H,
m, 7-H), 3.25 (1H, m, 7-H), 3.92 (1H, dd, J11,10 8.2, J11,5 2.2, 11-
H), 4.03 (1H, d, J10,11 8.2, 10-H), 4.88 (1H, dd, J5,11 2.2, J5,6 5.6,
5-H), 5.99 (1H, d, J6,5 5.6, 6-H) and 7.26–7.47 (5H, m, Ar-H);
m/z 313 (Mϩ, 20%) and 253 (100).
Conversion of compound 28 to (10R,11S)-10,11-di-[(R)-
methoxytrifluoromethylphenylacetoxy]-2-phenyl-2,3,5,7,8,8a-
hexahydro-1H-5,8a-ethanocyclobuta[c][1,2,4]triazolo[1,2-a]-
pyridazine-1,3-dione 29a
A solution of cycloadduct 28 (0.01 g, 0.03 mmol) in dry pyri-
dine (0.5 cm3) containing 4-dimethylaminopyridine (0.005 g)
was treated with (ϩ)-MTPA chloride (0.018 g, 0.07 mmol
derived from R-MTPA). The mixture was heated at 55 ЊC for
36 h. Pyridine was removed under reduced pressure from the
reaction mixture, by forming an azeotrope with toluene. The
residue was purified by PLC [MeOH :CHCl3 (2:98)] to afford
the di-MTPA ester 29a (0.014 g, 60%), mp 150–152 ЊC (CHCl3–
hexane); [α]D ϩ16 (CHCl3) (Found: C, 58.0; H, 3.7; N, 5.9.
C36H29F6N3O8 requires C, 58.0; H, 3.9; N, 5.6%); δH (500 MHz)
2.60 (1H, m, 8-H), 3.02 (1H, m, 8-H), 3.08 (3H, s, OMe), 3.56
(3H, s, OMe), 3.67 (2H, m, 7-H), 5.21 (1H, d, J10,11 8.6, 10-H),
5.25 (1H, dd, J5,11 2.2, J5,6 5.6, 5-H), 5.32 (1H, dd, J11,5 2.2, J11,10
8.6, 11-H), 6.12 (1H, m, J6,5 5.6, 6-H) and 7.30–7.47 (15H, m,
Ar-H).
(iii) Conversion of (؊)-(1R,2S)-bicyclo[4.2.0]octa-3,5-diene-1,2-
diol 7 to (؊)-(1R,2S)-cis-1,2-bis{(3,7,7-trimethyl-3-oxo-2-oxa-
bicyclo[2.2.1]heptan-1-yl)carbonyloxy}bicyclo[4.2.0]octa-3,5-
diene 27
The angular cis-monohydrodiol metabolite 7 (0.05 g, 0.36
mmol), [α]D Ϫ166 (CHCl3), on reaction with (Ϫ)-(1S)-3-oxo-
4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride
(camphanic chloride; 0.173 g, 0.8 mmol) in dry pyridine and
subsequent PLC purification [Et2O–hexane (70:30)] of the
crude product gave colourless crystals of the dicamphanate 27
(0.15 g, 83%), mp 163–164 ЊC (from MeOH); [α]D Ϫ229
(CHCl3) (Found: C, 67.1; H, 6.8. C28H34O8 requires C, 67.5; H,
6.9%); δH (500 MHz) 0.95 (3H, s, Me), 0.99 (3H, s, Me), 1.07
(6H, s, Me), 1.09 (3H, s, Me), 1.10 (3H, s, Me), 1.66 (1H, m,
Hcam), 1.91 (1H, m, Hcam), 2.07 (1H, m, Hcam), 2.15 (1H, m,
Hcam), 2.45 (2H, m, Hcam), 2.72 (2H, m, Hcam), 5.56 (1H, d, J2,3
9.8, 3-H), 5.83 (1H, m, 3-H), 5.88 (1H, s, 2-H) and 6.02 (1H, m,
4-H); m/z 498 (Mϩ, 2.5%), 120 (100).
Conversion of compound 28 to (10R,11S)-10,11-di-[(S)-
methoxytrifluoromethylphenylacetoxy]-2-phenyl-2,3,5,7,8,8a-
hexahydro-1H-5,8a-ethanocyclobuta[c][1,2,4]triazolo[1,2-a]-
pyridazine-1,3-dione 29b
Using (Ϫ)-MTPA-chloride (derived from S-MTPA) the cyclo-
adduct 28 was esterified to yield the di-MTPA ester 29b, mp
139–140 ЊC (from CHCl3–hexane); [α]D ϩ32 (CHCl3) (Found:
C, 57.8; H, 3.9; N, 5.9. C36H29F6N3O8 requires C, 57.8; H, 3.9;
N, 5.6%); δH (500 MHz) 2.84 (1H, m, 8-H), 3.05 (2H, m, 7-H,
8-H), 3.16 (3H, s, OMe), 3.46 (3H, s, OMe), 3.76 (1H, m, 7-H),
5.13 (1H, dd, J5,11 2.3, J5,6 5.3, 5-H), 5.16 (1H, dd, J11,10 8.6, J11,5
2.3, 11-H), 5.51 (1H, d, J10,11 8.6, 10-H), 6.11 (1H, m, J6,5 5.3,
6-H) and 7.31–7.56 (15H, m, Ar-H).
X-Ray crystal structure analysis of compound 27
Crystal data. C28H34O8, M = 498.6. Orthorhombic, a =
31.593(7), b = 11.267(7), c = 7.334(1) Å, V = 2610.6(8) Å3,
λ = 0.710 73 Å, space group P21212 (No. 18), Z = 4, Dx = 1.268 g
cmϪ3. Colourless prisms, dimensions 0.96 × 0.60 × 0.57 mm,
µ(Mo-Kα) = 0.92 cmϪ1, F(000) = 1064.
Data collection and processing. Siemens P3 diffractometer, ω
scan, scan width 1.0Њ, 4 < 2θ < 60Њ, h: 0→44, k: 0→15, l: 0→10;
graphite-monochromated Mo-Kα radiation; 4340 unique
reflections measured giving 2258 with I > 2σ(I).
Structure analysis and refinement. Direct methods
(SHELXS86).25 Full-matrix least-squares refinement on F 2
(SHELXL-93)26 with all non-hydrogen atoms anisotropic and
hydrogens in calculated positions using the riding model with
Uiso(H) = 1.2U(eq) for the attached atom. Final R1 = 0.065 (for
2258 data), wR2 = 0.269 (all data), GOF = 0.84, maximum
residual electron density 0.17 e ÅϪ3. A projection of the mol-
ecule is shown in Fig. 1.‡
X-Ray crystal structure analysis of compound 29b
Crystal data. C36H29F6N3O8, M = 745.6. Orthorhombic,
a = 11.970(3), b = 16.096(6), c = 17.972(6) Å, V = 3463(2) A3,
λ = 0.710 73 Å, space group P212121 (No. 19), Z = 4, Dx = 1.43 g
cmϪ3. Colourless blocks, dimensions 0.93 × 0.72 × 0.65 mm,
µ(Mo-Kα) = 1.22 cmϪ1
.
Data collection and processing. Siemens P3 diffractometer,
ω scan, scan width 1.2Њ, 3.5 < 2θ < 56Њ, h: 0→15, k: 0→21,
l: 0→23; graphite-monochromated Mo-Kα radiation; 4664
unique reflections measured giving 2468 with I > 2σ(I).
Structure analysis and refinement. Direct methods
(SHELXS86).25 Full-matrix least-squares refinement on F 2
(SHELXL-93)26 with all non-hydrogen atoms anisotropic and
hydrogens in calculated positions using the riding model with
Uiso(H) = 1.2U(eq) for the attached atom. Final R1 = 0.057 (for
2468 data), wR2 = 0.138 (all data), GOF = 1.03, maximum
residual electron density 0.18 e ÅϪ3. A projection of the
molecule is shown in Fig. 2.
(iv) Conversion of (؊)-(2R,3S)-bicyclo[4.2.0]octa-1(6),4-diene-
2,3-diol 14 to (10R,11S)-10,11-dihydroxy-2-phenyl-2,3,5,7,8,8a-
hexahydro-1H-5,8a-ethanocyclobuta[c][1,2,4]triazolo[1,2-a]-
pyridazine-1,3-dione 28
To a stirring solution of cis-diol metabolite 14 (0.02 g, 0.14
mmol; [α]D Ϫ16) in CH2Cl2 (1 cm3) was added, dropwise, a
solution of freshly sublimed 4-phenyl-1,2,4-triazoline-3,5-dione
(0.03 g, 0.17 mmol) in CH2Cl2 (1 cm3) at room temperature.
Upon completion of the reaction (ca. 3 h), CH2Cl2 was evapor-
(v) (؊)-(1S,2S,8S)-Bicyclo[4.2.0]octa-3,5-diene-1,2,8-triol 8
Triol 8 ([α]D Ϫ197, CHCl3) derived from the metabolism of
‡ Atomic coordinates, thermal parameters and bond length and angles
have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). See Instructions for Authors, J. Chem. Soc., Perkin Trans. 1,
1997, Issue 1. Any request to the CCDC for this material should quote
the full literature citation and the reference number 207/110.
(1S)-1,2-dihydrobenzocyclobuten-1-ol 13 was assigned
a
(1S,2S,8S) configuration based on CD spectral comparison
with (Ϫ)-(1R,2S)-bicyclo[4.2.0]octa-3,5-diene-1,2-diol 7 (Fig.
4).
J. Chem. Soc., Perkin Trans. 1, 1997
1885