Direct asymmetric entry into the cytotoxic 8,9-secokaurene diterpenoids. Total synthesis of (-)-O-methylshikoccin and (+)-O-(methylepoxy)shikoccin

Full text of DOI:10.1021/ja962799d

11990
J. Am. Chem. Soc. 1996, 118, 11990-11991
Scheme 1
Direct Asymmetric Entry into the Cytotoxic
8,9-Secokaurene Diterpenoids. Total Synthesis of
(-)-O-Methylshikoccin and
(+)-O-(Methylepoxy)shikoccin
Leo A. Paquette,* Dirk Backhaus, and Ralf Braun
EVans Chemical Laboratories, The Ohio State UniVersity
Columbus, Ohio 43210
ReceiVed August 12, 1996
Plants of the genus Rabdosia (Labiatae) are well recognized
to produce structurally unusual diterpenoids which exhibit potent
cytotoxicity against HeLa, KB, and FM 3A/B cells, Ehrlich
ascites and Walker intramuscular carcinomas, and P388 lym-
phocytic leukemia.1 In large part, these properties are concen-
trated within a small group of 8,9-seco-ent-kaurenes typified
by shikodomedin,2 shikoccin,3 rabdoshikoccin A and B,4 rab-
dolatifolin,5 rabdoumbrosanin,6 and O-methylshikoccin (1).7 In
a number of these cases, the corresponding epoxides such as
which had served so very well for the preparation of 38 was
not serviceable in more highly functionalized and more rigid
carbocyclic networks.
O-(methylepoxy)shikoccin (2) co-occur as equally potent an-
titumor constituents.1 The potential of these agents as biological
probes and the bridgehead olefinic nature of 1 and its analogs
provided the incentive for this synthetic undertaking. We report
here the first successful entry to this compound class in the
form of 1 and 2.
The strategy is based on the recognition that the oxygenated
bicyclo[7.2.1]dodecene subunit which is embodied within the
B/C rings of 1 can be quickly elaborated via oxy-Cope
rearrangement of a spirocyclopentenol. In the model reaction
previously reported,8 3 was transformed in 90% yield into 4
Accordingly, the assembly of 8 was accomplished by ap-
plication of a modified Knoevenagel procedure.9 This conve-
nient three-step maneuver (Scheme 1) features condensation of
enantiopure 1,3-dione 510 with aldehyde 611 under conditions
where the 2-alkylidene adduct is intercepted with phenylselenol
as in 7. The selection of 6 from among a host of related acetals
was predicated on the facility of the subsequent spirocyclization
and the feasibility of diastereomer separation at the stage of
9-11. Exposure of 7 to LiBF4 in moist acetonitrile12 resulted
in ready ring closure. Without purification, selenoxide elimina-
tion was undertaken to provide 8 as a 1:1 mixture of epimers
in 51% overall yield. That these two products differ in
stereochemistry uniquely at the site of the protected hydroxyl
became quite apparent from those chemical interconversions
described in Scheme 2 and ultimately by virtue of X-ray
crystallographic analysis of 12. Consequently, ring closure had
necessarily to occur totally via generation of an equatorial
carbon-carbon bond, thereby guaranteeing proper absolute
configuration at the bridgehead stereogenic center subsequent
to the impending Cope rearrangement.
Since the two carbonyl groups in 8 experience widely
different steric shielding, it was anticipated that chemoselectivity
would be reliably achieved during Dibal reduction. Indeed,
three alcohols were formed (Scheme 2) and these could be
obtained in individually pure condition by chromatography on
silica gel when the 2-(trimethylsilyl)ethyl protecting group was
in place. It is noteworthy that hydride delivery occurred only
from below when the C-ring oxygen was projected toward the
reaction center (see 9), a consequence of steric approach control.
In contrast, the R-isomer gave rise to both 10 and 11. Further
experimentation revealed that, while 9 is surprisingly resistant
to epimerization by retroaldol ring opening, 10 and 11 are slowly
when heated in decalin solution. Despite the success of this
sigmatropic reaction, a concern regarding its adaptability to the
proposed syntheses arose because of the conformational flex-
ibility of 3, a property which is not shared by any required trans-
fused decalin homolog. This appreciably reduced structural
mobility did indeed prove to be troublesome. In fact, early
studies quickly revealed that the spiroalkylation technology
(1) (a) Fuji, K.; Xu, H.-J.; Tatsumi, H.; Imahori, H.; Ito, N.; Node, M.;
Inaba, M. Chem. Pharm. Bull. 1991, 39, 685 and relevant references cited
therein. (b) Nagao, Y.; Ito, N.; Kohno, T.; Kuroda, H.; Fujita, E. Chem.
Pharm. Bull. 1982, 30, 727. (c) Fuji, K.; Node, M.; Ito, N.; Fujita, E.;
Takada, S.; Unemi, N. Chem. Pharm. Bull. 1985, 33, 1038.
(2) Fujita, T.; Takeda, Y.; Shingu, T.; Kido, M.; Taira, Z. J. Chem. Soc.,
Chem. Commun. 1982, 162.
(3) Fujita, E.; Ito, N.; Uchida, I.; Fuji, K.; Taga, T.; Osaki, K. J. Chem.
Soc., Chem. Commun. 1979, 806.
(4) Takeda, Y.; Futatsuishi, Y.; Matsumoto, T.; Terada, H.; Otsuka, H.
Phytochemistry 1994, 35, 1289.
(5) Takeda, Y.; Fujita, T.; Ueno, A. Phytochemistry 1983, 22, 2531.
(6) Takeda, Y.; Ichihara, T.; Fujita, Y.; Ueno, A. Chem. Pharm. Bull.
1989, 37, 1213.
(7) (a) Node, M.; Ito, N.; Fuji, K.; Fujita, E. Chem. Pharm. Bull. 1982,
30, 2639. (b) Node, M.; Ito, N.; Uchida, I.; Fujita, E.; Fuji, K. Chem. Pharm.
Bull. 1985, 33, 1029.
(8) (a) Ladouceur, G.; Paquette, L. A. Synthesis 1992, 185. (b) Paquette,
L. A.; Ladouceur, G. J. Org. Chem. 1989, 54, 4278.
(9) Fuchs, K.; Paquette, L. A. J. Org. Chem. 1994, 59, 528.
(10) Prepared from a Wieland-Mischer ketone of >99% enantiomeric
purity by the following sequence: (a) ethylene glycol, H+. (b) CH3I, KOt-
Bu, t-BuOH. (c) L-Selectride. (d) TMSCl, imid; CrO3, 3,5-Me2-pyrazole;
H3O+. (e) Li, NH3. (f) NaH, PMBCl, DMF; H3O+.
(11) Prepared from â-bromoacetaldehyde dimethyl acetal by displacement
with cyanide ion, acetal exchange with â-trimethylsilyl ethanol (TsOH,
toluene, heat), and Dibal-H reduction.
(12) Lisphutz, B. H.; Harvey, D. F. Synth. Commun. 1982, 12, 267.
S0002-7863(96)02799-0 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 47, 1996 11991
Scheme 2
Scheme 3
interconverted in methanol containing K2CO3. On this basis,
it is difficult to assess the degree of stereoselectivity with which
their ketone precursor is reduced. Application of the Mitsunobu
protocol to 10 provided additional 11, such that the net
proportion of 9 to 11 ultimately approximated 1:1.
Although the ensuing documentation focuses only on the
further use of 11, suffice it to say that 9 can also be transformed
into 1 and 2.13 Following the O-methylation of 11, the resultant
methoxy ketone was reacted with vinylmagnesium bromide.
This two-step process gave rise exclusively to 12 (Scheme 3).
The time had now come to evaluate the oxy-Cope rearrange-
ment. On the basis of several exploratory experiments, the
decision was made to proceed with DMF as the solvent of
choice. When heated to 230-240 °C for 19 h in this medium,
12 was transformed into a single detectable isomer (TLC and
NMR analysis). At this point, cesium fluoride was introduced
and the DMF solution was brought back to 210 °C in order to
effect hydroxyl deprotection directly. Subsequent workup
afforded 13 in 65% yield and set the stage for oxidation to
diketone 14 with the Dess-Martin periodinane reagent.14
Extensive COSY and NOE studies on 14 confirmed the
indicated stereochemistry.
The highly regioselective transformation of 14 into its exo-
methylene derivative was very efficiently accomplished by use
of the Eschenmoser salt.15 If the product of the Mannich
reaction is chromatographed on silica gel with ether that contains
peroxides, epoxidation occurs to deliver 16 ultimately two steps
later. Although Bredt’s rule is not at all violated in 15, sufficient
ring strain evidently resides in its bridgehead double bond to
endow this site with heightened reactivity. This phenomenon
proved to be nicely conducive to our goal, as deprotection16/
acetylation of 15 and 16 afforded high-quality samples of 1 and
2, respectively.17 That (-)-O-methylshikoccin and (+)-O-
(methylepoxy)shikoccin were indeed in hand derived from
1
careful direct comparison of H and 13C NMR data with those
recorded on authentic samples of 1 and 2.18
In summary, we have achieved a total synthesis of 1 in 15
steps and in 6.7% overall yield from 5 via only 11. Efficiency
is further heightened when 9 is also included. The route also
allows convenient access to the epoxy derivative 2.
(13) Backhaus, D. Unpublished results. This information will be included
in the full paper.
(14) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(15) (a) Holy, N.; Fowler, R.; Burnett, E.; Lorenz, R. Tetrahedron 1979,
35, 613. (b) Caputo, R.; Ferreri, C.; Mastroianni, D.; Palumbo, G.; Wenkert,
E. Synth. Commun. 1992, 22, 2305.
Acknowledgment. Financial support was provided by the National
Institutes of Health and Eli Lilly and Co. Fellowship support to D.B.
by the Alexander von Humboldt Foundation is gratefully acknowledged.
Comparison spectra and authentic samples of 1 and 2 were kindly
provided by Prof. E. Fujita and Prof. M. Node, respectively. We
particularly thank Drs. T. Underiner, K. Fuchs, and K. Lynch for their
early investigations in this area. D-Proline was generously donated by
Prof. D. Enders.
(16) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.
(17) Yields are reported for isolated compounds purified by flash
chromatography on silica gel. All new compounds exhibited IR, 1H/13C
NMR, and high-resolution mass spectra in complete accord with their
assigned structures. Elemental analyses were also obtained in many cases.
(18) In the original report,7b the signals due to H-13 (δ 3.20) and OCH3
(δ 3.26) were erroneously claimed to appear at δ 3.34 and 3.18, respectively.
The spectra graciously provided to us by the original authors immediately
revealed the source of confusion to be typographical.
Supporting Information Available: Text describing spectral
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