References and Notes
1a
Shi Y.-L.
Shi M.
Org.
Biomol. Chem.
2007,
5:
1499
1b
Bräse S.
Encinas A.
Keck J.
Nising CF.
Chem. Rev.
2009,
109:
3903
2a
Lesch B.
Bräse S.
Angew.
Chem. Int. Ed.
2004,
116:
118 ; Angew. Chem. 2004, 43, 115
2b
Nising CF.
Ohnemüller UK.
Friedrich A.
Lesch B.
Steiner J.
Schnöckel H.
Nieger M.
Bräse S.
Chem.
Eur. J.
2006,
12:
3647
2c
Gérard EMC.
Sahin H.
Encinas A.
Bräse S.
Synlett
2008,
2702
3a Diversonol: Nising CF.
Ohnemüller UK.
Bräse S.
Angew.
Chem. Int. Ed.
2006,
45:
307 ; Angew. Chem. 2006, 118, 313
3b For an alternative synthesis,
see: Titze LF.
Spiegl DA.
Stecker F.
Major J.
Raith C.
Große C.
Chem. Eur. J.
2008,
14:
8956
4a Blennolide: Gérard EMC.
Bräse S.
Chem. Eur. J.
2008,
14:
8089
4b See also: Nicolaou KC.
Li A.
Angew. Chem.
Int. Ed.
2008,
47:
6579
5 Hemisecalonic acid models: Ohnemüller UK.
Nising
CF.
Encinas A.
Bräse S.
Synthesis
2007,
2175
6 Otero, H.; Bräse, S. et al.,
unpublished results.
Synthesis of
7a from 5a:
7a To a solution of the
triol 5a (0.520 g, 2.22 mmol, 1.00 equiv)
in CH2Cl2 (50 mL) at 0 ˚C were successively
added KBr (0.748 g, 6.29 mmol, 2.83 equiv), TEMPO (0.070 g, 0.446
mmol, 0.200 equiv) and NaOCl (2.00 mL, 24.4 mmol, 11.0 equiv). The
suspension was stirred for 1 h at 0 ˚C and for 5 h at r.t.
After this time the mixture was washed with H2O (40 mL),
1 M HCl (40 mL) and brine (40 mL). The organic phase was dried over Na2SO4 and
evaporated under vacuum. The residue was purified by flash column
chromatography (cyclohexane-EtOAc, 3:1), yielding 7a (1.77 g, 26%) as a colorless
oil.
7b (b) DMP (5.66 mL, 2.00 mmol, 2.00
equiv, 15% in CH2Cl2) was added to
a solution of the triol 5a (0.236 g, 1.00
mmol, 1.00 equiv) in CH2Cl2 (50 mL). The suspension
was stirred for 18 h at r.t. After this time the mixture was quenched
with sat. NaHCO3 solution (50 mL) and extracted with
CH2Cl2
(3 × 30 mL). The
organic phase was dried over Na2SO4, evaporated,
and the residue was purified by flash column chromatography (cyclohexane-EtOAc,
3:1), yielding 7a
(46 mg, 20%)
as a colorless oil.
Synthesis
of 7a from 9a:
7c To a solution of the
diol 9a (0.372 g, 1.59 mmol, 1.00 equiv)
in CH2Cl2 (31.5 mL) and MeCN (6.30 mL) were
added NMO (0.560 g, 4.75 mmol, 3.00 equiv) and molecular sieve (1.00
g). After stirring for 30 min TPAP (0.112 g, 0.317 mmol 0.200 equiv)
was added and the mixture was refluxed for 2 h. The solvent was evaporated
and the residue was purified by flash column chromatography (cyclohexane-EtOAc,
3:1), yielding 7a (0.113 g, 22%)
as a colorless oil.
7d (d) DMP (5.66 mL, 2.00 mmol, 2.00
equiv, 15% in CH2Cl2) was added to
a solution of the diol 9a (0.234 g, 1.00
mmol, 1.00 equiv) in CH2Cl2 (10 mL) and the
suspension was stirred for 1 h at 0 ˚C and for 5 h at r.t.
After this time the mixture was quenched with sat. NaHCO3 solution
(10 mL) and extracted with CH2Cl2 (3 × 20
mL). The organic phase was dried over Na2SO4 and evaporated
under vacuum. The residue was purified by flash column chromatography
(cyclohexane-EtOAc, 3:1), yielding 7a (93
mg, 40%) as a colorless oil.
8
Characterization
Data for 7a: R
f
0.40
(cyclohexane-EtOAc, 3:1). ¹H NMR (400
MHz, CDCl3): δ = 1.87-1.98
(m, 1 H, CH2), 2.07-2.40 (m, 4 H, CH2),
2.84-2.98 (m, 1 H, CH2), 4.59 (s, 1 H, OH),
4.63 (dd, ³
J = 5.5,
2.3 Hz, 1 H, H-4a), 6.96 (dd, ³
J = 8.4
Hz, 4
J = 0.5 Hz,
1 H, Harom), 7.02-7.06 (m, 1 H, Harom),
7.47-7.53 (m, 1 H, Harom), 7.87 (dd, ³
J = 7.9 Hz, 4
J = 1.7 Hz, 1 H, Harom). ¹³C
NMR (100 MHz, CDCl3):
δ = 20.7
(CH2), 25.4 (CH2), 37.2 (CH2),
78.1 (C-9a), 83.1 (C-4a), 118.1 (Carom), 118.6 (C-8a),
121.9 (Carom), 127.2 (Carom), 136.9 (Carom),
160.5 (C-5a), 191.4 (C-9), 207.1 (C-1). IR (KBr): 3415 (w, OH),
1717 (m, C=O) cm-¹. MS (EI): m/z (%) = 232
(56) [M+], 176 (58), 121 (97),
84.0(100). HRMS (EI): m/z calcd for C13H12O4:
232.0736; found: 232.0733.
9
Synthesis of 7b:
To a solution of the triol 5a (0.600 g,
2.25 mmol, 1.00 equiv) in CH2Cl2 (10 mL) and
sat. aq NaHCO3 solution at 0 ˚C were successively
added Py×HBr3 (2.44 g, 7.63 mol, 3.00 equiv)
and TEMPO-O2CC6H5 (0.14 g, 0.505 mmol,
0.200 equiv). The suspension was stirred for 1 h at
0 ˚C
and for 2 h at r.t. After this time Na2S2O3 (ca.
1 g) was added and the mixture was stirred for 1 h. After extraction with
CH2Cl2 (3 Ž 70 mL) the organic phase
was dried over Na2SO4 and evaporated under
vacuum. The residue was purified by flash column chromatography
(cyclohexane-EtOAc, 3:1), yielding 7b (0.293
g, 37%) as a colorless oil;
R
f
0.41 (cyclohexane-EtOAc,
3:1). ¹H NMR (400 MHz, CDCl3): d = 1.87-2.03
(m, 1 H, CH2), 2.05-2.27 (m, 2 H, CH2),
2.27-2.50 (m, 2 H, CH2), 2.85-3.07
(m, 1 H, CH2), 4.49 (br s, 1 H, OH), 4.64 (dd, ³
J = 5.7, 2.8 Hz, 1 H, H-4a), 6.88
(d, ³
J = 8.9
Hz, 1 H, Harom), 7.59 (dd, ³
J = 8.9 Hz, 4
J = 2.5 Hz, 1 H, Harom),
7.98 (d, 4
J = 2.5
Hz, 1 H, Harom). ¹³C NMR
(100 MHz, CDCl3): d = 20.7 (CH2),
25.4 (CH2), 37.2 (CH2), 78.0 (Cq),
83.3 (C-4a), 114.6 (Cq), 119.9 (Cq), 120.2 (Carom),
129.5 (Carom), 139.5 (Carom), 159.4 (Cq),
190.3 (C-9), 206.7 (C-1). IR (KBr): 3418 (m, OH), 1698 (m, C=O)
cm-¹. MS (EI): m/z (%) = 310/312
(71/70) [M+], 254/256
(74/73), 199/201 (94/94), 43 (100). HRMS
(EI): m/z calcd
for C13H11BrO4: 309.9841; found:
309.9843.
Synthesis of 10a: To
a solution of the epoxide 8a (0.216 g, 1.00
mmol, 1.00 equiv) in toluene (10 mL) was added BF3×Et2O
(0.532 g, 3.75 mmol, 3.75 equiv). After stirring for 15 min at r.t.
the mixture was washed with sat. NaHCO3 solution (10
mL) and brine (10 mL). The organic phase was dried over Na2SO4 and
evaporated under vacuum, yielding 10a (158
mg, 73%) as colorless crystals; R
f
0.46 (cyclohexane-EtOAc,
2:1). ¹H NMR (400 MHz, CDCl3):
δ = 1.65-1.71
(m, 1 H, CH2), 1.91-2.07 (m, 2 H, CH2),
2.26-2.37 (m, 1 H, CH2), 2.40-2.53
(m, 2 H, CH2), 4.10 (d, 4
J = 1.8
Hz, 1 H, CH), 4.53 (td, ³
J = 4.5
Hz, 4
J = 1.8 Hz,
1 H, CH), 6.88 (d, ³
J = 8.1
Hz, 1 H, Harom), 6.93 (dt, ³
J = 7.5 Hz, 4
J = 1.1 Hz, 1 H, Harom),
7.08 (dd, ³
J = 7.6
Hz, 4
J = 1.6 Hz,
1 H, Harom), 7.13-7.20 (m, 1 H, Harom). ¹³C
NMR (100 MHz, CDCl3): δ = 19.8 (CH2),
34.0 (CH2), 43.1 (CH2), 64.4 (CH), 80.8 (CH),
117.3 (Carom), 121.0 (Cq), 123.0 (Carom),
129.9 (Carom), 130.0 (Carom), 153.3 (Cq),
202.7 (C = O), 206.3 (C=O). MS (EI): m/z (%) = 216
(10) [M+], 133 (100). HRMS (EI): m/z calcd
for C13H12O3: 216.0786; found:
216.0788.
10
Crystal Structure
Determinations: All single-crystal X-ray diffraction studies
were carried out on a Bruker-Nonius Kappa-CCD diffractometer
at 123 (2) K using MoKα radiation (λ = 0.71073 Å).
Direct Methods (SHELXS-97)¹³ were used
for structure solution (1b was solved by
Patterson methods) and refinement was carried out using SHELXL-97¹³ (full-matrix
least-squares on F
²
).
Hydrogen atoms were localized by difference electron density determination
and refined using a riding model [H(O) free].
A semi-absorption correction was applied for 1b and7b.
1b:
colorless crystals, C13H11O2Br, M = 279.13, crystal size: 0.50 × 0.30 × 0.20
mm, triclinic, space group P-1 (No. 2),
a = 5.7727
(4) Å, b = 8.4963 (5) Å, c = 11.4856 (9) Å, α = 87.249 (2)˚, β = 79.221 (2)˚, γ = 86.083 (3)˚, V = 551.74 (7) ų, Z = 2, ρ(calc) = 1.680
Mg m-³, F(000) = 280, µ = 3.705 mm-¹,
3778 reflections (2θ
max = 50˚),
1936 unique [R
int = 0.060],
145 parameters, R1 [I > 2σ(I)] = 0.041, wR2 (all data) = 0.104, S = 1.00, largest diff. peak
and hole 0.860 and
-0.663 e Å-³.
7a: colorless crystals, C13H12O4, M = 232.23, crystal size: 0.60 × 0.30 × 0.30
mm, monoclinic, space group P21/c
(No. 14), a = 12.2709 (9) Å, b = 7.1115 (5) Å, c = 13.3525 (12) Å, β = 108.490 (7)˚, V = 1105.05 (15) ų, Z = 4, ρ(calc) = 1.396
Mg m-³, F(000) = 488, µ = 0.104 mm-¹,
24122 reflections (2θ
max = 55˚),
2534 unique [R
int = 0.026],
157 parameters, 1 restraint, R1 [I > 2σ(I)] = 0.035, wR2 (all data) = 0.097, S = 1.05, largest diff. peak
and hole 0.356 and -0.198 e Å-³.
7b: colorless crystals, C13H11O4Br, M = 311.13, crystal size: 0.45 × 0.30 × 0.25
mm, monoclinic, space group P21/n
(No. 14), a = 11.419 (1) Å, b = 8.953 (1) Å, c = 11.685 (1) Å, β = 105.17 (1)˚, V = 1152.98 (19) ų, Z = 4, ρ(calc) = 1.792
Mg m-³, F(000) = 624, µ = 3.569 mm-¹,
10744 reflections (2θ
max = 55˚),
2631 unique [R
int = 0.036],
166 parameters, 1 restraint, R1 [I > 2σ(I)] = 0.038, wR2 (all data) = 0.100, S = 1.04,
largest diff. peak and hole 0.478 and -0.558 e Å-³.
8a: colorless crystals, C13H12O3, M = 216.23, crystal size: 0.32 × 0.16 × 0.08
mm, triclinic, space group P-1 (No. 2),
a = 8.757 (1) Å, b = 10.018 (1) Å, c = 12.550 (1) Å, α = 101.68 (1)˚, β = 91.88 (1)˚, γ = 102.74 (1)˚, V = 1048.18 (18) ų, Z = 4, ρ(calc) = 1.370
Mg m-³, F(000) = 456, µ = 0.097 mm-¹,
11652 reflections (2θ
max = 55˚),
4754 unique [R
int = 0.044],
289 parameters, R1 [I > 2σ(I)] = 0.055, wR2 (all data) = 0.122, S = 1.03, largest diff. peak
and hole 0.289 and -0.245 e Å-³.
9a: colorless crystals, C13H14O4,
M = 234.24, crystal size: 0.35 × 0.25 × 0.10
mm, triclinic, space group P-1 (No. 2),
a = 5.670 (1) Å, b = 9.363 (1) Å, c = 11.192 (2) Å, α = 68.76 (1)˚, β = 77.05 (1)˚, γ = 76.84 (1)˚, V = 532.65 (15) ų, Z = 2, ρ(calc) = 1.460
Mg m-³, F(000) = 248, µ = 0.108 mm-¹, 10734
reflections (2θ
max = 55˚),
2448 unique [R
int = 0.033], 157
parameters, 8 restraints, R1 [I > 2σ(I)] = 0.054, wR2 (all data) = 0.122, S = 1.09, largest diff. peak
and hole 0.428 and -0.566 e Å-³.
The atoms C9, O9 are disordered [3:1; s.o.f. (C9, H9, O9,
H9O) = 0.760 (3)].
11a:
colorless crystals, C13H14O4, M = 234.24, crystal size: 0.30 × 0.12 × 0.08
mm, triclinic, space group P-1 (No. 2),
a = 6.812 (1) Å, b = 7.036 (1) Å, c = 11.865 (1) Å, α = 94.62 (1)˚, β = 99.84 (1)˚, γ = 102.56 (1)˚, V = 542.79 (12) ų, Z = 2, ρ(calc) = 1.433
Mg m-³, F(000) = 248, µ = 0.106 mm-¹, 4857
reflections (2θ
max = 50˚),
1910 unique [R
int = 0.052], 160
parameters, 2 restraints, R1 [I > 2σ(I)] = 0.058, wR2 (all data) = 0.108, S = 1.06, largest diff. peak
and hole 0.200 and -0.284 e Å-³.
Crystallographic
data (excluding structure factors) for the structures reported
in this work have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers CCDC 742582 (1b), CCDC 740940 (7a),
CCDC 740941 (7b), CCDC 740942 (8a), CCDC 740943 (9a),
and CCDC 740944 (11a). Copies of the data can
be obtained free of charge on application to: The Director, CCDC,
12 Union Road, Cambridge DB2 1EZ, UK [Fax: +44
(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
11 For some hydrates of nonactivated,
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