Studies Directed toward the Synthesis of the Unusual Antileukemic Diterpene Jatrophatrione. 1. A Solution to the Problem of Chirality Merger during Elaboration of the Entire Carbotricyclic Framework

Article abstract of DOI:10.1021/jo9825254

A practical route for elaboration of the [5.9.5] tricyclic nucleus of jatrophatrione (1) is reported. The two key steps involve an oxyanionic Cope rearrangement and a Grob fragmentation. The building blocks required to reach 44 are the bicyclo[3.3.0]octanone 29 and the cyclopentadienyl bromide 35. The former was obtained in 12 steps from methylcyclopentadiene. The route to the latter began with 4,4-dimethylcyclopentenone. The charge-accelerated [3,3]-sigmatropic isomerization within 44 proceeds via a chairlike transition state to deliver, after enolate methylation, a highly strained product carrying a trans double bond in a medium-sized ring, one consequence of which is rapid transannular ring closure via an ene pathway. Acid hydrolysis of this enol ether and conversion to hydroxy mesylate 51 was followed by exposure to base. This sequence resulted in ring opening to provide the strategic advanced intermediate 52. The synthetic pathway developed here is expected to open a route to 9-epijatrophatrione (8) for the ultimate purpose of examining its anticipated isomerization to 1 under mildly basic conditions.

Full text of DOI:10.1021/jo9825254

3
244
J . Org. Chem. 1999, 64, 3244-3254
Stu d ies Dir ected tow a r d th e Syn th esis of th e Un u su a l
An tileu k em ic Diter p en e J a tr op h a tr ion e. 1. A Solu tion to th e
P r oblem of Ch ir a lity Mer ger d u r in g Ela bor a tion of th e En tir e
Ca r botr icyclic F r a m ew or k
Leo A. Paquette,* Shogo Nakatani, Thomas M. Zydowsky, Scott D. Edmondson,
Li-Qiang Sun, and Renato Skerlj
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received December 29, 1998
A practical route for elaboration of the [5.9.5] tricyclic nucleus of jatrophatrione (1) is reported.
The two key steps involve an oxyanionic Cope rearrangement and a Grob fragmentation. The
building blocks required to reach 44 are the bicyclo[3.3.0]octanone 29 and the cyclopentadienyl
bromide 35. The former was obtained in 12 steps from methylcyclopentadiene. The route to the
latter began with 4,4-dimethylcyclopentenone. The charge-accelerated [3,3]-sigmatropic isomer-
ization within 44 proceeds via a chairlike transition state to deliver, after enolate methylation, a
highly strained product carrying a trans double bond in a medium-sized ring, one consequence of
which is rapid transannular ring closure via an ene pathway. Acid hydrolysis of this enol ether
and conversion to hydroxy mesylate 51 was followed by exposure to base. This sequence resulted
in ring opening to provide the strategic advanced intermediate 52. The synthetic pathway developed
here is expected to open a route to 9-epijatrophatrione (8) for the ultimate purpose of examining
its anticipated isomerization to 1 under mildly basic conditions.
J atrophatrione (1) is an architecturally novel diterpene
that has been isolated from the roots of J atropha mac-
rorhiza Benth and shown to possess very respectable
inhibitory activity toward P-388 lymphocytic leukemia.1
The detailed molecular structures of 1 and citlalitrione
(
2), a related epoxy trione obtained from J atropha dioica
2
var. sessiliflora, have been independently secured by
X-ray crystallographic analysis. Unfortunately, no chem-
istry surrounding these compounds has been reported.
Their absolute configurations have instead been inferred
on the basis of an obviously close structural relationship
to jatrophone (3), previously isolated from J . gossypiifo-
lia.3 Early interest in 3 arose because of its strong
inhibitory action against several carcinomas.3
,4
Kupchan demonstrated that jatrophone (3) undergoes
Michael addition to the C8-C9 enone double bond with
concomitant transannular ring closure to give 4 when
subjected to 1-propanethiol under basic conditions (pH
ity that 1 is first subject to a retrograde Michael process
to give 5, which can be captured in a manner paralleling
the 3 f 4 conversion (Scheme 1). However, in a probe
5
9
.2). This susceptibility to nucleophilic conjugate addi-
tion was proposed to be responsible for the pronounced
anticancer activity of jatrophone (3).
To account for the fact that jatrophatrione (1) is
biologically effective despite its lack of unsaturation at
C8-C9, Torrance et al. proposed the interesting possibil-
1
experiment, no reaction involving 1 and butanethiol
occurred under conditions paralleling those described
above. Note that competitive conjugate addition does not
occur at C3 or C5 because of the lack of conjugation
between the associated double bonds and neighboring
carbonyl group. The crystallographically defined torsion
angle for C5-C6-C7-O3, for example, is 61.0°.
In our view, the assignment of a negative connotation
to this otherwise attractive concept is premature. It is
plausible, for example, that the reverse Michael step
would be facilitated (and therefore made more readily
apparent) if one were to begin with the C9 epimer 8. This
single configurational change is estimated on the basis
of MM2 calculations to cause 8 to be 6.5 kcal/mol more
strained than 1. As a consequence, the synthetic plan
developed by us for ultimate arrival at jatrophatrione
(
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) Villarreal, A. M.; Dominguez, X. A.; Williams, H. J .; Scott, A. I.;
Reibenspies, J . J . Nat. Prod. 1988, 51, 749.
3) (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) Taylor, M. D.; Smith, A. B., III.; Furst, G. T.; Gunasekara, S. P.;
Bevelle, C. A.; Cordell, G. A.; Farnsworth, N. R.; Kupchan, S. M.;
Uchida, H.; Branfman, A. R.; Dailey, R. G., J r.; Sneden, A. T. J . Am.
Chem. Soc. 1983, 105, 3177.
(5) Lillehaug, J . R.; Kleppe, K.; Sigel, C. W.; Kupchan, S. M.
Biochim. Biophys. Acta 1973, 327, 92.
1
0.1021/jo9825254 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/30/1999

Synthesis of the Antileukemic Diterpene J atrophatrione. 1
J . Org. Chem., Vol. 64, No. 9, 1999 3245
Sch em e 1
Sch em e 2
to the carbonyl group in 8. Several choices are also
available for Y. Ideally, it can be envisioned to be part of
a â-dicarbonyl subunit as required of the target. However,
these circumstances could eventuate in undesirable O-
methylation if steric crowding emerges as a serious
consideration. Otherwise, a double bond within the five-
membered ring could suffice.
Two assumptions are intrinsic to the proposed B f A
transformation. The first concerns the adoption of a
chairlike transition-state arrangement during the elec-
tronic reorganization within B in accord with precedent
derived from simpler structural analogues.9 The second
envisions that the entry of the angular methyl group will
proceed from the more sterically accessible â face. Un-
beknown to us at the outset was the ease and extent to
which transannular ring closure can operate within the
nine-membered ring of A under mild conditions.
Moving further along the retrosynthetic path, we
contemplated that B could be obtained directly by the
coupling of C with D. The 1,2-addition involved should
occur from the less crowded â surface of the folded
bicyclo[3.3.0]octanone. Beyond that, X and Y would need
to be recalcitrant to attack by a vinyllithium species such
as defined in D.
,10
consists of a convergent approach to 8, which we would
hope to equilibrate to the more thermodynamically
favored natural epimer by this mechanism. A perceived
difficulty with this concept arises from the fact that the
E-configured C8-C9 double bond in first-formed 7 must
be subject to internal rotation about the adjacent single
bonds prior to reclosure and delivery of 1. Molecular
mechanics calculations at the MACROMODEL version
5
.0 level have provided indication that 5 is only 1.3 kcal/
6
mol less stable than 7. The feasibility of attaining
stereocontrol in tricyclic medium-ring E-olefinic precur-
Con str u ction of Bu ild in g Block s C a n d D. The
strategy derived from the retrosynthetic analysis outlined
in Scheme 2 prompted the construction of diquinanes 24
and 29. Since our original plans called for ultimate base-
promoted elimination of the OR substituent in A, the
methoxy group was selected for the present purposes.
Scheme 3 summarizes the synthesis of bicyclic ketone 17
from methylcyclopentadiene (9). The initial reaction of
monomeric 9 with dichloroketene (generated in situ from
dichloroacetyl chloride and triethylamine) gave predomi-
nantly the known [2 + 2] adduct 10.11 Subsequent
dechlorination with zinc metal and ammonium chloride
in a methanol-THF solvent system led to 11 and set
the stage for regioselective ring expansion of the cyclobu-
tanone ring upon exposure to ethyl diazoacetate and
antimony pentachloride.13 Since the resulting product
was a mixture of keto and enol tautomers, viz. 12,
hydrolytic decarboxylation was implemented prior to
sors to taxusin has earlier been shown to be derivable
from this very same theoretical principle.7
Herein, we report the details surrounding a projected
racemic synthesis in which tactical advantage is taken
of anionic sigmatropy in combination with Grob frag-
mentation technology to deliver the complete tricyclic
framework of 8. The following paper describes a variety
of chemical reactions undertaken for the purpose of
setting the requisite assortment of functional groups in
their proper locale.8
Resu lts a n d Discu ssion
1
2
Retr osyn th etic Design . In its most concise form, the
retrosynthetic analysis was envisioned to involve the
formation of A from B via charge-accelerated oxy-Cope
rearrangement with direct methylation of the enolate
anion resulting from this [3,3]-sigmatropic shift (Scheme
2
). The substituent X could, of course, be hydrogen.
However, if it were an alkoxy group, its role in A would
be that of an enol ether and a more immediate precursor
(9) Kato, T.; Kondo, H.; Nishino, M.; Tanaka, M.; Hata, G.; Miyake,
A. Bull. Chem. Soc. J pn. 1980, 53, 2958.
(10) (a) Marvell, E. N.; Whalley, W. Tetrahedron Lett. 1970, 509.
(
b) Fan, W.; White, J . B. Tetrahedron Lett. 1993, 34, 957.
(11) Brady, W. T.; Hieble, J . P. J . Am. Chem. Soc. 1972, 94, 4278.
(12) Grieco, P. A. J . Org. Chem. 1972, 37, 2363.
(
6) We thank J ohn Hofferberth for performing these calculations.
(7) (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.
8) Paquette, L. A.; Edmondson, S. C.; Monck, N.; Rogers. R. D. J .
Org. Chem. 1999, 64, 3255.
(13) For the use of boron trifluoride etherate as the promoter in this
reaction, consult: Sugihara, Y.; Sugimura, T.; Murata, I. J . Am. Chem.
Soc. 1981, 103, 6738.
(

3
246 J . Org. Chem., Vol. 64, No. 9, 1999
Paquette et al.
Sch em e 3a
Sch em e 4a
a
Key: (a) Cl2CHCOCl, Et3N, hexanes; (b) Zn, NH4Cl, CH3OH,
THF, ∆, 48 h; (c) SbCl5, N2CHCOOC2H5, CH2Cl2, then NaHCO3;
(
d) K2CO3, H2O, dioxane, ∆, 24 h; (e) p-TsOH 2-ethyl-2-methyl 1,3-
dioxolane; (f) BH3‚THF, THF, then H2O2, NaOH, H2O; (g) CH3I,
NaH, THF; (h) p-TsOH, acetone, H2O, ∆.
a Key: (a) LDA, CH I, THF, HMPA; (b) KHMDS, allyl bromide,
3
THF; (c) ethylene glycol, p-TsOH, C6H6; (d) OsO4, NaIO4, dioxane,
H2O; (e) NaBH4, CH3OH, CH2Cl2; (f) 2-nitrophenyl selenocyanate,
characterization. The small amount of regioisomer was
removed during the chromatographic purification at this
stage.
(n-Bu)3P, THF; (g) H2O2, H2O, THF; (h) p-TsOH, acetone, H2O.
Sch em e 5a
Protection of the carbonyl group in 13 was achieved
efficiently by the method of Dauben.14 The regio- and
stereoselective transformation of 14 into 15 was readily
accomplished with the borane‚THF complex. Subsequent
O-methylation and mild acid hydrolysis gave the desired
ketone 17.
With 17 available in this manner, the stage was set
for introduction of the appropriate pair of R substituents.
Generation of the less substituted enolate, undertaken
with lithium diisopropylamide, made possible the regio-
controlled introduction of a methyl group by reaction with
methyl iodide. The â isomer 18 was favored by a factor
of 5:1 because of steric factors (Scheme 4). Of the
conditions screened for arrival at the geminally allylated
intermediate 20, deprotonation of the 18/19 mixture with
potassium hexamethyldisilazide in advance of the intro-
duction of allyl bromide proved most suitable (67%).
Following ketalization, a four-step procedure for de-
grading the allyl side chain to a vinyl substituent was
undertaken. This operation began with oxidative cleavage
to the acetaldehyde level by concomitant exposure of 21
to osmium tetraoxide and sodium periodate.15 The car-
bonyl group was reduced with sodium borohydride in
advance of 1,2-elimination via the primary o-nitrophenyl-
selenide.16 Hydrolysis of the resulting 23 afforded the
targeted 24.
a
Key: (a) Me3SiCl, Et3N, THF; (b) CH3Li, DME, HMPA,
CH COCl; (c) KOH, CH OH, rt; (d) HC(OCH ) , p-TsOH, CH OH
excess); (e) 450 °C, 0.4 Torr, quartz chips.
3
3
3
3
3
(
(
14) Dauben, H. J .; L o¨ ken, B.; Ringold, H. J . J . Am. Chem. Soc. 1954,
6, 1359.
15) Wee, A. G.; Liu, B. In Encyclopedia of Reagents for Organic
To reach the more highly oxygenated analogue 29, the
8/19 mixture was first transformed into the correspond-
7
1
(
Synthesis; Paquette, L. A., Editor-in-Chief: J ohn Wiley and Sons:
Chichester, 1995; pp 4616-4620.
ing silyl enol ether 25 under thermodynamic conditions
Scheme 5). Regeneration of the enolate anion by treat-
ment with methyllithium followed by trapping with
acetyl chloride in the presence of HMPA gave rise to the
(
(
16) Iwaoka, M.; Tomoda, S. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Editor-in-Chief; J ohn Wiley and Sons:
Chichester, 1995; p 3752.

Synthesis of the Antileukemic Diterpene J atrophatrione. 1
J . Org. Chem., Vol. 64, No. 9, 1999 3247
Sch em e 6a
Sch em e 7a
a
Key: (a) Br2, Et3N, CCl4; (b) Zn, CH3OH, NH4Cl, THF, ∆; (c)
HOCH2CH2OH, p-TsOH, C6H6, ∆; (d) NaBH4, CH3OH, CeCl3‚7H2O;
e) CH3SO2Cl, Et3N, CH2Cl2; (f) DBU, DMF, ∆.
(
easily separable isomers 26 and 27 in a ratio of 1:2.
Conveniently, enol acetate 26 could be hydrolyzed in
methanolic potassium hydroxide and reconverted to 18/
1
9, now with the R isomer predominating.
At this juncture, selective protection of the pendant
methyl ketone was achieved by means of trimethyl
orthoformate in excess methanol containing p-toluene-
sulfonic acid as catalyst. Exposure of the resulting ketal
2
8 to flash vacuum pyrolysis over quartz chips provided
the desired 29 efficiently.
The starting material selected for preparation of the
D subunit was the known 4,4-dimethylcyclopentenone
(
30).17 Careful examination of the retrosynthetic options
available to each of the diquinane ketones (see C, Scheme
) suggested that the cyclopentenyl bromides 32 and 35
would best serve our needs (Scheme 6). Both involved
initial generation of the bromo enone 31.18 Ketal 32 was
formed readily without any indication of steric retarda-
a
Key: (a) CeCl3, THF, -79 °C; 24; (b) p-TsOH, acetone, H2O;
2
(
c) KOt-Bu, 18-crown-6, THF, 0 °C; (d) CH3I.
sion. Prior to this event, the ketone carbonyl was
unmasked by acidic hydrolysis to deliver 38.
tion.
Alternatively, Luche reduction19 of 31 afforded the allyl
As alluded to earlier, the cisoid juxtapositioning of the
two olefinic centers in 38, while essential to the projected
sigmatropic rearrangement, does not of itself guarantee
the proper merger of chirality (i.e., matching of config-
uration at all stereogenic centers) so desirable to the
alcohol 33, reaction of which with methanesulfonyl
chloride and triethylamine led directly to chloride 34. The
latter substance is particularly prone to elimination.
Although this process operates on exposure of 34 to
sodium iodide in acetone, greater reproducibility was
noted with DBU in warm dimethylformamide. The
resulting volatile bromocyclopentadiene 35 was routinely
utilized as a solution in pentane for the critical coupling
step.
9
,10,21
direct acquisition of 8. On the basis of analogy
and
anticipated kinetic and thermodynamic control, the
expectation was held by us that advancement to product
would occur via chairlike transition state E rather than
G or more congested boatlike alternatives with resultant
introduction of two new double bonds as shown in F ()
39). The alternative concerted trajectories such as G
necessarily culminate in the formation of other double
bond isomers typified by H. Indeed, when 38 was
subjected to the action of potassium tert-butoxide and 18-
crown-6 in THF at 0 °C for 1 h with subsequent
introduction of excess methyl iodide, a 1:1.7 mixture of
the anticipated 40 and the unexpected 42 was formed in
Cou p lin g of th e C/D F r a gm en ts. The anhydrous
cerium trichloride-promoted reaction20 of cyclopentenyl-
lithium 36 with ketone 24 gave 37 in 94% yield without
any evidence for serious competing enolization (Scheme
7
). The highly stereocontrolled course of this 1,2-addition
was a most welcomed development that set the stage
admirably for examination of the projected ring expan-
8
8% yield. Quite obviously, the enolate anion 39 had been
(17) Magnus, P. D.; Nobbs, M. S. Synth. Commun. 1980, 10, 273.
generated efficiently and transformed via O- and C-
alkylation into 40 and 41, respectively. In our hands, the
subsequent transannular ene reaction of 41 to deliver 42
could not be was arrested and must therefore occur quite
(
18) This intermediate has previously been prepared by an alterna-
tive means: Wakui, T.; Otsuji, Y.; Imoto, E. Bull. Chem. Soc. J pn. 1974,
7, 2267.
19) (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.
978, 601.
20) Paquette, L. A. In Encyclopedia of Reagents for Organic
4
(
1
(
Synthesis; Paquette, L. A., Editor-in-Chief: J ohn Wiley and Sons:
Chichester, 1995; p 1031.
(21) (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Paquette,
L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609.

3
248 J . Org. Chem., Vol. 64, No. 9, 1999
Paquette et al.
rapidly.22 The relative stereochemistry of 40 was assigned
on the basis of the absence of NOE interaction between
the methyl group at C6 and vinyl proton at C7 and by
F igu r e 1. Computer-generated perspective drawing of 42 as
determined by X-ray crystallography.
analogy to related products prepared in this and the
related report.8 The structural character of 42 was
rigorously established by X-ray crystallographic analysis
Sch em e 8a
(Figure 1). The transoid B/C ring stereochemistry neces-
sitates that the geometry of the double bond in 39-41
be E as shown.2
3-27
Although use of the anionic oxy-Cope rearrangement
as a device for efficiently producing 40 and 42 from
building blocks 24 and 36 had been demonstrated, the
utility of tetracyclic product 42 was considered to be less
than optimal. Although a variety of possibilities for
central bond cleavage in this product can be identified,
the steps needed to accomplish this chemistry would
lengthen the synthesis appreciably. For these reasons,
attention was focused instead in Scheme 8.
Adaptation of the cerium(III) chloride-mediated reac-
tion conditions developed earlier to the coupling of 43
with 29 furnished 44 in 82% yield. The challenge of
performing the oxy-Cope rearrangement/methylation
step properly required only that molecular oxygen be
stringently excluded in order to curtail adventitious
oxygenation of enolate anion 45.28 In view of the excellent
combined yield of 47 (64%) and 48 (34%) realized in this
step, it follows that 45 experiences methylation exclu-
(22) The unwanted transannular ene reaction can be skirted if
enolate anion 39 is quenched directly with saturated NH Cl solution
4
at 0 °C. Under these circumstances, i was obtained in 92% yield. (Sun,
L.-Q. Unpublished results).
a
Key: (a) CeCl3, THF, -70 °C; 29; (b) KOt-Bu, 18-crown-6,
THF, 0 °C; (c) CH3I; (d) p-TsOH, acetone, H2O, ∆.
R
sively at C and from the â direction to generate 46. Once
formed, 46 experiences transannular ene cyclization
along a trajectory totally different from that followed by
4
1. In the earlier example, proton loss was incurred from
the extra-annular methyl substituent. In contrast, the
kinetically favored ene reaction in 46 operates along that
intra-annular pathway involving the allylic ring meth-
ylene adjacent to the methoxy group. In light of the ease
with which 47 is transformed into 48 under conditions
of acid hydrolysis, the real possibility exists that 48 is
generated during neutralization of the strongly basic
reaction medium.
(
(
(
(
23) Terada, Y.; Yamamura, S. Tetrahedron Lett. 1979, 18, 1623.
24) Wender, P. A.; Hubbs, J . C. J . Org. Chem. 1980, 45, 365.
25) Williams, J . R.; Callahan, J . F. J . Org. Chem. 1980, 45, 4475.
26) (a) Srinivasan, R.; Rajagopalan, K. Tetrahedron Lett. 1998, 39,
4
133. (b) J anardhanam, S.; Devan, B.; Rajagopalan, K. Tetrahedron
Lett. 1993, 34, 6761. (c) Balakumar, A.; J anardhanam, S.; Rajagopalan,
K. J . Org. Chem. 1993, 58, 5482.
(
27) (a) Shanmugam, P. Rajagopalan, K. Tetrahedron 1996, 52, 7737.
b) Shanmugam, P.; Devan, B.; Srinivasan, R.; Rajagopalan, K.
Tetrahedron 1997, 53, 12637.
28) Paquette, L. A.; DeRussy, D. T.; Pegg, N. A.; Taylor, R. T.;
Zydowsky, T. M. J . Org. Chem. 1989, 54, 4576.
(
Initially, 48 was difficult to characterize due to its
fluxional behavior, with interconversion between two or
(

Synthesis of the Antileukemic Diterpene J atrophatrione. 1
J . Org. Chem., Vol. 64, No. 9, 1999 3249
Sch em e 9a
framework of jatrophatrione. More specifically, the route
is very well tailored to cis alignment of the four ring
juncture positions as required for the C9 epimer. At least
two of the more advanced intermediates are expected to
play a crucial role in making possible a de novo synthesis
of 1. Included in this group are the tetracyclic aldol 48
and the tricyclic enone 52. The next step involved
development of the chemistry of these compounds. This
theme constitutes the substance of the accompanying
report.8
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. The
column chromatographic separations were performed with
Woelm silica gel (230-400 mesh). Solvents were reagent grade
and in most cases dried prior to use. The purity of all
1
compounds was shown to be >95% by TLC and high field H
and 13C NMR. The high-resolution and fast-atom-bombard-
ment mass spectra were recorded at The Ohio State University
Campus Chemical Instrumentation Center. Elemental analy-
ses were performed at the Scandinavian Microanalytical
Laboratory, Herlev, Denmark or at Atlantic Microlab, Inc.,
Norcross, GA.
a
Key: (a) LiAlH4, ether, 0 °C; (b) Ac2O, Et3N, DMAP, CH2Cl2;
(
c) CH3SO2Cl, Et3N, CH2Cl2; (d) KOt-Bu, t-BuOH, 40 °C.
cis-3-Meth ylbicyclo[3.2.0]h ep t-2-en -6-on e (11). To a me-
chanically stirred solution of 1011 (151 g, 0.79 mol) in 2400
more conformations occurring slowly on the NMR time
scale at room temperature. One consequence of this
behavior is the appearance of the olefinic protons as a
broad singlet instead of two sets of doublets. However,
warming the sample to 77 °C was adequate to record a
first-order spectrum.
4
mL of THF and 600 mL of methanol at 0 °C were added NH -
Cl (169 g, 3.16 mol) and activated zinc dust (207 g, 3.16 mol)
in portions over 1 h. The suspension was warmed to room
temperature and refluxed for 48 h. The solution was cooled to
room temperature, diluted with CH
2 2
Cl , filtered, and concen-
trated. Distillation (100 °C, 15 Torr) afforded 79.2 g (82%) of
-
1
1
1
(
1 as a pale yellow oil: IR (neat, cm ) 1750, 1680; H NMR
300 MHz, CDCl ) δ 5.39 (m, 1 H), 3.81 (m, 1 H), 3.37 (m, 1
H), 3.21 (ddd, J ) 17.2, 8.4, 2.9 Hz, 1 H), 2.62-2.37 (m, 3 H),
Product 48 was recognized to be a â-hydroxy ketone
3
and accordingly to be a substrate particularly well suited
to a Grob fragmentation sequence.2
9,30
To this end, 48
13
1
6
8
3
.71 (s, 3 H); C NMR (75 MHz, CDCl ) δ 213.3, 142.4, 126.6,
2.7, 54.0, 38.8, 37.0, 16.3; HRMS m/z (M - C H O) calcd
2 2
was reduced with lithium aluminum hydride in ether to
generate a carbinol mixture with 10:1 selectivity (Scheme
+
0.0626, obsd 80.0623.
9
). Since olefin geometry in the impending Grob product
ci s-3,3a ,6,6a -T e t r a h y d r o -5-m e t h y l-1(2H )-p e n t a le -
n on e (13). To a mechanically stirred solution of 11 (140 g,
.14 mol) in 4000 mL of CH Cl at -78 °C was added 1.0 M
SbF in CH Cl (80 mL, 0.08 mol). The amber solution was
is directly linked to the stereochemistry of the alcohol, it
was important to rigorously establish that 49 was the
major constituent. Although the H NMR spectrum of 49
1
2
2
1
5
2
2
stirred for 20 min before ethyl diazoacetate (202 g, 1.77 mol)
was added dropwise over a period of 1.5 h. The mixture was
stirred at -78 °C for 4 h, allowed to warm slowly to 0 °C, and
was too poorly resolved to permit unequivocal structural
assignment, conversion to the corresponding acetate 50
solved this problem. The application of HETCOR and
long-range C-H correlation techniques allowed each of
the four methyl groups to be distinguished. Further,
diagnostic NOE enhancements such as that shown on the
structural formula revealed the hydroxyl to be oriented
equatorially as a consequence of axial hydride delivery.
Following the conversion of 49 to its mesylate 51under
standard conditions, treatment with potassium tert-
butoxide in tert-butyl alcohol gave rise to 52 in excellent
yield. NOE enhancements confirmed the predicted Z
configuration of the double bond resident in ring B. The
stereoelectronic requirements for the Grob fragmentation
dictate that the leaving group be antiplanar to the σ-bond
experiencing scission. The requisite reactive conformation
must adopt a boat geometry to satisfy this requirement
as shown in 51. As a consequence, the double bond newly
introduced in 52 must have a Z configuration. The
significant NOE interaction depicted in the structural
formula corroborates this conclusion.
poured into a vigorously stirred saturated solution of NaHCO
3
(2 L). The yellow suspension was stirred at room temperature
for 14 h, separated, washed with water and brine, dried, and
concentrated to afford an approximate 2:1 mixture of the â-keto
ester and enol ester 12 as a cloudy orange oil. The crude
mixture was dissolved in dioxane (2.4 L) and water (0.7 L),
2 3
K CO (400 g, 2.89 mol) was added, and the mixture was
refluxed for 24 h. The red-black solution was cooled, diluted
with ether, and washed with brine. The aqueous layer was
extracted with ether, and the combined organic layers were
dried, filtered, and concentrated. The residue was purified by
flash chromatography on silica gel (elution with 39:1 petroleum
ether/ethyl acetate) to give 13 (88.7 g, 56%) as a light yellow
-
1
1
oil: IR (neat, cm ) 1730; H NMR (300 MHz, CDCl
(
3
) δ 5.20
s, 1 H), 3.49 (br s, 1 H), 2.67-1.89 (series of m, 7 H), 1.69 (s,
3
4
H); 13C NMR (75 MHz, CDCl
7.7, 41.2, 36.3, 25.5, 16.2; HRMS m/z (M ) calcd 136.0888,
3
) δ 224.2, 141.1, 127.5, 50.2,
+
obsd 136.0884.
Anal. Calcd for C
H, 8.93.
9
H12O: C, 79.37; H, 8.88. Found: C, 79.05;
cis-3′,3′a,6′,6′a-Tetr ah ydr o-5′-m eth ylspir o[1,3-dioxolan e-
2,1′(2′H)-p en ta len e] (14). A solution of 13 (22.0 g, 0.161 mol)
in 100 mL of 2-ethyl-2-methyl-1,3-dioxolane was treated with
p-toluenesulfonic acid (5.0 g, 26 mmol), stirred for 1 h at room
temperature, diluted with 2000 mL of ether, washed with
saturated NaHCO solution and brine, dried, filtered, and
3
concentrated. The crude oil was purified by column chroma-
tography (silica gel, elution with 2.5% ethyl acetate in petro-
The chemistry detailed herein defines a concise con-
vergent strategy for construction of the [5.9.5] tricyclic
(29) (a) Corey, E. J .; Mitra, R. B.; Uda, H. J . Am. Chem. Soc. 1963,
8
8
5, 362. (b) Corey, E. J .; Mitra, R. B.; Uda, H. J . Am. Chem. Soc. 1964,
6, 485.
(30) Tanabe, M.; Crowe, D. F. Tetrahedron Lett. 1964, 2955.

3
250 J . Org. Chem., Vol. 64, No. 9, 1999
Paquette et al.
leum ether) to give 19.5 g (67%) of 14 as a mobile oil: IR (neat,
chromatography on silica gel (elution with 19:1 petroleum
ether in ethyl acetate) to give a light yellow oil (43.4 g, 83%)
consisting of a 5:1 mixture of 18 and 19 ( H NMR analysis).
-
1
1
cm ) 1445, 1330, 1205; H NMR (300 MHz, CDCl ) δ 5.08 (t,
3
1
J ) 1.7 Hz, 1 H), 3.89 (series of m, 4 H), 3.21 (m, 1 H), 2.56
(
m, 1 H), 2.34 (s, 2 H), 1.83-1.55 (m, 3 H), 1.67 (s, 3 H), 1.40
For the major isomer, which was obtained pure by rechro-
1
3
-1
1
(m, 1 H); C NMR (75 MHz, C
6
D
6
) δ 139.5, 127.8, 119.1, 64.8,
3
matography: IR (neat, cm ) 1725; H NMR (300 MHz, CDCl )
+
6
1
3.6, 49.2, 48.1, 39.6, 33.1, 28.9, 16.2; HRMS m/z (M ) calcd
80.1550, obsd 180.1551.
3′a S*,4′S*,5′R*,6′a S*)-Hexa h yd r o-4′-h yd r oxy-5′-m eth -
δ 3.46 (s, 3 H), 3.04 (dd, J ) 8.7, 6.7 Hz, 1 H), 2.69-1.88 (series
of m, 6 H), 1.73 (m, 2 H), 1.06 (d, J ) 6.9 Hz, 3 H), 1.04 (d, J
(
) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl
) δ 222.9, 93.7, 58.2,
3
+
ylsp ir o[1,3-d ioxola n e-2,1′(2′H)-p en ta len e] (15). A solution
of 14 (13.0 g, 72.2 mmol) in 300 mL of dry THF at 0 °C was
48.1, 44.4, 41.7, 40.5, 34.8, 33.9, 17.6, 14.1; HRMS m/z (M )
calcd 182.1307, obsd 182.1306.
treated with BH
was stirred at 0 °C, treated sequentially with H
N NaOH (150 mL), and 30% H solution (150 mL), warmed
to room temperature, and stirred overnight prior to dilution
with ether and washing with water and brine. The organic
phase was dried, filtered, and concentrated. The crude oil was
purified by flash chromatography on silica gel (elution with
3
‚THF (144 mL, 1.0 M in THF). The solution
(2R*,3a R*,4R*,5S*,6a R*)-2-Allylh exa h yd r o-4-m eth oxy-
2,5-d im eth yl-1(2H)-p en ta len on e (20). To a solution of 18
(11.7 g, 64.2 mmol) and HMPA (13.4 mL, 77.0 mmol) in THF
(100 mL) at -78 °C was added potassium hexamethyldisilazide
(134.8 mL of 0.5 M in toluene, 67.4 mmol). The reaction
mixture was allowed to warm slowly to -10 °C during 1 h and
recooled to -78 °C prior to the introduction of allyl bromide
(10 mL, 128 mmol). After overnight stirring at room temper-
ature, water was added, and the organic phase was washed
with brine, dried, and concentrated. Flash chromatography of
the residue on silica gel (elution with 5% ethyl acetate in
2
O (30 mL), 6
2
O
2
1
1
:1 petroleum ether in ethyl acetate) to afford 12.4 g (87%) of
5 as a colorless viscous oil; IR (neat, cm ) 3400, 1455, 1340;
-
1
1
H NMR (300 MHz, CDCl
3
) δ 3.85 (m, 4 H), 3.18 (dd, J ) 9.4,
.3 Hz, 1 H), 2.40-2.15 (m, 2 H), 1.90-1.49 (m, 5 H), 1.46-
.34 (m, 2 H), 1.27-1.10 (m, 1 H), 1.01 (d, J ) 6.3 Hz, 3 H);
7
1
-1
1
hexanes) gave 9.5 g (67%) of 20: IR (neat, cm ) 1732; H NMR
(300 MHz, CDCl ) δ 5.71-5.61 (m, 1 H), 5.10-5.01 (m, 2 H),
1
3
C NMR (75 MHz, CDCl
2.7, 33.2, 33.0, 26.5, 16.4; HRMS m/z (M ) calcd 198.1256,
3
) δ 118.1, 85.7, 64.5, 63.5, 49.3, 46.1,
3
+
4
3.36 (s, 3 H), 3.07 (dd, J ) 6.8, 4.1 Hz, 1 H), 2.89 (ABq, J )
19.4, 9.5 Hz, 1 H), 2.59 (dq, J ) 9.0, 4.1 Hz, 1 H), 2.30 (dd, J
) 13.5, 8.1 Hz, 1 H), 2.26-1.98 (m, 4 H), 1.50 (dd, J ) 13.6,
8.8 Hz, 1 H), 1.33-1.22 (m, 1 H), 1.05 (s, 3 H), 1.02 (d, J ) 6.6
obsd 198.1269.
3a S*,4S*,5R*,6a S*)-H exa h yd r o-4-m et h oxy-5-m et h yl-
(2H)-p en ta len on e (17). A slurry of NaH (7.82 g, 326 mmol)
in 200 mL of dry THF at 0 °C was treated with 15 (29.37 g,
48 mmol) dissolved in 300 mL of dry THF, heated to reflux
(
1
Hz, 3 H); 13C NMR (75 MHz, CDCl
) δ 222.7, 133.1, 118.5, 96.2,
3
1
57.7, 51.5, 49.6, 43.0, 42.5, 42.2, 40.5, 34.0, 22.1, 18.1; HRMS
+
for 30 min, cooled to 0 °C, and treated with methyl iodide (16.8
mL, 0.266 mmol) over 30 min. The reaction mixture was
allowed to warm to room temperature and stirred for 3 h, at
which point TLC indicated the reaction to be complete. The
reaction mixture was carefully quenched with water at 0 °C
and concentrated. The resulting aqueous mixture was ex-
tracted with ether and the organic phases were combined and
washed with brine, dried, filtered, and concentrated. The crude
colorless oily 16 was used without further purification: IR
m/z (M ) calcd 222.1620, obsd 222.1626.
(2′R*,3′a R*,4′R*,5′S*,6′a R*)-2-Allylh exa h yd r o-4′-m eth -
oxy-2′,5′-d im et h ylsp ir o[1,3-d ioxola n e-2,1′(2′H )-p en t a l-
en e] (21). A solution of 20 (2.42 g, 10.9 mmol), ethylene glycol
(3.38 g, 54.5 mmol), and p-toluenesulfonic acid (121 mg) in
benzene (100 mL) was refluxed under a Dean-Stark trap for
24 h, cooled to room temperature, quenched with saturated
3
NaHCO solution, washed with brine, dried, and freed of
solvent. Purification of the residue by flash chromatography
on silica gel (elution with 5% ethyl acetate in hexanes) afforded
-
1
1
(
neat, cm ) 1748; H NMR (300 MHz, CDCl
3
) δ 3.84 (m, 4 H),
.36 (s, 3 H), 2.88 (dd, J ) 8.8, 5.9 Hz, 1 H), 2.38 (m, 2 H),
.96-1.53 (series of m, 6 H), 1.19-0.95 (m, 1 H), 1.02 (d, J )
-
1
1
3
1
6
6
2.75 g (95%) of 21: IR (neat, cm ) 1732; H NMR (300 MHz,
CDCl ) δ 5.85-5.72 (m, 1 H), 5.06-4.98 (m, 2 H), 3.93-3.77
3
1
3
.1 Hz, 3 H); C NMR (75 MHz, CDCl
3.7, 57.8, 47.1, 46.9, 41.3, 33.6, 33.5, 28.4, 17.2; HRMS m/z
M ) calcd 212.1412, obsd 212.1410.
3
) δ 117.9, 95.4, 64.6,
(m, 4 H), 3.31 (s, 3 H), 2.91 (dd, J ) 9.5, 7.2 Hz, 1 H), 2.74 (dt,
J ) 12.3, 9.0 Hz, 1 H), 2.33-2.04 (m, 3 H), 1.97-1.84 (m, 2
H), 1.69-1.60 (m, 1 H), 1.44-1.30 (m, 2 H), 1.01 (d, J ) 6.4
+
(
A solution of 16 dissolved in 500 mL of acetone and 50 mL
Hz, 3 H), 0.87 (s, 3 H); 13C NMR (75 MHz, CDCl
3
) δ 135.4,
of water was treated with p-toluenesulfonic acid (1.5 g), and
the reaction mixture was heated to reflux for 16 h, cooled to
room temperature, and concentrated. The residue was taken
117.9, 117.0, 95.2, 65.6, 65.3, 57.9, 51.2, 47.6, 44.8, 43.2, 40.9,
+
39.8, 30.4, 18.4, 17.4; HRMS m/z (M ) calcd 266.1882, obsd
266.1884.
up in petroleum ether, washed with saturated NaHCO
3
(2′R*,3′aS*,4′S*,5′R*,6′aR*)-Hexah ydr o-4′-m eth oxy-2′,5′-
d im eth ylsp ir o[1,3-d ioxola n e-2,1′(2′H)-p en ta len e]-2′-eth a -
n ol (22). A mixture of 21 (2.75 g, 10.3 mmol), osmium
tetraoxide (1 mL of 0.5 M in pyridine, 0.5 mmol), and sodium
metaperiodate (4.42 g, 20.7 mmol) in dioxane (25 mL) and
water (25 mL) was stirred for 24 h, filtered, and concentrated.
The residue was taken up in ethyl acetate, washed with brine,
dried, and freed of solvent prior to chromatography on silica
gel (elution with 10% ethyl acetate in hexanes). There was
solution and brine, dried, filtered, and concentrated. The crude
oil was purified by flash chromatography on silica gel (10%
ethyl acetate in petroleum ether) to give 24.58 g (99% over
-
1
two steps) of 17 as a colorless oil: IR (neat, cm ) 1730, 1455,
1
1
(
405, 1370; H NMR (300 MHz, CDCl
3
) δ 3.42 (s, 3 H), 3.05
dd, J ) 7.8, 5.1 Hz, 1 H), 2.65 (m, 2 H), 2.45-1.76 (series of
1
3
m, 6 H), 1.23 (m, 1 H), 1.05 (d, J ) 6.6 Hz, 3 H); C NMR (75
MHz, CDCl ) δ 221.1, 94.2, 57.8, 49.1, 46.9, 41.9, 37.2, 33.9,
5.3, 18.0; HRMS m/z (M ) calcd 168.1151, obsd 168.1151.
Anal. Calcd for C10 : C, 71.39; H, 9.59. Found: C, 71.27;
H, 9.57.
2S*,3a S*,4S*,5R*,6a S*)-Hexa h yd r o-4-m eth oxy-2,5-d i-
m eth yl-1(2H)-p en ta len on e (18) a n d (2R*,3a S*,4S*,5R*,-
a S*)-Hexa h yd r o-4-m eth oxy-2,5-d im eth yl-1(2H)-p en ta le-
n on e (19).Toa mechanicallystirred solution ofdiisopropylamine
47.0 mL, 335 mmol) dissolved in 1000 mL of dry THF at -78
C was added 1.4 M n-butyllithium in hexanes (225 mL, 315
3
+
-1
2
obtained 2.72 g (98%) of the aldehyde: IR (neat, cm ) 1717;
1
H
16
O
2
3
H NMR (300 MHz, CDCl ) δ 9.80 (m, 1 H), 3.96-3.78 (m, 4
H), 3.32 (s, 3 H), 2.95 (dd, J ) 9.3, 7.2 Hz, 1 H), 2.75 (dt, J )
12.2, 9.0 Hz, 1 H), 2.59 (dd, J ) 15.1, 3.2 Hz, 1 H), 2.42-2.29
(m, 1 H), 2.23 (dd, J ) 15.1, 2.7 Hz, 1 H), 2.01 (dd, J ) 13.1,
8.6 Hz, 1 H), 1.95-1.85 (m, 1 H), 1.73-1.63 (m, 1 H), 1.58
(dd, J ) 13.1, 8.6 Hz, 1 H), 1.38 (dt, J ) 12.6, 9.0 Hz, 1 H),
(
6
1
3
(
°
1.13 (s, 3 H), 1.03 (d, J ) 6.5 Hz, 3 H); C NMR (75 MHz,
CDCl ) δ 208, 117.3, 95.1, 65.9, 65.4, 58.0, 50.9, 50.1, 47.4,
3
+
mmol), and the resulting solution was warmed to 0 °C and
44.8, 43.2, 43.0, 30.4, 19.5, 17.3; HRMS m/z (M ) calcd
stirred for 20 min. Ketone 17 (48.1 g, 286 mmol) dissolved in
268.1675, obsd 268.1677.
1
00 mL of THF was added dropwise to this solution over 20
The above aldehyde (1.07 g, 4.0 mmol) was dissolved in CH
(5 mL) and methanol (5 mL), cooled to 0 °C, treated
carefully with NaBH (303 mg, 8.0 mmol), stirred for 1 h,
quenched with saturated NH Cl solution, and concentrated in
vacuo. The residue was taken up in ethyl acetate, washed with
brine, dried, and freed of solvent. Chromatography of the
residue on silica gel (elution with 50% ethyl acetate in hexanes)
2
-
min at -78 °C, and the mixture was stirred for 1 h at this
temperature. HMPA (100 mL, 574 mmol) followed by methyl
iodide (54 mL, 856 mmol) was added to the solution, and the
mixture was warmed to room temperature, stirred for 23 h,
quenched with water, diluted with ether, washed with brine,
dried, and concentrated. The residue was purified by flash
Cl
2
4
4

Synthesis of the Antileukemic Diterpene J atrophatrione. 1
J . Org. Chem., Vol. 64, No. 9, 1999 3251
afforded 1.07 g (98%) of 22: IR (neat, cm-1) 3415, 1455; H
1
temperature and stirred for 3 h. After the addition of HMPA
(120 mL, 690 mmol), the mixture was cooled to -78 °C, and
acetyl chloride (25.0 mL, 352 mmol) was introduced. The
temperature was allowed to warm slowly to 20 °C, and the
reaction mixture was stirred for 21 h, quenched with water,
diluted with ether, washed with water and brine, dried, and
concentrated. The crude oil was purified by flash chromatog-
raphy on silica gel (elution with 10% ethyl acetate in petroleum
ether) to give 26 (17.3 g, 33%) and 27 (34.6 g, 66%) as light
yellow oils.
NMR (300 MHz, CDCl ) δ 3.98-3.58 (m, 6 H), 3.32 (s, 3 H),
3
2
2
1
.93 (dd, J ) 9.5, 7.4 Hz, 1 H), 2.82 (dt, J ) 12.1, 9.0 Hz, 1 H),
.41-2.29 (m, 1 H), 1.98-1.83 (m, 3 H), 1.71-1.62 (m, 1 H),
.58-1.49 (m, 2 H), 1.38 (dd, J ) 12.5, 8.9 Hz, 1 H), 1.02 (d,
1
3
J ) 6.4 Hz, 3 H), 0.96 (s, 3 H) (OH not observed); C NMR
3
(75 MHz, CDCl ) δ 117.8, 95.1, 65.6, 59.4, 57.9, 50.4, 47.2, 44.7,
+
4
2
4.4, 43.1, 40.0, 30.2, 18.3, 17.3; HRMS m/z (M ) calcd
70.1831, obsd 270.1831.
2′R*,3′a S*,4′S*,5′R*,6′a S*)-Hexa h yd r o-4′-m eth oxy-2′,5′-
(
, cm- ) 1727, 1703; H NMR (300 MHz,
1
1
d im e t h yl-2′-vin ylsp ir o[1,3-d ioxola n e -2,1′(2′H )-p e n t a l-
en e] (23). To a solution of 22 (2.68 g, 10 mmol) and 2-nitro-
phenylselenocyanate (2.95 g, 13 mmol) in THF (100 mL) was
added a solution of tri-n-butylphosphine (2.76 g, 13 mmol) in
THF (20 mL). The mixture was stirred for 16 h, freed of THF,
and passed through silica gel (5 f 20% ethyl acetate in
hexanes) to give 4.5 g of crude selenide, which was dissolved
in THF (50 mL), cooled to 0 °C, and treated with 30% hydrogen
peroxide (10 mL). The reaction mixture was slowly warmed
to room temperature, stirred overnight, and freed of THF
below 25 °C. The residual aqueous phase was extracted with
ethyl acetate, washed in sequence with 6 N sodium hydroxide
For 26: IR (CHCl
CDCl
3
3
) δ 3.40 (s, 3 H), 3.35-3.29 (m, 1 H), 3.03 (t, J ) 6.9 Hz,
1 H), 2.70-2.60 (m, 1 H), 2.56-2.46 (m, 1 H), 2.20 (br d, J )
16.4 Hz, 1 H), 2.15 (s, 3 H), 1.98-1.83 (m, 2 H), 1.51 (t, J )
1
3
0.9 Hz, 3 H), 1.15-1.05 (m, 1 H), 1.02 (d, J ) 6.1 Hz, 3 H);
NMR (75 MHz,CDCl
C
3
) δ 168.6, 146.4, 120.4, 96.1, 57.9, 45.3,
+
44.1, 40.8, 39.2, 35.6, 20.7, 17.5, 12.1; HRMS m/z (M ) calcd
224.1413, obsd 224.1408.
-
1
1
For 27: IR (neat, cm ) 1730, 1695; H NMR (300 MHz,
CDCl
3
) δ 3.37 (s, 3 H), 3.06-3.00 (m, 1 H), 2.99-2.92 (m, 1
H), 2.88-2.80 (m, 1 H), 2.68-2.63 (m, 1 H), 2.12 (s, 3 H), 2.16-
2.01 (m, 1 H), 1.43-1.35 (m, 1 H), 1.35 (s, 3 H), 1.31-1.27 (m,
solution, water, saturated NaHSO
3
solution, and brine, and
1 H), 1.01 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz,CDCl
) δ
3
then dried and concentrated. Purification of the residue by
chromatography on silica gel (elution with 10% ethyl acetate
216.1, 204.4, 95.8, 67.7, 57.5, 50.0, 43.1, 42.4, 38.3, 33.7, 25.1,
+
20.9, 17.9; HRMS m/z (M ) calcd 224.1413, obsd 224.1403.
-1
in hexanes) furnished 2.20 g (88%) of 23: IR (neat, cm ) 1456,
Anal. Calcd for C13
H, 8.97.
20 3
H O : C, 69.61; H, 8.99. Found: C, 69.35;
1
1
122; H NMR (300 MHz, CDCl
3
) δ 6.05 (dd, J ) 17.6, 10.8
Hz, 1 H), 5.12 (dd, J ) 17.6, 1.3 Hz, 1 H), 5.04 (dd, J ) 10.8,
(2S*,3aS*,4S*,5R*,6aS*)-2-(1,1-Dim eth oxyeth yl)h exah y-
d r o-4-m eth oxy-2,5-d im eth yl-1(2H)-p en ta len on e (28). A
solution of 27 (16.4 g, 72.9 mmol) in 70 mL of dry methanol
was treated with trimethyl orthoformate (50.0 mL, 457 mmol)
and p-toluenesulfonic acid monohydrate (1.00 g, 5.26), and the
resulting solution was stirred for 2 h at room temperature,
1
9
1
.3 Hz, 1 H), 3.99-3.79 (m, 4 H), 3.36 (s, 3 H), 2.95 (dd, J )
.6, 7.8 Hz, 1 H), 2.68 (dt, J ) 12.3, 8.8 Hz, 1 H), 2.37 (dt, J )
2.3, 8.5 Hz, 1 H), 2.11 (dd, J ) 12.8, 8.6 Hz, 1 H), 1.96-1.84
(
m, 1 H), 1.70-1.58 (m, 2 H), 1.30 (dt, J ) 12.4, 8.4 Hz, 1 H),
.03 (d, J ) 6.5 Hz, 3 H), 1.00 (s, 3 H); 13C NMR (75 MHz,
CDCl ) δ 143.0, 117.5, 111.9, 95.1, 65.9, 65.6, 58.0, 54.5, 47.3,
1
3
2 3
treated with ether (100 mL) and K CO (35 g, 0.25 mmol),
+
4
2
4.8, 43.1, 41.0, 29.8, 19.5, 17.4; HRMS m/z (M ) calcd
52.1725, obsd 252.1724.
2R*,3a S*,4S*,5R*,6a S*)-2-H exa h yd r o-4-m et h oxy-2,5-
d im eth yl-2-vin yl-1(2H)-p en ta len on e (24). A solution of 23
2.20 g, 8.7 mmol) and p-toluenesulfonic acid (88 mg, 0.46
mmol) in acetone (50 mL) and water (5 mL) was refluxed for
4 h, cooled to room temperature, and worked up in the
predescribed manner for 17 to provide 1.73 g (95%) of 24: IR
filtered through a plug of Florisil, and concentrated. The crude
oil was purified by flash chromatography on silica gel (elution
with 1% triethylamine and 1% ethyl acetate in petroleum
ether) to give 28 as a light yellow oil (14.3 g, 72%): IR (neat,
(
-
1
1
(
6 6
cm ) 1740, 1465, 1385; H NMR (300 MHz, C D ) δ 3.19 (s, 3
H), 2.98 (s, 3 H), 2.97 (s, 3 H), 2.88-2.79 (m, 1 H), 2.50-2.22
(m, 1 H), 2.06-1.94 (m, 2 H), 1.46-1.33 (m, 2 H), 1.18 (s, 3
2
H), 1.16-1.04 (m, 2 H), 1.15 (s, 3 H), 0.89 (d, J ) 6.4 Hz, 3 H);
-
1
1
13
(neat, cm ) 1737; H NMR (300 MHz, CDCl
3
) δ 5.71 (dd, J )
6 6
C NMR (75 MHz, C D ) δ 220.3, 104.0, 96.3, 59.5, 57.6, 51.6,
1
1
2
7.2, 10.7 Hz, 1 H), 5.10 (d, J ) 10.7 Hz, 1 H), 5.05 (d, J )
7.2 Hz, 1 H), 3.37 (s, 3 H), 3.10 (dd, J ) 6.5, 3.7 Hz, 1 H),
.95 (q, J ) 9.6 Hz, 1 H), 2.64 (dq, J ) 10.1, 3.7 Hz, 1 H), 2.44
50.8, 50.1, 44.5, 42.3, 39.0, 33.6, 22.2, 18.2, 16.3; HRMS m/z
(M ) calcd 258.1831, obsd 258.1823.
+
(2S*,3a R*,4R*,5S*,6a R*)-H exa h yd r o-4-m et h oxy-2-(1-
m eth oxyvin yl)-2,5-d im eth yl-1(2H)-p en ta len on e (29). A 16
in. × 0.75 in. quartz tube containing freshly broken quartz
chips prewashed with dilute HCl solution was attached to a
two-necked flask containing a neat sample of 28 (3.24 g, 12.0
mmol) and preequilibrated at 460 °C and 0.7 Torr for 3 h. The
flask was heated with a heating mantle and later a naked
flame while the product was collected in a receiving tube cooled
(
1
dd, J ) 12.9, 8.7 Hz, 1 H), 2.15-2.00 (m, 2 H), 1.57 (dd, J )
3.3, 9.7 Hz, 1 H), 1.33-1.21 (m, 1 H), 1.15 (s, 3 H), 1.03 (d, J
1
3
)
9
3
6.6 Hz, 3 H); C NMR (75 MHz, CDCl ) δ 219.5, 140.5, 114.3,
6.1, 57.6, 55.7, 49.2, 43.0, 42.8, 41.3, 33.7, 22.4, 18.1; HRMS
+
m/z (M ) calcd 208.1663, obsd 208.1680.
Anal. Calcd for C13 : C, 74.96; H, 9.68. Found: C, 75.06;
H, 9.71.
[(3a S*,4S*,5R*,6a S*)-3,3a ,4,5,6,6a -Hexa h yd r o-4-m eth -
20 2
H O
[
2 2
with liquid N . After the transfer was complete, N was purged
oxy-2,5-d im eth yl-1-p en ta len yl]oxy]tr im eth ylsila n e (25).
Ketones 18 and 19 (7.2 g, 40 mmol) dissolved in 150 mL of
dry DMF and 90 mL of triethylamine were treated with 90
mL of chlorotrimethylsilane, and the reaction mixture was
heated to 85 °C for 23 h. The solution was cooled to room
temperature, and excess silyl chloride was blown off in a
stream of air. The reaction mixture was diluted with ether,
washed with water, dried, filtered, and concentrated. The
crude material was filtered through a pad of silica gel (elution
through the flask and the apparatus was cooled to room
temperature. The receiving tube was washed with ether and
concentrated, and the dark yellow oil was purified by flash
chromatography on SiO
2
(elution with 1% triethylamine in
hexanes) to give 29 (2.20 g, 88%) as a light yellow oil: IR (neat,
-
1
1
6 6
cm ) 1730, 1630, 1600; H NMR (300 MHz, C D ) δ 3.99 (d, J
) 3 Hz, 1 H), 3.77 (d, J ) 3 Hz, 1 H), 3.11 (s, 3 H), 3.05 (s, 3
H), 2.96-2.75 (series of m, 2 H), 2.68-2.56 (m, 2 H), 2.01-
1.85 (m, 2 H), 1.34 (s, 3 H), 1.31-1.23 (m, 2 H), 0.92 (d, J )
with petroleum ether) to give 9.3 g (92%) of 25 as a colorless
6.3 Hz, 3 H); 13C NMR (75 MHz, C
6 6
D ) δ 219.3, 164.4, 96.0,
1
oil: H NMR (300 MHz, CDCl
3
) δ 3.39 (s, 3 H), 2.96 (m, 1 H),
80.6, 57.8, 57.0, 55.2, 49.9, 43.7, 42.7, 41.0, 33.7, 22.2, 18.1;
+
2
0
.58-1.83 (series of m, 5 H), 1.49 (d, J ) 0.89 Hz, 3 H), 1.20-
.98 (m, 2 H), 1.02 (d, J ) 6.4 Hz, 3 H), 0.17 (s, 9 H); 13C NMR
) δ 149.0, 110.8, 96.3, 57.9, 47.3, 43.8, 40.9,
HRMS m/z (M ) calcd 238.1569, obsd 238.1569.
Anal. Calcd for C14
H, 9.36.
22 3
H O : C, 70.56; H, 9.30. Found: C, 70.29;
(75 MHz, CDCl
3
+
3
9.1, 36.1, 17.6, 12.0, 0.6 (3 C); HRMS m/z (M ) calcd 254.1702,
6-Br om o-8,8-dim eth yl-1,4-dioxaspir o[4.4]n on -6-en e (32).
A solution of 31 (9.45 g, 50 mmol), p-toluenesulfonic acid (380
mg, 2.0 mmol), and ethylene glycol (11.2 mL, 200 mmol) in
benzene (100 mL) was refluxed under a Dean-Stark trap for
24 h, cooled to room temperature, and quenched with satu-
obsd 254.1692.
2S*,3aR*,4R*,5S*,6aR*)-2-Acetylh exah ydr o-4-m eth oxy-
,5-d im eth yl-1(2H)-p en ta len on e (27). A solution of 25 (59.2
(
2
g, 223 mmol) dissolved in 350 mL of dry DME at 0 °C was
treated with methyllithium (233 mL, 1.5 M in ether, 350
mmol), and the resulting solution was warmed to room
rated NaHCO
3
solution. After solvent removal on a rotary
evaporator, the residue was dissolved in ethyl acetate, washed

3
252 J . Org. Chem., Vol. 64, No. 9, 1999
Paquette et al.
with brine, dried, and concentrated prior to chromatographic
purification on silica gel (elution with 10% ethyl acetate in
hexanes). There was obtained 10.95 g (94%) of 32 as a colorless
acetate in hexanes) furnished 2.21 g (94%) of 37 as a colorless
oil: IR (neat, cm ) 3495, 1110; H NMR (300 MHz, C D ) δ
6 6
-
1
1
6.05 (dd, J ) 17.6, 10.8 Hz, 1 H), 5.56 (s, 1 H), 5.19 (dd, J )
17.6, 1.5 Hz, 1 H), 5.06 (dd, J ) 10.8, 1.5 Hz, 1 H), 4.41 (s, 1
H), 3.62-3.56 (m, 1 H), 3.47-3.25 (m, 4 H), 3.43 (s, 3 H), 2.93-
2.87 (m, 1 H), 2.52 (dq, J ) 11.7, 8.1 Hz, 1 H), 2.32-2.17 (m,
3 H), 1.83-1.66 (m, 4 H), 1.47 (s, 3 H), 1.33 (d, J ) 6.5 Hz, 3
-
1
1
oil: IR (neat, cm ) 1619, 1321, 1158; H NMR (300 MHz,
CDCl ) δ 5.99 (s, 1 H), 4.21-4.15 (m, 2 H), 3.99-3.93 (m, 2
H), 1.99 (s, 2 H), 1.14 (s, 6 H); C NMR (75 MHz, CDCl
3
1
3
3
) δ
46.2, 121.9, 117.2, 65.7, 49.9. 42.0, 28.6; HRMS m/z (M ) calcd
32.0099, obsd 232.0088.
-Br om o-4,4-d im eth yl-2-cyclop en ten -1-ol (33). Ketone
1 (5.0 g, 26.5 mmol) dissolved in 100 mL of 0.4 M CeCl ‚7H
+
1
2
H), 1.08 (s, 3 H), 1.02 (s, 3 H); 13C NMR (75 MHz, C
6 6
D ) δ
2
147.5, 145.1, 136.9, 120.7, 111.2, 95.5, 83.6, 63.4, 63.3, 57.6,
57.5, 51.3, 51.0, 46.6, 43.1, 42.4, 39.4, 28.9, 28.6, 28.5, 20.4,
3
3
2
O
+
in methanol at 0 °C was carefully treated with sodium
borohydride (1.2 g, 32 mmol). The resulting white slurry was
stirred at 0 °C for 10 min, at which point the mixture was
17.8; HRMS m/z (M ) calcd 362.2457, obsd 362.2458.
4,4-Dim eth yl-2-[(1R*,2S*,3aR*,4R*,5S*,6aR*)-octah ydr o-
1-h yd r oxy-4-m eth oxy-2,5-d im eth yl-2-vin yl-1-p en ta len yl]-
2-cyclop en ten -1-on e (38). A solution of 37 (102 mg, 0.28
mmol) and p-toluenesulfonic acid (5 mg) in 10:1 acetone-water
(2 mL) was stirred at room temperature for 10 h, quenched
quenched with saturated NH
ether. The separated organic layer was washed with saturated
NH Cl solution, water, and brine, dried, and concentrated to
afford 4.9 g (97%) of 33 as a white solid: mp 58 °C; IR (CH
4
Cl solution and diluted with
4
2
-
3
with saturated NaHCO solution, and concentrated under
-
1
1
Cl
)
1
1
1
1
2
, cm ) 3380, 1620; H NMR (300 MHz, CDCl
3
) δ 5.87 (d, J
reduced pressure. The product was extracted into ethyl
acetate, dried, and freed of solvent prior to chromatography
on silica gel (elution with 10% ethyl acetate in hexanes) to
give 85 mg (95%) of 38 as a white solid: mp 86-87 °C; IR
0.5 Hz, 1 H), 4.72 (dd, J ) 7.5, 4.6 Hz, 1 H), 2.18 (dd, J )
3.4, 7.5 Hz, 1 H), 2.03 (br s, 1 H), 1.70 (dd, J ) 13.4, 4.6 Hz,
13
H), 1.17 (s, 3 H), 1.09 (s, 3 H); C NMR (75 MHz, CDCl ) δ
3
+
-1
1
43.9, 123.1, 78.9, 47.6, 44.1, 29.5, 28.7; HRMS m/z (M ) calcd
3
(neat, cm ) 3446, 1682; H NMR (300 MHz, CDCl ) δ 7.00 (s,
91.9929, obsd 199.9951.
1 H), 5.66 (dd, J ) 17.5, 10.8 Hz, 1 H), 5.28 (d, J ) 2.0 Hz, 1
H), 4.98 (dd, J ) 17.5, 1.4 Hz, 1 H), 4.96 (dd, J ) 10.9, 1.4 Hz,
1 H), 3.39 (s, 3 H), 3.11-3.08 (m, 1 H), 2.95-2.85 (m, 1 H),
2.40-2.33 (m, 1 H), 2.31 (s, 2 H), 2.05-1.86 (m, 3 H), 1.63-
1.53 (m, 2 H), 1.19 (s, 6 H), 1.04 (s, 3 H), 1.03 (d, J ) 6.7 Hz,
Anal. Calcd for C
3.85; H, 5.70.
7
H11BrO: C, 44.00; H, 5.80. Found: C,
4
1
-Br om o-5-ch lor o-3,3-d im eth yl-1-cyclop en ten e (34). Al-
cohol 33 (14.7 g, 76.9 mmol) dissolved in 250 mL of dry CH
Cl at 0 °C was treated with triethylamine (16 mL, 115 mmol)
2
-
3 H); 13C NMR (75 MHz, CDCl
112.5, 95.0, 82.3, 58.2, 57.8, 50.7, 49.2, 46.7, 42.9, 41.9, 38.3,
28.6, 27.6, 27.5, 19.4, 17.3; HRMS m/z (M ) calcd 318.2195,
) δ 212.0, 169.9, 143.4, 139.6,
2
3
and methanesulfonyl chloride (8.9 mL, 115 mmol). The result-
ing orange solution was stirred at 0 °C for 1 h, warmed to room
+
temperature, stirred for 16 h, diluted with CH
2
Cl
2
, washed
obsd 318.2187.
with water and brine, dried, and concentrated. The residue
was purified by flash chromatography on silica gel (elution
with petroleum ether) to afford 14.78 g (92%) of 34 as a
Anal. Calcd for C20
H, 9.49.
30 3
H O : C, 75.43; H, 9.50. Found: C, 75.32;
(3a R *,7a R *,8R *,9S *,10a R *)-2,3,3a ,4,7,7a ,8,9,10,10a -
Deca h yd r o-8,11-d im eth oxy-3,3,6,9-tetr a m eth yl-1H-d icy-
clop en ta [a ,d ]cyclon on en -1-on e (40) a n d (2R*,3S*,3a S*,-
5a R*,6a S*,9a R*,9bS*,9cS*)-Tetr a d eca h yd r o-9b-h yd r oxy-
3-m et h oxy-2,7,7,9a -t et r a m et h yl-5-m et h ylen e-9H -cyclo-
p en t[a ]-a s-in d a cen -9-on e (42). To a solution of potassium
tert-butoxide (168 mg, 1.5 mmol) and 18-crown-6 (420 mg, 1.59
-
1
1
colorless oil: IR (neat, cm ) 1615, 1330, 1225; H NMR (300
MHz, CDCl ) δ 5.95 (s, 1 H), 4.85 (dd, J ) 7.7, 2.5 Hz, 1 H),
.36 (dd, J ) 14.3, 7.7 Hz, 1 H), 2.17 (dd, J ) 14.3, 2.5 Hz, 1
3
2
1
3
H), 1.25 (s, 3 H), 1.12 (s, 3 H); C NMR (75 MHz, CDCl
1
2
3
) δ
46.5, 120.2, 67.7, 48.5, 45.5, 28.6, 28.3; HRMS m/z (M ) calcd
09.9625, obsd 209.9626.
+
Anal. Calcd for C
0.00; H, 4.79.
7
H
10BrCl: C, 40.13; H, 4.81. Found: C,
2
mmol) in THF (12 mL) at 0 °C under N was added 96 mg
4
(0.30 mmol) of 38. After 1 h of stirring at 0 °C, methyl iodide
(2 mL) was introduced, and the reaction mixture was allowed
to warm to room temperature and stirred for 2 h prior to
1
-Br om o-3,3-d im eth ylcyclop en ta -1,4-d ien e (35). A solu-
tion of 34 (1.05 g, 5.0 mmol) in 2.5 mL of dry DMF at room
temperature was treated with DBU (0.90 mL, 6.0 mmol),
heated to 100 °C for 5 h, cooled to room temperature, and
purified directly by flash chromatography on basic alumina
4
quenching with saturated NH Cl solution. The solvents were
removed in vacuo, and the product was extracted into ethyl
acetate, washed with water and brine, dried, and concentrated.
Chromatography of the residue on silica gel (gradient elution
with 2.5 f 20% ethyl acetate in hexanes) afforded 55 mg (55%)
of 40 and 33 mg (33%) of 42.
(
elution with pentane). The pentane eluant was distilled off
-1
at ambient pressure to give 0.37 g (43%) of 35: IR (neat, cm
)
1
1
2
5
1
1
578, 1523, 1346; H NMR (300 MHz, C
6
D
6
) δ 6.03 (dd, J )
-
1
1
.4, 1.5 Hz, 1 H), 5.99 (dd, J ) 5.3, 1.4 Hz, 1 H), 5.83 (dd, J )
For 40: colorless oil; IR (neat, cm ) 1649, 1574; H NMR
(300 MHz, C ) δ 5.09 (m, 1 H), 3.28 (s, 3 H), 3.21 (s, 3 H),
.3, 2.5 Hz, 1 H), 0.87 (s, 6 H); 13C NMR (75 MHz, C
D
) δ
6
6
6 6
D
+
48.0, 144.7, 131.2, 116.7, 53.9, 21.6; HRMS m/z (M ) calcd
73.9867, obsd 173.9852.
3.17-3.03 (m, 2 H), 2.78-2.71 (m, 2 H), 2.33-2.29 (m, 1 H),
2.11 (dd, J ) 16.5, 1.3 Hz, 1 H), 1.99-1.57 (m, 7 H), 1.55 (s, 3
1
3
(
1R *,2S *,3a R *,4R *,5S *,6a R *)-1-(8,8-D im e t h y l-1,4-
H), 1.07 (d, J ) 6.3 Hz, 3 H), 0.97 (s, 3 H), 0.82 (s, 3 H);
C
d ioxa sp ir o[4.4]n on -6-en -6-yl)oct a h yd r o-4-m et h oxy-2,5-
d im eth yl-2-vin yl-1-p en ta len ol (37). A 5.33 g (14.3 mmol)
sample of cerium trichloride heptahydrate was evacuated to
NMR (75 MHz, CDCl ) δ 198.8, 166.1, 140.8, 129.2, 118.2, 94.0,
3
58.9, 57.4, 52.0, 46.6, 43.9, 40.5, 36.6, 35.7, 34.9, 31.8, 31.2,
+
24.0, 20.4, 17.2 (1 C not observed); HRMS m/z (M ) calcd
0
7
.1 Torr and heated progressively at 50 °C (4 h), 60 °C (4 h),
0 °C (4 h), 80 °C (7 h), and 140 °C (14 h) while being stirred
332.2351, obsd 332.2349.
-1
1
For 42: colorless solid; IR (neat, cm ) 3528, 1735; H NMR
(300 MHz, C ) δ 4.96 (dd, J ) 1.6, 0.8 Hz, 1 H), 4.73 (d, J )
magnetically. After the mixture was returned to room tem-
perature, dry THF (40 mL) was introduced under nitrogen,
and the resulting milky mixture was stirred overnight prior
to titration with tert-butyllithium (1 mL of 1 M in pentane)
until a faint yellow-orange color persisted. Meanwhile, a
solution of 32 (3.03 g, 13 mmol) in cold (-78 °C) THF (30 mL)
was treated with tert-butyllithium (15.3 mL of 1.7 M in
pentane, 26 mmol), stirred for 0.5 h, and transferred via
cannula to the stirred cerium trichloride slurry. After an
additional 2 h of stirring at -78 °C, ketone 24 (1.35 g, 6.5
mmol) was introduced, and the mixture was stirred for 2 h
prior to warming to room temperature, quenching with water,
and filtration. The filtrate was diluted with ethyl acetate,
washed with brine, dried, and concentrated. Flash chroma-
tography of the residue on silica gel (elution with 5% ethyl
6 6
D
1.6 Hz, 1 H), 3.33 (s, 3 H), 3.00 (dd, J ) 9.7, 7.0 Hz, 1 H), 2.57
(m, 1 H), 2.53 (br s, 1 H), 2.23-2.14 (m, 2 H), 2.07-1.82 (m, 6
H), 1.74-1.52 (m, 3 H), 1.24 (d, J ) 6.3 Hz, 3 H), 1.04 (s, 3 H),
0.99 (s, 1 H), 0.93 (s, 3 H), 0.87 (s, 3 H); 13C NMR (75 MHz,
CDCl ) δ 216.5, 145.8, 110.7, 91.5, 83.8, 62.3, 59.4, 58.4, 53.6,
3
52.5, 46.7, 41.3, 39.4, 34.7, 33.3, 31.4, 30.8, 28.9, 24.9, 23.5,
+
19.5; HRMS m/z (M ) calcd 332.2351, obsd 332.2361.
(1S*,2R*,3a R*,4R*,5S*,6a R*)-1-(3,3-Dim eth yl-1,4-cyclo-
pen tadien -1-yl)octah ydr o-4-m eth oxy-2-(1-m eth oxyvin yl)-
2,5-d im eth yl-1-p en ta len ol (44). A sample of cerium trichlo-
ride heptahydrate (4.9 g, 13.05 mmol) was evacuated to 0.1
Torr and stirred overnight at 110 °C (with slow elevation to
this temperature). After additional heating to 130 °C for 60
min, the white solid was cooled slowly to room temperature

Synthesis of the Antileukemic Diterpene J atrophatrione. 1
over 3 h, flushed with N , and added to THF (60 mL) via
Schlenk glassware with vigorous stirring. The resulting white
slurry was stirred for 4.5 h at room temperature and titrated
with tert-butyllithium (1.8 mL) until a faint yellow-orange color
persisted. Meanwhile, freshly prepared vinyl bromide 35 (1.5
g, 8.7 mmol) dissolved in 40 mL of dry THF was cooled to -78
J . Org. Chem., Vol. 64, No. 9, 1999 3253
6 5
(75 MHz, C D Cl) δ 215.4, 142.1, 133.0, 97.7, 85.1, 57.9, 57.7,
2
54.7, 52.3, 49.4, 47.4, 44.7, 43.2, 38.2, 35.2, 32.6, 27.2, 24.8,
+
22.4, 17.8 (1 C not observed); HRMS m/z (M ) calcd 332.2351,
obsd 332.2360.
Anal. Calcd for C21
H, 9.67.
32 3
H O : C, 75.86; H, 9.70. Found: C, 75.56;
°
C and tert-butyllithium (10.7 mL, 18.3 mmol) was introduced
via syringe. The resulting dark yellow solution was stirred for
0 min at -78 °C, transferred via cannula to the stirred CeCl
Acid Hyd r olysis of 47. A solution of 47 (247 mg, 0.713
mmol) in acetone (5.4 mL) and water (0.6 mL) was treated
with p-toluenesulfonic acid (13.1 mg, 0.069 mmol), refluxed
for 8 h, cooled, and partitioned between ether and water. The
aqueous phase was extracted with ether, and the combined
organic layers were dried, and concentrated. The residue was
purified by flash chromatography (silica gel, elution with 19:1
f 9:1 petroleum ether in ethyl acetate) to give 175 mg (74%)
of 48.
3
3
slurry, and stirred at -78 °C for 1.5 h. Ketone 29 (1.04 g, 4.35
mmol) dissolved in 30 mL of dry THF at -78 °C was added to
this slurry via cannula. The reaction mixture was stirred at
-
78 °C for 90 min and at -30 °C for 3 h prior to quenching
with saturated NaHCO solution. This mixture was extracted
with ether, and the combined organic layers were washed with
saturated NaHCO solution and brine, dried, and concentrated.
3
3
(3a S*,5R*,5a R*,6a S*,7S*,8R*,9a S*,9bR*,9cR*)-3,3a ,4,5,-
5a ,6,6a ,7,8,9,9a ,9c-Dod eca h yd r o-7-m et h oxy-3,3,5a ,8,9c-
pen tam eth yl-9bH-cyclopen t[a ]-a s-in dacen e-5,9b-diol (49).
A solution of 48 (163 mg, 0.489 mmol) in 2 mL of dry ether at
0 °C was treated with lithium aluminum hydride (40 mg, 1.05
mmol), and the resulting mixture was stirred at 0 °C for 15
min and at room temperature for 2 h prior to being quenched
with methanol and water. The mixture was extracted with
ether, and the combined organic layers were dried and
concentrated. The residue was purified by MPLC (silica gel,
elution with 2:1 petroleum ether in ethyl acetate) to give 130
The crude material was immediately purified by flash column
on silica gel (elution with 1% triethylamine and 2% ethyl
acetate in hexanes) to give 1.19 g (82%) of 44 as a colorless oil
that forms transparent crystals upon standing at -20 °C: IR
-1
1
(
(
5
neat, cm ) 3490, 1645, 1600; H NMR (300 MHz, C
dd, J ) 5.3, 1.6 Hz, 1 H), 6.09 (dd, J ) 5.3, 2.3 Hz, 1 H), 5.74-
.73 (m, 1 H), 4.04 (d, J ) 2.6 Hz, 1 H), 3.76 (d, J ) 2.6 Hz, 1
H), 3.30-3.06 (series of m, 3 H), 3.30 (s, 3 H), 3.02 (s, 3 H),
6 6
D ) δ 6.11
2
2
1
.66-2.56 (m, 1 H), 2.37 (dd, J ) 13.0, 8.9 Hz, 1 H), 2.18-
.08 (m, 1 H), 1.98 (dd, J ) 13.0, 6.9 Hz, 1 H), 1.65-1.51 (m,
H), 1.43 (s, 3 H), 1.17 (d, J ) 6.5 Hz, 3 H), 1.11 (s, 3 H), 1.09
-
1
1
mg (79%) of 49: IR (neat, cm ) 3646-3131, 1461, 1375; H
1
3
(s, 3 H) (OH not observed); C NMR (75 MHz, C
6
D
6
) δ168.2,
46.1, 145.8, 140.6, 129.2, 95.8, 82.5, 81.0, 60.1, 57.7, 54.0, 51.8,
9.2, 49.1, 43.8, 43.4, 29.6, 22.5, 22.4, 20.4, 18.1; HRMS m/z
NMR (300 MHz, C ) δ 5.49 (d, J ) 5.6 Hz, 1 H), 5.25 (d, J
6 6
D
1
4
) 5.6 Hz, 1 H), 3.48 (dd, J ) 10.8, 3.5 Hz, 1 H), 3.29 (s, 3 H),
2.96 (dd, J ) 9.3, 6.0 Hz, 1 H), 2.58-2.47 (m, 2 H), 2.42-2.30
(m, 1 H), 2.16-2.02 (m, 1 H), 1.70-1.57 (m, 3 H), 1.55-1.40
(m, 2 H), 1.28 (dd, J ) 13.1, 8.2 Hz, 1 H), 1.20 (d, J ) 6.4 Hz,
3 H), 1.17 (s, 3 H), 1.084 (s, 3 H), 1.075 (s, 3 H), 0.95 (s, 3 H);
+
(
M ) calcd 318.2194, obsd 318.2188.
3a S*,5a S*,6a S*,7S*,8R*,9a S*,9b R*,9cR*)-3,3a ,5a ,6,-
a ,7,8,9,9a ,9c-Deca h yd r o-5,7-d im eth oxy-3,3,5a ,8,9c-p en -
(
6
1
3
t a m et h yl-9b H -cyclop en t [a ]-a s-in d a cen -9b -ol (47) a n d
3a S*,5a R*,6a S*,7S*,8R*,9a S*,9b R*,9cR*)-3,3a ,4,5,5a ,6,-
3
C NMR (75 MHz, CDCl ) δ 140.5, 133.8, 96.7, 83.6, 72.7, 57.8,
(
57.0, 53.4, 52.0, 49.6, 48.1, 47.5, 42.8, 40.4, 34.3, 32.5, 30.1,
26.4, 25.1, 24.4, 17.4; HRMS m/z (M ) calcd 334.2508, obsd
+
6
5
a ,7,8,9,9a ,9c-Dod eca h yd r o-9b-h yd r oxy-7-m eth oxy-3,3,-
a ,8,9c-p e n t a m e t h yl-9b H -cyclop e n t [a ]-a s-in d a ce n -5-
334.2530.
on e (48). A solution of potassium tert-butoxide (200 mg, 1.78
mmol) and 18-crown-6 (499 mg, 1.89 mmol) dissolved in 20
mL of dry THF at 0 °C was treated with a solution of 44 (120
mg, 0.36 mmol) in dry THF (5 mL), and the mixture was
stirred at 0 °C for 1 h. Methyl iodide (10.0 mL, 159 mmol)
was added to the yellow solution, and the resulting mixture
was stirred at 0 °C for 1 h and at room temperature for 1 h
prior to being quenched with water. The mixture was extracted
with ether, and the combined organic phases were washed with
brine, dried, and concentrated. The dark yellow oil was purified
by flash chromatography on silica gel (elution with 1% tri-
ethylamine in petroleum ether) to give 47 (80 mg, 64%) and
(3a S*,5R*,5a R*,6a S*,7S*,8R*,9a S*,9bR*,9cR*)-3,3a ,4,5,-
5a ,6,6a ,7,8,9,9a ,9c-Dod eca h yd r o-5-a cet oxy-7-m et h oxy-
3,3,5a ,8,9c-p en t a m et h yl-9b H -cyclop en t [a ]-a s-in d a cen -
9b-ol (50). Diol 49 (37 mg, 0.12 mmol) was dissolved in 1.5
mL of CH Cl and treated with 0.2 mL of triethylamine and
2 2
0.2 mL of acetic anhydride followed by 10 mg of DMAP. The
reaction mixture was stirred for 5 min, diluted with water,
and extracted with CH
washed with 10% HCl and saturated NaHCO
2
Cl
2
. The combined organic phases were
solution, dried,
3
and concentrated. The crude material was purified by flash
chromatography on silica gel (elution with 5% ethyl acetate
in hexanes) to give 38 mg (88%) of 50 as a colorless oil: IR
(neat, cm ) 3552, 3535, 1727, 1625; 1H NMR (300 MHz,
-
1
4
8 (41 mg, 34%).
For 47: white solid: mp 80-83 °C; IR (neat, cm-1) 3640-
3
CDCl ) δ 5.53 (d, J ) 5.6 Hz, 1 H), 5.52 (d, J ) 5.6 Hz, 1 H),
1
3
)
1
300 (br), 1670, 1460; H NMR (300 MHz, C
5.7 Hz, 1 H), 5.15 (d, J ) 5.7 Hz, 1 H), 4.26 (d, J ) 4.4 Hz,
H), 3.27 (s, 3 H), 3.25 (s, 3 H), 2.88 (dd, J ) 9.5, 7.1 Hz, 1
6
D
6
) δ 5.69 (d, J
4.81 (dd, J ) 7.9, 2.7 Hz, 1 H), 3.36 (s, 3 H), 3.03, (dd, J ) 9.3,
5.9 Hz, 1 H), 2.67 (q, J ) 10.0 Hz, 1 H), 2.31-2.18 (m, 2 H),
2.06 (s, 3 H), 1.92-1.31 (series of m, 8 H), 1.21 (s, 3 H), 1.13
(s, 3 H), 1.10 (s, 3 H), 1.06 (d, J ) 6.4 Hz, 1 H), 1.04 (s, 3 H);
H), 2.73 (dd, J ) 12.1, 9.3 Hz, 1 H), 2.68 (dd, J ) 12.0, 7.9 Hz,
H), 2.33-2.19 (m, 1 H), 2.15 (d, J ) 4.4 Hz, 1 H), 2.15-2.06
m, 1 H), 1.54 (t, J ) 9.6 Hz, 1 H), 1.51 (dd, J ) 10.7, 10.7 Hz,
H), 1.25 (s, 3 H), 1.20 (s, 3 H), 1.18 (s, 3 H), 1.17 (d, J ) 6.0
Hz, 3 H), 1.20-1.16 (s, 1 H), 0.98 (s, 3 H) (OH not observed);
1
3
1
(
1
3
C NMR (75 MHz, CDCl ) δ 170.4, 142.1, 132.8, 96.7, 83.1,
75.7, 58.0, 57.3, 51.0, 50.8, 49.5, 48.3, 47.3, 42.4, 41.0, 34.9,
32.4, 26.2, 26.0, 25.3, 24.4, 21.3, 17.4; HRMS m/z (M ) calcd
+
376.2614, obsd 376.2661.
1
3
C NMR (75 MHz, C
6
D
6
) δ 156.8, 137.2, 135.1, 95.7, 95.1, 82.8,
(3a S*,5R*,5a R*,6a S*,7S*,8R*,9a S*,9bR*,9cR*)-3,3a ,4,5,-
5a ,6,6a ,7,8,9,9a ,9c-Dod eca h yd r o-7-m et h oxy-3,3,5a ,8,9c-
p en ta m eth yl-9bH-cyclop en t[a ]-a s-in d a cen e-5,9b-d iol 5-
Meth a n esu lfon a te (51). A solution of 49 (16.6 mg, 0.050
5
3
7.8, 55.1, 54.5, 54.2, 53.4, 50.1, 49.6, 46.5, 43.9, 42.1, 33.2,
1.3, 27.6, 26.1, 20.7, 17.8; HRMS m/z (M ) calcd 346.2508,
+
obsd 346.2515.
Anal. Calcd for C22
H, 9.89.
H
34
O
3
: C, 76.26; H, 9.89. Found: C, 76.03;
2 2
mmol) in dry CH Cl (1 mL) at 0 °C was treated with
triethylamine (0.14 mL, 1.00 mmol) and methanesulfonyl
chloride (0.04 mL, 0.52 mmol), and the resulting mixture was
stirred at 0 °C for 15 min and room temperature for 30 min,
quenched with brine, and extracted with ether. The combined
organic phases were dried and concentrated to leave an oil
that was purified by flash chromatography on silica gel (elution
with 4:1 petroleum ether-ethyl acetate) to give 51 (16 mg,
For 48: faint yellow solid: mp 115-116 °C; IR (neat, cm-1)
1
3
593-3417 (br), 1704, 1456; H NMR (300 MHz, C
6
D
6
, 77 °C)
δ 5.30 (d, J ) 5.8 Hz, 1 H), 5.26 (d, J ) 5.7 Hz, 1 H), 3.18 (s,
H), 2.92 (dd, J ) 9.3, 6.3 Hz, 1 H), 2.67 (dd, J ) 13.6, 7.1
Hz, 1 H), 2.57-2.45 (m, 1 H), 2.48 (dd, J ) 13.7, 9.7 Hz, 1 H),
3
2
1
1
1
.24-2.10 (m, 1 H), 2.17 (dd, J ) 13.7, 8.6 Hz, 1 H), 2.02-
.88 (m, 1 H), 1.78 (dd, J ) 8.6, 7.1 Hz, 1 H), 1.66 (dd, J )
3.7, 6.5 Hz, 1 H), 1.57 (ddd, J ) 12.7, 12.4, 10.4 Hz, 1 H),
.53-1.42 (m, 1 H), 1.30 (s, 1 H), 1.26 (s, 3 H), 1.11 (d, J ) 6.3
-
1
1
79%): IR (neat, cm ) 3446-3390, 1459, 1332; H NMR (300
MHz, C
6
6
D ) δ 5.38 (d, J ) 5.6 Hz, 1 H), 5.25 (d, J ) 5.6 Hz, 1
H), 4.73 (dd, J ) 10.2, 3.6 Hz, 1 H), 3.24 (s, 3 H), 2.94 (dd, J
) 9.3, 5.7 Hz, 1 H), 2.47 (dd, J ) 12.4, 8.9 Hz, 1 H), 2.43-2.33
1
3
Hz, 3 H), 0.98 (s, 3 H), 0.95 (s, 3 H), 0.89 (s, 3 H); C NMR

3
254 J . Org. Chem., Vol. 64, No. 9, 1999
Paquette et al.
(
5
(
1
m, 2 H), 2.29 (s, 3 H), 2.12-2.00 (m, 1 H), 1.93 (ddd, J ) 13.9,
.4, 3.6 Hz, 1 H), 1.84-1.74 (m, 1 H), 1.69-1.64 (m, 1 H), 1.58
dd, J ) 12.7, 2.5 Hz, 1 H), 1.52-1.36 (m, 2 H), 1.27 (s, 1 H),
.18 (s, 3 H), 1.16 (d, J ) 6.4 Hz, 3 H), 1.09 (s, 3 H), 1.05 (s, 3
Hz, 1 H), 1.62 (s, 3 H), 1.28 (s, 3 H), 1.23 (s, 3 H), 1.15 (d, J )
1
3
6.6 Hz, 3 H), 1.12-1.06 (m, 1 H), 1.02 (s, 3 H); C NMR (75
6 6
MHz, C D ) δ 221.4, 142.3, 135.3, 133.9, 125.6, 92.6, 64.5, 62.9,
59.0, 50.6, 48.3, 43.0, 40.2, 35.2, 31.2, 30.4, 28.2, 26.2, 24.4,
1
3
+
H), 1.01 (s, 3 H); C NMR (75 MHz, C
8
3
ion too fleeting for accurate mass measurement.
2S*,3R*,3a R*,5Z,7a R*,10a S*,11a R*)-1,2,3,3a ,4,7,7a ,8,-
1
1
of 51 (41.8 mg, 0.101 mmol) in 3 mL of dry tert-butyl alcohol
at 40 °C was treated with potassium tert-butoxide (38.7 mg,
0
for 20 min. The reaction mixture was partitioned between
ether (100 mL) and brine (10 mL), and the organic layer was
dried, filtered, and concentrated. The residue was purified by
flash chromatography on silica gel (elution with 19:1 petroleum
ether-ethyl acetate) to give 27.0 mg (84%) of 52 as a colorless
6 6
oil: IR (neat, cm ) 1686, 1458, 1373; H NMR (300 MHz, C D )
δ 5.54 (d, J ) 5.6 Hz, 1 H), 5.09 (d, J ) 5.6 Hz, 1 H), 5.07 (dd,
J ) 12.4, 4.4 Hz, 1 H), 3.62 (dd, J ) 9.4, 8.7 Hz, 1 H), 3.31 (s,
6
D
6
) δ 140.9, 133.7, 96.8,
4.1, 83.7, 57.8, 57.1, 52.0, 49.8, 48.2, 47.8, 43.2, 41.8, 38.1,
4.6, 32.5, 30.8, 28.8, 26.2, 25.0, 24.6, 17.7; HRMS molecular
23.4, 19.3; HRMS m/z (M ) calcd 316.2402, obsd 316.2403.
Anal. Calcd for C H O : C, 79.70; H, 10.19. Found C, 79.56;
2
1
32
2
H, 10.33.
(
Ack n ow led gm en t. This research was supported by
the National Cancer Institute (Grant CA 12115). The
authors thank Prof. Robin Rogers (The University of
Alabama) for the crystallographic analysis of 42, Dr.
Kurt Loening for assistance with nomenclature, and Dr.
Darryl Cleary for some preliminary studies.
0a ,11a -Deca h yd r o-3-m eth oxy-2,5,8,8,10a -p en ta m eth yl-
1H-d icyclop en ta [a ,d ]cyclon on en -11-on e (52). A solution
.345 mmol) and the resulting solution was stirred at 40 °C
Su p p or tin g In for m a tion Ava ila ble: Tables giving the
crystal data and structure refinement information, bond
lengths and bond angles, atomic and hydrogen coordinates,
and isotropic and anisotropic displacement coordinates for 42,
-1
1
1
together with high-field H NMR spectra of those compounds
lacking combustion analysis. This material is available free
of charge via the Internet at http://pubs.acs.org.
3
1
1
H), 3.18 (ddd, J ) 9.1, 9.0, 4.7 Hz, 1 H), 2.68 (t, J ) 12.4 Hz,
H), 2.53-2.28 (m, 2 H), 1.98 (dd, J ) 12.9, 4.5 Hz, 1 H),
.98-1.84 (m, 1 H), 1.79-1.74 (m, 2 H), 1.70 (dd, J ) 8.9, 4.8
J O9825254