Synthetic studies toward the kempane diterpenes: Preparation of the ring system

Full text of DOI:10.1021/ja971769n

9584
J. Am. Chem. Soc. 1997, 119, 9584-9585
Synthetic Studies toward the Kempane Diterpenes:
Preparation of the Ring System
Scheme 1
Chunjian Liu and D. Jean Burnell*
Department of Chemistry
Memorial UniVersity of Newfoundland
St. John’s, Newfoundland A1B 3X7, Canada
ReceiVed May 29, 1997
The defensive secretions of nasute soldier termites include
tetracyclic diterpenes of two closely related types, the rippertanes
(
e.g., 1) and the kempanes (e.g., 2 and 3).1 We report herein
an approach to the synthesis of the ring system of the kempane
diterpenes in a manner that should allow access to all of the
known kempanes from one multifunctional pentacyclic com-
pound. Previous approaches to the kempanes have led to only
Scheme 2
2
one total synthesis. The Dauben group prepared kempene-2
(
2) by a clever route in which, at different points in the synthesis,
two rings were established by Diels-Alder additions of isoprene.
Paquette and co-workers reported an approach to kempane 3
3
that included a remarkably efficient palladium-catalyzed [3 +
2
] cycloaddition. An isomer of 3 was prepared in which the
double bond was conjugated with the ketone, but, unfortunately,
they were unable to transform this isomer into the less-stable
4
natural product. In the only enantioselective approach, Metz
5
et al. assembled a nor-methyl skeleton for 3R-hydroxy-15-
rippertene (1) from (-)-R-santonin.
Our strategy was to use a Diels-Alder reaction to establish
the relative stereochemistry for the central stereogenic centers
at C-10a, C-10b, and C-10c.6 The diene was required to have
oxygens at the same locations as in 2 and/or 3, and functionality
should already be present that would be needed for the closure
of the final, seven-membered ring. An appropriate diene (9)
was constructed from enone 4 by a route reminiscent of Corey’s
7
,8
work, as outlined in Scheme 1. The trapping of dichlo-
9
roketene by diene 5 proceeded regiospecifically, as did a
(
1) (a) Baker, R.; Walmsley, S. Tetrahedron 1982, 38, 1899-1910. (b)
Prestwich, G. D. Tetrahedron 1982, 38, 1911-1919.
2) Dauben, W. G.; Farkas, I.; Bridon, D. P.; Chuang, C.-P.; Henegar,
K. E. J. Am. Chem. Soc. 1991, 113, 5883-5884.
3) Paquette, L. A.; Sauer, D. R.; Cleary, D. G.; Kinsella, M. A.;
(
(
Blackwell, C. M.; Anderson, L. G. J. Am. Chem. Soc. 1992, 114, 7375-
subsequent Baeyer-Villiger reaction (6 f 7). Ring scission
of 7 and acid-mediated aldol gave enone 8, which was most
efficiently converted to the silyl enol ether 9 using the triflate
7
387.
(
4) Taber, D. F. Tetrahedron Lett. 1993, 34, 1883-1884.
(
5) Metz, P.; Bertels, S.; Fr o¨ hlich, R. J. Am. Chem. Soc. 1993, 115,
1
0
1
2595-12596.
and triethylamine.
(6) The numbering of kempane 3 is used for all of the compounds shown
in Scheme 2.
(9) Chemo- and regiospecific trapping of ketene with a 1-substituted 1,3-
cyclohexadiene can also be seen in: Harding, K. E.; Strickland, J. B.;
Pommerville, J. J. Org. Chem. 1988, 53, 4877-4883.
(10) (a) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1984, 25, 5953-
5956. (b) Ihara, M.; Ishida, Y.; Fukumoto, K.; Kametani, T. Chem. Pharm.
Bull. 1985, 33, 4102-4105.
(
7) For instance, see: Corey, E. J.; Ravindranathan, T. Tetrahedron Lett.
1
971, 4753-4755.
(
8) A lactone very similar to 7 has been resolved with (+)-1-(1-naph-
thyl)ethylamine: Corey, E. J.; Snider, B. B. J. Org. Chem. 1974, 39, 256-
2
58.
S0002-7863(97)01769-1 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 40, 1997 9585
6
As shown in Scheme 2, the Diels-Alder reaction of 9 with
the ketone at C-3 was reduced, predominantly by equatorial
13
2
,6-dimethyl-1,4-benzoquinone proceeded smoothly in a regio-,
stereo-, and facially-selective manner to provide adduct 10, in
which three of the four rings of the kempanes were already in
place. An examination of the relative accessibilities of the
two ketones in 10 to axial attack led to the correct prediction
of addition of ethoxyacetylide to provide 11 exclusively.
Release of the silyl group with fluoride ion gave 12 and 13 in
a 7:1 ratio, respectively. Formation of the hemiacetal 12
confirmed the relative stereochemistry at the carbinol center in
addition of hydride, with LiAl(O-t-Bu)3H, and the axial alcohol
was protected with (2-methoxyethoxy)methyl chloride to give
16. The equatorial position for the C-7 methyl in 17 developed
as a result of the dissolving-metal reduction of the enone in 16.
Reduction of the remaining ketone by equatorial attack with
L-Selectride provided 18. Dieckmann cyclization of the final
seven-membered ring with KO-t-Bu afforded the pentacyclic
target 19, which has all of the stereogenic centers of the kempane
diterpenes in their correct configurations (once again confirmed
by NOE measurements) and oxygen functionality on every ring.
The oxygen functions at C-1, C-3, and C-5 are as found in
various kempanes; the lactone can be reduced to a C-10 methyl
or may be used to facilitate methylation; and a remaining methyl
group (at C-2a) can be introduced by 1,4-addition to an R,â-
unsaturated C-1 ketone. Modification of 19 to 2 and 3 is
currently underway in our laboratory.
1
1
1
1. NOE measurements established that the minor product 13
had epimerized at C-4a. Reduction and solvolysis of the mixture
of 12 and 13 was carried out in a single operation with zinc in
refluxing acetic acid. This yielded the â,γ-unsaturated ketone
1
4, which included a minor component that was epimeric at
C-4a (6:1 cis to trans ratio). Treatment of 14 with HCl in
methanol completed the epimerization process, and the double
bond was brought into conjugation concomitantly providing only
one enone, 15. NOE measurements established that the methyl
at C-10c and C-4aH were now trans and that C-4aH and C-7aH
were cis, i.e., the ester chain had assumed the required,
thermodynamically-preferred equatorial position. Reduction of
Acknowledgment. We thank the Natural Sciences and Engineering
Research Council of Canada for financial support.
Supporting Information Available: Procedures for the preparation
1
2
1
13
1
5 with NaBH4 in 1:1 MeOH/CH2Cl2 at -78 °C was
of compounds 10-19 and H and C NMR spectra of 10-19 (31
pages). See any current masthead page for ordering and Internet access
instructions.
completely chemoselective but not stereoselective. A 1.5:1
mixture, epimeric at C-3, was obtained, undesired equatorial
alcohol was the major component. On the other hand, only
JA971769N
(
11) (a) Liotta, D.; Saindane, M.; Sunay, U.; Jamison, W. C. L.;
Grossman, J.; Phillips, P. J. Org. Chem. 1985, 50, 3243-3245. (b) Liu, C.;
(13) LiAl(O-t-Bu)3H provided the axial alcohol and its C-3 epimer in a
8:1 ratio and in a combined yield of 88%. The epimers were separable by
flash chromatography. The relative stereochemistry at the carbinol center
was assigned on the basis of NOE measurements.
Burnell, D. J. J. Org. Chem. 1997, 62, 3683-3687.
(
12) Ward, D. E.; Rhee, C. K.; Zoghaib, W. M. Tetrahedron Lett. 1988,
2
9, 517-520.