Total synthesis of manoalide

Article abstract of DOI:10.1055/s-1998-6105

Me₃Al/AlCl₃-mediated hetero-Diels-Alder (HDA) additions of 2-silyloxy-1,3-dienes to formylated butenolide 6 containing a protected hydroxy function afford, in one step, a variety of pyranofuranones including manoalide precursor 16, which is a stable monoprotected seco-manoalide.

Full text of DOI:10.1055/s-1998-6105

SYNTHESIS
September 1998
1367
Total Synthesis of Manoalide
J. Coombs, E. Lattmann, H. M. R. Hoffmann*
Department of Organic Chemistry, University of Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
Fax +49(511)7623011, E-mail: hoffmann@mbox.oci.uni-hannover.de
Received 17 February 1998; revised 6 March 1998
Abstract: Me3Al/AlCl3-mediated hetero-Diels–Alder (HDA)
additions of 2-silyloxy-1,3-dienes to formylated butenolide 6 con-
taining a protected hydroxy function afford, in one step, a variety
of pyranofuranones including manoalide precursor 16, which is a
stable monoprotected seco-manoalide.
Key words: hetero-Diels–Alder reaction, NSAIDs, γ-hydroxy-
butenolides, Me Al/AlCl , marine natural products, manoalide
3
3
Manoalide is a sesterterpene (C25), which has attracted in-
terest as an irreversible PLA2 inhibitor and functions as an
NSAID (nonsteroidal anti-inflammatory drug). The hy-
drophilic core of manoalide can be considered bioisosteric
with the tetracyclic steroidal skeleton (Figure).
Scheme 1
7 and 8. In these reactions, catalyst tuning (AlCl3/Me3Al)
was decisive for success. 2-Methyl-1-trimethylsilyloxy-
buta-1,3-diene, which is readily available from tiglic alde-
hyde, combined with aldehyde 6 to the protected 10 car-
bon eastern segment 9 of seco-manoalide (Scheme 2).
Figure. Manoalide, Bioactive Sesterpene (C25) of Marine Origin and
Bio-Isosteric NSAID
The required 20 carbon western silyloxydiene 15 was pre-
pared in 5 steps from inexpensive β-ionone. Following the
Kocienski procedure1d site-specific hydrogenation under
phase-transfer conditions provided ketone 11,1d which
was converted into cyclopropylcarbinyl alcohol 12. It was
important to carry out the Julia–Johnson reaction5,6 by ad-
dition of salt (LiBr, ZnBr2) and at low temperature
(–60°C). Under optimized conditions, the preparation of
homoallylic bromide 13 proceeded (E)-selectively, and
only two steps were required to convert methyl ketone 11
into 13 in good overall yield (Scheme 3).
Manoalide has been synthesized several times, namely by
Katsumura and Isoe,1a,c Garst,1b Kocienski1d.e and their
respective coworkers. The reported approaches have in
common that the sensitive γ-hydroxybutenolide moiety
was generated in the last step, by a Diels–Alder addition
of singlet oxygen to a 2-trialkylsilylfuran derivative. We
report here a new approach using a 3-formylated butenol-
ide, which was submitted to a Lewis acid mediated hetero-
Diels–Alder (HDA) reaction. Several silyloxydienes were
used in the key cycloaddition.
Specifically, furfural furnishes 4-bromo-5-methoxyfu-
ran-2(5H)-one (2) in two reliable steps.2a,b, 3 Transacetal-
ization of 2 was carried out via hemiacetal 3, which was
submitted to azeotropic distillation with 2-trimethylsi-
lylethanol, giving protected γ-hydroxybutenolide 4.
Cross-coupling4 with vinylstannane provided vinylated
butenolide 5, which on careful ozonolysis and anhydrous
workup furnished the desired 4-formyl-5-[2-(trimethyls-
ilyl)eth-1-oxy]furan-2(5H)-one 6 as key intermediate
(Scheme 1).
Combination of silyloxydiene 15 and aldehyde 6 under
the conditions of the model study (Scheme 2), afforded
the HDA cycloadduct which was desilylated in situ (silica
gel, H2O) at carbon C-24 giving monoprotected seco-
manoalide (16). Deprotection with trifluoroacetic acid
furnished manoalide (1b) (Scheme 4). As an alternative to
the usual photoisomerization1a–e,7 of 1b into 1a we cy-
clized 16 to monoprotected manoalide 17. Unlike the nat-
ural product 1a, the 2-(trimethylsilyl)ethyl derivative 17
gave a clean 1H NMR spectrum and showed no tendency
HDA model reactions between aldehyde
6 and to generate its precursor, i.e. open-chain tautomer 16.
Danishefsky’s diene or 2-trimethylsilyloxybuta-1,3-diene Deprotection led to the reported1d complex mixture of 8
gave peri- and regioselectively the cycloaddition products diastereomers.

SYNTHESIS
Papers
1368
Scheme 3
0.2 mm silica gel 60 F254 plates (E. Merck). E (Et2O) and PE (light
petroleum, bp 40–60°C).
4-Bromo-5-hydroxyfuran-2(5H)-one (3):
A suspension of compound 2 (1.9 g, 10 mmol), H2SO4 (30%, 130 mL)
and dioxane (180 mL) was heated to reflux for 1.5 h under vigorous
stirring. The mixture was cooled to r.t. and then poured onto ice. The
aqueous phase was extracted with Et2O (250 mL portions) and the
combined organic layer dried (MgSO4). After evaporation of the sol-
vent the crude product was purified by chromatography (E/PE, 1 : 1)
to afford 3 (1.7 g, 9.3 mmol, 93%) as colourless crystals; mp 73°C.
1H NMR (200 MHz, CDCl3/TMS), J(Hz): δ = 6.42 (s, 1 H, H-3), 6.09
(s, 1 H, H-5), 5.83 (br s, 1 H, OH).
Scheme 2
In conclusion, we have described a synthesis of pyrano-
furanones and manoalide by a convergent route, which is
also amenable to a combinatorial approach. A variety of
manoalide analogues are directly accessible, for the eval-
uation of biological activity. Aldehyde 6, in addition to
other 4-formyl- and 4-vinylfuran-2(5H)-ones prepared by
us,2a is a useful building block in the synthesis of bioreg-
ulatory natural products including heteroprostanoids.8a,b
13C NMR (50.32 MHz, APT, CDCl3/TMS): δ = 169.41 (+, C-2),
148.15 (+, C-4), 124.00 (–, C-3), 99.59 (–, C-5).
IR (CHCl3): ν = 3300, 3112, 1800, 1712, 1608, 1448, 1332, 1296,
1256, 1184, 1136, 1036, 952, 856, 716, 668, 452 cm–1.
MS (70 eV): m/z (%) = 180 (14), 178 (M+,14), 152 (15), 150 (15), 134
(100), 132 (97), 107 (21), 106 (44), 105 (23), 104 (42), 99 (55), 71 (13).
HRMS: m/z Calcd. for C4H3O3Br, 177.9266. Found 177.9263.
Melting points: Büchi apparatus. Infrared spectra: Perkin-Elmer 1710
spectrometer. 1H NMR spectra: Bruker WP 200 SY or AM 400 spec-
trometer. Chemical shifts are reported in δ values relative to TMS as
internal standard. 13C NMR spectra: Bruker WP 200 SY or a Bruker
AM 400 spectrometer. Chemical shifts are reported in δ values rela-
tive to TMS. APT (attached proton test): spin-echo-based selection of
multiplicities of 13C NMR signals. Quaternary C and CH2 carbon at-
oms give positive signals (+), while CH and CH3 give negative sig-
nals (–). Low- and high-resolution EI-MS: Finnigan MAT 312 spec-
trometer with an ionization potential of 70 eV at r.t., unless otherwise
stated. Microanalyses were performed in the Department of Organic
Chemistry of the University of Hannover. Preparative column chro-
matography was performed on J. T. Baker silica gel (particle size 30
60 µm). Analytical TLC was carried out on aluminium-backed
4-Bromo-5-[2-(trimethylsilyl)eth-1-oxy]furan-2(5H)-one (4):
To a solution of alcohol 3 (1.6 g, 9 mmol) and 2-(trimethylsilyl)ethan-
1-ol (3.9 mL, 27 mmol) in benzene (20 mL) was added p-TsOH (cat).
The mixture was distilled azeotropically (Dean–Stark separator) for
4 d. After cooling to r.t. the solvent was removed and the crude prod-
uct purified by chromatography [PE/E, 8 : 1, then 1 : 1 to recover
starting material (0.38 g, 2.1 mmol, 23%)] to yield 4 (1.7 g, 6.2 mmol,
69%, 90% based on recovered starting material); colourless solid; mp
44°C.
1H NMR (200 MHz, CDCl3), J(Hz): δ = 6.41 (d, J = 1, 1 H, H-3), 5.78
(d, J = 1, 1 H, H-5), 3.88 (m, 2 H, H-1'), 1.04 (m, 2 H, H-2'), 0.04 [s,
9 H, OSi(CH3)3].

SYNTHESIS
September 1998
1369
Scheme 4
13C NMR (50.32 MHz, APT, CDCl3): δ =167.98 (+, C-2), 145.71 (+,
C-4), 124.48 (–,C-3), 103.30 (–, C-5), 68.19 (+, C-1'), 17.97 (+, C-2'),
–1.46 [–, OSi(CH3)3].
IR (CHCl3): ν = 3040, 2956, 2856, 1792, 1764, 1612, 1408, 1340,
1128, 1068, 956, 852 cm–1. MS (70 eV): m/z (%) = 278 (M+, 0), 209
(M++2 –TMS, 48), 207 (M+–TMS, 48), 199 (14), 171 (13), 163 (14),
161 (13), 139 (15), 137 (15), 103 (18), 81 (13), 75 (50), 73 (100).
Anal. Calcd. for C9H15BrO3Si (279.2): C, 38.72; H 5.42. Found: C,
38.64; H, 5.34.
When the mixture became cloudy during ozonolysis, MeOH was add-
ed dropwise. After complete reaction thiourea (0.38 g, 5.0 mmol) in
MeOH (2 mL) was added. The mixture was allowed to reach 0°C,
silica gel was added and the solvent removed. Chromatography af-
forded 6 (866 mg, 3.80 mmol, 78%) as a colourless solid; mp 39°C.
1H NMR (200 MHz, CDCl3), J(Hz): δ = 10.04 (s, 1 H, CHO), 6.77 (d,
1 Hz, 1 H, H-3), 6.14 (d, 1 Hz, 1 H, H-5), 3.89 (m, 2 H, H-1'), 1.02
(m, 2 H, H-2'), 0.03 [s, 9 H, OSi(CH3)3].
13C NMR (50.32 MHz, APT, CDCl3): δ = 185.19 (–, CHO), 168.75
(+, C-2), 155.99 (+, C-4), 131.13 (–, C-3), 101.46 (–, C-5), 69.49 (+,
C-1'), 18.04 (+, C-2'), -1.41 [–, OSi(CH3)3].
5-[2-(Trimethylsilyl)eth-1-oxy]-4-vinylfuran-2(5H)-one (5):
To a suspension of 4 (558 mg, 2.00 mmol) and bis(triphenylphos-
phine)palladium dichloride (70 mg, 5 mol%) in MeCN (10 mL) and
THF (2 mL) was added tributylvinyl stannane (0.61 mL, 2.1 mmol) at
r.t. under N2 and exclusion of moisture. The yellow suspension be-
came clear within a few minutes. The solution was stirred for 3 d at
50°C. The resulting black solution was cooled to r.t., evaporated and
the residue was chromatographed (PE/E, 4 : 1) to give 5 (366 mg,
1.60 mmol, 81%) as colourless oil.
IR (CHCl3): ν = 3040, 2956, 2900, 1796, 1768, 1704, 1412, 1356,
1252, 1128, 1064, 1040, 956, 908, 860, 840 cm–1.
MS (70 eV): m/z (%) = 228 (M+, 0), 199 (8), 185 (29), 171 (4), 158
(6), 157 (47), 110 (12), 103 (79), 83 (6), 78 (5), 75 (31), 74 (9), 73
(100), 72 (4).
Anal. Calcd. for C10H16O4Si (228.3): C, 52.61; H, 7.06. Found C,
52.57; H, 7.10.
1H NMR (200 MHz, CDCl3), J(Hz): δ = 6.61 (dd, J = 18, 11, 1 H, H-
3'), 6.06 (d, J = 1, 1 H, H-3), 6.01 (d, J = 1, 1 H, H-5), 5.91 (d, J = 18,
1 H, H-4'), 5.70 (d, J = 11, 1 H, H-4'), 3.87 (m, 2 H, H-1'), 1.04 (m, 2
H, H-2'), 0.04 [s, 9 H, OSi(CH3)3].
4-[2,3-Dihydropyran-4-on-2-yl]-5-[2-(trimethylsilyl)eth-1-
oxy]furan-2(5H)-one (7):
To a solution of 6 (228 mg, 1.00 mmol) and Eu(fod)3 (52 mg,
0.050 mmol) in benzene (4 mL) was added freshly distilled Danishef-
sky’s diene (258 mg, 1.50 mmol) dropwise at 0°C under N2 and exclu-
sion of moisture. The mixture was stirred for 3 h at r.t., then glacial
AcOH (0.100 mL, 1.75 mmol) and silica gel (100 mg) were added. Af-
ter complete reaction (TLC monitoring) the solvent was removed and
the crude product chromatographed (PE/E, 5 : 1 to E) to afford 7
(88 mg, 0.33 mmol, 33%) as colourless oil (mixture of diastereomers).
1H NMR (400 MHz, CDCl3), J(Hz): δ = 7.48 (d, J = 6, 1 H, H-6'), 6.24
(d, J = 0.5, 1 H, H-3), 5.85 (d, J = 0.5, 1 H, H-5), 5.54 (d, J = 6, 1 H,
H-5'), 5.32 (m, 1 H, H-2'), 3.86 (m, 2 H, H-1''), 2.82 (m, 2 H, H-3'),
1.01 (m, 2 H, H-2''), 0.03 [s, 9 H, OSi(CH3)3].
13C NMR (50.32 MHz, APT, CDCl3): δ = 170.28 (+, C-2), 159.29 (+,
C-4), 126.71 (–, C-3'), 125.41 (+, C-4'), 118.15 (–, C-3), 101.56 (–, C-
5), 66.84 (+, C-1'), 17.93 (+, C-2'), –1.69 [–, OSi(CH3)3].
IR (CHCl3): ν = 3040, 2956, 2896, 1784, 1760, 1644, 1364, 1308, 1252,
1228, 1164, 1128, 1128, 1028, 988, 960s, 940, 904, 864, 836 cm–1.
MS (70 eV): m/z (%) = 227 (1), 226 (M+,1), 171 (11), 137 (20), 105
(12), 73 (100), 69 (12).
4-Formyl-5-[2-(trimethylsilyl)eth-1-oxy]furan-2(5H)-one (6):
A solution of 5 (1.1 g, 5.0 mmol) in CH2Cl2 (60 mL) and MeOH
(1 mL) was ozonized at –78°C until a light-blue colour was observed.

SYNTHESIS
Papers
1370
13C NMR (100.61 MHz, DEPT, CDCl3): δ = 189.88 (C-4'), 168.90
(C-2), 163.48 (C-6'), 161.25 (C-4), 119.77 (C-3), 107.90 (C-5'),
101.89 (C-5), 74.40 (C-2'), 68.99 (C-1''), 39.48 (C-3'),18.24 (C-2''),
–1.47 [OSi(CH3)3].
separated and the aqueous phase was extracted with Et2O (6 × 100
mL). The combined organic layers were washed with H2O (50 mL),
dried (MgSO4). Twofold chromatography (PE/E, 35 : 1) afforded di-
hydro-β-ionone 11 (5.9 g, 31 mmol, 61%) as light-yellow liquid.
IR (CHCl3): ν = 3000, 2956, 2932, 1796, 1768, 1680, 1600, 1456,
To a mixture of Mg turnings (1.1 g, 43 mmol) and I2 (catalytic
amounts) in THF (25 mL) was added cyclopropyl bromide (a few
drops, to start the reaction). Then the residual cyclopropyl bromide
(2.1 mL, 26 mmol) was added in such manner that the solution re-
fluxed gently. After complete addition the mixture was stirred for
30 min at 50°C, then cooled to r.t. A solution of dihydro-β-ionone 11
(3.8 g, 20 mmol) in THF (10 mL) was added. The resulting mixture
was stirred for 2 h at r.t. and 1.5 h at reflux temperature. After cooling
to 0°C, the reaction mixture was treated with satd aq NH4Cl solution,
until the precipitate of Mg(OH)2 had dissolved. The layers were sep-
arated and the aqueous layer was extracted with Et2O (5 × 50 mL).
The combined organic phase was dried (MgSO4), silica gel was added
and the solvent evaporated. The residue was purified by chromatog-
raphy (PE/E, 30 : 1) to give the tertiary alcohol 12 (4.4 g, 19 mmol,
95%) as colourless oil. To a suspension of anhyd LiBr (1.0 g,
12 mmol) and anhyd ZnBr2 (2.7 g, 12 mol) in THF (50 mL) was add-
ed a solution of alcohol 12 (2.4 g, 10 mmol) in THF (80 mL) at –60°C.
After 1 h PBr3 was added dropwise and the mixture was stirred for 5 h
at –60°C. Then PE (50 mL) and NaCl solution (50%, 50 mL) were
added. The mixture was allowed to reach r.t., the layers were separat-
ed and aqueous layer was extracted with PE (5 × 50 mL). The com-
bined organic phase was dried (MgSO4), evaporated and chromato-
graphed (PE/E, 30 : 1) to afford bromide 13 (2.5 g, 8.3 mmol, 83%)
(E/Z, 9 : 1) as colourless oil. The spectroscopic data were in agree-
ment with the literature.1d
1400, 1264, 1124, 1040, 964, 860, 840 cm–1.
MS (70 eV): m/z (%) = 268 (M+, 0), 243 (2), 198 (10), 111 (18), 105
(12), 74 (10), 73 (100), 69 (12).
5-[2-(Trimethylsilyl)eth-1-oxy]-4-[4-trimethylsilyloxy-3,6-dihy-
dro-2H-pyran-2-yl]furan-2(5H)-one (8):
To a solution of 6 (114 mg, 0.500 mmol) in benzene (2 mL) was add-
ed a solution of the catalyst (1 mL) [prepared from anhyd AlCl3
(133 mg, 1.00 mmol) in THF (1 mL) and AlMe3 (2 mL, 1 M solution
in toluene) at 0°C] followed by 2-trimethylsilyloxybuta-1,3-diene
(107 mg, 0.75 mmol) at 0°C under N2 and exclusion of moisture. The
mixture was stirred for max. 4 h at r.t. (TLC monitoring). The mixture
was cooled with an ice-bath and H2O was added carefully, until the
yellowish suspension did not foam during addition. The layers were
separated, the organic layer was dried, the solvent removed and the
residue chromatographed (PE/E, 1 : 1 to E) to give 8 (50 mg,
0.14 mmol, 27%) as yellow oil (mixture of diastereomers).
1H NMR (400 MHz, CDCl3), J(Hz): δ = 6.10 (dt, J = 2, 1, 1 H, H-3),
5.82 (d, J = 1, 1 H, H-5), 4.92 (m, 1 H, H-5'), 4.52 (ddd, J = 11, 3,
1.75, 1 H, H-2'), 4.28 (m, 2 H, H-6'), 3.88 (m, 2 H, H-1''), 2.10 (m, 2
H, H-2'), 1.02 (m, 2 H, H-2''), 0.21 [m, 9 H, OSi(CH3)3/pyran ring],
0.03 [s, 9 H, OSi(CH3)3/furan ring].
13C NMR (50.32 MHz, APT, CDCl3/TMS): δ = 170.18 (C-2), 161.24
(C-4), 146.13 (C-4'), 119.53 (C-3), 101.86 (C-5), 100.31 (C-5'), 70.73
(C-2'), 68.89 (C-1''), 64.81 (C-6'), 34.75 (C-3'), 18.24 (C-2''), 0.21
[OSi(CH3)3/pyran ring], –1.46 [OSi(CH3)3/ furan ring].
IR (CHCl3): ν = 3120, 3000, 2956, 2896, 1796, 1764, 1656, 1344,
(2E,6E)-7-Methyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,6-
dien-3-carbaldehyde (14).
1252, 1124, 1040, 948, 860 cm–1.
MS (70 eV): m/z (%) = 379 (M+, 0), 298 (17), 210 (39), 159 (43), 131
(25), 103 (18), 73 (100), 69 (7).
To a solution of LDA (16 mmol) were added DMPU (1.9 mL,
16 mmol) and freshly prepared imine (2.8 mL, 16 mmol) [prepara-
tion: to a mixture of freshly distilled cyclohexyl amine (18 mL,
160 mmol) and CaCl2 (2.5 g, 23 mmol) in Et2O (75 mL) was added
crotonaldehyde (6.1 mL, 75 mmol) at –15°C; the mixture was stirred
for 1 h at 0°C, then for 16 h at r.t.; workup and distillation at 90°C
afforded the imine]. The resulting yellow solution was stirred for 10
min at –78°C, the bromide 13 (5.0 g, 17 mmol) in THF (6.5 mL) was
added and the red solution was stirred for 5 h at –78°C. At 0°C satd
aq NH4Cl solution was added, the layers were separated and the aque-
ous layer was extracted with Et2O (50 mL portions). The combined
organic layer was dried (MgSO4) and evaporated. The residue was
mixed with Et2O (30 mL), H2O (15 mL), glacial AcOH (15 mL) and
NaOAc (3.5 g) and stirred for 1 h. After separation the aqueous phase
was extracted with Et2O (5 × 30 mL). The combined organic layers
were washed with brine, dried (MgSO4) and the solvent was removed.
The crude product was chromatographed (PE/E, 50 : 1) to give the
aldehyde 14 (2.4 g, 9.0 mmol, 53%) as light yellow oil.
4-[(2E)-5-Hydroxy-2-methylpent-2-enon-5-yl]-5-[2-(trimethylsi-
lyl)eth-1-oxy]furan-2(5H)-one (9):
Compound 6 (114 mg, 0.500 mmol) and 2-methyl-1-trimethylsilyl-
oxybuta-1,3-diene (117 mg, 0.750 mmol) were allowed to react at
0°C as described for 8. After chromatography 9 was obtained as yel-
lowish oil (80 mg, 0.26 mmol, 51%).
1H NMR (400 MHz, CDCl3), J(Hz): δ = 9.38 (s, 1 H, CHO), 6.54 (t,
J = 7, 1 H, H-3'), 6.10 (s, 1 H, H-3), 5.95 (s, 1 H, H-5), 4.78 (t, J = 7,
1 H, H-5'), 3.87 (m, 2 H, H-1''), 2.75 (m, 2 H, H-4'), 1.78 (s, 3 H, CH3),
1.60 (br, 1 H, OH), 1.02 (m, 2 H, H-2''), 0.03 [s, 9 H, OSi(CH3)3].
13C NMR (100.61 MHz, DEPT, CDCl3): δ = 195.10 (CHO), 172.90
(C-2), 169.05 (C-4), 148.32 (C-2), 145.87 (C-3'), 118.77 (C-3),
102.89 (C-5), 69.00 (C-1''), 66.87 (C-5'), 28.09 (C-4'), 19.21 (CH3),
18.24 (C-2''), –1.46 [OSi(CH3)3].
IR (CHCl3): ν = 3604, 3464, 3432, 3368, 3120, 3000, 2956, 2928,
2900, 1796, 1764, 1688, 1648, 1604, 1404, 1380, 1344, 1304, 1252,
1228, 1124, 960, 900, 860, 840, 616 cm–1.
1H NMR (400 MHz, CDCl3/TMS), J(Hz): δ = 9.38 (s, 1 H, CHO),
6.60 (br t, J = 7, 1 H, H-2), 5.15 (br t, J = 7, 1 H, H-6), 2.60 (m, 3 H,
H-1), 2.32 (m, 2 H, H-4), 2.15–1.87 (m, 8 H, H-5, H-8, H-9, H-3'),
1.66 (s, 3 H, H-10'), 1.61 (s, 3 H, H-9'), 1.58 (m, 2 H, H-5'), 1.42 (m,
2 H, H-4'), 0.98 (s, 6 H, H-8', H-7').
MS (70 eV): m/z (%) = 312 (M+, 0), 251 (2), 223 (4), 201 (13), 156
(15), 111 (18), 84 (19), 75 (40), 74 (9), 73 (100), 69 (8), 55 (18), 45
(9).
13C NMR (100.61 MHz, DEPT, CDCl3/TMS), J(Hz): δ = 195.21
(CHO), 150.20 (C-3), 144.38 (C-2), 137.09 (C-7), 137.00 (C-1'),
126.96 (C-2'), 122.70 (C-6), 40.23 (C-8), 39.86 (C-5'), 34.99 (C-4),
34.72 (C-6'), 32.76 (C-3'), 28.63 (C-8', C-7'), 27.79 (C-1), 26.91 (C-
5), 24.46 (C-9), 21.97 (C-9'), 19.80 (C-4'), 15.99 (C-10').
(3E)-1-Bromo-4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-
yl)hex-3-ene (13):
A mixture of β-ionone (10; 10 mL, 50 mmol), Bu4NHSO4 (2.6 g,
7.5 mmol), hexadecyltrimethylammonium chloride (2.8 g, 7.5 mmol)
and NaHCO3 (21 g, 75 mmol) in toluene (100 mL) and H2O (200 mL)
was stirred vigorously under N2. Sodium dithionite (11 g, 65 mmol)
was added in one portion at r.t., then the mixture was heated to reflux
for 30 min. The mixture was cooled to r.t and a second portion of
sodium dithionite (11 g, 65 mmol) was added. The mixture was heat-
ed to reflux for further 2 h and then cooled to r.t. The layers were
IR (CHCl3): ν = 2956, 2932, 2864, 1684, 1644, 1600, 1456, 1400,
1380, 1360, 1228, 1116, 1052, 972 cm–1.
MS (70 eV): m/z (%) = 288 (M+, 2), 287 (3), 151 (6), 137 (100), 136
(31), 121 (11), 95 (39), 81 (35), 79 (8), 69 (17), 67 (11).
Anal. Calcd. for C20H32O (288.5): C, 83.27; H, 11.18. Found C,
83.35; H, 11.21.

SYNTHESIS
September 1998
1371
Monoprotected seco-Manoalide, {4-[[(3E,7E)-10-(2,6,6-Trimeth-
ylcyclohex-1-en-1-yl]-8-methyl-4-formyl-1-hydroxydeca-3,7-
dien-1-yl]-5-[2-(trimethylsilyl)eth-1-oxy]furan-2(5H)-one} (16):
To a solution of aldehyde 14 (430 mg, 1.5 mmol) in benzene (2 mL)
was added TIPSOTf (0.44 mL, 1.7 mmol) and Et3N (0.30 mL,
2.2 mmol) at 0°C. The mixture was stirred for 30 min and was then
neutralized with dil HCl (pH control). The aqueous phase was extract-
ed with Et2O (5 × 10 mL), the combined organic layer was dried
(MgSO4) and the solvent removed. Diene 15 was obtained in quanti-
tative yield (670 mg, 1.50 mmol, ca. 100%). Furanone 6 (230 mg,
1.0 mmol) and diene 15 (670 mg, 1.5 mmol) were allowed to react at
r.t as described for compound 8. The crude product was purified by
chromatography (PE/E, 3 : 1) to afford 16 (130 mg, 0.4 mmol, 27%).
1H NMR (400 MHz, CDCl3), J(Hz): δ = 9.38 (s, 1 H, CHO), 6.53 (br
t, J = 6.5, 1 H, H-6), 6.08 (br, 1 H, H-25), 5.92 (s, 1 H, H-2), 5.11 (br
t, J = 6.5, 1 H, H-10), 4.72 (br, 1 H, H-4), 3.81 (m, 2 H, H-26), 2.80
(m, 2 H, H-5), 2.28 (m, 2 H, H-8), 2.14–1.85 (m, 8 H, H-16, H-13, H-
12, H-9), 1.61 (s, 3 H, H-23), 1.56 (s, 3 H, H-22), 1.55–1.51 (m, 2 H,
H-18), 1.45–1.30 (m, 3 H, OH, H-17), 1.00 (m, 2 H, H-27), 0.97 (s, 6
H, H-21, H-20), 0.03 [s, 9 H, OSi(CH3)3].
1.91 (t, J = 5.8, 2 H, H-12), 1.64 (s, 3 H, H-23), 1.59 (s, 3 H, H-22),
1.57–1.52 (m, 2 H, H-18), 1.44–1.35 (m, 3 H, OH, H-17), 1.02 (m, 2
H, H-27), 0.98 (s, 6 H, H-21, H-20), 0.03 [s, 9 H, OSi(CH3)3].
13C NMR (100.61 MHz, DEPT, CDCl3), J(Hz): δ = 170.56 (C-1),
169.09 (C-3), 137.91 (C-7), 137.40 (C-11), 136.91 (C-14), 127.01 (C-
15), 122.71 (C-10), 121.12 (C-6), 118.05 (C-2), 101.87 (C-25), 91.7
(C-24), 68.90 (C-26), 63.27 (C-4), 40.96 (C-8), 40.09 (C-12), 39.98
(C-18), 34.85 (C-19), 33.02 (C-5), 32.78 (C-16), 28.61 (C-21, C-20),
26.97 (C-9), 25.61 (C-13), 20.98 (C-22), 19.87 (C-17), 18.09 (C-27),
16.10 (C-23), –1.46 [OSi(CH3)3].
IR (CHCl3): ν = 3600, 3528, 3376, 2956, 2928, 2856, 1796, 1764,
1652, 1600, 1456, 1380, 1252, 1228, 1128, 1016, 956, 836 cm–1.
MS (70 eV): m/z (%) = 516 (M+, 1), 470 (1), 415 (1), 397 (1), 380 (1),
267 (1), 244 (1), 215 (2), 202 (3), 185 (3), 185 (3), 184 (4), 177 (3),
157 (5), 137 (100), 136 (26), 135 (8), 123 (12), 121 (13), 111 (11),
109 (14), 107 (11), 95 (55), 93 (13), 81 (42), 75 (20), 73 (51), 69 (23).
HRMS: m /z Calcd. for C30H48O5Si: 516.3195. Found 516.3172.
Manaolide (1a):
Monoprotected manoalide 17 was allowed to react with trifluoro-
acetic acid as described for seco-manoalide (1b) to afford manoalide
(1a) as the reported1d complex mixture of diastereomers and ring-
chain tautomers.
13C NMR (100.61 MHz, DEPT, CDCl3), J(Hz): δ = 194.50 (CHO),
169.88 (C-1), 167.49 (C-3), 147.51 (C-7), 145.85 (C-6), 137.48 (C-
11), 136.92 (C-14), 127.01 (C-15), 122.26 (C-10), 118.78 (C-2),
101.79 (C-25), 68.93 (C-26), 67.01 (C-4), 40.19 (C-12), 39.79 (C-18),
34.94 (C-8), 34.73 (C-19), 32.70 (C-16), 28.59 (C-21, C-20), 27.75
(C-5), 26.87 (C-9), 24.51 (C-13), 21.63 (C-22), 19.77 (C-17), 18.24
(C-27), 16.03 (C-23), –1.48 [OSi(CH3)3].
We thank Ulrike Eggert for her help and the Deutsche For-
schungsgemeinschaft and Janssen Research Foundation for their
support.
IR (CHCl3): ν = 3600, 3512, 3428 br, 2956, 2928, 2868, 1796, 1764,
1684, 1640, 1600, 1444, 1380, 1252, 1172, 1124, 1076, 960, 908,
860, 840 cm–1.
MS (70 eV): m/z (%) = 516 (M+, 1), 470 (1), 415 (1), 397 (1), 311 (1),
267 (1), 216 (4), 184 (4), 137 (100), 121 (11), 95 (44), 81 (33), 79
(12), 75 (15), 73 (45), 69 (12), 67 (11).
(1) a) Katsumura, S.; Fujiwara, S.; Isoe, S. Tetrahedron Lett. 1985,
26, 5827.
b) Garst, M.E.; Tallman, E.A.; Bonfiglio, J.N.; Harcourt, D.;
Ljungwe, E.B.; Tran, A. Tetrahedron Lett. 1986, 27, 4533.
c) Katsumura, S.; Fujiwara, S.; Isoe, S. Tetrahedron Lett. 1988,
29, 1173.
d) Bury, P.; Hareau, G.; Kocienski, P.J.; Dhanak, D. Tetrahedron
1994, 50, 8793.
HRMS: m/z Calcd. for C30H48O5Si, 516.3195. Found 516.3171.
seco-Manoalide, {5-Hydroxy-4-[[(3E,7E)-10-(2,6,6-trimethylcy-
clohex-1-en-1-yl]-8-methyl-4-formyl-1-hydroxydeca-3,7-dien-1-
yl]furan-2(5H)-one} (1b):
To a solution of the monoprotected seco-manoalide 16 (52 mg,
0.1 mmol) in CH2Cl2 (0.5 mL) was added trifluoro acetic acid (90%)
at 0°C. The mixture was stirred for 1 h at 0°C, then EtOAc (3 mL)
and toluene (6 mL) were added. After drying (MgSO4) the solvent
was evaporated and the residue was chromatographed (PE/E, 3 : 1 to
1 : 1) to afford seco-manoalide 1b (14 mg, 0.03 mmol, 34%) as violet
oil (mixture of diastereomers). The spectroscopic data were in agree-
ment with the literature.1d
e) Pommier, A.; Kocienski, P.J. J. Chem. Soc., Chem. Commun.
1997, 1139.
(2) a) Lattmann, E.; Hoffmann, H.M.R. Synthesis 1996, 155.
b) see also Farina, F.; Martin, M.R.; Martin, M.V. An. Quin.
1978, 74, 799.
(3) Note that two different names exist for the oxacyclic core, with
different atom numbering, based on open-chain 4-hydroxybut-2-
enoic acid and furan.
(4) Stille, J.K. Angew. Chem. 1986, 98, 504; Angew. Chem., Int. Ed.
Engl. 1986, 25, 508.
Monoprotected Manoalide, {4-[2,3-Dihydro-6-hydroxy-5-[(3E)-
4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)hex-3-en-1-yl]-
(5H)-pyran-2-yl]-5-[2-(trimethylsilyl)eth-1-oxy]furan-(5H)-one}
(17):
Stille, J.K.; Groh, B.L. J. Am. Chem. Soc. 1987, 109, 813.
McKean, D.R.; Parrinello, G.; Renaldo, A.F.; Stille, J.K. J. Org.
Chem. 1987, 52, 422.
Aldehyde 16 (22 mg, 0.04 mmol) was dissolved in benzene (15 mL)
and irradiated with a Philips HPK 125 W lamp at 0°C. After evapo-
ration of the solvent the crude product was chromatographed (PE/E,
1:1) to give 17 (12 mg, 0.02 mmol, 55%) as colourless oil (mixture of
diastereomers).
Stille, J.K.; Echavarren, A.M. J. Am. Chem. Soc. 1987, 109, 5478.
(5) Julia, M.; Julia, S.; Guegan, R. Bull. Soc. Chim. Fr. 1960, 1072.
Julia, M.; Julia, S.; Tshen, S-Y. Bull. Soc. Chim. Fr. 1961, 1849.
(6) Brady, S.F.; Ilton, M.A.; Johnson W.S. J. Am. Chem. Soc. 1968,
2882.
(7) de Silva, E.D:; Scheuer, P.J. Tetrahedron Lett. 1981, 22, 3147.
(8) a) Hoffmann, H.M.R.; Gerlach, K.; Lattmann, E. Synthesis 1996,
164.
1H NMR (400 MHz, CDCl3), J(Hz): δ = 6.07 (s, 1 H, H-25), 5.92 (s,
1 H, H-2), 5.72 (m, 1 H, H-6), 5.32 (s, 1 H, H-24), 5.14 (t, J = 7.8, 1
H, H-10), 4.76 (dd, J = 11, 3.5, 1 H, H-4), 3.98, 3.80 (m, 2 H, H-26),
2.39–2.25 (m, 2 H, H-5), 2.24–1.98 (m, 8 H, H-16, H-13, H-12, H-8),
b) Gerlach, K.; Hoffmann, H.M.R. Synlett 1998, 682.