The first total synthesis of (-)-methyl barbascoate

Article abstract of DOI:10.1021/jo0478499

(Chemical Equation Presented) The neo-trans-clerodane natural product, (-)-methyl barbascoate 1, has been synthesized for the first time starting from the known ketone 6 derived from (R)-(-)-Wieland-Miescher ketone analogue 5.

Full text of DOI:10.1021/jo0478499

The First Total Synthesis of (-)-Methyl Barbascoate
Hisahiro Hagiwara,*,† Kenta Hamano,† Masato Nozawa,† Takashi Hoshi,‡ Toshio Suzuki,‡ and
Fusao Kido§
Graduate School of Science and Technology, Niigata University, 8050, 2-Nocho, Ikarashi,
Niigata 950-2181, Japan, Faculty of Engineering, Niigata University, 8050, 2-Nocho, Ikarashi,
Niigata 950-2181, Japan, and Tsuruoka National College of Technology, 104 Sawada, Inooka,
Tsuruoka, Yamagata, 997-0842, Japan
hagiwara@gs.niigata-u.ac.jp
Received December 6, 2004
The neo-trans-clerodane natural product, (-)-methyl barbascoate 1, has been synthesized for the
first time starting from the known ketone 6 derived from (R)-(-)-Wieland-Miescher ketone analogue
5.
Clerodane diterpenoids constitute a large family of
more than 800 compounds.1 The structures of these
family members incorporate cis- or trans-decalin rings
with varying levels of oxygenation, often bearing pendant
furan or lactone rings. These substituents have different
stereochemical orientations. In addition, clerodanes exist
in two enantiomeric series typified by methyl barbascoate
12 and floribundic acid 2.3 The structural diversity and
intriguing biological activities, such as insect anti feedant
or antitumor activity, have stimulated the interest of
many synthetic organic chemists, although significant
synthetic challenges still surround a general approach
to clerodane diterpenoids.1
analysis, and the absolute stereochemistry was assigned
by comparison with the CD spectra of (-)-methyl hard-
wickiate 3. An interesting structural feature of 1 is that
the lactone ring has an unusual boat conformation with
an R-equatorial furan ring at C-12 (clerodane number-
ing).
In 1976, Wilson and co-workers reported the isolation
of (-)-methyl barbascoate 12 from the ethanol extract of
Croton californicus, which is common in the Mohave
Desert. Although the exact biological activity of 1 is
unexplored, the powdered leaves were used traditionally
as a pain reliever for rheumatism and the plant has been
used by fishermen to stun fish. The relative stereostruc-
ture of 1 was determined by a single-crystal X-ray
† Graduate School of Science and Technology, Niigata University.
‡ Faculty of Engineering, Niigata University.
§ Tsuruoka National College of Technology.
(1) Liu, H.-J.; Zhu, J.-L.; Chen, I.-C.; Jankowska, R.; Han, Y.; Shia,
K.-S. Angew. Chem., Int. Ed. 2003, 42, 1851 and earlier references
therein. Tokoroyama, T. Synthesis 2000, 611. Meritt, A. T.; Ley, S. V.
Nat. Prod. Rep. 1992, 9, 243.
Our ongoing program directed toward terpenoid syn-
thesis starting from Wieland-Miescher ketone analogue
5,4 and the lack of successful total synthesis of clerodane
natural products having a furo-lactone moiety, prompted
us to investigate the total synthesis of (-)-methyl bar-
(2) Wilson, S. R.; Neubert, L. A.; Huffman, J. C. J. Am. Chem. Soc.
1976, 98, 3669.
(3) Billet, D.; Durgeat, M.; Heitz, S.; Ahond, A. Tetrahedron Lett.
1975, 16, 3825.
10.1021/jo0478499 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/22/2005
2250
J. Org. Chem. 2005, 70, 2250-2255

Total Synthesis of (-)-Methyl Barbascoate
SCHEME 1. Synthetic Strategy
SCHEME 2a
bascoate 1. Our interest in the structural similarity of
methyl barbascoate 1 to the hallucinogenic clerodane
salvinorin A 45 provided an additional stimulus for
synthesizing 1.
Results and Discussion
Our synthetic strategy is outlined in Scheme 1. Known
decalone 6,6 previously synthesized from optically pure
57 during our total synthesis of clerodane antibiotics, was
chosen as the starting material. Decalone 6 contains
three of the five asymmetric centers in the target
molecule 1 in addition to having requisite oxygenated
functionalities for further transformations. The ready
availability of decalone 6 in enantiomerically pure form
stimulated three syntheses8 from this method since our
a Reagents and conditions: (i) Ph3PCH3 Br, NaHMDS, THF,
reflux, 87%; (ii) TBAF, THF, quant.; (iii) SO3-Pyr, DMSO, Et3N,
CH2Cl2, 88%; (iv) 3-furyllithium, t-BuLi, THF, -78 °C, 99% (13/
16 ) 4:1); (v) TBDMSCl, imidazole, DMAP, DMF, 91%; (vi) DEAD,
PPh3, p-NO2PhCO2H, THF, rt, 66% (15/18 ) 3:2); (vii) BH3-THF
then H2O2, NaOH, 32%; (viii) PDC, AcONa, MS-4A,CH2Cl2, 76%
in three steps; (xii) PPTS H2O, acetone, reflux, 40%.
(4) Our recent efforts in this area, Hagiwara, H.; Takeuchi, F.;
Nozawa, M.; Hoshi, T.; Suzuki, T. Tetrahedron 2004, 60, 1983. Nozawa,
M.; Hoshi, T.; Suzuki, T.; Hagiwara, H. Synth. Commun. 2004, 34,
187. Hagiwara, H.; Sakai, H.; Uchiyama, T.; Ito, Y.; Morita, N.; Hoshi,
T.; Suzuki, T.; Ando, M. J. Chem. Soc., Perkin Trans. 1 2002, 583.
Hagiwara, H.; Nagatomo, H.; Yoshii, F.; Hoshi, T. Suzuki, T.; Ando,
M. J. Chem. Soc., Perkin Trans. 1 2000, 2645. Hagiwara H.; Nagatomo
H.; Kazayama S.; Sakai H.; Hoshi T.; Suzuki T.; Ando M. J. Chem.
Soc., Perkin Trans. 1 1999, 457.
(5) Valdes, L. J. III; Butler, W. M.; Hatfield, G. M.; Paul, A. G.;
Koreeda, M. J. Org. Chem. 1984, 49, 4716. Ortega, A.; Blount, J. F.;
Marchand, P. S. J. Chem. Soc., Perkin Trans. 1 1982, 2505.
(6) Hagiwara, H.; Inome, K.; Uda, H. J. Chem. Soc., Perkin Trans.
1 1995, 757.
(7) Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308.
(8) Patin, A.; Kanazawa, A.; Philouze, C.; Greene, A. E.; Muri, E.;
Barreiro, E.; Costa, P. C. C. J. Org. Chem. 2003, 68, 3831. Ling, T.;
Rivas, F.; Theodorakis, E. A. Tetrahedron Lett. 2002, 43, 9019. Almsted,
J.-I. K.; Demuth, T. P., Jr.; Ledoussal, B. Tetrahedron: Asymmetry
1998, 9, 3179.
disclosure.8 A major issue in our present synthetic study
was how to install the furolactone moiety. To this end,
two divergent routes were designed for introducing the
furan containing side chain at C-9 and the carboxyl unit
at C-8 (Scheme 1).
We initially pursued route a, which introduces a furan
ring at the side chain (Scheme 2) prior to introduction of
the (8R)-carboxy unit. Initial attempts to directly intro-
duce various oxygenated carbon units at C-8 of decalin
J. Org. Chem, Vol. 70, No. 6, 2005 2251

Hagiwara et al.
stimulated a focus on route b, where the 8R formyl group
is introduced earlier (Scheme 3).
Hydroboration of the exo-methylene of 10 gave a 3.8:1
ratio of 8â and 8R alcohols 25 and 26 in 92% combined
yield. PDC oxidation of the minor 8R-alcohol 26 led to
8R-aldehyde 28, quantitatively. The configuration of C-8
was apparent from the coupling constants of the C-8
proton (δ. 2.6, J ) 11.3, 4.3, and 2.3 Hz). On the other
hand, PDC oxidation of the major 8â-alcohol 25, followed
by equilibration by sodium methoxide, provided 8R-
aldehyde 28 in 85% yield for two steps. The aldehyde 28
was protected as an acetal with 2-ethyl-2-methyl-1,3-
dioxolane in the presence of ethylene glycol and a
catalytic amount of p-toluenesulfonic acid (PTSA) to give
acetal 29 in 97% yield. Deprotection of the TIPS ether of
29 with TBAF in 97% yield followed by PDC oxidation
of the resulting alcohol 30 provided aldehyde 31 in 91%
yield. Addition of 3-furyllithium to the aldehyde 31 was
accomplished in 86% yield to give 12S and 12R-alcohol
32 and 33 in a 2:3 ratio. Stereochemistry was established
by the final transformation of 33 to methyl barbascoate
1. The modest preference for 33 is in the opposite sense
to the addition of 3-furyllithium to aldehyde 12 (Scheme
2). PM3 calculations locate the stable conformers of the
aldehydes 12 and 31 as illustrated in Figure 2, where
the re face is less congested in 12 and the si face is
slightly more accessible in 31. Addition of a Lewis acid
such as ZnCl2 or Ti(Oi-Pr)4 did not improve the selectiv-
ity.
FIGURE 1. Key nOe assignments.
6 failed, presumably since C-8 is a sterically hindered
neo-pentyl center. Fortunately, Wittig methylenation was
successful with triphenylphosphonium bromide and so-
dium bistrimethylsilylamide (NaHMDS) giving the exo-
methylene derivative 10 in 87% yield.
Deprotection of the TIPS ether of 10 with tetrabutyl-
ammonium fluoride (TBAF) proceeded quantitatively to
give alcohol 11 which was oxidized by DMSO-SO3/
pyridine complex9 to give aldehyde 12 in 88% yield.
Addition of 3-furyllithium to the aldehyde 12 provided a
4:1 ratio of 12S- and 12R-alcohols 13 and 16 in 99% yield.
The configuration of this newly introduced chiral center
was assigned by converting the minor diastereomer into
lactone 23 and observing key NOE enhancements (Figure
1). Since the minor 12R alcohol 16 is the desired
compound, the 12S-alcohol 13 was inverted under Mit-
sunobu reaction conditions which formed the 12S and
12R p-nitrobenzoates 15 and 18 in a 2:3 ratio. Although
the reaction proceeded mainly by an SN1 process due to
the electron-donating nature of the furan ring, a certain
amount of the desired 12R derivative 18 predominated.
Attempts to oxidize the 12S-alcohol 13, followed by
reduction, were not successful, since oxidation by Cr
oxidants or under Swern conditions led only to decom-
position and manganese dioxide oxidation was completely
ineffective.
Treatment of the acetal 33 with a catalytic amount of
PTSA in aqueous acetone at 45 °C resulted in deprotec-
tion of the two acetals and concomitant formation of the
hemi-acetal 34 which was oxidized with PDC to furnish
lactone 24.
Due to the sensitive nature of the furo-lactone moiety,
a mild procedure was required for the introduction of an
R,â-unsaturated ester moiety into 24. Thus, final conver-
sion to methyl barbascoate 1 was investigated by pal-
ladium-catalyzed carboxylation of enol triflate 35, which
was obtained from the decalone 24 by sequential treat-
ment with NaHMDS and Comins’ reagent [N-(5-chloro-
2-pyridyl)triflimide].10 In the presence of palladium ac-
etate, 1,1′-bis(diphenylphosphino)ferocene (DPPF), and
excess methanol11 in DMF under an atmosphere of
carbon monoxide the enol triflate 35 was successfully
carboxylated to complete the total synthesis of (-)-methyl
barbascoate 1. Repeated addition of catalytic Pd(OAc)2,
DPPF, and excess MeOH was a key requirement for
achieving a satisfactory yield. The spectral data (mp,
NMR, IR, [R]D), including the sign and value of optical
rotation were consonant with those previously reported,
confirming the absolute stereochemistry of 1 assigned by
Wilson et al. NOe enhancement between 8â-H and 12â-H
(15%) together with the coupling constants of 12â-H (J
) 9.8 and 7.6 Hz) indicated that the lactone ring of 1
has a boat conformation (Figure 3) not only in the solid
state but also in solution. Presumably, steric hindrance
between the furan at C-12 and the methyl group at C-9
forces the furan ring into equatorial orientation in a boat
conformation.
After protection of the 12R alcohol 16 as a TBDMS
ether in 91% yield, hydroboration of the exo-methylene
of TBDMS ether 17 proceeded solely from R-face of 17 to
give alcohol 19 in 32% yield. Equatorial attack of BH3
allows the nascent CH2BH2 group to avoid developing a
gauche interaction with the axial CH3 group. The yields
were not improved with other hydroborating reagents
although 17 was completely consumed. Pyridinium dichro-
mate oxidation (PDC) of the resulting alcohol 19 gave in
79% yield aldehyde 20 that was equilibrated by treat-
ment with sodium methoxide. Deprotecting the TBDMS
ether present in 21, with TBAF, resulted in spontaneous
ring closure to furnish an inseparable diastereomeric
mixture of hemiacetals 22. PDC oxidation of 22 afforded
lactone 23 in 75% yield from the aldehyde 20. The
relative stereochemistry and conformation of the lactone
23 was established by an nOe enhancement between
8â-H and 12â-H (Figure 1) together with the coupling
constants of 12â-H (J ) 11.2 and 6.6 Hz). Preliminary
MM2 calculations indicate the boat conformation to be
more stable than the chair conformation by 1.08 kcal/
mol. Hydrolysis of the ketal present in 23 provided ketone
24 in 40% yield.
Although the sequence assembles the carbocyclic frame-
work, the unsatisfactory hydroboration of 16 and the low
selectivity of the furyllithium addition to aldehyde 12
(10) Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org.
Synth. 1998, coll. vol 9, 165.
(11) Shishido, K.; Goto, K.; Miyoshi, S.; Takaishi, Y.; Shibuya, M.
J. Org. Chem. 1994, 59, 406.
(9) Parikh, J. R.; von E. Doering, W. J. Am. Chem. Soc. 1967, 89,
5505.
2252 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of (-)-Methyl Barbascoate
SCHEME 3a
a Reagents and conditions: (i) BH3-THF, THF then NaOH, H2O2, 92% (25/26 ) 3.8:1); (ii) PDC, AcONa, MS-4A,CH2Cl2, quant from
8R isomer, 89% from 8â isomer; (iii) MeONa, MeOH, rt, 95%; (iv) 2-ethyl-2-methyl-1,4-dioxolane, ethylene glycol, PTSA, 40 °C, 97%; (v)
TBAF, THF, rt, 97%; (vi) PDC, AcONA, MS-4A, CH2Cl2, 91%; (vii) 3-furyllithium, n-BuLi, THF, -78 °C, 86% (32/33 ) 2:3); (viii) PTSA,
H2O, acetone, reflux, 70% (a mixture of 1:1 diastereomers); (ix) PDC, AcONa, MS-4A,CH2Cl2, rt, quant; (x) NaHMDS, Comins’ reagent,
-78 to -30 °C, 80%; (xi) Pd(OAc)2, DPPF, n-Bu3N, CO, MeOH, DMF, 90 °C, 86%.
suspension of methyltriphenylphosphonium bromide (427 mg,
1.19 mmol) in THF (6 mL) was added sodium bis(trimethyl-
silyl)amide (0.995 mL, 1.0 M solution in THF, 0.995 mmol)
dropwise at 0 °C under nitrogen atmosphere. After being
stirred for 30 min, a solution of silyl ether 6 (175 mg, 0.399
mmol) in THF (2 mL) was added. The resulting solution was
stirred at 65 °C for 4 h. The reaction was quenched by addition
of aq ammonium chloride. The product was extracted with
ethyl acetate twice. The combined organic layer was washed
with brine, dried over anhydrous sodium sulfate, and evapo-
rated to dryness. MPLC purification of the residue (eluent:
ethyl acetate/n-hexane ) 1:6) provided methylene compound
10 (151 mg, 87%): [R]D -16.3 (c 0.984, CHCl3); IR (CCl4) 3100,
2943, 2866, 1635 cm-1; H NMR (200 MHz, CDCl3) δ 0.97 (s,
1
FIGURE 2. Stereochemistry of 3-furyllithium addition.
3H), 1.03-1.10 (m, 21H), 1.12 (s, 3H), 1.22-1.54 (m, 5H),
1.56-1.72 (m, 4H), 1.73-1.84 (ddd, J ) 9.5, 5.3, 3.2 Hz, 2H),
2.15 (dt like, 1H), 2.34 (m, 1H), 3.55-3.75 (m, 2H), 3.78-3.96
(m, 4H), 4.68 (s, 1H), 4.74 (s, 1H); 13C NMR (50 MHz, CDCl3)
δ 12.0 (CH × 3), 17.8, 18.0 (CH3 × 3), 21.4, 22.9, 23.8, 29.4,
30.3, 31.4, 41.5, 41.9, 43.3, 44.9, 59.5, 64.7, 65.1, 106.2, 113.2,
154.2. Anal. Calcd for C26H48O3Si: C, 71.5; H, 11.1. Found:
C, 71.3; H, 11.1.
((7R,8S,11R)-7-(2-(1,1-Bis(methylethyl)-2-methyl-1-sila-
propoxy)ethyl)-7,11-dimethylspiro(1,3-dioxolane-2,7′-
bicyclo[4.4.0]decane)-8-yl)methan-1-ol (25) and ((7R,8R,
11R)-7-(2-(1,1-Bis(methylethyl)-2-methyl-1-silapropoxy)-
ethyl)-7,11-dimethylspiro(1,3-dioxolane-2,7′-bicyclo[4.4.0]-
decane)-8-yl)methan-1-ol (26). To a stirred solution of
methylene compound 10 (500 mg, 1.15 mmol) in THF (6 mL)
was added borane-THF complex (2.7 mL, 1.04 M solution in
THF, 2.86 mmol) at -78 °C under nitrogen atmosphere. After
being stirred at room temperature for 1 h, 3 N aq sodium
hydroxide (7.6 mL, 23 mmol) followed by hydrogen peroxide
(2.6 mL, 30%, 23 mmol) were added at 0 °C. After the mixture
was stirred for 6 h at room temperature, the reaction was
quenched by addition of 1 N hydrochloric acid. The product
FIGURE 3. Conformation of methyl barbascoate 1.
In summary, we have completed the first total syn-
thesis of (-)-methyl barbascoate 1 (Scheme 3) in 12 steps
from the known decalone 6. The synthetic sequence is
general and would be applicable to other furo-lactone
clerodanes such as salvinorins.
Experimental Section
1-(2-((7S,11S)-7,11-Dimethyl-8-methylenespiro(1,3-di-
oxolane-2,7′-bicyclo[4.4.0]decane)-7-yl)ethoxy)-1,1-bis-
(methylethyl)-2-methyl-1-silapropane (10). To a stirred
J. Org. Chem, Vol. 70, No. 6, 2005 2253

Hagiwara et al.
was extracted with ethyl acetate twice. The combined organic
layer was washed with brine and evaporated to dryness. The
residue was purified by MPLC (eluent: ethyl acetate/n-hexane
) 1:3) to afford 8â-carbinol 25 (380 mg, 73%) and 8R-carbinol
26 (101 mg, 19%).
was extracted with ethyl acetate twice. The combined organic
layer was washed with brine, dried over anhydrous sodium
sulfate, and evaporated to dryness. Purification by column
chromatography (eluent: ethyl acetate/n-hexane ) 1:5) af-
forded 8R-aldehyde 28 (796 mg, 95%).
Alcohol 25: [R]D 0.32 (c 0.620, CHCl3); IR (CCl4) 3472, 2945,
1-[2-((7S,8R,11S)-8-(1,3-Dioxolan-2-yl)-7,11-dimethyl-
spiro(1,3-dioxolane-2,7′-bicyclo[4.4.0]decane)-7-yl)ethoxy]-
1,1-bis(methylethyl)-2-methyl-1-silapropane (29). A so-
lution of 8R-aldehyde 28 (796 mg, 1.76 mmol), ethylene glycol
(2 mL), and PTSA (17 mg, 0.088 mmol) in 2-ethyl-2-methyl-
1,3-dioxolane (5 mL) was stirred for 18 h at 40 °C under
nitrogen atmosphere. The solution was diluted with ethyl
acetate and washed with brine. Evaporation of the solvent
followed by column chromatography (eluent: ethyl acetate/n-
hexane ) 1:7) gave ketal 29 (851 mg, 97%): [R]D -5.65 (c 1.17,
CHCl3); IR (CCl4) 2945, 2868, 1462, 1383, 1178 cm-1; 1H NMR
(200 MHz, CDCl3) δ 0.85 (s, 3H), 1.00-1.11 (m, 24H), 1.20-
1.30 (m, 1H), 1.33-1.46 (m, 3H), 1.47-1.64 (m, 5H), 1.66-
1.81 (m, 3H), 3.55-3.98 (m, 11H), 4.96 (d, J ) 2.21 Hz, 1H);
13C NMR (50 MHz, CDCl3) δ 12.0 (CH × 3), 16.6, 17.0, 18.0
(CH3 × 3), 19.6, 20.2, 22.8, 29.6, 30.6, 37.6, 41.2, 43.5, 44.7,
45.9, 59.0, 64.2, 64.8, 65.1, 65.2, 104.2, 113.2, 206.6. Anal.
Calcd for C28H52O5Si: C, 67.7; H, 10.5. Found: C, 67.6; H, 10.4.
1
2870, 1462, 1383 cm-1; H NMR (200 MHz, CDCl3)δ 0.75 (s,
3H), 1.04 (s, 3H), 1.06-1.13 (m, 21H), 1.19-1.91 (m, 13H), 2.11
(m, 1H), 3.34 (dd, J ) 10.7, 4.0 Hz, 1H), 3.58-3.99 (m, 8H);
13C NMR (50 MHz, CDCl3) δ 11.9 (CH × 3), 17.0, 18.0 (CH3 ×
3), 18.5, 20.1, 21.8, 22.8, 29.8, 30.5, 38.0, 40.6, 43.4, 44.2, 45.6,
59.5, 64.8, 65.2, 65.1, 113.2; m/z 454 (M+, 3), 201 (71), 175
(100), 131 (27), 119 (27), 99 (100), 87 (36), 75 (31); HRMS m/z
calcd for C26H50O4Si 454.3478, found 454.3478.
Alcohol 26: [R]D 16.2 (c 0.827, CHCl3); IR (CCl4) 3450, 2945,
1
2868, 1383, 1186 cm-1; H NMR (200 MHz, CDCl3) δ 0.97 (s,
3H), 1.01-1.09 (m, 21H), 1.12 (s, 3H), 1.20-1.46 (m, 4H),
1.47-1.60 (m, 4H), 1.61-1.83 (m, 6H), 3.68-4.02 (m, 9H); 13
C
NMR (50 MHz, CDCl3) δ 11.9 (CH × 3), 17.8, 18.0 (CH3 × 3),
18.5, 20.1, 21.3, 22.9, 23.8, 30.2, 37.1, 41.8, 43.5, 44.1, 44.2,
59.4, 60.7, 64.7, 65.1, 113.3. Anal. Calcd for C26H50O4Si: C,
68.6; H, 11.0. Found: C, 68.3; H, 10.9.
(7S,8S,11S)-7-(2-(1,1-Bis(methylethyl)-2-methyl-1-sila-
propoxy)ethyl)-7,11-dimethylspiro(1,3-dioxolane-2,7′-
bicyclo[4.4.0]decane)-8-carbaldehyde (28). To a stirred
suspension of pyridinium dichromate (147 mg, 0.392 mmol),
sodium acetate (33 mg, 0.392 mmol), and anhydrous molecular
sieves 4A powder (67 mg) in dichloromethane (1.2 mL) was
added 8R-carbinol 26 (59 mg, 0.131 mmol) in dichloromethane
(1.7 mL) at room temperature. After being stirred for 2 h, the
organic layer was passed through silica gel short column with
the aid of ethyl acetate. Evaporation of the solvents gave
aldehyde 28 (60 mg, quant): [R]D -15.1 (c 0.956, CHCl3); IR
(CCl4) 2943, 2868, 1720, 1462, 1385 cm-1; 1H NMR (200 MHz,
CDCl3)δ 0.91 (s, 3H), 1.01-1.12 (m, 24H), 1.19-1.85 (m, 13H),
2.61 (ddd, J ) 11.3, 4.3, 2.3 Hz, 1H), 3.64-3.96 (m, 6H), 9.91
(d, J ) 2.1 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 11.9 (CH ×
3), 16.8, 18.0 (CH3 × 3), 18.2, 19.5, 19.8, 22.6, 28.7, 30.4, 38.3,
41.8, 43.1, 44.1, 55.6, 59.3, 64.8, 65.2, 112.9, 206.6; m/z 452
(M+, 20%), 411 (23), 410 (88), 409 (80), 348 (24), 347 (83), 235
(100), 199 (29), 73 (68); HRMS m/z calcd for C26H48O4Si
452.3322, found 452.3328.
2-((7S,8R,11S)-8-(1,3-Dioxolan-2-yl)-7,11-dimethylspiro-
(1,3-dioxolane-2,7′-bicyclo[4.4.0]decane)-7-yl)ethan-1-ol
(30). To a stirred solution of silyl ether 29 (179 mg, 0.36 mmol)
in THF (4 mL) was added TBAF (469 µL, 1.0 M in THF, 0.469
mmol) at 0 °C under nitrogen atmosphere. After the mixture
was stirred for 2.7 h, the reaction was quenched by addition
of aq ammonium chloride. The product was extracted with
ethyl acetate twice. The combined organic layer was washed
with brine, dried over anhydrous sodium sulfate, and evapo-
rated to dryness. The residue was purified by MPLC (eluent:
ethyl acetate ) 1) to provide alcohol 30 (119 mg, 97%): [R]D
4.56 (c 0.613, CHCl3); IR (CCl4) 3520, 2953, 2882, 1383, 1049
1
cm-1; H NMR (200 MHz, CDCl3) δ 0.86 (s, 3H), 1.05 (s, 3H),
1.19-1.58 (m, 9H), 1.59-1.82 (m, 5H), 1.89 (br s, 1H), 3.51-
3.78 (m, 2H), 3.79-4.00 (m, 8H), 4.87 (d, J ) 3.71 Hz, 1H);
13C NMR (50 MHz, CDCl3) δ 17.0, 17.6, 19.5, 20.0, 22.8, 29.6,
30.5, 37.8, 41.0, 43.3, 44.6, 46.1, 58.6, 64.4, 64.7 (CH2 × 3),
65.2, 104.5, 113.2; m/z 340 (M+, 6), 263 (61), 177 (64), 150 (76),
73 (100); HRMS m/z calcd for C19H32O5 340.2250, found M+,
340.2246.
(7S,8R,11S)-7-(2-(1,1-Bis(methylethyl)-2-methyl-1-sila-
propoxy)ethyl)-7,11-dimethylspiro(1,3-dioxolane-2,7′-
bicyclo[4.4.0]decane)-8-carbaldehyde (27). To a stirred
suspension of pyridinium dichromate (128 mg, 0.34 mmol),
sodium acetate (29 mg, 0.34 mmol), and anhydrous molecular
sieves 4A powder (58 mg, microwave dried) in dichloromethane
(1 mL) was added 8â-carbinol 25 (52 mg, 0.113 mmol) in
dichloromethane (1.5 mL) at room temperature. After being
stirred for 2 h, the organic layer was passed through silica
gel short column with the aid of ethyl acetate. Evaporation of
the solvents and subsequent MPLC purification (eluent: ethyl
acetate/n-hexane ) 1:4) gave 8â-aldehyde 27 (46 mg, 89%):
[R]D 11.8 (c 0.985, CHCl3); IR (CCl4) 2943, 2868, 1716, 1464,
1383 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.00-1.09 (m, 24H),
1.13 (s, 3H), 1.18-1.40 (m, 2H), 1.41-1.74 (m, 6H), 1.75-1.93
(m, 4H), 2.01 (dd, J ) 11.9, 2.2 Hz, 1H), 3.69 (t, J ) 7.1 Hz,
2H), 3.73-3.99 (m, 4H), 10.0 (d, J ) 2.8 Hz, 1H); 13C NMR
(50 MHz, CDCl3) δ 11.9 (CH × 3), 17.0, 18.0 (CH3 × 3), 19.8,
20.3, 21.0, 22.8, 25.5, 30.2, 36.8, 42.1, 43.4, 45.9, 54.0, 59.3,
64.8, 65.2, 113.0, 206.5; m/z 452 (M+, 20), 411 (23), 410 (88),
409 (80), 348 (24), 347 (83), 235 (100), 199 (29), 173 (68); HRMS
m/z calcd for C26H48O4Si 452.3322, found 452.3328.
2-((7S,8R,11S)-8-(1,3-Dioxolan-2-yl)-7,11-dimethylspiro-
(1,3-dioxolane-2,7′-bicyclo[4.4.0]decane)-7-yl)ethanal (31).
To a stirred suspension of pyridinium dichromate (310 mg, 0.83
mmol), sodium acetate (69 mg, 0.83 mmol), and anhydrous
molecular sieves 4A powder (100 mg, microwave dried) in
dichloromethane (1.5 mL) was added alcohol 30 (94 mg, 0.28
mmol) in dichloromethane (2 mL) at room temperature. After
being stirred for 2.5 h, the organic layer was passed through
silica gel short column with the aid of ethyl acetate. Evapora-
tion of the solvents and subsequent column chromatography
(eluent: ethyl acetate/n-hexane ) 1:1) gave aldehyde 31 (85
mg, 91%): IR (CCl4) 2951, 2882, 1716, 1475, 1452, 1385 cm-1
;
1H NMR (200 MHz, CDCl3) δ 0.94 (s, 3H), 1.06 (s, 3H), 1.35-
1.68 (m, 6H), 1.69-1.81 (m, 5H), 1.93 (m, 1H), 2.46 (dd, J )
15.6, 4.1 Hz, 1H), 2.76 (dd, J ) 15.6, 2.2 Hz, 1H), 3.69-4.05
(8H, m), 4.89 (d, J ) 4.8 Hz, 1H), 9.87 (dd, J ) 4.1, 2.2 Hz,
1H); 13C NMR (50 MHz, CDCl3) δ 18.2, 18.3, 20.0, 20.9, 22.4,
29.2, 30.2, 39.5, 43.4, 46.6, 47.3, 52.1, 64.4, 64.6, 64.7, 65.1,
104.8, 112.7, 203.7; m/z 338 (M+, 5), 113 (8), 112 (11), 100 (10),
99 (100), 86 (10), 73 (24); HRMS m/z calcd for C19H30O5
338.2093, found 338.2088.
Epimerization of Aldehyde 27. Sodium hydride (240 mg,
55% in mineral oil, 5.5 mmol) was washed with n-hexane and
dried in vacuo. To sodium hydride was added methanol (20
mL) at 0 °C under nitrogen atmosphere. To the solution was
added a solution of 8â-aldehyde 27 (832 mg, 1.84 mmol) in
methanol (30 mL) at 0 °C, and the resulting solution was
stirred at room temperature for 4 h. The reaction was
quenched by addition of aq. ammonium chloride and product
(1R)-2-((7S,8R,11S)-8-(1,3-Dioxolan-2-yl)-7,11-dimethyl-
spiro(1,3-dioxolane-2,7′-bicyclo[4.4.0]decane)-7-yl)-1-(3-
furyl)ethan-1-ol (33) and (1S)-2-((7S,8R,11S)-8-(1,3-Di-
oxolan-2-yl)-7,11-dimethylspiro(1,3-dioxolane-2,7′-bi-
cyclo[4.4.0]decane)-7-yl)-1-(3-furyl)ethan-1-ol (32). To a
stirred solution of 3-bromofuran (39 µL, 0.43 mmol) in THF
(1.0 mL) was added t-BuLi (556 µL, 1.45 M solution in
n-pentane, 0.81 mmol) at -78 °C under nitrogen atmosphere.
2254 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of (-)-Methyl Barbascoate
After the mixture was stirred at -78 °C for 1 h, a solution of
aldehyde 31 (97 mg, 0.29 mmol) in THF (2 mL) was added,
and the resulting solution was stirred at -78 °C for 2 h. The
reaction was quenched by addition of aq ammonium chloride.
After extraction with ethyl acetate twice, combined organic
layer was washed with brine, dried over anhydrous sodium
sulfate, and evaporated to dryness. Column chromatography
of the residue (eluent: ethyl aceate/dichloromethane ) 1:3)
afforded 12R-furano alcohol 33 (59 mg, 51%) and 12S-furano
alcohol 32 (41 mg, 35%) as an amorphous powder.
(12R)-Furano alcohol 33: [R]D -13.99 (c 1.222, CHCl3); IR
(CCl4) 3491, 2951, 2882, 1502, 1475, 1452, 1385 cm-1; 1H NMR
(200 MHz, CDCl3) δ 0.87 (s, 3H), 1.07 (s, 3H), 1.19-1.37 (m,
2H), 1.38-1.59 (m, 5H), 1.63-1.98 (m, 5H), 2.06 (dd, J ) 16.1,
8.7 Hz, 1H), 2.23 (m, 1H), 3.31 (d, J ) 5.1 Hz, 1H), 3.75-4.05
(m, 8H), 4.82 (br s, 1H), 4.83 (d, J ) 5.7 Hz, 1H), 6.36 (m, 1H),
7.32-7.41 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 17.1, 18.9,
19.4, 20.0, 22.6, 29.6, 30.4, 38.3, 43.4, 43.8, 46.2, 46.6, 63.2,
64.2, 64.6, 64.8, 65.3, 105.3, 108.4, 113.2, 131.4, 138.1, 143;
m/z 407 (28), 406 (M+, 100), 345 (25), 344 (36), 295 (24), 293
(45); HRMS m/z calcd for C23H34O6 406.2355, found 406.2359.
(12S)-Furano alcohol 32: [R]D -10.7 (c 0.810, CHCl3); IR
(CCl4) 3491, 2951, 2882, 1502, 1475, 1452, 1385 cm-1; 1H NMR
(200 MHz, CDCl3) δ 0.88 (s, 3H), 1.08 (s, 3H), 1.18-1.51 (m,
4H), 1.52-1.86 (m, 7H), 1.88-2.11 (m, 3H), 3.67-4.00 (m, 8H),
4.76 (d, J ) 3.4 Hz, 1H), 4.91 (dd, J ) 7.4, 2.9 Hz, 1H), 6.4 (m,
1H), 7.33-7.41 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 17.0,
17.6, 19.0, 20.7, 22.7, 29.5, 30.7, 38.5, 43.5, 45.0, 45.9, 46.4,
63.6, 64.4, 64.8, 65.3, 104.6, 108.6, 113.5, 131.2, 138.4, 143.0;
m/z 407 (18), 406 (74), 388 (26), 345 (21), 344 (35), 295 (22),
294 (23), 293 (100), 113 (25), 112 (30), 100 (22), 86 (29); HRMS
m/z calcd for C23H34O6 406.2355, found 406.2345.
7.52 (m, 2H); 13C NMR (67.5 MHz, CDCl3) δ 18.0, 19.0, 21.2,
21.4, 26.2, 31.6, 37.4, 37.5, 45.3, 47.4, 48.8, 55.3, 69.9, 108.5,
124.3, 139.4, 143.6, 173.8, 213.6; m/z 316 (M+, 56), 99 (72), 95
(66), 94 (100), 81 (55); HRMS m/z calcd for C19H24O4 316.1674,
found 316.1683.
(7S,10R,13R)-13-(3-Furyl)-1,7-dimethyl-12-oxa-11-
oxotricyclo[8.4.0.02,7]tetradec-5-en-6-yl (Trifluorometh-
yl)sulfonate (35). To a stirred solution of ketone 24 (34 mg,
0.11 mmol) in THF (2.0 mL) was added sodium bistrimethyl-
silylamide (434 mL, 1 M solution in THF, 0.43 mmol) at -78
°C under nitrogen atmosphere. After being stirred for 2 h,
Comins’s reagent (170 mg, 0.43 mmol) in THF (3.0 mL) was
added. The resulting solution was stirred at -30 °C for 1.3 h.
The reaction was quenched by addition of aq ammonium
chloride. After extraction with ethyl acetate twice, combined
organic layer was washed with brine, dried over anhydrous
sodium sulfate, and evaporated to dryness. Column chroma-
tography of the residue (eluent: ethyl acetate/n-hexane ) 1:3)
provided enol triflate 35 (39 mg, 80%) as crystals: mp 125 °C;
[R]D -7.75 (c 0.774, CHCl3); IR (CCl4) 3038, 2255, 1746, 1410
and 1142 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.01 (s, 3H), 1.19
(s, 3H), 1.35-1.67 (m, 4H), 1.68-2.09 (m, 5H), 2.16-2.22 (m,
2H), 2.55 (dd, J ) 11.7, 3.6 Hz, 1H), 5.36 (dd, J ) 10.1, 7.5
Hz, 1H), 5.59 (dd, J ) 4.7, 3.0 Hz, 1H), 6.42 (dd like, 1H), 7.42
(t, J ) 1.7 Hz, 1H), 7.46 (m, 1H); 13C NMR (50 MHz, CDCl3)
δ 20.1, 20.3, 22.0, 22.5, 26.4, 34.9, 38.7, 41.1, 47.1, 49.6, 55.6,
72.1, 110.6, 116.9, 126.5, 141.6, 145.8, 157.7, 175.7; m/z 448
(M+, 21), 295 (17), 105 (18), 95 (30), 94 (100), 91 (21), 81 (26);
HRMS m/z calcd for C20H23F3O6S 448.1167, found 448.1165.
Methyl (7S,10R,13R)-13-(3-Furyl)-1,7-dimethyl-12-oxa-
11-oxotricyclo[8.4.0.02,7]tetradec-5-ene-6-carboxylate
(Methyl Barbascoate, 1). A solution of enol triflate 35 (51.5
mg, 0.155 mmol), Pd(OAc)2 (1.3 mg, 0.006 mmol), n-Bu3N (38
µL, 0.207 mmol), DPPF (3.8 mg, 0.007 mmol), and methanol
(412 µL) in DMF (906 µL) was stirred under carbon monoxide
atmosphere at 90 °C for 20 min. Extra MeOH (412 µL), Pd-
(OAc)2 (1.3 mg, 0.006 mmol), and DPPF (3.8 mg, 0.007 mmol)
were added, and stirring was continued for 20 min. Further
MeOH (412 µL), Pd(OAc)2 (3.8 mg, 0.007 mmol), and DPPF
(3.8 mg, 0.007 mmol) were added, and stirring was continued
for 23 min. After addition of ethyl acetate, the organic layer
was passed through a silica gel short column and evaporated
to dryness. The residue was purified by column by chroma-
tography (eluent: ethyl acetate/n-hexane ) 1:3) to provide
methyl barbascoate 1 (35.4 mg, 86%) as crystals: mp 152 °C
(lit.2 mp 152-153 °C); [R]D -73.6 (c 0.425, MeOH) (lit.2 [R]D
-70); UV λ max (MeOH) 211 nm (14,874); IR (CCl4) 2991, 2949,
(7S,10R,11S,13R)-13-(3-Furyl)-11-hydroxy-1,7-dimeth-
yl-12-oxatricyclo[8.4.0.02,7]tetradecan-6-one (34). A solu-
tion of (12R)-furano alcohol 33 (59 mg, 0.145 mmol) and PTSA
(8.3 mg, 0.044 mmol) in acetone (4 mL) and water (263 µL, 15
mmol) was heated at 50 °C for 21 h. The product was extracted
with ethyl acetate twice. The combined organic layer was
washed with brine and evaporated to dryness. Column chro-
matography of the residue (eluent: ethyl aceate/dichlo-
romethane ) 1:5) afforded hemiacetal 34 (33 mg, 70%) as a
1:1 mixture of diastereomers as powder: mp 194 °C; [R]D -27.6
(c 0.722, CHCl3); IR (CCl4) 3600, 3072, 2992, 2943, 2872, 1703
1
cm-1; H NMR (200 MHz, CDCl3) δ 1.14 (s, 3H), 1.16 (s, 3H),
1.35-1.60 (m, 5H), 1.61-1.73 (m, 4H), 1.74-1.92 (m, 2H), 2.05
(m, 1H), 2.21 (m, 1H), 2.58 (dt, J 13.8, 6.6 Hz, 1H), 3.01-3.26
(m, 1H), 4.92 (dd, J 7.9, 2.9 Hz, 1H), 5.04 (dd, J 10.4, 6.6 Hz,
1H), 6.39 (m, 1H), 7.33-7.44 (m, 2H)); 13C NMR (50 MHz,
CDCl3) δ 19.0, 19.4, 20.4, 26.2, 32.3, 35.7, 37.6, 46.5, 46.6, 49.0,
55.9, 62.3, 95.9, 96.0, 108.7, 127.2, 138.9, 143.3, 214.8; m/z 300
(18), 152 (33), 121 (24), 95 (31), 94 (100); HRMS m/z calcd for
C19H24O3 (M+ - H2O) 300.1725, found 300.1725.
2860, 1759, 1720, 1242 cm-1 1H NMR (500 MHz, CDCl3) δ
;
1.02 (s, 3H), 1.28 (s, 3H), 1.45 (dd, J ) 11.2, 3.1 Hz, 1H), 1.54-
1.69 (m, 4H), 1.83-2.01 (m, 3H), 2.18-2.39 (m, 2H), 2.51 (dd,
J ) 11.6, 3.7 Hz, 1H), 2.55 (dt, J ) 13.1, 3.4 Hz, 1H), 3.70 (s,
3H), 5.34 (dd, J ) 9.8, 7.6 Hz, 1H), 6.42 (m, 1H), 6.63 (dd, J )
4.0, 3.1 Hz, 1H), 7.42 (m, 1H), 7.45 (m, 1H); 13C NMR (50 MHz,
CDCl3) δ 18.3 (t), 18.4 (t), 20.5 (q), 20.7 (q), 27.0 (t), 34.4 (t),
36.9 (s), 37.2 (s), 45.5 (t), 47.8 (d), 51.3 (q), 53.8 (d), 70.0 (d),
108.5 (d), 124.6 (s), 137.1 (d), 139.4 (d), 141.0 (s), 143.7 (d),
167.2 (s), 174.2 (s); m/z 358 (M+, 78), 205 (51), 107 (52), 105
(77), 96 (92), 91 (100); HRMS m/z calcd for C21H26O5 358.1780,
found 358.1775.
(7S,10R,13R)-13-(3-Furyl)-1,7-dimethyl-12-oxatricyclo-
[8.4.0.02,7]tetradecane-6,11-dione (24). To a stirred suspen-
sion of pyridinium dichromate (98 mg, 0.264 mmol), sodium
acetate (22 mg, 0.264 mmol), and anhydrous molecular sieves
4A powder (40 mg, microwave dried) in dichloromethane (1
mL) was added hemiacetal 34 (28 mg, 0.088 mmol) in dichlo-
romethane (1.5 mL) at room temperature. After the mixture
was stirred for 6 h, the organic layer was passed through a
silica gel short column with the aid of ethyl acetate. Evapora-
tion of the solvents gave lactone 24 (29 mg, quantitative) as
an amorphous solid: [R]D 31.2 (c 0.686, CHCl3); IR (CCl4) 2945,
Supporting Information Available: Experimental de-
tails of compounds 11-13, 16, 17, 19, and 21-23 and 1H and
13C NMR spectra of compounds 1, 10-13, 16, 17, and 19-35.
This material is available free of charge via the Internet at
http://pubs.acs.org.
2868, 1759, 1712, 1103 cm-1 1H NMR (270 MHz, CDCl3) δ
;
1.06, (s, 3H), 1.10 (s, 3H), 1.33-1.78 (m, 7H), 1.79-2.01 (m,
3H), 2.04-2.32 (m, 2H), 2.44 (m, 1H), 2.61 (dt, J ) 13.5, 6.5
Hz, 1H), 5.32 (dd, J ) 10.2, 7.1 Hz, 1H), 6.41 (m, 1H), 7.38-
JO0478499
J. Org. Chem, Vol. 70, No. 6, 2005 2255