Studies directed toward the total synthesis of cerorubenic acid-III. 5. A radical cyclization route leading to the methyl ester of the natural isomer

Article abstract of DOI:10.1021/ja980691n

The first total synthesis of cerorubenic acid-III methyl ester is detailed. Enantiopure 4, obtained by anionic oxy-Cope rearrangement of 3, was transformed via diol 11 into lactol 20. Following proper establishment of both side chains as in 25, a 6-exo radical cyclization was employed to set the configuration of the remaining stereogenic centers. This very useful process set the stage for construction of the pendant side chain. The complete route to 2 from 3-methylcyclohexenone required 30 steps (0.3% overall yield) confirmed the initial complex structural assignment and established the absolute configuration of the natural kairomone.

Full text of DOI:10.1021/ja980691n

J. Am. Chem. Soc. 1998, 120, 5953-5960
5953
Studies Directed toward the Total Synthesis of Cerorubenic Acid-III.
5. A Radical Cyclization Route Leading to the Methyl Ester of the
Natural Isomer1
Leo A. Paquette* and Brian P. Dyck
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
ReceiVed March 2, 1998
Abstract: The first total synthesis of cerorubenic acid-III methyl ester is detailed. Enantiopure 4, obtained by
anionic oxy-Cope rearrangement of 3, was transformed via diol 11 into lactol 20. Following proper establishment
of both side chains as in 25, a 6-exo radical cyclization was employed to set the configuration of the remaining
stereogenic centers. This very useful process set the stage for construction of the pendant side chain. The
complete route to 2 from 3-methylcyclohexenone required 30 steps (0.3% overall yield) confirmed the initial
complex structural assignment and established the absolute configuration of the natural kairomone.
Cerorubenic acid-III (1), an architecturally unique sesterter-
pene first isolated in 1983 by Yoko Naya and his collaborators
at the Suntory Institute for Bioorganic Research from secretions
of the scale insect Ceroplastes rubens Maskell,2 merits consid-
eration as a synthetic target in that it qualifies as the most
complex substance currently recognized to play an important
role in insect communication.3 Indeed, this novel tetracyclo-
[8.4.1.0.0]pentadecane system functions very effectively as a
kairomone responsible for control of the ovipositional behavior
and feeding traits of the encyrtid wasp Anicetus beneficus.4 The
1
structural assignment to 1 was based on detailed H and 13C
NMR spectral analysis of its methyl ester 2. Central to the
molecular architectural features in these molecules are a
vinylcyclopropane fragment whose double bond occupies a
bridgehead site, an array of seven stereogenic centers all of
which are contiguous, and a pendant side chain in which the
only oxygenated functionality resides.
Despite the fact that 1 and 2 have been known for well over
a decade, neither structure has yet been confirmed either by
(1) (a) Part 4: Paquette, L. A.; Hormuth, S.; Lovely, C. J. J. Org. Chem.
X-ray analysis or by total synthesis. Our early work in this
area has documented the readiness with which carbinol 3 can
be assembled and subjected to anionic oxy-Cope rearrangement5
in a notably direct route to the entire ABC substructure.6 The
conciseness with which 4 can be produced and its ready
acquisition in either antipodal form1b were regarded as particu-
larly attractive. From the retrosynthetic perspective, modest
functional group manipulation within 4 in various ways appeared
1995, 60, 4813. (b) Part 3: Paquette, L. A.; Deaton, D. N.; Endo, Y.;
Poupart, M.-A. J. Org. Chem. 1993, 58, 4262. (c) Part 2: Paquette, L. A.;
Lassalle, G. Y.; Lovely, C. J. J. Org. Chem. 1993, 58, 4254. (d) Part 1:
Paquette, L. A.; Poupart, M.-A. J. Org. Chem. 1993, 58, 4245.
(2) Tempesta, M. S.; Iwashita, T.; Miyamoto, F.; Yoshihara, K.; Naya,
Y. J. Chem. Soc., Chem. Commun. 1983, 1182.
(3) (a) Noda, T.; Kitamura, A.; Takahashi, S.; Tagaki, K.; Kashio, T.;
Tanaka, M. Appl. Ent. Zool. 1982, 3, 350. (b) Takahashi, S.; Takabayashi,
J. Appl. Ent. Zool. 1984, 19, 1117; 1985, 20, 173.
(4) (a) Yasumatsu, K.; Tachikawa, T. J. Fac. Agri., Kyushu UniVersity
2949, 9, 99. (b) Ishii, T.; Yasumatsu, K. Mushi (Fukuoka) 1954, 27, 69.
(c) Ohgushi, R. Mem. Coll. Sci. UniVersity Kyoto (B) 1956, 23, 55; 1058,
25, 31.
(5) Paquette, L. A. Tetrahedron 1997, 53, 13971.
(6) Poupart, M.-A.; Paquette, L. A. Tetrahedron Lett. 1988, 29, 269.
S0002-7863(98)00691-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/05/1998

5954 J. Am. Chem. Soc., Vol. 120, No. 24, 1998
Paquette and Dyck
to be ideally suited to the construction of ring D. However,
the adaptation of a Diels-Alder tactic for the elaboration of 5
was thwarted by the facility with which epimerization to the
trans-fused isomer 6 occurs.1d,7 The lessons learned from
attempts to bring about extraannular (as in 7)1c and intraannular
(as in 8)1b Robinson annulation were that no diastereomer was
suited to dehydrative cyclization under any of the basic or acidic
conditions examined. Analogously, the crucial six-membered
cyclization of intermediates of type 9 by metal-mediated means
was not kinetically favored.1a
Scheme 2
Herein, we record the first total synthesis of cerorubenic acid-
III methyl ester (2) in its naturally occurring levorotatory
configuration. Worthy of advance notice is the fact that a radical
cyclization protocol was deployed in order to generate a properly
functionalized D ring. Significantly, the route that elaborates
the necessary intermediate is short, highly efficient, and
Scheme 1
13 with (methoxymethylene)triphenylphosphorane9 in the pres-
ence of HMPA and 18-crown-6 were found to provide only
modest yields of enol ether, a more advantageous route was
pursued which involved the lithium salt of (methoxymethyl)-
diphenylphosphine oxide.10 Nucleophilic attack on 13 was
expected to occur exclusively from the exterior of the cup-
shaped tricyclic nucleus. Indeed, only the diastereomeric
adducts 14 and 15 were produced in a 1.1:1 ratio and 95%
combined yield. The chromatographic separation of 14 from
15 was straightforward. The stereochemical assignments of
these diastereomers rest on the stereoselectivity of their base-
promoted elimination reactions which are recognized to proceed
in cis fashion. Strikingly, whereas 14 underwent smooth
conversion (84%) to the (Z)-enol ether 16, the identical
elimination of its epimer 15 to the (E)-enol ether 18 proved
sluggish and less efficient (41%).
effectively stereocontrolled. Furthermore, the synthesis serves
to confirm Naya’s original assignment.
Results and Discussion
The strategic selection of levorotatory diol 11, readily
available by alkylation of 4 with ethyl iodoacetate with ensuing
lithium aluminum hydride reduction,1a was seen as the corner-
stone of the present approach in that it was anticipated that the
resident dual functionality would lend itself conveniently to
regiochemical control. In fact, the two hydroxyl groups in 11
are easily distinguished as is evident in its efficient conversion
to the monosilyl ether 12 (Scheme 1). The viability of this
selective protection step provided for the elaboration of ketone
13 via perruthenate oxidation.8 When attempts to homologate
In an attempt to facilitate this important transformation, the
primary hydroxyl substituents were unmasked prior to exposure
to sodium hydride. Under these circumstances, a substantial
improvement in the yield of both enol ethers was observed. The
(9) Soderquist, J. A.; Ramos-Veguilla, J. Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; pp 3363-
3365.
(10) (a) Earnshaw, C.; Wallis, C. J.; Warren, S. J. Chem. Soc., Perkin
Trans. 1 1979, 3099. (b) Evans, E. H.; Hewson, A. T.; March, L. A.; Nowell,
I. W.; Wadsworth, A. H. J. Chem. Soc., Perkin Trans. 1 1987, 137. (c)
Patel, D. V.; Schmidt, R. J.; Gordon, E. M. J. Org. Chem. 1992, 57, 7143.
(7) Paquette, L. A.; Poupart, M.-A. Tetrahedron Lett. 1988, 29, 273.
(8) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13.

Synthesis of Cerorubenic Acid III. 5
J. Am. Chem. Soc., Vol. 120, No. 24, 1998 5955
intense NOE interaction exhibited between the vinylic and allylic
methine protons in 16 (see formula) attests to their close
proximity.
stereoselective radical cyclization, it was necessary to arrive at
the homologated iodide 25. In the event, reaction of 24 with
iodomethylzinc iodide in the presence of copper(I) iodide and
lithium iodide according to Knochel and co-workers14 led
directly to 25 in 70% yield from 23 when performed at room
temperature. The minor geometrical isomer produced during
the formation of 21 was transformed via the same sequence to
the Z isomer of 25.
We had now arrived at the stage where the extension of both
side chains required consideration. The plan called for initial
homologation of the enol ether segment to an R-methyl R,â-
unsaturated ester, whose ultimate role was to serve as the radical
acceptor.11 Central to this scenario was the availability of lactol
20. Although both epimers of this key intermediate proved to
be rather labile,12 it was ultimately found that 35% aqueous
perchloric acid acted on 17 to deliver a nearly equimolar mixture
of the â- and R-forms of 20 (Scheme 2). Convinced that the
most kinetically feasible pathway for ring closure would involve
that aldehyde isomer predisposed with cis functional groups,
we directed our attention to establishing the cis fusion of the D
ring by NMR methods. Although the chemical shifts of the
relevant protons clearly parallel those known for 2, a more
definitive correlation was not possible due to the unresolved
and overlapping features of selected proton signals. Notwith-
standing, since the next step was to involve strongly basic
reaction conditions, all indications suggested that equilibration
would operate at the enolizable site if it had not already
materialized in order to position this side chain on the exterior
of the concave-convex ABC core.
At this juncture, the time had arrived to explore the 6-exo
cyclization of 25 under free radical conditions.15 In light of
the activated status of the alkene acceptor in 25, the customary
deceleration seen for these processes in the absence of an
electron-withdrawing substituent16,17 was not observed. The
expectation was that the two low-energy transition states would
be A and B, structures which are chairlike with one stretched
bond. These two conformers, which can be interconverted
simply by rotation around the exocyclic allylic bond specified
When the lactols were treated with the sodium salt of triethyl
2-phosphonopropionate in DMF, three-carbon homologation was
successfully accomplished. Only two geometric isomers were
produced, with 21 predominating by a factor of 2:1. Since both
the (Z)- and (E)-hydroxy esters are homogeneous compounds,
the inference can be drawn that the starting lactols differed only
as a consequence of configurational inhomogeneity at the
carbinol carbon. As before, the chemical shifts and coupling
constants exhibited by 21 were fully consistent with the
stereochemical assignment drawn. Also, the specific rotations
for 20, 21, and later intermediates all proved to be levorotatory
as in 2, thereby providing early suggestive evidence that the
natural enantiomer was being pursued.
Adaptation of the one-pot Swern oxidation/methylenation
sequence earlier developed by Takano et al.13 to 21 afforded
the triene aldehydo ester 22 in 60% yield. Reduction to give
alcohol 23 was effectively accomplished by treatment of 22 with
sodium borohydride in methanol. Replacement of the hydroxyl
group in 23 by iodide was uncomplicated when mediated by
transient formation of the mesylate. To set the stage for
in B, possess distinctive structural features. When other
energetic factors are more or less equal, it is recognized that
the major product will derive from the transition state where
the acceptor resides in an equatorial disposition.15 In A,
however, projection of the R,â-unsaturated ester into the
equatorial plane is met with substantial nonbonded steric
compression between the R-methyl substituent and cyclopropyl
methine carbon. Since the axial alternative B experiences
appreciably less nonbonded interaction, our expectation was that
the major product would be formed via this rotamer to deliver
26 in highly stereoselective fashion. At the experimental level,
two cyclized products were formed in a 4.9:1 ratio. That both
stereoisomers reflect the preferred reaction pathway via B was
supported by formation of the identical pair of tetracyclic esters
in the same ratio upon comparable treatment of the Z isomer of
1
25. Although 26 and 27 proved to be inseparable, several H
and 13C NMR patterns exhibited by 26 were clearly seen to be
comparable to those of 2.
(11) A reversal in the sequencing of the chain extensions was also
accorded brief attention. As indicated below, the generation of both
geometric isomers of i and ii was not at all problematic. However, proper
conditions for the effective hydrolysis of ii to either iii or iv were not found.
The remarkable capacity of 25 and its Z isomer to undergo
cyclization with exclusive formation of radical C leads to a
second stereoselectivity issue. In the present instance, the
radical center is adjacent to a carbonyl group, the single occupied
orbital is very likely sp2-hybridized, and this orbital is most apt
(12) The sensitivity of the vinylcyclopropane moiety embedded in the
ABC substructure of this structural type has previously been commented
on.1d,7 The lability of 20 to the acidic conditions necessary for hydrolysis
of the enol ether functionality is attributed to competitive attack at the
bridgehead site.
(13) Takano, S.; Inomata, K.; Samizu, K.; Shun’ichi, T.; Yanase, M.;
Suzuki, M.; Iwabuchi, Y.; Sugihara, T.; Ogasawara, K. Chem. Lett. 1989,
1283.
(14) Knochel, P.; Chou, T.-S.; Chen, H. G.; Yeh, M. C. P.; Rozema, M.
J. J. Org. Chem. 1989, 54, 5202.
(15) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions: Concepts, Guidelines, and Synthetic Applications; VCH
Publishers: Weinheim; 1995.
(16) (a) Porter, N. A.; Roe, A. N.; McPhail, A. T. J. Am. Chem. Soc.
1980, 102, 7574. (b) Roe, A. N.; McPhail, A. T.; Porter, N. A. J. Am. Chem.
Soc. 1983, 105, 1199.
(17) Hanessian, S.; Dhanoa, D. S.; Beaulieu, P. L. Can. J. Chem. 1987,
65, 1859.

5956 J. Am. Chem. Soc., Vol. 120, No. 24, 1998
Paquette and Dyck
to be aligned with the σ-bond of the largest R-substituent due
to a combination of steric and electronic factors.18 Given these
requirements, the two possible conformations D and E, which
differ with respect to orientation of the carboethoxy or methyl
substituent over the cyclohexane ring, are plausibly adopted.
The minimization of gauche interactions is achieved by posi-
tioning the smaller methyl group in this region as in D.
Donation of a hydrogen atom to the more sterically accessible
lobe in D leads preferentially to 26. The observation that both
Scheme 3
25 and its Z isomer preferentially give rise to 26 as the major
product is consistent with the intervention of a relatively long-
lived radical which has the opportunity to equilibrate as in D
a E prior to capture by the tin hydride reagent.
The dominant formation of ester 26, precisely as required
for arriVal at cerorubenic acid-III, is representative of a manner
in which a customarily favored transition state model can
become disfavored as a direct consequence of global structural
considerations. Such crossovers in diastereoselection are not
without precedent.16,17,19-21
Our final objective was to install the remaining carbon atoms
of the pendant side chain as a single unit. Since the alkylation
of extended enolates with alkyl halides is recognized to favor
R-substitution overwhelmingly,22 iodide 30 (Scheme 3) was not
(18) (a) Hart, D. J.; Krishnamurthy, R. J. Org. Chem. 1992, 57, 4457.
(b) Guindon, Y.; Faucher, A.-M.; Bourque, EÄ .; Caron, V.; Jung, G.; Landry,
S. R. J. Org. Chem. 1997, 62, 9276 and relevant references therein.
(19) (a) Kates, S. A.; Dombroski, M. A.; Snider, B. B. J. Org. Chem.
1990, 55, 2427. (b) Curran, D. P.; Morgan, T. M.; Schwartz, C. E.; Snider,
B. B.; Dombroski, M. A. J. Am. Chem. Soc. 1991, 113, 6607. (c) Mori,
M.; Kanda, N.; Ban, Y.; Aoe, K. J. Chem. Soc., Chem. Commun. 1988, 12.
(d) Yoo, S.; Yi, K. Y.; Lee, S.-H.; Jeong, N. Synlett 1990, 575. (e) Naito,
T.; Honda, Y.; Miyata, O.; Ninomiya, I. Heterocycles 1991, 32, 2319.
(20) (a) Burke, S. D.; Rancourt, J. J. Am. Chem. Soc. 1991, 113, 2335.
(b) Burke, S. D.; Jung, K. W. Tetrahedron Lett. 1994, 35, 5837. (c) Lolkema,
L. D. M.; Hiemstra, H.; Ghouch, A. A. A.; Speckamp, W. N. Tetrahedron
Lett. 1991, 32, 1491. (d) Lee, E.; Tae, J. S.; Chong, Y. H.; Park, Y. C.;
Yun, M.; Kim, S. Tetrahedron Lett. 1994, 35, 129. (e) Arnone, A.; Bravo,
P.; Cavicchio, G.; Friegerio, M.; Viani, F. Tetrahedron-Asymmetry 1992,
3, 9. (f) Arnone, A.; Bravo, P.; Frigerio, M.; Viani, F.; Cavicchio, G.;
Crucianelli, M. J. Org. Chem. 1994, 59, 3459.
(21) (a) Ihara, M.; Taniguchi, N.; Fukumoto, K.; Kametani, T. J. Chem.
Soc., Chem. Commun. 1987, 1438. (b) Hatakeyama, S.; Ochi, N.; Numata,
H.; Takano, S. J. Chem. Soc., Chem. Commun. 1988, 1202. (c) Marco-
Contelles, J.; Mart´ınez, L.; Mart´ınez-Grau, A.; Pozuelo, C.; Jimeno, M. L.
Tetrahedron Lett. 1991, 32, 6437. (d) Marco-Contelles, J.; Sa´nchez, B. J.
Org. Chem. 1993, 58, 4293. (e) Ogura, K.; Kayano, A.; Fujino, T.; Sumitani,
N.; Fujita, M. Tetrahedron Lett. 1993, 34, 8313. (f) Koreeda, M.; Hamann,
L. G. J. Am. Chem. Soc. 1990, 112, 8175. (g) Rao, A. V. R.; Sharma, G.
V. M.; Bhanu, M. N. Tetrahedron Lett. 1992, 33, 3907. (h) Ihara, M.; Yasui,
K.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1990, 1469.
(22) (a) Herrmann, J. L.; Kieczykowski, G. R.; Schlessinger, R. H.
Tetrahedron Lett. 1973, 2433. (b) Savu, P. M.; Katzenellenbogen, J. A. J.
Org. Chem. 1981, 46, 239.
serviceable in this capacity. However, this intermediate proved
to be highly crystalline, thereby permitting complete corrobora-
tion of the earlier stereochemical assignments by X-ray crystal-
lographic analysis (Figure 1).23
From a different vantage point, aldehydes are recognized to
often give favorable γ/R ratios with extended enol silanes,
including tiglate derivatives.24 In the present context, however,
subsequent deoxygenation of the resulting carbinol was predicted
to be problematic,25 and this route was not pursued. Alterna-
tively, an R-chloro sulfide was viewed to be an attractive masked
aldehyde equivalent since such electrophiles have been reported
to give high γ/R ratios in alkylations involving extended enolate
(23) In actuality, the X-ray study was performed on ent-30, which was
prepared from ent-4 during the course of exploratory studies.
(24) See, for example: Patron, A. P.; Richter, P. K.; Tomaszewski, M.
J.; Miller, R. A.; Nicolaou, K. C. J. Chem. Soc., Chem. Commun. 1994,
1147.
(25) The difficulty lies in the fact that the great majority of deoxygenation
maneuvers proceed via radical pathways. Radical intervention in the present
instance would very likely evenuate in 6-exo cyclization by intramolecular
attack at the methylene double bond.15

Synthesis of Cerorubenic Acid III. 5
J. Am. Chem. Soc., Vol. 120, No. 24, 1998 5957
The route to 2 also makes use of the Knochel chain extension
in the context of a total synthesis.33 Importantly, the completed
synthesis substantiates the original structural assignment to 1
and 2 while simultaneously establishing their absolute config-
uration.
Experimental Section
General Methods. 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 compounds was shown to be >95% by
1
TLC and high field H and 13C NMR. The high-resolution and fast-
atom-bombardment spectra were recorded at The Ohio State University
Campus Chemical Instrument Center. Elemental analyses were per-
formed at the Scandinavian Microanalytical Laboratory, Herlev,
Denmark or at Atlantic Microlab, Inc., Norcross, GA.
(1R,2R,3R,4R,11S)-4-[2-(tert-Butyldimethylsiloxy)ethyl]-11-
methyltricyclo[5.4.0.02,11]undec-7-en-3-ol (12). tert-Butyldimethylsilyl
chloride (2.77 g, 18.4 mmol) was added to an ice-cooled solution of
111a (3.71 g, 16.7 mmol) and imidazole (2.00 g, 29.4 mmol) in CH2-
Cl2 (60 mL). After 30 min, the reaction mixture was washed with
water, dried, and concentrated under reduced pressure. Chromatography
of the residue on silica gel (elution with 5% ethyl acetate in hexanes)
furnished 5.45 g (97%) of 12 as a colorless oil: IR (neat, cm-1) 3459,
Figure 1. ORTEP diagram of ent-30.
equivalents.26 Furthermore, reductive desulfurization of the
product was expected to pose no problem. Unfortunately,
however, the necessary R-chlorination of 31 could not be
1
1101; H NMR (300 MHz, CDCl3) δ 5.72 (d, J ) 6.4 Hz, 1 H), 4.16
(dd, J ) 13.2, 6.4 Hz, 1 H), 3.72-3.57 (m, 2 H), 2.36-2.25 (m, 1 H),
2.22-2.11 (m, 2 H), 2.09-1.97 (m, 2 H), 1.94-1.41 (series of m, 7
27
accomplished, as refluxing with N-chlorosuccinimide in CCl4
H), 1.14 (s, 3 H), 1.00-0.93 (m, 2 H), 0.87 (s, 9 H), 0.04 (s, 6 H); 13
C
only returned unreacted starting material, and reaction with
sulfuryl chloride28 induced its complete decomposition.
NMR (75 MHz, CDCl3) ppm 140.2, 127.1, 75.8, 61.8, 39.2, 35.2, 33.2,
31.3, 29.1, 28.4, 28.2, 25.9, 25.8, 23.5, 22.6, 18.3, -5.3, -5.4; MS
m/z (M+) calcd 336.2485, obsd 336.2491; [R]20D -130 (c 0.33, CHCl3).
Anal. Calcd for C20H36O2Si: C, 71.37; H, 10.78. Found: C, 71.47;
H, 10.86.
In light of the above developments, the side chain was
introduced in stepwise fashion. Swern oxidation of the major
alcohol 28, which proved to be readily separable from 29, led
to 32. Homologation according to the Wadsworth-Emmons
protocol29 gave rise to unsaturated ester 33 in a diastereomeric
ratio of 7:1. Following chemoselective reduction of the
conjugated double bond with magnesium in methanol,30 low-
temperature exposure of 34 to Dibal-H and condensation with
R-(carbomethoxyethylidene)triphenylphosphorane31 furnished
(1R,2R,4R,11S)-4-[2-(tert-Butyldimethylsiloxy)ethyl]-11-
methyltricyclo[5.4.0.02,11]undec-7-en-3-one (13). Alcohol 12 (7.57
g, 22.5 mmol), N-methylmorpholine N-oxide (3.16 g, 27.0 mmol), and
4 Å molecular sieves (7.6 g) were stirred in CH2Cl2 (150 mL) for 15
min, at which time TPAP (240 mg, 0.67 mmol) was introduced in
portions. After 2 h, more NMO (1.05 g, 8.97 mmol) was added, and
the mixture was stirred for 1 h, concentrated under reduced pressure,
taken up in 5% ethyl acetate in hexanes, and poured directly atop a
silica gel column. Elution with the same solvent system provided 6.45
g (86%) of 13 as a colorless oil; IR (neat, cm-1) 1696, 1108: 1H NMR
(300 MHz, CDCl3) δ 5.71 (d, J ) 6.9 Hz, 1 H), 3.69-3.58 (m, 1 H),
2.42-2.36 (m, 1 H), 2.26-1.96 (series of m, 5 H), 1.82-1.48 (series
of m, 6 H), 1.27 (d, J ) 9.5 Hz, 1 H), 1.18 (s, 3 H), 0.87 (s, 9 H),
0.030 (s, 3 H), 0.028 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 210.0,
137.7, 127.7, 61.3, 50.2, 38.9, 34.9, 33.2, 30.2, 27.7, 26.6, 25.9, 23.8,
22.9, 22.4, 18.3, -5.4; MS m/z (M+) calcd 334.2328, obsd 334.2348;
ester 2 in very good yield. Synthetic 2 showed H and 13C
NMR properties that were indistinguishable from those of the
authentic material.
1
Summary
The first total synthesis of the methyl ester of (-)-cerorubenic
acid-III was accomplished in 30 steps and with an overall yield
of 0.3% from 3-methyl-2-cyclohexenone. The enantioselective
route is characterized by two key strategic elements. The first
is an oxyanionic Cope rearrangement of 3 which occurs in high
yield and under complete stereocontrol. The formation of 4 in
this manner constitutes a particularly expedient means for setting
three of the four rings of the target. Fusion of a substituted
methylenecyclohexane unit to 4 with proper setting of the four
additional stereocenters is shown to be possible via a radical
cyclization pathway. This remarkable aspect of our first-
generation approach to the cerorubenic acid ring system has
elucidated several stereocontrol elements that merit possible
attention in other synthetic undertakings.
[R]20 +10.2 (c 0.31, CHCl3).
D
Anal. Calcd for C20H34O2Si: C, 71.80; H, 10.24. Found: C, 71.53;
H, 10.25.
[(R)-[(1R,2R,3R,4R,11S)-4-[2-(tert-Butyldimethylsiloxy)ethyl]-3-
hydroxy-11-methyltricyclo[5.4.0.02,11]undec-7-en-3-yl]methoxymethyl]-
diphenylphosphine Oxide (14) and [(S)-[(1R,2R,3R,4R,11S)-4-[2-
(tert-Butyldimethylsiloxy)ethyl]-3-hydroxy-11-methyl-
tricyclo[5.4.0.02,11]undec-7-en-3-yl]methoxymethyl]diphenylphos-
phine Oxide (15). (Methoxymethyl)-diphenylphosphine oxide (5.70
g, 23.1 mmol) in dry THF (60 mL) was added to an ice-cooled solution
of LDA [from n-butyllithium (14.8 mL, 19.2 mmol) and diisopropy-
lamine (3.0 mL, 21 mmol) in THF (50 mL) at 0 °C for 20 min]. After
15 min at 0 °C, the solution was cooled to -78 °C, 13 (1.29 g, 3.86
mmol) dissolved in THF (10 mL) was introduced dropwise, and the
resulting mixture was stirred for 30 min, quenched with saturated NH4-
Cl solution, and warmed to room temperature. The aqueous phase was
extracted with ether, the combined organic layers were dried and
concentrated, and the residue was chromatographed on silica gel (elution
(26) Fleming, I.; Goldhill, J.; Paterson, I. Tetrahedron Lett. 1979, 3205,
3209.
(27) For example: (a) Paterson, I. Tetrahedron 1988, 44, 4207. (b) Tsai,
Y.-M.; Chang, F.-C.; Huang, J.; Shiu, C.-L.; Kao, C.-L.; Liu, J.-S.
Tetrahedron 1997, 53, 4291.
(28) Paquette, L. A. Org. React. 1977, 25, 1.
(29) Wadsworth, W. S., Jr. Org. React. 1977, 25, 73.
(30) Hudlicky, T.; Natchus, M. G.; Sinai-Zingde, G. J. Org. Chem. 1987,
52, 4641.
(31) Isler, O.; Gutmann, H.; Montavon, M.; Ru¨egg, R.; Ryser, G.; Zeller,
P. HelV. Chim. Acta 1957, 40, 1242.
(32) Seyferth, D.; Andrews, S. B. J. Organomet. Chem. 1971, 30, 151.
(33) For a different application of this protocol in a natural product
synthesis, consult Snider, B. B.; He, F. Tetrahedron Lett. 1997, 38, 5453.

5958 J. Am. Chem. Soc., Vol. 120, No. 24, 1998
Paquette and Dyck
with 10-20% ethyl acetate in hexanes). There was isolated 1.12 g
(50%) of 14 followed by 1.00 g (45%) of 15, both as white powders.
For 14: mp 153-154 °C; IR (CH2Cl2, cm-1) 3346, 1470; 1H NMR
(300 MHz, CDCl3) δ 8.21-8.14 (m, 2 H), 7.77-7.30 (m, 2 H), 7.54-
7.40 (m, 6 H), 5.61 (d, J ) 6.1 Hz, 1 H), 4.72 (br s, 1 H), 3.93 (d, J
) 7.7 Hz, 1 H), 3.71-3.64 (m, 1 H), 3.58-3.50 (m, 1 H), 3.15 (s, 3
H), 2.38 (ddd, J ) 13.1, 12.8, 4.9 Hz, 1 H), 2.23-1.74 (series of m,
8 H), 1.57-1.51 (m, 1 H), 1.33 (dd, J ) 13.8, 3.5 Hz, 1 H), 0.87 (s,
9 H), 0.85-0.72 (m, 2 H), 0.29 (s, 3 H), 0.03 (s, 3 H), 0.02 (s, 3 H);
13C NMR (75 MHz, CDCl3) ppm 139.5, 134.3 (d, JC,P ) 93.9 Hz),
concentrated to leave a residue, purification of which by chromatog-
raphy on silica gel (elution with 15% ethyl acetate in hexanes) gave
17 (26 mg, 95%) as a white solid: mp 58-62 °C; IR (neat, cm-1
)
1
3342, 1660, 1446, 1128; H NMR (300 MHz, CDCl3) δ 5.94 (d, J )
2.1 Hz, 1 H), 5.65 (d, J ) 7.0 Hz, 1 H), 3.71-3.57 (m, 2 H), 3.48 (s,
3 H), 2.34-2.28 (m, 1 H), 2.14-1.93 (m, 4 H), 1.84-1.52 (m, 4 H),
1.44 (br s, 1 H), 1.25-0.99 (series of m, 4 H), 1.18 (s, 3 H); 13C NMR
(75 MHz, CDCl3) ppm 145.7, 141.5, 126.4, 116.5, 61.6, 59.2, 40.0,
38.1, 34.3, 31.9, 30.8. 28.2, 26.6, 26.4, 24.3, 24.0; MS m/z (M+) calcd
248.1776, obsd 248.1767; [R]20 -104 (c 0.31, CHCl3).
D
132.6 (d, JC,P ) 8.4 Hz), 131.8, 131.7, 131.4, 130.0, 128.5 (d, JC,P
)
Anal. Calcd for C16H24O2: C, 77.36; H, 9.75. Found: C, 77.25;
H, 9.69.
11.0 Hz), 128.3 (d, JC,P ) 11.1 Hz), 124.2, 91.9 (d, JC,P ) 83.7 Hz),
80.5, 62.4, 61.8, 46.0, 31.9, 31.2, 29.6, 27.4, 27.1, 26.3, 26.0, 25.8,
25.4, 23.6, 18.4, -5.38, -5.41; MS m/z (M+) calcd 580.3138, obsd
(1R,2R,4R,11S)-3-[(E)-Methoxymethylene]-11-methyltricyclo-
[5.4.0.02,11]undec-7-ene-4-ethanol (19). The title alcohol, prepared in
an entirely similar manner, was obtained in 63% yield as a white
solid: mp 69-70 °C: IR (CH2Cl2, cm-1) 3613, 1449, 1121; 1H NMR
(300 MHz, CDCl3) δ 5.63-5.62 (m, 2 H), 3.64 (dd, J ) 7.4, 5.3 Hz,
2 H), 3.54 (s, 3 H), 3.02-2.93 (m, 1 H), 2.17-1.98 (m, 3 H), 1.92-
1.73 (m, 4 H), 1.68-1.49 (m, 2 H), 1.31-1.19 (m, 3 H), 1.16 (s, 3 H),
1.06 (d, J ) 9.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3) ppm 148.4,
139.9, 125.7, 115.4, 61.5, 59.5, 35.4, 35.0, 32.2, 32.1, 29.1, 28.8, 27.2,
580.3170; [R]20 -96.4 (c 1.6, CHCl3).
D
Anal. Calcd for C34H49O4PSi: C, 70.31; H, 8.50. Found: C, 70.39;
H, 8.48.
For 15: mp 190-192 °C; IR (CH2Cl2, cm-1) 3366, 1472, 1437; 1H
NMR (300 MHz, CDCl3) δ 8.02-7.87 (m, 4 H), 7.54-7.41 (m, 6 H),
5.58 (d, J ) 6.6 Hz, 1 H), 3.97 (d, J ) 5.8 Hz, 1 H), 3.70-3.65 (m,1
H), 3.53-3.45 (m, 1 H), 3.22 (br s, 1 H), 2.95 (s, 3 H), 2.33-2.28 (m,
1 H), 2.16-1.56 (series of m, 8 H), 1.10-0.90 (m, 3 H), 0.86 (s, 9 H),
0.85 (s, 3 H), 0.81-0.72 (m, 1 H), 0.01 (s, 6 H); 13C NMR (75 MHz,
CDCl3) ppm 140.0, 133.7 (d, JC,P ) 93.4 Hz), 132.5 (d, JC,P ) 9.0
26.5, 23.7, 23.2; MS m/z (M+) calcd 248.1776, obsd 248.1772; [R]20
-60.9 (c 0.23, CHCl3).
D
Anal. Calcd for C16H24O2: C, 77.36; H, 9.75. Found: C, 77.17;
H, 9.76.
Hz), 131.6, 131.5, 131.4 (d, JC,P ) 8.8 Hz), 130.4, 128.4 (d, JC,P
)
11.0 Hz), 127.7 (d, JC,P ) 12.0 Hz), 124.2, 84.6 (d, JC,P ) 85.0 Hz),
82.0, 62.4, 61.5, 41.0, 40.9, 31.4, 31.2, 29.4, 28.1, 27.0, 26.5, 26.0,
25.9, 23.5, 18.4, -5.40, -5.42; MS m/z (M+) calcd 580.3138, obsd
(4aR,7aR,8R,8aS,8bS)-4,4a,5,6,7a,8,8a,8b-Octahydro-8-methyl-
3H-8,7-[1]propanyl[3]ylidene-1H-cyclopropa[6,7]cyclohepta[1,2-c]-
pyran-1-ol (20). Perchloric acid (35%, 0.50 mL) was added to a
magnetically stirred solution of 17 (17 mg, 0.068 mmol) in 9:1 dioxane-
water (2 mL), and the resulting mixture was stirred for 24 h, poured
into saturated NaHCO3 solution, and extracted with ether. The
combined organic phases were dried and concentrated, and the residue
was chromatographed on silica gel (elution with 10% ethyl acetate in
hexanes). There was isolated 8 mg (50%) of a 1.2:1 mixture of â-
and R-lactols 20 as a colorless oil. Attempts to purify these compounds
resulted in decomposition; IR (neat, cm-1) 3378, 1649, 1443, 1378;
1H NMR (300 MHz, CDCl3) δ (major epimer) 5.66-5.63 (m, 1 H),
4.58 (d, J ) 7.1 Hz, 1 H), 4.05-3.96 (m, 1 H), 3.49 (ddd, J ) 12.0,
12.0, 2.4 Hz, 1 H), 2.99 (d, J ) 7.1 Hz, 1 H), 2.36-1.91 (series of m,
3 H), 1.89-1.24 (series of m, 9 H), 1.19 (s, 3 H), 1.10-0.83 (m, 2 H);
(minor epimer) 5.01 (s, 1 H), 3.61 (ddd, J ) 11.1, 4.9, 1.2 Hz, 1 H),
1.14 (s, 3 H), (the remaining signals were obscured); 13C NMR (75
MHz, C6D6) ppm 139.9, 139.8, 125.0, 124.8, 98.2, 95.3, 66.1, 59.6,
39.6, 38.1, 37.5, 33.4, 33.3, 32.3, 32.2. 32.0, 31.5, 29.7, 29.4, 28.8,
28.2, 27.23, 27.18, 26.9, 24.5, 24.0, 23.7, 23.1, 21.1, 20.5; MS m/z
580.3180; [R]20 -56.4 (c 0.64, CHCl3).
D
Anal. Calcd for C34H49O4PSi: C, 70.31; H, 8.50. Found: C, 70.38;
H, 8.48.
tert-Butyl[2-[(1R,2R,4R,11S)-3-[(Z)-methoxymethylene]-11-
methyltricyclo[5.4.0.02,11]undec-7-en-4-yl]ethoxy]dimethylsilane (16).
Sodium hydride (136 mg, 5.67 mmol) was added in portions to an
ice-cooled solution of 14 (330 mg, 0.568 mmol) in dry THF (5 mL).
After the addition was complete, the ice bath was removed and the
reaction mixture was stirred at 20 °C for 3 h, carefully quenched with
water, and extracted with ether. The combined organic phases were
dried and concentrated to leave a residue that was purified by
chromatography on silica gel (elution with 1% ethyl acetate in hexanes).
There was obtained 172 mg (84%) of 16 as a colorless oil: IR (neat,
1
cm-1) 1661, 1472, 1255, 1132, 1102; H NMR (300 MHz, CDCl3) δ
5.89 (d, J ) 2.1 Hz, 1 H), 5.64 (d, J ) 6.9 Hz, 1 H), 3.65-3.50 (m,
2 H), 3.48 (s, 3 H), 2.32-2.27 (m, 1 H), 2.13-2.10 (m, 2 H), 2.04-
1.93 (m, 2 H), 1.83-1.52 (m, 4 H), 1.26-0.98 (series of m, 4 H), 1.19
(s, 3 H), 0.90 (s, 9 H), 0. 0.05 (s, 6 H); 13C NMR (75 MHz, CDCl3)
ppm 145.7, 141.8, 126.3, 116.5, 61.8, 59.2, 39.9, 37.9, 34.5, 32.0, 30.8,
28.3, 26.54, 26.50, 26.0, 24.2, 24.0, 18.3, -5.3; MS m/z (M+) calcd
362.2642, obsd 362.2643.
(M+) calcd 234.1620, obsd 234.1652; [R]20 -133 (c 0.20, CHCl3).
D
Ethyl (rE,1R,2R,3R,4R,11R)-4-(2-Hydroxyethyl)-r,11-dimethyl-
tricyclo[5.4.0.02,11]undec-7-ene-3-acrylate (21). Triethyl 2-phospho-
nopropionate (3.71 mL, 17.3 mmol) was added to a stirred suspension
of sodium ethoxide (0.985 g, 14.5 mmol) in DMF (55 mL). After 1 h,
the mixture was cooled to 0 °C, added to an ice-cooled solution of 20
(0.675 g, 2.88 mmol) in DMF (25 mL), stirred for 4.5 h, and poured
into ether. The organic phase was washed with water and brine, dried,
and concentrated under reduced pressure. The residue was chromato-
graphed on silica gel (elution with 10% ethyl acetate in hexanes) to
afford 0.220 g (24%) of the (Z)-isomer and 0.422 g (46%) of (E)-
isomer 21.
Anal. Calcd for C22H38O2Si: C, 72.87; H, 10.56. Found: C, 73.03;
H, 10.53.
tert-Butyl[2-[(1R,2R,4R,11S)-3-[(E)-methoxymethylene]-11-
methyltricyclo[5.4.0.02,11]undec-7-en-4-yl]ethoxy]dimethylsilane (18).
Submission of 15 to the identical reaction conditions gave rise to 18 in
41% yield: colorless oil; IR (neat, cm-1) 1663, 1462, 1254, 1218, 1125,
1
1104; H NMR (300 MHz, CDCl3) δ 5.61 (d, J ) 7.1 Hz, 1 H), 5.56
(d, J ) 1.9 Hz, 1 H), 3.68-3.54 (m, 2 H), 3.51 (s, 3 H), 2.98-2.93
(m, 1 H), 2.14-1.91 (m, 3 H), 1.81-1.72 (m, 2 H), 1.65-1.43 (m, 3
H), 1.29-1.09 (series of m, 3 H), 1.16 (s, 3 H), 1.04 (d, J ) 9.0 Hz,
1 H), 0.90 (s, 9 H), 0.06 (s, 6 H); 13C NMR (75 MHz, CDCl3) ppm
148.0, 140.6, 125.7, 115.9, 62.5, 59.4, 36.1, 34.3, 32.6, 31.9, 29.7, 29.6,
29.0, 27.2, 26.9, 26.0, 23.9, 23.8, -5.1, -5.2; MS m/z (M+) calcd
362.2641, obsd 362.2648.
For the (Z)-isomer: colorless oil; IR (neat, cm-1) 3394, 1712, 1642,
1
1451, 1375; H NMR (300 MHz, CDCl3) δ 6.05 (dd, J ) 10.0, 1.1
Hz, 1 H), 5.63 (d, J ) 6.7 Hz, 1 H), 4.24-4.06 (m, 2 H), 3.73-3.56
(m, 2 H), 3.05 (dd, J ) 10.0, 10.0 Hz, 1 H), 2.21-1.91 (series of m,
6 H), 1.88 (s, 3 H), 1.85-1.65 (m, 2 H), 1.60 (dd, J ) 13.7, 2.4 Hz,
1 H), 1.54-1.15 (series of m, 6 H), 1.11 (s, 3 H), 0.95 (d, J ) 9.0 Hz,
1 H), 0.58 (dd, J ) 9.6, 9.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
ppm 168.0, 146.5, 140.6, 125.5, 124.3, 61.9, 60.1, 40.7, 38.8, 35.7,
33.0, 31.7, 30.2, 28.3, 27.1, 26.6, 23.6, 23.2, 21.0, 14.3; MS m/z (M+)
Anal. Calcd for C22H38O2Si: C, 72.87; H, 10.56. Found: C, 72.96;
H, 10.52.
(1R,2R,4R,11S)-3-[(Z)-Methoxymethylene]-11-methyltricyclo-
[5.4.0.02,11]undec-7-ene-4-ethanol (17). A solution of tetra-n-buty-
lammonium fluoride in THF (0.17 mL, 0.17 mmol) was added to a
magnetically stirred solution of 14 (65 mg, 0.11 mmol) in THF (3 mL).
After 4 h, the mixture was cooled to 0 °C, treated with sodium hydride
(15 mg, 0.63 mmol), stirred at 20 °C for 4 h, poured into water, and
extracted with ether. The combined organic phases were dried and
calcd 318.2195, obsd 318.2232; [R]20 -208 (c 0.22, CHCl3).
D
For the (E)-isomer 21: colorless oil; IR (neat, cm-1) 3426, 1707,
1446, 1367; 1H NMR (300 MHz, CDCl3) δ 6.86 (dd, J ) 9.6, 1.3 Hz,
1 H), 5.63 (d, J ) 6.7 Hz, 1 H), 4.17 (q, J ) 7.1 Hz, 2 H), 3.73-3.55
(m, 2 H), 2.34 (dd, J ) 9.8, 9.8 Hz, 1 H), 2.20-2.14 (m, 2 H), 2.08-
1.79 (series of m, 7 H), 1.77 (d, J ) 1.2 Hz, 3 H), 1.65 (ddd, J ) 13.7,

Synthesis of Cerorubenic Acid III. 5
J. Am. Chem. Soc., Vol. 120, No. 24, 1998 5959
1
4.0, 1.8 Hz, 1 H), 1.33-1.16 (m, 5 H), 1.10 (s, 3 H), 0.98 (d, J ) 9.0
Hz, 1 H), 0.70 (dd, J ) 9.5, 9.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
ppm 168.6, 146.2, 140.5, 126.2, 124.7, 61.5, 60.5, 39.5, 39.1, 36.1,
32.0, 31.6, 30.0, 28.9, 27.0, 26.6, 23.6, 23.3, 14.2, 12.9; MS m/z (M+)
as a colorless oil: IR (neat, cm-1) 1713, 1643, 1443, 1279, 1237; H
NMR (300 MHz, CDCl3) δ 6.72 (dd, J ) 9.9, 1.0 Hz, 1 H), 5.70 (d,
J ) 6.1 Hz, 1 H), 5.24 (s, 1 H), 4.97 (s, 1 H), 4.24-4.12 (m, 2 H),
3.20-3.14 (m, 2 H), 2.62-2.40 (m, 4 H), 2.33-2.21 (m, 2 H), 2.15-
1.99 (m, 2 H), 1.86-1.82 (m, 1 H), 1.79 (d, J ) 0.9 Hz, 3 H), 1.68-
1.52 (m, 1 H), 1.51-1.45 (m, 1 H), 1.30 (t, J ) 7.1 Hz, 3 H), 1.26-
1.20 (m, 1 H), 1.13 (s, 3 H), 1.05 (d, J ) 8.9 Hz, 1 H), 0.85 (dd, J )
9.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) ppm 168.3, 139.1, 145.4,
149.9, 126.0, 124.8, 113.4, 60.5, 47.5, 43.0, 37.8, 34.6, 33.0, 31.3, 28.3,
27.0, 25.9, 23.5, 22.2, 14.3, 12.9, 3.5; MS m/z (M+) calcd 454.1369,
calcd 318.2195, obsd 318.2194; [R]20 -140 (c 0.32, CHCl3).
D
Ethyl (rE,1R,2R,3S,4S,11R)-4-(1-Formylvinyl)-r,11-dimethyl-
tricyclo[5.4.0.02,11]undec-7-ene-3-acrylate (22). Dimethyl sulfoxide
(0.20 mL, 4.1 mmol) was added to a cold (-70 °C) solution of oxalyl
chloride (0.18 mL, 2.1 mmol) in CH2Cl2 (10 mL). After 15 min, 21
(220 mg, 0.69 mmol) in CH2Cl2 (2 mL) and triethylamine (1.10 mL,
7.95 mmol) were added in succession, and the mixture was allowed to
warm to 20 °C over 1 h. N,N,N-Dimethyl(methylene)ammonium
chloride (123 mg, 1.31 mmol) was introduced, and the mixture was
stirred for 48 h with more ammonium salt (2 × 150 mg) and
triethylamine (2 × 0.2 mL) being added after 18 and 28 h, poured into
water, and extracted with CHCl3. The combined organic layers were
dried, concentrated, and dissolved in 2:1 ether-chloroform (6 mL).
Iodomethane (4 mL) was added and stirring was continued for 10 h.
The resulting mixture was concentrated, taken up in CHCl3 (15 mL),
and stirred vigorously with aqueous K2CO3 solution (10 mL) for 6 h.
Extraction with CHCl3 preceded drying, concentration, and chroma-
tography of the residue on silica gel. Elution with 5% ethyl acetate in
hexanes furnished 135 mg (60%) of 22 as a colorless oil: IR (neat,
cm-1) 1711, 1691, 1644, 1453, 1366, 1278, 1236; 1H NMR (300 MHz,
CDCl3) δ 9.40 (s, 1 H), 6.77 (s, 1 H), 6.40 (dd, J ) 9.9, 1.3 Hz, 1 H),
6.15 (s, 1 H), 5.72 (d, J ) 6.1 Hz, 1 H), 4.11 (br q, J ) 7.1 Hz, 2 H),
3.18-3.12 (m, 1 H), 2.63 (dt, J ) 4.5, 10.0 Hz, 1 H), 2.30-2.26 (m,
2 H), 2.03-1.79 (m, 3 H), 1.77 (d, J ) 1.3 Hz, 3 H), 1.66 (ddd, J )
13.8, 4.4, 1.9 Hz, 1 H), 1.53-1.44 (m, 1 H), 1.32 (dd, J ) 13.3, 4.7
Hz, 1 H), 1.23 (t, J ) 7.1 Hz, 3 H), 1.12 (s, 3 H), 1.07 (d, J ) 8.8 Hz,
1 H), 0.77 (dd, J ) 9.4, 9.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
ppm 194.5, 168.2, 150.9, 144.0, 139.5, 136.4, 126.4, 125.3, 60.3, 37.4,
37.2, 34.3, 32.8, 31.7, 28.3, 27.0, 26.1, 23.5, 22.5, 14.2, 12.8; MS m/z
(M+) calcd 328.2038, obsd 328.1994; [R]S(22,D) -93.8 (c 0.15,
CHCl3).
obsd 454.1359; [R]20 -80.3 (c 0.12, CHCl3).
D
Ethyl (rR,1R,1aR,4aS,8R,8aS,8bR)-1a,3,4,4a,5,6,7,8,8a,8b-Decahy-
dro-r,1-dimethyl-5-methylene-1H-1,2[1]propanyl[3]ylidene-benzo-
[a]cyclopropa[c]cycloheptene-8-acetate (26) and Ethyl (rR,1R,1aR,-
4aS,8R,8aS,8bR)-1a,3,4,4a,5,6,7,8,8a,8b-Decahydro-r,1-dimethyl-5-
methylene-1H-1,2-[1]propanyl[3]ylidenebenzo[a]cyclopropa-
[c]cycloheptene-8-acetate (27). Iodide 25 (44 mg, 0.097 mmol),
tributyltin hydride (37 mg, 0.13 mmol), and AIBN (4 mg) were refluxed
in benzene (4 mL) for 90 min, cooled to 20 °C, and concentrated. The
residue was purified by chromatography on silica gel (elution with
hexanes to remove tin residues, followed by 0.5% ethyl acetate in
hexanes) to provide 25 mg (78%) of an inseparable mixture of 26
containing 17% of 27.
For 26: IR (neat, cm-1) 1731, 1637, 1455, 1173, 1153; H NMR
1
(800 MHz, C6D6) δ 5.66 (d, J ) 6.6 Hz, 1 H), 4.91 (s, 1 H), 4.83 (s,
1 H), 4.02-3.94 (m, 2 H), 3.78 (dq, J ) 10.9, 6.9 Hz, 1 H), 2.48-
2.46 (m, 1 H), 2.37 (ddd, J ) 13.2, 13.2, 4.4 Hz, 1 H), 2.24-2.15 (m,
4 H), 2.06-2.00 (m, 1 H), 1.94-1.91 (m, 2 H), 1.90-1.85 (m, 1 H),
1.74-1.70 (m, 1 H), 1.67-1.65 (m, 1 H), 1.55 (br d, J ) 13.4 Hz, 1
H), 1.48-1.42 (m, 2 H), 1.13 (d, J ) 6.9 Hz, 3 H), 0.98 (s, 3 H), 0.96
(t, J ) 7.2 Hz, 3 H), 0.91 (d, J ) 9.0 Hz, 1 H), 0.80 (dd, J ) 10.0,
10.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3) ppm 176.9, 151.0, 140.3,
124.4, 106.6, 60.0, 41.3, 40.5, 39.6, 35.1, 32.2, 32.0, 29.2, 28.7, 28.0,
27.1, 26.4, 24.8, 23.8, 20.8, 16.1, 14.3; MS m/z (M+) calcd 328.2402,
obsd 328.2393.
(rR,1R,1aR,4aS,8R,8aS,8bR)-1a,3,4,4a,5,6,7,8,8a,8b-Decahydro-
r,1-dimethyl-5-methylene-1H-1,2-[1]propanyl[3]ylidenebenzo[a]-cy-
clopropa[c]cycloheptene-8-ethanol (28) and (rS,1R,1aR,4aS,8R,
8aS,8bR)-1a,3,4,4a,5,6,7,8,8a,8b-Decahydro-r,1-dimethyl-5-methyl-
ene-1H-1,2-[1]propanyl[3]ylidenebenzo[a]cyclopropa[c]cycloheptene-
8-ethanol (29). A solution of the 26/27 mixture (37 mg, 0.11 mol) in
dry THF (1 mL) was added to a stirred suspension of lithium aluminum
hydride (43 mg, 1.13 mmol) in THF (2 mL) at -78 °C. The mixture
was allowed to warm to 20 °C during 1 h, treated sequentially with
water (0.043 mL), 15% NaOH solution (0.043 mL), and water (0.13
mL), filtered, and concentrated. Chromatography of the residue on
silica gel (elution with 5% ethyl acetate in hexanes) furnished 5.3 mg
(16%) of 29 and 26 mg (80%) of 28.
Ethyl (rE,1R,2R,3S,4S,11R)-4-[1-(Hydroxymethyl)vinyl]-r,11-
dimethyltricyclo[5.4.0.02,11]undec-7-ene-3-acrylate (23). Sodium boro-
hydride (23 mg, 0.61 mmol) was added to a magnetically stirred solution
of 22 (77 mg, 0.23 mmol) in methanol (5 mL), and the resulting mixture
was stirred for 20 min, quenched with saturated NH4Cl solution, and
extracted with ethyl acetate. The combined organic phases were dried
and concentrated to leave a residue, purification of which by chroma-
tography on silica gel (elution with 15% ethyl acetate in hexanes)
delivered 73 mg (96%) of 23 as a colorless oil: IR (neat, cm-1) 3436,
1
1711, 1644, 1453, 1366, 1283, 1247; H NMR (300 MHz, CDCl3) δ
6.69 (dd, J ) 9.9, 1.3 Hz, 1 H), 5.69 (d, J ) 6.7 Hz, 1 H), 5.28 (s, 1
H), 5.24 (d, J ) 1.1 Hz, 1 H), 4.16 (q, J ) 7.1 Hz, 2 H), 3.95 (s, 2 H),
2.56 (dt, J ) 4.2, 10.1 Hz, 1 H), 2.44-1.80 (series of m, 7 H), 1.77 (d,
J ) 1.3 Hz, 3 H), 1.64 (ddd, J ) 13.8, 4.3, 1.7 Hz, 1 H), 1.55-1.32
(m, 1 H), 1.31-1.18 (m, 1 H), 1.27 (t, J ) 7.1 Hz, 3 H), 1.12 (s, 3 H),
1.06-1.03 (m, 1 H), 0.84 (dd, J ) 9.6, 9.6 Hz, 1 H); 13C NMR (75
MHz, CDCl3) ppm 168.5, 149.8, 145.6, 139.9, 126.0, 124.7, 111.2,
67.3, 60.5, 44.7, 37.7, 34.8, 33.2, 31.5, 28.4, 26.9, 26.1, 23.5, 22.3,
14.2, 12.8; MS m/z (M+) calcd 330.2195, obsd 330.2197; [R]20D -93.9
(c 0.12, CHCl3).
For 28: white solid, mp 107-109 °C; IR (CH2Cl2, cm-1) 3390, 1637,
1455, 1020; 1H NMR (300 MHz, CDCl3) δ 5.67 (d, J ) 6.6 Hz, 1 H),
4.79 (s, 1 H), 4.71 (d, J ) 1.1 Hz, 1 H), 3.70 (dd, J ) 10.6, 3.4 Hz,
1 H), 3.47 (dd, J ) 10.6, 6.8 Hz, 1 H), 2.50-2.41 (m, 1 H), 2.35-
2.27 (m, 1 H), 2.25-2.12 (m, 4 H), 2.05-1.94 (m, 1 H), 1.92-1.69
(m, 4 H), 1.67-1.60 (m, 2 H), 1.58-1.42 (m, 1 H), 1.40-1.26 (m, 3
H), 1.10 (s, 3 H), 1.01-0.94 (m, 1 H), 0.98 (d, J ) 6.8 Hz, 3 H), 0.75
(dd, J ) 10.7, 9.3 Hz, 1 H); 13C NMR (75 MHz, C6D6) ppm 151.3,
140.6, 124.4, 106.7, 66.1, 40.9, 40.4, 36.3, 35.2, 32.9, 32.5, 30.4, 29.0,
28.5, 27.2, 25.1, 24.9, 24.2, 20.9, 16.2; MS m/z (M+) calcd 286.2297,
Ethyl (rE,1R,2R,3S,4S,11R)-4-(1-(2-Iodoethyl)vinyl)-r,11-dimeth-
yltricyclo[5.4.0.02,11]undec-7-ene-3-acrylate (25). Methanesulfonyl
chloride (0.035 mL, 0.45 mmol) was added to a stirred solution of 23
(75 mg, 0.23 mmol) and triethylamine (0.10 mL) in CH2Cl2 (10 mL)
at 0 °C. After 20 min, lithium iodide (305 mg, 2.28 mmol) and THF
(3 mL) were introduced, the ice bath was removed, and the mixture
was stirred at room temperature for 30 min, poured into water, and
extracted with hexanes. The combined extracts were dried and
concentrated. The unpurified allylic iodide, together with copper(I)
iodide (381 mg, 2.00 mmol) and lithium iodide (535 mg, 4.00 mmol),
was taken up in dry THF (20 mL), cooled to -10 °C, treated during
25 min with a 1.4 M solution of iodomethylzinc iodide in THF32 (3.0
mL, 4.2 mmol), and allowed to warm to room temperature during 2 h.
The mixture was poured into saturated NH4Cl solution and extracted
with ether. The combined organic phases were dried and concentrated
to leave a residue which was chromatographed on silica gel. Elution
with 1% ethyl acetate in hexanes afforded 74 mg (70% overall) of 25
obsd 286.2329; [R]20 -161 (c 0.27, CHCl3).
D
For 29: white solid, mp 61-64 °C; IR (neat, cm-1) 3351, 1638,
1
1453, 1022; H NMR (300 MHz, C6D6) δ 5.72-5.68 (m, 1 H), 4.94
(s, 1 H), 4.88 (d, J ) 1.0 Hz, 1 H), 3.33 (dd, J ) 10.3, 5.2 Hz, 1 H),
3.20 (dd, J ) 10.3, 6.2 Hz, 1 H), 2.53-2.47 (m, 1 H), 2.28-2.02 (m,
5 H), 1.87-1.19 (series of m, 10 H), 1.05 (s, 3 H), 1.03-0.82 (m, 2
H), 0.79 (d, J ) 6.8 Hz, 3 H), 0.72 (dd, J ) 10.4, 9.2 Hz, 1 H); 13C
NMR (75 MHz, C6D6) ppm 151.5, 140.2, 124.2, 106.5, 66.3, 40.5, 40.2,
36.3, 34.9, 32.5, 30.7, 30.2, 28.5, 28.2, 27.0, 24.5, 23.9, 23.6, 20.4,
14.2; MS m/z (M+) calcd 286.2297, obsd 286.2280; [R]20 -139 (c
D
0.34, CHCl3).
(1R,1aR,4aS,8R,8aS,8bR)-1a,3,4,4a,5,6,7,8,8a,8b-Decahydro-8-
[(R)-2-iodo-1-methylethyl]-1-methyl-5-methylene-1H-1,2-[1]propanyl-
[3]ylidenebenzo[a]cyclopropa[c]cycloheptene (30). Methanesulfonyl

5960 J. Am. Chem. Soc., Vol. 120, No. 24, 1998
Paquette and Dyck
chloride (0.005 mL, 0.07 mmol) was added to an ice-cold, stirred
solution of 28 (12 mg, 0.042 mmol) and triethylamine (0.050 mL, 0.36
mmol) in CH2Cl2 (3 mL). After 30 min, the mixture was poured into
water and extracted with CHCl3. The combined organic layers were
dried and concentrated to give 17 mg (100%) of the mesylate, which
was directly heated with sodium iodide (132 mg, 0.88 mmol) in acetone
(5 mL) for 10 h. After being cooled, the mixture was concentrated
and chromatographed on silica gel (elution with hexanes) to afford 18
mg (100%) of 30 as a white powder. Crystals suitable for X-ray
(elution with 1% ethyl acetate in hexanes) afforded 12 mg (98%) of a
7.1:1 mixture of 33 and its Z isomer as a colorless oil.
1
For 33: IR (neat, cm-1) 1725, 1655, 1455, 1267, 1179; H NMR
(300 MHz, CDCl3) δ 6.84 (dd, J ) 15.6, 9.2 Hz, 1 H), 5.79 (d, J )
15.6 Hz, 1 H), 5.67 (br d, J ) 6.7 Hz, 1 H), 4.78 (s, 1 H), 4.71 (s, 1
H), 3.73 (s, 3 H), 2.64-2.54 (m, 1 H), 2.51-2.41 (m, 1 H), 2.35-
1.22 (series of m, 14 H), 1.11 (s, 3 H), 1.02 (d, J ) 6.7 Hz, 3 H),
0.99-0.97 (m, 1 H), 0.75 (dd, J ) 11.6, 9.4 Hz, 1 H); 13C NMR (75
MHz, CDCl3) ppm 167.2, 154.3, 151.0, 140.3, 124.4, 119.9, 106.7,
51.4, 43.1, 39.9, 37.0, 35.6, 32.1, 31.9, 29.7, 28.5, 28.2, 27.1, 25.5,
24.8, 23.8, 20.7, 18.5; MS m/z (M+) calcd 340.2402, obsd 340.2400;
analysis were grown from methanol: mp 76-78 °C; IR (CH2Cl2, cm-1
)
1708, 1108, 1091; 1H NMR (300 MHz, CDCl3) δ 5.69-5.66 (m, 1 H),
4.80 (d, J ) 0.9 Hz, 1 H), 4.72 (d, J ) 1.5 Hz, 1 H), 3.38 (dd, J ) 9.7,
2.7 Hz, 1 H), 3.14 (dd, J ) 9.7, 6.7 Hz, 1 H), 2.47-2.45 (m, 1 H),
2.29-1.99 (m, 5 H), 1.87-1.80 (m, 2 H), 1.72-1.46 (m, 6 H), 1.37-
1.26 (m, 2 H), 1.11 (s, 3 H), 1.01-0.96 (m, 1 H), 1.00 (d, J ) 6.5 Hz,
3 H), 0.72 (dd, J ) 10.8, 9.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
ppm 150.8, 140.3, 124.3, 106.8, 43.2, 40.5, 35.9, 33.6, 32.2, 32.0, 29.9,
28.3, 28.2, 27.1, 24.6, 24.0, 23.8, 20.7, 19.8, 17.7; MS m/z (M+) calcd
[R]20 -115 (c 0.17, CHCl3).
D
Methyl (γS,1R,1aR,4aS,8S,8aS,8bR)-1a,3,4,4a,5,6,7,8,8a,8b-Decahy-
dro-γ,1-dimethyl-5-methylene-1H-1,2[1]propanyl[3]ylidenebenzo-
[a]cyclopropa[c]cycloheptene-8-butyrate (34). The E/Z mixture of
esters 33 (11.8 mg, 0.035 mmol) and magnesium (32 mg, 1.3 mg-at)
was stirred in methanol (1 mL) for 4 h. Hydrochloric acid (1 N) was
added with vigorous stirring until the mixture became homogeneous
(ca. 5 mL). The product was extracted into ether, and the combined
organic extracts were washed with saturated NaHCO3 solution, dried,
and concentrated. The residue was chromatographed on silica gel
(elution with 0.5% ethyl acetate in hexanes) to afford 8.9 mg (74%) of
34 as a colorless oil: IR (neat, cm-1) 1741, 1453; 1H NMR (300 MHz,
CDCl3) δ 5.65 (dd, J ) 6.0, 1.1 Hz, 1 H), 4.77 (s, 1 H), 4.70 (d, J )
1.5 Hz, 1 H), 3.66 (s, 3 H), 2.50-2.10 (m, 9 H), 2.04-1.92 (m, 1 H),
1.88-1.75 (m, 3 H), 1.74-1.41 (m, 6 H), 1.39-1.25 (m, 2 H), 1.22-
1.14 (m, 1 H), 1.10 (s, 3 H), 0.95 (d, J ) 9.0 Hz, 1 H), 0.86 (d, J )
6.7 Hz, 1 H), 0.69 (dd, J ) 10.4, 9.3 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) ppm 174.5, 151.5, 140.4, 124.1, 106.2, 51.5, 44.1, 40.2, 35.9,
32.4, 32.3, 31.82, 31.76, 30.5, 29.0, 28.5, 28.4, 27.2, 24.6, 23.83, 23.78,
20.6, 17.7; MS m/z (M+) calcd 342.2559, obsd 342.2559; [R]20D -126
(c 0.24, CHCl3).
396.1273, obsd 396.1326; [R]20 -109 (c 0.14, CHCl3).
D
(1R*,1aR*,4aS*,8R*,8aS*,8bR*)-1a,3,4,4a,5,6,7,8,8a,8b-Decahy-
dro-1-methyl-5-methylene-8-[(R*)-1-methyl-2-(phenylthio)ethyl]-1-
1H-1,2-[1]propanyl[3]ylidenebenzo[a]cyclopropa[c]cycloheptene (31).
Thiophenol (0.050 mL, 0.49 mmol) was added to a stirred suspension
of 80% sodium hydride mineral oil dispersion (13 mg, 0.43 mmol) in
dry THF (1 mL). After 30 min, a solution of 30 (12 mg, 0.031 mmol)
in THF (1 mL) was introduced, and the mixture was stirred for 1 h,
poured into saturated NH4Cl solution, and extracted with ether. The
combined organic layers were dried and concentrated to leave a residue
that was chromatographed on silica gel. Elution with hexanes afforded
11 mg (92%) of 31 as a colorless oil: IR (neat, cm-1) 1639, 1583,
1478, 1436, 1376; 1H NMR (300 MHz, CDCl3) δ 7.35-7.13 (m, 5 H),
5.66 (br d, J ) 5.6 Hz, 1 H), 4.78 (s, 1 H), 4.71 (s, 1 H), 3.15 (dd, J
) 12.2, 2.9 Hz, 1 H), 2.65 (dd, J ) 12.2, 9.1 Hz, 1 H), 2.49-2.44 (m,
1 H), 2.31-2.11 (m, 5 H), 2.09-1.95 (m, 2 H), 1.89-1.59 (m, 5 H),
1.55-1.21 (m, 3 H), 1.10 (s, 3 H), 1.06 (d, J ) 6.7 Hz, 3 H), 1.02-
0.93 (m, 1 H), 0.71 (dd, J ) 10.5, 9.3 Hz, 1 H); 13C NMR (75 MHz,
C6D6) ppm 151.1, 140.3, 137.6, 129.1, 128.8, 125.7, 124.2, 106.4, 43.5,
40.1, 39.8, 36.1, 34.8, 32.8, 32.3, 30.3, 28.7, 28.3, 27.2, 24.8, 24.3,
23.8, 20.8, 18.0; MS m/z (M+) calcd 378.2381, obsd 378.2378.
Cerorubenic Acid-III Methyl Ester (2). A 1.0 M solution of
Dibal-H in hexanes (0.028 mL, 0.028 mmol) was added to a stirred
solution of 34 (8.9 mg, 0.026 mmol) in toluene (2 mL) at -78 °C.
After 1 h, 1 M HCl (3 mL) was added, the reaction mixture was warmed
to room temperature, and the product was extracted into ether. The
combined extracts were washed with saturated NaHCO3 solution, dried,
and concentrated. Chromatography of the residue on silica gel (elution
with 0.5% ethyl acetate in hexanes) provided 6.6 mg (81%) of the
aldehyde, which was directly stirred with R-(carbomethoxyethylidene)-
triphenylphosphorane (14 mg, 0.040 mmol) in CH2Cl2 (2 mL) for 20
h, concentrated, and again chromatographed on silica gel. Elution with
0.5% ethyl acetate in hexanes gave 7.3 mg (91%) of 2 as a colorless
oil, the spectral properties of which are indistinguishable from those
(rR,1R,1aR,4aS,8R,8aS,8bR)-1a,3,4,4a,5,6,7,8,8a,8b-Decahydro-
r,1-dimethyl-5-methylene-1H-1,2-[1]propanyl[3]ylidenebenzo[a]-
cyclopropa[c]cycloheptene-8-acetaldehyde (32). Dimethyl sulfoxide
(0.035 mL, 0.49 mmol) was added to a stirred solution of oxalyl chloride
(0.021 mL, 0.24 mmol) in CH2Cl2 (3 mL) at -70 °C. After 15 min,
28 (12 mg, 0.042 mmol) dissolved in CH2Cl2 (2 mL) was introduced,
followed by triethylamine (0.13 mL, 0.93 mmol). The mixture was
allowed to warm to room temperature over 2 h, quenched with saturated
NH4Cl solution, and extracted with ether. The combined organic phases
were dried and concentrated, and the residue was chromatographed on
silica gel (elution with 1% ethyl acetate in hexanes). There was isolated
10 mg (84%) of 32 as a colorless oil: IR (neat, cm-1) 1725, 1455; 1H
NMR (300 MHz, C6D6) δ 9.30 (d, J ) 3.3 Hz, 1 H), 5.66-5.64 (m, 1
H), 4.89 (s, 1 H), 4.82 (d, J ) 1.6 Hz, 1 H), 2.49-2.42 (m, 1 H),
2.39-2.27 (m, 1 H), 2.27-1.99 (m, 6 H), 1.94-1.51 (m, 4 H), 1.50-
1.21 (m, 4 H), 1.01 (s, 3 H), 0.90 (d, J ) 9.4 Hz, 1 H), 0.77 (d, J )
6.9 Hz, 3 H), 0.69 (dd, J ) 10.5, 9.4 Hz, 1 H); 13C NMR (75 MHz,
C6D6) ppm 203.4, 150.4, 140.2, 124.6, 107.3, 46.7, 40.2, 39.6, 35.6,
32.4, 32.3, 29.8, 28.8, 28.5, 27.1, 25.9, 25.0, 24.1, 20.8, 12.4; MS m/z
1
of the natural sample: IR (neat, cm-1) 1717, 1648, 1435, 1264; H
NMR (300 MHz, C6D6) δ 6.92 (dt, J ) 1.4, 7.5 Hz, 1 H), 5.70-5.67
(m, 1 H), 4.95 (s, 1 H), 4.88 (d, J ) 0.8 Hz, 1 H), 3.45 (s, 3 H), 2.55-
2.48 (m, 1 H), 2.34-1.72 (series of m, 13 H), 1.65-1.30 (m, 8 H),
1.23-1.17 (m, 1 H), 1.05 (s, 3 H), 0.92 (d, J ) 9.7 Hz, 1 H), 0.81 (d,
J ) 6.7 Hz, 3 H), 0.70 (dd, J ) 10.2, 9.4 Hz, 1 H); 13C NMR (75
MHz, C6D6) ppm 168.1, 151.3, 142.6, 140.5, 124.4, 106.9, 51.2, 44.9,
40.6, 36.3, 32.8, 32.6, 32.2, 31.1, 30.0, 28.9, 28.7, 27.3, 26.5, 24.8,
24.2, 23.9, 20.7, 18.0, 12.5 (the signal for the enoate carbon is obscured
by solvent peaks, in line with earlier observations2); MS m/z (M+) calcd
382.2872, obsd 382.2852; [R]20D -139 (c 0.16, CHCl3); -124 (c 0.001,
CHCl3) [lit2 -60 (c 0.001, CHCl3)].
Acknowledgment. This work was financially supported by
the National Institutes of Health. We thank Dr. Yoko Naya for
copies of the spectra of natural 2, Dr. Claudio Sturino for early
experiments and helpful suggestions, and Dr. Kurt Loening for
assistance with nomenclature.
(M+) calcd 284.2140, obsd 284.2165; [R]20 -130 (c 0.18, CHCl3).
D
Methyl (rE,γS,1R,1aR,4aS,8S,8aS,8bR)-1a,3,4,4a,5,6,7,8,8a,8b-
Decahydro-γ,1-dimethyl-5-methylene-1H-1,2[1]propanyl[3]-
ylidenebenzo[a]cyclopropa[c]cycloheptene-8-crotonate (33). Trim-
ethyl phosphonoacetate (0.050 mL, 0.31 mmol) was added to an ice-
cooled, stirred suspension of 80% sodium hydride mineral oil suspension
(8.6 mg, 0.29 mmol) in dry THF (2 mL). The ice bath was removed,
stirring was continued for 20 min, and the mixture was returned to 0
°C prior to the addition of 32 (10 mg, 0.035 mmol) dissolved in THF
(2 mL). After 80 min at 0 °C, saturated NH4Cl solution was introduced,
the product was extracted into ether, and the combined extracts were
dried and concentrated. Chromatography of the residue on silica gel
Supporting Information Available: Tables of X-ray crystal
data, bond distances and angles, final atomic coordinates, and
anisotropic/isotropic displacement parameters for ent-30 (5
pages, print/PDF). See any current masthead page for ordering
information and Web access instructions.
JA980691N