Chemoenzymatic route to both enantiomers of a 1-isopropyl-3a- methyloctahydroinden-4-one derivative: A synthetic intermediate for sesqui- and diterpenoids

Article abstract of DOI:10.1002/adsc.200505034

On the way to a chemoenzymatic synthesis of a key intermediate for sesquiterpenoids and diterpenoids, 2-methyl-2-(4-methyl-3-oxopentyl)-1,3- cyclohexanedione was reduced with the whole cells of yeast biocatalysts. Torulaspora delbrueckii NBRC10921 reduced

Full text of DOI:10.1002/adsc.200505034

FULL PAPERS
Chemoenzymatic Route to Both Enantiomers of a
1-Isopropyl-3a-methyloctahydroinden-4-one Derivative:
A Synthetic Intermediate for Sesqui- and Diterpenoids
Shigeo Fujieda, Mina Tomita, Ken-ichi Fuhshuku, Shigeru Ohba,
Shigeru Nishiyama, Takeshi Sugai*
Department of Chemistry, Keio University, Hiyoshi, Yokohama 223-8522, Japan
Fax ( þ81)-45-566-1697, e-mail: sugai@chem.keio.ac.jp
Received: January 22, 2005; Accepted: March 29, 2005
Abstract: On the way to a chemoenzymatic synthesis separated as the ꢀsynꢁ or ꢀcisꢁ isomer exclusively exist
of a key intermediate for sesquiterpenoids and diter- in the intramolecular hemiacetal structure, while
penoids, 2-methyl-2-(4-methyl-3-oxopentyl)-1,3-cy- ꢀantiꢁ or ꢀtransꢁ isomer being an equilibrated mixture
clohexanedione was reduced with the whole cells of of cyclic hemiacetal and open-chain hydroxyketone
yeast
biocatalysts.
Torulaspora
delbrueckii (ca. 0.7:1). Starting separately from the enantiomeri-
NBRC10921 reduced a cyclic ketone of three carbon- cally enriched products as above, both enantiomers of
yl groups in an enantiofacially selective manner (re- the target compound, a key intermediate for terpe-
face attack), but there was poor enantiotopic group noids, were efficiently prepared via stereoselective
selectivity between two carbonyl groups on the cyclo- ring closure under pinacol coupling reaction condi-
hexane ring to yield a mixture of diastereomeric prod- tions. Furthermore, a daucane sesquiterpene inter-
ucts. Candida floricola IAM13115 reduced mainly the mediate, a hydroazulene derivative, was provided af-
pro-(R) carbonyl group. In contrast, the reduction ter one-carbon homologation of the six-membered
proceeded in an enantiofacially poorly selective man- ring.
ner to give another set of diastereomeric products. In
both cases, another carbonyl group on the side chain Keywords: chiral building block; desymmetrization;
worked as a ꢀtrapping armꢁ of the resulting secondary prochiral substrate; terpenoid synthesis; whole-cell bi-
alcohol. The diastereomeric products were effectively ocatalyst; yeast reduction
Introduction
If we attempt to synthesize both enantiomers of 1, the
(R)- and (S)-enantiomers of hydroxyketone (B), at least
Many naturally occurring sesquiterpenoids[1] as well as in regard to the quaternary chiral center, are required.
diterpenoids[2] have a common partial structure (A) as The whole cell-mediated reduction meets this criterion,
shown in Figure 1. (1S,6R,9S)-9-Isopropyl-6-methyl- as the multiple enzymes exist in the microbial cells, and
10,12-dioxatricyclo[7.3.0.01,6]dodecane-5,11-dione (1, they sometimes show opposite enantiotopic group selec-
Scheme 1) and its antipode, (1R,6S,9R)-1 are potentially tivity, to give the desired (R)- and (S)-isomers simulta-
good synthetic intermediates on account of the five- neously. For example, yeast-catalyzed reduction of
¼
membered ring on which an isopropyl and a methyl such a diketone (C, R¼CH2CH CH2) yielded a mix-
group are located in the proper positions in a stereo- ture of hydroxy ketones (D) and (E);[4] however, these
chemically defined manner. Toward this molecule, the two products are hardly separable with conventional
stereoselective ring closure through an intramolecular silica gel column chromatography. In the present study,
pinacol coupling and subsequent protection of the re- a ꢀtrapping armꢁ was introduced in the substrate mole-
sulting diol implies a simple precursor, a hydroxyketone cule to facilitate the separation, by means of the forma-
(B). The regio- and stereoselctive reduction of a trike- tion of an intramolecular cyclic hemiacetal (G),[5,6] pref-
tone (2), which would be easily prepared by Michael ad- erentially on the ꢀsynꢁ or ꢀcisꢁ diastereomer from the
dition of an enolate of diketone (3) to the side chain in ꢀantiꢁ or ꢀtransꢁ open-chain hydroxyketone (H).
the form of an enone, is the key step, and the enzyme-
catalyzed reduction of 2,2-asymmetrically disubstituted
1,3-diketones (C), by means of the whole cell yeast[3] is
very attractive.
Adv. Synth. Catal. 2005, 347, 1099–1109
DOI: 10.1002/adsc.200505034
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1099

Shigeo Fujieda et al.
FULL PAPERS
Results and Discussion
For the preparation of the substrate triketone (2), the
Michael acceptor is isopropyl vinyl ketone. As the
known procedure for generating the vinyl ketone by
way of a quaternary ammonium salt[7] was a tedious mul-
tistep transformation, another route was developed as
shown in Scheme 2. Isobutyl aldehyde was treated
with vinylmagnesium bromide to give a volatile allylic
alcohol 5. The partially purified 5 was oxidized under
Swern conditions to give an enone.[8] The crude solution
of enone was treated with diketone 3 in the presence of
triethylamine to give 2 in total 70% yield from 3.
On the occasion of the whole cell-mediated reduction
of 2, introduction of a sterically bulky isopropyl group
greatly affected the stereoselectivity, in comparison to
the methyl and ethyl groups,[6,9] although the substituent
is located apart from the quaternary carbon atom. So far,
in the case of substrates with methyl and ethyl groups,
the Torulaspora delbrueckii NBRC10921-catalyzed re-
action had yielded a single hemiacetal isomer in a
good enantiotopic group-selective manner: the pro-(R)
carbonyl group was reduced. In the case of 2, the enan-
tiotopic group selectivity was very low, and the product
seemed a complex mixture, due to the reduction of pro-
(S) carbonyl group. Silica gel TLC analysis indicated a
stable component with an Rf value (0.6, hexane-
EtOAc¼1:1), which was a nearly pure hemiacetal
[(1S,6S)-6] in 40% yield (99.2% ee). Another compo-
nent showed a broad band on TLC with a long tailing
(Rf ¼0.5–0.3) and this was an equilibrated mixture
(ca. 0.7:1) of another hemiacetal [(1S,6R)-6] and a hy-
droxy ketone [(2R,3S)-7a] in 51% yield (97.6% ee) as
shown in Scheme 3. The relative and absolute configura-
tions as well as the stereochemical purity are discussed
later. In this case, the introduction of the ꢀtrapping
armꢁ workedvery effectively on theseparation, by virtue
of the difference in intramolecular hemiacetal forma-
tion[10] between diastereomers, as expected at the initial
event.
Figure 1.
When we changed the microorganism to another
strain, Candida floricola IAM13115, a contrasting sense
of stereoselection was observed. The diastereomeric
profile of the resulting products was very different
from that of the example shown in the previous case.
This strain contains a similar enzyme to give hemiacetal
[(1S,6S)-6] in 68% yield (94.4% ee), but the action on
the pro-(S) carbonyl group was negligibly low. On the
other hand, another enzyme reduces the pro-(R) car-
Scheme 1.
Scheme 2.
1100
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 1099–1109

Synthetic Intermediate for Sesqui- and Diterpenoids
FULL PAPERS
Scheme 3.
bonyl group, however, the reduction proceeds in the op-
posite enantiofacially selective manner, to give another
diastereomeric product, an equilibrated mixture of
hemiacetal (1R,6S)-6 and hydroxy ketone [(2S,3R)-7a]
in 20% yield (94.3% ee) as shown in Scheme 4.
Scheme 5.
The hemiacetal [(1S,6S)-6] provided by T. delbrueckii
was submitted to acetylation to provide an acetoxy ke-
tone [(1S,2S)-7b] with a concomitant ring-opening reac- of the crystalline nature of the intermediate 8a, its ee
tion. The pinacol coupling reaction with TiCl3/Zn-Cu in was easily raised to 100% by a single recrystallization
THF[11] proceeded in a completely stereoselective man- (mp 129.5–130.08C).
ner to give a diol [(1S,2S,6S,7S)-8a]. An attempt for the
In the same manner, the cyclic hemiacetal [(1S,6S)-6]
further deoxygenation toward an olefin from diol under prepared by C. floricola-mediated reduction was de-
forced McMurry conditions[12] only resulted in a com- rived to (1R,6S,7S)-9 with 94.0% ee, and the enhance-
plex mixture of the products, as such an olefinic product ment of its ee was also successful. The total relative
was unstable even on silica gel TLC. The hydrolysis of and absolute configurations of 8b were confirmed by
the acetate and the subsequent oxidation of the secon- the X-ray crystallographic analysis of the corresponding
dary alcohol gave a bicyclic ketone [(1R,6S,7S)-9], which (ꢀ)-camphanic acid ester 8c as depicted in Figure 2.
was analyzed by HPLC with a chiral stationary phase
Another chiral product, a mixture of hemiacetal
(ChiralCel OD) to be 99.2% ee (Scheme 5). By virtue [(1S,6R)-6] and open-chain hydroxy ketone [(2R,3S)-
7a] prepared by the reduction with T. delbrueckii, was
converted into (1S,6R,7R)-9 (97.6% ee) in a similar
manner as described above via (1R,2S,6R,7R)-8a
(Scheme 6). The acetate [(1R,2S,6R,7R)-8a], which is
in a diastereomeric relationship with (1S,2S,6S,7S)-8a
was also crystalline, and the enantiomerically pure com-
pound was obtained by a single recrystallization (mp
84.5–85.08C).
The third diastereomer of the yeast-mediated chiral
product, (2S,3R)-7a, the open-chain hydroxy ketone
prepared by the action of C. floricola, was equally trans-
formed to (1R,6S,7S)-9 (94.3% ee). This was converged
to (1S,2S,6S,7S)-8a, whose ee can be raised at this stage,
as described above, by LiAlH4-mediated diastereoselec-
tive reduction and the subsequent acetylation of the sec-
ondary alcohol (Scheme 6).
The diol functional group of (1S,2S,6S,7S)-8a could be
protected as the cyclic carbonate to give 10 in 86% yield.
As the contiguous tertiary alcohols have poor nucleo-
Scheme 4.
Adv. Synth. Catal. 2005, 347, 1099–1109
asc.wiley-vch.de
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1101

Shigeo Fujieda et al.
FULL PAPERS
Scheme 6.
Figure 2.
philicity and are very unstable under acidic conditions,
both diacylation and protection with acetonide failed.
Then the acetyl group in 10 was selectively hydrolyzed
and followed by oxidation of the resulted secondary al-
cohol to give (1S,6R,9S)-1 in 87% yield in two steps
(Scheme 7). In a similar manner (1R,2S,6R,7R)-8a was
protected, and the subsequent transformations afforded
(1R,6S,9R)-1 in 84% yield in three steps. The diol moiety
in (1S,2S,6S,7S)-8a was very sterically hindered so that
the cyclic carbonate formation was much slower than
that of(1R,2S,6R,7R)-8a. An attempt at cycliccarbonate
formation of the less sterically hindered ketone 9 result-
ed in a lower yield, due to the labile properties of 9 under
basic conditions.
Towards daucane sesquiterpenes, the homologation
reaction of a six-membered cyclic ketone was elaborat-
ed. Due to the highly congested space around the ketone
Scheme 7.
carbonyl group itself as well as the adjacent methylene homolylic fashion (I–J–L) by Fe(III),[14] to give the
group, many kinds of nucleophilic and/or electrophilic ring-expanded enone [(1S,7R,10S)-12] in 42% yield
substitution reactions failed. The enol silyl ether of from 1, followed by the treatment with DBU
(1S,6R,9S)-1 was reacted with zinc carbenoid generated (Scheme 8). A possible way to the side product which
[13]
from Et2Zn/CH2I2 to give an unstable cyclopropane would lower the yield is the undesired primary radical
derivative 11. The cyclopropane ring was cleaved in a formation (I–K–M), to result in a six-membered ring
1102
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 1099–1109

Synthetic Intermediate for Sesqui- and Diterpenoids
FULL PAPERS
Conclusion
Yeast-catalyzed asymmetric reduction of cyclic ketones
could provide new chiral starting materials for natural
product synthesis. The ꢀtrapping armꢁ worked very
well as an internal tether, in the practical sense, to sepa-
rate the resulting otherwise inseparable diastereomeric
products. Inaddition, we wereable to find some interest-
ing aspects of the reductive enzymes, both depending
upon the structure of the substrates, and the sort of yeast
strain. The resulting products were converted to bicyclic
terpenoid intermediates by an intramolecular pinacol
coupling reaction.
Experimental Section
All mps are uncorrected. IR spectra were measured as films for
oils or KBr disks of solids on a Jasco FT/IR-410 spectrometer.
1H NMR spectra were measured in CDCl3 at 270 MHz on a
Jeol JNM EX-270 or at 400 MHz on a Jeol JNM GX-400 spec-
trometer. High resolution mass spectra were recorded on a Jeol
JMS-700 spectrometer. HPLC data were recorded on Jasco
PU-2080 and MD-2010 liquid chromatographs. Optical rota-
tion values were recorded on a Jasco DIP 360 polarimeter.
Merck silica gel 60 F254 thin-layer plates (1.05744, 0.5 mm thick-
ness) and silica gel 60 (spherical and neutral; 100–210 mm,
37560–79) from Kanto Chemical Co., were used for prepara-
tive thin-layer chromatography and column chromatography,
respectively. Peptone and yeast extract were purchased from
Kyokuto Pharmaceutical Co., for the cultivation of microor-
ganism.
T. delbruekii NBRC10921 is available from the Biological
Resources to the Biological Resource Center (NBRC), Inde-
pendent Administrative Institution the National Institute of
Technology and Evaluation (NITE), 2-5-8, Kazusakamatari,
Kisarazu, Chiba 292-0818, Japan. C. floricola IAM13115 is
available from Institute of Applied Microbiology Culture Col-
lection; Institute of Molecular and Cellular Biosciences, Uni-
versity of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Ja-
pan.
Scheme 8.
exomethylene compound. This side reaction was con-
firmed by the detection of a methanol Michael adduct
13 by way of the enone, under the conditions of NaOAc
in methanol, instead of DBU in DMF, was applied as the
base treatment.
2-Methyl-2-(4-methyl-3-oxopentyl)-1,3-
cyclohexanedione (2)
Finally, the 1,4-addition of Me2CuLi to the enone 12
and the subsequent trapping as a silyl ether provided
14. Pd(0)-catalyzed oxidation[15] of silyl ether gave an
The preparation of allylic alcohol and the subsequent treat-
ment were according to a slightly modified procedure reported
before.[18] To a solution of vinylmagnesium bromide (1.0 mol/L
enone [(1S,7R,10S)-15], bearing the complete carbon in THF, 115 mL, 0.115 mol) was added isobutylaldehyde (4,
8.65 g, 0.120 mol) dropwise at 08C and the mixture was stirred
for 3 h at 08C. The reaction was quenched by the addition of sa-
turated aqueous ammonium chloride solution and the mixture
was extracted with ether. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and partially con-
centrated under vacuum to a volume of ca. 20 mL. To the resul-
tant solution of 5 was added molecular sieves 4 ꢃ (7.3 g) and
the mixture was stirred for 1 h at room temperature. Separate-
ly, a mixture of dichloromethane (120 mL), oxalyl chloride
(12 mL, 0.132 mol), and DMSO (20 mL) was prepared at
ꢀ788C, and the above solution of 5, which was further diluted
skeleton of daucane sesquiterpenes and the stereochem-
ically defined methyl group at the angular position, in
21% yield. A by-product, saturated ketone 16 (44%),
could be recycled to the silyl ether 14 again. The oxida-
tion of 14 with IBX[16] slightly improved the yield of 15
(25%) with the formation of 16 (25%). The selective for-
mation of 15 (67%) became successful by means of
DDQ[17] oxidation.
Adv. Synth. Catal. 2005, 347, 1099–1109
asc.wiley-vch.de
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1103

Shigeo Fujieda et al.
FULL PAPERS
with dichloromethane (30 mL), was slowly added. The mixture
was stirred for 6 h at ꢀ788C. Then triethylamine (65 mL,
0.466 mol) was added, and the mixture was gradually allowed
to warm to room temperature during 1 h. To the crude solution
of enone was added diketone (3, 15.47 g, 0.123 mol) was added
and the mixture was stirred for 12 h. The reaction was
quenched by the addition of saturated aqueous ammonium
chloride solution and the mixture was extracted with ethyl ace-
tate. The organic layer was washed with brine, dried over anhy-
drous sodium sulfate, and concentrated under vacuum. The
residue was charged on a silica gel column (300 g), and eluted
with hexane/ethyl acetate (3/1) to give pure fractions. Combi-
nation with the further isolated material from repeated chro-
matography of the fraction of a mixture with some impurities
afforded 2 as a colorless oil; yield: 19.70 g (71% based on 3);
Pre-Incubation of C. floricola IAM13115
A small portion of yeast cells of C. floricola IAM13115 grown
on the agar-plate culturewas aseptically inoculated to a glucose
medium [containing glucose (5.0 g), peptone (2.0 g), yeast ex-
tract (0.5 g), KH2PO4 (0.3 g), K2HPO4 (0.2 g), at pH 6.5, total
volume 100 mL] in a 500-mL baffled Erlenmeyer cultivating
flask with two internal projections and then shaken on a gyro-
rotary shaker (180 rpm) for 2 days at 308C. The wet cells were
harvested by centrifugation (3,000 rpm) and washed with phos-
phate buffer (0.1 M, pH 6.5). The weight of combined wet cells
was ca. 2.7 g from 100 mL of the broth.
1
IR: nmax ¼1710, 1695 cmꢀ1; H NMR (400 MHz, CDCl3): d¼
Reduction of 2 with C. floricola IAM13115
1.06 (d, J¼6.8 Hz, 6 H), 1.24 (s, 3 H), 1.83–1.94 (m, 1 H),
2.01–2.11 (m, 1 H), 2.05 (t, J¼7.3 Hz, 2 H), 2.36 (t, J¼
7.3 Hz, 3 H), 2.54 (q, J¼6.8 Hz, 1 H), 2.58–2.66 (m, 2 H),
2.71–2.79 (m, 2 H); 13C NMR (100 MHz, CDCl3): d¼17.5,
18.0, 19.5, 29.7, 34.8, 37.5, 40.7, 64.2, 209.5, 212.9; anal. calcd.
for C11H16O3: C 69.61, H 8.99; found: C 69.59, H 8.94.
The combined wet cells of C. floricola IAM13115 (2.0 g) incu-
bated as described above were re-suspended in a reaction me-
dium [containing glucose (0.5 g), phosphate buffer (0.1 M,
pH 7.5), total volume of 10 mL] in a test tube (21 mmꢁ
20 cm), together with 2 (104.6 mg, 0.466 mmol) and shaken
on a reciprocal shaker (250 cpm) for 24 h at 308C. The reaction
mixture was filtered through a Celite pad and extracted with
ethyl acetate. The filter cake was further extracted with ace-
tone. The combined organic layer was washed with brine, dried
over anhydrous sodium sulfate, and concentrated under vac-
uum. The residue was purified as described before to give
(1S,6S)-6 (yield: 71.5 mg, 68%) and a mixture of (2S,3R)-7a
and (1R,6S)-6 (yield: 21.0 mg, 20%).
(1S,6S)-6: Its spectral data were identical with those describ-
ed above. Recrystallization from hexane/diethyl ether gave an
analytical sample; mp 93.0–93.58C; [a]2D0: ꢀ90.28 (c 1.03,
EtOH); anal. calcd. for C13H22O3: C 68.99, H 9.80; found: C
69.00, H 9.75.
A mixture of (2S,3R)-7a and (1R,6S)-6: nearly no optical ro-
tation; its spectral data were identical with those of the antipo-
dal mixture obtained by the incubation with T. delbrueckii as
described above.
Reduction of 2 with T. delbrueckii NBRC10921
The wet cells of T. delbrueckii NBRC10921 (0.6 g) incubated
according to the reported procedure[6] were re-suspended in
a reaction medium [containing glucose (0.5 g), phosphate buf-
fer (0.1 M, pH 6.5), total volume of 10 mL] in a test tube
(21 mmꢁ20 cm), together with 2 (101.5 mg, 0.453 mmol) and
shaken on a reciprocal shaker (250 cpm) for 24 h at 308C.
The reaction mixture was filtered through a Celite pad and ex-
tracted with ethyl acetate. The combined organic layer was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated under vacuum. The residue was charged on a sili-
ca gel column (10 g). Elution with hexane/ethyl acetate (7/1 to
3/1) afforded (1S,6S)-6 and a mixture of (2R,3S)-7a and
(1S,6R)-6.
(1S,6S)-3-Hydroxy-3-isopropyl-6-methyl-2-oxabicy-
clo[4.4.0]decan-7-one (6): yield: 39.9 mg (39%). Recrystalliza-
tion from hexane/diethyl ether gave an analytical sample of
(1S,6S)-6 as needles; mp 94.0–95.08C; [a]2D0: ꢀ92.08 (c 1.07,
(1S,2S)-2-(4-Methyl-3-oxopentyl)-2-methyl-3-
oxocyclohexyl Acetate (7b)
EtOH); IR: nmax ¼3514, 1700 cmꢀ1
;
1H NMR (400 MHz,
A mixture of (1S,6S)-6 (4.09 g, 18 mmol), anhydrous pyridine
(20 mL), acetic anhydride (10 mL), and a catalytic amount of
4-dimethylaminopyridine was stirred overnight at room tem-
perature. The reaction mixture was poured into 1 M hydro-
chloric acid and extracted with ethyl acetate. The combined or-
ganic layer was washed with saturated aqueous sodium hydro-
gen carbonate solution and brine, dried over anhydrous so-
dium sulfate, and concentrated under vacuum. The residue
was charged on a silica gel column (200 g). Elution with hex-
ane/ethyl acetate (3/1) afforded (1S,2S)-7b as a colorless oil;
CDCl3): d¼0.88 (d, J¼7.3 Hz, 3 H), 0.91 (d, J¼7.3 Hz, 3 H),
0.93–1.00 (m, 1 H), 1.13 (s, 3 H), 1.41–1.67 (m, 5 H), 1.84 (s,
2 H), 1.99–2.28 (m, 4 H), 2.40–2.59 (m, 1 H), 4.20 (s, 1 H);
13C NMR (100 MHz, CDCl3): d¼16.4, 16.8, 21.4, 24.3, 26.3,
26.5, 27.4, 37.9, 39.1, 47.5, 75.2, 98.7, 214.4; anal. calcd. for C13
H22O3: C 68.99, H 9.80; found: C 68.96, H 9.68.
A mixture of (2R,3S)-3-hydroxy-2-(4-oxopentyl)-2-methyl-
cyclohexanone (7a) and (1S,6R)-6: yield: 52.2 mg (51%) as a
colorless oil; nearly no optical rotation; IR: nmax ¼3465, 1704,
1
1074 cmꢀ1; H NMR (400 MHz, CDCl3): d¼0.96–1.15 (m,
yield: 4.86 g (quant.); [a]2D2: þ18.98 (c 1.19, EtOH); IR: nmax
¼
1
9 H), 1.47–2.06 (m, 7 H), 2.16–2.72 (m, 4 H), 3.09 (s, 0.59 H),
3.51 (d, J¼8.7 Hz, 0.59 H), 3.94 (dd, J¼4.3, 11.7 Hz, 0.41 H).
This was revealed to an equilibrated mixture of (2R,3S)-7a
and (1S,6R)-6 as judged from the signals of d¼3.09, 3.51, and
3.94. 13C NMR (100 MHz, CDCl3): d¼15.1, 16.2, 16.8, 18.3,
18.4, 20.3, 20.8, 25.3, 26.0, 26.2, 27.3, 27.9, 35.6, 36.4, 36.5,
37.4, 38.8, 40.8, 48.3, 54.8, 73.0, 73.3, 98.3, 213.9, 214.1, 216.3.
1739, 1712, 1236 cmꢀ1; H NMR (400 MHz, CDCl3): d¼1.08
(d, J¼6.1 Hz, 6 H), 1.09 (s, 3 H), 1.63–1.72 (m, 1 H), 1.76–
1.84 (m, 1 H), 1.89–2.14 (m, 6 H), 2.06 (s, 3 H), 2.33–2.42 (m,
3 H), 2.51–2.62 (m, 1 H), 4.87 (dd, J¼3.9 Hz, 3.9 Hz, 2 H);
13C NMR (100 MHz, CDCl3): d¼18.2, 18.3, 19.0, 20.5, 21.0,
25.6, 25.9, 34.3, 37.5, 41.0, 52.1, 78.2, 169.9, 211.9, 213.7; anal.
calcd. for C15H24O4: C 67.14, H 9.01; found: C 67.32, H 8.91.
1104
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 1099–1109

Synthetic Intermediate for Sesqui- and Diterpenoids
FULL PAPERS
(1S,2R,6S,7S)-8a intwo steps as colorlessneedles;yield: 877 mg
(88%); mp 84.0–84.58C; [a]D25: ꢀ9.38 (c 0.58, EtO H). Its spec-
tral data were identical with those reported for (1R,2S,6R,7R)-
8a; anal. calcd. for C15H26O4: C 66.64, H 9.69; found: C 66.60, H
9.68.
(1S,2R)-2-(4-Methyl-3-oxopentyl)-2-methyl-3-
oxocyclohexyl Acetate (7b)
In the same manner as described above, an equilibrated mix-
ture of (2R,3S)-7a and (1S,6R)-6 (6.92 g, 30.6 mmol) provided
(1S,2R)-7b as a colorless oil; yield: 8.21 g (quant.); [a]2D0: ꢀ15.28
(c 0.94, EtOH); IR: nmax ¼1737, 1710, 1236 cmꢀ1; H NMR
1
(400 MHz, CDCl3): d¼1.04 (s, 3 H), 1.07 (d, J¼6.8 Hz, 3 H),
1.08 (d, J¼6.8 Hz, 3 H), 1.73–2.62 (m, 11 H), 5.05 (bs, 1 H);
13C NMR (100 MHz, CDCl3): d¼17.8, 18.3, 18.3, 20.7, 21.0,
25.4, 29.2, 34.6, 37.7, 41.0, 52.0, 77.4, 169.9, 212.5, 213.3; anal.
calcd. for C15H24O4: C 67.14, H 9.01; found: C 67.24, H 8.97.
(1S,5S,6S,9S)-9-Isopropyl-6-
methylbicyclo[4.3.0]nonane-1,5,9-triol (8b)
Acetate (1S,2S,6S,7S)-8a (34.1 mg, 0.126 mmmol) was treated
with a methanolic potassium hydroxide solution (10%) in the
conventional manner. The reaction mixture was poured into
1 M hydrochloric acid, saturated with sodium chloride, and ex-
tracted with ethyl acetate. The combined organic layer was
washed with saturated aqueous sodium hydrogen carbonate
solution and brine, dried over anhydrous sodium sulfate, and
concentrated under vacuum to afford (1S,5S,6S,9S)-8b; yield:
(1S,2S,6S,7S)-6,7-Dihydroxy-7-isopropyl-1-
methylbicyclo[4.3.0]non-2-yl Acetate (8a)
To THF (5 mL, degassed by applying ultrasonic under vacuum
three times), titanium trichloride-tris-THF complex (561 mg,
1.514 mmol) and zinc-copper couple (240 mg, 3.674 mmol)
were added and the mixture was stirred under reflux under ar-
gon to give a black slurry. To this was added dropwise a solution
of (1S,2S)-7b (0.076 mmol) in THF (1 mL) over 10 min. The re-
sulting mixture was stirred under reflux again for 1 h. After
cooling, the slurry was filtered through a Celite pad and ex-
tracted with diethyl ether. The combined organic layer was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated under vacuum. The residue was charged on a sili-
ca gel column (3 g). Elution with hexane/ethyl acetate (10/1 to
2/1) afforded (1S,2S,6S,7S)-8a; yield: 19.1 mg (93%). Recrystal-
lization from hexane/diethyl ether gave an analytical sample of
(1S,2S,6S,7S)-8a as needles; mp 129.5–130.08C; [a]2D2: þ12.88
1
31.7 mg (quant.); IR: nmax ¼3421, 1009, 978 cmꢀ1; H NMR
(400 MHz, CDCl3): d¼0.90 (d, J¼6.8 Hz, 3 H), 0.93 (d, J¼
6.8 Hz, 3 H), 1.31–1.44 (m, 3 H), 1.35 (s, 3 H), 1.55–1.73 (m,
4 H), 1.77–1.90 (m, 4 H), 1.99 (s, 1 H), 2.04 (s, 1 H), 2.29 (s,
1 H), 3.51 (dd, J¼4.9, 11.7 Hz, 1 H). This was employed for
the next step without further purification.
(1S,2S,6S,7S)-6,7-Dihydroxy-7-isopropyl-1-
methylbicyclo[4.3.0]non-2-yl Camphanate (8c)
Triol (1S,5S,6S,9S)-8b (30.1 mg, 0.132 mmmol) was treated
with (ꢀ)-camphanic chloride in the presence of DMAP in a
conventional manner to give 8c; yield: 54.6 mg (quant.). Re-
crystallization from hexane/diethyl ether gave an analytical
sample of 8c as colorless needles; mp 129.5–130.08C; [a]2D2:
(c 1.01, EtOH); IR: nmax ¼3531, 3479, 1710, 1261 cmꢀ1; H
1
NMR (400 MHz, CDCl3): d¼0.91 (d, J¼6.8 Hz, 3 H), 0.93
(d, J¼6.8 Hz, 3 H), 1.19 (s, 3 H), 1.29 (s, 3 H), 1.34–1.46 (m,
3 H), 1.59–1.92 (m, 9 H), 2.02 (s, 1 H), 2.03 (s, 3 H), 2.29 (s,
1 H), 4.75 (dd, J¼5.1, 11.5 Hz, 1 H); 13C NMR (100 MHz,
CDCl3): d¼16.9, 18.0, 19.6, 21.3, 21.4, 26.8, 27.0, 31.3, 33.6,
34.5, 48.6, 78.0, 83.5, 83.9, 170.9; anal. calcd. for C15H26O4: C
66.64, H 9.69; found: C 66.75, H 9.66.
þ12.68 (c 1.07, EtOH); IR: nmax ¼3531, 3500, 1760, 1724 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d¼0.91 (d, J¼6.8 Hz, 3 H),
0.94 (d, J¼6.4 Hz, 3 H), 0.96 (s, 3 H), 1.05 (s, 3 H), 1.11 (s,
3 H), 1.21–1.52 (m, 3 H), 1.23 (s, 3 H), 1.64–2.04 (m, 11 H),
1.95 (s, 1 H), 2.36–2.43 (m, 1 H), 2.40 (s, 1 H), 4.92 (dd, J¼
4.9, 11.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3): d¼9.8, 16.9,
16.9, 18.0, 19.4, 21.5, 21.5, 27.0, 27.2, 29.0, 30.6, 31.2, 33.6,
34.6, 48.6, 54.0, 54.8, 79.9, 83.6, 84.0, 91.3, 167.1, 178.3; anal.
calcd. for C23H36O6: C 67.62, H 8.88; found: C 67.35, H 8.78.
(1R,2S,6R,7R)-6,7-Dihydroxy-7-isopropyl-1-
methylbicyclo[4.3.0]non-2-yl Acetate (8a)
In the similar manner as described above, (1S,2R)-7b (21.4 mg,
0.08 mmol) provided (1R,2S,6R,7R)-8a as colorless needles;
yield: 20.2 mg (94%); mp 84.0–84.58C; [a]2D4: þ11.98 (c 1.03,
(1R,6S,7S)-6,7-Dihydroxy-7-isopropyl-1-
methylbicyclo[4.3.0]non-2-one (9)
EtOH); IR: nmax ¼3534, 1731, 1242 cmꢀ1
;
1H NMR
To a solution of (1S,5S,6S,9S)-8b (31.7 mg, 0.139 mmol) in di-
chloromethane (1.5 mL) was added N-methylmorpholine N-
oxide (44.3 mg, 0.378 mmol), molecular sieves 4 ꢃ (ca.
50 mg), and TPAP (2.2 mg, 0.006 mmol), and the mixture was
stirred for 2 h at room temperature. The mixture was concen-
trated under vacuum and the residue was charged on a silica
gel column (3 g). Elution with hexane/ethyl acetate (3/1) af-
forded (1R,6S,7S)-9 as colorless solid; yield: 27.6 mg (97%);
(400 MHz, CDCl3): d¼0.89 (d, J¼6.4 Hz, 3 H), 0.90 (d, J¼
6.4 Hz, 3 H), 1.22 (s, 3 H), 1.42–1.54 (m, 3 H), 1.58–1.66 (m,
1 H), 1.70–1.82 (m, 6 H), 2.07 (s, 3 H), 2.58 (s, 1 H), 2.67 (s,
3 H), 4.85 (bs, 1 H); 13C NMR (100 MHz, CDCl3): d¼16.0,
16.8, 17.9, 21.3, 22.3, 25.6, 30.7, 31.1, 33.4, 33.9, 47.0, 77.7,
82.3, 83.9, 169.9; anal. calcd. for C15H26O4: C 66.64, H 9.69;
found: C 66.60, H 9.61.
IR: nmax ¼3539, 3437, 1687, 1188, 1012 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d¼0.92 (d, J¼6.8 Hz, 3 H), 0.99 (d, J¼
6.8 Hz, 3 H), 1.30 (s, 3 H), 1.39–1.46 (m, 1 H), 1.55–1.68 (m,
3 H), 1.76–1.96 (m, 4 H), 1.87 (s, 1 H), 2.11–2.25 (m, 2 H),
2.30–2.38 (m, 1 H), 2.52–2.60 (m, 1 H), 2.92 (s, 1 H); 13C
NMR (100 MHz, CDCl3): d¼16.6, 18.1, 19.0, 21.6, 31.1, 31.5,
(1S,2R,6S,7S)-6,7-Dihydroxy-7-isopropyl-1-
methylbicyclo[4.3.0]non-2-yl Acetate (8a)
In the similar manner as described above, an equilibrated mix-
ture of (2S,3R)-7a and (1R,6S)-6 (954 mg, 4.22 mmol) provided
Adv. Synth. Catal. 2005, 347, 1099–1109
asc.wiley-vch.de
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1105

Shigeo Fujieda et al.
FULL PAPERS
32.8, 34.6, 35.8, 59.1, 84.9, 85.4, 216.1; HPLC analysis [column,
Daicel Chiralcel OD, 0.46 cmꢁ25 cm; hexane/2-propanol
(30/1); flow rate 1.0 mL/min, detected at 211 nm]: tR¼
15.7 min for (1S,7aS)-9, 17.1 min for (1R,6S,7S)-9, the ee of
(1S,6R,7R)-9 was determined to be 99.2%.
Recrystallization from hexane/diethyl ether gave an analyt-
ical sample of (1R,6S,7S)-9 as needles; mp 102.5–103.08C;
[a]2D3: ꢀ36.08 (c 0.54, EtOH); anal. calcd. for C13H22O3: C
68.99, H 9.80; found: C 66.86, H 9.74. The recrystallized sample
at the stage of (1S,2S,6S,7S)-8a either from 99.4% (T. del-
brueckii) or 94% ee (C. floricola) was revealed to be enantio-
merically pureasjudgedfromthe HPLCanalysis of 9 asdescrib-
ed above.
Acetylation of this sample (18.4 mg, 0.081 mmol) in the con-
ventional manner provided (1S,2S,6S,7S)-8a; yield: 20.0 mg
(91%). Its spectral data were identical with those for the au-
thentic (1S,2S,6S,7S)-8a as described above; mp 129.5–
130.08C; [a]2D0: þ12.58 (c 0.98, EtOH).
(1S,5S,6S,9S)-9-Isopropyl-6-methyl-11-oxo-10,12-
dioxatricyclo[7.3.0.01,6]dodec-5-yl Acetate (10)
To a solution of (1S,2S,6S,7S)-8a (2.277 g, 8.424 mmol) in di-
chloromethane (50 mL) and pyridine (13.6 mL) was added a
solution of triphosgene (12.5 g, 0.042 mmol) in dichlorome-
thane (30 mL) at ꢀ788C. The reaction mixture was warmed
to room temperature, then heated under reflux with stirring
for 16 h. The reaction was quenched by the addition of saturat-
ed aqueous ammonium chloride solution and the mixture was
extracted with ethyl acetate. The combined organic layer was
washed with 1 M hydrochloric acid, saturated aqueous sodium
hydrogen carbonate solution and brine, dried over anhydrous
sodium sulfate, and concentrated under vacuum. The residue
was charged on a silica gel column (200 g). Elution with hex-
ane/ethyl acetate (5/1 to 3/1) afforded (1S,5S,6S,9S)-10; yield:
2.15 g (86%). Recrystallization from hexane/diethyl ether
gave an analytical sample of (1S,5S,6S,9S)-10 as colorless
prisms; mp 85.5–86.08C; [a]2D0: ꢀ23.68 (c 0.48, EtOH); IR:
On the other hand, the sample (1R,6S,7S)-9 was 94.3% ee,
prepared from (1S,2R,6S,7S)-8a originating from the incuba-
tion with C. floricola, as judged from the HPLC analysis. Re-
crystallization from hexane/diethyl ether gave an analytical
sample of (1R,6S,7S)-9 as needles; mp 102.5–103.08C; [a]2D4:
ꢀ37.08 (c 1.02, EtOH). The intermediate, (1S,5R,6S,9S)-8b
1
showed the following H NMR (400 MHz, CDCl3): d¼0.88
(d, J¼6.4 Hz, 6 H), 1.32–1.59 (m, 4 H), 1.34 (s, 3 H), 1.66–
1.81 (m, 5 H), 1.86–1.97 (m, 2 H), 2.58 (s, 1 H), 3.21 (s, 1 H),
3.64 (bs, 1 H).
(1S,6R,7R)-6,7-Dihydroxy-7-isopropyl-1-
methylbicyclo[4.3.0]non-2-one (9)
nmax ¼1797, 1739, 1240, 1020 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): d¼1.06 (d, J¼6.8 Hz, 3 H), 1.08 (d, J¼6.4 Hz, 3 H),
1.14 (s, 3 H), 1.52–1.80 (m, 5 H), 1.86–2.14 (m, 6 H), 4.94
(dd, J¼4.4, 4.9 Hz, 1 H); 13C NMR (100 MHz, CDCl3): d¼
15.9, 17.2, 18.7, 21.5, 21.9, 24.9, 26.9, 32.2, 33.6, 33.7, 49.6,
77.2, 93.9, 99.1, 154.5, 169.7; anal. calcd. for C16H24O5: C
64.84, H 8.16; found: C 64.96, H 8.05.
In the same manner as described for (1R,6S,7S)-9,
(1R,2S,6R,7R)-8a
(32.6 mg,
0.121 mmol)
provided
(1S,6R,7R)-9 in two steps; yield: 20.0 mg (73%). Its spectral
data were identical with those for (1R,6S,7S)-9. The ee of
(1S,6R,7R)-9 was determined to be 97.6% HPLC analysis as
described above.
Recrystallization from hexane/diethyl ether gave an analyt-
ical sample of (1S,6R,7R)-9 as needles; mp 102.5–103.08C;
[a]2D4: þ37.78 (c 0.62, EtOH); HR-MS (FABþ): calcd. for
C13H22O3: [MþNaþ]: 249.1467; found: m/z¼249.1449. The re-
crystallized sample at the stage of (1R,2S,6R,7R)-8a was re-
vealed to be enantiomerically pure as judged from the HPLC
analysis of 9.
(1S,6R,9S)-9-Isopropyl-6-methyl-10,12-
dioxatricyclo[7.3.0.01,6]dodecane-5,11-dione (1)
Through the deprotection of acetate and subsequent oxidation
in a similar manner as described for (1S,5S,6S,9S)-8b and
(1R,6S,7S)-9; the cyclic carbonate (1S,5S,6S,9S)-10 (871.3 mg,
2.94 mmol) provided (1S,6R,9S)-1; yield: 648.6 mg (87%). Re-
crystallization from hexane/diethyl ether gave an analytical
sample of (1S,6R,9S)-1 as needles; mp 118.5–119.08C; [a]2D1:
(1S,2S,6S,7S)-6,7-Dihydroxy-7-isopropyl-1-
methylbicyclo[4.3.0]non-2-yl Acetate (8a)
ꢀ42.58 (c 1.0, EtOH); IR: nmax ¼1778, 1714 cmꢀ1; H NMR
1
(400 MHz, CDCl3): d¼1.01 (d, J¼6.8 Hz, 3 H), 1.10 (d, J¼
6.8 Hz, 3 H), 1.29 (s, 3 H), 1.31–1.48 (m, 1 H), 1.66–1.71 (m,
1 H), 1.91 (q, J¼6.8, 6.8 Hz, 3 H), 2.01–2.08 (m, 2 H), 2.14–
2.37 (m, 3 H), 2.57–2.65 (m, 2 H); 13C NMR (100 MHz,
CDCl3): d¼17.2, 18.8, 18.8, 20.7, 28.7, 30.1, 31.7, 34.5, 36.4,
61.4, 95.0, 98.5, 153.7, 210.6; anal. calcd. for C14H20O4: C
66.65, H 7.99; found: C 66.44, H 7.97.
Toa solution of the ketone (1R,6S,7S)-9 (31.3 mg, 0.138 mmol),
which was prepared from (1S,2R,6S,7S)-8a originated from the
incubation with C. floricola, in anhydrous diethyl ether
(1.5 mL) was added lithium aluminum hydride (10 mg,
0.264 mmol) at 08C and the mixture was stirred at room tem-
perature. Then the reaction was quenched with an excess
amount of 1 M hydrosulfuric acid the mixture was extracted
several times with ethyl acetate. The combined organic layer
was washed with brine, dried over anhydrous sodium sulfate,
and concentrated under vacuum. The residue was charged on
a silica gel column (2 g). Elution with hexane/ethyl acetate
(4/1) afforded the recovery of (1R,6S,7S)-9 (9.8 mg, 31%) and
(1S,5S,6S,9S)-8b; yield: 19.1 mg (60%). Its 1H NMR was identi-
cal with that of (1S,5S,6S,9S)-8b as described before and easily
distinguished with that of the diastereomeric (1S,5R,6S,9S)-8b
as above.
(1R,6S,9R)-9-Isopropyl-6-methyl-10,12-
dioxatricyclo[7.3.0.01,6]dodecane-5,11-dione (1)
In a similar manner as described for (1S,2S,6S,7S)-8a, the diol
moiety of (1R,2S,6R,7R)-8a (49.8 mg, 0.184 mmol) was pro-
tected as the cyclic carbonate to provide (1R,5S,6R,9R)-10 as
colorless oil; yield: 49.4 mg (90%); IR: nmax ¼1780, 1734, 1238,
1026 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d¼1.08 (d, J¼
1106
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 1099–1109

Synthetic Intermediate for Sesqui- and Diterpenoids
FULL PAPERS
6.8 Hz, 3 H), 1.12 (d, J¼6.8 Hz, 3 H), 1.16 (s, 3 H), 1.40–1.54
(m, 3 H), 1.58–1.66 (m, 4 H), 1.76–1.87 (m, 3 H), 1.93–2.11
(m, 3 H), 2.08 (s, 3 H), 2.19–2.25 (m, 1 H), 4.70 (dd, J¼4.4,
11.7 Hz, 1 H). This was employed for the next step without fur-
ther purification. The deprotection of acetate of
(1R,5S,6R,9R)-10 (15.2 mg, 0.051 mmol) and the subsequent
oxidation as in the similar manner for (1S,5S,6S,9S)-10 provid-
ed (1R,6S,9R)-1; yield: 12.1 mg (93%). Recrystallization from
hexane/diethyl ether gave an analytical sample of
(1R,6S,9R)-1 as needles; mp 118.5–119.08C; [a]2D4: þ43.08 (c
0.19, EtOH); anal. calcd. for C14H20O4: C 66.65, H 7.99; found:
C 66.45, H 7.98. Its IR and NMR spectra were identical with
those for (1S,6R,9S)-1.
ture was extracted with diethyl ether. The organic layer was
washed with brine, dried over anhydrous sodium sulfate, and
partially concentrated under vacuum. The residue was charged
on a silica gel column (10 g). Elution with hexane/ethyl acetate
(3/1) afforded (1S,7R,10S)-12; yield: 42.9 mg (42%). Recrystal-
lization from hexane/diethyl ether gave an analytical sample of
(1S,7R,10S)-12 as colorless prisms; mp 149.0–149.58C; [a]2D4:
þ43.48 (c 0.19, EtOH); IR: nmax ¼1801, 1671, 1259, 1026 cmꢀ
1; H NMR (400 MHz, CDCl3): d¼0.97 (d, J¼6.9 Hz, 3 H),
1
1.07 (d, J¼6.6 Hz, 3 H), 1.35 (s, 3 H), 1.46–1.59 (m, 1 H),
1.69–1.96 (m, 3 H), 2.01–2.09 (m, 1 H), 2.39–2.59 (m, 3 H),
2.72–2.84 (m, 1 H), 5.97 (dd, J¼3.3, 11.6 Hz, 1 H), 5.94–6.00
(m, 1 H); 13C NMR (100 MHz, CDCl3): d¼17.6, 19.0, 23.1,
26.5, 31.4, 32.5, 32.8, 34.4, 65.2, 93.6, 100.0, 130.2, 143.6, 153.6,
203.0; anal. calcd. for C15H20O4: C 68.16, H 7.63; found: C
68.16, H 7.54.
(1S,7R,10S)-10-Isopropyl-7-methyl-11,13-
dioxatricyclo[8.3.0.01,7]tridec-4-ene-6,12-dione (12)
To an LDA solution, separately obtained by the addition of n-
butyllithium (2.71 M in hexane, 700 mL, 1.897 mmol) to a solu-
tion of diisopropylamine (330 mL, 2.355 mmol) in THF
(1S,7R,10S)-10-Isopropyl-4,7-dimethyl-11,13-
dioxatricyclo[8.3.0.01,7]tridec-4-ene-6,12-dione (15)
(3.0 mL) at 08C,
a solution of (1S,6R,9S)-1 (96.5 mg,
0.382 mmol) in THF (2.0 mL) was added at ꢀ788C and the
mixture was stirred for 30 min. Then trimethylsilyl chloride
(240 mL, 1.891 mmol) was added and the mixture was further
stirred at ꢀ788C for 2 h. The reaction was quenched by the ad-
dition of saturated aqueous sodium hydrogen carbonate solu-
tion and the mixture was extracted with ethyl acetate. The or-
ganic layer was washed with brine, dried over anhydrous so-
dium sulfate, and partially concentrated under vacuum. The
residue was diluted with dichloromethane (8.0 mL) and dieth-
ylzinc (1.0 M in hexane, 2.0 mL, 2.0 mmol) and diiodomethane
(300 mL, 3.72 mmol) were added and the mixture was stirred
under reflux for 1 d. Then diethylzinc (1.0 M in hexane,
2.0 mL, 2.0 mmol) and diiodomethane (300 mL, 3.72 mmol)
were further added and the mixture was stirred again under re-
flux for another 1 d. The reaction was quenched by the addition
of saturated aqueous sodium hydrogen carbonate solution and
the mixture was extracted with ethyl acetate. The organic layer
was washed with brine, dried over anhydrous sodium sulfate,
and partially concentrated under vacuum to give a crude cyclo-
propane derivative 11; 1H NMR (400 MHz, CDCl3): d¼0.01 (s,
9 H), 0.27 (dd, J¼6.4, 6.4 Hz , 1 H), 0.60–0.78 (m, 1 H), 0.73 (d,
J¼6.8 Hz, 3 H), 0.86 (d, J¼6.4 Hz, 3 H), 1.07–1.13 (m, 1 H),
1.21–1.46 (m, 5 H), 1.27 (s, 3 H), 1.50–1.68 (m, 2 H), 1.81
(dd, J¼6.8, 7.3 Hz, 1 H), 1.89–1.96 (m, 1 H). This was em-
ployed for the next step without further purification.
Ferric chloride(450 mg, 2.77 mmol) was dried by evacuation
(at 10 mmHg) at 808C for 2 h. This was suspended in anhydrous
DMF (2.0 mL) and pyridine (224 mL, 2.77 mmol) and the mix-
ture was degassed by applying ultrasonics under vacuum three
times. Then a solution of the above crude 11 in anhydrous DMF
(2.0 mL) was added and further degassed in the same manner.
The mixture was stirred at 808C for 30 min and then at 1208C
for 6 h. The reaction was quenched by the addition of 1 M hy-
drochloric acid and the mixture was extracted with diethyl
ether. The organic layer was washed with brine, dried over an-
hydrous sodium sulfate, and partially concentrated under vac-
uum. The residue was diluted again with anhydrous DMF
(4.0 mL) and DBU (57 mL, 0.381 mmol) was added, and the re-
sulting mixture was stirred at 808C for 1 h. The reaction was
quenched bythe additionof 1 M hydrochloric acid and the mix-
To a lithium dimethylcuprate solution, separately prepared by
the addition of methyllithium (0.98 M in diethyl ether,
1.80 mL, 1.76 mmol) to a suspension of cuprous iodide
(170 mg, 0.89 mmol) in diethyl ether (3.0 mL) at 08C, trime-
thylsilyl chloride (106 mL, 0.84 mmol) and a solution of
(1S,7R,10S)-12 (23.3 mg, 0.088 mmol) in THF (0.5 mL) were
added at ꢀ788C and the mixture was stirred for 30 min. The
reaction was quenched by the addition of saturated aqueous
ammonium chloride solution and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous sodium sulfate, and concentrated under
vacuum. The residue was charged on a silica gel column
(1 g). Elution with hexane/ethyl acetate (5/1) afforded
(1S,4RS,7R,10S)-10-isopropyl-4,7-dimethyl-6-trimethylsilyl-
oxy-11,13-dioxatricyclo[8.3.0.01,7]tridec-5-en-12-one (14) as a
colorless oil; yield: 24.2 mg (78%); IR: nmax ¼1710, 1695 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d¼0.19 (s, 9 H), 0.97 (d, J¼
6.4 Hz, 3 H), 1.05 (d, J¼6.8 Hz, 3 H), 1.06 (d, J¼6.8 Hz,
3 H), 1.24–1.43 (m, 2 H), 1.39 (s, 3 H), 1.62–1.82 (m, 5 H),
1.92–2.13 (m, 4 H), 4.66 (d, J¼5.8 Hz, 1 H). This was em-
ployed for the next step without further purification.
Silyl ether 14 (11.4 mg, 0.032 mmol) was diluted with anhy-
drous acetonitrile (1.0 mL) and palladium acetate (10 mg,
0.045 mmol) was added, and the resulting mixture was stirred
under reflux overnight. The mixture was filtered through a Cel-
ite pad and the filter cake was washed with ethyl acetate. The
combined filtrate and washings were concentrated under vac-
uum and the residue was purified on silica gel preparative
TLC [10 cmꢁ10 cm, developed with hexane/ethyl acetate
(3/2)] to provide the desired (1S,7R,10S)-15 and
(1S,4RS,7R,10S)-16 as a byproduct.
(1S,7R,10S)-10-Isopropyl-4,7-dimethyl-11,13-dioxatricy-
clo[8.3.0.01,7]tridec-4-ene-6,12-dione (15): yield: 1.9 mg (21%)
1
as colorless solid; IR: nmax ¼1803, 1666, 1254, 1030 cmꢀ1; H
NMR (400 MHz, CDCl3): d¼0.96 (d, J¼6.8 Hz, 3 H), 1.06
(d, J¼6.4 Hz, 3 H), 1.25–1.28 (m, 1 H), 1.32 (s, 3 H), 1.45–
1.53 (m, 1 H), 1.69–1.77 (m, 1 H), 1.81–2.05 (m, 2 H), 1.93 (s,
3 H), 2.31–2.50 (m, 3 H), 2.79–2.86 (m, 1 H), 5.82 (s, 1 H).
This was employed for the next step without further purifica-
tion.
Adv. Synth. Catal. 2005, 347, 1099–1109
asc.wiley-vch.de
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1107

Shigeo Fujieda et al.
FULL PAPERS
(1S,4RS,7R,10S)-10-Isopropyl-4,7-dimethyl-11,13-dioxa-
tricyclo[8.3.0.01,7]tridecane-6,12-dione (16): yield: 3.9 mg
(44%) as a diastereomeric mixture; IR: nmax ¼1795, 1703,
The absolute structure was assigned based on the known ab-
solute configuration of (þ)-camphor (2-bornanone). There are
ꢀ
intramolecular and intermolecular O H...O hydrogen bonds,
1
1460, 1271, 1028 cmꢀ1; H NMR (400 MHz, CDCl3): d¼0.98
forming molecular chains along the a axis. Calculations were
performed using the TEXSAN crystallographic software pack-
age (Version 1.11) of Molecular Structure Corporation.
Crystallographic data have been deposited at the CCDC, 12
Union Road, Cambridge CB21EZ, UK and copies can be ob-
tained on request, free of charge, by quoting the publication ci-
tation and the deposition number CCDC-258374.
(d, J¼6.8 Hz, 3 H), 1.04 (d, J¼5.9 Hz, 6 H), 1.25–1.36 (m,
2 H), 1.38 (s, 3 H), 1.62–1.78 (m, 4 H), 1.76 (dd, J¼6.4,
6.8 Hz, 1 H), 2.01–2.10 (m, 3 H), 2.22–2.30 (m, 2 H), 2.75–
2.80 (m, 1 H). Its conversion to the trimethylsilyl ether (14)
confirmed the saturated structure.
In a separate procedure, starting from enone 12 (11.1 mg,
0.042 mmol), the enol silyl ether 14 was prepared in a same
manner. The crude 14 was dissolved in a mixture of DMSO
(0.25 mL) and toluene (0.5 mL), IBX (24 mg, 0.086 mmol)
was added and the mixture was stirred at 808C for 15 h. The re-
action was quenched by the addition of saturated aqueous so-
dium hydrogen carbonate solution and the mixture was ex-
tracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and concentrated
under vacuum. The residue was purified with a silica gel prep-
arative TLC [10 cmꢁ10 cm, developed with hexane/ethyl ace-
tate (3/2)]. The desired enone 15 (2.9 mg, 25%) and the saturat-
ed byproduct 16 (3.0 mg, 25%) were obtained, and the spectral
data were identical with those reported as above.
Acknowledgements
The authors thank Mr. Hideharu Nagano for his measurement
of mass spectra. This work was supported both by a Grant-in-
Aid for Scientific Research (No. 16580092) and the 21st Century
COE Program (KEIO LCC) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan, which are ac-
knowledged with thanks.
References and Notes
[1] a) Daucene: G. V. Pigulevskii, V. I. Kovaleva, Dokl.
Acad. Nauk SSSR 1961, 141, 1384–1385; b) aphanamol
I: M. Nishizawa, A. Inoue, Y. Hayashi, S. Sastrapradja,
S. Kosela, T. Iwashita, J. Org. Chem. 1984, 49, 3660–
3662.
[2] a) Araneosene: J. Luzi, H.-J. Borschberg, Helv. Chim.
Acta 1995, 78, 715–731; b) allocyatin B2: W. A. Ayer,
S. P. Lee, Can. J. Chem. 1979, 57, 3332–3337; c) hami-
geran B: K. D. Wellington, R. C. Cambie, P. S. Rutledge,
P. R. Bergquist, J. Nat. Prod. 2000, 63, 79–85; d) dola-
triol: G. R. Pettit, R. H. Ode, C. L. Herald, R. B. Von
Dreele, C. Michel, J. Am. Chem. Soc. 1976, 98, 4677–
4678.
[3] a) S. Servi, Synthesis 1990, 1–25; b) R. Csuk, B. I. Glꢄnz-
er, Chem. Rev. 1991, 91, 49–97; c) T. Sugai, Curr. Org.
Chem. 1999, 3, 373–406; d) K. Fuhshuku, S. Oda, T. Su-
gai, Recent Res. Devel. Org. Chem. 2002, 6, 57–74; e) K.
Nakamura, R. Yamanaka, T. Matsuda, T. Harada, Tetra-
hedron: Asymmetry 2003, 14, 2659–2681.
[4] a) D. W. Brooks, H. Mazdiyasni, P. G. Grothaus, J. Org.
Chem. 1987, 52, 3223–3232; b) Z.-L. Wei, Z.-Y. Li, G.-
Q. Lin, Synthesis 2000, 1673–1676.
An Improved Oxidation with DDQ
To a stirred solution of DDQ (400 mg, 1.76 mmol) and HMDS
(372 mL, 1.76 mmol) in dry benzene (2.0 mL), a solution of
(1S,4RS,7R,10S)-14 (24.2 mg, 0.069 mmol) in dry benzene
(1.0 mL) was added, and the resulting mixture was heated un-
der reflux with stirring for 30 min. The reaction was quenched
by the addition of saturated aqueous sodium hydrogen carbo-
nate solution and the mixture was extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated under vacuum. The residue
was charged on a silica gel column (2 g) and eluted with ethyl
acetate to remove most of the excess DDQ. The eluent was
concentrated under vacuum, and the residue was charged
again on a silica gel column (2 g). Elution with hexane/ethyl
acetate (5/1) afforded (1S,7R,10S)-15; yield: 16.5 mg (86%).
Recrystallization from hexane/diethyl ether gave an analytical
sample as colorless needles; mp 140.0–140.58C; [a]2D0: þ48.98
(c 0.18, EtOH). Its IR and 1H NMR data were identical with
those given above. 13C NMR (100 MHz, CDCl3): d¼17.7,
19.0, 23.4, 25.5, 31.4, 31.5, 32.6, 32.8, 34.0, 64.7, 93.4, 100.1,
126.8, 153.7, 155.0, 202.2; anal. calcd. for C16H22O4: C 69.04,
H 7.97; found: C 68.89, H 7.92.
[5] W. Zhou, D. Huang, Z. Wang, Kexue Tongbao 1980, 25,
741–742.
[6] K. Fuhshuku, N. Funa, T. Akeboshi, H. Ohta, H. Hoso-
mi, S. Ohba, T. Sugai, J. Org. Chem. 2000, 65, 129–135.
[7] C. Rochin, O. Babot, J. Dungues, F. Duboudin, Synthesis
1986, 667–668.
[8] D. H. Philip, C. B. Andrew, L. N. David, Synth. Commun.
1991, 21, 2157–2163.
[9] K. Fuhshuku, M. Tomita, T. Sugai, Adv. Synth. Catal.
2003, 345, 766–774.
[10] K. Mori, H. Watanabe, Tetrahedron 1985, 41, 3423–3428.
X-Ray Crystal Structure Analysis of 8c
Crystal data: orthorhombic, P212121, a¼11.4474(10), b¼
30.547(5), c¼6.4964(10) ꢃ, V¼2271.7(5) ꢃ3, Z¼4, Dx ¼
1.194 g cmꢀ3. A colorless needle crystal grown from hexane-
Et2O was used. The X-ray intensities were measured on a Riga-
ku AFC-7R four-circle diffractometer with Mo Ka irradiation.
The positional and anisotropic displacement parameters of
non-H atoms were refined. The hydroxy H atoms were located
from difference syntheses and the other H atoms were posi-
tioned geometrically (R¼0.0433).
´
[11] I. Ben, L. Castedo, J. M. Saa, J. A. Seijas, R. Suau, G.
Tojo, J. Org. Chem. 1985, 50, 2236–2240.
[12] M. Ephritikhine, Chem. Commun. 1998, 2549–2554.
1108
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 1099–1109

Synthetic Intermediate for Sesqui- and Diterpenoids
FULL PAPERS
[13] S. E. Denmark, J. P. Edwards, J. Org. Chem. 1991, 56,
[16] K. C. Nicolaou, D. L. F. Gray, T. Montagnon, S. T. Harri-
son, Angew. Chem. Int. Ed. 2002, 41, 996–1000.
[17] I. Ryu, S. Murai, Y. Hatayama, N. Sonoda, Tetrahedron
Lett. 1978, 3455–3458.
6974–6981.
[14] Y. Ito, S. Fujii, T. Saegusa, J. Org. Chem. 1976, 41, 2073–
2074.
[15] Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43,
[18] M. M. Midland, R. W. Koops, J. Org. Chem. 1990, 55,
5058–5065.
1011–1013.
Adv. Synth. Catal. 2005, 347, 1099–1109
asc.wiley-vch.de
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1109