Synthesis of (-)-nakamurol A and assignment of absolute configuration of diterpenoid (+)-nakamurol A

Article abstract of DOI:10.1021/jo034838r

The total synthesis of the enantiomer of the marine sponge diterpenoid nakamurol A and determination of the absolute configuration of this natural product are reported. This first synthetic entry to thelepogane-type diterpenoids involves the use of the bi

Full text of DOI:10.1021/jo034838r

Syn th esis of (-)-Na k a m u r ol A a n d Assign m en t of Absolu te
Con figu r a tion of Diter p en oid (+)-Na k a m u r ol A
Sandra D´ıaz, J avier Cuesta, Asensio Gonza´lez, and J osep Bonjoch*
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, Universitat de Barcelona,
Av. J oan XXIII s/ n, 08028-Barcelona, Spain
josep.bonjoch@ub.edu
Received J une 17, 2003
The total synthesis of the enantiomer of the marine sponge diterpenoid nakamurol A and
determination of the absolute configuration of this natural product are reported. This first synthetic
entry to thelepogane-type diterpenoids involves the use of the bicyclic enone (-)-3, which after a
tandem difunctionalization process and elongation of the side chain leads to the formation of the
ketone (-)-13. From (-)-13, two approaches to ent-nakamurol A (1) are reported: the straight-
forward but nonselective way, by reaction with vinylmagnesium bromide, and a longer but
stereocontrolled route, through the primary allylic alcohol 20, which is submitted to a Sharpless
epoxidation followed by a tellurium-promoted reductive-epoxide ring-opening cascade reaction.
In tr od u ction
Marine sponges Agelas nakamurai have proved to be
rich sources of unusual diterpenoids with interesting
biological activities as well as unique structures. Naka-
murol A was isolated from Agelas nakamurai Hoshino
collected from Okinawa island and its structure eluci-
dated in 19961 (Figure 1), although neither its relative
configuration at C(13) nor its absolute configuration was
established. The diterpenoid nakamurol A is made up of
a cis-decalin embodying four contiguous stereogenic
centers and a side chain containing an allylic tertiary
alcohol. Its previously unknown skeletal arrangement,2
which has been named thelepogane due to its similarity
with the alkaloid thelepoghine,3 is related to that of
labdanes [Me(19) is linked at C(5) instead of C(4)] and
clerodanes [Me(20) is linked at C(10) instead of C(9)].4
Interestingly, this particular backbone of the cis-decalin
unit, which contains side chains at C(4), C(5), C(8), C(9),
and C(10), is also found in a family of natural products
isolated from Aspergillius sp.5
F IGURE 1. Thelepogane, labdane, and clerodane skeletal
diterpene types.
the natural product (+)-nakamurol A to be established.
Our synthetic planning (Scheme 1) was based on the use
of the enantiopure bicyclic enone I as the advanced
synthetic intermediate, which not only ensures a known
configuration for the two stereogenic centers at C(4) and
C(5)7 but could also allow good stereocontrol in the
genesis of the stereogenic centers at C(9) and C(10)
through a tandem vicinal difunctionalization. Subsequent
elaboration of the side chain and a methylenation would
afford the methyl ketone II, from which a stereoselective
elaboration of the tertiary allylic alcohol should be carried
out to achieve nakamurol A.
In this paper, we describe the first total synthesis of
(-)-nakamurol A,6 which constitutes the first synthetic
entry to the thelepogane skeleton and allows the relative
configuration at C(13) and the absolute configuration of
(1) Shoji, N.; Umeyama, A.; Teranaka, M.; Arihara, S. J . Nat. Prod.
1996, 59, 448-450.
(2) A compound with the same bicyclic skeleton possesing a 9-me-
thyladenium moiety in the side chain was later isolated: Iwagawa,
T.; Kaneko, M.; Okamura, H.; Nakatani, M.; van Soest, R. W. M. J .
Nat. Prod. 1998, 61, 1310-1312.
(3) Thelepogine, isolated from the terrestrial grass Thelepogan
elegans, is the only diterpenoid alkaloid with this backbone reported
so far: Crow, W. D. Aust. J . Chem. 1962, 15, 159-161.
(4) For reviews in this field, see: (a) Tokoroyama, T. Synthesis 2000,
611-633. (b) Klein Gebbinck, E. A.; J ansen, B. J . M.; de Groot, A.
Phytochemistry 2002, 61, 737-770.
(5) Gloer, J . B. Acc. Chem. Res. 1995, 28, 343-350.
(6) For our preliminary studies in the racemic series, see: Bonjoch,
J .; Cuesta, J .; D´ıaz, S.; Gonza´lez, A. Tetrahedron Lett. 2000, 41, 5669-
5672.
Resu lts a n d Discu ssion
As point of departure for the synthesis of nakamurol,
the commercially available (R)-3-methylcyclohexanone
(7) Throughout the discussion, the numbering of the nakamurol
skeleton is followed as given by Umeyama in ref 1.
10.1021/jo034838r CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/21/2003
7400
J . Org. Chem. 2003, 68, 7400-7406

Synthesis of Nakamurol A
SCHEME 1. Retr osyn th esis of Na k a m u r ol
F IGURE 2. Preferred conformation of 4 and 5.
the NMR spectral data, which allowed the configuration
as well as the preferred conformation for this decalone
to be determined. The most noteworthy data in the 13C
NMR spectrum of 5 were the chemical shift of C-27
(δ 21.4), which is a diagnostic value for the cis-fused
decalone ring,17 and that of C-1 (δ 31.8), which is shifted
upfield by the hydroxymethyl substituent, equatorially
located at C-9 with a 1,3-relationship with the H-1eq (in
the C-9 unsubstituted derivative, C-1 resonates at δ 35.9).
For the elongation of the carbon chain from the
primary alcohol group of 5, we first attempted an
alkylation process by treating the corresponding mesylate
6 with the sodium salt of the dimethyl malonate, which
afforded a mixture of the desired diester 7 (33%) and the
enol lactone 8 (14%) as an epimeric mixture. After this
unfruitful result, we decided to again temporarily sacri-
fice the stereogenic center at C(9), working from enone
9 to construct the 3-hydroxy-3-methyl-4-pentenyl side
chain at C(9).
was converted to the enantiopure Piers’ enol lactone 2
following our previously reported procedure.8 Treatment
of 2 with the lithium salt of the dimethyl methylphos-
phonate9 gave the bicyclic enone (-)-310,11 in 60% yield
(75% based on consumed material), which was a reliable
alternative to the original protocol that used methyl-
lithium as the nucleophile for the cleavage of the enol
lactone 2 giving a methyl ketone that had to be submitted
to an aldol process.8
According to our synthetic plan, to build the required
all-cis tetrasubstituted decalone from ketone 3, it was
necessary to introduce the methyl group C(20) by a
conjugate addition and trap the enolate12 by a reagent
that furnishes a functionality that would allow further
elaboration of the side chain at C(9) (Scheme 2). Initially,
we explored the dimethyl cuprate reagent for the genera-
tion of the quaternary center at C(10)13 and used methyl
bromopropionate for quenching, but only the trimethyl-
decalone 4 (Figure 2) was isolated.14 So, to obtain the
R-functionalization, we then tried a more electrophilic
reagent such as formaldehyde to trap the enolate15
generated after the â-addition to the R,â-unsaturated
ketone 3. Although the desired alcohol 5 was isolated,
using Me2CuLi‚MeS in the first step, the result was not
always reproducible (the yields ranged from 15 to 60%)
and even the 1,2-adduct was formed in some runs. In
contrast, exposure of bicyclic enone 3 to the ZnMe2-Ni-
16
(acac)2 gave keto alcohol 5 in reproducible 52% yield
Mesylation of alcohol 5 followed by an elimination
process induced by DBU gave R-methylene ketone 9. The
problem foreseen in the use of the R-methylene ketone 9
for this synthesis was the known susceptibility of such a
after the enolate was captured with gaseous formalde-
hyde. The process was stereoselective since 5 is a single
diastereomer, whose stereochemistry was inferred from
SCHEME 2. Syn th esis of (-)-Na k a m u r ol A (1)
J . Org. Chem, Vol. 68, No. 19, 2003 7401

D´ıaz et al.
system toward Diels-Alder-type dimerization.18 How-
ever, treatment of freshly prepared enone 9 with allyl-
trimethylsilane (2.5 equiv) and TiCl4 (1 equiv), according
to the usual protocol for a Sakurai reaction,19 afforded
keto alkenes 10 and 11 in 94% yield as a 3:2 mixture of
C-9 epimers enriched in the desired isomer. Although
adjusting the reaction conditions had little impact on this
ratio, it was possible to equilibrate the mixture to achieve
adequate all-cis stereochemistry. Thus, exposure of a
mixture of epimers 10 and 11 to KF in refluxing ethanol
over a period of 48 h led to pure 10, showing the butenyl
side chain equatorially located. The signal for H-9ax, in
the 1H NMR spectrum, allowed the stereochemical as-
signment for 10 either from its multiplicity (doublet) and
coupling constants or its NOESY interrelationhips, es-
pecially with the axial protons at H-2, H-4, and H-7.
Moreover, since this signal appeared to be isolated in the
NMR spectrum of the mixture of epimers 10 and 11, it
can be used as a pattern for a quick evaluation of the
ratio of isomers after the Sakurai reaction. As observed
in compound 5 (see above), the upfield-shifted signal of
C(1) in the 13C NMR spectrum of 10 corroborated its
stereostructure. The transformation of ketoalkene 10 to
the target diterpenoid was accomplished as outlined.
Wittig olefination of 10 afforded the bisalkene derivative
12, which was oxidized chemoselectively under the
Wacker conditions (PdCl2, CuCl, O2) to afford the methyl
ketone 13 in convenient yield.20 Finally, reaction of 13
with vinylmagnesium bromide gave a 1.2:1 mixture of 1
and its C-13 epimer 14 (vide infra),21 but unfortunately
this mixture could not be separated by chromatography.
1
Although the H NMR spectroscopic data for the major
isomer formed were consistent with those reported for
the natural product, it was not possible to assign either
the absolute configuration of nakamurol A or unequivo-
cally the configuration at C(13) of the major component
of the epimeric mixture.22
A careful analysis of the 1H NMR spectrum of the
mixture of epimers 1 and 14 allowed us to carry out a
tentative assignment of the configuration of C(13) in both
compounds and hence propose the relative configuration
of nakamurol A. The stereochemical assignment of C(13)
for 1 and its epimer 14 was based specifically on the
chemical shifts of the vinyl protons at C(17) in the two
isomers. These protons were observed at a lower field and
with a smaller ∆δ between them in compound 1, trends
that have been consistently observed for related labdane
diterpenoids with a (S,S)- relationship for the stereogenic
centers at C(9) and C(13), when compared with their
epimers of (13R)-configuration (see Table 2 in Supporting
Information).21,23,24 Consequently, considering that com-
pound 1 has a (9R)-configuration, since we are working
in the enantiomeric series with respect to manool and
related labdane diterpenoids, the (13R)-configuration was
assigned for 1. In summary, taking into account all data
reported so far about labdane diterpenoids that incorpo-
rate a 3-hydroxy-3-methyl-4-pentenyl group at C(9) and
a methylene goup at C(17), the NMR signals of the latter
vinylic protons can be used for the assignment of the
configuration of the C(13) of natural compounds if the
NMR data of both epimers are available.
(8) Cuesta, X.; Gonza´lez, A.; Bonjoch, J . Tetrahedron: Asymmetry
1999, 10, 3365-3370.
(9) For the application of this method to the synthesis of R-vetivone,
see: Revial, G.; J abin, I.; Pfau, M. Tetrahedron: Asymmetry 2000, 11,
4975-4983. See also: Revial, G.; J abin, I.; Redolfi, M.; Pfau, M.
Tetrahedron: Asymmetry 2001, 12, 1683-1688.
(10) For another synthesis of (-)-3, see: Schenato, R. A.; dos Santos,
E. M.; Tenius, B. S. M.; Costa, P. R. R.; Caracelli, I.; Zukerman-
Schpector, J . Tetrahedron: Asymmetry 2001, 12, 579-584.
(11) Synthesis of (+)-3 has been described from the Wieland-
Mischer ketone (Paquette, L. A.; Wang, T.-Z.; Philippo, C. M. G.; Wang,
S. J . Am. Chem. Soc. 1994, 116, 3367-3374) and from carvone
(Verstegen-Haaksma, A. A.; Swarts, H. J .; J ansen, B. J . M.; de Groot,
A. Tetrahedron 1994, 50, 10073-10082).
(12) For a review about tandem vicinal difunctionalization of R,â-
unsaturated carbonyl substrates, see: Chapdelaine, M. J .; Hulce, M.
Org. React. 1990, 38, 225-653.
(13) For studies of organocuprates with bicyclic rigid R,â-unsatur-
ated ketones, see: Vellekoop, A. S.; Smith, R. A. J . Tetrahedron 1998,
54, 11971-11994 and references therein.
(14) Compound 4 has been previously reported, but without NMR
characterization: Cory, R. M.; Burton, L. P. J .; Chan, D. M. T.;
McLaren, F. R.; Rastall, M. H.; Renneboog, R. M. Can. J . Chem. 1984,
62, 1908-1921.
(15) For a related tandem process, see: Tokoroyama, T.; Fujimori,
K.; Shimizu, T.; Yamagiwa, Y.; Monden, M.; Iio, H. Tetrahedron 1988,
44, 6607-6622.
We then decided to explore other synthetic approaches
with the aim of diastereoselectively obtaining the allylic
alcohol of the side chain of nakamurol A in order to
achieve exclusively compound 1. We briefly examined the
possibility of employing sulfone 17 as the platform for
introducing the side chain of the target compound,25 since
the addition of the R-carbanion of 17 to (3R)-isoprene
oxide26 could produce 1. Initially, we addressed the
preparation of the key sulfone intermediate 17 (Scheme
3) by conjugate addition of thiophenol27 to the R,â-
unsaturated ketone 9 followed by Wittig olefination of
keto sulfide 15 and chemoselective oxone oxidation of 16.
Alternatively, sulfone 17 was synthesized by oxidation
of 15 followed by a nonbasic methylenation of the ketone
(20) For a similar approach in the synthesis of copalol, see: Toshima,
H.; Oikawa, H.; Toyomasu, T.; Sassa, T. Tetrahedron 2000, 56, 8443-
8450.
(16) For the use of these reagents in related processes, see: (a)
Luche, J . L.; Petrier, C.; Lansard, J . P.; Greene, A. E. J . Org. Chem.
1983, 48, 3837-3839. (b) Smith, A. B., III; Leenay, T. L. Tetrahedron
Lett. 1988, 29, 2787-2790. (c) Fox, M. E.; Li, C.; Marino, J . P.;
Overman, L. E. J . Am. Chem. Soc. 1999, 121, 5467-5480.
(17) For 13C NMR studies in cis-10-methyl-2-decalones, see: (a)
Browne, L. M.; Klinck, R. E.; Stothers, J . B. Org. Magn. Reson. 1979,
12, 561-568. (b) Gramain, J . C.; Quirion, J . C. Magn. Reson. Chem.
1986, 24, 938-946. (c) Di Maio, G.; Migneco, L. M.; Vecchi, E.;
Iavarone, C. Magn. Reson. Chem. 2000, 38, 108-114.
(18) For examples of dimerization of enones in the steroid field,
see: (a) Romann, E.; Frey, A. J .; Stadler, P. A.; Eschenmoser, A. Helv.
Chim. Acta 1957, 40, 1900-1917. (b) DellaGreca, M.; Monaco, P.;
Previtera, L.; Zarrelli, A.; Fiorentino, A.; Giordano, F.; Mattia, C. A.
J . Org. Chem. 2001, 66, 2057-2060.
(19) This methodology for the elaboration of the side chain [C(11)-
C(16)] has been studied in the synthesis of rac-nakamurol A; see ref
6.
(21) Same epimeric ratio has been previously noted in the manool-
related labdane diterpenes: Yasui, K.; Kawada, K.; Kagawa, K.;
Tokura, K.; Kitadokoro, K.; Ikenishi, Y. Chem. Pharm. Bull. 1993, 41,
1698-1707.
(22) Due to the dearth of the natural product (personal communica-
tion of Prof. A. Umeyama, University of Tokyo) we were unable to
obtain a sample of nakamurol A for chromatographic comparisons.
(23) Barrero, A. F.; Sa´nchez, J . F.; Alvarez-Manzaneda, E. J .; Mun˜oz
Dorado, M.; Haidour, A. Phytochemistry 1993, 32, 1261-1265.
(24) Kagawa, K.; Tokura, K.; Uchida, K.; Kakushi, H.; Shike, T.;
Kikuchi, J .; Nakai, H.; Dorji, P.; Subedi, L. Chem. Pharm. Bull. 1993,
41, 1604-1607.
(25) For a seminal work, see: Cane, D. E.; Yang, G. J . Org. Chem.
1994, 59, 5794-5798.
(26) Ohwa, M.; Kogure, T.; Eliel, E. L. J . Org. Chem. 1986, 51, 2599-
2601.
(27) Tamura, R.; Watabe, K.; Kamimura, A.; Hori, K.; Yokomori, Y.
J . Org. Chem. 1992, 57, 4903-4905.
7402 J . Org. Chem., Vol. 68, No. 19, 2003

Synthesis of Nakamurol A
SCHEME 3. Stu d ies th r ou gh Su lfon e 17
F IGURE 3. Structure of nakamurol A.
treating 13 with the sodium salt of trimethyl phospho-
noacetate in THF to give a 5:1 mixture of the chromato-
graphically nonseparated diastereomers (E)-unsaturated
ester 18 and its (Z)-isomer. However, this was not a major
problem since the corresponding products formed from
each diastereomer were easily separated in the next step
of the synthesis. Thus, the reduction of the mixture of
18 and its (Z)-isomer with DIBALH31 provided the pure
allylic alcohol 19 (60% overall yield from 13) needed for
the asymmetric epoxidation, the alcohol 20 also being
isolated as the minor isomer. Stereoselective epoxidation
of the allylic alcohol 19 by the asymmetric Sharpless
method32 using D-(-)-diethyl tartrate (DET) gave the
desired (13R,14R)-epoxide 21 in 53% yield after removal
of the minor epoxide diastereomer (dr ) 9:1). The (13R,-
14R)-stereochemistry of the major diastereomer 21 was
assigned on the basis of the expected reagent-directed
epoxidation preference,33 as well as from the NOESY data
from its 600 MHz spectrum. To obtain the tertiary allylic
alcohol 1 from 21, the latter was transformed into the
corresponding tosylate, which was treated with Te in the
presence of rongalite (HOCH2SO2Na) in aqueous me-
dium. This procedure generated Te2-, which induces an
initial SN upon tosylate followed by an opening of the
epoxide ring, forming an epi-telluride, which loses el-
emental Te.34,35 After this stereocontrolled process, com-
SCHEME 4. Ster eocon tr olled Syn th esis of
en t-Na k a m u r ol A
1
pound 1 was isolated, showing H and 13C NMR spectro-
scopic data identical to those reported for the natural
product. All that remained to establish the absolute
stereochemistry of natural nakamurol A was to measure
the optical rotation of the synthetic nakamurol A (1). The
data obtained, [R]D ) -36.3 (c ) 0.02, CHCl3) for 1,
resulted in the assignment of the ent-nakamurol A for 1
and the shown (4S,5R,9S,10R,13S)- absolute configura-
tion for the natural (+)-nakamurol A [Lit1 [R]D +39.1 (c
1.6, CHCl3)] (Figure 3). Both the enantioselective total
synthesis of ent-nakamurol A and the assignment of its
absolute configuration were thus achieved.
group,28 although the overall yield was lower than in the
aforementioned sequence. Unfortunately, sulfone 17
proved to be an unusually inert compound and thus was
recovered unchanged after treatment with different basic
reagents and (3R)-isoprene oxide. On the other hand,
attempts to generate the corresponding lithium deriva-
tive from the ethylene acetal of sulfide 15 (not shown) or
sulfide 16 by reaction with LDBB (lithium 4,4′-di-tert-
butylbiphenylide)29 and coupling with the (3R)-isoprene
epoxide in each case resulted only in the recovery of the
starting sulfide.
Secon d Gen er a tion Syn th esis of Na k a m u r ol A (1).
We finally directed our efforts toward enantiopure 1
using the reductive ring-opening of the epoxide 21
(Scheme 4). For this purpose we chose as a precursor the
methyl ketone 13, used in the first approach. The
elongation of the side chain30 was accomplished by
In conclusion, the first total synthesis of ent-nakamurol
A (1) was achieved in 16 steps and 3% overall yield
(together with 14) from (-)-3-methylcyclohexanone. A
(31) Ohba, M.; Kawase, N.; Fujii, T. J . Am. Chem. Soc. 1996, 118,
8250-8257.
(32) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780 and
references therein.
(33) (a) Pfenninger, A. Synthesis 1986, 89-116. (b) Katsuki, T.;
Martin, V. S. Org. React. 1996, 48, 1-299.
(34) (a) Dittmer, D. C.; Discordia, R. P.; Zhang, Y.; Murphy, C. K.;
Kumar, A.; Pepito, A. S.; Wang, Y. J . Org. Chem. 1993, 58, 718-731.
(b) Kumar, A.; Dittmer, D. C. Tetrahedron Lett. 1994, 35, 5583-5586.
(35) For an alternative procedure, working through the correspond-
ing iodide, to convert epoxy tosylates upon tertiary allylic alcohols,
see: (a) Nicolaou, K. C.; Duggan, M. E. Tetrahedron Lett. 1984, 25,
2069-2072. (b) Rodr´ıguez, C. M.; Mart´ın, T.; Ram´ırez, M. A.; Mart´ın,
V. S. J . Org. Chem. 1994, 59, 4461-4472.
(28) Hibino, J .; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett.
1985, 26, 5579-5580.
(29) Cohen, T.; Zhang, B.; Cherkauskas, J . P. Tetrahedron 1994,
50, 11569-11584.
(30) For an alternative process to convert
a side chain from
3-oxobutyl to 5-hydroxy-3-methyl-3-pentenyl in the terpene field, see:
Barrero, A. F.; Alvarez-Manzaneda, E. J .; Chahboun, R.; Rodr´ıguez
Rivas, A.; Linares Palomino, P. Tetrahedron 2000, 56, 6099-6113.
J . Org. Chem, Vol. 68, No. 19, 2003 7403

D´ıaz et al.
J ) 8.4, 2.2 Hz, 1H), 4.18 (dd, J ) 9.6, 2.6 Hz, 1H), 4.62 (dd,
J ) 9.6, 8.4 Hz, 1H).
second-generation total synthesis of 1, in which the C(13)
stereocenter was established using catalyst rather than
substrate control, was slightly longer but furnished 1
stereoselectively without forming its epimer 14. These
two syntheses are the first to be reported for a diterpe-
noid with the thelepogane-type skeleton and have al-
lowed the absolute configuration of nakamurol A to be
established.
A solution of the above mesylate 6 (175 mg) in THF (10 mL)
was treated with DBU (0.2 mL, 1.3 mmol) and heated at reflux
for 15 h. The reaction mixture was cooled to room temperature
and diluted with Et2O, and the organic layer was washed with
2 N HCl. The dried organic extracts were concentrated and
purified by chromatography (5% EtOAc/hexane) to give 9 (120
mg, 98% from alcohol 5): [R]D -31.6 (c 0.8, CH2Cl2); 1H NMR
(300 MHz) δ 0.83 (d, J ) 6.9 Hz, 3H), 0.90 (s, 3H), 0.99 (s,
3H), 1.4-1.53 (m, 4H), 1.67-1.87 (m, 5H), 2.41 (m, 2H), 5.28
(d, J ) 1.5 Hz, 1H), 6.06 (d, J ) 1.5 Hz, 1H); 13C NMR (75
MHz, DEPT) δ 15.7 (2q), 21.5 (t), 27.2 (q), 28.9 (t), 30.4 (t),
32.2 (t), 32.6 (d), 35.3 (t), 38.3 (s), 44.8 (s), 120.5 (t), 152.4 (s),
203.2 (s); HRMS calcd for C28H24O2 (the dimer species)17
412.3341, found 412.3331.
(1S,4a S,5R,8a S)-1-(Bu t -3-en yl)-4a ,5,8a -t r im et h yl-3,4,-
4a,5,6,7,8,8a-octah ydr o-1H-n aph th alen -2-on e (10). A cooled
(-78 °C) solution of enone 9 (100 mg, 0.48 mmol) in CH2Cl2 (3
mL) was treated sequentially with TiCl4 (0.06 mL, 0.49 mmol)
and allyltrimethylsilane (0.2 mL, 1.25 mmol). After the
mixture was stirred at -78 °C for 3 h, the reaction was
quenched by addition of water (1 mL) and allowed to reach
room temperature. The resulting two-phase mixture was
separated, and the aqueous layer was extracted with CH2Cl2.
The organic extracts were washed with brine, dried, and
concentrated. The residue was purified by chromatography (1%
EtOAc/hexane) to afford a 3:2 mixture of 10 and its epimer
11 (110 mg, 94%). A solution of this mixture in EtOH (15 mL),
containing KF (418 mg, 7.2 mmol), was heated at reflux for
72 h. EtOH was removed, the residue dissolved in CH2Cl2, and
the solution washed with water. The organic layer was dried
and concentrated to give quantitatively enantiopure (+)-10:
[R]D +16.5 (c 0.8, CH2Cl2); 1H NMR (500 MHz, COSY, NOESY)
δ 0.66 (s, 3H, Me-20), 0.82 (s, 3H, Me-19), 0.90 (d, J ) 6.6 Hz,
3H, Me-18), 1.18 (m, 1H, H-2eq), 1.36-1.47 (m, 3H, H-1. H-3),
1.47-1.50 (m, 3H, H-2ax, H-11. H-12), 1.56 (dm, J ) 9.5 Hz,
1H, H-3eq), 1.67, (td, J ) 14.5, 4.5 Hz, 1H, H-6ax), 1.86 (m, 1H,
H-11), 1.89 (ddd, J ) 14, 4, 2 Hz, 1H, H-6eq), 2.16 (ddd, J )
14, 4.5, 2 Hz, 1H, H-7eq), 2.18 (m, 1H, H-12), 2.40 (m, 1H, H-4),
2.45 (td, J ) 14.5, 6 Hz, 1H, H-7ax), 2.98 (d, J ) 9.5 Hz, H-9ax),
4.95 (d, J ) 11 Hz, 1H, H-16), 4.98 (d, J ) 18 Hz, 1H, H-16),
5.78 (m, 1H, H-13); 13C NMR (75 MHz, HSQC) δ 16.0 (C-18),
16.5 (C-19), 18.9 (C-20), 21.6 (C-2), 21.7 (C-11), 30.7 (C-3), 30.9
(C-4), 32.2 (C-6), 33.3 (C-1), 33.4 (C-12), 38.6 (C-7), 39.4 (C-5),
46.4 (C-10), 50.6 (C-9), 114.8 (C-16), 139.0 (C-13), 213.6 (C-8);
HRMS calcd for C17H28O 248.2140, found 248.2147
Exp er im en ta l Section 36
(4aS,5R)-4a,5-Dim eth yl-4,4a,5,6,7,8-h exah ydr o-3H-n aph -
th a len -2-on e (-)-3. n-BuLi (1.6 M in hexanes, 7.5 mL, 12.3
mmol) was added dropwise to a cooled (-78 °C) solution of
dimethyl methylphosphonate (1.25 mL, 14 mmol) in THF (20
mL). After 5 min, a solution of lactone 2 (740 mg, 4.11 mmol)
in THF (20 mL) was added, the temperature was raised to
-20 °C and the stirring maintained for 6 h. The solution was
poured into water-Et2O, and the aqueous layer was extracted
with Et2O. The organic extracts were dried and concentrated,
and the residue was purified by chromatography (from hexane
to 98:2 hexane/EtOAc) to give 38 (437 mg, 60%). When, after
the ethereal extraction, the aqueous layer was acidified with
6 N HCl and extracted with Et2O, 160 mg of the (1S,2R)-1,2-
dimethyl-6-oxocyclohexanepropionic acid,7 the synthetic pre-
cursor of enol lactone 2, were recovered.
(1R,4a S,5R,8a S)-1-H yd r oxym et h yl-4a ,5,8a -t r im et h yl-
3,4,4a ,5,6,7,8,8a -octa h yd r o-1H-n a p h th a len -2-on e (5). Me2-
Zn (2 M in toluene, 3.36 mL, 6.7 mmol) was added dropwise
to a cooled (0 °C) dispersion of LiBr (1.17 g, 13.5 mmol) and
Ni(acac)2 (17 mg, 0.067 mmol) in Et2O (9 mL). After the
mixture was stirred for 5 min, a solution of 3 (300 mg, 1.68
mmol) in Et2O (9 mL) was added dropwise, and the stirring
was maintained for 24 h at room temperature. The mixture
was cooled at -20 °C and exposed to a stream of formaldehyde
gas that was passed through it for 30 min. After being allowed
to reach room temperature, the reaction mixture was stirred
for 1 h, poured into 10% aqueous NH4Cl solution and Et2O,
and filtered through Celite, after which the filter pad was
washed with Et2O. The resulting two-phase mixture was
separated and the aqueous layer extracted with Et2O, and the
organic extracts were washed with water and brine. The
concentrated dried organic extracts were purified by chroma-
tography (from hexane to 5% EtOAc/hexane) to give 5 (268
mg, 72%): [R]D -17.9 (c 1, CH2Cl2); 1H NMR (500 MHz, COSY)
δ 0.64 (s, Me-20), 0.73 (s, Me-19), 0.81 (d, J ) 7 Hz, Me-18),
1.26-1.38 (m, 3H, H-1 and H-3), 1.45-1.53 (m, 3H, H-2 and
H-3), 1.61 (td, J ) 14.5, 4.8 Hz, H-6ax), 1.80 (ddd, J ) 14.5, 7,
2.5 Hz, H-6eq), 2.12 (dq, J ) 14.5, 4.5 Hz, H-7eq), 2.27 (dqd, J
) 12, 7.5, 5 Hz, H-4), 2.35 (tdd, J ) 14.5, 6.6, 1 Hz, H-7ax),
2.48 (br, OH), 3.12 (dd, J ) 9, 3 Hz, H-9), 3.43 (dd, J ) 11.5,
3.5 Hz, 1H, H-11), 3.90 (dd, J ) 11.5, 9.0 Hz, 1H, H-11); 13C
NMR (75 MHz, HSQC) δ 15.2 (C-19), 16.3 (C-18), 19.7 (C-20),
21.4 (C-2), 30.3 (C-3), 30.7 (C-4), 31.8 (C-1), 32.2 (C-6), 38.0
(C-7), 39.1 (C-5), 44.6 (C-10), 53.5 (C-9), 58.3 (C-11), 216.2 (C-
8); HRMS calcd for C14H24O2 224.1776, found 224.1782.
(4a S ,5R ,8a R )-4a ,5,8a -T r im e t h y l-1-m e t h y le n e -3,4,-
4a ,5,6,7,8,8a -octa h yd r o-1H-n a p h th a len -2-on e (9). A cooled
(0 °C) solution of 5 (133 mg, 0.6 mmol) in CH2Cl2 (3 mL) was
treated sequentially with i-Pr2EtN (0.2 mL, 1.2 mmol) and
methanesulfonyl chloride (0.08 mL, 0.9 mmol). After being
stirred at room temperature for 4 h, the mixture was poured
into saturated aqueous NaHCO3 and extracted with CH2Cl2.
The organic extracts were washed with 0.5 N HCl and
saturated aqueous NaHCO3, dried, and concentrated to give
the mesylate 6, which was used in the next step without
additional purification: 1H NMR (200 MHz) δ 0.70 (s, 3H),
0.84 (s, 3H), 0.92 (d, J ) 10 Hz, 3H), 3.08 (s, 3H), 3.45 (dd,
(1R,4a S,5R,8a S)-1-(Bu t-3-en yl)-2-m eth ylen e-4a ,5,8a -tr i-
m eth yld eca h yd r on a p h th a len e (12). To a dispersion of
methyltriphenylphosphonium bromide (1.6 g, 4.63 mmol) in
THF (3 mL) at 0 °C was added n-BuLi (1.6 M in hexanes, 2.8
mL, 4.63 mmol), and the mixture was stirred for 1 h. A solution
of ketone 10 (115 mg, 0.46 mmol) in THF (2 mL) was added,
and the reaction was heated at reflux for 16 h. After the
mixture was cooled to room temperature, the reaction was
quenched with water, and the aqueous layer extracted with
EtOAc. The organic extracts were washed with brine, dried,
and concentrated. Purification of the residue by chromatog-
raphy (hexane) gave 12 (90 mg, 79%): bp (135 °C, 0.2 mbar);
1
[R]D -28.7 (c 0.8, CH2Cl2); H NMR (400 MHz, COSY) δ 0.63
(s, 3H, Me-20?), 0.74 (s, 3H, Me-19?), 0.79 (d, J ) 7.2 Hz, 3H,
Me-18), 1.25 (m, 1H, H-3), 1.30 (m, 1H, H-6ax), 1.40 (m, 3H,
H-1, H-2), 1.45 (m, 3H, H-3, H-11), 1.50 (m, 1H, H-1), 1.59
(dm, J ) 14 Hz, 1H, H-6eq), 1.91 (td, J ) 16.5, 7.2 Hz, 1H,
H-7ax), 2.05 (dq, J ) 13.2, 2.8 Hz, 1H, H-12), 2.17 (m, 1H,
H-12), 2.25 (m, 1H, H-7), 2.34 (m, 1H, H-4), 2.64 (d, J ) 9.6
Hz, 1H, H-9), 4.49 (d, J ) 1.2 Hz, 1H, H-17), 4.84 (d, J ) 1.6
Hz, 1H, H-17), 4.94 (d, J ) 10.4 Hz, 1H, H-16), 4.99 (d, J )
17.2 Hz), 5.83 (ddt, J ) 17.2, 10.4, 6.6 Hz, 1H, H-13); 13C NMR
(75 MHz, HSQC) δ 16.4 (C-18), 16.5 (C-19), 18.4 (C-20), 21.4
(C-2), 23.6 (C-11), 30.4 (C-4), 31.2 (C-3), 31.9 (C-1), 32.8 (C-7),
33.0 (C-12), 33.9 (C-6), 39.5 (C-5), 41.9 (C-9), 42.1 (C-10), 106.2
(36) Terpene numbering was used in the NMR assignation of all
compounds, and the IUPAC nomenclature is followed in the headings.
7404 J . Org. Chem., Vol. 68, No. 19, 2003

Synthesis of Nakamurol A
(C-17), 114.1 (C-16), 139.5 (C-13), 149.3 (C-8); HRMS calcd for
50.8 (q), 106.3 (t), 114.7 (d), 149.2 (s), 161.2 (s), 167.2 (s). Anal.
Calcd for C21H34O2: C, 79.19; H, 10.76. Found: C, 78.88; H,
10.94.
C
17H27 (M-15) 231.2113, found 231.2112.
(1R,4a S,5R,8a S)-2-Met h ylen e-1-(3-oxob u t yl)-4a ,5,8a -
(E)-(1R,4a S,5R,8a S)-3-Met h yl-5-(4a ,5,8a -t r im et h yl-2-
m eth ylen e-decah ydr on aph th alen -1-yl)-pen t-2-en -1-ol (19).
A solution of a 5:1 mixture of esters 18 and its (Z)-isomer (35
mg, 0.11 mmol) in CH2Cl2 (1.5 mL) was cooled to -78 °C, and
DIBALH (1.5 M in toluene, 0.23 mL, 0.34 mmol) was added
dropwise over 10 min. After being stirred at -78 °C for 45
min, the reaction was quenched by adding AcOH (5 M, 1 mL)
in CH2Cl2 at -78 °C. The resulting mixture was allowed to
reach room temperature, and 10% aqueous tartaric acid (2 mL)
and H2O (2 mL) were added. The layers were separated, and
the aqueous phase was extracted with CH2Cl2. The combined
CH2Cl2 extracts were washed with saturated aqueous NaHCO3
and brine, dried, and concentrated to leave a colorless oil,
which was purified by chromatography (9:1 hexanes-EtOAc)
to give 19 (22 mg, 69%; 85% based on 18) and 20 (5 mg, 16%).
Com p ou n d 19: [R]D -22.3 (c 0.11, CH2Cl2); 1H NMR (300
MHz) δ 0.63 (s, 3H), 0.73 (s, 3H), 0.79 (d, J ) 6.9 Hz, 3H),
1.10-1.60 (m, 10H), 1.69 (s, 3H), 1.75-1.95 (m, 1H), 2.05 (m,
1H), 2.10-2.25 (m, 3H), 2.35 (m, 1H), 2.61 (d, J ) 9.6 Hz, 1H),
4.15 (d, J ) 6.9 Hz, 2H), 4.50 (s, 1H), 4.84 (s, 1H), 5.41 (tq, J
) 6.9, 1.2 Hz, 1H); 13C NMR (75 MHz, DEPT) δ 16.3 (q), 16.4
(q), 16.5 (q), 18.3 (q), 21.4 (t), 22.6 (t), 30.4 (d), 31.2 (t), 31.9
(t), 33.1 (t), 33.9 (t), 38.7 (t), 39.5 (s), 42.2 (d), 42.4 (s), 59.5 (t),
tr im eth yld eca h yd r on a p h th a len e (13). A suspension of
CuCl (20 mg, 0.20 mmol) and PdCl2 (8 mg, 0.04 mmol) in DMF
(0.5 mL) and H2O (0.13 mL) was saturated with oxygen and
stirred at 45 °C for 90 min. A solution of alkene 12 (33 mg,
0.13 mmol) in DMF (0.5 mL) was added, and the reaction was
stirred under an oxygen atmosphere at 45 °C for 20 h. The
mixture was poured into 3 N HCl and extracted with CH2Cl2.
The organic layer was filtered through Celite, after which the
filter pad was washed with hexane. The filtrate was dried and
concentrated, and the residue was purified by chromatography
(1% EtOAc/hexane) to afford 13 (25 mg, 71%): [R]D -29.4 (c
0.8, CH2Cl2); 1H NMR (500 MHz, COSY) δ 0.65 (s, 3H, Me-
20), 0.74 (s, 3H, Me-19), 0.78 (d, J ) 7 Hz, 3H, Me-18), 1.23-
1.60 (m, 9H), 1.75 (dddd, J ) 13, 11.5, 7, 2 Hz, H-11), 2.03
(ddd, J ) 13, 4.5, 2.5 Hz, H-7eq), 2.10 (s, 3H, H-16), 2.14 (td, J
) 13.5, 4 Hz, H-7ax), 2.27(m, H-4), 2.33 (ddd, J ) 17, 9.5, 7
Hz, 1H, H-12), 2.57 (br d, J ) 11.5 Hz, H-9), 2.62 (ddd, J )
17.5, 9.5, 4.5 Hz, H-12), 4.40 (d, J ) 1 Hz, 1H, H-17), 4.84 (d,
J ) 1.5 Hz, 1H, H-17); 13C NMR (75 MHz, HSQC) 16.4 (C-18
and C-19), 18.1 (C-11), 18.2 (C-20), 21.3 (C-2), 30.1 (C-16), 30.5
(C-4), 31.1 (C-3), 31.9 (C-1), 33.1 (C-7), 34.0 (C-6), 39.5 (C-5),
42.2 (C-9), 42.4 (C-10), 43.0 (C-12), 106.3 (C-17), 149.2 (C-8),
209.0 (C-13). Anal. Calcd for C18H30O: C, 82.38; H, 11.52.
Found: C, 82.02; H, 11.71.
106.2 (t), 122.9 (d), 140.7 (s), 149.5 (s); HRMS calcd for C20H34
290.2610, found 290.2614.
O
(3R)- a n d (3S)-5-[(1R,4a S,5R,8a S)-4a ,5,8a -Tr im eth yl-2-
m eth ylen edecah ydr o-1-n aph th alen yl)-3-m eth yl-1-pen ten -
3-ol (1 a n d 14). Vinylmagnesium bromide (1 M in THF, 1.21
mL, 1.21 mmol) was added to a solution of 13 (32 mg, 0.122
mmol) in THF (2 mL) at 0 °C. After the mixture was stirred
for 2 h, the reaction was quenched with aqueous NH4Cl and
extracted with Et2O. The organic layer was dried and concen-
trated to leave a colorless oil, which was purified by chroma-
tography (3% EtOAc/hexane) to give a mixture (1.2:1) of 1 and
(1R,4a S,5R,8a S)-{3-Met h yl-3-[2-(4a ,5,8a -t r im et h yl-2-
m et h ylen e-d eca h yd r on a p h t h a len -1-yl)-et h yl]-(2R,3R)-
oxir a n yl}-m eth a n ol (21). D-(-)-Diethyl tartrate (13 µL, 0.062
mmol) and titanium(IV) isopropoxide (20 µL, 0.062 mmol) were
added sequentially to a cooled (-20 °C) suspension of activated
4 Å molecular sieves and CH2Cl2 (0.5 mL). After the mixture
was stirred at -20 °C for 10 min, tert-butyl hydroperoxide (23
µL, 5.5 M in decane, 0.128 mmol) was added and stirring was
resumed for 45 min. Then, a mixture of 19 (18 mg, 0.062 mmol)
in CH2Cl2 (0.5 mL) and activated 4 Å molecular sieves, cooled
to -20 °C and previously stirred for 10 min, was added
dropwise. After the mixture was stirred at -20 °C for 20 h,
the reaction was quenched by addition of 10% aqueous tartaric
acid (3 mL), resulting in the freezing of the aqueous layer. The
cooling bath was removed and stirring was continued at room
temperature. Hydrolysis of tartrates was effected by adding 2
mL of a 1 N aqueous NaOH solution and 2 mL of Et2O. After
30 min of vigorous stirring at 0 °C, phase separation occurred.
The organic phase was removed and combined with two
extracts of the aqueous phase (CH2Cl2). The combined organic
extracts were dried and filtered through Celite to give a clear,
colorless solution. Concentration followed by purification of the
oil by chromatography (85:15 hexanes-EtOAc) gave the ep-
1
its epimer 14 (117 mg, 47% overall yield). Com p ou n d 1: H
NMR (500 MHz, COSY) δ 0.63 (s, Me-20), 0.73 (s, Me-19), 0.79
(d, J ) 6.6 Hz, Me-18), 1.28 (s, Me-16), 1.29 (m, H-12), 1.34
(m, H-3), 1.35 (m, H-11), 1.36 (m, H-6), 1.42 (m, 3H), 1.48 (m,
H-3, H-11), 1.53 (m, H-1), 1.59 (ddd, J ) 14.5, 5, 2.5 Hz, H-6),
1.82 (ddd, J ) 13,5, 13,5, 4,8 Hz, H-12); 2,05 (ddd, J ) 14.5, 5,
2.5 Hz, H-7eq), 2.18 (ddd, J ) 14.5, 14.5, 5 Hz, H-7ax), 2.33 (m,
H-4), 2.56 (d, J ) 11 Hz, H-9ax), 4.50 (d, J ) 1.5 Hz, H-17),
4.82 (d, J ) 1.5 Hz, H-17), 5.05 (dd, J ) 11, 1 Hz, H-15), 5.21
(dd, J ) 17.5, 1.5 Hz, H-15), 5.92 (dd, J ) 17.5, 11 Hz, H-14);
13C NMR (100 MHz) δ 16.3 (C-18), 16.4 (C-19), 18.2 (C-11),
18.3 (C-20), 21.4 (C-2), 27.6 (C-16), 30.4 (C-4), 31.1 (C-3), 31.9
(C-1), 33.1 (C-7), 33.9 (C-6), 39.5 (C-5), 41.7 (C-12), 42.4 (C-
10), 43.2 (C-9), 73.6 (C-13), 106.5 (C-17), 111.5 (C-15), 145.3
(C-14), 149.6 (C-8).
1
oxide 21 (10 mg, 53%): [R]D -14.2 (c 0.06, CHCl3); H NMR
(E)-3-Met h yl-5-[(1R,4a S,5R,8a S)-4a ,5,8a -t r im et h yl-2-
m eth ylen ed eca h yd r on a p h th a len -1-yl]-p en t-2-en oic Acid
Meth yl Ester (18). To a stirred slurry of NaH (64 mg, 1.58
mmol) in THF (3 mL) was added at 5 °C a solution of trimethyl
phosphonoacetate in THF (2 mL). The reaction mixture was
stirred for 2 h, after which a solution of 13 (52 mg, 0.198 mmol)
in THF (3 mL) was added. The resulting mixture was heated
at reflux for 10 h, allowed to reach room temperature; the
reaction was quenched with aqueous NH4Cl, and the mixture
was extracted with EtOAc. The organic extract was washed
with brine, dried, and concentrated to leave a colorless oil,
which was purified by chromatography (1% EtOAc/hexane) to
give 54 mg (85%) of a mixture (5:1) of 18 and its (Z)-isomer.
Com p ou n d 18: 1H NMR (500 MHz) δ 0.63 (s, 3H), 0.74 (s,
3H), 0.79 (d, J ) 6 Hz, 3H), 1.20-1.60 (m, 8H), 1.54 (s, 3H),
1.55-1.60 (m, 2H), 1.90-2.15 (m, 3H), 2.20-2.40 (m, 2H), 2.62
(d, J ) 11 Hz), 3.69 (s, 3H), 4.48 (d, J ) 1 Hz), 4.86 (d, J ) 1.5
Hz, 1H). 5.68 (s, 1H); 13C NMR (75 MHz, DEPT) δ 16.3 (q),
16.4 (q), 18.3 (q), 19.1 (q), 21.4 (t), 22.4 (t), 30.4 (d), 31.2 (t),
32.0 (t), 33.1 (t), 33.9 (t), 39.5 (s), 40.1 (t), 42.3 (s), 42.4 (d),
(600 MHz, COSY) δ 0.64 (s, 3H, Me-20), 0.74 (s, 3H, Me-19),
0.79 (d, J ) 7.2 Hz, Me-18), 1.31 (s, Me-16), 1.25 (m, 1H, H-12),
1.29 (m, 1H, H-3), 1.34 (m, 1H, H-11), 1.36 (m, 1H, H-6), 1.47
(m, 1H, H-3), 1.49 (m, 1H, H-11), 1.59 (dddd, J ) 3, 4,2, 13,8
Hz, 1H, H-6), 1.88 (ddd, J ) 4.2, 10.8, 15 Hz, H-12), 2.05 (dddd,
J ) 12.6, 6.6, 4.2, 2.4 Hz, 1H, H-7ec), 2.17 (ddd, J ) 4,2, 13,8
Hz, H-7ax), 2.32 (m, 1H, H-4), 2.59 (d, J ) 10.2 Hz, H-9ax), 2.96
(dd, J ) 6.6, 4.2 Hz H-14), 3.70 (dd, J ) 11.5, 6.6 Hz, 1H, H-15),
3.85 (d, J ) 11,5 Hz, 1H, H-15), 4.45 (brs, 1H, H-17), 4.83 (d,
J ) 1.2 Hz, 1H, H-17); 13C NMR (100 MHz, HSQC) δ 16.3 (C-
18), 16.4 (C-19), 16.9 (C-16), 18.3 (C-20), 19.2 (C-11), 21.4 (C-
2), 31.1 (C-3), 30.4 (C-4), 31.9 (C-1), 33.9 (C-6), 33.0 (C-7), 37.6
(C-12), 39.5 (C-5), 42.3 (C-10), 42.7 (C-9), 61.5 (C-15), 62.5 (C-
14), 62.7 (C-13), 106.6 (C-17), 149.4 (C-8); HRMS calcd for
C
20H35O2 (MH+) 307.2637, found 307.2644.
en t-Na k a m u r ol A (1). To a solution of epoxide 21 (10 mg,
0.033 mmol) in CH2Cl2 (0.5 mL) were added p-toluenesulfonyl
chloride (7 mg, 0.036 mmol) and DMAP (5 mg, 0.04 mmol) in
CH2Cl2 (0.2 mL). The reaction mixture was stirred for 5 h at
room temperature. The crude was poured into hexanes (1.5
J . Org. Chem, Vol. 68, No. 19, 2003 7405

D´ıaz et al.
mL), and the resulting precipitate was removed by filtration.
The filtrate was concentrated, diluted with Et2O, and filtered
again. The organic layer was dried and concentrated to give
the corresponding tosylate (10 mg, 77%), which was used in
the next step without purification. A solution of the above
tosylate (9 mg, 0.025 mmol) in THF (0.5 mL) was added to a
solution of sodium telluride at 50 °C prepared by reduction of
elemental Te (6 mg, 0.047 mmol) with rongalite (14 mg, 0.075
mmol) and 1 M aqueous NaOH (80 µL, 0.075 mmol). After 5.30
h, the reaction was complete as indicated by TLC. The reaction
mixture was exposed to air, and a stream of air was passed
through it (0.5 h) to oxidize excess Te2- to Te0. The elemental
tellurium was removed by filtration through Celite, after which
the filter pad was washed with hexane. The aqueous layer was
separated from the organic layer and extracted with CH2Cl2.
The combined CH2Cl2 extracts were dried and concentrated
to leave an oil, which was purified by chromatography (8:2
hexanes-EtOAc) to give ent-nakamurol-A (1, 2.8 mg, 30%);
[R]D -36.3 (c 0.02, CHCl3) [lit.1 [R]D +39.1 (c 1.6, CHCl3)]. The
1H NMR (500 MHz, COSY) and 13C NMR (100 MHz, HSQC)
data of 1 matched those reported in the literature for the
natural product1 as well as those of compound 1 obtained from
13 (see above): HRMS (FAB) calcd for C20H34O 290.2610,
found 290.2627.
Ack n ow led gm en t. This work was supported by the
MCYT, Spain (project BQU2001-3551). Thanks are also
due to the DURSI, Catalonia, for Grant 2001SGR-00083
and a fellowship for S.D.
Su p p or tin g In for m a tion Ava ila ble: Experimental and/
or NMR data for compounds 4, 7, 8, 11, 15-17, and 20, a table
of 13C NMR chemical shifts of all compounds reported, copies
1
of H and 13C NMR spectra of all new compounds, as well as
COSY and HSQC spectra when available. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O034838R
7406 J . Org. Chem., Vol. 68, No. 19, 2003