Stereoselective construction of the dicyelopenta[a,d]cyclooctene core of the ceroplastin sesterterpenes by way of the anionic oxy-cope rearrangement

Article abstract of DOI:10.1021/jo952165+

Bicyclo[3.2.1]oetanediones such as 9, which are readily available by double carbonylation of (1,3-cyclohexadiene)iron tricarbonyl complexes according to Eilbracht, are amenable to regiospecific methylenation under Wittig conditions. Reduction of 10 with copper hydride leads to 11, which can be resolved by application of Johnson's sulfoximine technology and oxidized to give the enantiopure antipodes of 10. Variously substituted cyclopentenyl anions undergo 1,2-addition to 10, providing carbinols which are capable of anionic oxy-Cope rearrangement via chair transition states. These structural reorganizations are fully stereocontrolled and lead directly to functionalized dicyclopenta[a,d]cyclooctenes. When 11 is treated analogously, only [1,3] sigmatropy is observed and inversion of stereochemistry at the migrating carbon prevails. Both processes exhibit impressive scaffolding powers and are characterized by brevity.

Full text of DOI:10.1021/jo952165+

3268
J . Org. Chem. 1996, 61, 3268-3279
Ster eoselective Con str u ction of th e Dicyclop en ta [a ,d ]cycloocten e
Cor e of th e Cer op la stin Sester ter p en es by Wa y of th e An ion ic
Oxy-Cop e Rea r r a n gem en t
Leo A. Paquette,* Shaowo Liang,1 and Hui-Ling Wang2
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received December 5, 1995X
Bicyclo[3.2.1]octanediones such as 9, which are readily available by double carbonylation of (1,3-
cyclohexadiene)iron tricarbonyl complexes according to Eilbracht, are amenable to regiospecific
methylenation under Wittig conditions. Reduction of 10 with copper hydride leads to 11, which
can be resolved by application of J ohnson’s sulfoximine technology and oxidized to give the
enantiopure antipodes of 10. Variously substituted cyclopentenyl anions undergo 1,2-addition to
10, providing carbinols which are capable of anionic oxy-Cope rearrangement via chair transition
states. These structural reorganizations are fully stereocontrolled and lead directly to functionalized
dicyclopenta[a,d]cyclooctenes. When 11 is treated analogously, only [1,3] sigmatropy is observed
and inversion of stereochemistry at the migrating carbon prevails. Both processes exhibit impressive
scaffolding powers and are characterized by brevity.
The carbocyclic ring system shared by the ceroplastin
medium-ring cyclization reactions,3,4,7 fragmentation of
a suitably functionalized bicyclo[3.3.1]nonanone,5 and
adaptation of a Tebbe olefination/Claisen ring expansion
sequence.6 The present report details an alternative
approach for gaining rapid access to the entire dicyclo-
penta[a,d]cyclooctene core. The strategy takes advantage
of the charge-accelerated oxy-Cope rearrangement8,9 for
molecular construction, with full control over the relevant
stereochemical features. More specifically, the [3,3]
sigmatropic interrelationship of enolate anion 5 with
alkoxide 6 was recognized to represent a direct means
for establishing the requisite carbocyclic framework.10
Several additional advantages were also apparent. Thus,
the structurally enforced geometry in effect during the
rearrangement was guaranteed to resolve the stereo-
chemical issue of fixing the distal H-6 and C-11 methyl
substituent in a cis relationship. Furthermore, two of
the three unsaturated centers in 5 would be set in locales
identical to those present in the target. The third π-bond
forms part of a reactive enolate system, whose destiny it
was ultimately to allow for side chain attachment to ring
C.
sesterterpenes and the fusicoccin diterpenes is the rela-
tively uncommon dicyclopenta[a,d]cyclooctene substruc-
ture. The pharmacological effects attributed to this class
of natural products are as diverse as their level of
unsaturation, extent of oxygenation, and ring juncture
stereochemistry. Widespread interest in these sub-
stances has led to the successful total synthesis of albolic
acid (1),3 ophiobolin C (2),4 ceroplastol I (3),4,5 and
cotylenol (4).7 Our goal for the present research program
was to develop an enantioselective route to 1 that would
prove more expedient and generally applicable than that
originally devised by this group.6
The challenge of elaborating the central eight-mem-
bered ring has previously been addressed by appropriate
Resu lts a n d Discu ssion
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) Present address: Eastman Chemical Company, Kingsport, TN.
(2) On leave from the Department of Chemistry, National Tsing Hua
University, Hsinshu 30043, Taiwan, Republic of China.
(3) Kato, N.; Takeshita, H.; Kataoka, H.; Ohbuchi, S.; Tanaka, S.
J . Chem. Soc., Perkin Trans. 1 1989, 165.
(4) (a) Rowley, M.; Tsukamoto, M.; Kishi, Y. J . Am. Chem. Soc. 1989,
111, 2735. (b) Rowley, M.; Kishi, Y. Tetrahedron Lett. 1988, 29, 4909.
(5) Boeckman, R. K., J r.; Arvanitis, A.; Voss, M. E. J . Am. Chem.
Soc. 1989, 111, 2737.
P r ep a r a tion a n d Resolu tion of Keton e 10. The
plan contemplated for arrival at intermediates such as
6 was exo 1,2-addition of a cyclopentenyl anion to bicyclic
unsaturated ketone 10. The methodology developed by
Eilbracht for smoothly effecting the 2-fold carbonylation
(6) Paquette, L. A.; Wang, T.-Z., Vo, N. H. J . Am. Chem. Soc. 1993,
115, 1676.
(7) Okamoto, H.; Arita, H.; Kato, N.; Takeshita, H. Chem. Lett. 1994,
2335.
(8) Paquette, L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609.
(9) Wilson, S. R. Org. React. (N.Y.) 1993, 43, 93.
(10) Preliminary communication: Paquette, L. A.; Liang, S.; Galat-
sis, P. Synlett 1990, 663.
S0022-3263(95)02165-7 CCC: $12.00 © 1996 American Chemical Society

Stereoselective Construction of Ceroplastin Core
J . Org. Chem., Vol. 61, No. 10, 1996 3269
Sch em e 1
Sch em e 2
F igu r e 1. Computer-generated perspective drawing of 14 as
determined by X-ray crystallography.
purpose. When attempts were first undertaken to add
the R-lithio derivative 12 to 10, no reaction was observed.
Enolization at the γ-position of the enone was considered
to be responsible for this observation. Alternative cou-
pling of 12 to 11 initially gave low conversion to adducts,
with starting materials again being recovered. However,
exposure of 12 to anhydrous cerium trichloride14 prior
to the introduction of 11 led to satisfactory conversion
(Scheme 2). The three major adducts 14 (31%), 15 (13%),
and 16 (12%) were obtained pure by chromatography on
silica gel with increasing solvent polarity. A trace
amount of the endo adduct 13 was also present, but was
not fully characterized. The unreacted 11 recovered from
this process proved to be enriched in the levorotatory
enantiomer to the extent of 25% ee.
The separation of 14 from the other diastereomers
could be easily accomplished by direct crystallization of
the adduct mixture from ethyl acetate-petroleum ether.
The absolute configuration of 14 was convincingly estab-
lished by X-ray crystallographic analysis (Figure 1).38 The
structural assignments to 15 and 16 rest upon appropri-
ate analysis of coupling constants and NOE measure-
ments as summarized in A and B. Thermolysis of
individual samples of 14-16 in refluxing toluene oc-
curred smoothly to deliver enantiopure samples of (+)-
11 and (-)-11.
of 1,3-cyclohexadienes11 was expected to play an espe-
cially useful role. At the experimental level, the iron
tricarbonyl complex 7 was found to be conveniently
transformed via 8 to 9 in the previously detailed manner
(Scheme 1). The two carbonyl groups in 9 exhibit widely
divergent reactivity, such that conventional Wittig ole-
fination can be utilized to produce 10 efficiently (89%).
In order to evaluate the difference in steric screening
surrounding the two faces of the enone chromophore in
10, its reduction with copper hydride was performed
under the Saegusa conditions.12 Only 11 resulted (86%
isolated), indicating exo approach to be strongly favored
kinetically. The stereochemistry of 11 was defined on
the basis of convincing NOE experiments (see Experi-
mental Section).
Deprotonation of either antipode with potassium hex-
amethyldisilazide (KHMDS) in THF at -78 °C followed
At this juncture, it was considered advisable to inves-
tigate means for the resolution of 10, and the sulfoximine
method pioneered by J ohnson13 was selected for this
(13) (a) J ohnson, C. R.; Zeller, J . R. J . Am. Chem. Soc. 1982, 104,
4021. (b) J ohnson, C. R.; Schroeck, C. W.; Shanklin, J . R. J . Am. Chem.
Soc. 1973, 95, 7424.
(14) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392.
(11) Eilbracht, P.; J elitte, R.; Trabold, P. Chem. Ber. 1986, 119, 169.
(12) Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T.
J . Org. Chem. 1986, 51, 537.

3270 J . Org. Chem., Vol. 61, No. 10, 1996
Paquette et al.
Sch em e 3
Sch em e 5
Sch em e 4
These complications led us to pursue a more rapid and
efficient route to 22. Thermodynamic deprotonation of
2-methylcyclopentanone with LDA followed by exposure
to N-phenyltriflimide gave rise to 23. Adaptation of
Wulff’s palladium-catalyzed stannylation conditions20 to
23 gave 24, bromination of which at -23 °C afforded 22
in 81% yield.
Once halogen-metal exchange involving 22 had been
effected with sec-butyllithium in THF, racemic 10 was
introduced at -20 °C. As expected, exo attack prevailed,
and alcohol 25 was obtained in 57% yield; starting enone
was also recovered (12%) (Scheme 5). An alternative
approach involving tert-butyllithium in ether as solvent
resulted in the formation of a 6.9:1 ratio of 25 and its
endo counterpart (50% combined), alongside 36% of
unreacted enone. The relative stereochemistry depicted
for 25 follows from the remarkable rapidity (less than
30 min at 20 °C) with which this alcohol underwent oxy-
Cope rearrangement once it was converted to its potas-
sium salt. Quenching of the enolate with ethanol re-
sulted in the installation of a cis B/C ring junction in 26
as determined by NOE methods. This stereochemical
outcome is as expected if 25- adopts the energetically
favorable chairlike transition state C in the course of its
unidirectional pathway to product.
by the addition of solid N-(phenylseleno)phthalimide
(NPSP)15 gave the exo R-phenylseleno ketones 17 and 18
(Scheme 3). Less than 5% of the endo isomers were
1
apparent by H NMR analysis at 300 MHz. Treatment
of these intermediates with hydrogen peroxide in the
presence of pyridine16 furnished (-)-10 and (+)-10,
respectively, in 65-75% overall yield.
P ilot Stu d ies In volvin g 1-Br om o-2-m eth ylcyclo-
p en ten e. In order to establish the feasibility of projected
oxy-Cope rearrangements of the 6 f 5 type, attention
was turned to bromide 22 as the first nucleophilic
reaction partner. Two routes for its preparation were
examined (Scheme 4). In the first, the unsaturated
carboxylic acid 20 was readily arrived at by adopting
Harding’s method.17 Thus, cyclohexane was treated with
acetyl chloride and aluminum chloride in chloroform and
the crude product was exposed to potassium hydroxide
in methanol to provide ketone 19. Subsequent haloform
oxidation of 19 afforded 20 in 75% yield. The acid
chloride derived from 20 was reacted with 3-hydroxy-4-
methylthiazole-2(3H)-thione18 to give 21, an ester which
proved easy to purify and was entirely stable at rt. Slow
addition of 21 to a refluxing solution of AIBN in bromo-
trichloromethane18,19 produced 22. The low yield of
isolated 22 (10%) stems from the close similarities of its
boiling point to that of BrCCl3 which was present in
excess.
When the analogous process was applied to 27, which
was obtained in a parallel manner from 11, no [3,3]
sigmatropic rearrangement materialized. Instead, a
base-promoted [1,3] shift occurred,9,21 and the resultant
potassium alkoxide was silylated to afford 28. Direct
(15) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P.
J . Am. Chem. Soc. 1979, 101, 3704.
(16) Reich, H. J .; Renga, J . M.; Reich, I. L. J . Am. Chem. Soc. 1975,
97, 5434.
(17) Harding, K. E.; Clement, K. S. J . Org. Chem. 1984, 49, 2049.
(18) Barton, D. H.; Crich, D.; Kretzschmar, G. J . Chem. Soc., Perkin
Trans. 1 1986, 39.
(19) Paquette, L. A.; Dahnke, K.; Doyon, J .; He, W.; Wyant, K.;
Friedrich, D. J . Org. Chem. 1991, 56, 6199.
(20) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron,
K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J .
Org. Chem. 1986, 51, 277.

Stereoselective Construction of Ceroplastin Core
J . Org. Chem., Vol. 61, No. 10, 1996 3271
Sch em e 6
characterization of alcohol 29 was thwarted because of
its exceptional sensitivity to dehyration during purifica-
tion to give triene 30 along with a trace amount of isomer
31. The inability of 27 to enter into oxy-Cope rearrange-
ment is believed to stem from the serious nonbonded
steric compression that necessarily must arise between
the cyclopentenyl methyl group and the cyclohexyl me-
thine carbon as depicted in D. When compared to C, it
can be seen that the added double bond so alters the
conformation of the six-membered ring that heightened
proximity considerations no longer apply.
Con sid er a tion of Dir ect In tr od u ction of th e Sid e
Ch a in . If a suitably functionalized cyclopentenyl halide
was added to 10 and the alcohol so formed subjected to
[3,3] sigmatropic rearrangement, an unrivaled opportu-
nity could exist to arrive most expediently at targets such
as 1. As a result, the pursuit of 44, 45, and allied
compounds proved unresistable. The requirement that
two adjacent stereogenic centers in 44/45 be properly
established was met, as shown in Scheme 6. In light of
existing precedent,22 it was anticipated that Cu(I)-
promoted conjugate addition of Grignard reagent 3223 to
4-methylcyclopentenone (33)24 would result in formation
of the trans product 34. Indeed, with chlorotrimethyl-
silane present,25 34 was formed in highly stereoselective
fashion (14:1, capillary GC analysis). Subsequent acidic
hydrolysis furnished diketone 35 in 86% overall yield.
Intramolecular aldol condensation within 35, achieved
by heating with potassium tert-butoxide in tert-butyl
alcohol at 50 °C, resulted initially in the formation of 36,
which underwent double-bond migration to arrive at â,γ-
unsaturated ketone 37 in 60% yield. The conjugated
isomer can be isolated if shorter reaction times are
employed. The formation of 37, which is well prece-
dented,26 is thermodynamically controlled and results
because disconnection of the two π-systems generates a
more stable compound. A driving force of ca. 2.4 kcal/
mol has been estimated for related cis-bicyclo[3.3.0]octan-
2-ones.26 NOE studies performed on 37 confirmed that
the cuprate had indeed been guided to the π-face of 33
opposite to that occupied by the methyl group.
Baeyer-Villiger oxidation27 of 37 was smoothly ac-
complished by heating with 30% hydrogen peroxide in
alkaline methanol. Recourse to 3 equiv each of H2O2 and
NaOH provided the highest yield (80%) of 38 at short
reaction times. When m-chloroperbenzoic acid was used
in the presence of NaHCO3,28 no 38 was formed and only
epoxides resulted.
Hydride reduction of 38 gave rise to diol 39 (93%),
which was regioselectively silylated so as to lead to 40
(92%). Manganese dioxide oxidation29,30 of 40 proceeded
smoothly at rt without any evidence of epimerization to
make enone 41 available (95%). In contrast, Swern
oxidation proved inefficient in this instance, and the use
of PCC resulted in erosion of stereochemical integrity,31
particularly with prolongation of the reaction time.
Reduction of 41 with L-Selectride32 resulted in 1,4-
addition to the enone and regiospecific formation of the
enolate, which was trapped in turn as the triflate (82%
of 42). A key requirement for the success of this reaction
was that 41 be added to a slight excess (1.2 equiv) of the
hydride reagent in THF at -78 °C. The reverse order of
(21) (a) Berson, J . A. Acc. Chem. Res. 1968, 1, 152. (b) Berson, J .
A.; Nelson, G. L. J . Am. Chem. Soc. 1967, 89, 5503. (c) Roth, W. R.;
Friedrich, A. Tetrahedron Lett. 1969, 2607. (d) Masamune, S.; Takada,
S.; Nakatsuka, N.; Vukov, R.; Cain, E. N. J . Am. Chem. Soc. 1969, 91,
4322.
(22) Smith, A. B., III; Dunlap, N. K.; Sulikowski, G. A. Tetrahedron
Lett. 1988, 29, 439.
(23) Ponaras, A. A. Tetrahedron Lett. 1976, 3105
(24) Kjeldsen, G.; Knudsen, J . S.; Raun-Petersen, L. S. Tetrahedron
1983, 39, 2237.
(25) Lipshutz, B. H.; Sengupta, S. Org. React. (N.Y.) 1992, 41, 135.
(26) Agosta, W. C.; Wolff, S. J . Org. Chem. 1975, 40, 1699.
(27) (a) Trost, B. M.; Buhlmayer, P.; Mao, M. Tetrahedron Lett. 1982,
23, 1443. (b) Trost, B. M.; Bernstein, P. R.; Funfschilling, P. C. J . Am.
Chem. Soc. 1979, 101, 4378.
(28) Whitesell, J . K.; Matthews, R. S.; Minton, M. A.; Helbling, A.
M. J . Am. Chem. Soc. 1981, 103, 3468.
(29) (a) Gritter, R. J .; Wallace, T. J . J . Org.Chem. 1959, 24, 1051.
(b) Papadopoulos, E. P.; J arrar, A.; Issidorides, C. H. J . Org. Chem.
1966, 31, 615.
(30) Dollimore, D.; Tonge, K. H. J . Chem. Soc. B 1967, 1380.
(31) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
(32) (a) Crisp, G. T.; Scott, W. J .; Stille, J . K. J . Am. Chem. Soc.
1984, 106, 7500. (b) Crisp, G. T.; Scott, W. J . Synthesis 1985, 335.

3272 J . Org. Chem., Vol. 61, No. 10, 1996
Paquette et al.
Sch em e 7
52 by exposure to fluoride ion. The more polar 50
behaved analogously. In light of our ability to establish
the stereochemistry of 53b by a detailed analysis of
COSY and NOE data,33 the structural assignments to
51-54 were thereby confirmed. The finding that the
[1,3] shifts proceed suprafacially with inversion of con-
figuration at the migrating carbon (that bearing the
alkoxide group) is consistent with operation of a concerted
unimolecular rearrangement.9,21,34
P r ein cor p or a tion of a Lea vin g Gr ou p in th e
Nu cleop h ilic Com p on en t. The results just detailed
indicate that the size of the side chain in 44 and 45 is
too cumbersome to allow operation of the necessary [3,3]
sigmatropic shift. In an unrelated study, we have
demonstrated that proper positioning of a leaving group
â to an incipient enolate anion results in kinetically
controlled elimination and regiocontrolled formation of
an R,â-unsaturated ketone.35 The relevance of this
innovation in the present context is reflected in the
structural ensemble 55-57. Past experience has shown
addition is particularly conducive to epimerization. With
arrival at vinyl stannane 43 as before,20,33 direct treat-
ment with either elemental bromine or iodine resulted
in conversion to 44 and 45, respectively. These cycloal-
kenyl halides were easily purified by means of chroma-
tography on silica gel which had been pretreated with
20% triethylamine in petroleum ether. Elution with a
solvent system consisting of 1% triethylamine in petro-
leum ether was particularly advantageous.
While metal-halogen exchange of bromide 44 with n-
or sec-butyllithium at -10 °C could not be driven to
completion even after 24 h, the conversion of either 43
or 45 into the cyclopentenyllithium was accomplished at
-78 °C in less than 20 min by treatment with 2.2 equiv
of tert-butyllithium. Attempts to couple this intermediate
with (()-10 were again thwarted by competing enoliza-
tion. This problem was overcome by prior conversion to
the cerate. In this way, alcohol 46 was obtained as the
only detectable diastereomer in 27% yield (Scheme 7).
The relative stereochemistry of this adduct has not been
unequivocally determined.
Quite unexpectedly, attempted base-promoted rear-
rangement of 46 resulted principally in recovery of
unreacted carbinol alongside a small amount of desily-
lated 47. This diol was identical to that obtained by
treatment of 46 with tetra-n-butylammonium fluoride.
Prolongation of the reaction time or modest increases in
reaction temperature simply generated increased propor-
tions of 47. Attempted thermal rearrangement of 46 in
benzene at 180 °C in a sealed NMR tube uniquely gave
the tetraene 48 (87%), the obvious product of dehydra-
tion.
that recourse to a methoxy substituent for X allows not
only for ready formation of the alkenyl anion but for
ultimate ejection once the enolate anion has been formed
as in 56.35,36 Consequently, the functionalized cyclopen-
tenyl bromide 59b was prepared, subjected to lithium-
halogen exchange with sec-butyllithium, and coupled to
(()-10 at -10 °C (Scheme 9). All four possible diaster-
eomers (60-63) resulted in a combined yield of 85%. The
2.1:1.0:1.3:1.8 ratio of these carbinols proved to be
virtually unchanged by solvent modification (ether vs
THF) or base (sec- vs tert-butyllithium). A sensitivity to
reaction temperature was noted. For example, at -78
°C, the product ratio (1.0:1.5:0.8:3.3) reflected an in-
creased preference for endo attack. Direct crystallization
of the crude product allowed for the isolation of pure 63.
Flash chromatography of the mother liquor afforded clean
60 and a mixture of 61 and 62. The last two isomers
were more difficult to separate.
Not unexpectedly, the exo alcohols 61 and 63 proved
unreactive to base-promoted isomerization. Endo alcohol
62 was equally unreactive toward potassium hydride or
potassium hexamethyldisilazide and 18-crown-6 in THF
at 0 °C. This inability on the part of 62 to engage in [3,3]
sigmatropy can be traced to severe nonbonded interaction
The cerate-mediated coupling of 44 to (+)-11 occurred
in a highly diastereoselective manner to afford 49 and
50 in a 10:1 ratio (Scheme 8). Base-promoted rearrange-
ment of these adducts occurred readily in the presence
of potassium hexamethyldisilazide and 18-crown-6 in
THF at 0 °C, being complete in less than 30 min.
Spectral analysis of the products immediately revealed
that [1,3] sigmatropy had prevailed. The isomerization
of less polar adduct 49 gave rise to a mixture of 51a , 51b,
and 52, which was directly transformed into pure diol
(34) Frey, H. M.; Hopkins, R. G.; O’Neal, H. E.; Bond, F. T. Chem.
Commun. 1969, 1069.
(35) Paquette, L. A.; Doyon, J . J . Am Chem. Soc. 1995, 117, 6799.
(36) (a) Paquette, L. A.; Shi, Y.-J . J . Org. Chem. 1989, 54, 5205. (b)
Paquette, L. A.; Reagan, J .; Shreiber, S. L.; Teleha, C. A. J . Am. Chem.
Soc. 1989, 111, 2331. (c) Paquette, L. A.; Shi, Y.-J . J . Am. Chem. Soc.
1990, 112, 8478.
(33) Liang, S. Ph.D. Thesis, The Ohio State University, 1991.

Stereoselective Construction of Ceroplastin Core
J . Org. Chem., Vol. 61, No. 10, 1996 3273
Sch em e 8
Sch em e 9
under mild conditions in the projected manner, introduc-
tion of a double bond in the C-ring in this manner is
accompanied by strain which is alleviated under the
present circumstances by π-bond shifting to give 64.
Although the translocation associated with the unbridled
postisomerization of 55 to 64 might be subsequently
rectified, the inefficiency of the 10 f 60 f 64 sequence
was not considered to be either useful or promising.
Con clu sion
The synthetic effort described above illustrates several
possibilities for realizing direct enantioselective construc-
tion of the dicyclopenta[a,d]cyclooctene core of the cero-
plastin sesterterpenes and fusicoccin diterpenes. At the
most basic level, full stereocontrolled assembly of the
novel carbocyclic framework can be accomplished in only
five steps from 2-methylcyclopentanone or six steps from
1,3-dimethyl-1,3-cyclohexadiene. The ease with which
bicyclic ketones such as 10 and 11 can be resolved is
detailed herein. However, it should be recognized that
dieneiron tricarbonyl complexes such as 7 are equally
amenable to separation into their enantiomers.37
While certain of the coupling reactions reported here
are highly diastereoselective, others are not. These
significant variations are considered to be dependent on
the characteristics of the organolithium nucleophile. For
example, the lithium derivative produced from the meth-
oxy-substituted cyclopentenyl bromide 59b is undoubt-
between the methoxy and tertiary methyl substituents
as the chair alignment depicted in E develops. In 60,
the configuration of the methoxy carbon is now matched,
such that progress is realized along this reaction channel.
In this instance, however, 64 is isolated in only 30% yield
along with two unidentified products. While it is neces-
sary that trienone 55 be formed first, no conditions were
found to retard deconjugation of the double bond internal
to the medium-sized ring, a process which operates very
readily. Thus, although the methoxy group is expelled
(37) Eilbracht, P.; Hittinger, C.; Kufferath, K.; Schmitz, A.; Gilsing,
H.-D. Chem. Ber. 1990, 123, 1089.
(38) The authors have deposited the atomic coordinates for the X-ray
structures with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.

3274 J . Org. Chem., Vol. 61, No. 10, 1996
Paquette et al.
edly internally chelated, whereas that derived from 22
does not have this option. If the logical assumption is
made that internally chelated lithium anions are less
aggregated and significantly smaller than normal tet-
rameric species, their smaller size could facilitate a more
closely balanced partitioning of exo and endo attack.
Finally, a new base-promoted [1,3] sigmatropic rear-
rangement has been discovered. The scaffolding poten-
tial of this process in total synthesis remains to be tested.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. Melting points are uncorrected.
The column chromatographic separations were performed with
Woelm silica gel (230-400 mesh). Solvents were reagent
grade and in most cases dried prior to use. The purity of all
compounds was shown to be >95% by TLC and high-field 1H
(300 MHz) and 13C NMR (75 MHz). The high-resolution and
fast-atom-bombardment mass spectra were obtained at The
Ohio State University Campus Chemical Instrumentation
Center. Elemental analyses were performed at the Scandi-
navian Microanalytical Laboratory, Herlev, Denmark.
(15 mL) was treated with sec-butyllithium (4.6 mL of 1.3 M
solution in cyclohexane, 6 mmol) at -78 °C under argon. After
30 min of stirring, the solution containing 12 was transferred
to the cerium chloride suspension via cannula at -78 °C. The
resulting mixture was stirred for 3 h at this temperature before
introduction of a solution of ketone 11 (821.2 mg, 5 mmol) in
THF (15 mL) via cannula. After 16 h of stirring at -78 °C,
the mixture was slowly warmed to rt and then quenched with
brine at 0 °C. The aqueous phase was extracted with ether,
and the combined organic phases were dried and evaporated.
Treatment with 10% ethyl acetate in petroleum ether afforded
380 mg of 14. The mother liquor was subjected to MPLC (silica
gel, elution with 10% ethyl acetate in petroleum ether) to give
an additional 140 mg of 14 (total 520 mg, 31%), 215 mg (13%)
of 15, and 198 mg (12%) of 16, along with 300 mg (37%) of
recovered 11 which was 25% enriched in the levorotatory
enantiomer.
(+)-(S )-S -[[(1S ,2R ,4S ,5S )-2-H yd r oxy-1,4-d im e t h yl-8-
m e t h yle n e b icyclo[3.2.1]oct -2-yl]m e t h yl]-N -m e t h yl-S -
p h en ylsu lfoxim in e (14): white crystals, mp 164-165 °C
(from ethyl acetate); IR (KBr, cm-1) 3270, 1470, 1450, 1410,
1400, 1390, 1365, 1355, 1295, 1265, 1250, 1230, 1215, 1155,
1110, 1085, 1075, 1035, 995, 945, 900, 855; 1H NMR (300 MHz,
CDCl3) δ 7.88-7.83 (m, 2 H), 7.66-7.54 (m, 3 H), 6.65 (br s, 1
H), 4.78 (d, J ) 0.8 Hz, 1 H), 4.43 (d, J ) 0.8 Hz, 1 H), 3.33 (d,
J ) 14.1 Hz, 1 H), 3.20 (dd, J ) 14.1, 2.0 Hz, 1 H), 2.72 (dd,
J ) 14.2, 4.4 Hz, 1 H), 2.60 (s, 3 H), 2.29-2.19 (m, 2 H), 1.85-
1.67 (m, 1 H), 1.62-1.41 (m, 3 H), 1.26-1.15 (m, 1 H), 1.00 (s,
3 H), 0.88 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 159.5, 139.3, 133.0, 129.6 (2 C), 129.0 (2 C), 102.1, 77.2,
58.5, 50.7, 49.4, 39.4, 35.0, 32.4, 28.8, 21.9, 18.8, 16.1; MS m/z
(M+) calcd 333.1763, obsd 333.1766; [R]23D +7.4 (c 0.01, CHCl3).
Anal. Calcd for C19H27NO2S: C, 68.43; H, 8.16. Found: C,
68.35; H, 8.16.
1,4-Dim e t h yl-8-m e t h yle n e b icyclo[3.2.1]oct -3-e n -2-
on e (10). A suspension of methyltriphenylphosphonium
bromide (2.6 g, 7.3 mmol) in THF (40 mL) was treated with
n-butyllithium (4.2 mL of 1.6 M in hexane, 6.7 mmol). After
15 min, the reaction mixture was cooled to -78 °C and a
solution of 911 (1.0 g, 6.7 mmol) in THF (14 mL) was introduced
via cannula. The mixture was allowed to warm slowly to rt
and after a total of 3 h was poured into saturated NaHCO3
solution. The aqueous phase was extracted with CH2Cl2 (4×),
and the combined organic phases were dried and evaporated.
Chromatography of the residue on silica gel (elution with 10%
ethyl acetate in petroleum ether) afforded 0.88 g (89%) of 10
as a colorless liquid: IR (neat, cm-1) 1680, 1660, 1630, 1440,
1
1340, 1180, 1100, 900; H NMR (300 MHz, CDCl3) δ 5.68 (br
s, 1 H), 4.71 (s, 1 H), 4.59 (s, 1 H), 3.09 (d, J ) 6.2 Hz, 1 H),
2.20-1.95 (m, 1 H), 2.04 (d, J ) 1.4 Hz, 3 H), 1.85-1.70 (m, 2
H), 1.70-1.55 (m, 1 H), 1.31 (s, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 202.7, 167.7, 157.8, 123.3, 100.1, 55.8, 51.2, 33.6, 28.4,
22.4, 15.2; MS m/z (M+) calcd 162.1045, obsd 162.1006.
Anal. Calcd for C11H14O: C, 81.44; H, 8.70. Found: C,
81.33; H, 8.76.
1,4-Dim eth yl-8-m eth ylen ebicyclo[3.2.1]octan -2-on e (11).
To a suspension of copper(I) iodide (0.36 g, 1.85 mmol) in THF
at 0 °C was added methyllithium (1.3 mL of 1.4 M in ether,
1.85 mmol). The reaction mixture was cooled to -50 °C prior
to the addition of HMPA (10 mL) and diisobutylaluminum
hydride (24.7 mL of 1.0 M in toluene, 24.7 mmol). After 30
min of stirring, a solution of 10 (1.0 g, 6.17 mmol) in THF (7
mL) was introduced via cannula. The mixture was stirred for
1.5 h and poured into a 10% hydrochloric acid solution, the
aqueous phase was extracted with ether (4×), and the com-
bined organic extracts were washed with 10% hydrochloric acid
prior to drying. After removal of solvent, chromatography of
the residue on silica gel (elution with 10% ethyl acetate in
petroleum ether) gave 0.87 g (86%) of 11 as a colorless oil: IR
(neat, cm-1) 1710, 1660, 1470, 1450, 1420, 1380, 1350, 1330,
1165, 1150, 1120, 1070, 1030, 900; 1H NMR (300 MHz, CDCl3)
δ 4.90 (s, 1 H), 4.66 (s, 1 H), 2.59 (br s, 1 H), 2.35-2.20 (m, 1
H), 2.20-2.06 (m, 1 H), 2.05-1.90 (m, 1 H), 1.88-1.75 (m, 3
H), 1.72-1.60 (m, 1 H), 1.17 (s, 3 H), 1.00 (d, J ) 6.5 Hz, 3 H);
13C NMR (75 MHz, CDCl3) ppm 210.1, 157.2, 103.0, 56.4, 48.8,
42.9, 37.2, 35.7, 20.9, 18.7, 15.2; MS m/z (M+) calcd 164.1201,
obsd 164.1191.
(+)-(S)-S-[[(1R,2S,4R,5R)-2-H yd r oxy-1,4-d im et h yl-8-
m e t h yle n e b icyclo[3.2.1]oct -2-yl]m e t h yl]-N -m e t h yl-S -
p h en ylsu lfoxim in e (15): colorless oil; IR (neat, cm-1) 3490,
1660, 1650, 1475, 1440, 1420, 1390, 1370, 1295, 1270, 1240,
1195, 1150, 1110, 1085, 1045, 1000, 975, 950, 890, 840, 780,
1
740, 690; H NMR (300 MHz, CDCl3) δ 7.85-7.82 (m, 2 H),
7.62-7.51 (m, 3 H), 5.97 (br s, 1 H), 4.76 (s, 1 H), 4.54 (s, 1 H),
3.48 (d, J ) 4.9 Hz, 1 H), 3.29 (dd, J ) 4.9, 1.5 Hz, 1 H), 2.75
(s, 3 H), 2.18-2.08 (m, 2 H), 1.90 (dd, J ) 12.5, 3.7 Hz, 1 H),
1.48-1.40 (m, 2 H), 1.27-1.07 (m, 3 H), 1.05 (s, 3 H), 0.58 (d,
J ) 6.4 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 159.0, 140.3,
132.9, 129.4 (2 C), 128.9 (2 C), 102.3, 74.9, 59.9, 50.5, 49.1,
39.6, 34.7, 32.5, 29.2, 21.6, 18.4, 16.12; MS m/z (M)+ calcd
333.1763, obsd 333.1750; [R]23 +35.3 (c 0.01, CHCl3).
D
Anal. Calcd for C19H27NO2S: C, 68.43; H, 8.16. Found: C,
68.28; H, 8.17.
Anal. Calcd for C11H16O: C, 80.44; H, 9.82. Found: C,
80.55; H, 9.93.
(+)-(S)-S-[[(1R,2R,4R,5R)-2-H yd r oxy-1,4-d im et h yl-8-
m e t h yle n e b icyclo[3.2.1]oct -2-yl]m e t h yl]-N -m e t h yl-S -
p h en ylsu lfoxim in e (16): white crystals, mp 131-131.5 °C
(from petroleum ether at -20 °C); IR (film, cm-1) 3260, 1660,
1440, 1375, 1340, 1230, 1170, 1150, 1110, 1080, 1055, 1025,
1000, 980, 950, 875, 860; 1H NMR (300 MHz, CDCl3) δ 7.89-
7.80 (m, 2 H), 7.66-7.25 (m, 3 H), 6.39 (br s, 1 H), 4.89 (s, 1
H), 4.61 (s, 1 H), 3.30 (d, J ) 13.5 Hz, 1 H), 3.10 (d, J ) 13.5
Resolu tion of Keton e 11. Anhydrous cerium trichloride
(1.85 g, 7.5 mmol) was further dried at 140 °C under high
vacuum for 16 h and then cooled under argon. To this was
added THF (25 mL), and the suspension was stirred for 2 h
before being cooled to -78 °C and treated with several drops
of sec-butyllithium until a pale yellow color persisted.
A
solution of enantiopure sulfoximine (846 mg, 5 mmol)13 in THF

Stereoselective Construction of Ceroplastin Core
J . Org. Chem., Vol. 61, No. 10, 1996 3275
Hz, 1 H), 2.58 (s, 3 H), 2.42 (dd, J ) 14.3, 4.6 Hz, 1 H), 2.35
(br d, J ) 4.6 Hz, 1 H), 2.25-2.11 (m, 1 H), 1.59-1.39 (m, 4
H), 1.32-1.19 (m, 1 H), 0.98 (s, 3 H), 0.92 (d, J ) 6.8 Hz, 3 H);
13C NMR (75 MHz, CDCl3) ppm 159.2, 139.2, 133.1, 129.6 (2
C), 129.0 (2 C), 101.8, 78.1, 61.6, 49.6, 49.2, 38.8, 35.0, 32.9,
28.8, 20.8, 18.9, 16.8; MS m/z (M+ + H) calcd 334.1841, obsd
µL of 1.3 M in cyclohexane, 0.70 mmol) at -20 °C under argon.
The reaction mixture was stirred for 40 min before 10 (81.1
mg, 0.5 mmol) dissolved in THF (1 mL) was introduced. The
mixture was stirred for 1 h at -20 °C and for 1 h at rt, cooled
to -20 °C, and quenched with brine. The aqueous phase was
extracted with ether, and the combined organic phases were
washed with saturated NaHCO3 solution and brine and then
dried and evaporated. Chromatography of the residue on silica
gel (elution with 0.5% ethyl acetate in petroleum ether) gave
70 mg (57%) of 25. Starting enone 10 (26 mg, 12%) was
recovered by increasing the eluant polarity (5% ethyl acetate
in petroleum ether). The yield of alcohol 25 based on recovery
of starting enone was 65%: IR (neat, cm-1) 3490, 1680, 1440,
334.1859; [R]23 +54.8 (c 0.004, CHCl3).
D
Anal. Calcd for C19H27NO2S: C, 68.43; H, 8.16. Found: C,
68.66; H, 8.17.
(+)-(1S,4S,5S)-1,4-Dim eth yl-8-m eth ylen ebicyclo[3.2.1]-
octa n -2-on e ((+)-11). A solution of 14 (293 mg, 0.879 mmol)
in toluene (50 mL) was deoxygenated for 30 min with argon
and heated to reflux. After 12 h, the cooled solution was placed
on silica gel and eluted with petroleum ether to remove toluene
followed by 5% ethyl acetate in petroleum ether to give 125
1
1375, 1150, 1030, 990, 885; H NMR (300 MHz, C6D6) δ 4.84
(d, J ) 1.1 Hz, 1 H), 4.69 (d, J ) 1.0 Hz, 1 H), 4.56 (d, J ) 1.0
Hz, 1 H), 2.65-2.35 (m, 4 H), 2.35-2.20 (m, 2 H), 1.97-1.82
(m, 3 H), 1.76-1.20 (series of m, 6 H), 1.54 (d, J ) 1.5 Hz, 3
H), 1.25 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 158.6, 139.3,
138.1, 134.8, 127.2, 100.6, 82.9, 50.7, 49.6, 41.5, 38.8, 32.1, 29.8,
22.6, 21.3, 18.5, 16.9; MS m/z (M+) calcd 244.1827, obsd
244.1860.
mg (87%) of (+)-11, [R]23 +38.4 (c 0.01, CHCl3).
D
(-)-(1R,4R,5R)-1,4-Dim eth yl-8-m eth ylen ebicyclo[3.2.1]-
octa n -2-on e ((-)-11). A. By Clea va ge of 16. A solution of
16 (19 mg, 0.057 mmol) in toluene (3 mL) was heated as
described above to give 8.7 mg (93%) of (-)-11, [R]23 -37.9 (c
D
0.01, CHCl3).
Anal. Calcd for C17H24O: C, 83.54; H, 9.91. Found: C,
83.35; H, 9.87.
B. By Clea va ge of 15. Heating 15 as above gave the same
levorotatory ketone as did 16 in 90% yield.
B. Use of ter t-Bu tyllith iu m in Eth er . A solution of 22
(76 mg, 0.46 mmol) in anhydrous ether (1.5 mL) was treated
with tert-butyllithium (0.9 mL of 1.7 M in pentane, 1.53 mmol)
at -78 °C and stirred for 1 h. The reaction mixture was
allowed to warm to 0 °C for 15 min, at which time a solution
of 10 (72 mg, 0.45 mmol) in ether (4.1 mL) was introduced.
The resulting mixture was stirred at 0 °C for 2 h and warmed
to rt for 2 h before being quenched with brine (2 mL). Workup
in the predescribed manner gave 54 mg (50%) of a 6.9:1
mixture of 25 and i, together with 26 mg (36%) of recovered
10.
(-)-(1R,5R)-1,4-Dim eth yl-8-m eth ylen ebicyclo[3.2.1]oct-
3-en -2-on e ((-)-10). A solution of (-)-11 (32.8 mg, 0.2 mmol)
in THF (4 mL) was treated with KHMDS (0.6 mL, 0.5 M in
toluene, 0.3 mmol) at -78 °C under argon. After 30 min, solid
N-(phenylseleno)phthalimide (60.4 mg, 0.2 mmol) was added.
The resulting mixture was stirred at this temperature for 2 h
before being allowed to warm slowly to rt and quenched with
brine. The aqueous phase was extracted with ether, and the
combined organic phases were washed with brine and dried.
After solvent removal, the residue was purified by chroma-
tography on silica gel (elution with 2.5% ethyl acetate in
petroleum ether) to give 52 mg (81%) of selenide 17 as a yellow
oil: IR (neat, cm-1) 1710, 1660, 1575, 1475, 1445, 1435, 1370,
1325, 1300, 1290, 1270, 1250, 1160, 1110, 1070, 1050, 1025,
1
1000, 900; H NMR (300 MHz, CDCl3) δ 7.48-7.44 (m, 2 H),
7.19-7.15 (m, 3 H), 4.81 (s, 1 H), 4.62 (s, 1 H), 3.48 (d, J )
11.3 Hz, 1 H), 2.61 (br s, 1 H), 1.95-1.55 (series of m, 5 H),
1.20 (s, 3 H), 1.18 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 205.7, 155.5, 134.7 (2 C), 129.4, 128.9 (2 C), 127.5,
104.0, 56.9, 56.8, 49.5, 43.9, 35.7, 21.2, 18.9, 16.5; MS m/z (M+)
calcd for 320.0679, obsd 320.0646.
For i: colorless oil; IR (neat, cm-1) 3472, 1666, 1625, 1455,
1377, 1347, 1173, 1070, 894, 694; 1H NMR (300 MHz, C6D6) δ
5.19 (d, J ) 1.7 Hz, 1 H), 4.68 (s, 1 H), 4.62 (s, 1 H), 2.56 (d,
J ) 7.7 Hz, 1 H), 2.47-2.30 (m, 1 H), 2.28 (m, 1 H), 2.17 (t, J
) 7.2 Hz, 1 H), 1.79-1.66 (m, 4 H), 1.56 (s, 3 H), 1.64-1.40
(m, 2 H), 1.35 (s, 3 H), 1.37-1.22 (m, 2 H), 1.05 (s, 3 H); 13C
NMR (75 MHz, C6D6) ppm 160.0, 146.2, 136.2, 134.9, 130.5,
100.3, 74.9, 54.7, 46.0, 38.7, 38.1, 38.0, 24.4, 23.8, 22.7, 18.0,
14.9; MS m/ z (M+) calcd 244.1827, obsd 244.1843.
To a mixture of 17 (32 mg, 0.1 mmol) and pyridine (8.1 µL)
in CH2Cl2 (1 mL) was added 34 mL of 30% H2O2 at 0 °C. This
mixture was warmed to rt, stirred for 30 min, and poured into
saturated NaHCO3 solution. The aqueous phase was extracted
with ether, and the combined organic phases were washed with
brine, dried, and evaporated. Purification of the residue by
chromatography on silica gel (elution with 5% ethyl acetate
in petroleum ether) gave 13 mg (80%) of (-)-10, [R]23 -52.7
D
(c 0.01, CHCl3).
(+)-(1S,5S)-1,4-Dim eth yl-8-m eth ylen ebicyclo[3.2.1]oct-
3-en -2-on e ((+)-11). A solution of (+)-11 (32.8 mg, 0.2 mmol)
in THF (4 mL) was treated with KHMDS (0.6 mL, 0.5 M in
toluene, 0.3 mmol) at -78 °C under argon. After 30 min, solid
N-(phenylseleno)phthalimide (60.4 mg, 0.2 mmol) was added.
The resulting mixture was stirred at this temperature for 2 h
before being allowed to warm slowly to rt and quenched with
brine. The aqueous phase was extracted with ether, and the
combined organic phases were washed with brine and dried.
After solvent removal, selenide 18 was dissolved in CH2Cl2 (2
mL), treated with pyridine (18 µL), and cooled to 0 °C prior to
treatment with 70 µL of 30% H2O2. The reaction mixture was
warmed to rt, stirred for 30 min, and poured into saturated
NaHCO3 solution. The aqueous phase was extracted with
ether, and the combined organic phases were washed with
brine prior to drying and solvent evaporation. Purification of
the residue by chromatography on silica gel (elution with 5%
ethyl acetate in petroleum ether) gave 24 mg (74% overall) of
Anal. Calcd for C17H24O: C, 83.54; H, 9.91. Found: C,
83.55; H, 9.95.
(3a S,6a S,10a S)-1,3,3a ,6a ,7,8,10,10a -Octa h yd r o-6,9,10a -
tr im eth yld icyclop en ta [a ,d ]cycloocten -4(2H)-on e (26). A
mixture of 18-crown-6 (21.7 mg, 0.082 mmol), alcohol 25 (16.7
mg, 0.0683 mmol), and dry THF (2 mL) was treated with
potassium hexamethyldisilazide (0.18 mL of 0.5 M solution in
toluene, 0.26 mmol) at 0 °C under argon. The reaction mixture
was allowed to warm to rt and stirred for 30 min before being
cooled to 0 °C and quenched with absolute ethanol (0.5 mL).
The mixture was filtered through neutral alumina (the filter
cake was washed with ether), the solvent was removed, and
the residue was purified chromatographically on silica gel
(elution with 2.5% ethyl acetate in petroleum ether) to give
10 mg (61%) of 26 as a colorless oil:
1H NMR (300 MHz, C6D6)
δ 6.23 (s, 1 H), 3.97 (br s, 1 H), 2.87 (m, 1 H), 2.65-2.40 (m, 1
H), 2.30-1.80 (m, 3 H), 1.80-1.55 (m, 3 H), 1.53 (s, 3 H), 1.45
(s, 3 H), 1.40-1.00 (m, 2 H), 0.98-0.78 (m, 3 H), 0.74 (s, 3 H);
13C NMR (75 MHz, C6D6) ppm 201.5, 152.0, 134.3, 132.6, 132.5,
58.7, 54.9, 50.7, 39.4, 37.5, 34.7, 26.0, 25.8, 25.2, 24.0, 21.6,
14.5; MS m/z (M - CH3)+ calcd 229.1592, obsd 229.1644.
(1R,2R,4R,5R)-1,4-Dim eth yl-2-(2-m eth yl-1-cyclop en ten -
1-yl)-8-m eth ylen ebicyclo[3.2.1]octa n -2-ol (27). A solution
(+)-11, [R]23 +53.0 (c 0.01, CHCl3).
D
(1R,2R,5R)-1,4-Dim eth yl-2-(2-m eth yl-1-cyclop en ten -1-
yl)-8-m eth ylen ebicyclo[3.2.1]oct-3-en -2-ol (25). A. Use of
sec-Bu tyllith iu m in THF . A solution of 22 (120.8 mg, 0.75
mmol) in THF (3 mL) was treated with sec-butyllithium (538.5

3276 J . Org. Chem., Vol. 61, No. 10, 1996
Paquette et al.
of 22 (121 mg, 0.75 mmol) in THF (3 mL) was treated with
tert-butyllithium (0.97 mL of 1.7 M in pentane, 1.65 mmol) at
-78 °C under argon. After 40 min of stirring, a solution of 11
(82 mg, 0.5 mmol) in THF (1 mL) was introduced via syringe.
The reaction mixture was stirred for 30 min at -78 °C before
being warmed to rt. After an additional hour of stirring, the
reaction mixture was quenched with brine, the aqueous phase
was extracted with ether, and the combined organic phases
were washed with brine, dried, and evaporated. After solvent
removal, chromatography of the residue on silica gel (elution
with 3% ethyl acetate in petroleum ether) gave 69 mg (56%)
of 27 as a colorless oil and 32 mg (39%) of recovered 11.
For 27: IR (neat, cm-1) 3540, 1650, 1470, 1450, 1370, 1330,
1320, 1280, 1040, 1000, 890, 690; 1H NMR (300 MHz, CDCl3)
δ 4.97 (d, J ) 0.9 Hz, 1 H), 4.70 (d, J ) 0.9 Hz, 1 H), 2.60-
2.40 (m, 2 H), 2.36-2.25 (m, 3 H), 2.19 (s, 1 H), 2.05-1.94 (m,
2 H), 1.93 (dd, J ) 0.9, 0.8 Hz, 3 H), 1.75-1.27 (series of m, 7
H), 1.04 (s, 3 H), 0.88 (d, J ) 6.66 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 161.6, 136.4, 134.7, 102.7, 79.8, 52.2, 49.3, 40.9,
40.3, 38.3, 35.2, 33.4, 22.4, 20.6, 18.9, 17.7, 17.2; MS m/z (M+)
calcd 246.1983, obsd 246.2001.
s, 1 H), 2.35-2.17 (m, 2 H), 2.03-1.88 (m, 2 H), 1.73 (s, 3 H),
1.72-1.63 (m, 1 H), 1.56-1.32 (m, 2 H), 0.89 (s, 9 H), 0.78 (d,
J ) 6.9 Hz, 3 H), 0.04 (s, 6 H); 13C NMR (75 MHz, CDCl3)
ppm 144.5, 129.5, 118.5 (q, J ) 319.9 Hz, CF3), 61.2, 47.6, 37.7,
32.2, 29.8, 25.9 (3 C), 20.5, 18.3, 13.7, 12.3, -5.4, -5.5; MS
m/z (M+ - C4H9) calcd 359.0961, obsd 359.0973.
Anal. Calcd for C17H31F3O4SSi: C, 49.02; H, 7.50. Found:
C, 48.67; H, 7.38.
Sequ en tia l P a lla d iu m -Ca ta lyzed Sta n n yla tion a n d
Ha logen a tion of Vin yl Tr ifla te 42. A mixture of 42 (1.50
g, 3.6 mmol), lithium chloride (916 mg, 21.6 mmol), hexa-
methylditin (1.31 g, 4.0 mmol), and Pd(Ph3P)4 (416 mg, 0.36
mmol) in THF (60 mL) was deoxygenated for 30 min with
argon and heated gently at reflux for 16 h under argon. After
cooling, petroleum ether was added, followed by saturated
NaHCO3 solution. The aqueous layer was extracted with
petroleum ether, and the combined organic phases were
washed with saturated NaHCO3 solution and brine prior to
drying and solvent removal. The product was taken up in
petroleum ether and filtered through silica gel (pretreated with
20% triethylamine in petroleum ether; elution with 1% tri-
ethylamine in petroleum ether) to give crude vinyltin 43 (1.56
g, which contained a trace amount of methylated compound
ii and a small amount of hexamethylditin) as a colorless oil.
This material was dissolved in CH2Cl2 (50 mL) and treated
with bromine (1 M solution in dichloromethane) at -78 °C
until the reaction mixture turned slightly yellow. After 5 min,
pentane (30 mL) was added, and the mixture was poured into
saturated Na2SO3 solution. The aqueous phase was extracted
with petroleum ether, and the combined organic phases were
washed with 1.5% aqueous NH4OH solution prior to drying
and solvent evaporation. The crude product was purified by
column chromatography on silica gel (elution with petroleum
ether) to give 456 mg (37% overall) of vinyl bromide 44 as a
colorless oil; 180 mg (12%) of triflate 42 was recovered. The
overall yield of 44 based on the recovered starting material
was 43%.
Anal. Calcd for C17H26O: C, 82.87; H, 10.64. Found: C,
82.64; H, 10.72.
[[(5S,7S,7a S)-2,4,5,6,7,7a -Hexa h yd r o-3,7-d im eth yl-5-(2-
m et h yl-1-cyclop en t en -1-yl)in d en -5-yl]oxy]t r im et h ylsi-
la n e (28). A solution of 18-crown-6 (63.4 mg, 0.24 mmol) and
27 (49.3 mg, 0.2 mmol) in THF (3 mL) was treated with
potassium hexamethyldisilazide (0.25 mL of 0.5 M in toluene,
0.26 mmol) via syringe at 0 °C under argon. The reaction
mixture was allowed to warm to rt, stirred for 30 min, and
cooled to -78 °C prior to being quenched with freshly distilled
chlorotrimethylsilane (76.2 mL, 0.6 mmol). After 30 min of
stirring, the mixture was warmed to rt and poured into a
stirred mixture of ether and saturated NaHCO3 solution. The
aqueous phase was extracted with ether, and the combined
organic phases were washed with saturated NaHCO3 solution
and brine, dried, and evaporated. The crude product was
filtered through Florisil (elution with 0.5% ether in petroleum
ether) to give 51 mg (81%) of silyl ether 28 as a colorless oil:
IR (neat, cm-1) 1440, 1250, 1075, 1050, 1035, 840, 755; 1H
NMR (300 MHz, C6D6) δ 3.01 (dd, J ) 13.4, 1.9 Hz, 1 H), 2.77
(br s, 1 H), 2.65-1.92 (series of m, 10 H), 1.91 (dd, J ) 1.0, 0.9
Hz, 3 H), 1.85-1.45 (series of m, 4 H), 1.57 (br s, 3 H), 0.75 (d,
J ) 7.4 Hz, 3 H), 0.18 (s, 9 H); 13C NMR (75 MHz, C6D6) ppm
140.6, 136.0, 133.9, 130.5, 76.0, 50.4, 47.0, 40.7, 40.2, 38.4, 35.1,
31.8, 24.1, 22.5, 16.8, 14.7, 14.0, 2.4 (3 C); MS m/z (M+) calcd
318.2379, obsd 318.2435.
ter t-Bu tyld im eth yl[(3S)-3-[(1R)-3-m eth yl-2-(tr im eth yl-
sta n n yl)-2-cyclop en ten -1-yl]bu toxy]sila n e (43): IR (neat,
cm-1) 1615, 1470, 1460, 1440, 1385, 1370, 1360, 1190, 1110,
1005, 980, 900, 835, 810, 775; 1H NMR (300 MHz, C6D6) δ
3.68-3.62 (m, 2 H), 2.99 (br s, 1 H), 2.28-2.22 (m, 2 H), 2.10-
1.90 (m, 1 H), 1.80-1.30 (series of m, 4 H), 1.74 (dd, J ) 0.8,
0.9 Hz, 3 H), 1.00 (s, 9 H), 0.74 (d, J ) 6.9 Hz, 3 H), 0.26 (s, 9
H), 0.09 (s, 6 H); 13C NMR (75 MHz, C6D6) ppm 149.5, 140.2,
61.6, 57.1, 39.8, 39.7, 33.0, 26.2 (3 C), 24.1, 18.5, 18.4, 13.5,
-5.1, -5.2, -8.8 (3 C); MS m/z (M+) calcd for C19H40OSi120Sn
432.1870, obsd 432.1634.
ter t-Bu t yl[(3S)-3-[(1R)-2,3-d im et h yl-2-cyclop en t en -1-
yl]bu toxy]d im eth ylsila n e (ii): 1H NMR (300 MHz, CDCl3)
δ 3.70-3.60 (m, 2 H), 2.59 (br s, 1 H), 2.18 (m, 2 H), 2.00-
1.85 (m, 1 H), 1.80-1.64 (m, 1 H), 1.61 (br s, 3 H), 1.52 (br s,
3 H), 1.60-1.40 (m, 3 H), 0.90 (s, 9 H), 0.63 (d, J ) 6.8 Hz, 3
H), 0.60 (s, 6 H); 13C NMR (75 MHz, CDCl3) ppm 132.4, 131.7,
61.6, 53.6, 38.6, 37.3, 29.8, 25.8 (3 C), 21.6, 18.2, 13.7, 13.2,
11.8, -5.4 (2 C); MS m/z (M+ - C4H9) calcd 225.1674, obsd
225.1653.
ter t-Bu t yld im et h yl[(3S)-3-[(1R)-2-b r om o-3-m et h yl-2-
cyclop en ten -1-yl]bu toxy]sila n e (44): IR (neat, cm-1) 1655,
1465, 1460, 1435, 1375, 1355, 1250, 1100, 1000, 985, 935, 900,
835, 810, 775; 1H NMR (300 MHz, C6D6) δ 3.71-3.57 (m, 2
H), 2.90 (br s, 1 H), 2.41-2.31 (m, 1 H), 2.04-1.84 (m, 2 H),
1.65 (dd, J ) 0.9, 1.0 Hz, 3 H), 1.61-1.40 (m, 4 H), 1.06 (s, 9
H), 0.80 (d, J ) 6.9 Hz, 3 H), 0.14 (s, 6 H); 13C NMR (75 MHz,
C6D6) ppm 137.3, 121.3, 61.5, 54.2, 38.3, 35.7, 30.7, 26.2 (3 C),
21.7, 18.5, 15.7, 13.3, -5.2, -5.2; MS m/z (M+ - CH3) calcd
331.1093, obsd 331.1093, (M+ - C4H9) calcd 289.0623, obsd
289.0619.
Anal. Calcd for C20H34OSi: C, 75.40; H, 10.76. Found: C,
75.42; H, 10.80.
(7S,7a S)-2,6,7,7a -Tetr a h yd r o-3,7-d im eth yl-5-(2-m eth yl-
1-cyclop en ten -1-yl)in d en e (30). When silyl ether 28 was
treated with silica gel, triene 30 was obtained as a colorless
oil contaminated with a trace of isomer 31. For the major
triene 30: 1H NMR (300 MHz, C6D6) δ 6.43 (br s, 1 H), 3.05-
2.80 (m, 1 H), 2.70-2.50 (m, 3 H), 2.50-2.00 (series of m, 6
H), 1.88-1.50 (series of m, 4 H), 1.86 (s, 3 H), 1.78 (br s, 3 H),
0.94 (d, J ) 6.9 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 137.6,
134.1, 133.9, 133.3, 132.8, 119.3, 48.6, 40.7, 38.3, 38.1, 36.5,
29.6, 26.0, 22.2, 16.2, 13.7, 13.3; MS m/z (M+) calcd 228.1878,
obsd 228.1843.
(5R)-5-[(1S)-3-(ter t-Bu tyld im eth ylsiloxy)-1-m eth ylp r o-
pyl]-1-h ydr oxy-2-m eth ylcyclopen ten yl Tr iflu or om eth an e-
su lfon a te (42). To a solution of L-Selectride (4.25 mL of 1 M
solution, 4.25 mmol) in THF (50 mL) was added a solution of
41 (1.00 g, 3.54 mmol) in THF (5 mL) via cannula at -78 °C
under argon. After 30 min, solid N-phenyltriflimide (1.52 g,
4.25 mmol) was added and the mixture was allowed to warm
to rt. After 16 h, the mixture was poured into cold saturated
NaHCO3 solution, the aqueous phase was extracted with
petroleum ether, and the combined organic phases were
washed with saturated NaHCO3 solution and brine prior to
drying and solvent removal. Chromatography of the residue
on silica gel (elution with 1.25% ethyl acetate in petroleum
ether) gave 1.21 g (82%) of 42 as a colorless oil: IR (neat, cm-1
)
1460, 1420, 1380, 1250, 1210, 1145, 1105, 1055, 1000, 940, 900,
850, 780; 1H NMR (300 MHz, CDCl3) δ 3.63 (m, 2 H), 3.01 (br

Stereoselective Construction of Ceroplastin Core
J . Org. Chem., Vol. 61, No. 10, 1996 3277
ter t-Bu t yld im et h yl[(3S)-3-[(1R)-2-iod o-3-m et h yl-2-cy-
clop en ten -1-yl]bu toxy]sila n e (45). To a solution of 43 (1
equiv) in CH2Cl2 (50 mL/g vinyltin) was added iodine crystals
(1.1 equiv) at rt. After 15 min, the mixture was diluted with
pentane and poured into saturated NaHSO3 solution. The
organic phase was washed with 1.5% aqueous NH4OH solu-
tion, dried, and freed of solvent. The crude product was
purified by column chromatography on silica gel (elution with
1% triethylamine in petroleum ether) to give vinyl iodide 45
as a colorless oil: IR (neat, cm-1) 1640, 1470, 1460, 1430, 1375,
3.54 (ddd, J ) 7.0, 2.0, 2.0 Hz, 2 H), 2.62 (br d, J ) 5.3 Hz, 1
H), 2.77 (br d, J ) 8.7 Hz, 1 H), 2.45-2.25 (m, 3 H), 2.10-
1.90 (m, 2 H), 1.97 (s, 3 H),1.73 (d, J ) 1.4 Hz, 3 H), 1.72-
1.25 (m, 9 H), 1.15 (s, 3 H), 0.72 (d, J ) 7.0 Hz, 3 H); MS m/z
(M+) calcd 316.2402, obsd 316.2415.
ter t-Bu tyld im eth yl[(3S)-3-[(1R)-3-m eth yl-2-[(1S,5S)-1-
m eth yl-4,8-d im eth ylen ebicyclo[3.2.1]oct-2-en -2-yl]-2-cy-
clop en ten -1-yl]bu toxy]sila n e (48). A solution of 46 (6 mg,
0.014 mmol) in C6D6 was sealed in an NMR tube (nonbase
washed) and heated at 180 °C for 20 h. The NMR spectrum
indicated that clean dehydration had occurred. Purification
was achieved by filtration through silica gel (elution with 2%
ethyl acetate in petroleum ether) to give 5 mg (87%) of pure
48: IR (neat, cm-1) 1620, 1465, 1460, 1435, 1400, 1375, 1365,
1
1250, 1100, 1005, 985, 940, 900, 835, 810, 775; H NMR (300
MHz, C6D6) δ 3.65 (m, 2 H), 2.87 (br s, 1 H), 2.36 (m, 1 H),
2.01 (m, 2 H), 1.68 (t, J ) 0.8 Hz, 3 H), 1.66-1.41 (m, 4 H),
1.08 (s, 9 H), 0.75 (d, J ) 6.8 Hz, 3 H), 0.15 (s, 6 H); 13C NMR
(75 MHz, C6D6) ppm 144.1, 100.1, 61.5, 56.8, 38.4, 36.4, 31.7,
1
1255, 1100, 1005, 985, 890, 860, 840, 775, 735; H NMR (300
29.2 (3 C), 22.3, 19.1, 18.5, 13.0, -5.1, -5.2; MS m/z (M+
CH3) calcd 379.0913, obsd 379.0962.
-
MHz, CDCl3) δ 5.57 (s, 1 H), 4.68 (s, 1 H), 4.63 (d, J ) 1.5 Hz,
1 H), 4.53 (s, 1 H), 4.48 (d, J ) 1.5 Hz, 1 H), 3.62 (m, 2 H),
3.22 (d, J ) 7.0 Hz, 1 H), 2.93 (br s, 1 H), 2.26 (m, 2 H), 2.15-
1.98 (m, 2 H), 1.85-1.30 (series of m, 7 H), 1.67 (br s, 3 H),
1.20 (s, 3 H), 0.88 (s, 9 H), 0.56 (d, J ) 6.7 Hz, 3 H), 0.03 (s, 6
H); 13C NMR (75 MHz, CDCl3) ppm 159.7, 153.6, 139.1, 137.1,
127.5, 100.6, 104.4, 97.5, 62.0, 51.3, 45.5, 41.5, 39.2, 37.5, 31.1,
30.5, 26.0 (3 C), 22.5, 19.1, 18.3, 15.4, 13.8, 5.2, -5.3 (2 C);
MS m/z (M+) calcd 412.3161, obsd 412.3158.
(1S,2R,5S)-2-[(5R)-5-[(1S)-3-(ter t-Bu tyld im eth ylsiloxy)-
1-m e t h ylp r op yl]-2-m e t h yl-1-cyclop e n t e n -1-yl]-1,4-d i-
m eth yl-8-m eth ylen ebicyclo[3.2.1]oct-3-en -2-ol (46). An-
hydrous cerium trichloride (160 mg, 0.648 mmol) was further
dried at 140 °C under high vacuum for 16 h and then cooled
under argon. To this solid was added anhydrous THF (2 mL),
and the suspension was stirred for 3 h before being cooled to
-78 °C and treated with several drops of tert-butyllithium
until a slightly yellow color persisted. A solution of 44 (75
mg, 0.216 mmol) in THF (2 mL) was treated with tert-
butyllithium (0.28 mL of 1.7 M solution in pentane, 0.475
mmol) at -78 °C under argon. After 2 h of stirring, this
solution was transferred to the cerium chloride suspension via
cannula at -78 °C. The resulting mixture was stirred for 1 h
at this temperature before a solution of (()-10 (70 mg, 0.216
mmol) in THF (2 mL) was introduced via cannula. After being
stirred for 8 h at -78 °C and 4 h at -20 °C, the mixture was
slowly warmed to rt and quenched with brine at 0 °C. The
aqueous phase was extracted with ether, and the combined
organic phases were dried and evaporated. Purification of the
residue by chromatography on silica gel (elution with 2.5%
ethyl acetate in petroleum ether) gave 25 mg (27%) of 46 as a
colorless oil and 40 mg of recovered starting enone 10.
Cou p lin g of (+)-Keton e 44 to (+)-10. Cerium chloride
heptahydrate (537 mg, 1.44 mmol) was dried at 140 °C under
high vacuum for 16 h and then cooled under argon. To this
solid was added THF (5 mL), and the suspension was stirred
for 3 h before being cooled to -78 °C and treated with several
drops of tert-butyllithium until a pale yellow color persisted.
A solution of 44 (250 mg, 0.72 mmol) in THF (3 mL) was
treated with tert-butyllithium (0.932 mL of 1.7 M solution in
pentane, 1.58 mmol) at -78 °C under argon. After 2 h, the
solution was transferred to the cerium chloride suspension via
cannula at -78 °C. The resulting mixture was stirred for 1 h
at this temperature before introduction of a solution of (+)-10
(118 mg, 0.72 mmol) in THF (2 mL) via cannula. After 3 h at
-78 °C, the mixture was slowly warmed to rt and then
quenched with brine at 0 °C. The aqueous phase was
extracted with ether, and the combined organic phases were
dried and evaporated. Purification of the residue by chroma-
tography on silica gel (elution with 1% ethyl acetate in
petroleum ether) gave 75 mg (17%) of 49 as a colorless oil
followed by 8 mg (2%) of the more polar 50 and 60 mg (51%)
of 10. The combined yield of adducts was 39%, based on the
recovered enone.
For 46: IR (neat, cm-1) 3490, 1660, 1460, 1440, 1375, 1260,
1
1095, 1020, 880, 840, 780; H NMR (300 MHz, CDCl3) δ 5.04
(d, J ) 1.2 Hz, 1 H), 4.68 (d, J ) 0.8 Hz, 1 H), 4.54 (d, J ) 0.8
Hz, 1 H), 3.50 (dd, J ) 7.6, 7.7 Hz, 2 H), 2.70 (br d, J ) 8.5
Hz, 1 H), 2.59 (br d, J ) 5.1 Hz, 1 H), 2.43-2.27 (m, 2 H),
2.08-1.98 (m, 1 H), 1.96 (s, 3 H), 1.93-1.80 (m, 1 H), 1.71 (d,
J ) 1.4 Hz, 3 H), 1.69-1.50 (m, 4 H), 1.62 (s, 1 H), 1.42-1.30
(m, 3 H), 1.14 (s, 3 H), 0.90 (s, 9 H), 0.68 (d, J ) 7.0 Hz, 3 H),
0.04 (s, 6 H); 13C NMR (75 MHz, CDCl3) ppm 158.3, 138.7,
138.2, 137.7, 126.6, 100.1, 83.6, 62.7, 54.3, 50.9, 49.3, 41.0, 39.7,
33.3, 32.1, 29.7, 26.1 (3 C), 23.5, 21.3, 18.4, 18.2, 17.4, 13.7,
-5.2 (2 C); MS m/z (M+) calcd 430.3267, obsd 430.3255.
(1S,2R,4S,5S)-2-[(5R)-5-[(1S)-3-(ter t-Bu t yld im et h ylsi-
loxy)-1-m eth ylp r op yl]-2-m eth yl-1-cyclop en ten -1-yl]-1,4-
dim eth yl-8-m eth ylen ebicyclo[3.2.1]octan -2-ol (49): IR (neat,
cm-1) 3540, 1650, 1465, 1460, 1405, 1370, 1355, 1340, 1310,
1275, 1250, 1220, 1090, 1000, 990, 890, 830, 810, 775, 660; 1H
NMR (300 MHz, CDCl3) δ 4.96 (s, 1 H), 4.68 (s, 1 H), 3.64 (dd,
J ) 7.5, 7.1 Hz, 2 H), 2.82 (m, 1 H), 2.46-2.37 (m, 2 H), 2.26
(m, 1 H), 2.16-1.78 (series of m, 4 H), 1.97 (s, 3 H), 1.68-1.41
(series of m, 7 H), 1.30-1.18 (m, 2 H), 1.02 (s, 3 H), 0.89 (s, 9
H), 0.88 (d, J ) 6.7 Hz, 3 H), 0.71 (d, J ) 7.1 Hz, 3 H), 0.05 (s,
6 H); 13C NMR (75 MHz, CDCl3) ppm 162.0, 139.9, 133.5, 102.8,
79.6, 62.6, 54.7, 54.4, 49.1, 42.6, 40.1, 40.0, 35.7, 33.7, 32.3,
26.0 (3 C), 22.7, 20.3, 18.9, 18.7, 18.4, 17.5, 14.2, -5.2 (2 C);
Attem p ted Ba se-P r om oted Rea r r a n gem en t of 46.
A
solution of 46 (11 mg, 0.0255 mmol) and 18-crown-6 (13.5 mg,
0.051 mmol) in THF (3 mL) was treated with KHMDS (0.102
mL, 0.5 M in toluene). After 2 h of stirring at rt, the mixture
was quenched with brine and the aqueous phase was extracted
with ether. The combined organic phases were dried, solvent
was removed, and the residue was subjected to chromatogra-
phy on silica gel (elution first with 2.5% ethyl acetate in
petroleum ether followed by 20% ethyl acetate in petroleum
ether) to give 6 mg of recovered 46 and 2 mg of 47, spectro-
scopically identical to the product obtained from fluoride-
induced desilylation (see below).
(1S,2R,5S)-2-[(5R)-5-[(1S)-3-Hyd r oxy-1-m eth ylp r op yl]-
2-m e t h y l-1-c y c lo p e n t e n -1-y l]-1,4-d im e t h y l-8-m e t h -
ylen ebicyclo[3.2.1]oct-3-en -2-ol (47). A solution of 46 (2 mg,
0.0046 mmol) in THF (1 mL) was treated with tetrabutylam-
monium fluoride (0.014 mL, 1 M solution in THF, 0.014 mmol).
After 16 h of stirring at rt, the mixture was diluted with ether
and poured into ice water, the aqueous phase was extracted
with ether, and the combined organic phases were washed with
brine prior to drying. After solvent removal, the residue was
purified by chromatography on silica gel (elution with 30%
ethyl acetate in petroleum ether) to give 1.2 mg (82%) of 47:
1H NMR (300 MHz, CDCl3) δ 5.06 (br s, 1 H), 4.71 (s, 1 H),
MS m/z (M+) calcd 432.3424, obsd 432.3407; [R]23 +9.0 (c
D
0.007, CHCl3).
(1S,2R,4S,5S)-2-[(5S)-5-[(1R)-3-(ter t-Bu t yld im et h ylsi-
loxy)-1-m eth ylp r op yl]-2-m eth yl-1-cyclop en ten -1-yl]-1,4-
dim eth yl-8-m eth ylen ebicyclo[3.2.1]octan -2-ol (50): IR (neat,
cm-1) 3540, 1650, 1470, 1460, 1385, 1375, 1360, 1320, 1255,
1100, 1035, 1000, 980, 890, 830, 810, 780; 1H NMR (300 MHz,
CDCl3) δ 4.97 (s, 1 H), 4.02 (s, 1 H), 3.68 (m, 2 H), 2.79 (br d,
J ) 6.4 Hz, 1 H), 2.36-2.23 (m, 2 H), 2.19-1.86 (series of m,
4 H), 1.97 (s, 3 H), 1.79-1.66 (m, 2 H), 1.64-1.44 (m, 6 H),
1.45-1.11 (m, 2 H), 1.04 (s, 3 H), 0.91 (s, 9 H), 0.88 (d, J ) 6.7
Hz, 3 H), 0.76 (d, J ) 6.9 Hz, 3 H), 0.06 (s, 6 H); 13C NMR (75
MHz, CDCl3) ppm 162.0, 139.6, 136.4, 102.7, 80.4, 61.6, 54.0,
52.9, 49.3, 41.5, 40.6, 39.9, 35.6, 33.4, 33.2, 26.1 (3C), 24.3,
20.7, 19.0, 18.4, 18.0, 17.8, 13.4, -5.3 (2 C); MS m/z (M+) calcd
432.3424, obsd 432.3425; [R]23 -73.8 (c 0.002, CHCl3).
D

3278 J . Org. Chem., Vol. 61, No. 10, 1996
Paquette et al.
(5S,7S,7a S)-2,4,5,6,7,7a -Hexa h yd r o-5-[(5R)-5-[(1S)-3-h y-
d r oxy-1-m eth ylp r op yl]-2-m eth yl-1-cyclop en ten -1-yl]-3,7-
d im eth ylin d en -5-ol (52). A solution of alcohol 49 (29 mg,
0.067 mmol) and 18-crown-6 (53 mg, 0.201 mmol) in THF (5
mL) was treated with KHMDS (0.402 mL, 0.5 M in toluene,
0.201 mmol) at 0 °C. After 30 min, the mixture was quenched
with brine, the aqueous phase was extracted with ether, and
the combined organic phases were dried and evaporated. The
residue was filtered through silica gel (elution with 30% ethyl
acetate in petroleum ether) to give a mixture of 51a , 51b, and
52, which was not separated but dissolved directly in THF (10
mL) and treated with tetrabutylammonium fluoride (0.70 mL,
1 M in THF, 0.7 mmol). After being stirring for 2 h at rt, the
mixture was diluted with ether and poured in ice water, the
aqueous phase was extracted with ether, and the combined
organic phases were washed with brine and dried. After
solvent removal, purification of the residue by chromatography
on silica gel (elution with 25% ethyl acetate in petroleum ether)
gave 18 mg (84% overall) of 52 as white crystals, mp 80-81
°C (from ether-petroleum ether): IR (CCl4, cm-1) 3620, 3400,
1455, 1440, 1380, 1090, 1065, 1040; 1H NMR (300 MHz, C6D6)
δ 3.50 (m, 2 H), 2.94 (br s, 1 H), 2.90 (br s, 1 H), 2.87 (br s, 1
H), 2.45-2.05 (series of m, 8 H), 1.92-1.45 (series of m, 9 H),
1.82 (br s, 3 H), 1.64 (br s, 3 H), 0.92 (d, J ) 7.2 Hz, 3 H), 0.82
(d, J ) 6.9 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 145.4,
134.9, 133.5, 131.5, 74.4, 60.7, 50.9, 47.9, 44.2, 40.7, 39.5, 39.3,
37.6, 32.3, 27.9, 26.1, 23.1, 17.1, 16.1, 14.3, 14.0; MS m/z (M+
3 H), 0.79 (d, J ) 6.9 Hz, 3 H), 0.17 (s, 9 H), 0.07 (s, 6 H); MS
m/z (M+) calcd 504.3819, obsd 504.3812.
(5S,7S,7a S)-2,4,5,6,7,7a -H exa h yd r o-5-[(5S)-5-[(1R)-3-
(ter t-b u t yld im et h ylsiloxy)-1-m et h ylp r op yl]-2-m et h yl-1-
cyclop en ten -1-yl]-3,7-d im eth ylin d en -5-ol (53b): IR (neat,
cm-1) 3600, 3480, 1470, 1460, 1435, 1380, 1360, 1255, 1100,
1010, 980, 900, 840, 810, 780; 1H NMR (500 MHz, C6D6) δ 3.70
(m, 2 H), 3.11 (br s, 1 H), 3.01 (br d, J ) 9.4 Hz, 1 H), 2.89 (d,
J ) 15.6 Hz, 1 H), 2.50-2.20 (series of m, 5 H), 2.18-2.10 (m,
2 H), 1.83-1.50 (series of m, 9 H), 1.76 (br s, 3 H), 1.60 (br s,
3 H), 1.00 (s, 9 H), 0.90 (d, J ) 7.1 Hz, 3 H), 0.84 (d, J ) 6.9
Hz, 3 H), 0.10 (s, 6 H); 13C NMR (125 MHz, C6D6) ppm 145.1,
135.4, 132.8, 131.2, 74.7, 61.9, 52.3, 47.1, 43.9, 41.0, 39.9, 38.9,
37.5, 32.8, 27.8, 26.4, 26.2 (3 C), 23.1, 18.5, 17.8, 16.0, 14.0,
13.8, -5.1 (2 C); MS m/z (M+ - H2O) calcd 414.3318, obsd
414.3305; [R]23 +11.5 (c 0.002, CHCl3).
D
Cou p lin g of 59b to (()-10. To solution of 58 (4.43 g, 25.3
mmol) in dry methanol (70 mL) was added cerium trichloride
heptahydrate (10.38 g, 27.8 mmol), and the mixture was cooled
to 0 °C while sodium borohydride (1.05 g, 27.8 mmol) was
introduced in portions. Stirring was maintained for 30 min
prior to quenching with water (50 mL) and extraction with
ethyl acetate. The combined organic phases were washed with
brine, dried, and concentrated to leave a residue, purification
of which by chromatography on silica gel (elution with 2:1
hexanes/ethyl acetate) afforded 59a as a colorless oil (4.15 g,
93%): 1H NMR (300 MHz, C6D6) δ 4.40 (m, 1 H), 2.01-1.82
(m, 3 H), 1.71-1.52 (m, 2 H), 1.47 (s, 3 H); 13C NMR (75 MHz,
C6D6) ppm 140.5, 121.4, 79.8, 34.1, 31.5, 15.8; MS m/ z (M+)
calcd 175.9817, obsd 175.9827.
- H2O) calcd 300.2453, obsd 300.2448; [R]23 +26.1 (c 0.01,
D
CCl4).
[[(5S,7S,7aS)-5-[(5R)-5-[(1S)-3-(ter t-Bu tyldim eth ylsiloxy)-
1-m eth ylpr opyl]-2-m eth yl-1-cyclopen ten -1-yl]-2,4,5,6,7,7a-
h exa h yd r o-3,7-d im et h ylin d en -5-yl]oxy]t r im et h ylsila n e
(51a ): IR (neat, cm-1) 1460, 1375, 1360, 1250, 1090, 1040,
1020, 980, 940, 900, 840, 775, 750; 1H NMR (300 MHz, C6D6)
δ 3.69 (m, 2 H), 3.06 (d, J ) 15.0 Hz, 1 H), 2.90 (m, 1 H), 2.81
(br d, J ) 8.0 Hz, 1 H), 2.60 (br d, J ) 15.0 Hz, 1 H), 2.40-
1.93 (series of m, 6 H), 1.91 (br s, 3 H), 1.89-1.40 (series of m,
8 H), 1.60 (br s, 3 H), 1.00 (s, 9 H), 0.91 (d, J ) 7.0 Hz, 3 H),
0.80 (d, J ) 7.0 Hz, 3 H), 0.20 (s, 9 H), 0.10 (s, 6 H); MS m/z
(M+ - HOSiC3H9) calcd 414.3318, obsd 414.3316.
A solution of 59a (3.58 g, 20.2 mmol) and iodomethane (2.52
mL, 40.4 mmol) in THF (40 mL) was cooled to 0 °C and treated
with sodium hydride (730 mg, 30.3 mmol). The reaction
mixture was allowed to warm to rt, stirred for 3 h, quenched
with water (20 mL), and extracted with ether. The combined
organic phases were washed with brine, dried, and concen-
trated. Chromatography of the residue on silica gel (elution
with 50:1 hexanes/ethyl acetate) furnished 59b as a colorless
oil (3.72 g, 96%): 1H NMR (300 MHz, CDCl3) δ 4.36 (m, 1 H),
3.35 (s, 3 H), 2.48-2.37 (m, 1 H), 2.25-2.12 (m, 2 H), 1.98-
1.83 (m, 1 H), 1.78 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
142.8, 117.4, 88.1, 55.6, 34.5, 27.9, 15.9; MS m/ z (M+) calcd
174.9797, obsd 174.9778.
(5S,7S,7a S)-2,4,5,6,7,7a -H exa h yd r o-5-[(5R)-5-[(1S)-3-
(ter t-bu tyl-d im eth ylsiloxy)-1-m eth ylp r op yl]-2-m eth yl-1-
cyclop en ten -1-yl]-3,7-d im eth ylin d en -5-ol (51b): IR (neat,
cm-1) 3620, 3450, 1650, 1440, 1375, 1360, 1255, 1100, 1010,
A solution of 59b (700 mg, 3.66 mmol) in anhydrous ether
(18.3 mL) was cooled to -10 °C under N2, treated with sec-
butyllithium (2.81 mL of 1.3 M in cyclohexane, 3.65 mmol),
and stirred for 40 min prior to the addition of (()-10 (296 mg,
1.83 mmol). After an additional hour of stirring, the reaction
mixture was quenched with brine (100 mL) and the aqueous
phase was extracted with ether. The combined organic layers
were washed with brine, dried, and concentrated. The crude
product was taken up in benzene (0.5 mL) and stored overnight
at rt. The deposited colorless crystals were filtered and dried
to give 123 mg (25%) of 63. The mother liquor was chromato-
graphed on silica gel (elution with 20:1 hexanes/ethyl acetate)
to give pure 60 (146 mg, 29%) and a mixture of 61 and 62
(156 mg, 31%) in a 1.5:2.0 ratio. Rechromatography was
necessary to achieve separation of the latter two carbinols.
For 60: colorless oil; IR (neat, cm-1
1
840, 775; H NMR (300 MHz, C6D6) δ 3.67 (m, 2 H), 2.99 (br
d, J ) 15.5 Hz, 1 H), 2.92 (br d, J ) 8.0 Hz, 2 H), 2.40-2.01
(series of m, 6 H), 1.98-1.85 (m, 1 H), 1.82 (br s, 3 H), 1.81-
1.40 (series of m, 9 H), 1.61 (br s, 3 H), 1.00 (s, 9 H), 0.87 (d,
J ) 6.9 Hz, 3 H), 0.79 (d, J ) 6.9 Hz, 3 H), 0.10 (s, 6 H); MS
m/z (M+ - H2O) calcd 414.3318, obsd 414.3312.
(5S,7S,7a S)-2,4,5,6,7,7a -Hexa h yd r o-5-[(5S)-5-[(1R)-3-h y-
d r oxy-1-m eth ylp r op yl]-2-m eth yl-1-cyclop en ten -1-yl]-3,7-
d im eth ylin d en -5-ol (54). Adaptation of the predescribed
procedure to the rearrangement of 50 gave a mixture of 53,
53b, and 54, which was directly subjected to desilylation
conditions. Diol 54 was obtained in 79% overall yield.
For 54: white crystals, mp 110-111 °C (petroleum ether
at -20 °C); IR (CCl4, cm-1) 3620, 3400, 1460, 1435, 1375, 1090,
1060, 1015, 960; 1H NMR (300 MHz, C6D6) δ 3.71-3.51 (m, 2
H), 3.09 (br d, J ) 9.0 Hz, 1 H), 2.98 (m, 1H), 2.86 (br d, J )
15.3 Hz, 1 H), 2.40-2.05 (series of m, 8 H), 1.90-1.25 (series
of m, 9 H), 1.68 (br s, 3 H), 1.56 (br s, 3 H), 0.89 (d, J ) 7.1
Hz, 3 H), 0.82 (d, J ) 7.0 Hz, 3 H); 13C NMR (75 MHz, C6D6)
ppm 145.4, 135.4, 131.6, 131.4, 75.1, 60.6, 50.6, 47.1, 43.8, 41.2,
39.3, 38.9, 37.4, 32.1, 27.5, 26.4, 22.6, 17.7, 15.8, 14.2, 14.0;
MS m/z (M+ - H2O) calcd 300.2453, obsd 300.2447; [R]23D +7.0
(c 0.003, CCl4).
) 3471, 1668, 1446, 1375,
1076, 1018, 1005, 994, 880;
1H NMR (300 MHz, C6D6) δ 5.12
(s, 1 H), 4.66 (d, J ) 8.2 Hz, 2 H), 4.50 (s, 1 H), 4.48 (br s, 1
H), 3.19-3.11 (m, 1 H), 2.93 (s, 3 H), 2.49 (d, J ) 4.0 Hz, 1 H),
2.46-2.36 (m, 1 H), 1.98 (dd, J ) 16.4, 8.0 Hz, 1 H), 1.73 (s, 3
H), 1.68-1.37 (m, 8 H), 1.28 (s, 3 H); 13C NMR (75 MHz, C6D6)
ppm 158.7, 142.7, 137.8, 136.4, 129.0, 100.6, 91.2, 81.0, 54.8,
51.0, 49.8, 39.0, 31.7, 29.8, 25.4, 21.3, 18.7, 16.9; MS m/ z (M+
calcd 274.1933, obsd 274.1947.
)
Anal. Calcd for C18H26O2: C, 78.78; H, 9.56. Found: C,
78.82; H, 9.56.
[[(5S,7S,7aS)-5-[(5S)-5-[(1R)-3-(ter t-Bu tyldim eth ylsiloxy)-
1-m eth ylpr opyl]-2-m eth yl-1-cyclopen ten -1-yl]-2,4,5,6,7,7a-
h exa h yd r o-3,7-d im et h ylin d en -5-yl]oxy]t r im et h ylsila n e
(53a ): IR (neat, cm-1) 1650, 1465, 1440, 1380, 1360, 1250,
1100, 1040, 970, 890, 840, 780, 760; 1H NMR (300 MHz, C6D6)
δ 3.65 (m, 2 H), 3.34 (br s, 1 H), 2.90 (br d, J ) 9.5 Hz, 1 H),
2.80 (br d, J ) 17.5 Hz, 1 H), 2.62 (br d, J ) 17.5 Hz, 1 H),
2.40-2.00 (series of m, 7 H), 1.95 (br s, 3 H), 1.90-1.30 (series
of m, 7 H), 1.60 (br s, 3 H), 0.97 (s, 9 H), 0.90 (d, J ) 7.0 Hz,
For 61: colorless oil; IR (neat, cm-1) 3473, 1669, 1446, 1376,
1352, 1078, 993, 880; 1H NMR (300 MHz, C6D6) δ 5.68 (d, J )
1.3 Hz, 1 H), 4.75 (d, J ) 0.6 Hz, 1 H), 4.63 (d, J ) 1.0 Hz, 1
H), 4.16 (d, J ) 5.2 Hz, 1 H), 3.10 (s, 3 H), 3.10-2.56 (m, 1 H),
2.46 (d, J ) 5.9 Hz, 1 H), 1.97 (s, 3 H), 1.98-1.88 (m, 3 H),
1.76-1.60 (m, 3 H), 1.58 (d, J ) 1.5 Hz, 3 H), 1.46-1.38 (m, 2
H), 1.36 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 159.8, 143.6,

Stereoselective Construction of Ceroplastin Core
J . Org. Chem., Vol. 61, No. 10, 1996 3279
141.8, 136.9, 128.6, 100.5, 90.3, 80.9, 55.6, 52.4, 49.6, 38.3, 32.3,
29.5, 28.5, 21.6, 18.7, 17.7; MS m/ z (M+) calcd 274.1933, obsd
274.1929.
was purified by chromatography on silica gel (elution with 20:
1:0.1 hexanes/ethyl acetate/triethylamine). There were iso-
lated 33 mg (30%) of 64 and two unidentified oils (32%).
For 64: colorless solid, mp 127-128 °C; IR (film, cm-1) 1667,
1651, 1600, 1434, 1257; 1H NMR (300 MHz, CDCl3) δ 6.65 (t,
J ) 2.6 Hz, 1 H), 4.20 (d, J ) 12.0 Hz, 1 H), 2.75 (d, J ) 15.1
Hz, 1 H), 2.60 (d, J ) 12.0 Hz, 1 H), 2.54 (d, J ) 15.1 Hz, 1 H),
2.50-2.13 (m, 6 H), 1.95-1.84 (m, 1 H), 1.79 (s, 3 H), 1.72 (s,
3 H), 1.69-1.20 (m, 1 H), 1.14 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 195.3, 149.3, 146.0, 145.4, 142.2, 134.3, 113.4,
49.1, 47.7, 38.4, 37.0, 35.2, 29.1, 28.7, 27.7, 22.7, 15.6; MS m/ z
(M+) calcd 242.1671, obsd 242.1678.
For 62: colorless oil; IR (neat, cm-1) 3459, 1666, 1446, 1375,
1352, 1080, 993, 885; 1H NMR (300 MHz, C6D6) δ 5.24 (d, J )
0.7 Hz, 1 H), 4.91 (d, J ) 16.1 Hz, 2 H), 4.45 (d, J ) 5.8 Hz, 1
H), 4.22 (s, 1 H), 2.97 (s, 3 H), 2.55 (d, J ) 5.9 Hz, 1 H), 2.45-
2.38 (m, 1 H), 1.97-1.85 (m, 2 H), 1.78-1.33 (series of m, 5
H), 1.69 (s, 3 H), 1.57 (d, J ) 1.5 Hz, 3 H), 1.40 (s, 3 H); 13C
NMR (75 MHz, C6D6) ppm 158.1, 141.8, 139.7, 137.5, 128.6,
100.5, 90.7, 79.7, 55.0, 51.1, 49.2, 37.9, 31.8, 28.9, 26.5, 21.3,
18.9, 16.5; MS m/ z (M+) calcd 274.1933, obsd 274.1934.
For 63: colorless crystals, mp 155-156 °C; IR (film, cm-1
)
Anal. Calcd for C17H22O: C, 84.24; H, 9.16. Found: C,
84.18; H, 9.02.
1
3429, 1666, 1462, 1377, 1346, 1072, 893; H NMR (300 MHz,
C6D6) δ 5.35 (d, J ) 0.9 Hz, 1 H), 4.67 (d, J ) 1.1 Hz, 1 H),
4.51 (s, 1 H), 4.09 (br s, 1 H), 3.00 (s, 3 H), 2.85-2.75 (m, 1 H),
2.50 (d, J ) 5.0 Hz, 1 H), 2.49-2.42 (m, 1 H), 2.00-1.91 (m, 1
H), 1.90 (s, 3 H), 1.75-1.52 (m, 5 H), 1.64 (d, J ) 1.4 Hz, 3 H),
1.41 (ddd, J ) 13.5, 10.7, 2.8 Hz, 1 H), 1.26 (s, 3 H); 13C NMR
(75 MHz, C6D6) ppm 158.8, 141.6, 139.0, 128.8, 128.0, 99.7,
91.3, 82.5, 55.6, 50.8, 49.5, 37.9, 31.8, 29.9, 27.5, 21.2, 18.8,
17.5; MS m/ z (M+) calcd 274.1933, obsd 274.1938.
Ack n ow led gm en t. It is a pleasure to acknowledge
the support of this investigation by the National Insti-
tutes of Health through Grant GM-28468. We also
thank Dr. Kurt Loening for his nomenclature expertise
and Prof. Robin Rogers (Northern Illinois University)
for the X-ray crystal structure analysis.
Anal. Calcd for C18H26O2: C, 78.78; H, 9.56. Found: C,
78.76; H, 9.52.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of 21-24 and 35-41 as well as
1H and/or 13C NMR spectra of those compounds lacking
combustion data (32 pages). This material is contained in
libraries, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Rea r r a n gem en t-Elim in a tion of 60. A slurry of potas-
sium hydride (158 mg, 1.34 mmol) in dry THF (4 mL) cooled
to 0 °C was treated with a solution of 60 (123 mg, 0.44 mmol)
and 18-crown-6 (135 mg, 0.51 mmol) in dry THF (6 mL), stirred
for 1 h, and quenched with brine. The separated aqueous
phase was extracted with ether, and the combined organic
layers were dried and concentrated to leave a yellow oil, which
J O952165+