which suggested the presence of a tertiary alcohol in
edaxadiene, which could readily lose H2O to give the high
mass peak corresponding to C20H32. The 1H NMR spectrum
of edaxadiene shows doubling of peaks for the vinyl protons
indicating the presence of a 1:1 mixture of diastereomers.
Scheme 2
.
Retrosynthesis of Nosyberkol (Isotuberculosinol,
Revised Structure of Edaxadiene)
Scheme 1. Conversion of Halimadienyl Diphosphate (1) to
Nosyberkol (Isotuberculosinol, Revised Structure of Edaxadiene,
4)
1 week afforded 74% of Diels-Alder adducts with 60%
selectivity for the exo adduct 12.7 Most significantly,
Danishefsky reported that the EtAlCl2-catalyzed reaction of
diene 7 with vinyl ketone 13 provided exclusively the desired
exo Diels-Alder adduct 14, which was converted to ma-
manuthaquinone.8 Steric interactions between the aryl group
of dienophile 13 and the methyl substituents on the cyclo-
hexene of diene 7 retard the endo Diels-Alder reaction,
whereas the methyl groups on the dienophile are small
enough so that steric interactions with the methyl group of
7 have no effect on the exo Diels-Alder reaction. Steric
interactions are still significant with the smaller methyl ester
of 10, which gave 60% of the exo adduct 12, whereas the
aldehyde of 8 is small enough that the undesired endo adduct
9 is formed almost exclusively.
This analysis suggested that the structure of edaxadiene
is a mixture of stereoisomers of the tertiary alcohol nosyberkol
(4), which can be easily formed by hydrolysis of 1 with
allylic rearrangement. Nosyberkol (4) was isolated by
Kashman from the Nosy be Islands (Madagascar) sponge
Raspailia sp. in 2004 as a single stereoisomer.4 In 2005,
Nakano reported the isolation of a 1:1 mixture of tubercu-
losinol (2) and 4 (as a 3:1 mixture of stereoisomers), which
he called isotuberculosinol, by treatment of 1 with Rv3378c
encoded enzyme.3b,c The 1H and 13C NMR spectra of
edaxadiene in C6D6 are similar to those reported for
nosyberkol in CDCl3, but the different solvents used preclude
a definitive comparison. Only partial data were reported by
Nakano for isotuberculosinol.3b,c We therefore set out to
synthesize nosyberkol (isotuberculosinol, 4) to establish that
it is identical to edaxadiene and to provide a ready source
of material for further biological evaluation.
Our retrosynthetic analysis is shown in Scheme 2.
Nosyberkol (isotuberculosinol, 4) should be available as a
mixture of isomers by addition of vinylmagnesium bromide
to ketone 5. A Wittig reaction on aldehyde 6 should give an
enone that will be reduced to ketone 5 with Li/NH3. An exo
Diels-Alder reaction of diene 75 and tiglic aldehyde (8)
could give the required bicyclic aldehyde 6.
A tigloyl dienophile was needed that (1) has a large
substituent that would sterically retard the endo Diels-Alder
reaction as observed by Danishefsky with the aroyl group
of 13 and (2) could be converted to aldehyde 6 after the
Diels-Alder reaction. The two methyl groups on the
dienophile decrease its reactivity as shown by the harsh
conditions needed for the thermal Diels-Alder reaction with
methyl tiglate (10). Although exo adduct 14 was isolated in
85% yield by Danishefsky, the yield dropped to 43% without
1 equiv of THF and to 0% with other Lewis acids. A
substituent was also needed that would enhance the reactivity
of the dienophile.
N-Tigloylisoxazolidinone (15)9 seemed well suited for this
purpose. Evans developed asymmetric Diels-Alder reactions
with chiral acryloyl and crotonyl oxazolidinones catalyzed
by 2 equiv of Et2AlCl.10 These reactions are not very
(6) (a) Brohm, D.; Waldmann, H. Tetrahedron Lett. 1998, 39, 3995–
3998. (b) Brohm, D.; Philippe, N.; Metzger, S.; Bhargava, A.; Mu¨ller, O.;
Lieb, F.; Waldmann, H. J. Am. Chem. Soc. 2002, 124, 13171–13178.
(7) de Miranda, D. S.; da Conceic¸a˜o, G. J. A.; Zukerman-Schpector, J.;
Guerrero, M. A.; Schuchardt, U.; Pinto, A. C.; Rezende, C. M.; Marsaioli,
A. J. J. Braz. Chem. Soc. 2001, 12, 391–402.
Unfortunately, the Lewis acid-catalyzed Diels-Alder
reaction of diene 7 with tiglic aldehyde (8) is known to give
the expected, but undesired, endo Diels-Alder adduct 9 with
91-96% selectivity (see Scheme 3).6 On the other hand,
heating diene 7 in excess methyl tiglate (10) at 170 °C for
(8) Yoon, T.; Danishefsky, S. J.; de Gala, S. Angew Chem., Int. Ed.
1994, 33, 853–855.
(9) (a) Miyata, O.; Shinada, T.; Nimomiya, I.; Naito, T.; Date, T.;
Okamura, K.; Inagaki, S. J. Org. Chem. 1991, 56, 6556–6564. (b) Sibi,
M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. J. Am. Chem. Soc.
2003, 125, 11796–11797.
(4) Rudi, A.; Aknin, M.; Gaydou, E.; Kashman, Y. J. Nat. Prod. 2004,
67, 1932–1935.
(5) (a) Knapp, S.; Sharma, S. J. Org. Chem. 1985, 50, 4996–4998. (b)
Tanis, S. P.; Abdallah, Y. M. Synth. Commun. 1986, 16, 251–259.
(10) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238–1256.
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