Core structure of eremophilanes and bakkanes through niobium catalyzed Diels-Alder reaction: Synthesis of (±)-bakkenolide A

Article abstract of DOI:10.1021/jo061722x

A suitable intermediate for the synthesis of eremophilanes and bakkanes was prepared by a highly regioselective and stereoselective one-step synthesis through a niobium catalyzed Diels-Alder reaction. As a demonstration of the versatility of this intermed

Full text of DOI:10.1021/jo061722x

(Petasites japonicus); two research groups realized the isolation
independently. Kitahara et al.3a named the new product after
the local name of the plant (“bakke”). Similarly, Naya et al.3b
used another local name (“fuki”) of the plant, proposing the
nowadays less used name “fukinanolide” for this natural product.
Since the first synthesis of bakkenolide A (1) by Evans,6 a
number of alternative syntheses, more or less efficient, have
been described.7 The challenging structural features of these
compounds have also attracted the attention of our research
group; in a number of papers we have described the synthesis
of model â-methylene-γ-spirolactones8 and some efforts toward
the use of the Diels-Alder reaction for building the main frame.9
Core Structure of Eremophilanes and Bakkanes
through Niobium Catalyzed Diels-Alder
Reaction: Synthesis of (()-Bakkenolide A
Mauricio G. Constantino,*,† Kleber T. de Oliveira,†
Ellen C. Polo,† Gil V. J. da Silva,† and
Timothy J. Brocksom‡
Departamento de Qu´ımica, Faculdade de Filosofia Cieˆncias e
Letras de Ribeira˜o Preto, UniVersidade de Sa˜o Paulo, AVenida
dos Bandeirantes, 3900, 14040-901, Ribeira˜o Preto, SP, Brazil,
and Departamento de Qu´ımica, UniVersidade Federal de Sa˜o
Carlos, 13565-905, Sa˜o Carlos, Brazil
Recently, we have become interested in investigating the use
of niobium pentachloride as a Lewis acid catalyst for a number
of reactions.10 We have found that many Diels-Alder reactions
are highly accelerated by NbCl5 and can be carried out even at
a temperature of -78 °C,11 thus markedly improving stereose-
lectivity and regioselectivity, as well as reducing polymerization
byproducts. We have thus sought a novel method of producing
the eremophilane and bakkane skeleton using this catalyst and
obtained excellent results. We have synthesized for the first time
the intermediate 4, containing all the main relative stereochem-
istry of eremophilanes and bakkanes and having reactive
functionalities which allow its transformation into most of these
natural products. As a demonstration of the versatility of
compound 4, we have carried out the synthesis of (()-
bakkenolide A (1) from 4 incorporating one of our previously
described methods for preparing the â-methylene-γ-spirolactone
moiety.8 Diene 3 was prepared from the corresponding alcohol12
by protection of the hydroxyl group with the benzyl group.13
The synthesis of the adduct 4 was realized through the Diels-
mgconsta@usp.br
ReceiVed August 18, 2006
A suitable intermediate for the synthesis of eremophilanes
and bakkanes was prepared by a highly regioselective and
stereoselective one-step synthesis through a niobium cata-
lyzed Diels-Alder reaction. As a demonstration of the
versatility of this intermediate, a total synthesis of (()-
bakkenolide A is described.
Eremophilanes are sesquiterpene natural products derived
biosynthetically by rearrangement of eudesmanes, containing a
cis-decalin system with an uncommon cis-1,2-dimethyl substitu-
tion pattern.1 Bakkane sesquiterpenes comprise a relatively rare
class of natural products biosynthetically derived from the
eremophilanes. The bakkanes contain a â-methylene-γ-butyro-
lactone spiro ring fused to a cis-dimethyl-cis-hydrindane carbon
skeleton;2 bakkenolide A (1) is the most well-known member
(Figure 1).3
Several different biological activities have been described for
eremophilanes and bakkanes.2 Bakkenolide A (1), for instance,
shows cytotoxic activity,4 as well as influences on larval
growth.5 This natural product was isolated for the first time from
the stems of a Japanese plant of the Compositae family
(6) (a) Evans, D. A.; Sims, C. L. Tetrahedron Lett. 1973, 4691. (b) Evans,
D. A.; Sims, C. L.; Andrews, G. C. J. Am. Chem. Soc. 1977, 99, 5453.
(7) (a) Hayashi, K.; Nakamura, H.; Mitsuhashi, H. Chem. Pharm. Bull.
1973, 21, 2806. (b) Greene, A. E.; Depre´s, J. P.; Coelho, F.; Brocksom, T.
J. J. Org. Chem. 1985, 50, 3943. (c) Back, T, G.; Payne, J. E. Org. Lett.
1999, 1, 663. (d) Back, T, G.; Nava-Salgado, V. O.; Payne, J. E. J. Org.
Chem. 2001, 66, 4361. (e) Brocksom, T. J.; Coelho, F.; Depre´s, J. P.; Greene,
A. E.; de Lima, M. E. F.; Hamelin, O.; Hartmann, B.; Kanazawa, A. M.;
Wang, Y. J. Am. Chem. Soc. 2002, 124, 15313. (f) Reddy, D. S. Org. Lett.
2004, 6, 3345.
(8) (a) Campbell, S. F.; Constantino, M. G.; Brocksom, T. J.; Petragnani,
N. Synth. Commun. 1975, 5, 353. (b) Petragnani, N.; Brocksom, T. J.; Ferraz,
H. M. C.; Constantino, M. G. Synthesis 1977, 112. (c) Petragnani, N.;
Brocksom, T. J.; Ferraz, H. M. C.; Constantino, M. G. Quim. NoVa 1978,
1, 8. (d) Brocksom. T. J.; Constantino, M. G.; Ferraz, H. M. C. Synth.
Commun. 1977, 7, 483.
(9) (a) Brocksom, T. J.; Constantino, M. G. An. Acad. Brasil. Cieˆnc.
1982, 54, 655. (b) Brocksom, T. J.; Constantino, M. G. J. Org. Chem. 1982,
47, 3450.
(10) (a) Constantino, M. G.; Lacerda, V., Jr.; Silva Filho, L. C.; Silva,
G. V. J. Lett. Org. Chem 2004, 1, 369. (b) Constantino, M. G.; Lacerda,
V., Jr.; Silva, G. V. J. J. Heterocyclic Chem. 2003, 40, 369. (c) Constantino,
M. G.; Lacerda, V., Jr.; Silva, G. V. J. Molecules 2002, 7, 456. (d)
Constantino, M. G.; Lacerda, V., Jr.; Araga˜o, V. Molecules 2001, 6, 770.
(11) (a) Constantino, M. G.; Silva Filho, L. C.; Cunha Neto, A. Heleno,
V. C. G; da Silva, G. V. J; Lopes, J. L. C Spectrochim. Acta A 2005, 61,
171. (b) Silva Filho, L. C.; Lacerda, V., Jr.; Constantino, M. G.; da Silva,
G. V. J. Unpublished results.
* To whom correspondence should be addressed. Phone: (+55)-16-602-3747.
Fax: (+55)-16-602-4838.
† Universidade de Sa˜o Paulo.
‡ Universidade Federal de Sa˜o Carlos.
(1) Porter, J.; Spurgeon, S. L. Biosynthesis of Isoprenoid Compounds;
John Wiley & Sons, New York, 1981; Vol. 1.
(2) Silva Jr., L. F. Synthesis 2001, 671.
(3) (a) Abe, N.; Onoda, R.; Shirahata, K.; Kato, T.; Woods, M. C.;
Kitahara, Y. Tetrahedron Lett. 1968, 369. (b) Naya, K.; Takagi, I.; Hayashi,
M.; Nakamura, S.; Kobayashi, M.; Katsumura, S. Chem. Ind. 1968, 318.
(c) Naya, K.; Hayashi, M.;Takagi, I.; Nakamura, S.; Kobayashi, M. Bull.
Chem. Soc. Jpn. 1972, 45, 3673.
(12) (a) Muskat, I. E.; Becker, B. C.; Lowenstein, J. S. J. Am. Chem.
Soc. 1930, 52, 326. (b) Peck, R. L. Chem. Abstr. 1960, 54, 6719h. (c) Oida,
S.; Ohki, E. Chem. Pharm. Bull. 1969, 17, 1996.
(4) Jamieson, G. R.; Reid, E. H.; Turner, B. P.; Jamieson, A. T.
Phytochemistry 1976, 15, 1713.
(5) Nawrot, J.; Harmatha, J.; Novotny, L. Biochem. Syst. Ecol. 1984,
12, 99.
(13) (a) Du, X.; Chu, H. V.; Kwon, O. Org. Lett. 2003, 5, 1923. (b)
Lubineau, A. Auge´, J. Lubin, N. Tetrahedron 1993, 49, 4639.
(14) Cunha, S.; Lia˜o, L. M.; Bonfim, R. R.; Bastos, R. M.; Monteiro,
A. P. M.; Alencar, K. S. Quim. NoVa 2003, 26, 425.
10.1021/jo061722x CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/18/2006
9880
J. Org. Chem. 2006, 71, 9880-9883

FIGURE 1. Natural products with similar core structures.
SCHEME 1. Structural Model for the Synthesis of
Eremophilane and Bakkane Systems
except that now we have additional stereochemical issues to
take into account.
Alkylation of 7 with the anion of methyl 3,3-dimethylacrylate
proceeded with high chemoselectivity: only the products
alkylated at the less-hindered iodide were isolated (85% yield
of the mixture of 8a and 8b, epimers at R-carbonyl carbon).
This relative stereochemistry is irrelevant for the synthesis, as
both epimers will give the same enolate during the ring closure
step; we could therefore use the mixture directly, thus avoiding
a tedious separation process which was carried out only for
analytical purposes.
SCHEME 2. Regioselective and Stereoselective Diels-Alder
Reaction Catalyzed by NbCl5
The cyclization process, on the other hand, produces a new
stereogenic center that is a matter of major concern: only the
epimer 10, obtained as minor product, could give (()-bakkeno-
lide A (1). Examining a molecular model of the enolate from
8, we could see that the preference for the transformation of
this enolate into 10 or 11 should be determined by the difference
in steric hindrance between the groups CO2R and C(CH3)d
CH2; it seems that a larger ester group would improve the
preference for the desired epimer 10.
Alder reaction between diene 3 and tiglic aldehyde (2) in
anhydrous dichloromethane, using NbCl5 (0.25 equiv) as a
catalyst (Scheme 1). Product 4 is formed through an ortho-endo
transition state, usually favored with this type of substrate
(Scheme 2).
These considerations were confirmed when we were able to
improve the ratio of epimers from 18:82 (10/11) to 50:50 (12/
13) just by changing the ester group from -CO2Me to -CO2t-
Bu.
For the following steps, we have used the mixture of epimers
(12/13): treatment with NBS followed by lactonization with
Ag2O gave a mixture of (()-bakkenolide A (1) and (()-7-epi-
bakkenolide A (16) in 65% yield and thus 13.3% overall yield
in eight steps. As already described in the literature,7d (()-
bakkenolide A (1) can be obtained from this mixture. For
analytical purposes we have realized the separation by HPLC.
The one-step preparation of a cis-1,2-dimethylated cyclohex-
ane, already properly substituted to allow further transforma-
tions, with high regioselectivity and stereoselectivity, is the most
remarkable aspect of this process. Compounds 2 and 3 do not
react in the absence of Lewis acids; the role of NbCl5 is very
important because it increases reactivity so much that it can
now be carried out from -78 to -50 °C, thus reducing diene
polymerization and improving stereoselectivity (Scheme 3).
Product 4 was isolated by silica gel chromatography with 45%
yield. For the purpose of synthesizing bakkenolide A, however,
it is more convenient to reduce the crude product directly with
LiAlH4, thus obtaining alcohol 5 in 42% yield over two steps,
because reduction of purified 4 with LiAlH4 (84% yield) gives
a lower (38%) overall yield.
The reduction of the double bond of 5 and the hydrogenolysis
of its benzyl ether were accomplished in one step by treatment
with hydrogen and Pd-C.15 The resulting diol 6 was trans-
formed into the corresponding diiodide 7 with Me3SiI,7e thus
avoiding possible complications that usually occur when treating
1,4-diols with PX3.16
In conclusion, compound 4, a useful intermediate for the
synthesis of bakkanes and eremophilanes, was prepared through
a low-temperature niobium pentachloride catalyzed Diels-Alder
reaction. A notable aspect of this reaction is the production, in
just one step, of three stereogenic centers with the correct relative
configuration and with high regioselectivity. The parent bakkane,
bakkenolide A, was prepared in racemic form in 10 steps from
â-vinylacrylic acid. The overall yield of a 1:1 mixture of (()-
bakkenolide A and its epimer at C7 is 8.9%.
Experimental Section
(()-{(1R,2S,6S)-2-[(Benzyloxy)methyl]-1,6-dimethylcyclohex-
3-en-1-yl}methanol (5) Obtained Directly from 2 and 3. To a
solution of NbCl5 (405 mg, 1.50 mmol) in 7 mL of CH2Cl2 at -78
°C was added a solution of tiglic aldehyde 2 (2.02 g, 24.0 mmol)
in 7 mL of CH2Cl2 at -78 °C. After the mixture was stirred for 2
min, we added a solution of diene 3 (1.05 g, 6.00 mmol) in 7 mL
of CH2Cl2 at -78 °C. After 30 min, the temperature was raised to
-50 °C and the stirring was maintained for 72 h. After that, water
From this point on, we have used essentially the same
methodology previously described for the model compound,8a,d
(15) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; John Wiley & Sons: New York, 1991.
(16) Constantino, M, G.; Souza, A. X.; da Silva, G. V. J. Molecules
2002, 7, 475.
J. Org. Chem, Vol. 71, No. 26, 2006 9881

SCHEME 3. Synthesis of (()-Bakkenolide A (1) and 7-epi-(()-Bakkenolide A (16)a
a Conditions: (a) (i) NbCl5, CH2Cl2, -78 °C f -50 °C, 72 h; (ii) LiAlH4, THF, 0 °C, 1 h (42%, two steps). (b) H2, Pd-C, ethanol, 4 atm, 4 h (99%).
(c) Me3SiI, CHCl3, rt, 120 h (70%). (d) Methyl 3,3-dimethylacrylate, LDA/HMPA/THF, -78 °C f 0 °C, 30 min (85% of diastereoisomeric mixture). (e)
tert-Butyl 3,3-dimethylacrylate,14 LDA/HMPA/THF, -78 °C f 0 °C, 30 min (92% of diastereoisomeric mixture). (f) LDA/HMPA/THF, -78 °C (3 h for
R ) Me in 57% yield; 7 h for R ) t-Bu in 77% yield). (g) NBS, benzoyl peroxide, CCl4, hν, 3 h (95%). (h) Ag2O, CCl4, reflux, 3 h (68%).
(20 mL) was added and the aqueous phase was extracted with CH2-
Cl2 (4 × 30 mL). The combined organic phase was washed with
brine and dried (MgSO4). After solvent evaporation, the crude
product was dissolved in 20 mL of THF and added to a suspension
of LiAlH4 (1.0 g, 25 mmol) in 20 mL of THF at 0 °C. The reaction
mixture was stirred for 1 h and quenched with water (50 mL) at 0
°C. The aqueous phase was extracted with ether (4 × 50 mL), and
the combined organic layer was washed with brine and dried
(MgSO4). After solvent evaporation, the clear oil was purified by
column chromatography (silica gel, hexanes with 5% ethyl acetate)
to afford the alcohol 5 (656 mg, 2.52 mmol) in 42% yield. 1H NMR
(CDCl3, 400 MHz) δ (ppm): 0.82 (d, 3H, J ) 6.6 Hz), 0.89 (s,
3H), 1.60-1.74 (m, 2H), 1.94 (dddd, 1H, J1 ) 13.0 Hz, J2 ) 4.8
Hz, J3 ) 2.3 Hz, and J4 ) 1.0 Hz), 2.27 (dddd, 1H, J1 ) 8.8 Hz,
J2 ) 5.2 Hz, J3 ) 2.4 Hz, and J4 ) 1.7 Hz), 3.36 (dd, 1H, J1 )
10.1 Hz and J2 ) 2.4 Hz), 3.38 (d, 1H, J ) 11.9 Hz), 3.50 (d, 1H,
J ) 11.9 Hz), 3.55 (dd, 1H, J1 ) 10.1 Hz and J2 ) 8.8 Hz), 4.53
(br, 2H), 5.48 (ddt, 1H, J1 ) 10.0 Hz, J2 ) 5.2 Hz, and J3 ) 1.0
Hz), 5.65 (ddt, 1H, J1 ) 10.0 Hz, J2 ) 4.8 Hz, and J3 ) 1.7 Hz),
7.27-7.40 (m, 5H). 13C NMR (CDCl3, 100 MHz) δ (ppm): 15.0
(CH3), 16.1 (CH3), 29.3 (CH), 31.9 (CH2), 39.0 (C), 43.7 (CH),
68.2 (CH2), 71.0 (CH2), 73.6 (CH2), 126.4 (CH), 128.0 (CH), 128.0
(CH), 127.6 (CH), 128.1 (CH), 128.6 (CH), 137.2 (C). IR νmax (neat
KBr) (cm-1): 698, 736, 1092, 1494, 2880, 2962, 3024, 3140-
261.1849; found, 261.1859 (∆ ) 3.8 ppm). Anal. Calcd for
C17H24O2: C, 78.42; H, 9.29. Found: C, 78.80; H, 9.54.
(()-(2S) and (()-(2R)-tert-Butyl 2-{[(1R,2R,3S)-2-(Iodo-
methyl)-2,3-dimethyl-cyclohexyl]methyl}-3-methylbut-3-enoate
(9a) and (9b). To a solution of diisopropylamine (0.33 mL, 239
mg, 2.36 mmol) in 4 mL of THF at 0 °C was added 1.00 mL (2.15
mmol) of a 2.15 mol/L solution of n-butyllithium in hexanes. The
mixture was stirred for 15 min, and HMPA (0.46 mL, 2.65 mmol)
was added and stirred for an additional time of 15 min. The solution
of LDA/HMPA was cooled to -78 °C, and a solution of tert-butyl
3,3-dimethylacrylate (343 mg, 2.20 mmol) in 0.5 mL of THF was
added and stirred for 20 min. The diiodide 7 (420 mg, 1.07 mmol)
in 2 mL of THF cooled to -78 °C was then added, and the reaction
mixture was stirred for 3 min. The temperature of the reaction
system was slowly increased up to 0 °C (∼30 min), and the mixture
was stirred for 30 min. The reaction was quenched with water (20
mL), and the aqueous phase was extracted with ether (3 × 40 mL).
The combined organic phases were washed with brine and dried
(MgSO4). After solvent evaporation, the yellow oil was purified
by column chromatography (silica gel, hexanes with 5% ethyl
acetate) to afford a mixture of diastereoisomers 9a and 9b (416
mg, 0.99 mmol) in 92% yield. The analysis of 9a/9b was realized
1
by comparison of the H NMR data of the mixture of 8a/8b. IR
+
3658. HRMS (ESI-TOF): calculated for C17H25O2 (MH+),
ν
max (neat KBr) (cm-1): 896, 1148, 1460, 1648, 1726, 2930, 2972.
9882 J. Org. Chem., Vol. 71, No. 26, 2006

HRMS (ESI-TOF): calculated for C19H34IO2+ (MH+), 421.1598;
found, 421.1585 (∆ ) 3.1 ppm).
Hz, and J4 ) 2.3 Hz), 4.74 (ddd, 1H, J1 ) 12.8 Hz, J2 ) 2.3 Hz,
and J3 ) 2.1 Hz), 4.80 (ddd, 1H, J1 ) 12.8 Hz, J2 ) 2.3 Hz, and
J3 ) 2.1 Hz), 5.03 (t, 1H, J ) 2.1 Hz), 5.11 (t, 1H, J ) 2.3 Hz).
13C NMR (CDCl3, 100 MHz) δ (ppm): 16.4 (CH3), 19.2 (CH3),
21.0 (CH2), 23.3 (CH3), 30.9 (CH2), 33.9 (CH), 42.4 (CH2), 44.0
(C), 46.2 (CH), 48.5 (CH2), 49.9 (C), 70.4 (CH2), 105.8 (CH2),
150.4 (C), 182.6 (C). (()7-epi-Bakkenolide A (16).7d 1H NMR
(CDCl3, 500 MHz) δ (ppm): 0.82 (d, 3H, J ) 6.7 Hz), 0.97 (s,
3H), 1.02-1.18 (m, 1H), 1.42-1.65 (m, 5H), 1.52 (d, 1H, J )
14.1 Hz), 1.66 (dd, 1H, J1 ) 12.5 Hz and J2 ) 6.6 Hz), 1.91 (dqd,
1H, J1 ) 12.5 Hz, J2 ) 6.7 Hz, and J3 ) 3.0 Hz), 1.95-2.03 (m,
1H), 2.40 (d, 1H, J ) 14.1 Hz), 2.46 (dd, 1H, J1 ) 13.7 Hz and J2
) 12.5 Hz), 4.76 (ddd, 1H, J1 ) 12.9 Hz, J2 ) 2.2 Hz, and J3 )
1.8 Hz), 4.81 (dd, 1H, J1 ) 12.9 Hz, J2 ) 2.2 Hz, and J3 ) 1.8
Hz), 4.99 (t, 1H, J ) 1.8 Hz), 5.07 (t, 1H, J ) 2.2 Hz). 13C NMR
(CDCl3, 100 MHz) δ (ppm): 16.6 (CH3), 19.7 (CH3), 21.0 (CH2),
23.6 (CH3), 30.8 (CH2), 33.0 (CH), 41.5 (CH2), 44.1 (C), 46.9 (CH),
50.0 (C), 50.1 (CH2), 70.1 (CH2), 105.5 (CH2), 152.0 (C), 182.3
(C). IR νmax (neat KBr) (cm-1): 894, 1030, 1124, 1236, 1462, 1672,
1778, 2958. HRMS (ESI-TOF): calculated for C15H23O2+ (MH+),
235.1693; found, 235.1695 (∆ ) 0.8 ppm).
(()-tert-Butyl (2R,3aR,4S,7aR)-2-Isopropenyl-3a,4-dimethyl-
octahydro-1H-indene-2-
carboxylate (12) and (()-tert-Butyl(2S,3aR,4S,7aR)-2-Isopro-
penyl-3a,4-dimethyloctahydro-
1H-indene-2-carboxylate (13). To a solution of diisopropylamine
(0.35 mL, 253 mg, 2.50 mmol) in 4 mL of THF at 0 °C was added
1.10 mL (2.32 mmol, 2.10 mol/L) of a solution of n-butyllithium
in hexanes. The mixture was stirred at 15 min, and HMPA (0.42
mL, 2.40 mmol) was added and stirred for 15 min. The solution of
LDA/HMPA was cooled to -78 °C, a solution of 9a/9b (490 mg,
1.16 mmol) in 2.5 mL of THF cooled to -78 °C was added, and
the reaction mixture was then stirred for 7 h. The temperature of
the reaction system was slowly increased up to 0 °C (∼30 min)
and then quenched with water (20 mL). The aqueous phase was
extracted with ether (3 × 40 mL), and the combined organic phases
were washed with brine and dried (MgSO4). After solvent evapora-
tion, the yellow oil was purified by column chromatography (silica
gel, hexanes with 5% ethyl acetate) to afford a mixture of 12 and
13 in a ratio of 1:1 (270 mg, 0.89 mmol) in 77% yield. This
proportion was determined by analysis of the 1H NMR data of the
epimeric mixture. IR νmax (neat KBr) (cm-1): 1152, 1460, 1638,
Acknowledgment. The authors thank Professor Thomas G.
Back for suggestions about HPLC separations, Professor Norb-
erto P. Lopes and Jose´ C. Tomaz for the HRMS (ESI-TOF)
analyses, the Companhia Brasileira de Mineralogia e Minerac¸a˜o
(CBMM) for samples of NbCl5, the Fundac¸a˜o de Amparo a`
Pesquisa do Estado de Sa˜o Paulo (FAPESP), the Conselho
Nacional de Desenvolvimento Cient´ıfico e Tecnolo´gico (CNPq),
the Financiadora de Estudos e Projetos (FINEP), and the
Coordenadoria de Aperfeic¸oamento de Pessoal do Ensino
Superior (CAPES) for financial support.
+
1720, 2926, 2964. HRMS (ESI-TOF): calculated for C19H33O2
(MH+), 293.2475; found, 293.2471 (∆ ) 1.4 ppm).
(()-Bakkenolide A (1) and (()-7-epi-Bakkenolide (A) (16).
To a solution of esters 14 and 15 (70 mg, 0.19 mmol, 1:1 epimeric
mixture) in 3 mL of CCl4 was added 130 mg (0.56 mmol) of Ag2O.
The reaction mixture was refluxed for 3.5 h. The solid residue was
filtered (silica gel and celite layer) and washed with CCl4 (3 × 5
mL). After solvent evaporation, the yellow oil was purified by
column chromatography (silica gel, hexanes with 5% ethyl acetate)
to afford a mixture of epimers 1 and 16 in a 1:1 ratio. The natural
product 1 and the epi-isomer 16 were separated by HPLC (UV-
vis at 212 nm detector) with an analytical column (4.6 cm internal
diameter and 25 cm length with 5 mm particles and 100 Å of pore)
using hexane as an eluent (0.5 mL min-1). (()-Bakkenolide A
(1).7d-f 1H NMR (CDCl3, 500 MHz) δ (ppm): 0.85 (d, 3H, J )
6.8 Hz), 0.99 (s, 3H), 1.10-1.22 (m, 1H), 1.40-1.68 (m, 6H), 1.95
(d, 1H, J ) 14.2 Hz), 1.98 (dd, 1H, J1 ) 12.9 Hz and J2 ) 7.0
Hz), 1.98 (d, 1H, J ) 14.2 Hz), 2.09 (dd, 1H, J1 ) 13.3 Hz and J2
) 12.9 Hz), 2.27 (dddd, 1H, J1 ) 13.3 Hz, J2 ) 7.0 Hz, J3 ) 4.9
Supporting Information Available: The detailed experimental
section includes the transformations of 2 + 3 to 4, 5 to 6, 6 to 7,
1
7 to 8a/8b, 8a/8b to 10/11, and 12/13 to 14/15 and H NMR and
13C NMR spectra for key intermediates and final products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO061722X
J. Org. Chem, Vol. 71, No. 26, 2006 9883