Concise total syntheses of the bioactive mesotricyclic diterpenoids jatrophatrione and citlalitrione

Article abstract of DOI:10.1021/ja021177r

The highly functionalized [5.9.5] tricyclic framework resident in jatrophatrione (1) and citlalitrione (2) has been synthesized. The route begins with the tandem anionic oxy-Cope rearrangement/methylation/transannular ene cyclization of 21 and subsequent introduction of a conjugated enone double bond. Hydroxyl-directed 1,4-reduction of this functionality in 25 with LiAlH₄/Cul/hexamethylphosphoramide/tetrahydrofuran sets the stage for the implementation of a Grob fragmentation and expedited generation of 27. Stereocontrolled intramolecular hydrosilylation allows for the subsequent introduction of a cyclic carbonate as in 53. This intermediate undergoes remarkably efficient, fully regiocontrolled Treibs reaction to generate 54, with this maneuver serving as a pivotal step for making 1 available five steps later. Treatment of 1 with m-chloroperbenzoic acid leads to 2, with attack occurring preferentially on a α-face of the double bond more remote to the carbonyl.

Full text of DOI:10.1021/ja021177r

Published on Web 01/11/2003
Concise Total Syntheses of the Bioactive Mesotricyclic
Diterpenoids Jatrophatrione and Citlalitrione
Jiong Yang, Yun Oliver Long, and Leo A. Paquette*
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity,
Columbus, Ohio 43210
Received September 12, 2002 ; E-mail: paquette.1@osu.edu
Abstract: The highly functionalized [5.9.5] tricyclic framework resident in jatrophatrione (1) and citlalitrione
(2) has been synthesized. The route begins with the tandem anionic oxy-Cope rearrangement/methylation/
transannular ene cyclization of 21 and subsequent introduction of a conjugated enone double bond. Hydroxyl-
directed 1,4-reduction of this functionality in 25 with LiAlH4/CuI/hexamethylphosphoramide/tetrahydrofuran
sets the stage for the implementation of a Grob fragmentation and expedited generation of 27.
Stereocontrolled intramolecular hydrosilylation allows for the subsequent introduction of a cyclic carbonate
as in 53. This intermediate undergoes remarkably efficient, fully regiocontrolled Treibs reaction to generate
54, with this maneuver serving as a pivotal step for making 1 available five steps later. Treatment of 1 with
m-chloroperbenzoic acid leads to 2, with attack occurring preferentially on a R-face of the double bond
more remote to the carbonyl.
In 1976, Torrance et al.1 disclosed the isolation from Jatropha
microrhiza of an architecturally novel diterpenoid, which they
called jatrophatrione (1). In the same account, the University
of Arizona team revealed that this tumor-inhibitory agent was
particularly active toward the P-388 (3PS) lymphocytic leukemia
test system. The structural features of jatrophatrione, secured
by a combination of spectroscopic and X-ray crystallographic
techniques, are such that the dienone chromophore is substan-
Previous papers from this laboratory have described an
approach that focused on the initial acquisition of 9-epijatro-
phatrione (3).5 The intent behind this decision was to provide a
forum for the potential isomerization of this more strained (ca.
6.5 kcal/mol) isomer into 1 via 4 and 5 (Scheme 1). Should
ring opening in 3 prove feasible and 4 be capable of intercon-
version with 5 in advance of cyclization to give 1, much of the
conjecture surrounding the biological mechanism of action
would be substantiated. The advanced polycyclic intermediates
that were reached in the course of the earlier investigation were
instrumental in providing insight concerning how jatrophatrione
and citlalitrione might be concisely approached.
tially twisted and consequently devoid of significant through-
conjugation. As a result, the mechanism of action suggested
for 1 involves a retrograde Michael reaction that unmasks a
highly electrophilic C8-C9 enone double bond set to capture
protein-bound sulfhydryl groups covalently.2
More than a decade later, extraction of the roots of “tlapelex
patli,” the Aztec term for Jatropha dioica, obtained in north-
eastern Mexico led to the isolation of citlalitrione (2).3 This
plant source is widely recognized by the natives to have
beneficial effects in the treatment of skin cancer. The closely
related structural features of 1 and 2, which include an un-
precedented [5.9.5] tricyclic core, and their therapeutic properties
hold particular fascination. As part of our program dealing with
the de novo construction of anti-cancer agents, we have pursued
and accomplished total syntheses of 14 and 2. We are unaware
of equivalent successful ventures involving these unusual
compounds.
Retrosynthetic Analysis and Strategy
The synthetic plan called for the initial construction of the
building blocks D and E in Scheme 2. The carbinol resulting
from 1,2-addition of the cerate reagent derived from E to the
exo surface of D defines a substrate that was expected to be
(1) Torrance, S. J.; Wiedhopf, R. M.; Cole, J. R.; Arora, S. K.; Bates, R. B.;
Beavers, W. A.; Cutler, R. S. J. Org. Chem. 1976, 41, 1855.
(2) (a) Kupchan, S. M.; Sigel, C. W.; Matz, M. J.; Saenz Renauld, J. A.;
Haltiwanger, R. C.; Bryan, R. F.; J. Am. Chem. Soc. 1970, 92, 4476. (b)
Haltiwanger, R. C.; Bryan, R. F. J. Chem. Soc. B 1971, 1598. (c) Kupchan,
S. M.; Sigel, C. W.; Matz, M. J.; Gilmore, C. J.; Bryan, R. F. J. Am. Chem.
Soc. 1976, 98, 2295.
(4) For a preliminary communication delineating our concise approach to
jatrophatrione, consult Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem.
Soc. 2002, 124, 6542.
(5) (a) Paquette, L. A.; Nakatani, S.; Zydowski, T. M.; Edmondson, S. D.;
Sun, L.-Q.; Skerlj, R. J. Org. Chem. 1999, 64, 3244. (b) Paquette, L. A.;
Edmondson, S. D.; Monck, N.; Rogers, R. D. J. Org. Chem. 1999, 64,
3255.
(3) Villarreal, A. M.; Dominguez, X. A.; Williams, H. J.; Scott, A. I.;
Reibenspies, J. J. Nat. Prod. 1988, 51, 749.
9
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J. AM. CHEM. SOC. 2003, 125, 1567-1574
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A R T I C L E S
Yang et al.
Scheme 1
Scheme 2
responsive to [3.3] oxyanionic sigmatropy. The operation of this
ring expansion allows for generation of the highly reactive
enolate anion F. The latter intermediate was expected to ex-
perience stereocontrolled R-methylation from the convex sur-
face, thereby setting the stage for an anticipated transannular
ene reaction as illustrated in G. Moving further along the
retrosynthetic path, there was made clearly apparent the need
to invert the configuration at C9 in C as the mesocyclic7 nature
of the central ring was reestablished. The first tactic was to be
addressed by hydroxyl-directed reduction of a derived enone,
the second by utilization of a Grob fragmentation.8 The
generation of B in this fashion was to be followed by reduction
to the R-alcohol and regiocontrolled oxygenation at C12 by
intramolecular hydrosilylation.9 In this way, dehydration to
(6) The feasibility of attaining stereocontrol by rotation around the σ bonds
flanking an olefinic linkage has been previously demonstrated by us in a
tricyclic precursor to taxusin: (a) Paquette, L. A.; Zhao, M. J. Am. Chem.
Soc. 1993, 115, 354. (b) Paquette, L. A.; Zhao, M. J. Am. Chem. Soc. 1998,
120, 5203.
(7) See footnote 4 in Leonard, N. J.; Milligan, T. W.; Brown, T. L. J. Am.
Chem. Soc. 1960, 82, 4075.
(8) Review: Becker, K. B.; Grob, C. A. Chem. Double-Bonded Funct. Groups
1977, 2, 653-723.
(9) Magnus, P. D.; Nobbs, M. S. Synth. Commun. 1980, 10, 273.
9
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Syntheses of Jatrophatrione and Citlalitrione
A R T I C L E S
Scheme 3 a
not scale-limited and offers excellent throughput. The correct
number of carbon atoms is set at the outset by C-allylation of
the isobutyronitrile anion, as generated with lithium diethyl-
amide.10 The Dibal-H reduction11 that immediately follows gave
aldehyde 10, which proved to be an excellent substrate for
Wacker oxidation as earlier recognized.9
a (a) (CH3O)3CH, CH3OH, TsOH (88%). (b) BH3‚THF; H2O2, NaOH
(81%). (c) KH, BnBr, Bu4NI (95%). (d) TsOH, acetone, H2O (98%). (e)
LDA, CH3I, THF, HMPA (75%). (f) Me3SiCl, Et3N (90%). (g) AcCl, ZnCl2
(60%). (h) (CH3O)3CH, CH3OH, TsOH (71%). (i) 450 °C, 0.4 Torr, quartz
chips (95%).
It was now time to couple 8 and 13, and use was made of
dried cerium trichloride12 to curtail the ready enolizability of
the ketone component (Scheme 5). The generation of this adduct
will be recognized to establish the cisoid relationship of the
enol ether and cyclopentadiene double bonds necessary for
successful oxy-Cope rearrangement. In light of considerable
precedent,13 advancement to ring-expanded product was ex-
pected to proceed via a chairlike transition state to set the
configuration of the cyclononadienyl olefinic centers as in F
(Scheme 2). Methylation of this strained enolate anion generates
a species of type G, the structural distortion in which orients
the carbonyl oxygen in close proximity to an allylic hydrogen
atom across the ring. The ensuing transannular hydrogen atom
transfer with ring closure to furnish 14 is thereby facilitated.
Scheme 4
With the availability of 14, we were in a position to
investigate an efficacious means for effecting epimerization at
C9. Treatment with N-bromosuccininide (NBS) in aqueous
tetrahydrofuran (THF) resulted in the concurrent generation of
an R-bromo ketone moiety and a bromo oxetane ring.5 This
intermediate was then carried through the stage where heating
with lithium bromide and lithium carbonate in dimethylforma-
mide (DMF)14 gave rise to the R,â-unsaturated ketone. Since
the deployment of reducing conditions was about to begin, it
became first necessary to remove the remaining bromine atom.
The optimum conditions for the conversion to 15 involved
stirring with powdered zinc in methanol.
introduce the C3-C4 double bond would precede unmasking
of the sensitive 1,3-dicarbonyl functionality.
This retrosynthetic plan can most conveniently be divided
into three subsequences: the construction of a diquinane of type
D; the structural reorganization and other key factors associated
with formation of the tricyclic framework defined in B; and
proper introduction of the remaining functional groups.
With arrival at 15 came opportunities to screen various
protocols that are offered by hydroxyl-directed hydrogenation.15
As expected from the classical work of Henbest and Wilson,16
exposure of 15 to buffered peracetic acid resulted in the
stereoselective formation of R-epoxide 18 (Scheme 6). To
further enrich the number of substrates available for study, 18
was subjected to Luche reduction,17 from which only the isomer
with a second R-hydroxyl group was obtained. The slow rate
of this process served to highlight the heightened steric
congestion prevailing in 18. The stereochemical assignment to
19 was founded on an 8.7% nuclear Overhauser enhancement
(NOE) at H7 when H15 was irradiated. Our rather extensive
efforts to accomplish proper saturation of the C8-C9 double
bond in both 18 and 19 were singularly unsuccessful. We shall
therefore restrict our comments to a few more notable observa-
tions. Thus, hydrogenation of 19 over Crabtree’s catalyst15d at
Synthesis of the Diquinane Subunit
A means for the construction of a structural analogue of 8
has been described in a preceding paper.5 Only the significant
changes involved in the chemical modification of 6 will therefore
be stressed (Scheme 3). Presently, the carbonyl group in 6 was
protected as the dimethyl acetal in order to take advantage of
efficiency greater than that associated with 1,3-dioxolane
production. Following conventional hydroboration, the â-hy-
droxyl group was transformed into the benzyl ether. This tactic
ultimately proved well suited to the eventual return to an
unmasked OH at this site. As expected, the benzyloxy substitu-
ent proved resistant to the Lewis acid-catalyzed acetylation of
the intermediate silyl enol ether and to the flash vacuum
pyrolysis conditions required to achieve the thermal extrusion
of methanol. The efficiency with which 8 was isolated (95%)
is noteworthy.
(10) Julia, S.; Julia, M.; Linstrumelle, G. Bull. Soc. Chim. Fr. 1966, 3499.
(11) Marshall, J. A.; Andersen, N. H.; Schlicher, J. W. J. Org. Chem. 1970, 35,
858.
(12) Paquette, L. A. In Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; John Wiley and Sons: Chichester, U.K., 1995; p 1031.
(13) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Paquette, L. A. Angew.
Chem., Int. Ed. Engl. 1990, 29, 609.
(14) For lead references, see Wang, X.; Paquette, L. A. Tetrahedron Lett. 1993,
34, 4579.
(15) (a) Thompson, H. W.; McPherson, E. J. Am. Chem. Soc. 1974, 96, 6232.
(b) Brown, J. M.; Naik, R. G. J. Chem. Soc., Chem. Commun. 1982, 348.
(c) Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072. (d) Crabtree,
R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655. (e) Paquette, L. A.;
Peng, X.; Bondar, D. Org. Lett. 2002, 4, 937.
(16) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958.
(17) (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226. (b) Luche, J.-L.;
Rodriguez-Hahn, L.; Crabbe´, P. J. Chem. Soc., Chem. Commun. 1978, 601.
Construction of the Tricyclic Nucleus
The strategy derived from the retrosynthetic analysis presented
earlier required the availability of 1-bromo-3,3-dimethylcyclo-
penta-1,3-diene (13), the precursor to which is 4,4-dimethyl-
2-cyclopentenone (12, Scheme 4). This ketone has traditionally
been prepared by the Magnus method,9 the steps in which have
long been realized to be capricious and labor-intensive. The
significantly more convenient route summarized in Scheme 4
was therefore implemented here. This sequence of reactions is
9
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A R T I C L E S
Yang et al.
Scheme 5 a
a (a) t-BuLi; CeCl3, 8 (80%). (b) KOt-Bu, 18-cr-6; CH3I (70%). (c) NBS, THF, H2O (92%). (d) LiBr, Li2CO3, DMF, ∆ (81%). (e) Zn, MeOH (83%). (f)
LiAlH4, CuI, HMPA. (g) LiAlH4, ether (88%). (h) MsCl, (i-Pr)2NEt (98%). (i) KOtBu, t-BuOH (87%).
Scheme 6
elevated pressures gave rise to ill-defined multicomponent
reaction mixtures. At lower pressures, no reaction was seen.
Palladium on carbon (5%) afforded similar results. When
reduction was allowed to proceed at 400-1100 psi for 3 days,
there could be isolated 11% of the unwanted diastereomer 20.
When similar attempts were made to saturate 18 by means of
catalysis involving [Rh(NBD)(DIPHOS-4)]BF4,18 reduction of
the phenyl group as in 21 and hydrogenolysis as in 22 were
uniquely observed (ratio 1:2).
were attracted to a brief report by Saegusa and co-workers19 in
which the ability of CuI to promote the efficient 1,4-reduction
of enones by LiAlH4 in the presence of hexamethylphosphor-
amide (HMPA) as cosolvent was touted. In our hands, these
conditions proved to be more useful than we had hoped. The
major product (77%) was the dihydro ketone in which hydride
delivery had occurred predominantly syn to the hydroxyl. The
stereoselectivity was greater than 14:1. Diol 22 was also
produced (12%). When we recognized this outcome, the initially
formed mixture was routinely reduced with LiAlH4 to convert
all of the product to 16 (88% isolated, Scheme 5),20 the
The demise of this strategy prompted our return to an
examination of the conjugate reduction of 15. In particular, we
(18) (a) Corey, E. J.; Engler, T. A. Tetrahedron Lett. 1984, 25, 149 (b) Evans,
D. A.; Morrissey, M. M. J. Am. Chem. Soc. 1984, 106, 3866.
(19) Tsuda, T.; Fujii, T.; Kawasaki, K.; Saegusa, T. J. Chem. Soc., Chem.
Commun. 1980, 1013.
9
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A R T I C L E S
Scheme 7
stereochemical features of which were corroborated by 2D NMR
spectroscopic techniques and direct comparison with the 9â
epimer, which was already available to us.
approximately equal amounts. The separation of these regio-
isomers was easily accomplished by chromatography on silica
gel, and their structural assignments could be made with
confidence by comparative analysis of chemical shifts and 2D
NMR analysis. For example, C13 in 24 is flanked by two
carbonyl groups and is consequently shifted more downfield
(65.5 ppm) than its counterpart in 25 (54.3 ppm). Similarly,
C10 in 24 (38.1 ppm) is more upfield than that in 25 (48.7
ppm).
Tricyclic ketone 17 was subsequently synthesized by forma-
tion of the monomesylate of 16 and exposure of this intermediate
to potassium tert-butoxide in tert-butyl alcohol at room tem-
perature for 1 h. The efficiency of this two-step sequence (85%)
was matched by the welcome appearance of the cyclononenone
carbonyl absorption at 1677 cm-1 21
.
The dehydration of 24 became our next goal. After a series
of experiments showed this to be an erratic transformation, we
settled on the use of thionyl chloride in pyridine for this purpose.
Only the exocyclic olefin isomer 26 could be characterized.
Careful examination of the literature suggested that exposure
of 26 to silica gel on which 10% FeCl3 had been previously
adsorbed might provide the activation required for internal
migration of the double bond with subsequent elimination of
benzyl alcohol.23 If successful, these relatively mild conditions
would introduce the targeted dienone moiety in rather efficient
fashion. This optimism was dashed, however, when it was
determined that this solid-phase reagent only brought about
unprecedented debenzylation without dehydration as in 27. We
note here our inability to generate the xanthate of 27 as a direct
result of the general sensitivity of this class of triketones to
basic reagents.
Exploratory Functionalization Studies
In our first experiments involving 17, we were concerned
with establishing the dienone functionality along the leading
edge (C3-C7). Accordingly, this intermediate was allowed to
react with osmium tetraoxide and pyridine in THF (Scheme 7).
Even under stoichiometric conditions, dihydroxylation proceeded
slowly and stereoselectively. Significantly, only the C6-C7
double bond was attacked to furnish 23 (78% based on recovered
17), and no tendency was exhibited by this product for
transannular hemiketalization. The subsequent hydroboration of
23 was followed by o-iodoxybenzoic acid (IBX) oxidation.22
This two-step sequence afforded triketones 24 and 25 in
(20) In contrast, the direct reduction of 25 with LiAlH4 in the absence of CuI
and HMPA afforded 26 in only 11% yield.
(21) Paquette, L. A.; Pegg, N. A.; Toops, D.; Maynard, G. D.; Rogers, R. D. J.
Am. Chem. Soc. 1990, 112, 277.
(22) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
(23) Keinan, E.; Mazur, Y. J. Org. Chem. 1978, 43, 1020.
9
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A R T I C L E S
Yang et al.
Scheme 8
Scheme 10
Scheme 9
in its original interior position. This alternative plan, outlined
in Scheme 10, was initiated by the reduction of ketone 17 to
alcohol 37 with lithium aluminum hydride. The conversion of
37 to the homoallylic carbonate was accomplished by bubbling
CO2 into a THF solution of the corresponding lithium alkoxide
as originally described by Cardillo et al.26 On the basis of earlier
work by the Bologna group, the treatment of this intermediate
with iodine was expected to result in cyclofunctionalization of
the cyclopentene ring and regioselective formation of an
iodocarbonate structurally related to 36. This process did not
materialize, iodo ether 38 being formed instead in modest yield.
Although halo etherifications have been known for some
time,27 we are unaware of any prior example that proceeds with
initial decarboxylation of a lithium carbonate. The disincentive
of these systems for entering into carbonate formation across
C12 and C14 was further reinforced by our inability to bring
about the conversion of 39 into 40.
To validate these observations, 25 was subjected to hydro-
genolysis, and the resulting 28 was subjected to a series of
dehydration experiments. Under no circumstances was evidence
for conversion to 29 uncovered.
Inasmuch as 23 could be monoacetylated to give 30 (Scheme
8), we were led to scrutinize as well its response to attempted
dehydration. Like 24, an exclusive tendency to position the
newly formed double bond external to the nine-membered ring
as in 31 was seen. In light of these developments, it was not
surprising to find that conditions for transforming 32 into 33
were not found despite a considerable expenditure of effort.
Most notable among these studies was our discovery that the
highly touted KAPA reagent24 had no effect on 32.
Operating on the belief that a change in conformational
topology would be contributory to more facile dehydration, we
were attracted to the iodocyclization of the homoallylic tert-
butyl carbonate 35 (Scheme 9). Were the conversion to 36 to
be realizable, a significant ensemble of dihedral angle alterations
would be set in place relative to the state of affairs resident in
35 and its congeners. To this end, diol 34 was readily formed
by sodium borohydride reduction of 30 and lent itself conve-
niently to conversion to 35. The real issue that lay before us,
the cyclization of 35 in the presence of iodine, could, however,
not be implemented under a variety of conditions.25
The End Game Protocol
With identification of the problematic step discussed above,
we moved to consider the possibility of implementing intramo-
lecular hydrosilylation technology for ultimately bonding an
oxygen atom cleanly to C12. This tactic is not predicated on
the initial generation of a halonium ion in a highly congested
environment and proceeds instead by platinum-catalyzed internal
capture of a silyl hydride.28 At the experimental level, the
(24) (a) Brown, C. A. Synthesis 1978, 754. (b) Abrams, S. R.; Shaw, A. C.
Organic Syntheses; Wiley: New York, 1993; Collect. Vol. VIII, p 146.
(25) (a) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.; Jernstedt,
K. K. J. Org. Chem. 1982, 47, 4013. (b) Duan, J. J.-W.; Smith, A. B., III
J. Org. Chem. 1993, 58, 3703.
(26) Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J. Chem. Soc., Chem. Commun.
1981, 465.
(27) Bartlett, P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3B, Chapt. 6.
In light of the preceding observations, our attention was
redirected to intermediates having the cyclononene double bond
9
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Syntheses of Jatrophatrione and Citlalitrione
A R T I C L E S
Scheme 11
generation of 41 from 37 proved to be a spectacularly successful
and efficient step (Scheme 11). We envisioned that the carbon-
silicon bond formed in this manner would be preserved until
rather late into the synthesis, and some effort was expended in
this direction because of the economy of chemical steps that it
offered. However, this oxidative cleavage could not be deferred
because of the conditions necessarily implemented during
installation of the dienone sector. Therefore, the oxidation of
41 with potassium fluoride and hydrogen peroxide was merged
with subsequent heating of diol 42 with carbonyldiimidazole29
to arrive at cyclic carbonate 43. The oxidative step proceeded
very slowly under the conventional conditions that prescribe
the co-use of potassium bicarbonate in aqueous THF.30 How-
ever, when alternative recourse was made to DMF as the
reaction medium,31 the reaction time was shortened to 8 h and
a 97% yield of 42 was consistently realized.
The task of elaborating the functionality present in the carbon
atoms defined by C3-C7 now had to be addressed. When
(28) (a) Tamao, K.; Nakajima, T.; Sumiya, R.; Arai, H.; Higuchi, N.; Ito, Y. J.
Am. Chem. Soc. 1986, 108, 6090. (b) Tamao, K.; Tanaka, T.; Nakajima,
T.; Sumiya, R.; Arai, H.; Ito, Y. Tetrahedron Lett. 1986, 27, 3377.
(29) Kutney, J. P.; Ratcliffe, A. H. Synth. Commun. 1975, 5, 47.
(30) Review: Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
9
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A R T I C L E S
Yang et al.
possible solutions based on regiodirected epoxide ring cleavages
or on conventional allylic oxidation schemes proved to no avail,
it was made clear that this challenge had to be resolved in a
different manner. In 1948, Treibs briefly described his observa-
tions involving the allylic acetoxylation of olefins upon heating
with mercuric acetate in acetic acid.32 This process has been
adopted only infrequently since that time,33-35 seemingly
because the conditions have generally come to be regarded as
somewhat too forcing. At the mechanistic level, the mercuric
reagent presumably attacks the π bond to generate a mer-
curinium ion, the rearrangement of which to an allylic organo-
mercurial sets the stage for solvolysis with formation of Hg(0)
and one or both epimeric allylic acetates.33,36 On this basis, it
was anticipated that heating 43 with mercuric trifluoroacetate
in benzene followed by stirring with aqueous sodium bicarbonate
might possibly lead stereoselectively to 44 in a simple one-pot
operation. Indeed, these conditions led smoothly to the formation
of 44 in an isolated yield of 77%. We attribute the remarkably
good regioselectivity of this transformation to the unsymmetrical
nature of the putative mercurinium ion, whose biased “open
character” places a modicum of positive charge on the methyl-
substituted carbon (C6) and induces more facile deprotonation
at C5 as allylic mercurial character develops.37 No allylic alcohol
having an exocyclic double bond was noted, a feature that hints
at the possible operation of thermodynamic control.
sion of 47 to 48 was complete in 3 h (88%). This reaction time
is significantly longer than the 5 min required to perform the
quantitative saponification of 44 under identical conditions.41
This kinetic inequality can be traced to a more elevated level
of ring strain in 44. The 2-fold oxidation of 48 to jatrophatrione
(1) was mediated by IBX in dimethyl sulfoxide (DMSO).22 The
synthetic material produced in this manner exhibited a 500 MHz
1H NMR spectrum fully consistent with that of the natural
sample recorded earlier at lower field strength.42 However, the
13C NMR data originally reported differs from our measurements
made at 100 and 125 MHz in a systematic way (F ) 0.998).
As detailed elsewhere,43 a minor complication associated with
the dwell clock in their Fourier transform spectrometer of those
involved in the isolation of 1 is likely responsible for this
phenomenon.
Notwithstanding, we can confidently assert that the total
synthesis of racemic jatrophatrione has indeed been accom-
plished since the treatment of 1 prepared as detailed above with
m-chloroperbenzoic acid in CH2Cl2 at room temperature leads
unmistakably to citlalitrione (2, 22%) alongside a greater
proportion of the unnatural R-epoxide 49 (67%). In this instance,
1
the H and 13C NMR spectra of synthetic 2 were identical to
those registered for the natural sample, whose structural features
had previously been secured by means of X-ray crystallography.
Summary
With the preparation of 44 accomplished, oxidation with tetra-
n-propylammonium perruthenate (TPAP)38 was undertaken to
give 45, the benzyloxy group in which was cleaved with boron
trichloride in CH2Cl2.39 The last major hurdle, the regiodirected
dehydration of 46, now had to be addressed. Two considerations
held central importance as we assessed this step. First, a syn
elimination of the C3 hydroxyl was mandated in either of the
two regiochemical options. Also, pilot studies carried out on
less advanced analogues of 46 revealed a strong kinetic
preference for avoidance of the site of ring fusion. Since these
model systems lacked the C5-C6 double bond, our working
proposition was that the enone segment might well induce a
higher level of acidification at H4 relative to H2 despite the
nonplanarity of this chromophore.
We initially engaged 46 in xanthate formation, only to
discover that this hydroxy ketone is sensitive to basic reagents.
Its vinylogous aldol character is likely responsible for this
behavior. In contrast, the targeted dehydration could be brought
about without event simply by heating 46 with thiocarbonyl-
diimidazole in 1,2-dichlorobenzene.40 This tactic lent itself to
the formation of a two-component product mixture, chromato-
graphic separation of which furnished in 37% yield the target
dienone 47 and 10% of the ∆2,3-regioisomer.
The first total syntheses of two representative [5.9.5] tricyclic
diterpenoids have been accomplished. The several noteworthy
facets of this venture include an anionic oxy-Cope rearrangement
that conveniently sets in place a tetracyclic structural framework
(viz., 14) capable of ready chemical modification. With arrival
at 17 only seven steps later, it becomes possible to hydroxylate
C12 and C14 via intramolecular hydrosilylation and to protect
this pair of R-OHs as a cyclic carbonate. Application of the
Treibs reaction to 43 constituted a particularly productive step,
with the resulting allylic alcohol 44 serving as a reliable platform
for regiocontrolled dehydration as defined by 46 f 47. Finally,
the 1,3-diketone segment is introduced to deliver jatrophatrione
(1), subsequent peracid oxidation of which gives (()-citlalitrione
(2). The length of the linear sequence from the point of
convergence is 20 steps. We anticipate that the successful route
to 1 and 2 detailed herein will significantly facilitate the rational
synthesis of other diterpenoids of this class.
Acknowledgment. We thank Professor Robert Bates (The
University of Arizona) for his attempts to locate a sample and/
or the spectra of jatrophatrione and Dr. Howard Williams (Texas
1
A&M University) for the H and 13C NMR spectra of citlal-
itrione.
We could now undertake hydrolysis of the cyclic carbonate
ring. With K2CO3 in methanol at room temperature, the conver-
Supporting Information Available: Complete experimental
procedures and spectral data for all previously unreported
compounds described herein, including copies of the 1H NMR
spectra of synthetic jatrophatrione as well as natural and
synthetic citlalitrione (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(31) Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120.
(32) Treibs, W. Naturwissenschaften 1948, 35, 125.
(33) Arzoumanian, H.; Metzger, J. Synthesis 1971, 527.
(34) Massiot, G.; Husson, H.-P.; Potier, P. Synthesis 1974, 722.
(35) Reischl, W.; Kalchhauser, H. Tetrahedron Lett. 1992, 33, 2451.
(36) Wiberg, K. B.; Nielsen, S. D. J. Org. Chem. 1964, 29, 3353.
(37) In THF, CH2Cl2, or HMPA, the allylic mercury intermediate was the only
product isolated. The generation of this species appears to be rapid in all
media. The ensuing step in which Hg(II) is reduced to Hg(0) is believed to
be the rate-determining step. If so, the role of nonpolar benzene is to
stabilize the transition state and accelerate the overall rate.
(38) (a) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13. (b) Ley, S.
V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
(39) Williams, D. R.; Brown, D. C.; Benbow, J. W. J. Am. Chem. Soc. 1989,
111, 1923.
JA021177R
(40) Williams, D. R.; Coleman, P. J.; Henry, S. S. J. Am. Chem. Soc. 1993,
115, 11654.
(41) Yang, J. Unpublished observations in this laboratory.
(42) In response to our request for a copy of the 1H NMR spectrum or a sample
of natural jatrophatrione, Professor Robert Bates responded (letter dated
December 15, 1995) that neither could be located at that time.
(43) Footnote 15 of ref 4.
9
1574 J. AM. CHEM. SOC. VOL. 125, NO. 6, 2003