First synthesis of cytotoxic 8,9-secokaurene diterpenoids. An enantioselective route to (-)-O-methylshikoccin and (+)- O-methylepoxyshikoccin

Article abstract of DOI:10.1021/ja971527n

A practical route for the total synthesis of 8,9-secokaurene diterpenes is described. The central step is the 3.3]sigmatropic rearrangement of spirocyclic intermediates such as 35, 40, and 41. All three compounds must necessarily respond identically to pr

Full text of DOI:10.1021/ja971527n

9662
J. Am. Chem. Soc. 1997, 119, 9662-9671
First Synthesis of Cytotoxic 8,9-Secokaurene Diterpenoids. An
Enantioselective Route to (-)-O-Methylshikoccin and
(+)-O-Methylepoxyshikoccin
Leo A. Paquette,* Dirk Backhaus, Ralf Braun, Ted L. Underiner, and Klaus Fuchs
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity,
Columbus, Ohio 43210
ReceiVed May 12, 1997X
Abstract: A practical route for the total synthesis of 8,9-secokaurene diterpenes is described. The central step is the
[3.3]sigmatropic rearrangement of spirocyclic intermediates such as 35, 40, and 41. All three compounds must
necessarily respond identically to properly install the absolute configuration of the bridgehead methine carbon. The
total synthesis of (-)-O-methylshikoccin (2b) was realized in 8% overall yield from the Wieland-Miescher ketone
9. Its naturally occurring epoxide 47 was prepared with comparable efficiency. The preparative route developed
herein should provide a general entry into this important class of diterpenoids.
Rabdolatifolin (1b),1 shikodomedin (1c),2 and O-meth-
directions. From one perspective, the four trigonal carbons in
ring C form a rather planar cyclopentenone platform to which
the remainder of the alicyclic framework is attached in a 1,3-
cyclophane arrangement. A strategy and supporting technology
must be developed for the enantiocontrolled construction of this
framework, with proper introduction of the bridgehead double
bond.9 Moreover, all of the oxygen-containing functional
groups must be capable of being correctly positioned without
the inducement of unwanted transannular bond formation.
In light of our previous finding that the bicyclo[7.2.1]-
dodecene 5, closely related in structural detail to the B/C
composite of 1-3, could be quickly elaborated by the thermal
[3.3]sigmatropic rearrangement of 4,10 we wished to explore
related, more advanced application of this process to the
synthesis of 2b and its epoxide. In so doing, we were unaware
at the outset that the need would develop to devise an expedient
alternative to the assembly of spirocyclic systems related to 4.
In fact, the total syntheses detailed herein11 proved to be a
particularly informative setting for evaluating the usefulness of
this new methodology.
ylshikoccin (2b)3 are the most well-known members of a
relatively small group of structurally unusual 8,9-seco-ent-
kaurenes. These Rabdosia metabolites, their close relatives such
as rabdoumbrosanin (1a),4 shikoccin (2a),5 rabdoshikoccin A
and B,6 and the corresponding epoxides 3 are reputed to exhibit
potent cytotoxicity against HeLa, KB, and FM 3A/B cells,
Ehrlich ascites and Walker intramuscular carcinomas, and P388
lymphocytic leukemia.7 This biological activity has been
attributed to the ability of 1-3 to act as Michael acceptors of
bionucleophiles. On this basis, the exo- and endocyclic double
bonds must both be responsive since both classes of compounds
are cytotoxic.8
Results
As crucial as the C-ring domain in these diterpenoids is to
their potentially useful biological activity, it is the structural
ensemble that poses interesting synthetic challenges from several
Studies Oriented toward Spirocycle Construction. Our
first generation solution to the construction of 4 took advantage
of sequential intramolecular Claisen rearrangement and allyl-
X Abstract published in AdVance ACS Abstracts, October 1, 1997.
(1) Takeda, Y.; Fujita, T.; Ueno, A. Phytochemistry 1983, 22, 2531.
(2) (a) Fujita, T.; Takeda, Y.; Shingu, T. Phytochemistry 1979, 18, 299.
(b) Fujita, T.; Takeda, Y.; Shingu, T.; Kido, M.; Taira, Z. J. Chem. Soc.,
Chem. Commun. 1982, 162.
(3) (a) Node, M.; Ito, N.; Fuji, K.; Fujita, E. Chem. Pharm. Bull. 1982,
30, 2639. (b) Node, M.; Ito, N.; Uchida, I.; Fujita, E.; Fuji, K. Chem. Pharm.
Bull. 1985, 33, 1029.
(7) (a) Nagao, Y.; Ito, N.; Kohno, T.; Kuroda, H.; Fujita, E. Chem.
Pharm. Bull. 1982, 30, 727. (b) Fuji, K.; Node, M.; Ito, N.; Fujita, E.;
Takada, S.; Unemi, N. Chem. Pharm. Bull. 1985, 33, 1038. (c) Fuji, K.;
Xu, H.-J.; Tatsumi, H.; Imahori, H.; Ito, N.; Node, M.; Inaba, M. Chem.
Pharm. Bull. 1991, 39, 685.
(8) Perry, N. B.; Burgess, E. J.; Tangney, R. S. Tetrahedron Lett. 1996,
37, 9387.
(4) Takeda, Y.; Ichihara, T.; Fujita, T.; Ueno, A. Chem. Pharm. Bull.
1989, 37, 1213.
(5) (a) Fujita, E.; Ito, N.; Uchida, I.; Fuji, K.; Taga, T.; Osaki, K. J.
Chem. Soc., Chem. Commun. 1979, 806. (b) Taga, T.; Osaki, K.; Ito, N.;
Fujita, E. Acta Cryst. 1982, B38, 2941.
(6) Takeda, Y.; Futatsuishi, Y.; Matsumoto, T.; Terada, H.; Otsuka, H.
Phytochemistry 1994, 35, 1289.
(9) For an overview of our past research involving the synthesis of natural
products endowed with bridgehead olefinic centers, consult Paquette, L.
A. Chem. Soc. ReV. 1995, 24, 9.
(10) (a) Paquette, L. A.; Ladouceur, G. J. Org. Chem. 1989, 54, 4278.
(b) Ladouceur, G.; Paquette, L. A. Synthesis 1992, 185.
(11) Preliminary communication: Paquette, L. A.; Backhaus, D.; Braun,
R. J. Am. Chem. Soc. 1996, 118, 11990.
S0002-7863(97)01527-8 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Cytotoxic 8,9-Secokaurene Diterpenoids
J. Am. Chem. Soc., Vol. 119, No. 41, 1997 9663
Scheme 1
Scheme 2
silane-carboxaldehyde cyclization steps. Although this protocol
proved to be very efficient and highly stereocontrolled, the
framework is insufficiently oxygenated for the present purposes.
An alternate plan, designed to incorporate an additional meth-
oxyl group as projected retrosynthetically in Scheme 1, begins
with the Wieland-Miescher ketone 9.12 Following functional
group manipulation, including buildup of the 1,3-dicarbonyl
system resident in 8, the needed spiroalkylation as in 7 should
set the stage for arrival at 6. When preliminary studies revealed
to us that the 8 f 7 transposition could not be accomplished as
before, a new approach that suitably melded the stereochemical
demands with the resident functionality was developed.
In practice, protection of the saturated carbonyl group in R-9
(g98% ee) was achieved readily by either the transketalization
method of Pietrasantra13 or the direct ketalization tactic reported
by Kametani.14 Subsequent Woodward methylation15,16 pro-
vided 10 efficiently (Scheme 2). Reduction of 10 with
L-Selectride proceeded with high stereoselectivity (>95:5) to
deliver the â-alcohol 11. Protection of this hydroxyl group is
necessary to facilitate the allylic oxidation programmed to
follow. Formation of the trimethylsilyl ether in advance of
exposure to the chromium trioxide/3,5-dimethylpyrazole com-
plex17 is adequate to allow progression to 12 in 66% overall
yield. Subsequent dissolving metal reduction of 12 resulted in
clean establishment of the trans ring fusion. Most often, the
basic conditions that develop during the lithium-liquid ammonia
procedure were adequate to induce â-elimination with opening
of the ketal ring as in 13. Occasionally, a modest amount of
14 could be isolated simultaneously. This feature was incon-
sequential since treatment of either 13 or 14 with excess sodium
hydride and p-methoxybenzyl chloride afforded doubly protected
13. Direct acidic hydrolysis of this intermediate provided 15,
which was destined to serve as a key intermediate en route to
the shikoccins.
Scheme 3
two reactants and thiophenol results in interception by the sulfur
nucleophile to give a polyfunctional adduct.19 Especially
noteworthy is the fact that the phenylthio substituent resides at
a position ideally suited to subsequent introduction of the
cyclopentene double bond via sulfoxide thermolysis.
Application of this procedure to 15, bifunctional aldehyde
16,20 and thiophenol in the presence of silica gel did indeed
give rise to adduct 17 (Scheme 3). Submission of 17 to the
hydrolysis-cyclization conditions earlier found to be highly
successful for achieving the desired ring closure in many
analogues led instead to the generation of the diastereomeric
acetals 18 and 19. The structural assignments to these products
were confirmed by a combination of NMR experiments. Thus,
an LR-COSY 90 study revealed the singlets at δ 0.94 and 0.97
Conventional Knoevenagel reactions involving cyclic 1,3-
diketones and aliphatic aldehydes cannot be arrested at the
monoaddition level because of very rapid second-stage 1,4-
addition of the enolate anion with formation of bis-adducts.18
In order to redirect the latter phases of this multistep condensa-
tion in a useful direction, we have previously demonstrated that
simple stirring of a three-component mixture consisting of the
(12) (a) Wieland, P.; Miescher, K. HelV. Chim. Acta 1950, 33, 2215. (b)
Li, Y.; Bahman, N.; Crabbe´, P. J. Chem. Soc., Perkin Trans. 1 1983, 2349.
(c) Harada, N.; Sugioka, T.; Uda, H.; Kuriki, T. Synthesis 1990, 53. (d)
Buchschacher, P.; Fu¨rst, A. Org. Syn., Coll. Vol. 7 1990, 368.
(13) Bauduin, G.; Pietrasanta, Y. Tetrahedron 1973, 29, 4225.
(14) Kametani, T.; Suzuki, K.; Nemoto, H. J. Org. Chem. 1980, 45, 2204.
(15) Woodward, R. B.; Patchett, A. A.; Barton, D. H. R.; Ives, D. A. J.;
Kelly, R. B. J. Am. Chem. Soc. 1954, 76, 2852.
(16) (a) Schmidt, C.; Kokosi, J. Synth. Commun. 1985, 15, 341. (b) Ciceri,
P.; Denmitz, F. W. J. Tetrahedron Lett. 1997, 38, 389.
(17) (a) Corey, E. J.; Fleet, G. W. J. Tetrahedron Lett. 1973, 4459. (b)
Wright, J.; Drtina, G. J.; Roberts, R. A.; Paquette, L. A. J. Am. Chem. Soc.
1988, 110, 5806.
(18) (a) Jones, G. Org. React. 1967, 15, 204. (b) Bolte, M. L.; Crow,
W. D.; Yoshida, S. Aust. J. Chem. 1982, 35, 1421. (c) Hobel, K.;
Margaretha, P. HelV. Chim. Acta 1989, 72, 975. (d) Nagarajan, K.; Shenoy,
S. J. Ind. J. Chem., Sect. B 1992, 31, 73.
(19) Fuchs, K.; Paquette, L. A. J. Org. Chem. 1994, 59, 528.
(20) (a) Drauz, K.; Kleemann, A.; Samson, M. Chem. Ztg. 1984, 108,
391. (b) Kleemann, A.; Samson, M. Eur. Pat. Appl. EP 52,200, May 26,
1982; Chem. Abstr. 1982, 97, 163497j.

9664 J. Am. Chem. Soc., Vol. 119, No. 41, 1997
Paquette et al.
Scheme 4
Scheme 6
Scheme 5
rapidly than complete hydrolysis to the aldehyde. The latter
reaction course dominates when additional water is present; at
the 33% level, 23 is formed as the exclusive product. The minor
spirocycle was identified as the cis isomer 24 on the strength
of a significant NOE interaction between the two methine
protons shown. The conversion of 24 and 25 to 26 was most
efficiently performed by the method of Detty.23
Stereoselection during Spirocyclization. The success as-
sociated with the expedient generation of 26 led to two important
matters now requiring immediate attention. The first was the
replacement of the methoxy group by an alternative substituent
that could ultimately be smoothly deprotected to the free
hydroxy level. Of the several candidates that were carried
through careful exploratory studies, 2-(trimethylsilyl)ethoxy
emerged as the candidate of choice. Additionally, for the
proposed approach to be successful, it was imperative that the
spirocyclization be accomplished in a highly stereoselective
manner since, as will be demonstrated below, the configuration
of the stereogenic center generated in the ten-membered ring
during oxy-Cope rearrangement depends entirely on the con-
figuration of the spirocyclic carbon.
to belong to the angular methyl groups in the major (18) and
minor acetals (19), respectively. This information was then
utilized in a 7.5 Hz-tuned semiselective DEPT 45 experiment
that established the proximity of these methyl substituents to
3
the carbonyl functionality via JC-H coupling. On this basis,
isomeric structures in which the more sterically congested
carbonyl group had been incorporated into the heterocyclic
network could be ruled out. The two mechanistic options
outlined in Scheme 4 account concisely for this phenomenon.
While we have not distinguished between them, it is clear that
the â-dicarbonyl part structure plays a key role.
Alternate conditions had to be found for effecting the critical
spirocyclization. Concomitantly, the discovery was made that
the temperatures required for bringing about sulfoxide elimina-
tion in model systems were unduly destructive. Because
selenoxides are lost with much greater ease than sulfoxides, the
substitution of PhSeH for PhSH was implemented as well. Not
surprisingly, dimedone (20) reacted rapidly with aldehyde 2121
and phenylselenol in the presence of silica gel to deliver 22 in
good yield (Scheme 5). When diketone 22 was subjected to
the action of lithium tetrafluoroborate in acetonitrile containing
2% water,22 ionization of the dimethyl acetal was effected, and
intramolecular cyclization to give 24 and 25 occurred more
Acetal exchange involving 27 and 2-(trimethylsilyl)ethanol
proceeded efficiently under acidic conditions. Arrival at alde-
hyde 28 was accomplished by controlled reduction of the nitrile
functionality with Dibal-H (Scheme 6). Following the standard-
(21) Prepared by Dibal-H reduction of 27, the product of SN2 displace-
ment by cyanide ion on â-bromoacetaldehyde dimethylacetal.
(22) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982, 12, 267.
(23) Detty, M. R. J. Org. Chem. 1980, 45, 274.

Synthesis of Cytotoxic 8,9-Secokaurene Diterpenoids
J. Am. Chem. Soc., Vol. 119, No. 41, 1997 9665
ized conditions developed earlier, diketone 15 underwent smooth
condensation with aldehyde 28 in the presence of phenylselenol
to make alkylated diketone 29 available. Without purification,
this diastereomeric mixture was cyclized in the presence of
lithium tetrafluoroborate as before and immediately subjected
to selenoxide elimination. The applied conditions led to the
isolation of 30 in 51% overall yield as a 1:1 mixture of epimers.
Although chromatographic separation was not feasible at this
stage, proof that the two products differed in stereochemistry
uniquely at the site of the protected hydroxyl was ultimately
derived from subsequent chemical interconversions and an X-ray
crystallographic analysis of 34.
We see therefore that intramolecular aldolization in this
conformationally restricted trans-decalindione carboxaldehyde
exhibits a marked preference for carbon-carbon bond formation
on the equatorial π-surface of the intermediate enol. While we
are unaware of other closely parallel aldol analogies, previous
studies of Claisen rearrangements,24 cationic 3-aza-Cope reac-
tions,25 and [2.3]sigmatropic isomerizations26 all have been
shown to evince a similar preference for bonding to the
equatorial face of cyclohexane systems. Consequently, the
generation of 30 which necessarily must also pass through a
cyclic transition state can be regarded as precedented. Evidently
the groups on the carbons resident on the cyclic assembly
involved in the bond-forming process can lead to marked
energetic differences in the available diastereomeric transition
states, with ring closure from the equatorial direction represent-
ing that of minimal enthalpic cost.
With 30 in hand, attention was next directed to the consider-
able difference in steric shielding surrounding its two carbonyl
groups. The anticipation was that Dibal-H would attack the
“front” carbonyl chemoselectively and skirt approach to the
doubly neopentylic “rear” alternative. Indeed, the three alcohols
31-33 were formed, and these could be conveniently obtained
in individually pure condition only when the 2-(trimethylsilyl)-
ethyl protecting group was in place. In that diastereomer of 30
in which the C-ring oxygen is projected â and toward the site
of reduction, steric approach control operates with delivery of
hydride from below as seen in 31. In contrast, the R-diastere-
omer gives rise to both 32 and 33.
This triad of aldols proved to be fascinatingly distinctive in
certain chemical properties. Thus, while 31 is surprisingly
resistant to epimerization, 32 and 33 are slowly interconverted
in methanol containing potassium carbonate. For this reason,
no accurate assessment can be made of the stereoselectivity with
which their diketone precursor is reduced. This widely different
susceptibility to retroaldolization gains importance because of
the pending need to methylate these hydroxylic sites. Despite
the sensitivity of 32, it proved possible to effect its epimerization
to 33 under Mitsunobu conditions27 such that the net proportion
of 31 and 33 ultimately approximated 1:1. In order to
accomplish this epimerization effectively, saponification of the
p-nitrobenzoate intermediate had to be carefully controlled.
Oxy-Cope Rearrangement and Arrival at O-Methylshikoc-
cin. The kinetic instability of 33 under strongly basic conditions
required that conversion to the O-methyl derivative 34 be
effected with silver(I) oxide and methyl iodide in the presence
of calcium sulfate.28 The highly crystalline nature of 34 proved
Figure 1. Crystallographically determined molecular structure of 34
as drawn with 50% thermal ellipsoids.
conducive to X-ray diffraction analysis. As seen in Figure 1,
this study confirmed the absolute configurational assignments
made above. Addition of vinylmagnesium bromide to 34
proceeded from that direction opposite to the methoxy substitu-
ent (NOE analysis). When attempts to induce diene 35 into
anionically accelerated oxy-Cope rearrangement resulted in
decomposition, recourse was made instead to purely thermal
conditions. Of the solvents examined, DMF proved to be the
most effective solvent of those examined. When 35 was heated
at 230-240 °C for 19 h in DMF, only one cyclodecenone was
formed. This compound was inferred to be 36a as a result of
consideration of transition states, a conclusion later confirmed
by a successful synthesis. At this point, cesium fluoride was
introduced, and the reaction mixture brought back to 210 °C (6
h) in order to effect hydroxyl deprotection directly. Subsequent
oxidation of 36b so obtained with the Dess-Martin periodinane
reagent29 led to diketone 37. Extensive COSY and NOE studies
on 37 served to corroborate the three-dimensional structural
features of this advanced intermediate (Figure 2).
The mechanistic details of the [3.3] sigmatropic shifts
associated the 35 f 36a, 40 f 42, and 41 f 43a transforma-
tions (the latter two to be discussed below) hold particular
relevance (Scheme 8). When the double bonds involved are
arranged trans as in 35, only in the chair-boat-chair arrange-
ment is their proximity realized. Conformation B reveals that
these sites of unsaturation are too distal to permit necessary
interaction. Accordingly, the expectation is that A will evolve
into the (Z)-configured enol C and subsequently to ketone D.
In those examples in which an R-vinyl substituent is present,
rearrangement is likely to proceed via both E and F. In
accordance with these transition state models, the chair-chair-
chair arrangement E would give rise to the (E)-enol G, whereas
adoption of the higher energy chair-boat-boat construct F
would lead directly to the (Z)-enol H. Tautomerism in F and
H results in convergence to I. The important issue here is that
the absolute configuration of the newly formed bridgehead
carbon in D and I (note arrows) is uniquely dependent on the
configuration of the spirocyclic carbon. Stated differently, 35,
40, and 41 must respond identically in installing this key element
(24) House, H. O.; Lubinkowski, J.; Good, J. J. J. Org. Chem. 1975, 40,
86.
(25) Gilbert, J. C; Senaratne, K. P. A. Tetrahedron Lett. 1984, 25, 2303.
(26) (a) Evans, D. A.; Sims, C. L.; Andrews, G. C. J. Am. Chem. Soc.
1977, 99, 5453. (b) Mander, L. N.; Turner, J. V. Aust. J. Chem. 1980, 33,
1559.
(27) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(28) Martin, S. F.; Ru¨eger, H.; Williamson, S. A.; Grzejzczak, S. J. Am.
Chem. Soc. 1987, 109, 6124.
(29) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.

9666 J. Am. Chem. Soc., Vol. 119, No. 41, 1997
Paquette et al.
Scheme 7
Scheme 8
material was produced in this manner to allow linkup with
cyclodecenone 37.
Once Scheme 9 had been reduced to practice, attention was
turned to the preparation of O-methylshikoccin (2b). The highly
regioselective conversion of 37 into its exo-methylene derivative
began by conversion to silyl enol ether 44 (Scheme 10). No
tendency was seen under ordinary conditions for this cyclo-
pentadiene to undergo one or more [1.5] hydrogen shifts.
Condensation of 44 with Eschenmoser’s salt in DMF at 50 °C30
followed by conversion of the Mannich product to the methio-
dide in advance of Hoffmann elimination delivered 45 in a
satisfactory 66% overall yield. Deprotection31 /acetylation of
45 afforded high quality samples of natural (levorotatory)
O-methylshikoccin (2b), which was identical in all respects to
an authentic specimen provided by Professor Fujita.32
Synthesis of (+)-O-Methylepoxyshikoccin. The challenge
of introducing an oxiranyl oxygen into 2b was answered in a
straightforward manner. While repeating the three-step se-
quence associated with the conversion of 44 into 45, the Man-
nich base was purified by chromatography on silica gel. This
protocol had been utilized before. Presently, however, a quantity
of ether that had experienced a buildup in peroxide content was
inadvertently employed as eluant. Epoxidation took place
Figure 2. NOE interactions determined for 37.
of ent-secokaurene chirality, irrespectiVe of the transition state
adopted.
In this light, the efficiency of the overall conversion to 37
would be reinforced significantly if its elaboration from 31 could
also be implemented. These studies, detailed in Scheme 9, drew
in large part on the earlier successes. Interestingly, vinylmag-
nesium bromide underwent 1,2-addition to 31 exclusively from
the R-face, thus making possible direct experimental assessment
of the postulate advanced in Scheme 8. The necessary inversion
of alcohol stereochemistry, best deferred until after the vinylation
step, was most effectively accomplished by oxidation of 38 to
ketone 39 with subsequent hydride reduction. Regiocontrolled
O-methylation of diol 41 was brought about with sodium hydride
and methyl iodide under conditions of proper stoichiometric
control.
The synthesis of 43b was easily completed from two
directions. The oxy-Cope rearrangements of 40 and 41 were
accomplished with comparably modest efficiency, although 40
was unquestionably the more reactive compound. With arrival
at 43a, unmasking of the hydroxyl group was undertaken as
before. Perhaps because steric crowding is not now extant,
elimination of the exo-oriented trimethylsilylethyl group was
accomplished only in an unoptimized yield of 22%. Sufficient
(30) (a) Holy, N.; Fowler, R.; Burnett, E.; Lorenz, R. Tetrahedron 1979,
35, 613. (b) Caputo, R.; Ferreri, C.; Mastroianni, D.; Palumbo, G.; Wenkert,
E. Synth. Commun. 1992, 22, 2305.
(31) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.
(32) In the original report,3b the signals due to H-3 (δ 3.20) and OCH3
(δ 3.26) were erroneously claimed to appear at δ 3.34 and 3.18, respectively.
The spectra graciously provided by the Japanese group and our re-recording
of these data revealed the source of the confusion to be typographical.

Synthesis of Cytotoxic 8,9-Secokaurene Diterpenoids
J. Am. Chem. Soc., Vol. 119, No. 41, 1997 9667
Scheme 9
Scheme 11
also allows convenient access to the epoxy derivative 47. Much
has been learned about the chemical nature of secokaurene-
like structures and about polycyclic analogues en route to this
interesting diterpenoid framework.
Experimental Section34
(4aR,6S,8sR)-Hexahydro-6-[(p-methoxybenzyl)oxy]-5,5,8a-trim-
ethyl-1,3(2H,4H)-naphthalenedione (15). A solution of 13 (5.00 g,
18.6 mmol) in dry DMF (50 mL) was added to a suspension of sodium
hydride (1.34 g, 55.8 mmol) in the same solvent (30 mL), and the
mixture was stirred at 20 °C for 1 h, cooled to 0 °C, and treated with
p-methoxybenzyl chloride (7.6 mL, 55.8 mmol). After overnight
stirring, an additional 0.89 g (37.2 mmol) of sodium hydride and 5.1
mL (37.2 mmol) of p-methoxybenzyl chloride were introduced, and
stirring was continued for a total of 36 h. The reaction mixture was
hydrolyzed at 0 °C by the careful addition of water (10 mL) and
partitioned between ether (300 mL) and water (100 mL). The separated
aqueous phase was extracted with ether (3×), and the combined organic
layers were washed with brine, dried, and evaporated. The residue
was subjected to Kugelrohr distillation at 100 °C and 0.2 Torr to remove
unreacted p-methoxybenzyl chloride and the corresponding alcohol.
The nonvolatile portion was dissolved in THF (450 mL), refluxed with
1 N HCl (180 mL) for 18 h, cooled to 0 °C, and neutralized with
saturated NaHCO3 solution (220 mL). After the removal of THF on a
rotary evaporator, the aqueous solution was extracted with ethyl acetate
(5×) and CH2Cl2 (3×), and the combined organic phases were washed
with brine, dried, and concentrated. The white solid was triturated with
ether/hexanes (1:1), cooled to 0 °C, and filtered to give 3.05 g (48%)
of 15. The filtrate was evaporated and resubjected to Kugelrohr
distillation to remove residual volatiles. Crystallization of the residue
as above gave an additional 0.51 g (total of 56%) of 15 as colorless
crystals, mp 185 °C (from ethyl acetate): IR (CHCl3, cm-1) 1735, 1710,
1615; 1H NMR (300 MHz, CDCl3) δ 7.26-7.21 (m, 2 H), 6.89-6.84
(m, 2 H), 4.52 (d, J ) 11.2 Hz, 1 H), 4.27 (d, J ) 11.2 Hz, 1 H), 3.80
(s, 3 H), 3.43 (d, J ) 18.3 Hz, 1 H), 3.33 (d, J ) 18.3 Hz, 1 H), 3.15
(br s, 1 H), 2.55 (2d, J ) 9.3 Hz, 2 H), 2.16 (t, J ) 9.3 Hz, 1 H),
2.04-1.90 (m, 2 H), 1.82-1.71 (m, 1 H), 1.64-1.57 (m, 1 H), 1.17
(s, 3 H), 1.02 (s, 3 H), 0.98 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
208.2, 205.0, 159.1, 138.8, 129.2, 113.7, 81.9, 70.7, 55.3, 54.4, 47.1,
38.6, 38.5, 37.5, 27.9, 26.4, 22.1, 19.5, 17.4; FAB MS (M+ + H) calcd
Scheme 10
smoothly to deliver 46 ultimately two steps later (Scheme 11).
Evidently, the bridgehead double bond is sufficiently strained
to be more reactive than the tertiary nitrogen under these circum-
stances. Conversion of the PMB group in 46 into an acetate as
before delivered dextrorotatory 47. This material could not be
distinguished spectroscopically from the natural specimen.
The synthesis of 2b summarized herein was sufficiently
efficient that adequate quantities of advanced intermediates were
available for additional biosynthetic-like interconversions.33 The
overall yield of enantiopure O-methylshikoccin was approxi-
mately 8% when 31-33 were all brought forward. The route
345.5, obsd 345.5; [R]20 +67.8° (c 0.5, chloroform).
D
Anal. Calcd for C21H28O4: C, 72.23; H, 8.19. Found: C, 72.98;
H, 8.20.
(2S,4aR,6S,8aR)-2-[4,4-[2-(trimethylsilyl)ethoxy]-1-(phenylsele-
no)butyl]hexahydro-6-[(p-methoxybenzyl)oxy]-5,5,8a-trimethyl-1,3-
(2H,4H)-naphthalenedione (29). A solution of 27 (810 mg, 6.27
mmol) and 2-(trimethylsilyl)ethanol (3.0 g, 4 equiv) in toluene (20 mL)
was treated with 20 mg of p-toluenesulfonic acid and heated in a Dean-
Stark trap so that methanol could be removed by azeotropic distillation.
(34) For general experimental procedures, see: Wang, T.-Z.; Pinard, E.;
(33) Backhaus, D.; Paquette, L. A. Tetrahedron Lett. 1997, 38, 29.
Paquette, L. A. J. Am. Chem. Soc. 1996, 118, 1309.

9668 J. Am. Chem. Soc., Vol. 119, No. 41, 1997
Paquette et al.
As the toluene distilled off, it was replaced with fresh solvent. After
5 h, the reaction mixture was cooled, diluted with ether (100 mL), and
washed with saturated NaHCO3 solution and brine prior to drying and
solvent evaporation. The residual material was purified by flash
chromatography on silica gel (elution with 10% ether in petroleum
ether) to provide 1.66 g (88%) of the corresponding bis(trimethylsily)
1 H), 3.80 (s, 3 H), 3.52-3.29 (m, 2 H), 3.16 (m, 1 H), 2.71-2.50 (m,
4 H), 2.03-1.64 (m, 4 H), 1.03 (s, 6 H), 0.98 (s, 3 H), 0.88-0.78 (m,
2 H), -0.06 (s, 9 H); 13C NMR (75 MHz, CDCl3) (â-isomer) ppm
210.9, 109.8, 158.9, 133.6, 131.1, 129.0, 128.8, 113.6, 85.9, 81.3, 78.8,
70.3, 68.0, 55.1, 47.1, 38.5, 38.0, 36.2, 30.3, 27.6, 26.2, 22.0, 19.9,
17.8, 17.7, -1.5; MS m/z (M+) calcd 512.2957, obsd 512.2963.
Anal. Calcd for C30H44O5Si: C, 70.28; H, 8.64. Found: C, 70.19;
H, 8.69.
Hydride Reduction of 30. Dibal-H (4.14 mL of 1 M in hexanes,
4.14 mmol) was added dropwise at -10 °C to 752 mg (1.48 mmol) of
30 in 170 mL of THF. After 1.5 h of stirring at this temperature, the
excess reducing agent was destroyed by the careful addition of
methanol. After treatment with 10% citric acid and dilution with ether
(150 mL), the organic layer was separated and washed with water,
saturated NaHCO3 solution, and brine. After drying and solvent
evaporation, the residue was subjected to flash chromatography on silica
gel. Elution with 18% ethyl acetate in petroleum ether resulted in the
isolation of three pure diastereomers: 271 mg (36%) of 31, 101 mg
(14%) of 33, and 258 mg (35%) of 32.
1
acetal as a colorless oil: IR (neat, cm-1) 2249; H NMR (300 MHz,
CDCl3) δ 4.53 (t, J ) 5.2 Hz, 1 H), 3.71-3.63 (m, 2 H), 3.55-3.43
(m, 2 H), 2.26 (t, J ) 7.4 Hz, 2 H), 1.90 (td, J ) 7.4, 5.2 Hz, 2 H),
0.90 (t, J ) 8.2 Hz, 4 H), 0.00 (s, 18 H); 13C NMR (75 MHz, CDCl3)
ppm 119.4, 100.3, 64.2, 29.7, 18.2, 12.3, -1.5; MS m/z (M+) calcd
301.1893, obsd 301.1899.
A solution of this nitrile (21.7 g, 72 mmol) in CH2Cl2 (250 mL)
was cooled to -78 °C and treated dropwise with Dibal-H (86 mL of
1 M in hexanes, 86 mmol) within 30 min. The reaction mixture was
allowed to warm to room temperature during 6 h, diluted with CH2Cl2
(400 mL) and saturated sodium potassium tartrate solution (200 mL)
with ice bath cooling, and stirred overnight at 20 °C. The separated
organic layer was washed with water and, brine, dried, evaporated to
leave a residue that was diluted with CH2Cl2 and filtered through a
plug of silica gel. After concentration of the filtrate, purification was
realized by flash chromatography on silica gel. Elution with 10% ethyl
acetate in hexanes furnished 16.2 g (71%) of 28 as a colorless oil: IR
For 31: colorless oil; IR (CHCl3, cm-1) 3505, 1694; 1H NMR (300
MHz, CDCl3) δ 7.26-7.22 (m, 2 H), 6.87-6.82 (m, 2 H), 5.80-5.76
(m, 1 H), 5.71-5.68 (m, 1 H), 4.65 (dd, J ) 5.5, 1.7 Hz, 1 H), 4.53 (d,
J ) 11.6 Hz, 1 H), 4.28 (d, J ) 11.6 Hz, 1 H), 4.22 (m, 1 H), 4.08 (br
s, 1 H), 3.80 (s, 3 H), 3.68-3.62 (m, 1 H), 3.47-3.38 (m, 1 H), 3.03
(br s, 1 H), 2.71 (m, 1 H), 2.50 (dd, J ) 11.7, 4.0 Hz, 1 H), 2.40 (m,
1 H), 1.98-1.70 (m, 5 H), 1.50-1.44 (m, 1 H), 1.10 (s, 3 H), 1.02 (s,
3 H), 0.93 (s, 3 H), 0.96-0.90 (m, 2 H), -0.01 (s, 9 H); 13C NMR (75
MHz, CDCl3) ppm 214.6, 158.8, 131.5, 131.3, 131.0, 129.0, 113.4,
82.8, 81.9, 71.9, 70.5, 70.4, 66.5, 55.2, 48.5, 38.3, 37.8, 37.6, 28.2,
27.6, 25.8, 22.5, 20.1, 19.2, 18.6, -1.5; MS m/z (M+) calcd 514.3114,
1
(neat, cm-1) 1723; H NMR (300 MHz, C6D6) δ 9.39 (t, J ) 1.3 Hz,
1 H), 4.34 (t, J ) 5.3 Hz, 1 H), 3.67 (dt, J ) 8.7, 2.5 Hz, 2 H), 3.46
(dt, J ) 8.7, 7.5 Hz, 2 H), 2.13 (dt, J ) 7.0, 1.3 Hz, 2 H), 1.82 (dt, J
) 7.0, 5.3 Hz, 2 H), 0.91 (t, J ) 7.8 Hz, 4 H), 0.01 (s, 18 H); 13C
NMR (75 MHz, C6D6) ppm 200.3, 102.0, 33.1, 26.8, 18.4, -1.2; MS
m/z (M+) calcd 304.1890, obsd 304.1876.
Anal. Calcd for C14H32O3Si2: C, 55.21; H, 10.59. Found: C, 55.33;
H, 10.61.
obsd 514.3146; [R]21 +164.2° (c 0.92, chloroform).
D
Three-Step Conversion to (1S,4′aR,6′S,8′aR)-4′a,5′,6′,7′,8′,8′a-
Hexahydro-6′-[(p-methoxybenzyl)oxy]-5′,5′,8′a-trimethyl-5-[2-(tri-
methylsilyl)ethoxy]spiro[2-cyclopentene-1,2′(1′H)-naphthalene]-
1′,3′(4′H)-dione (30). A flame-dried flask was charged with 15 (300
mg, 0.87 mmol), powdered 4 Å molecular sieves (1.2 g), TLC grade
silica gel (3.0 g), CH2Cl2 (15 mL), and a solution of benzeneselenol in
CH2Cl2 (2.8 mL of 1.1 M, 3.0 mmol). The suspension was stirred at
room temperature as aldehyde 28 (2.4 mL of 0.41 M in CH2Cl2, 1.0
mmol) was added. After 2 h, the solvent was removed under reduced
pressure and the slightly yellow powder was placed atop a pad of silica
gel housed in a Buchner funnel. Fast elution with 10-50% ether in
hexanes (400 mL total) gave 29 in the more polar fractions. Solvent
evaporation from these combined fractions gave 650 mg (95%) of 29
as a yellow foam which was immediately carried on to the next step.
The above sample was dissolved in acetonitrile (27 mL) and 2%
aqueous acetonitrile (0.36 mL), cooled to -10 °C, and treated with a
solution of lithium tetrafluoroborate in acetonitrile (0.82 mL of 1 M).
The reaction mixture was warmed to 0 °C during 1.5 h and stirred at
20 °C for an additional 1.5 h, at which point it was diluted with ether
(100 mL) and hexanes (70 mL) and washed with saturated NaHCO3
solution, water (2×), and brine. After drying and solvent evaporation,
the crude material was rapidly purified by chromatography on silica
gel (elution with 15% ether in hexanes). There was obtained 409 mg
(74%) of a pale yellow foam that was directly oxidized.
A 381 mg (0.57 mmol) sample of the spiro compound was dissolved
in CH2Cl2 (15 mL), cooled to 0 °C, and treated sequentially with
pyridine (0.09 mL, 1.14 mmol), ethyl vinyl ether (1.63 mL, 30 equiv),
and 10% hydrogen peroxide (0.27 mL, 1.4 equiv). The reaction mixture
was stirred vigorously overnight at room temperature, diluted with CH2-
Cl2 (50 mL), washed with saturated NaHCO3 solution and brine, then
dried, and concentrated. Chromatography on silica gel (elution with
20% ether in hexanes) gave 212 mg (73%) of 30 as a colorless, oily
1:1 mixture of diastereomers: IR (CHCl3, cm-1) 1720, 1691; 1H NMR
(300 MHz, CDCl3) (â-isomer) δ 7.25-7.20 (m, 2 H), 6.84-6.81 (m,
2 H), 6.09-6.03 (m, 1 H), 5.45-5.43 (m, 1 H), 4.51 (d, J ) 11.9 Hz,
2 H), 4.31 (d, J ) 11.9 Hz, 2 H), 4.19 (dd, J ) 6.3, 5.3 Hz, 1 H), 3.77
(s, 3 H), 3.51-3.31 (m, 2 H), 3.09 (br s, 1 H), 2.87 (dd, J ) 13.3, 6.2
Hz, 1 H), 2.72 (dd, J ) 19.0, 6.2 Hz, 1 H), 2.69-2.47 (m, 3 H), 2.04-
1.63 (m, 4 H), 1.01 (s, 3 H), 0.97 (s, 3 H), 0.92 (s, 3 H), 0.89-0.82
(m, 2 H), -0.12 (s, 9 H); (R-isomer) δ 7.24-7.21 (m, 2 H), 6.87-
6.83 (m, 2 H), 6.12-6.08 (m, 1 H), 5.40-5.37 (m, 1 H), 4.55 (d, J )
11.4 Hz, 1 H), 4.34 (dd, J ) 6.6, 4.4 Hz, 1 H), 4.30 (d, J ) 11.4 Hz,
Anal. Calcd for C30H46O5Si: C, 70.00; H, 9.01. Found: C, 69.95;
H, 8.95.
For 32: colorless oil; IR (CHCl3, cm-1) 3570, 1703; 1H NMR (300
MHz, CDCl3) δ 7.24-7.20 (m, 2 H), 6.87-6.82 (m, 2 H), 6.08-6.05
(m, 1 H), 5.48-5.44 (m, 1 H), 4.51 (d, J ) 12.3 Hz, 1 H), 4.33 (d, J
) 12.3 Hz, 1 H), 4.27 (dd, J ) 5.4, 2.6 Hz, 1 H), 4.02 (dd, J ) 8.2,
7.6 Hz, 1 H), 3.80 (s, 3 H), 3.52-3.31 (m, 2 H), 3.01 (br s, 1 H),
2.53-2.45 (m, 3 H), 2.20 (m, 1 H), 1.85-1.56 (m, 6 H), 1.04 (s, 3 H),
1.01 (s, 3 H), 0.92 (s, 3 H), 0.88-0.78 (m, 2 H), -0.11 (s, 9 H); 13C
NMR (75 MHz, CDCl3) ppm 215.2, 158.9, 134.3, 131.3, 131.1, 129.1,
113.5, 81.4, 80.0, 72.5, 70.2, 68.4, 67.0, 55.2, 46.2, 40.1, 38.1, 36.5,
27.8, 27.0, 26.7, 21.8, 20.1, 19.8, 17.6, -1.5; MS m/z (M+) calcd
514.3114, obsd 514.3103; [R]22 -30.0° (c 1.02, chloroform).
D
Anal. Calcd for C30H46O5Si: C, 70.00; H, 9.01. Found: C, 69.80;
H, 8.94.
For 33: white crystals, mp 125 °C (from ether-petroleum ether);
1
IR (CHCl3, cm-1) 3610, 1702; H NMR (300 MHz, CDCl3) δ 7.25-
7.22 (m, 2 H), 6.86-6.83 (m, 2 H), 5.98-5.94 (m, 1 H), 5.79-5.76
(m, 1 H), 4.51 (d, J ) 11.8 Hz, 1 H), 4.28 (d, J ) 11.8 Hz, 1 H), 4.06
(dd, J ) 6.7, 5.1 Hz, 1 H), 3.86 (t, J ) 6.7 Hz, 1 H), 3.79 (s, 3 H),
3.60-3.36 (m, 2 H), 3.03 (br s, 1 H), 2.70 (m, 1 H), 2.53 (m, 1 H),
2.19 (ddd, J ) 13.5, 7.1, 3.7 Hz, 1 H), 2.06 (dd, J ) 13.4, 3.6 Hz, 1
H), 1.85-1.51 (m, 6 H), 1.16 (s, 3 H), 1.01 (s, 3 H), 0.91 (s, 3 H),
0.93-0.83 (m, 2 H), -0.08 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm
214.5, 158.8, 133.1, 131.2, 131.0, 129.1, 113.4, 83.3, 81.8, 71.5, 70.4,
70.3, 67.3, 55.1, 47.2, 38.4, 38.2, 37.2, 28.2, 28.1, 27.3, 22.3, 20.1,
19.2, 17.8, -1.4; MS m/z (M+) calcd 514.3114, obsd 514.3115; [R]22
+13.5° (c 1.14, chloroform).
D
Anal. Calcd for C30H46O5Si: C, 70.00, H, 9.01. Found: C, 69.91;
H, 8.95.
Mitsunobu Inversion on 32. A solution of 32 (198 mg, 0.385
mmol) in benzene (10 mL) was treated successively with triph-
enylphosphine (202 mg, 0.77 mmol), p-nitrobenzoic acid (116 mg, 0.69
mmol), and diethyl azodicarboxylate (0.12 mL, 0.77 mmol). The
reaction mixture was stirred at room temperature for 4 h and transferred
directly to the top of a prepacked silica gel column. Following elution
with 20% ether in petroleum ether, the p-nitrobenzoate ester (254 mg)
was dissolved in 5:3 methanol/THF (10 mL), and a solution of
potassium carbonate (110 mg) in water (1 mL) was added. This mixture
was stirred for 2 h, diluted with ether (100 mL), and washed
successively with water (2×) and brine. After drying and solvent

Synthesis of Cytotoxic 8,9-Secokaurene Diterpenoids
J. Am. Chem. Soc., Vol. 119, No. 41, 1997 9669
evaporation, the residue was subjected to flash chromatography on silica
gel (elution with 18% ethyl acetate in petroleum ether) to give 145 mg
(74%) of 33 and return 22 mg (11%) of unreacted 32.
H), 1.03 (s, 3 H), 1.00 (s, 3 H), 0.96-0.88 (m, 2 H), 0.90 (s, 3 H),
-0.06 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm 216.9, 158.8, 142.9,
136.0, 131.6, 128.9, 113.5, 84.7, 80.8, 76.1, 69.4, 67.2, 55.9, 55.2, 54.0,
42.1, 39.4, 35.9, 35.2, 34.6, 31.0, 28.7, 28.2, 28.1, 23.5, 19.9, 18.3,
16.5, -1.5; MS m/z (M+) calcd 556.3583, obsd 556.3581; [R]22D +16.8°
(c 1.10, chloroform).
Anal. Calcd for C33H52O5Si: C, 71.18; H, 9.41. Found: C, 71.09;
H, 9.43.
(3S,4aR,6R,8R,10S,13aR)-1,2,3,4,4a,5,6,9,10,11,12,13a-Dodecahy-
dro-8-hydroxy-6-methoxy-3-[(p-methoxybenzyl)oxy]-4,4,13a-trim-
(1R,3′R,4′aR,5R,6′S,8′aR)-3′,4′,4′a,5′,6′,7′,8′,8′a-Octahydro-3′-
methoxy-6′-[(p-methoxybenzyl)oxy]-5′,5′,8′a-trimethyl-5-[2-(trimeth-
ylsilyl)ethoxy]spiro[2-cyclopentene-1,2′(1′H)-naphthalen]-1′-one (34).
A solution of 33 (255 mg, 0.495 mmol) in methyl iodide (4 mL) was
treated with silver oxide (230 mg, 0.99 mmol) and calcium sulfate (500
mg), stirred in the dark for 20 h, diluted with ether, and filtered through
a plug of Celite. The filtrate was concentrated in vacuo, and the residue
was purified by flash chromatography on silica gel. Elution with 15%
ether in petroleum ether afforded 34 (253 mg, 96%) as white crystals,
mp 119 °C (from ether-petroleum ether): IR (CHCl3, cm-1) 1702;
1H NMR (300 MHz, CDCl3) δ 7.25-7.22 (m, 2 H), 6.86-6.83 (m, 2
H), 5.85-5.77 (m, 2 H), 4.51 (d, J ) 11.8 Hz, 1 H), 4.28 (d, J ) 11.8
Hz, 1 H), 4.02 (dd, J ) 6.7, 4.8 Hz, 1 H), 3.80 (s, 3 H), 3.56-3.38 (m,
2 H), 3.33 (s, 3 H), 3.31 (m, 2 H), 2.71-2.62 (m, 1 H), 2.55-2.45 (m,
1H), 2.21-2.08 (m, 1 H), 2.07 (dd, J ) 12.9, 4.0 Hz, 1 H), 1.79-1.56
(m, 5 H), 1.13 (s, 3 H), 1.02 (s, 3 H), 0.92 (s, 3 H), 0.90-0.82 (m, 2
H), -0.08 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm 214.5, 158.8,
132.8, 131.3, 130.4, 129.1, 113.5, 83.2, 81.8, 80.9, 70.3, 69.8, 67.3,
57.3, 55.2, 47.2, 38.3 (2 C), 37.1, 28.2, 27.4, 23.4, 22.3, 20.1, 19.3,
17.8, -1.4; MS m/z (M+) calcd 528.3271, obsd 528.3255; [R]22D -10.7°
(c 1.33, chloroform).
ethyl-10,7-metheno-7H-benzocycloundecen-13(8H)-one (36b).
A
102 mg sample of 35 (0.18 mmol) in dry DMF (10 mL) was heated as
described above for 19 h at 230-240 °C. The sealed tube was cooled,
opened in order to allow cesium fluoride (10 equiv) to be introduced,
resealed, and heated at 210 °C for 6 h. Workup in the predescribed
manner afforded 60 mg (65% overall) of 36b as a colorless oil: IR
1
(CHCl3, cm-1) 3500, 1690, 1608, 1508, 1246, 1094; H NMR (300
MHz, CDCl3) δ 7.35-7.25 (m, 2 H), 6.91-6.85 (m, 2 H), 5.44 (s, 1
H), 4.66 (d, J ) 8.8 Hz, 1 H), 4.58 (d, J ) 11.4 Hz, 1 H), 4.31 (d, J
) 11.4 Hz, 1 H), 3.81 (s, 3 H), 3.75 (dd, J ) 11.8, 4.2 Hz, 1 H), 3.18
(s, 3 H), 3.14 (br s, 1 H), 3.10-2.90 (m, 2 H), 2.56 (dt, J ) 14.8, 8.9
Hz, 1 H), 2.55-2.25 (m, 3 H), 1.90-1.70 (m, 5 H), 1.40-1.10 (m, 4
H), 1.07 (s, 3 H), 1.01 (s, 3 H), 0.97 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 216.7, 158.7, 143.6, 136.4, 131.6, 128.6 (2 C), 113.5 (2
C), 82.6, 78.4, 76.0, 70.3, 56.0, 55.2, 53.8, 41.9, 39.1, 38.5, 36.3, 34.1,
31.1, 29.0, 27.0, 27.6, 22.1, 20.1, 16.7; MS m/z (M+) calcd 456.2876,
Anal. Calcd for C31H48O5Si: C,70.41; H, 9.15. Found: C, 70.46;
H, 9.17.
obsd 456.2884; [R]22 +41.5° (c 1.17, chloroform).
D
(1R,1′S,3′R,4′aR,5R,6′S,8′aR)-3′,4′,4′a,5′,6′,7′,8′,8′a-Octahydro-3′-
methoxy-6′-[(p-methoxybenzyl)oxy]-5′,5′,8′a-trimethyl-5-[2-(trimeth-
ylsilyl)ethoxy]-1′-vinylspiro[2-cyclopentene-1,2′(1′H)-naphthalen]-
1′-ol (35). A solution of 34 (172 mg, 0.325 mmol) in dry THF (2 mL)
was treated at 0 °C with vinylmagnesium bromide (10 mL of 0.55 M
in THF, 5.5 mmol), stirred at room temperature for 12 h, returned to
0 °C, and treated successively with isopropyl alcohol (1 mL) and
saturated NH4Cl solution (25 mL). After dilution with ether (100 mL),
the organic phase was separated, washed with saturated NaHCO3
solution and brine, dried, and evaporated. Purification of the residue
by flash chromatography on silica gel (elution with 10% ether in
petroleum ether) gave 173 mg (96%) of 35 as a colorless oil: IR
(CHCl3, cm-1) 3424; 1H NMR (300 MHz, CDCl3) δ 7.30-7.28 (m, 2
H), 6.89-6.85 (m, 2 H), 6.35 (dd, J ) 16.8, 10.8 Hz, 1 H), 6.19-6.17
(m, 1 H), 6.04-6.02 (m, 1 H), 5.38-5.28 (m, 2 H), 4.65 (s, 1 H), 4.53
(d, J ) 11.4 Hz, 2 H), 4.23 (d, J ) 11.4 Hz, 2 H), 3.82 (s, 3 H), 3.60
(d, J ) 4.1 Hz, 1 H), 3.41-3.17 (m, 3 H), 3.27 (s, 3 H), 3.01 (br s, 1
H), 2.50-2.43 (m, 1 H), 2.07 (dd, J ) 16.0, 2.0 Hz, 1 H), 1.83-1.70
(m, 5 H), 1.28 (s, 3 H), 0.97 (s, 3 H), 0.86 (s, 3 H), 0.80-0.76 (m, 2
H), -0.02 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm 158.8, 140.6,
133.4, 131.8, 130.8, 128.9, 114.5, 113.5, 89.1, 84.7, 82.6, 81.3, 69.9,
67.4, 66.7, 57.6, 55.2, 43.0, 40.1, 39.0, 38.1, 28.7, 26.5, 23.8, 22.2,
20.3, 18.4, 17.3, -1.5; MS m/z (M+ - TMSCH2CH2OH) calcd
Anal. Calcd for C28H40O5: C, 73.65; H, 8.83. Found: C, 73.76;
H, 8.83.
(3S,4aR,6R,10S,13aR)-1,2,3,4,4a,5,6,9,10,11,12,13a-Dodecahydro-
6-methoxy-3[(p-methoxybenzyl)oxy]-4,4,13a-trimethyl-10,7-metheno-
7H-benzocycloundecene-8,13-dione (37). A solution of 36b (41.1 mg,
9.0 × 10-5 mol) in CH2Cl2 (5 mL) was diluted with 1.8 mL of a 0.5
M solution of pyridine in CH2Cl2 and treated with the Dess-Martin
periodinane reagent (76 mg, 1.8 × 10-4 mol). The reaction mixture
was stirred for 1.5 h, diluted with ether (5 mL) and saturated NaHCO3
(1 mL) and Na2S2O3 solutions (1 mL), and poured into a 1:1 mixture
of ether and water. The separated aqueous phase was extracted with
ether (3×), and the combined organic layers were washed with brine,
dried, and evaporated. Purification of the residue by chromatography
on silica gel (elution with 30% ether in hexanes) provided 38.7 mg
(95%) of 37 as a colorless oil: IR (neat, cm-1) 1699, 1513, 1240, 1099;
1H NMR (300 MHz, CDCl3) δ 7.37-7.32 (m, 2 H), 7.23 (d, J ) 2.9
Hz, 1 H), 6.96-6.91 (m, 2 H), 4.56 (d, J ) 11.8 Hz, 1 H), 4.39 (d, J
) 11.8 Hz, 1 H), 4.13 (dd, J ) 11.7, 4.8 Hz, 1 H), 3.83 (s, 3 H),
3.26-3.20 (m, 1 H), 3.17 (s, 3 H), 3.12 (br s, 1 H), 2.58 (dd, J ) 18.7,
6.1 Hz, 1 H), 2.48 (dd, J ) 12.8, 3.7 Hz, 1 H), 2.44-2.33 (m, 1 H),
2.20 (td, J ) 12.8, 5.1 Hz, 1 H), 2.01 (d, J ) 18.7 Hz, 1 H), 1.95-
1.55 (m, 6 H), 1.12 (td, J ) 7.8, 1.4 Hz, 1 H), 1.12 (s, 3 H), 1.02-
0.90 (m, 1 H), 0.97 (s, 3 H), 0.95 (s, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 215.0, 207.9, 164.7, 158.9, 144.7, 131.6, 128.1 (2 C), 113.6 (2
C), 81.8, 73.1, 70.0, 56.4, 55.3, 53.3, 40.4, 39.1, 37.5, 36.7, 33.5, 30.0,
29.2, 27.2, 25.2, 22.6, 20.0, 16.7; MS m/z (M+) calcd 454.2719, obsd
438.2769, obsd 438.2762; [R]22 -34.6° (c 0.92, chloroform).
D
Anal. Calcd for C33H52O5Si: C, 71.18; H, 9.41. Found: C, 71.32;
H, 9.50.
(3S,4aR,6R,8R,10S,13aR)-1,2,3,4,4a,5,6,9,10,11,12,13a-Dodecahy-
dro-6-methoxy-3-[(p-methoxybenzyl)oxy]-4,4,13a-trimethyl-8-[2-
(trimethylsilyl)ethoxy]-10,7-metheno-7H-benzocycloundecen-13-
(8H)-one (36a). A solution of 35 (100 mg, 0.18 mmol) in dry DMF
(10 mL) was placed in a thick wall tube, deoxygenated by bubbling
N2 through for 5 min, sealed, and heated in a Woods metal bath at
230-240 °C for 16 h. After cooling, the reaction mixture was diluted
with water (20 mL) and ether (40 mL). The layers were separated,
the organic phase was washed twice with water, and the combined
aqueous solutions were extracted with ether (3×). The ethereal layers
were washed with brine, dried, and evaporated. The residue was
purified by chromatography on silica gel (elution with 15% ether in
hexanes) to give 87 mg (87%) of 36a as a colorless crystalline solid,
mp 130 °C (from ether-petroleum ether): IR (CHCl3, cm-1) 1687;
1H NMR (300 MHz, CDCl3) δ 7.31-7.27 (m, 2 H), 6.89-6.84 (m, 2
H), 5.43 (br s, 1 H), 4.55 (d, J ) 12.7 Hz, 1 H), 4.42 (d, J ) 12.7 Hz,
1 H), 4.25 (br d, J ) 8.4 Hz, 1 H), 3.81 (s, 3 H), 3.72 (dd, J ) 11.8,
4.0 Hz, 1 H), 3.60-3.39 (m, 2 H), 3.20 (s, 3 H), 3.14 (dd, J ) 17.3,
12.3 Hz, 1 H), 3.02 (br s, 1 H), 2.99-2.94 (m, 1 H), 2.55 (d, J ) 5.3
Hz, 1 H), 2.49-2.24 (m, 3 H), 1.86-1.64 (m, 4 H), 1.36-1.09 (m, 4
454.2719; [R]22 +4.5° (c 0.77, chloroform).
D
Anal. Calcd for C28H38O5: C, 73.98; H, 8.42. Found: C, 73.93;
H, 8.50.
(1R,1′R,3′S,4′aR,5S,6′S,8′aR)-3′,4′,4′a,5′,6′,7′,8′,8′a-Octahydro-6′-
[(p-methoxybenzyl)oxy]-5′,5′,8′a-trimethyl-5-[2-(trimethylsilyl)ethoxy]-
1′-vinylspiro[2-cyclopentene-1,2′(1′H)-naphthalene]-1′,3′-diol (38).
A solution of 31 (205 mg, 0.40 mmol) in dry THF (2 mL) was treated
at 0 °C with vinylmagnesium bromide (10 mL of 0.55 M in THF),
stirred at 20 °C for 12 h, cooled to 0 °C, and treated successively with
isopropyl alcohol and saturated NH4Cl solution. After dilution with
ether, the organic layer was separated, washed with saturated NaHCO3
solution and brine, dried, and evaporated. Purification of the residue
by flash chromatography on silica gel (elution with 10% ether in
petroleum ether) gave 38 (176 mg, 82%) as a colorless oil: IR (CHCl3,
cm-1) 3438; 1H NMR (300 MHz, CDCl3) δ 7.30-7.27 (m, 2 H), 6.89-
6.83 (m, 2 H), 5.78 (dd, J ) 17.0, 10.9 Hz, 1 H), 5.78-5.70 (m, 2 H),
5.42 (dd, J ) 17.0, 2.9 Hz, 1 H), 5.14 (dd, J ) 10.9, 2.9 Hz, 1 H),
5.10 (d, J ) 1.8 Hz, 1 H), 4.94 (s, 1 H), 4.58 (d, J ) 11.7 Hz, 1 H),
4.39 (dd, J ) 6.5, 1.7 Hz, 1 H), 4.28 (d, J ) 11.7 Hz, 1 H), 4.08 (m,

9670 J. Am. Chem. Soc., Vol. 119, No. 41, 1997
Paquette et al.
1 H), 3.80 (s, 3 H), 3.65-3.56 (m, 1 H), 3.46-3.37 (m, 1 H), 3.01 (br
s, 1 H), 2.51-2.41 (m, 2 H), 2.29-2.07 (m, 2 H), 1.84-1.60 (m, 5
H), 1.01 (s, 3 H), 0.99 (s, 3 H), 0.95-0.89 (m, 2 H), 0.87 (s, 3 H),
0.00 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm 158.7, 137.1, 133.6,
131.8, 130.6, 128.8, 116.3, 113.5, 84.3, 82.6, 81.0, 73.4, 70.2, 66.2,
63.3, 55.2, 42.5, 38.1, 37.8, 33.9, 28.6, 26.2, 25.6, 22.3, 20.2, 18.8,
H), 5.45 (dd, J ) 17.0, 2.7 Hz, 1 H), 5.24 (dd, J ) 10.7, 2.7 Hz, 1 H),
4.60 (d, J ) 12.0 Hz, 1 H), 4.29 (d, J ) 12.0 Hz, 1 H), 4.14 (t, J ) 8.1
Hz, 1 H), 3.89-3.79 (m, 1 H), 3.81 (s, 3 H), 3.60-3.53 (m, 1 H),
3.50-3.35 (m, 1 H), 3.34 (s, 3 H), 3.25 (s, 1 H), 2.97 (br s, 1 H),
2.45-2.15 (m, 4 H), 2.01 (m, 1 H), 1.90-1.60 (m, 3 H), 1.35-1.15
(m, 1 H), 1.03 (s, 3 H), 1.00 (s, 3 H), 1.00-0.85 (m, 2 H), 0.83 (s, 3
H), 0.02 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm 158.7, 140.1, 135.3,
132.5, 132.1, 131.7, 130.6, 129.1, 116.1, 113.4, 83.0, 82.3, 82.2, 79.1,
70.1, 66.2, 62.0, 42.5, 39.0, 38.0, 36.0, 28.8, 25.2, 23.6, 22.5, 20.0,
18.3, -1.5; MS m/z (M+ + H) calcd 543.3573, obsd 543.3529; [R]22
D
+87.0° (c 0.74, chloroform).
(1R,1′R,3′R,4′aR,6′S,8′aR)-3′,4′,4′a,5′,6′,7′,8′,8′a-Octahydro-6′-[(p-
methoxybenzyl)oxy]-5′,5′,5′a-trimethyl-5-[1-(trimethylsilyl)ethoxy]-
1′-vinylspiro[2-cyclopentene-1,2′(1′H)-naphthalene]-1′,3′-diol (40).
A solution of 38 (174 mg, 0.321 mmol) in CH2Cl2 (10 mL) was treated
successively with 1.3 mL of a 0.5 M solution of pyridine in CH2Cl2 (2
equiv) and 272 mg (0.642 mmol) of the Dess-Martin periodinane
reagent. The suspension was stirred for 2 h and diluted with ether (20
mL), saturated NaHCO3 solution (2 mL), and saturated Na2S2O3 solution
(2 mL). After several minutes of stirring, the reaction mixture became
a clear solution. Following the addition of more ether (100 mL), the
organic phase was separated, washed with water (2×) and brine, dried,
filtered through a pad of Celite, and evaporated. The resulting
yellowish, oily ketone 39 decomposed on attempted chromatographic
purification and was therefore reduced directly: IR (CHCl3, cm-1) 3434,
18.8, 17.7, -1.5; MS m/z (M+) calcd 556.3584, obsd 556.3583; [R]22
D
+15.4° (c 1.03, chloroform).
(3S,4aR,6R,8S,10S,13R)-1,2,3,4,4a,5,6,9,10,11,12,13a-Dodecahy-
dro-6-hydroxy-3-[(p-methoxybenzyl)oxy]-4,4,13a-trimethyl-8-[2-(tri-
methylsilyl)ethoxy]-10,7-metheno-7H-benzocycloundecen-13(8H)-
one (42). A solution of 40 (35.8 mg, 6.6 × 10-6 mol) in DMF (10
mL) was placed in a thick-walled Carius tube, deoxygenated by
bubbling N2 through for several minutes, sealed, and heated at 230 °C
in a Woods metal bath for 3 h. Workup in the predescribed manner
(elution with 40% ether in hexanes) returned 7.9 mg of unreacted 40
and furnished 15.2 mg (54% corrected) of 42, a colorless oil: IR (neat,
cm-1) 3431, 1695, 1513, 1248; 1H NMR (300 MHz, CDCl3) δ 7.32-
7.28 (m, 2 H), 6.90-6.85 (m, 2 H), 5.62 (d, J ) 1.5 Hz, 1 H), 4.60 (d,
J ) 11.2 Hz, 1 H), 4.50 (m, 1 H), 4.32 (d, J ) 11.2 Hz, 1 H), 4.17 (dd,
J ) 11.5, 4.5 Hz, 1 H), 3.81 (s, 3 H), 3.79-3.49 (m, 1 H), 3.29-3.25
(m, 1 H), 3.18 (m, 1 H), 3.07 (m, 1 H), 2.45-2.20 (m, 3 H), 1.95-
1.70 (m, 6 H), 1.30-1.10 (m, 3 H), 1.02 (s, 3 H), 1.00 (s, 3 H), 0.96
(s, 3 H), 1.00-0.80 (m, 3 H), -0.03 (s, 9 H); 13C NMR (75 MHz,
CDCl3) ppm 215.2, 158.9, 147.0, 136.7, 131.5, 128.4, 113.6, 87.9, 82.3,
70.2, 67.2, 66.5, 55.2, 53.5, 42.4, 39.1, 37.7, 36.8, 36.6, 31.8, 27.5,
22.3, 19.9, 18.6, 18.0, 16.7, -1.4; MS m/z (M+) calcd 542.3427, obsd
542.3439.
1
1702, 1612, 1513, 1250; H NMR (300 MHz, CDCl3) δ 7.31-7.28
(m, 2 H), 6.89-6.86 (m, 2 H), 5.93 (dd, J ) 16.8, 10.5 Hz, 1 H),
5.97-5.86 (m, 2 H), 5.59 (dd, J ) 16.8, 2.6 Hz, 1 H), 5.32 (dd, J )
2.9, 16.8 Hz, 1 H), 4.32 (s, 1 H), 4.62 (d, J ) 12.0 Hz, 1 H), 4.31 (d,
J ) 12.0 Hz, 1 H), 4.26 (t, J ) 8.3 Hz, 1 H), 3.82 (s, 3 H), 3.68-3.64
(m, 1 H), 3.48-3.42 (m, 1 H), 3.03 (br s, 1 H), 2.92 (dd, J ) 13.0, 5.3
Hz, 1 H), 2.78-2.65 (m, 1 H), 2.55-2.27 (m, 3 H), 2.12-2.02 (m, 1
H), 1.87-1.68 (m, 3 H), 1.15 (s, 3 H), 1.05-0.90 (m, 2 H), 0.95 (s, 3
H), 0.87 (s, 3 H), 0.02 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm 210.0,
173.6, 158.7, 134.6, 131.9, 131.6, 129.0, 117.0, 113.5, 83.8, 82.9, 81.5,
70.1, 69.3, 67.2, 55.2, 42.1, 38.0, 37.8, 37.4, 34.3, 28.1, 25.3, 21.8,
(3S,4aR,6R,8S,10S,13R)-1,2,3,4,4a,5,6,9,10,11,12,13a-Dodecahy-
dro-6-methoxy-3-[(p-methoxybenzyl)oxy]-4,4,13a-trimethyl-8-[2-
(trimethylsilyl)ethoxy]-10,7-metheno-7H-benzocycloundecen-13-
(8H)-one (43a). A. O-Methylation of 42. A solution of 42 (15.2
mg, 0.028 mmol) in methyl iodide (1 mL) was stirred with silver(I)
oxide (20 mg, 3 equiv) and calcium sulfate (20 mg, 0.15 mmol) in the
dark for 3 days. An identical quantity of Ag2O was added again after
4 and 9 days. On the 14th day, the reaction mixture was filtered through
Celite, and the filter pad was washed with ether. The filtrate was
evaporated and the residue was chromatographed on silica gel (elution
with 9% ethyl acetate in hexanes) to give 8.5 mg (55%) of 43a as a
colorless oil: IR (neat, cm-1) 1698, 1614, 1514, 1248, 1089; 1H NMR
(300 MHz, CDCl3) δ 7.33-7.30 (m, 2 H), 6.90-6.85 (m, 2 H), 5.92
(d, J ) 2.6 Hz, 1 H), 4.61 (d, J ) 11.2 Hz, 1 H), 4.43 (m, 1 H), 4.32
(d, J ) 11.2 Hz, 1 H), 3.82 (s, 3 H), 3.70 (dd, J ) 11.6, 4.5 Hz, 1 H),
3.58-3.49 (m, 1 H), 3.37-3.22 (m, 1 H), 3.19 (s, 3 H), 3.19-3.06
(m, 2 H), 2.45-2.20 (m, 3 H), 2.00-1.65 (m, 6 H), 1.53-1.40 (m, 1
H), 1.35-1.10 (m, 2 H), 1.03 (s, 3 H), 1.00 (s, 3 H), 0.97 (s, 3 H),
0.95-0.80 (m, 3 H), -0.03 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm
214.9, 159.0, 144.4, 136.3, 131.6, 128.4, 113.6, 87.8, 82.4, 76.1, 70.2,
66.7, 56.0, 55.3, 53.6, 42.3, 39.1, 38.0, 36.2, 35.3, 31.7, 29.3, 27.7,
27.6, 22.3, 19.9, 18.6, 16.6, -1.3, MS m/z (M+) calcd 556.3584, obsd
20.0, 18.4, 16.9, -1.5; [R]22 -24.1° (c 1.18, chloroform).
D
The above material was dissolved in dry THF (10 mL), cooled to
-78 °C, treated dropwise with a solution of lithium aluminum hydride
in THF (0.96 mL of 0.5 M), and stirred at this temperature for 2 h.
The reaction mixture was allowed to warm to 20 °C during 1 h, returned
to -30 °C, and hydrolyzed by the careful addition of isopropyl alcohol.
After dilution with ether (80 mL) and 10% aqueous citric acid (10
mL), the aqueous phase was separated and extracted with ether. The
combined organic layers were washed with saturated NaHCO3 solution
and brine, dried, and evaporated. Chromatography of the residue on
silica gel (elution with 15% ether in hexanes) gave 118 mg (68%
overall) of 40 and returned 10 mg of 38 (ratio 11:1).
For 40: colorless oil; IR (neat, cm-1) 3486, 1613, 1513, 1258, 1078,
1
836; H NMR (300 MHz, CDCl3) δ 7.28-7.25 (m, 2 H), 6.88-6.85
(m, 2 H), 5.99-5.90 (m, 3 H), 5.31 (dd, J ) 17.1, 2.0 Hz, 1 H), 5.17
(dd, J ) 10.9, 2.0 Hz, 1 H), 4.54 (d, J ) 11.7 Hz, 1 H), 4.31-4.25 (m,
3 H), 4.16 (dd, J ) 7.0, 3.4 Hz, 1 H), 3.80 (s, 3 H), 3.65-3.43 (m, 2
H), 2.99 (br s, 1 H), 2.44 (ddt, J ) 16.7, 7.1, 2.0 Hz, 1 H), 2.29-2.15
(m, 3 H), 1.84-1.67 (m, 4 H), 1.56-1.43 (m, 1 H), 1.03 (s, 3 H), 1.01
(s, 3 H), 0.97-0.87 (m, 2 H), 0.85 (s, 3 H), -0.02 (s, 9 H); 13C NMR
(75 MHz, CDCl3) ppm 158.8, 138.9, 131.8 (2 C), 131.5, 129.0, 115.3,
113.5 (2 C), 83.8, 82.1, 81.6, 70.3, 70.0, 67.1, 66.2, 55.2, 42.4, 38.9 (2
C), 38.0, 28.7, 27.5, 25.8, 22.3, 20.1, 18.6, 17.8, -1.5; MS m/z (M+)
calcd 542.3427, obsd 542.3423.
556.3546; [R]22 +37.0° (c 0.77, chloroform).
D
B. Sigmatropic Rearrangement of 41. A solution of 41 (26.6
mg, 4.78 × 10-5 mol) in DMF (8 mL) was deoxygenated by bubbling
N2 through for several minutes, sealed, and heated at 210 °C for 11 h.
Workup in the customary fashion returned 11.0 mg of unreacted 41
and gave 7.8 mg (50% corrected) of 43a.
Anal. Calcd for C32H50O5Si: 70.81; H, 9.28. Found: C, 70.89; H,
9.35.
(1R,1′R,3′R,4′aR,5S,6′S,8′aR)-3′,4′,4′a,5′,6′,7′,8′,8′a-Octahydro-3′-
methoxy-6′-[(p-methoxybenyzl)oxy]-5′,5′,5′a-trimethyl-5[2-(trimeth-
ylsilyl)ethoxy]-1′-vinylspiro[2-cyclopentene-1,2′(1′H)-naphthalen]-
1′ol (41). A solution of 40 (93.5 mg, 0.172 mmol) in dry THF (4 mL)
was blanketed with N2, treated with methyl iodide (0.21 mL, 20 equiv)
and sodium hydride (62 mg, 15 equiv), stirred for 24 h, and hydrolyzed
by the addition of saturated NH4Cl solution. After dilution with water
and ethyl acetate, the separated aqueous layer was extracted with ethyl
acetate (2×), and the combined organic layers were washed with brine,
dried, and concentrated. Purification of the residue by chromatography
on silica gel furnished 75.9 mg (79%) of 41 as a colorless oil: IR
(neat, cm-1) 3500, 1613, 1587, 1514, 1249, 1087; 1H NMR (300 MHz,
CDCl3) δ 7.31-7.27 (m, 2 H), 6.89-6.85 (m, 2 H), 5.92-5.84 (m, 3
Deprotection of 43a. A solution of 43a (6.1 mg, 1.10 × 10-6 mol)
in DMF (3 mL) was deoxygenated, treated with cesium fluoride (25
mg, 15 equiv), sealed, and heated at 210 °C for 6 h. The customary
workup was followed by chromatography on silica gel (elution with
25% ethyl acetate in hexanes) and provided 1.1 mg (22%) of 43b as a
white crystalline solid, mp 166-169 °C: IR (neat, cm-1) 3442, 1695,
1613, 1513, 1092; 1H NMR (300 MHz, CDCl3) δ 7.36-7.28 (m, 2 H),
6.92-6.86 (m, 2 H), 5.54 (s, 1 H), 4.75 (m, 1 H), 4.58 (d, J ) 11.5
Hz, 1 H), 4.35 (d, J ) 11.5 Hz, 1 H), 3.83 (s, 3 H), 3.76 (dd, J ) 11.3,
3.7 Hz, 1 H), 3.22 (s, 3 H), 3.16 (br s, 1 H), 3.08 (m, 1 H), 2.45-2.17
(m, 3 H), 2.10-1.95 (m, 1 H), 1.95-1.70 (m, 5 H), 1.55-1.10 (m, 3
H), 1.05 (s, 3 H), 0.99 (s, 3 H), 0.96 (s, 3 H), 1.00-0.85 (m, 2 H); 13
NMR (75 MHz, CDCl3) ppm 215.0, 158.8, 145.4, 136.8, 131.4, 128.6,
C

Synthesis of Cytotoxic 8,9-Secokaurene Diterpenoids
J. Am. Chem. Soc., Vol. 119, No. 41, 1997 9671
113.7, 82.0, 80.8, 76.3, 70.2, 56.0, 55.3, 53.3, 42.0, 41.0, 39.1, 36.4,
2b as a white solid, mp 161-165 °C: 1H NMR (300 MHz, CDCl3) δ
7.17 (d, J ) 2.3 Hz, 1 H), 6.15 (s, 1 H), 5.44 (s, 1 H), 4.74 (br s, 1 H),
4.17 (dd, J ) 11.6, 4.9 Hz, 1 H), 3.65 (br s, 1 H), 3.17 (s, 3 H), 2.70-
2.55 (m, 1 H), 2.48-2.35 (m, 1 H), 2.20-2.05 (m, 1 H), 2.11 (s, 3 H),
1.95-1.80 (m, 4 H), 1.43 (d, J ) 6.3 Hz, 1 H), 1.30-1.00 (m, 2 H),
1.01 (s, 6 H), 0.97 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 214.4,
195.3, 170.1, 159.3, 146.5, 146.0, 116.2, 77.0, 73.5, 56.5, 53.0, 42.3,
38.0, 36.7, 33.4, 30.8, 28.3, 27.2, 25.7, 21.9 (2 C), 20.9, 16.7; MS m/z
(M+) calcd 388.2250, obsd 388.2250; [R]22D -4.9° (c 0.41, methanol).
(3S,4aR,6R,7R,10S,13aR,14R)-7,14-Epoxydodecahydro-6-meth-
oxy-3-[(p-methoxybenzyl)oxy]-4,4,13a-trimethyl-9-methylene-7,10-
methano-2H-benzocycloundecene-8,13-dione (46). An 8.9 mg (1.96
× 10-5 mol) sample of 37 was converted to silyl enol ether 44 in the
predescribed manner. Condensation of 44 with Eschenmoser’s salt (18
mg, 5 equiv) in a parallel manner afforded the amine, which was
chromatographed on silica gel. Elution was effected with ether
containing peroxides. The epoxy amine which eluted was stirred with
methyl iodide (0.2 mL) for 20 h and processed as before to give 2.9
mg (31% overall) of 46 as a colorless oil: IR (neat, cm-1) 1727, 1698,
1642, 1243, 1104; 1H NMR (300 MHz, CDCl3) δ 7.35-7.32 (m, 2 H),
6.93-6.89 (m, 2 H), 6.28 (d, J ) 1.0 Hz, 1 H), 5.46 (d, J ) 1.0 Hz,
1 H), 4.55 (d, J ) 11.6 Hz, 1 H), 4.39 (d, J ) 11.6Hz, 1 H), 4.22 (dd,
J ) 12.0, 4.0 Hz, 1 H), 3.83 (s, 3 H), 3.64 (s, 1 H), 3.34 (s, 3 H),
3.19-3.16 (m, 2 H), 2.78-2.58 (m, 2 H), 2.23 (td, J ) 13.0, 5.2 Hz,
1 H), 1.94-1.65 (m, 6 H), 1.30-1.10 (m, 2 H), 1.22 (s 3 H), 1.01 (s,
3 H), 0.99 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 214.7, 196.4,
158.7, 145.2, 131.6, 128.0, 122.5, 113.6, 82.5, 71.9, 70.2, 64.0, 60.1,
59.0, 55.3, 53.0, 40.0, 39.6, 35.6, 31.5, 31.3, 29.2, 26.8, 25.0, 22.3,
19.9, 16.6; MS m/z (M+) calcd 482.2668, obsd 482.2669; [R]22D -24.6°
(c 0.39, chloroform).
35.1, 31.5, 30.0, 27.5, 27.4, 22.3, 20.0, 16.6; MS m/z (M+) calcd
456.2876, obsd 456.2887; [R]22 +33.4° (c 0.91, chloroform).
D
(3S,4aR,6R,10R,13aR)-1,2,3,4,4a,5,6,9,10,11,12,13a-Dodecahydro-
6-methoxy-3-[(p-methoxybenzyl)oxy]-4,4,13a-trimethyl-9-methylene-
10,7-metheno-7H-benzocycloundecene-8,13-dione (45). A nitrogen-
blanketed solution of 37 (50.6 mg, 0.111 mmol) and chlorotrimethylsilane
(0.28 mL, 20 equiv) in dry THF (7 mL) was cooled to -78 °C and
treated dropwise with 0.78 mL of 0.5 M potassium hexamethyldisilazide
(in toluene, 3.5 equiv). After 2 h of stirring at -78 °C, the reaction
mixture was quenched with triethylamine (0.47 mL, 30 equiv), diluted
with pentane (10 mL), allowed to warm to room temperature, and
evaporated under reduced pressure. The residue was triturated with
pentane, filtered through glass wool, and re-evaporated in vacuo to
give 44 which was used directly: 1H NMR (300 MHz, C6D6) δ 7.27-
7.20 (m, 2 H), 6.91-6.85 (m, 1 H), 6.25 (t, J ) 1.9 Hz, 1 H), 4.81 (t,
J ) 2.2 Hz, 1 H), 4.39 (d, J ) 11.9 Hz, 1 H), 4.27 (dd, J ) 11.5, 4.5
Hz, 1 H), 4.15 (d, J ) 11.9 Hz, 1 H), 3.36 (s, 3 H), 3.36-3.34 (m, 1
H), 3.26 (s, 3 H), 2.90 (br s, 1 H), 2.73 (td, J ) 12.5, 4.2 Hz, 1 H),
2.47 (dd, J ) 17.0, 12.1 Hz, 1 H), 2.20-2.05 (m, 3 H), 1.85 (m, 1 H),
1.71 (t, J ) 17.1 Hz, 1 H), 1.54-1.44 (m, 1 H), 1.29 (dd, J ) 16.9,
6.3 Hz, 1 H), 1.17 (s, 3 H), 1.15 (s, 3 H), 1.16-1.00 (m, 1 H), 0.79 (s,
3 H), 0.80-0.65 (m, 1 H), 0.23 (s, 9 H); 13C NMR (75 MHz, C6D6)
ppm 213.9, 159.6, 156.6, 143.2, 139.5, 129.4, 114.0, 105.7, 82.3, 74.7,
70.4, 56.0, 54.8, 53.9, 46.5, 39.3, 38.0, 36.2, 29.5, 29.4, 27.8, 24.1,
23.3, 22.6, 20.2, 17.0, -0.20.
Eschenmoser’s salt (103 mg, 5 equiv) was dissolved in dry DMF (6
mL), placed under N2, and heated to 50 °C. A solution of the sample
of 44 from above in DMF (2 mL) was added, and stirring was
maintained at 50 °C for 2.5 h. At this point, 2.5 N sodium hydroxide
(3 mL) was introduced, and the mixture was poured into 1:1 chloroform/
water. The separated aqueous layer was extracted with chloroform
(2×), and the combined organic phases were dried and concentrated.
The residual DMF was removed by heating the sample to 60 °C and 1
Torr in a Kugelrohr distillation apparatus.
(+)-O-(Methylepoxy)shikoccin (47). Epoxy ketone 46 (2.2 mg,
4.9 × 10-6 mol) was dissolved in CH2Cl2 (2 mL) containing one drop
of water, treated with DDQ (1.7 mg, 1.3 equiv), and stirred at room
temperature for 1 h. The reaction mixture was quenched with saturated
NaHCO3 solution and ethyl acetate. The separated aqueous phase was
extracted with ethyl acetate (2×), and the combined organic layers were
washed with brine, dried, and concentrated. The residue was dissolved
in CH2Cl2 (1 mL) and pyridine (0.5 mL), treated with acetic anhydride
(0.2 mL) and 4-(dimethylamino)pyridine (0.11 mg), and stirred over-
night. Workup in the predescribed manner gave 1.5 mg (76%) of 47:
IR (neat, cm-1) 1728, 1698, 1244, 1109; 1H NMR (300 MHz, CDCl3)
δ 6.32 (d, J ) 0.9 Hz, 1 H), 5.52 (d, J ) 1.2 Hz, 1 H), 4.78 (t, J ) 2.5
HZ, 1 H), 4.14 (dd, J ) 11.9, 4.4 Hz, 1 H), 3.65 (s, 1 H), 3.34 (s, 3H),
3.23 (br s, 1 H), 2.85-2.60 (m, 2 H), 2.25-2.15 (m, 1 H), 2.14 (s, 3
H), 2.10-1.55 (m, 6 H), 1.30-1.10 (m, 2 H), 1.10 (s, 3 H), 1.05 (s, 3
H), 1.03 (s, 3 H); 13C NMR (125 MHz, CDCl3) ppm 213.8, 197.0,
170.3, 145.7, 122.1, 77.2, 71.9, 63.9, 59.9, 59.1, 52.7, 40.0, 38.5, 35.5,
31.5, 31.1, 28.3, 27.0, 25.0, 21.9, 21.7, 20.9, 16.6; MS m/z (M+) calcd
The amine was dissolved in ether (5 mL), stirred with methyl iodide
(1 mL) for 24 h, and evaporated. The residue was dissolved in CH2-
Cl2 (6mL), stirred vigorously with 4 mL of saturated K2CO3 solution
for 24 h, diluted with CH2Cl2, and washed with water. The aqueous
layer was extracted with ethyl acetate, and the combined organic layers
were washed with brine, dried, and concentrated. Purification of the
residue by chromatography on silica gel (elution with 15% ethyl acetate
in hexanes) gave 34.2 mg (66% overall) of 45 as a colorless oil: IR
(neat, cm-1) 1698, 1651, 1513, 1246, 1099; 1H NMR (300 MHz, CDCl3)
δ 7.32-7.29 (m, 2 H), 7.14 (d, J ) 2.4 Hz, 1 H), 6.94-6.90 (m, 2 H),
6.16 (s, 1 H), 5.41 (s, 1 H), 4.53 (d, J ) 11.7 Hz, 1 H), 4.37 (d, J )
11.7 Hz, 1 H), 4.25 (dd, J ) 11.8, 4.8 Hz, 1 H), 3.83 (s, 3 H), 3.61 (br
s, 1 H), 3.18 (s, 3 H), 3.12 (br s, 1 H), 2.67-2.31 (m, 1 H), 2.45-2.31
(m, 1 H), 2.11 (td, J ) 12.5, 5.3 Hz, 1 H), 1.93-1.82 (m, 1 H), 1.80-
1.62 (m, 4 H), 1.57 (d, J ) 6.4 Hz, 1 H), 1.30-1.10 (m, 2 H), 1.15 (s,
3 H), 0.97 (s, 3 H), 0.96 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
215.2, 195.0, 159.0, 158.6, 146.6, 145.7, 131.6, 127.8, 116.5, 113.6,
82.1, 73.6, 70.0, 56.5, 55.3, 53.3, 44.3, 39.1, 36.8, 33.7, 30.7, 29.2,
27.0, 25.7, 22.6, 20.0, 16.8; MS m/z (M+) calcd 466.2719, obsd
404.2199, obsd 404.2193; [R]22 +20.8° (c 0.71, methanol).
D
Acknowledgment. This research was financially supported
by grants from the National Institutes of Health and Eli Lilly
and Co. An Alexander von Humboldt Feodor Lynen Fellowship
to D.B., a National Institutes of Health Postdoctoral Fellowship
to T.L.U., and a Deutsches Forschungsgemeinshaft Postdoctoral
Fellowship to K.F. are acknowledged with gratitude. We thank
Prof. E. Fujita and Prof. M. Node for providing us with
comparison spectra and authentic samples of O-methylshikoccin
and O-(methylepoxy)shikoccin, respectively, Prof. D. Enders
for a generous gift of D-proline, and Dr. K. LaTessa (formerly
Lynch) for some early experiments.
466.2718; [R]22 -58.1° (c 1.30, chloroform).
D
Anal. Calcd for C29H38O5: C, 74.65; H, 8.20. Found: C, 74.40;
H, 8.30.
(-)-O-Methylshikoccin (2b). To a solution of 45 (32.1 mg, 7.06
× 10-5 mol) in CH2Cl2 (10 mL) containing 3 drops of water was added
DDQ (21 mg, 3 equiv). The reaction mixture was stirred for 1 h,
quenched with saturated NaHCO3 solution, and diluted with ethyl
acetate. The separated aqueous layer was extracted with ethyl acetate
(2×), and the combined organic layers were washed with brine, dried,
and evaporated. The crude alcohol was dissolved in CH2Cl2 (2 mL)
and treated with pyridine (1 mL), acetic anhydride (0.5 mL), and
4-(dimethylamino)pyridine (22 mg). After being stirred overnight, the
reaction mixture was diluted with ethyl acetate and saturated NaHCO3
solution. The aqueous phase was extracted with ethyl acetate (3×),
and the combined organic layers were washed with 2 N HCl (2×),
saturated NaHCO3 solution, and brine prior to drying and solvent
evaporation. After chromatography on silica gel (elution with 15 f
25% ethyl acetate in hexanes), there was isolated 24.0 mg (88%) of
Supporting Information Available: Experimental details
for the preparation of 11-14, 17-19, and 22-26, along with
tables giving the crystal data and structure refinement informa-
tion, bond lengths and bond angles, atomic and hydrogen
coordinates, and isotropic and anisotropic displacement coor-
dinates for 34 (16 pages). See any current masthead page for
ordering and Internet access instructions.
JA971527N