Total synthesis of (+)-epoxydictymene. Application of alkoxy-directed cyclization to diterpenoid construction

Article abstract of DOI:10.1021/ja971526v

An enantioselective synthesis of (+)-epoxydictymene (1) is reported. Condensation of the enantiopure aldehydo ester 5 with (S)-3-isopropylcyclopentenyllithium proceeds selectively to afford 13. Once this lactone was methylenated with the Tebbe reagent, th

Full text of DOI:10.1021/ja971526v

8438
J. Am. Chem. Soc. 1997, 119, 8438-8450
Total Synthesis of (+)-Epoxydictymene. Application of
Alkoxy-Directed Cyclization to Diterpenoid Construction
Leo A. Paquette,* Li-Qiang Sun, Dirk Friedrich,1a and Paul B. Savage1b
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity,
Columbus, Ohio 43210
ReceiVed May 12, 1997X
Abstract: An enantioselective synthesis of (+)-epoxydictymene (1) is reported. Condensation of the enantiopure
aldehydo ester 5 with (S)-3-isopropylcyclopentenyllithium proceeds selectively to afford 13. Once this lactone was
methylenated with the Tebbe reagent, the newly formed allyl vinyl ether was induced into Claisen rearrangement
under catalysis with triisobutylaluminum. Sequential hydroboration-oxidation of the resulting dicyclopentacy-
clooctenone derivative was followed by angular methylation and deoxygenation of the carbonyl functionality.
Following epimerization at C-11, an R-hydroxyl was introduced regio- and stereoselectively. Some functional group
manipulation led to 57 and 58, both of which underwent efficient cyclization to deliver the complete framework of
the target molecule when irradiated with visible light in cyclohexane solution containing iodosobenzene diacetate
and iodine. The generality of this key reaction, which efficiently constructs the strained oxabicyclo[3.3.0]octane
subunit of 1, is demonstrated. This significant development permitted the conversion of 57 to 1 in two additional
steps.
In the early 1980s, Matsumoto and co-workers at Hokkaido
thrusts carried out in support of this venture. These latter studies
feature some unique aspects of the chemistry of cyclooctane
rings.6
University were actively investigating the nature of the con-
stituents produced by brown algae of the Dictyotaceae family.
Their focus on Dictyota dichotoma was initially rewarded with
the isolation of cyclononane and hydroazulene diterpenoids of
novel structure.2
Results and Discussion
Synthetic Planning. In line with the general guidelines set
above, we considered 2 (X being a substituent capable of E2
elimination) to be a reasonable penultimate precursor to the
target molecule. Elaboration of its entire tricyclic framework
was expected to best be realized by subjecting 4 to Claisen
rearrangement (Scheme 1).7-11 The chairlike characteristics of
the transition state expected to be adopted during this
interconversion12-17 would serve to interrelate properly the rather
distal stereogenic centers in rings A and C. Left unspecified
for the moment was the manner in which the oxygen-substituted
center in 3 would be transposed, the angular methyl group
introduced, and one ring-juncture hydrogen atom epimerized.
Although one can imagine a variety of ways to achieve the
orderly functionalization of 3 in mandated fashion, particular
Subsequently, they identified epoxydictymene (1) to be
present as well.3 The fusicoccin-like tricyclic framework of 1,
established by X-ray crystal structure analysis of a derivative,
was recognized to feature a strained trans-fused 3-oxabicyclo-
[3.3.0]octane subunit. This unusual constitutional characteristic
arguably defines 1 as the most complex of the fusicoccanes.
The absolute configuration of epoxydictymene is as depicted.3
(5) Paquette, L. A.; Sun, L.-Q.; Friedrich, D.; Savage, P. B. Tetrahedron
Lett. 1997, 38, 195.
(6) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757.
(7) Paquette, L. A. In Stereocontrolled Organic Synthesis; Trost, B. M.,
Ed.; Blackwell Scientific Publications: Oxford, England, 1994; pp 313-
336.
(8) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, England, 1991; Vol. 5, Chapter 7.2.
(9) Ziegler, F. E. Chem. ReV. 1988, 88, 1423.
(10) Hill, R. K. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, Chapter 8.
(11) Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1.
(12) (a) Kinney, W. A.; Coghlan, M. J.; Paquette, L. A. J. Am. Chem.
Soc. 1984, 106, 6868. (b) Kinney, W. A.; Coghlan, M. J.; Paquette, L. A.
J. Am. Chem. Soc. 1985, 107, 7352.
(13) Paquette, L. A.; Sweeney, T. J. J. Org. Chem. 1990, 55, 1703.
(14) (a) Kang, H.-J.; Paquette, L. A. J. Am. Chem. Soc. 1990, 112, 3252.
(b) Paquette, L. A.; Kang, H.-J. J. Am. Chem. Soc. 1991, 113, 2610.
(15) (a) Philippo, C. M. G.; Vo, N. H.; Paquette, L. A. J. Am. Chem.
Soc. 1991, 113, 2762. (b) Paquette, L. A.; Philippo, C. M. G.; Vo, N. H.
Can. J. Chem. 1992, 70, 1356.
Schreiber et al. succeeded in 1994 to access natural (+)-1
by deployment of a Pauson-Khand reaction in a key step.4 This
ring-building protocol delivered a dehydro derivative of epoxy-
dictymene, from which the target molecule was produced only
after cleavage and reconstruction of the C ring.
We have successfully exploited an alkoxy-directed cyclization
route to 1 which highlights the facility and efficiency with which
the strained tetrahydrofuran sector (ring D) can be assembled
late in the synthesis.5 Herein are described the full experimental
details of this route, along with details of other exploratory
X Abstract published in AdVance ACS Abstracts, September 1, 1997.
(1) Current address: (a) Hoechst Marion Roussel, Inc., 2110 East
Galbraith Road, Cincinnati, OH 45215-6300. (b) Department of Chemistry,
Brigham Young University, Salt Lake City, UT 84602.
(2) (a) Enoki, N.; Ishida, R.; Matsumoto, T. Chem. Lett. 1982, 1749. (b)
Enoki, N.; Ishida, R.; Urano, S.; Ochi, M.; Tokoroyama, T.; Matsumoto,
T. Chem. Lett. 1982, 1837.
(3) Enoki, N.; Furusaki, A.; Suehiro, K.; Ishida, R.; Matsumoto, T.
Tetrahedron Lett. 1983, 24, 4341.
(4) (a) Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J.
Am. Chem. Soc. 1994, 116, 5505. (b) J. Am. Chem. Soc. 1997, 119, 4353.
(16) Paquette, L. A.; Wang, T.-Z.; Vo, N. H. J. Am. Chem. Soc. 1993,
115, 1676.
(17) Paquette, L. A.; Friedrich, D.; Rogers, R. D. Q. ReV., Chem. Soc.
1991, 56, 3841.
S0002-7863(97)01526-6 CCC: $14.00 © 1997 American Chemical Society

Total Synthesis of (+)-Epoxydictymene
J. Am. Chem. Soc., Vol. 119, No. 36, 1997 8439
Scheme 1
Scheme 2
attention had to be accorded to those hazards inherent in the
chemistry of medium-sized rings.6,18
The stereocontrol projected for the condensation of 5 with 6
was founded on the results of model studies involving closely
related systems.19 A key consideration in this scenario was the
anticipation that nucleophilic attack at the aldehyde carbonyl
would occur most readily on the conformer depicted in A from
the front right quadrant. This trajectory has previously been
considered to involve the minimum level of nonbonded steric
interactions.19
PCC to the homogeneous ketone 15. Oshima and co-workers
had earlier recognized the appreciable capability of Tribal for
accelerating the Claisen rearrangement.24 Concomitant reduc-
tion of the carbonyl products under the mild reaction conditions
was also noted. The stereocontrolled conversion to 15 provides
clear indication that 14 makes exclusive use of the chairlike
arrangement depicted in B.25,26 Although nonbonded steric in-
teractions involving the isopropyl substitutent are notably ap-
parent in B, the major driving force behind adoption of this
geometry is the Z selectivity with which the newly developing
double bond is being generated within the eight-membered
ring.7,17 The stereochemical assignment to 15 was initially de-
rived from decoupling, NOED, and H,H-COSY/C,H-COSY ex-
periments and was later corroborated by X-ray crystallographic
analysis of a more advanced intermediate (see Scheme 4).
With 15 in hand, we initially chose to examine the option of
its possible conversion into the carbonyl-transposed conjugated
ketone 26. This prospect was alluring in that suitable deploy-
ment of existing functionalities within this enone could plausibly
be exploited for arrival at 1. With 26 as the interim goal, the
kinetic enolate of 15 was generated and allowed to be captured
by diphenyl disulfide.27 These sulfenylating conditions gave
rise exclusively to 16 (94%), which underwent Dibal-H reduc-
tion smoothly again from the â face to produce 17 quantitatively
(Scheme 4). Two methods for oxidizing 17 to the sulfoxide
stage were screened. In the first approach, the two-phase H2O2/
PhSeO2H combination devised by Reich28 served as the reagent
The Sigmatropic Event and First Attempt at Function-
alization of the Cyclooctane Core. Whereas 6 was generated
from (R)-carvone and was therefore of high enantiomeric
purity,20 it was necessary to resolve racemic 719 prior to arrival
at 5. This task was easily accomplished by means of Johnson’s
sulfoximine technology.21 The adducts 9 and 10 produced upon
coupling of (S)-(+)-8 to 7 were readily amenable to chromato-
graphic separation. Elucidation of absolute stereochemistry was
accomplished by the conversion of 10 into (-)-isoiridomyrmecin
(11) of well established configuration22 (Scheme 2). Following
the thermal cracking of 9 to return (+)-7, sequential formation
of the silyl enol ether, ozonolysis, and esterification with
diazomethane delivered enantiopure 5.
Addition of the cycloalkenyllithium reagent derived from
(S)-6 to 5 in THF at -78 °C did indeed prove to be usefully
diastereoselective, providing a mixture of 12 and 13 rich in the
latter (71%). Treatment of the chromatographically purified 13
with carefully generated Tebbe reagent23 provided vinyl ether
14 in high yield. Without delay, this sensitive compound
was immediately exposed to triisobutylaluminum (Tribal) in
CH2Cl2 at -78 °C. Following warming to room temperature,
the resulting mixture of cyclooctenols was directly oxidized with
(23) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611. (b) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H.
J. Am. Chem. Soc. 1980, 102, 3270. (c) Brown-Wensley, K. A.; Buchwald,
S. L.; Cannizzo, L.; Clawson, L.; Ho, S.; Meinhardt, D.; Stille, J. R.; Straus,
D.; Grubbs, R. H. Pure Appl. Chem. 1983, 55, 1733. (d) Pine, S. H.; Pettit,
R. J.; Geib, G. D.; Cruz, S. G.; Gallego, C. H.; Tijerina, T.; Pine, R. D. J.
Org. Chem. 1985, 50, 1212.
(24) (a) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1981, 22, 3985. (b) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Bull. Chem.
Soc. Jpn. 1984, 57, 446. (c) Mori, I.; Takai, K.; Oshima, K.; Nozaki, H.
Tetrahedron 1984, 40, 4013. See, also: Lutz, R. P. Chem. ReV. 1984, 84,
205.
(25) Although Yamamoto has proposed an axial orientation for the
complexation of bulky aluminum reagents to ether oxygen,26 recent
crystallographic and spectroscopic evidence suggests that the geometries
of these complexes may be rather planar, and we have therefore adopted
this formulation in B.
(26) (a) Maruoka, K.; Nonoshita, K.; Banno, H.; Yamamoto, H. J. Am.
Chem. Soc. 1988, 110, 7922. (b) Nonoshita, K.; Banno, H.; Maruoka, K.;
Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 316.
(18) Cope, A. C.; Martin, M. M.; McKervey, M. A. Q. ReV., Chem. Soc.
1966, 20, 119.
(19) Friedrich, D.; Paquette, L. A. J. Org. Chem. 1991, 56, 3831.
(20) Paquette, L. A.; Dahnke, K.; Doyon, J.; He, W.; Wyant, K.;
Friedrich, D. J. Org. Chem. 1991, 56, 6199.
(21) Johnson, C. R.; Zeller, J. R. J. Am. Chem. Soc. 1982, 104, 4021.
(22) Cavill, G. W. K.; Whitfield, F. B. Aust. J. Chem. 1964, 17, 1245.
See also Takacs, J. M.; Myoung, Y. C. Tetrahedron Lett. 1992, 33, 317
and references cited therein.
(27) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976,
98, 4887.
(28) Reich, H. J.; Chow, F.; Peake, S. L. Synthesis 1978, 299.

8440 J. Am. Chem. Soc., Vol. 119, No. 36, 1997
Paquette et al.
Scheme 3
Scheme 4
system. Reaction was complete in less than 5 min at 20 °C.
The major product was the less polar isomer 18 (74%), which
was accompanied by the highly polar diastereomer 19 (20%)
along with 2% of the sulfone. The infrared and 1H NMR spectra
of 18 and the sulfone are convincingly diagnostic of the
existence of intramolecular hydrogen bonding. Inspection of
molecular models showed that only that sulfoxide with the R
configuration on sulfur (18) is able to engage in this type of
interaction without experiencing strong repulsion between the
phenyl and isopropyl substituents. As will be seen, these
considerations carry over as well into the thermal extrusion
processes described below.
Our attempt to alter the 18/19 ratio through use of Kagan’s
chiral reagent system29 gave an unexpected result. Use of either
(+)- or (-)-diethyl tartrate afforded the identical inverse
composition of these sulfoxides (now 1:4). Reagent control was
obviously ineffective here.
Sequential brominative cyclization and reduction of 19
proceeded smoothly via 20 to 21. Elimination on a preparative
scale was performed in chlorobenzene at 160 °C (sealed tube)
and afforded 22 in good yield. The same sequence of steps
involving 18 was found to occur with diminished efficiency
such that the amount of 22 obtained by this route was lower. In
agreement with the stereochemical formulations, however, the
rate at which 22 is generated in the elimination step differs
significantly, with 21 (t1/2 ≈ 10 h, reaction still incomplete after
24 h) being appreciably less reactive than the R-sulfoxide (t1/2
< 60 min; complete reaction after 7 h). The hydroboration of
22 required several hours at 20 °C for completion and afforded
the lone alcohol 23 formed by attack on the R surface, as verified
at the stage of ketone 24 obtained by PCC oxidation. In this
advanced intermediate, the observed bidirectional NOEs between
H-8 and H-10 (2%) can only be accommodated by the relative
configuration shown. The desired â-alkoxide elimination to
form enone 26 was next attempted by means of LiN(SiMe3)2
(29) Kagan, H. B.; Rebiere, F. Synlett 1990, 643.

Total Synthesis of (+)-Epoxydictymene
J. Am. Chem. Soc., Vol. 119, No. 36, 1997 8441
Scheme 5
Scheme 6
in toluene, benzene, or THF. However, even after prolonged
exposure the only observed product was 25. Molecular models
show the â epimer to be considerably less strained than 24,
supporting the NMR-derived stereochemical assignment. At-
tempts to cleave the furanone ring in the opposite direction by
reductive cleavage of the R-alkoxy functionality in 25 with
samarium iodide in anhydrous THF30 was also to no avail.
Prolonged standing at room temperature left 25 unchanged,
while further addition of water led simply to ketone reduction
and formation of 27.
echolborane additions by lithium borohydride.31 Gratifyingly,
the presence of LiBH4 in reactions involving 29 gave rise to
much improved reproducibility and dramatically increased
efficiency. The distribution of 30:31 was consistently 2:5, a
ratio which could not be manipulated by making recourse to
more bulky boranes since the latter failed to react at all.
The oxidation of 31 to 32 was followed by monomethylation
under conventional conditions. The misalignment of H-3 in
32 with the carbonyl π bond was recognized early in the tactical
design stages. In contrast, the stereodisposition of C(1)-H is
ideally suited to conjugative overlap, although abstraction of
H-1 is confronted with significant steric hindrance. Accord-
ingly, while LDA did not effect deprotonation of 32 at -78
°C, warmup to -15 °C for 1 h followed by introduction of
methyl iodide at -78 °C succeeded in producing 33 exclusively.
That the methyl group in 33 was â-oriented as required was
clearly apparent from a strong NOE between H-15 and H-11
and a diagnostic W-coupling between H-15 and H-13R.
Now that the angular methylation was complete, the time had
arrived to remove the C-2 oxygen that had served us so well.
The steric crowding at this position came to the fore when an
attempt at Wolff-Kishner reduction under quite forcing condi-
tions returned only a mixture of 33 and its epimer 34. Ketone
33 was therefore reduced with LiAlH4 to pursue radical
deoxygenation of an alcohol derivative (Scheme 6). While the
resulting diastereomerically pure alcohol 35 proved unreactive
Ultimately, it proved more expedient to prepare ketone 32
and to take advantage of its expected tendency to undergo
regioselective deprotonation (Scheme 5). The conformation
adopted by 15, previously recognized to be conducive to
kinetically controlled â-attack by electrophiles in the southern
sector of the central ring, also enabled stereospecific reduction
with Dibal-H to provide 28. In this instance, the assignment
of relative stereochemistry was founded on direct comparison
1
of diagnostic H NMR features with those earlier observed in
model series, where extensive stereochemical studies had been
undertaken.17
An abbreviated protocol for the conversion of lactone 13 to
alcohol 28 was subsequently developed, which takes advantage
of the significantly greater rate at which ketone 15 is reduced
by Dibal-H compared to Tribal. Sequential addition to vinyl
ether 14 of Tribal and Dibal-H at -78 °C effected Claisen
rearrangement followed by stereospecific reduction to produce
solely 28 of sufficient purity for direct conversion to MOM ether
29. This modification raised the overall efficiency of the 13 to
29 conversion to 88% (see Experimental Section).
As a consequence of the very sluggish rate of hydroboration
of 29 and the associated erratic efficiencies, our attention was
drawn to a report describing the strong acceleration of cat-
(30) (a) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135. (b)
Pratt, D. W.; Hopkins, P. B. Tetrahedron Lett. 1987, 28, 3065. (c) Hamelin,
O.; Depre´s, J.-P.; Greene, A. E. J. Am. Chem. Soc. 1996, 118, 9992.
(31) Arase, A.; Nunokawa, Y.; Masuda, Y.; Hoshi, M. J. Chem. Soc.,
Chem. Commun. 1991, 205.

8442 J. Am. Chem. Soc., Vol. 119, No. 36, 1997
Paquette et al.
Table 1. Comparison of Two Sets of Energy Minimized
Scheme 7
Diastereomersa
a MODEL version 2.99 was employed. b MODEL version 2.96 was
utilized. c All values in kcal/mol.
to xanthate formation under a variety of conditions, conversion
to the selenocarbonate32a proceeded smoothly to produce 36.
Exposure to tris(trimethylsilyl)silane32b and AIBN in refluxing
benzene led to formation of 37 (ca. 1:1 mixture of epimers) as
well as 38, which is taken as evidence that transannular
hydrogen abstraction by the initially formed secondary radical
had occurred. Conversion to 38 was completed by sequential
hydrolysis and oxidation of 37.
The overall strategy next called for the specific epimerization
of C-11. To this end, 38 was deprotonated under kinetically
controlled conditions33 in advance of conversion to the less
substituted silyl enol ether. Oxidation of this reactive interme-
diate with DDQ34 gave rise to 39 in acceptably high yield. This
cyclooctenone underwent dissolving metal reduction to provide
uniquely the trans-fused isomer 40 in 90% yield. The thermo-
dynamic bias made evident in this experiment was in direct
agreement with MM2 calculations35 performed on model
ketones which unmistakingly reveal the trans isomers to be more
stable (Table 1).
The critical introduction of the ethereal oxygen projected to
reside in ring D, with proper regard for the preservation of
unsaturation in ring B, was first attempted from the cis-fused
tricyclic ketone 38 (Scheme 7). Under kinetically-controlled
deprotonation conditions, formation of the less substituted silyl
enol ether was heavily favored. When this intermediate was
oxidized with m-chloroperbenzoic acid, the R-ketol 41 was
formed as the major product. When initial experiments designed
to transform 41 into cyclooctene 44 proved unrewarding,
recourse was made to formation of the enol phosphate 43 in
preparation for dissolving metal reduction.36 By proper opti-
mization of concentration, reaction temperature, and the rela-
tive amount of lithium metal, the yield of 44 was maximized
(81%) at the expense of competing overreduction. Careful
monitoring of the subsequent deprotection of the MOM ether
under a variety of conditions revealed 44 to be prone to acid-
promoted elimination. In order to skirt this unwanted reaction
pathway, use was made of bromocatecholborane.37 When
somewhat more than 1 equiv of this reagent was employed, the
conversion to 45 proceeded quantitatively, allowing for subse-
quent perruthenate oxidation38 to enone 47. On one occasion,
an insufficient amount of bromocatecholborane was mistakingly
introduced, an event which led to isolation of the highly
crystalline methylene acetal 46. The opportunity to confirm
the stereochemical assignments made to this advanced stage of
the synthesis was seized in the form of an X-ray analysis. As
shown in Figure 1, all seven stereogenic centers in each half of
this symmetric structure possess the absolute configuration
assigned to them. Beyond that, the cyclooctene rings adopt as
much of a tub formation as the cyclopentanes cis-annealed along
the periphery allow.
Despite these successes, ketone 47 proved not to be a notably
useful precursor to epoxydictymene. Although MM2 calcula-
tions suggested that the trans isomer of 47 is about 6.7 kcal/
mol more stable (Table 1), means were not found to effect
(32) (a) Pfenninger, J.; Heuberger, C.; Graf, W. HelV. Chim. Acta 1980,
63, 2328. (b) Chatgilialoglu, C.; Griller, D.; Lesage, M. J. Org. Chem. 1988,
53, 3641.
(33) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
(34) Fleming, I.; Paterson, I. Synthesis 1979, 736.
(35) MODEL version 2.96 and 2.99 obtained from Prof. K. Steliou was
utilized.
(37) Boeckman, R. K., Jr.; Potenza, J. C. Tetrahedron Lett. 1985, 26,
1411.
(38) (a) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13. (b)
Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(36) Ireland, R. E.; Pfister, G. Tetrahedron Lett. 1969, 2145.

Total Synthesis of (+)-Epoxydictymene
J. Am. Chem. Soc., Vol. 119, No. 36, 1997 8443
Scheme 9
Figure 1. ORTEP drawing of 46. The non-hydrogen atoms are
represented by 50% probability thermal ellipsoids.
Scheme 8
reactivity of the tertiary allylic center as seen earlier in a different
context.
In order to override the regioselectivity of those processes
characterized by the production of D and 51, we chose to
epoxidize 50 and to reduce the oxirane 52 with lithium
aluminum hydride (Scheme 9). Although steric factors con-
tributed in an important way to kinetic retardation of the C-O
bond cleavage, formation of tertiary carbinol 53 was not
adversely affected. The latter could be unidirectionally dehy-
drated to the exomethylene derivative 54 in the presence of
Martin’s sulfurane.
With this protected alcohol in hand, we recognized that little
chance existed for its direct conversion to 1 via alkoxy-directed
cyclization. The disadvantage materializes because of the fact
that oxygen-centered radical E has open to it a facile ring-
cleavage fragmentation that would generate the delocalized
allylic radical F. Indeed, when this reaction was attempted,
only ill-defined products resulted. Since it was our intention
to exploit formation of the tetrahydrofuran ring in this manner,
the dihydro derivatives G available from the catalytic hydro-
epimerization at this position. In every instance, deprotonation
occurred to generate the extended enolate C, protonation of
which gave rise to D with obliteration of a key stereogenic
center. Under no circumstances did the double bond provide
indication that it could be migrated to the exocyclic site.
Consequently, attention was directed alternatively to the trans-
fused ketone 40.
Once the R-MOM substituent had been introduced as before
(Scheme 8), a critical improvement in the introduction of the
cyclooctene double bond was realized.
Through sequential hydride reduction and alcohol dehydration
with the Martin sulfurane reagent,39 the conversion to 50 could
be accomplished conveniently without painstaking provisions
to monitor and control reaction parameters closely. Note, how-
ever, that all attempts to functionalize 50 at its allylic methyl
group proved unsuccessful. The conversion to 51 under the
influence of selenium dioxide is illustrative of the greater
genation of 54 were subjected to irradiation in cyclohexane
(39) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327.
solution containing iodobenzene diacetate and iodine.40 Both

8444 J. Am. Chem. Soc., Vol. 119, No. 36, 1997
Paquette et al.
Scheme 10
Experimental Section
Melting points are uncorrected. 1H NMR spectra were recorded at
300 MHz and 13C NMR spectra at 75 MHz unless otherwise noted.
Elemental analyses were performed at the Scandinavian Microanalytical
Laboratory, Herlev, Denmark. All MPLC separations were conducted
with Merck Lobar columns (Lichroprep Si-60) with a Fluid Metering
INC pump and a Waters Associates Model R403 differential refrac-
tometer detector. The organic extracts were dried over anhydrous
MgSO4. Solvents were reagent grade and in most cases dried prior to
use. All other commercially available reagents were used as received.
(S)-N-Methyl-S-[[(1S,2S,3aS,4R,6aR)-octahydro-2-hydroxy-1,4-
dimethyl-2-pentalenyl]methyl]-S-phenylsulfoximine (9) and (S)-N-
Methyl-S-[[(1R,2R,3aR,4S,6aS)-octahydro-2-hydroxy-1,4-dimethyl-
2-pentalenyl]-methyl]-S-phenylsulfoximine (10). A solution of (S)-
(+)-821 (9.86 g, 58.3 mmol), [R]19D +178.4° (c 1.60, acetone) (g 97%
ee) in dry THF (100 mL) was treated at -10 °C with n-butyllithium
(33.8 mL of 1.6 M in hexanes, 54.1 mmol). After 10 min, racemic 7
(6.34 g, 41.6 mmol) in dry THF (20 mL) was added during 10 min at
-78 °C. Two hours later, saturated NH4Cl solution was introduced at
-78 °C, and the product was extracted into ether. The combined
organic phases were washed with 5% HCl and brine, dried, and
evaporated to provide a brown residue. Flash chromatrography on silica
gel (elution with 10:1 hexanes-ethyl acetate) gave 6.0 g (45%) of 9,
mp 124-125 °C (from ether), as the more polar diastereomer and 5.35
g (40%) of 10, mp 137-138 °C.
1
For 9: IR (CHCl3, cm-1) 3480, 1240, 1210, 1145; H NMR (300
MHz, CDCl3) δ 7.89-7.83 (m, 2 H), 7.64-7.51 (m, 3 H), 5.98 (br s,
1 H), 3.26 (d, J ) 14 Hz, 1 H), 3.20 (dd, J ) 14, 1 Hz, 1 H), 2.70 (s,
3 H), 2.23 (dd, J ) 12.5, 8 Hz, 1 H), 1.92-1.63 (m, 5 H), 1.52 (dddd,
J ) 9, 8, 8, 5 Hz, 1 H), 1.43-1.32 (m, 1 H), 1.33 (br dd, J ) 12.5, 8
Hz, 1 H), 1.20-1.06 (m, 1 H), 0.89 (d, J ) 7 Hz, 3 H), 0.78 (d, J )
6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 139.9, 133.0, 129.4,
128.8, 82.0, 60.4, 51.4, 48.8, 47.3, 43.6, 41.6, 34.5, 31.0, 29.2, 19.8,
14.2; MS m/z (M+) calcd 321.1763, obsd 321.1753; [R]20 +74.4 (c
D
1.22, CHCl3).
isomers underwent intramolecular abstraction of the tertiary
isopropyl hydrogen and subsequent cyclization to generate the
strained trans-oxabicyclo[3.3.5]octanes H.
With this precedent established, 54 was sequentially hydrobo-
rated, deprotected to the diols 56, and monoacetylated. Ideally,
the primary acetates 57 and 58 proved to be chromatographically
separable. When each isomer was independently subjected to
irradiation in the predescribed manner, cyclization to 59 and
60, respectively, proceeded once again with exceptional ef-
ficiency (Scheme 10).
Anal. Calcd for C18H27NO2S: C, 67.25; H, 8.47. Found: C, 67.17;
H, 8.54.
For 10: IR (CHCl3, cm-1) 3350, 1245, 1215, 1155; H NMR (300
1
MHz, CDCl3) δ 7.90-7.84 (m, 2 H), 7.66-7.53 (m, 3 H), 6.72 (s, 1
H), 3.20 (dd, J ) 13.5, 2 Hz, 1 H), 3.10 (dd, J ) 13, 8 Hz, 1 H), 2.98
(d, J ) 13.5 Hz, 1 H), 2.59 (s, 3 H), 1.94 (br dddd, J ) 9.5, 9, 8.5, 3.5
Hz, 1 H), 1.88-1.72 (m, 4 H), 1.61 (dq, J ) 9, 7 Hz, 1 H), 1.45 (ddd,
J ) 13, 9.5, 2 Hz, 1 H), 1.26-1.19 (m, 2 H), 0.89 (d, J ) 6.5 Hz, 1
H), 0.79 (d, J ) 7 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 139.1,
133.1, 129.6, 128.9, 82.2, 58.9, 51.9, 47.4, 47.1, 43.5, 41.4, 33.7, 30.3,
28.9, 19.9, 12.6; MS m/z (M+) calcd 321.1763, obsd 321.1771; [R]20
+15.3 (c 0.95, CHCl3).
Anal. Calcd for C18H27NO2S: C, 67.25; H, 8.47. Found: C, 67.06;
H, 8.48.
Following acetate hydrolysis, the more reactive exo alcohol
61 was dehydrated via the Scheme 10 o-nitrophenylselenide 6241
to deliver (+)-epoxydictymene (1), spectroscopically identical
to the natural material.3
D
Conversion of 10 to (-)-Isoiridomyrmecin (11). A 218 mg (0.68
mmol) sample of 10 was placed in a flask and heated at 170 °C under
1 mm in a Kugelrohr apparatus until the ketone was completely
liberated. Filtration of the crude product through TLC grade silica gel
Conclusion
A total synthesis of (+)-epoxydictymene has been success-
fully realized. The most rewarding aspects of the synthesis were
the ability to carry out effective closure of the oxabicyclooctane
ring in a complex structural setting and to fix the majority of
the relevant stereogenic centers in a catalyzed Claisen rear-
rangement. The introduction of an angular methyl group and
other approaches to regio- and stereocontrol provide additional
information of tactical value. The least satisfying stage in the
synthetic route revolves about our inability to expedite the
conversion of 50 to the target molecule. Notwithstanding, the
study defines useful limits within which a significantly strained
C-O bond can be formed strategically as part of the “end game”
of a complex synthesis. Further exploitation of this tactic
appears to be warranted.
afforded 86 mg (83%) of (-)-7, [R]20 -34.9° (c 1.0, CHCl3). This
D
material was converted in turn into its kinetic silyl enol ether, subjected
to ozonolytic cleavage, and reduced with sodium borohydride in a
manner paralleling that detailed previously.19 There was isolated 36
mg (65%) of 11, [R]20 -58.0 (c 1.01, CCl4).
D
Conversion of 9 to (1S,3aS,4R,6aR)-Hexahydro-1,4-dimethyl-
2(1H)-pentalenone (7). A 2.32 g (7.22 mmol) sample of 9 was heated
from 60 °C to 170 °C during 10 min in a Kugelrohr apparatus evacuated
to 1 mm. The distillate was chromatographed on silica gel (elution
with 4:1 petroleum ether-ether) to give 1.07 g (97%) of pure 7 as a
colorless oil, [R]20 +40.1° (c 2.23, CHCl3). This ketone was
D
transformed into 5 via the silyl enol ether with 86% overall efficiency,
as described previously for the racemic compound.19
(1S,4S,4aR,7R,7aS)-Hexahydro-1-[(3S)-3-isopropyl-1-cyclopenten-
1-yl]-4,7-dimethylcyclopenta[c]pyran-3(1H)-one (12) and (1R,4S,-
4aR,7R, 7aS)-Hexahydro-1-[(3S)-3-isopropyl-1-cyclopenten-1-yl]-
4,7-dimethylcyclopenta[c]pyran-3(1H)-one (13). tert-Butyllithium in
pentane (42 mL of 1.7 M, 71.4 mmol) was added dropwise during 15
(40) Concepcio´n, J. I.; Francisco, C. G.; Herna´ndez, R.; Salazar, J. A.;
Sua´rez, E. Tetrahedron Lett. 1984, 25, 1953.
(41) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485.

Total Synthesis of (+)-Epoxydictymene
J. Am. Chem. Soc., Vol. 119, No. 36, 1997 8445
min at -78 °C to a solution of (S)-6 (8.10 g, 42.8 mmol) in dry THF
(300 mL). After 2.5 h of further stirring at -78 °C, the resulting
alkenyllithium was slowly (ca. 30 min) transferred via a cooled cannula
into a cold (-78 °C) stirred solution of 15 (6.14 g, 31.0 mmol) in dry
THF (500 mL). After 3 h, the reaction mixture was quenched with
saturated NH4Cl solution and partitioned between ether and water. The
organic phase was washed with 5% HCl (2×) and brine, dried, and
evaporated. The partially lactonized product (10.66 g) was stirred
overnight at 20 °C with 10 equiv of aqueous potassium hydroxide in
sufficient methanol to produce a homogeneous solution. After evapora-
tive removal of the methanol, the neutrals were removed by extraction
with CH2Cl2. Acidification with dilute HCl and exhaustive CHCl3
extraction was followed by washing of the combined CHCl3 extracts
with brine, drying, and solvent evaporation. 1H NMR analysis showed
the 12/13 ratio to be 14:86. Flash chromatography of the mixture on
silica gel (elution with 2:1 petroleum ether-ether) afforded pure 12
(850 mg, 10%) and pure 13 (5.22 g, 61%).
NMR analysis of this material showed it to be a 4:1 mixture of the R-
and â-alcohols, which was directly oxidized with pyridinium chloro-
chromate (150 mg, 696 mmol) and pyridine (0.1 mL) in dry CH2Cl2
(5 mL) during 3 h at room temperature to give 46 mg (88%) of 15 as
a colorless oil: IR (CCl4, cm-1) 1710; 1H NMR (300 MHz, CDCl3) δ
5.43 (dddd, J )9, 2.5, 2.5, 1 Hz, 1 H), 3.20 (br ddd J ) 13, 6, 5 Hz,
1 H), 2.78 (br dq, J ) 11, 6.5 Hz, 1 H), 2.54 (dd, J ) 13, 5 Hz, 1 H),
2.45 (ddddd, J ) 17, 10, 2.5, 2, 1.5 Hz, 1 H), 2.30 (br dddd, J ) 17,
10, 9, 2.5 Hz, 1 H), 2.23-2.10 (br m, 1 H), 2.09-1.92 (m, 2 H), 2.02
(br dd, J ) 13, 12.5 Hz, 1 H), 1.92-1.62 (m, 4 H), 1.55 (dddd, J )
13.5, 9, 5, 2.5 Hz, 1 H), 1.50-1.29 (m, 2 H), 1.11 (dddd, J ) 12.5, 10,
7.5, 5 Hz, 1 H), 1.00 (pair of unresolved d, J ) 6.5 Hz, 2 × 3 H), 0.94
(d, J ) 6.5 Hz, 3 H), 0.90 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 216.4, 148.0, 120.8, 52.0, 51.6, 46.9, 45.5, 43.5, 40.1,
36.5, 32.0, 31.0, 28.8, 27.8, 26.3, 22.1, 21.4, 20.4, 17.1; MS m/z (M+)
calcd 274.2297, obsd 274.2299; [R]20 +18.5 (c 1.9, CHCl3).
D
Anal. Calcd for C19H30O: C, 83.15; H, 11.02. Found: C, 83.10;
H, 10.99.
For 12: colorless crystals, mp 85-86 °C (from pentane); IR (CCl4,
1
cm-1) 1750; H NMR (300 MHz, CDCl3) δ 5.73 (ddd, J ) 2, 2, 1.5
(1R,3aR,4S,5R,6aR,7S,10aS)-1,2,3,3a,4,5,6,6a,7,8,9,10a-Dodecahy-
dro-7-isopropyl-1,4-dimethyldicyclopenta[a,d]cycloocten-5-ol (28).
A solution of 15 (52 mg, 0.19 mmol) in CH2Cl2 (5 mL) at -78 °C
was treated with Dibal-H (0.6 mL of 1 M in toluene, 0.60 mmol),
allowed to warm to 20 °C during 4 h, and quenched at -20 °C with
saturated NH4Cl solution. After dilution with ether, the separated
organic phase was washed with 5% HCl, water, and brine, dried, and
concentrated. Purification of the residue on silica gel (elution with
3:1 petroleum ether-ether) gave 50 mg (95%) of 28 as a colorless
Hz, 1 H), 4.66 (br d, J ) 11 Hz, 1 H), 2.56-2.38 (m, 2 H), 2.37-1.94
(m, 5 H), 1.94-1.80 (m, 2 H), 1.70-1.48 (m, 3 H), 1.36-1.17 (m, 2
H), 1.20 (d, J ) 6.5 Hz, 3 H), 0.91 (d, J ) 6.5 Hz, 3 H), 0.90 (d, J )
6.5 Hz, 3 H), 0.86 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 176.2, 140.6, 133.6, 80.3, 52.6, 48.0, 43.8, 39.2, 38.6, 35.8, 33.1,
32.4, 30.1, 27.5, 20.6, 20.4, 19.5, 14.0; MS m/z (M+) calcd 276.2089,
obsd 276.2091.
Anal. Calcd for C18H28O2: C, 78.21; H, 10.21. Found: C, 78.13;
H, 10.30.
crystalline solid, mp 114-116 °C (from pentane): IR (CCl4, cm-1
)
For 13: colorless crystals, mp 90-91 °C (from pentane); IR (CCl4,
cm-1) 1745; 1H NMR (300 MHz, CDCl3) δ 5.82 (dddd, J ) 2, 2, 2, 2
Hz, 1 H), 5.10 (br s, 1 H), 2.53-2.41 (m, 1 H), 2.51 (dq, J ) 1.5, 7.5
Hz, 1 H), 2.35 (dddd, J ) 9, 7, 7, 2.5 Hz, 1 H), 2.32-2.22 (m, 2 H),
2.07-1.85 (m, 4 H), 1.73 (dddd, J ) 12, 6.5, 6, 4.5 Hz, 1 H), 1.58
(dddd, J ) 13, 8, 8, 6 Hz, 1 H), 1.52 (dqq, J ) 7, 7, 7 Hz, 1 H), 1.34
(d, J ) 7.5 Hz, 3 H), 1.31-1.07 (m, 2 H), 0.90 (d, J ) 6.5 Hz, 3 H),
0.89 (d, J ) 7 Hz, 3 H), 0.85 (d, J ) 7 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 175.8, 139.8, 129.3, 76.9, 52.8, 46.5, 43.7, 41.3, 34.3,
34.1, 33.8, 33.0, 32.7, 27.4, 20.8, 20.5, 20.3, 18.2; MS m/z (M+) calcd
3620; 1H NMR (300 MHz, CDCl3) (most signals are very broad at 25
°C) δ 4.87 (m, 1 H), 3.69 (br ddd, J ) 9.5, 7.5, 1.5 Hz, 1 H), 2.75 (m,
1 H), 2.45-0.75 (series of m, 16 H), 1.03 (d, J ) 7 Hz, 3 H), 0.96 (d,
J ) 7 Hz, 3 H), 0.83 (d, J ) 7 Hz, 3 H), 0.73 (d, J ) 6.5 Hz, 3 H)
(OH not observed); 13C NMR (75 MHz, CDCl3) ppm 146.2, 124.0,
78.1, 48.3, 46.2, 44.7, 43.7, 41.9, 37.0, 33.3, 32.7, 30.9, 30.7, 27.8,
22.7, 22.3, 22.2, 18.9, 17.6; MS m/z (M+) calcd 276.2453, obsd 26.2446.
Anal. Calcd for C19H32O: C, 82.55; H, 11.67. Found: C, 82.65;
H, 12.09.
(1R,3aR,4S,5R,6aR,7S,10aS)-1,2,3,3a,4,5,6,6a,7,8,9,10a-Dodecahy-
dro-7-isopropyl-5-(methoxymethoxy)-1,4-dimethyldicyclopenta[a,d]-
cyclooctene (29). A solution of 28 (600 mg, 2.17 mmol) and
diisopropylethylamine (3.02 mL, 17.4 mmol) in CH2Cl2 (30 mL) was
treated with methoxymethyl chloride (0.66 mL, 8.68 mmol) at -10
°C. The reaction mixture was allowed to warm slowly to 20 °C, stirred
for 8 h, and quenched with 5% HCl. The organic phase was washed
with brine, dried, and concentrated to leave a residue that was
chromatographed on silica gel (elution with 20:1 hexanes-ether) to
give 660 mg (95%) of 29 as a colorless oil: IR (CCl4, cm-1) 1465,
1445, 1365, 1145, 1095, 1085; 1H NMR (300 MHz, C6D6) (all signals
except the upfield doublets are broad at 25 °C) δ 4.98 (br s, 1 H), 4.27
(d, J ) 7 Hz, 1 H), 4.56 (d, J ) 7 Hz, 1 H), 3.53 (br dd, J ) 9.5, 7.5
Hz, 1 H), 3.25 (s, 3 H), 2.92 (m, 1 H), 2.44-2.25 (m, 2 H), 2.25-1.96
(m, 4 H), 1.96-1.65 (m, 6 H), 1.58-1.46 (m, 2 H), 1.24-0.98 (m, 2
H), 1.11 (d, J ) 7 Hz, 3 H), 0.95 (d, J ) 7 Hz, 3 H), 0.81 (d, J ) 7
Hz, 3 H), 0.79 (d, J ) 7 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm
146.5, 124.9, 96.1, 83.3, 55.3, 48.8, 46.7, 45.1, 44.0, 43.5, 37.1, 33.7,
31.2, 31.0, 30.2, 28.2, 23.0, 22.7, 22.5, 19.6, 17.9, 17.9; MS m/z (M+)
calcd 320.2715, obsd 320.2726.
Abbreviated Procedure for Preparation of 29 from Lactone 13.
Lactone 13 (5.22 g, 18.9 mmol) was reacted with Tebbe reagent (40
mL of 0.88 M in toluene, 35 mmol) as described earlier. The resulting
vinyl ether 14 was immediately dissolved in dry CH2Cl2 (400 mL) and
treated with triisobutylaluminum (50 mL of 1.0 M in toluene, 50 mmol)
at -78 °C. After 1 h of stirring, Dibal-H (50 mL of 1.0 M in hexanes,
50 mmol) was introduced at -78 °C followed by slow warmup to 20
°C during 4 h. Customary workup afforded alcohol 28 (5.00 g) of
sufficient purity to be carried forward without purification. This
material and diisopropylethylamine (25 mL, 144 mmol) were dissolved
in CH2Cl2 (200 mL) and treated with methoxymethyl chloride (5.6 mL,
74 mmol) at -10 °C followed by slow warmup to 20 °C and overnight
stirring. Excess reagent was then destroyed by addition of methanol,
and workup and purification as above provided pure 29 (5.30 g, 88%
overall from 13) as a colorless oil.
276.2089, obsd 276.2059; [R]20 +2.1 (c 0.86, CHCl3).
D
Anal. Calcd for C18H28O2: C, 78.21; H, 10.21. Found: C, 78.27;
H, 10.31.
(1R,4S,4aR,7R,7aS)-Octahydro-1-[(3S)-3-isopropyl-1-cyclopenten-
1-yl]-4,7-dimethyl-3-methylenecyclopenta[c]pyran (14). To a solu-
tion of 13 (2.00 g, 7.25 mmol) in a cold (-55 °C) mixture of THF (29
mL), toluene (58 mL), and pyridine (0.6 mL) was added the Tebbe
reagent (29 mL of 0.44 M in toluene, 12.8 mmol), and stirring was
maintained under N2 for 1 h. The reaction mixture was diluted with
petroleum ether, quenched with 20% NaOH solution (7.25 mL) at -55
°C, allowed to warm to room temperature, washed with 20% NaOH
and with brine, quickly dried, and evaporated. Flash chromatography
of the residue on grade III basic alumina (elution with petroleum ether)
afforded 1.94 g (98%) of 14 as a colorless oil: IR (CCl4, cm-1) 1645,
1465, 1215, 1100, 1085, 1010; 1H NMR (300 MHz, C6D6) δ 6.03 (dddd,
J ) 2, 2, 2, 2 Hz, 1 H), 4.75 (d, J ) 0.5 Hz, 1 H), 4.58 (br s, 1 H),
4.22 (d, J ) 1 Hz, 1 H), 2.56-2.45 (m, 1 H), 2.38-2.15 (m, 3 H),
2.06 (dddq, J ) 7, 7, 1, 0.5 Hz, 1 H), 1.99 (dddd, J ) 12.5, 8.5, 8.5,
4.5 Hz, 1 H), 1.87 (dddd, J ) 12.5, 8, 7.5, Hz, 1 H), 1.80 (dddd, J )
7.5, 7, 7, 4.5 Hz, 1 H), 1.67-1.37 (m, 4 H), 1.54 (ddd, J ) 9.5, 8, 3
Hz, 1 H), 1.09 (dddd, J ) 12.5, 9, 8, 6 Hz, 1 H), 1.07 (d, J ) 7 Hz,
3 H), 0.97 (d, J ) 6.5 Hz, 3 H), 0.95 (d, J ) 6.5 Hz, 3 H), 0.92 (d, J
) 6.5 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 165.1, 143.6, 127.3,
90.1, 77.0, 53.3, 48.7, 46.2, 35.8, 33.9, 33.4, 33.3, 32.4, 30.8, 27.9,
21.6, 20.8, 20.6, 19.2; MS m/z (M+) calcd 274.2297, obsd 274.2273.
This material was utilized without delay.
(1R,3aR,5S.6aR.7S,10S)-2,3,3a,4,6,6a,7,8,9,10a-Decahydro-7-iso-
propyl-1,4-dimethyldicyclopenta[a,d]cycloocten-5(1H)-one (15). A
solution of 14 (52.4 mg, 0.19 mmol) in dry CH2Cl2 (10 mL) was treated
at -78 °C with triisobutylaluminum (0.70 mL of 1.0 M in toluene,
0.70 mmol) during 2 min, allowed to warm slowly to 20 °C, and stirred
overnight prior to quench with saturated NH4Cl solution. The product
was extracted into ether, and the combined organic phases were washed
with 5% HCl, water, and brine prior to drying and concentration. 1H

8446 J. Am. Chem. Soc., Vol. 119, No. 36, 1997
Paquette et al.
(1R,3aR,4S,5R,6aR,7S,9aS,10aS)-Dodecahydro-7-isopropyl-5-
(methoxymethoxy)-1,4-dimethyldicyclopenta[a,d]cycloocten-9a(1H)-
ol (30) and (1R,3aS,4S,5R,6aR,7S,9aS,10R,10aS)-Tetradecahydro-
7-isopropyl-5-(methoxymethoxy)-1,4-dimethyldicyclopenta[a,d]-
cycloocten-10-ol (31). The protected cyclooctenol 29 (4.13 g, 12.9
mmol) and lithium borohydride (350 mg, 16.1 mmol) were dissolved
in dry THF (250 mL), cooled to -15 °C, and treated with the borane-
THF complex (50 mL of 1 M in THF, 50 mmol) during 5 min. The
reaction mixture was stirred overnight at 20 °C, carefully quenched
with water (15 mL) followed by 20% NaOH (15 mL) and 30%
hydrogen peroxide solutions (15 mL), stirred for an additional 3 h,
and diluted with ether (250 mL). The combined organic layers were
washed with 5% HCl (200 mL), water (200 mL), and brine (200 mL),
then dried, and concentrated. Flash chromatography of the residue on
silica gel (elution with 4:1 petroleum ether-ether) afforded 1.02 g
(23%) of 30 and 2.56 g (59%) of 31.
For 30: colorless gum; IR (film, cm-1) 3529, 1466, 1150, 1028; 1H
NMR (300 MHz, C6D6) δ 4.44 (d, J ) 7.0 Hz, 1 H), 4.26 (d, J ) 7.0
Hz, 1 H), 4.17 (br s, 1 H), 3.37 (ddd, J ) 11.8, 6.3, 2.9 Hz, 1 H), 3.07
(s, 3 H), 2.28-2.24 (m, 1 H), 1.95-0.90 (series of m, 18 H), 1.34 (d,
J ) 6.7 Hz, 3 H), 1.17 (d, J ) 7.1 Hz, 3 H), 0.81 (d, J ) 6.6 Hz, 3 H),
0.69 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 96.1, 85.8
(2 C), 59.9, 55.4, 50.5, 47.6, 47.3, 43.7, 41.1, 40.9, 37.0, 33.9, 31.5,
30.4, 28.5, 23.7, 22.7, 22.5, 18.3, 16.5; MS m/z (M+) calcd 338.2821,
obsd 338.2819.
7 Hz, 1 H), 3.39 (s, 3 H), 3.33 (ddd, J ) 11, 5.5, 3 Hz, 1 H), 3.31 (dd,
J ) 9, 5 Hz, 1 H), 2.39 (dddq, J ) 9.5, 7, 5, 7 Hz, 1 H), 2.30-2.10
(m, 2 H), 2.05-1.83 (m, 5 H), 1.86 (ddd, J ) 15, 10.5, 10.5 Hz, 1 H),
1.72-1.25 (m, 6 H), 1.14 (s, 3 H), 1.04 (dddd, J ) 12, 12, 10, 6 Hz,
1 H), 0.99 (d, J ) 7 Hz, 3 H), 0.96 (d, J ) 6.5 Hz, 3 H), 0.92 (d, J )
7 Hz, 3 H), 0.88 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm
218.3, 96.9, 83.7, 58.9, 57.4, 55.3, 52.5, 47.9, 44.4, 39.9, 36.9, 34.9,
33.8, 32.3, 30.0, 28.7, 27.9, 26.1, 22.6, 21.5 (2 C), 17.7; MS m/z (M+)
calcd 350.2821, obsd 350.2854; [R]20 -48.2 (c 1.02, CHCl3).
D
Anal. Calcd for C22H38O3: C, 75.38; H, 10.93. Found: C, 75.33;
H, 11.08.
(1R,3aS,4S,5R,6aR,7S,9aS,10R,10aS)-Tetradecahydro-7-isopro-
pyl-5-(methoxymethoxy)-1,4,9a-trimethyldicyclopenta[a,d]cycloocten-
10-ol (35). To a cold (-78 °C) slurry of LiAlH4 (600 mg, 15.8 mmol)
in dry ether (100 mL) was added a solution of 33 (2.40 g, 3.99 mmol)
in the same solvent (30 mL) under N2. The reaction mixture was stirred
at room temperature for 2 h, cooled to -20 °C, quenched with ethyl
acetate, and triturated extensively with ether. The ether extracts were
washed with brine, dried, and concentrated. Chromatography of the
residue on silica gel (elution with 9:1 hexanes-ethyl acetate) furnished
2.41 g (100%) of 35 as a colorless oil: IR (CCl4, cm-1) 3630, 3600-
3300; 1H NMR (300 MHz, C6D6) δ 4.74 (d, J ) 6.5 Hz, 1 H), 4.61 (d,
J ) 6.5 Hz, 1 H), 3.49 (ddd, J ) 11, 5, 2.5 Hz, 1 H), 3.26 (s, 3 H),
3.19 (br d, J ) 3 Hz, 1 H), 3.01 (ddq, J ) 10.5, 2.5, 7 Hz, 1 H), 2.32
(dddd, J ) 13, 10.5, 9.5, 6 Hz, 1 H), 1.97 (br dd, J ) 10, 7.5 Hz, 1 H),
1.90-1.38 (series of m, 11 H), 1.21 (m, 1 H), 1.20-0.90 (series of m,
3 H), 1.16 (d, J ) 7 Hz, 3 H), 0.97 (d, J ) 6.5 Hz, 3 H), 0.92 (d, J )
6.5 Hz, 3 H), 0.90 (d, J ) 6 Hz, 3 H) (OH not observed); 13C NMR
(75 MHz, C6D6) ppm 96.6, 84.6, 83.8, 55.3, 52.4, 50.5, 48.2, 44.1,
42.7, 41.7, 34.7, 34.4, 34.1, 34.0, 31.2, 27.8, 26.9, 25.9, 22.4, 21.7,
20.5, 18.1; MS m/z (M+ - CH3OH) calcd 320.2715, obsd 320.2738.
(1R,3aS,4S,5R,6aR,7S,9aS,10R,10aS)-Tetradecahydro-7-isopro-
pyl-5-(methoxymethoxy)-1,4,9a-trimethyldicyclopenta[a,d]cycloocten-
10-ol Se-Phenyl Selenocarbonate (36). A solution of 35 (2.41 g, 6.84
mmol), pyridine (3.0 mL, 37.2 mmol), and DMAP (114 mg) in dry
THF (100 mL) at 0 °C was treated with phosgene (23.4 mL of 1.93 M
in toluene, 45.1 mmol), allowed to warm to room temperature, and
stirred for 1 h. Solvent evaporation left a residue that was dissolved
in benzene (50 mL), THF (50 mL), and pyridine (6 mL). Phenylselenol
(1.61 g, 1.03 mmol) was introduced, and stirring was maintained for 4
h prior to quenching with water and extraction with ether. The
combined organic layers were washed with 5% HCl, water, and
saturated NaHCO3 solution in advance of drying and concentration.
The residue was chromatographed on silica gel (elution with 40:1
hexanes-ethyl acetate) to give 3.48 g (95%) of 36 as a colorless gum
which slowly crystallized when stored neat in the refrigerator: IR (CCl4,
cm-1) 1725, 1700; 1H NMR (300 MHz, C6D6) δ 7.64-7.56 (m, 2 H),
7.00-6.93 (m, 3 H), 5.34 (s, 1 H), 4.69 (d, J ) 6.5 Hz, 1 H), 4.57 (d,
J ) 6.5 Hz, 1 H), 3.38 (ddd, J ) 11, 5, 2.5 Hz, 1 H), 3.25 (s, 3 H),
2.50 (ddq, J ) 10.5, 2.5, 7 Hz, 1 H), 2.37-2.23 (m, 1 H), 2.12 (br dd,
J ) 10, 7 Hz, 1H), 1.99 (dddq, J ) 10.5, 7, 7, 6.5 Hz, 1 H), 1.90-
0.85 (series of m, 13 H), 1.12 (s, 3 H), 1.08 (d, J ) 7 Hz, 3 H), 0.94
(d, J ) 6.5 Hz, 3 H), 0.88 (d, J ) 6.5 Hz, 3 H), 0.85 (d, J ) 6.5 Hz,
3 H); 13C NMR (75 MHz, C6D6) ppm 167.2, 136.0, 129.3, 129.0, 127.0,
96.6, 89.9, 84.0, 55.3, 52.0, 50.3, 48.4, 43.0, 42.8, 41.5, 34.6, 33.9,
33.8, 33.7, 31.1, 27.1, 26.7, 25.6, 22.3, 21.7, 20.3, 18.2; MS m/z (M+
- C6H5SeH - CO2) calcd 334.2872, obsd 334.2843.
For 31: colorless gum; IR (CCl4, cm-1) 3620; 1H NMR (300 MHz,
C6D6) δ 4.74 (d, J ) 6.5 Hz, 1 H), 4.60 (d, J ) 6.5 Hz, 1 H), 3.52
(ddd, J ) 11.5, 5.5, 2.5 Hz, 1 H), 3.45 (br d, J ) 2 Hz, 1 H), 3.26 (s,
3 H), 3.00 (ddq, J ) 10.5, 2.5, 7 Hz, 1 H), 1.88-0.95 (series of m, 17
H), 1.16 (d, J ) 7 Hz, 3 H), 0.95 (d, J ) 6 Hz, 3 H), 0.91 (d, J ) 6.5
Hz, 3 H), 0.89 (d, J ) 6.5 Hz, 3 H) (OH not observed); 13C NMR (75
MHz, C6D6) ppm 96.5, 84.4, 77.6, 55.3, 55.1, 52.4, 46.9, 43.4, 41.2,
36.3, 34.6, 34.4, 34.3, 30.3, 26.6, 26.4, 25.3, 22.2, 21.9, 20.6, 18.6;
MS m/z (M+) calcd 338.2821, obsd 338.2839.
(1R,3aS,4S,5R,6aR,7S,9aS,10aS)-Dodecahydro-7-isopropyl-5-(meth-
oxymethoxy)-1,4-dimethyldicyclopenta[a,d]cycloocten-10(1H)-one (32).
To a solution of 31 (2.56 g, 7.55 mmol) in CH2Cl2 (250 mL) and ether
(150 mL) was added pyridinium chlorochromate on alumina (60 g, 54
mmol). After 3 h, the reaction mixture was filtered through Celite
and concentrated. The concentrate was chromatographed on silica gel
(elution with 9:1 petroleum ether-ether) to provide 2.11 g (83%) of
32 as colorless crystals, mp 109.5-110 °C (from petroleum ether):
1
IR (CCl4, cm-1) 1680; H NMR (300 MHz, C6D6) δ 4.63 (d, J ) 7
Hz, 1 H), 4.49 (d, J ) 7 Hz, 1 H), 3.30 (ddd, J ) 10.5, 6, 2.5 Hz, 1
H), 3.20 (s, 3 H), 3.11 (dd, J ) 9.5, 4.5 Hz, 1 H), 2.80-2.62 (m, 2 H),
2.39 (dddd, J ) 11.5, 11.5, 9.5, 6.5 Hz, 1 H), 2.04-1.93 (m, 1 H),
1.88-1.50 (m, 9 H), 1.44 (dqq, J ) 9.5, 6.5, 6.5 Hz, 1 H), 1.24-0.87
(m, 3 H), 0.94 (d, J ) 7 Hz, 3 H), 0.89 (d, J ) 7 Hz, 3 H), 0.80 (d, J
) 6.5 Hz, 3 H), 0.78 (d, J ) 6.5 Hz, 3 H); 13C NMR (62.5 MHz,
C6D6) ppm 217.3, 96.7, 83.5, 60.1, 56.1, 55.4, 53.9, 43.9, 40.0, 38.6,
36.6, 34.6, 32.5, 29.7, 28.0, 25.8, 25.6, 22.3, 21.6, 21.5, 18.4; MS m/z
(M+) calcd 336.2664, obsd 336.2669; [R]20 -60.1 (c 0.57, CHCl3).
D
Anal. Calcd for C21H36O3: C, 74.95; H, 10.78. Found: C, 75.03;
H, 11.06.
(1R,3aS,4S,5R,6aR,7S,9aS,10aS)-Dodecahydro-7-isopropyl-5-(meth-
oxymethoxy)-1,4,9a-trimethyldicyclopenta[a,d]cycloocten-10(1H)-
one (33). Diisopropylamine (10 mL, 71 mmol) was dissolved in THF
(200 mL), cooled to 0 °C, and treated dropwise with n-butyllithium
(20 mL of 1.6 M in hexanes, 32 mmol). After 30 min, this solution
was cooled to -78 °C, and 32 (2.62 g, 7.8 mmol) in THF (25 mL)
was introduced dropwise. The temperature was then raised to -15 °C
for 1 h prior to the addition of methyl iodide (10 mL, 160 mmol) in
HMPA (20 mL) and THF (20 mL) at -78 °C. The reaction mixture
was allowed to warm to room temperature during 4 h, quenched with
saturated NH4Cl solution (20 mL), and diluted with 1:1 petroleum
ether-ether (250 mL). The organic phase was washed with 5% HCl
(250 mL), water (250 mL), and brine (250 mL) prior to drying and
concentration. Silica gel chromatographic purification of the residue
(elution with 9:1 petroleum ether-ether) provided 0.48 g of unreacted
32 and 2.18 g of 33 (98% corrected).
Radical Reduction of 36. A solution of 36 (590 mg, 1.10 mmol)
and tris(trimethylsilyl)silane (2.20 g, 8.80 mmol) in benzene (30 mL)
was heated to reflux, and AIBN (45 mg, 0.28 mmol) dissolved in
benzene (10 mL) was introduced dropwise over 30 min. After a heating
period of 2 h, the reaction mixture was concentrated, and the residue
was chromatographed on silica gel. Elution with 19:1 petroleum ether-
ether returned 237 mg (64%) of the epimeric mixture 37 and 80 mg
(25%) of 38, which is characterized below.
For 37: colorless gum; IR (CCl4, cm-1) 1030; 1H NMR (300 MHz,
C6D6) (major diasteromer) δ 4.69 (d, J ) 7 Hz, 1 H), 4.46 (d, J ) 7
Hz, 1 H), 3.29 (s, 3 H), 3.19 (ddd, J ) 10, 3.5, 2 Hz, 1 H), 1.95-0.90
(series of m, 19 H), 1.13 (d, J ) 6.5 Hz, 3 H), 1.01 (s, 3 H), 0.98 (d,
J ) 6.5 Hz, 3 H), 0.96 (d, J ) 6.5 Hz, 3 H), 0.93 (d, J ) 6.5 Hz, 3 H);
(minor diastereomer) δ 4.72 (d, J ) 7 Hz, 1 H), 4.59 (d, J ) 7 Hz, 1
H), 3.40 (ddd, J ) 11.5, 5, 2.5 Hz, 1 H), 3.25 (s, 3 H), 2.31 (dddd, J
For 33: colorless crystals, mp 58-60 °C; IR (CCl4, cm-1) 1680;
1H NMR (300 MHz, CDCl3) δ 4.69 (d, J ) 7 Hz, 1 H), 4.60 (d, J )

Total Synthesis of (+)-Epoxydictymene
J. Am. Chem. Soc., Vol. 119, No. 36, 1997 8447
) 12.5, 10.5, 9.5, 6 Hz, 1 H), 1.95-0.90 (series of m, 18 H), 1.09 (d,
J ) 7 Hz, 3 H), 1.00 (d, J ) 6.5 Hz, 3 H), 0.97 (s, 3 H), 0.92 (pair of
d, J ) 6.5 Hz, 2 × 3 H); 13C NMR (75 MHz, C6D6) ppm (major
diastereomer) 95.4, 82.6, 56.1, 52.8, 47.0, 45.9, 45.8, 44.2, 42.8, 35.5,
33.8, 33.7, 33.1, 32.3, 29.4, 26.6, 24.2, 22.4, 21.7, 20.3, 17.1 (1 C not
observed); (minor diastereomer) 96.5, 84.7, 55.3, 52.4, 47.2, 45.5, 45.1,
44.1, 41.1, 34.6, 33.9, 33.7, 32.6, 32.2, 31.0, 26.8, 26.5, 22.4, 21.8,
20.5, 18.2 (1 C not observed); MS m/z (M+) calcd 336.3028, obsd
336.3028.
1H NMR (300 MHz, C6D6) δ 2.64 (dd, J ) 12.6, 6.5 Hz, 1 H), 2.35-
2.22 (m, 2 H), 2.08 (dt, J ) 12.2, 1.0 Hz, 1 H), 1.98-1.89 (m, 1 H),
1.77-1.58 (m, 1 H), 1.57-0.78 (series of m, 13 H), 0.94 (s, 3 H),
0.91 (d, J ) 6.7 Hz, 3 H), 0.82 (d, J ) 6.7 Hz, 3 H), 0.80 (d, J ) 6.1
Hz, 3 H), 0.73 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm
214.9, 54.5, 49.9, 46.6, 45.4, 44.2, 43.5, 41.9, 39.9, 37.5, 37.0, 34.5,
32.4, 28.7, 22.0 (2 C), 20.7, 18.8, 18.2, 16.8; MS m/z (M+) calcd
290.2610, obsd 290.2612.
(1R,3aR,4S,6S,6aR,7S,9aR,10aS)-Dodecahydro-6-hydroxy-7-iso-
propyl-1,4,9a-trimethyldicyclopenta[a,d]cycloocten-5(1H)-one (41).
Ketone 38 (84 mg, 0.29 mmol) and chlorotrimethylsilane (158 mg,
1.45 mmol) was dissolved in dry THF (5 mL), cooled to -78 °C, treated
dropwise with LDA in THF (2.4 mL of 0.3 M, 0.72 mmol), allowed to
warm to 20 °C, and stirred for 30 min. The reaction mixture was cooled
to -78 °C, triethylamine (1 mL) was introduced, and the solvents were
removed in vacuo after warming. The resulting oily solid was stirred
with petroleum ether (10 mL), filtered through a Celite plug, and
concentrated to give the silyl enol ether, which was taken up in
CH2Cl2 (8 mL) and added to a mixture of MCPBA (200 mg of 50%
purity, 1.16 mmol) and NaHCO3 (200 mg, 2.30 mmol) in the same
solvent (5 mL). The oxidation was allowed to proceed for 3 h, at which
point washing with saturated NaHCO3 solution was implemented (2
× 10 mL). The CH2Cl2 phase was concentrated, and the residue was
dissolved in methanol (10 mL), admixed with K2CO3 (105 mg), and
stirred for 1 h. The methanol was removed in vacuo, and the resulting
oil was taken up in petroleum ether (10 mL), washed with brine (2 ×
10 mL), dried, and concentrated. Silica gel chromatography (elution
with 24:1 petroleum ether-ether) gave 64 mg (72%) of 41 as a
colorless, crystalline solid, mp 60-61 °C: IR (CCl4, cm-1) 3550, 1700;
1H NMR (300 MHz, C6D6) δ 4.39 (dd, J ) 10.5, 10 Hz, 1 H), 2.49 (d,
J ) 10.5 Hz, 1 H), 2.35 (dqq, J ) 9, 6.5, 6.5 Hz, 1 H), 2.23 (dq, J )
12, 7 Hz, 1 H), 2.05-0.77 (series of m, 15 H), 1.10 (d, J ) 6.5 Hz, 3
H), 0.99 (d, J ) 7 Hz, 3 H), 0.97 (s, 3 H), 0.97 (d, J ) 6.5 Hz, 3 H),
0.83 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 220.1, 70.1,
57.8, 52.4, 49.7, 46.6, 43.5, 42.7, 41.5, 39.7, 36.6, 36.0, 33.1, 30.4,
28.8, 28.5, 24.5, 22.7, 18.8, 17.6; MS m/z (M+) calcd 306.2559, obsd
(1R,3aR,4S,5R,6aR,7S,9aR,10aS)-Dodecahydro-7-isopropyl-1,4,-
9a-trimethyldicyclopenta[a,d]cycloocten-5(1H)-one (38). A 237 mg
(0.70 mmol) sample of 37 was dissolved in methanol (4 mL), treated
with concentrated HCl (0.5 mL), and heated at reflux for 1 h. After
cooling, solid NaHCO3 was carefully added, the methanol was removed
in vacuo, and the mixture was dissolved in ether (20 mL), washed with
water (20 mL) and brine (20 mL), dried, and evaporated. The
unpurified alcohol was taken up in CH2Cl2 (10 mL), treated with
pyridinium chlorochromate on alumina (1.5 g, 1.4 mmol), stirred for
30 min, and placed directly atop a column of silica gel. Elution with
CH2Cl2 gave 204 mg (100%) of 38 as a white solid, mp 68-70 °C:
IR (CCl4, cm-1) 1700; 1H NMR (300 MHz, C6D6) δ 2.43-2.21 (ABm,
2 H), 2.16 (dq, J ) 11.5, 7 Hz, 1 H), 2.03-1.91 (m, 1 H), 1.85-1.55
(series of m, 6 H), 1.56 (dd, J ) 16, 10.5 Hz, 1 H), 1.38 (dddd, J )
10.5, 10.5, 8.5, 2 Hz, 1 H), 1.29-0.99 (series of m, 5 H), 1.23 (dd, J
) 16, 2 Hz, 1 H), 0.97-0.87 (m, 1 H), 0.96 (s, 3 H), 0.95 (d, J ) 6.5
Hz, 3 H), 0.92 (d, J ) 7 Hz, 3 H), 0.88 (d, J ) 6.5 Hz, 3 H), 0.86 (d,
J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 217.5, 51.3, 50.9,
50.5, 47.2, 45.4, 45.1, 41.5, 39.2, 34.6, 33.6, 33.4, 33.1, 30.4, 29.7,
28.7, 22.2, 21.7, 19.0, 17.4; MS m/z (M+) calcd 290.2610, obsd
290.2596; [R]20 +37.3 (c 1.54, CHCl3).
D
Anal. Calcd for C20H34O: C, 82.69; H, 11.80. Found: C, 82.60;
H, 11.83.
(1R,3aR,4S,5R,7S,9aR,10aS)-2,3,3a,4,7,8,9,9a,10,10a-Decahydro-
7-isopropyl-1,4,9a-trimethyldicyclopenta[a,d]cycloocten-5(1H)-
one (39). To a cold (-78 °C), magnetically stirred solution of 38 (29
mg, 0.10 mmol) and chlorotrimethylsilane (108 mg, 1.0 mmol) in
anhydrous THF (4 mL) was added 1.66 mL of 0.3 M LDA in THF
under N2. This solution was allowed to warm slowly to 20 °C, stirred
for 30 min, and returned to -78 °C when triethylamine (0.8 mL) was
introduced. The solvents were removed in vacuo, and the resulting
oily solid was stirred with hexanes and filtered through a plug of Celite
and basic alumina (elution with hexanes). The filtrate was concentrated
and the silyl enol ether was used directly.
306.2572; [R]20 +44.5 (c 1.5, CHCl3).
D
Anal. Calcd for C20H34O2: C, 78.38; H, 11.18. Found: C, 78.02;
H, 11.14.
(1R,3aR,4S,6S,6aR,7S,9aR,10aS)-Dodecahydro-7-isopropyl-6-
(methoxymethoxy)-1,4,9a-trimethyldicyclopenta[a,d]cycloocten-
5(1H)-one (42). R-Ketol 41 (64 mg, 0.21 mmol) was dissolved in
CH2Cl2 (10 mL), diisopropylethylamine (2.0 mL) and methoxymethyl
chloride (1.0 mL) were added, and the mixture was stirred for 6 h prior
to being washed with saturated NaHCO3 solution (2 × 10 mL), passed
through a plug of silica gel (washed with CH2Cl2), and concentrated.
Chromatography of the residue on silica gel (elution with 32:1
petroleum ether-ether) resulted in the isolation of 42 (63 mg, 86%)
and recovery of 41 (4 mg).
To a solution of DDQ (340 mg, 1.5 mmol) in benzene (4 mL) at 4
°C was added a solution of collidine (196 mg, 1.62 mmol) in benzene
(2 mL). After 20 min at room temperature, this solution was cooled
to 0 °C, the silyl enol ether dissolved in benzene (4 mL) was added,
and the mixture was stirred at 20 °C for 30 h, filtered through a short
pad of Celite and basic alumina (elution with 9:1 hexanes-ethyl
acetate), and concentrated. Flash chromatography of the residue on
silica gel (elution with 60:1 hexanes-ethyl acetate) provided 26 mg
1
For 42: colorless oil; IR (neat, cm-1) 1708, 1459, 1150, 1099; H
NMR (300 MHz, C6D6) δ 4.42 (d, J ) 6.9 Hz, 1 H), 4.40 (d, J ) 6.9
Hz, 1 H), 4.39 (d, J ) 10 Hz, 1 H), 3.12 (s, 3 H), 2.89 (dq, J ) 11.7,
6.9 Hz, 1 H), 2.37 (dd, J ) 6.8, 6.7 Hz, 1 H), 2.31-2.07 (series of m,
3 H), 1.91-0.83 (series of m, 12 H), 1.10 (d, J ) 6.4 Hz, 3 H), 1.08
(d, J ) 6.8 Hz, 3 H), 1.04 (s, 3 H), 0.98 (d, J ) 6.6 Hz, 3 H), 0.91 (d,
J ) 6.4 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 218.4, 96.1, 79.1,
57.3, 55.6, 51.7, 46.4, 46.1, 45.4, 44.1, 43.4, 39.1, 37.0, 36.9, 33.8,
32.2, 29.2, 28.9, 23.2, 22.6, 18.8, 17.0; MS m/z (M+) calcd 350.2821,
1
(90%) of 39 as a colorless oil: IR (neat, cm-1) 1687, 1461; H NMR
(300 MHz, C6D6) δ 5.61 (d, J ) 2.3 Hz, 1 H), 2.41-2.34 (m, 1 H),
2.32-2.25 (m, 2 H), 1.74-1.60 (m, 3 H), 1.59-1.48 (m, 3 H), 1.40-
1.24 (m, 3 H), 1.19-1.06 (m, 2 H), 1.05 (s, 3 H), 0.99 (d, J ) 6.8 Hz,
3 H), 0.97-0.84 (m, 2 H), 0.83 (d, J ) 6.5 Hz, 6 H), 0.71 (d, J ) 6.8
Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 213.3, 157.2, 118.9, 52.9,
48.5, 47.1, 46.9, 44.1, 40.3, 37.9, 37.3, 33.8, 30.5 (2 C), 30.4, 23.1,
22.2, 18.4, 18.3, 16.9; MS m/z (M+) calcd 288.2453, obsd 288.2451;
obsd 350.2823; [R]20 +5.1 (c 3.7, CHCl3).
D
[R]20 -45.5 (c 0.87, EtOAc).
D
(1R,3aR,6S,6aR,7S,9aR,10aS)-1,2,3,3a,6,6a,7,8,9,9a,10,10a-
Dodecahydro-7-isopropyl-6-(methoxymethoxy)-1,4,9a-trimethyldi-
cyclopenta[a,d]cycloocten-5-ol Diethyl Phosphate (43). A solution
of 42 (36 mg, 0.10 mmol) and HMPA (100 µL) in dry THF (5 mL)
was cooled to -78 °C, treated with potassium hexamethyldisilazide in
toluene (0.41 mL of 0.5 M, 0.20 mmol), and stirred at room temperature
for 1 h. The reaction mixture was returned to -78 C, treated dropwise
with diethylchlorophosphate in THF (0.36 mL of 0.5 M, 0.25 mmol),
allowed to warm to 20 °C, and stirred for 1 h. Ether (10 mL) was
introduced, and the solution was washed with saturated NaHCO3
solution (2 × 10 mL), dried, and concentrated. Gradient elution
chromatography on silica gel (elution with 5 f 50% ether in petroleum
ether) returned 3 mg (8%) of 42 and afforded 34 mg (70%) of 43 as a
(1R,3aR,4S,6aS,7S,9aR,10aS)-Dodecahydro-7-isopropyl-1,4,9a-
trimethyldicyclopenta[a,d]cycloocten-5(1H)-one (40). A cold (-78
°C) solution of 39 (40 mg, 0.14 mmol) in dry THF (8 mL) and liquid
NH3 (4 mL) was treated under N2 with excess lithium metal (14 mg,
2 mmol) until a blue color persisted. After 30 min, the reaction mixture
was allowed to warm to 20 °C, quenched with saturated NH4Cl solution
at -30 °C, and extracted with ether. The combined organic phases
were washed with brine, dried, and concentrated. The residue and 40
mg of the PCC/Al2O3 mixture used above in CH2Cl2 (6 mL) was stirred
for 3 h and processed as described earlier. Purification by flash
chromatography on silica gel (elution with 30:1 hexanes-ethyl acetate)
gave 36 mg (90%) of 40 as a colorless oil: IR (neat, cm-1) 1692, 1462;

8448 J. Am. Chem. Soc., Vol. 119, No. 36, 1997
Paquette et al.
colorless gum: IR (neat, cm-1) 1676, 1456, 1379, 1273, 1167, 1149,
1036; 1H NMR (300 MHz, C6D6) δ 5.14 (d, J ) 7.3 Hz, 1 H), 4.87 (d,
J ) 11.4 Hz, 1 H), 4.52 (d, J ) 7.3 Hz, 1 H), 4.15-3.96 (m, 4 H),
3.25 (s, 3 H), 2.67 (m, 1 H), 2.48 (dd, J ) 11.4, 5.1 Hz, 1 H), 2.00-
0.80 (series of m, 26 H), 1.89 (d, J ) 2.0 Hz, 3 H), 1.19 (s, 3 H), 0.88
(d, J ) 6.2 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 143.1 (d, J )
19.4 Hz), 127.2 (d, J ) 21.5 Hz), 94.4, 70.5, 63.6 (d, J ) 22.0 Hz),
63.5 (d, J ) 22.2 Hz), 56.7, 54.3, 49.7, 49.5, 45.1, 44.8, 42.4, 42.3,
36.3, 35.4, 34.8, 30.2, 29.5, 29.3, 28.6, 24.1, 24.0, 18.5, 16.1 (d, J )
6.8 Hz), 16.0 (d, J ) 6.9 Hz); MS m/z (M+ - C2H6O2) calcd 424.2742,
h, the reaction mixture was filtered to remove the solids, and the filtrate
was concentrated. Purification of the residue by chromatography on
silica gel (elution with 49:1 petroleum ether-ether) furnished 7.8 mg
(89%) of 47 as a colorless, crystalline solid: IR (neat, cm-1) 1688,
1
1639, 1458, 1376; H NMR (300 MHz, C6D6) δ 5.77 (m, 1 H), 3.09
(m, 1 H), 2.51 (d, J ) 5.9 Hz, 1 H), 2.27 (dd, J ) 10.3, 6.5 Hz, 1 H),
2.17-1.50 (series of m, 7 H), 1.54 (t, J ) 1.3 Hz, 3 H), 1.38-0.81
(series of m, 6 H), 0.98 (s, 3 H), 0.93 (d, J ) 6.6 Hz, 3 H), 0.86 (d, J
) 6.6 Hz, 3 H), 0.77 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz, C6D6)
ppm 209.1, 141.1, 130.1, 61.6, 51.2, 47.5, 46.0, 45.0, 44.1, 43.5, 33.6,
33.5, 32.9, 29.5, 29.2, 29.1, 23.0, 22.9, 22.5, 20.6; MS m/z (M+) calcd
obsd 424.2743; [R]20 +82.6 (c 2.2, CHCl3).
D
228.2435, obsd 288.2442; [R]20 -126.9 (c 1.7, CHCl3).
(1R,3aR,6R,6aR,7S,9aR,10aS)-1,2,3,3a,6,6a,7,8,9,9a,10,10a-
Dodecahydro-7-isopropyl-6-(methoxymethoxy)-1,4,9a-trimethyldi-
cyclopenta[a,d]cyclooctene (44). A solution of lithium (25 mg) in
ethylamine (10 mL) was slowly added via cannula to a cold (-100
°C), magnetically stirred solution of 43 (34 mg, 0.07 mmol) in THF (4
mL) and ethylamine (1 mL) until a blue color persisted for more than
a few seconds. Saturated NH4Cl solution (2 mL) was introduced, and
the mixture was allowed to warm to room temperature. The ethylamine
was blown off with air, and the residue was taken up in ether (10 mL),
washed with brine (2 × 10 mL), dried, and evaporated. Chromatog-
raphy of the residue on silica gel (gradient elution with 5 f 50% ether
in petroleum ether) returned 5 mg (14%) of 43 and gave 14 mg (81%
corrected) of 44 as a colorless gum: IR (neat, cm-1) 1458, 1377, 1150,
D
Anal. Calcd for C20H32O: C, 83.27; H, 11.18. Found: C, 83.16;
H, 11.40.
(1R,3aR,4S,6R,6aS,7S,9aR,10aS)-Dodecahydro-6-hydroxy-7-iso-
propyl-1,4,9a-trimethyldicyclopenta[a,d]cycloocten-5(1H)-one (48).
A solution of 40 (119 mg, 0.41 mmol) and chlorotrimethylsilane (445
mg, 4.1 mmol) in dry THF (20 mL) was cooled to -78 °C under N2
and treated with LDA (6.83 mL of 0.3 M in THF, 2.05 mmol). The
reaction mixture was allowed to warm slowly to room temperature,
stirred for 30 min, and returned to -78 °C prior to the addition of
triethylamine (3.6 mL, 25.9 mmol). After warming again to 20 °C,
the volatiles were removed in vacuo, hexanes were added, and the solids
were removed by filtration through a plug of Celite-basic alumina
(hexane elution). Concentration of the filtrate gave the silyl enol ether,
which was dissolved in CH2Cl2 (10 min) and added to a mixture of
MCPBA (283 mg of 70% purity) and NaHCO3 (253 mg, 3.28 mmol)
in CH2Cl2 (20 mL). After 5 h of stirring, saturated NaHCO3 solution
(13 mL) was added in addition to 30 mL of CH2Cl2, and the organic
phase was dried and concentrated. This oil was dissolved in methanol
(10 mL), admixed with K2CO3 (200 mg, 1.45 mmol), stirred for 1 h,
and concentrated. The product was taken up in ethyl acetate, washed
with brine, dried, and concentrated in advance of chromatography on
silica gel (elution with 20:1 hexanes-ethyl acetate) to deliver 90 mg
1
1092, 1032; H NMR (300 MHz, C6D6) δ 5.17 (d, J ) 8.3 Hz, 1 H),
4.81 (d, J ) 6.4 Hz, 1 H), 4.55 (dd, J ) 10.6, 8.9 Hz, 1 H), 4.35 (d,
J ) 6.5 Hz, 1 H), 3.23 (s, 3 H), 3.16 (m, 1 H), 2.63 (m, 1 H), 2.00-
0.78 (series of m, 14 H), 1.62 (s, 3 H), 1.30 (d, J ) 6.3 Hz, 3 H), 1.11
(s, 3 H), 1.06 (d, J ) 6.6 Hz, 3 H), 0.93 (d, J ) 6.2 Hz, 3 H); 13C
NMR (75 MHz, C6D6) ppm 139.5, 129.1, 93.3, 71.2, 56.2, 54.0, 53.5,
48.5, 45.5, 44.9, 44.1, 43.3, 36.7, 35.7, 35.0, 29.8, 29.5, 28.4, 24.2,
23.8, 22.9, 18.8; MS m/z (M+) calcd 334.2872, obsd 334.2872; [R]20
-65.6 (c 2.1, CHCl3).
D
(3S,3aR,4R,6aR,9R,9aS,10aR)-1,2,3,3a,4,6a,7,8,9,9a,10,10a-
Dodecahydro-3-isopropyl-6,9,10a-trimethyldicyclopenta[a,d]cy-
cloocten-4-ol (45) and (3S,3′S,3aR,3′aR,4R,4′R,6aR,6′aR,9R,9′R,-
9aS,9′aS,10aR,10′aR)-4,4′-(Methylenedioxy)bis[1,2,3,3a,4,6a,7,8,-
9,9a,10,10a-dodecahydro-3-isopropyl-6,9,10a-trimethyldicyclopenta-
[a,d]cyclooctene (46). Bromocatecholborane (0.11 mL of 0.2 M in
CH2Cl2, 0.022 mmol) was added dropwise at -78 °C to a solution of
44 (6.4 mg, 0.019 mmol). The reaction mixture was stirred for 15
min, treated with saturated NaHCO3 solution (1 mL), and allowed to
warm to room temperature. After dilution with petroleum ether (5 mL),
the organic phase was washed with 10% KOH (2 × 5 mL) and saturated
NaHCO3 solutions (5 mL), dried, and concentrated. The residue was
immediately passed through a plug of silica gel (elution with 9:1
petroleum ether-ether) to give 6.2 mg (100%) of 45 as a clear colorless
1
(72%) of 48 as a colorless oil: IR (neat, cm-1) 3424, 1680; H NMR
(300 MHz, C6D6) δ 3.93 (dd, J ) 9.5, 5.1 Hz, 1 H), 2.70-2.60 (m, 1
H), 2.30-1.90 (m, 3 H), 1.96 (d, J ) 5.1 Hz, 1 H), 1.86 (t, J ) 10.0
Hz, 1 H), 1.72 (m, 1 H), 1.54-1.00 (series of m, 11 H), 1.15 (d, J )
7.1 Hz, 3 H), 0.92 (d, J ) 7.2 Hz, 3 H), 0.90 (s, 3 H), 0.86 (d, J ) 6.7
Hz, 3 H), 0.81 (d, J ) 6.3 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm
215.1, 83.0, 51.0, 49.7, 49.1, 45.6, 43.7, 42.7, 41.1, 39.5, 38.3, 34.3,
32.0, 29.6, 22.7, 21.6, 20.9, 18.9, 18.5, 15.5; MS m/z (M+) calcd
306.2558, obsd 306.2553; [R]20 -41.7 (c 0.53, CH2Cl2).
D
(1R,3aR,4S,6R,6aS,7S,9aR,10aS)-Dodecahydro-7-isopropyl-6-
(methoxymethoxy)-1,4,9a-trimethyldicyclopenta[a,d]cycloocten-
5(1H)-one (49). To a solution of 48 (92 mg, 0.30 mmol) and
diisopropylethylamine (2.09 mL, 12 mmol) in CH2Cl2 (6 mL) was added
methoxymethyl chloride (0.69 mL, 9.0 mmol) dissolved in CH2Cl2 (2
mL). The reaction mixture was stirred under N2 for 6 days, quenched
with saturated NaHCO3 solution, 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 30:1
hexanes-ethyl acetate) returned 24 mg of 48 and provided 76 mg (97%
corrected) of 49 as a colorless oil: IR (neat, cm-1) 1690, 1025, 1009;
1H NMR (300 MHz, C6D6) δ 4.46 (d, J ) 6.4 Hz, 1 H), 4.26 (d, J )
6.4 Hz, 1 H), 4.12 (d, J ) 10.0 Hz, 1 H), 3.10 (s, 3 H), 2.90-2.78 (m,
1 H), 2.38-2.25 (m, 2 H), 2.18 (t, J ) 10.0 Hz, 1 H), 2.00-1.92 (m,
1 H), 1.82-1.74 (m, 1 H), 1.55-1.00 (series of m, 11 H), 1.13 (d, J
) 7.4 Hz, 3 H), 0.91 (d, J ) 6.7 Hz, 3 H), 0.89 (d, J ) 7.1 Hz, 3 H),
0.87 (s, 3 H), 0.82 (d, J ) 6.1 Hz, 3 H); 13C NMR (75 MHz, C6D6)
ppm 212.6, 95.8, 88.9, 56.3, 53.7, 50.1, 47.6, 46.5, 43.3, 42.9, 40.1,
39.0, 37.2, 34.7, 32.6, 29.1, 22.8, 21.1, 21.0, 19.2, 18.1, 15.4; MS m/z
1
oil: IR (neat, cm-1) 3318, 1458, 1376, 1074; H NMR (300 MHz,
C6D6) δ 5.20 (d, J ) 8.3 Hz, 1 H), 4.35 (dd, J ) 11.0, 8.3 Hz, 1 H),
2.91 (q, J ) 9.9 Hz, 1 H), 2.64 (dd, J ) 8.9, 6.5 Hz, 1 H), 1.94-0.95
(series of m, 15 H), 1.63 (s, 3 H), 1.32 (d, J ) 6.3 Hz, 3 H), 1.13 (s,
3 H), 1.09 (d, J )6.7 Hz, 3 H), 1.02 (d, J ) 6.0 Hz, 3 H); 13C NMR
(75 MHz, C6D6) ppm 131.8, 127.3, 68.3, 55.4, 53.3, 48.5, 45.1, 44.1,
43.0, 36.7 (2 C), 35.1, 30.2, 29.5, 29.2, 28.1, 24.6, 23.4, 22.8, 19.1;
MS m/z (M+) calcd 290.2610, obsd 290.2627; [R]20 -4.6 (c 0.65,
D
CHCl3).
When a lesser amount of bromocatecholborane was employed,
bimolecular “coupling” occurred to give variable amounts of 46, a
colorless crystalline solid: 1H NMR (300 MHz, C6D6) δ 5.07 (d, J )
8.7 Hz, 2 H), 4.74 (s, 2 H), 4.64 (dd, J ) 10.9, 8.7 Hz, 2 H), 3.24 (br
q, J ) 8.9 Hz, 2 H), 2.69 (m, 2 H), 2.02-0.82 (series of m, 30 H),
1.60 (s, 6 H), 1.31 (d, J ) 6.2 Hz, 6 H), 1.13 (d, J ) 6.5 Hz, 6 H),
1.12 (s, 6 H), 1.11 (2d, J ) 7 Hz, 6 H); 13C NMR (75 MHz, C6D6)
ppm 139.9, 129.7, 72.2, 54.3, 53.6, 48.5, 45.7, 45.0, 44.3, 43.7, 36.7,
36.1, 35.5, 30.4, 29.6, 29.2, 24.4, 24.3, 22.8, 18.9.
(M+) calcd 350.2820, obsd 350.2817; [R]25 +37.2 (c 0.54, CH2Cl2).
D
(1R,3aR,6S,6aS,7S,9aR,10aS)-1,2,3,3a,6,6a,7,8,9,9a,10,10a-
Dodecahydro-7-isopropyl-6-(methoxymethoxy)-1,4,9a-trimethyldi-
cyclo-penta[a,d]cyclooctene (50). Lithium aluminum hydride (6.5 mg,
0.17 mmol) was added to a solution of 49 (30 mg, 0.085 mmol) in
ether (5 mL) at -78 °C under N2, slowly warmed to room temperature,
quenched with ethyl acetate, and extracted with ether. The combined
organic layers were washed with water and brine, dried, and evaporated
to leave the alcohol, which was taken up in benzene (5 mL), treated
with the Martin sulfurane reagent (228 mg, 0.34 mmol), stirred at 60
The stereochemistry of 46 was established by X-ray crystallographic
analysis.
(3S,3aR,6aR,9R,9aS,10aR)-2,3,3a,6a,7,8,9,9a,10,10a-Decahydro-
3-isopropyl-6,9,10a-trimethyldicyclopenta[a,d]cycloocten-4(1H)-
one (47). A solution of 45 (8.6 mg, 0.029 mmol) in CH2Cl2 (5 mL)
was treated sequentially with NMO (6.8 mg, 0.058 mmol), 4 Å
molecular sieves (5 mg), and TPAP (5 mg). After being stirred for 2

Total Synthesis of (+)-Epoxydictymene
J. Am. Chem. Soc., Vol. 119, No. 36, 1997 8449
°C under N2 for 5 h, cooled, quenched with saturated NaHCO3 solution,
and extracted with ether. The combined ethereal solutions were washed
with brine, dried, and concentrated. Flash chromatography of the
residue on silica gel (elution with 99:1 hexanes-ethyl acetate) gave
50 (26 mg, 90%) as a colorless oil: IR (film, cm-1) 1038: 1H NMR
(300 MHz, C6D6) δ 5.76-5.72 (m, 1 H), 4.93 (d, J ) 6.5 Hz, 1 H),
4.43 (d, J ) 6.5 Hz, 1 H), 3.96 (dd, J ) 10.0, 7.2 Hz, 1 H), 3.86 (m,
1H), 3.23 (s, 3 H), 2.62-2.53 (m, 1 H), 2.39 (t, J ) 9.5 Hz, 1 H),
2.05-1.90 (m, 1 H), 1.65-1.02 (series of m, 12 H), 1.56 (d, J ) 1.4
Hz, 3H), 1.00 (d, J ) 6.4 Hz, 3 H), 0.98 (d, J ) 7.1 Hz, 3 H), 0.92 (d,
J ) 5.8 Hz, 3 H), 0.90 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 144.4,
125.4, 94.1, 76.6, 55.2, 51.5, 51.3, 50.1, 43.1, 41.4, 40.4, 39.6, 35.3,
29.5, 26.6, 24.6, 24.2, 23.1, 21.0, 18.8, 15.7 (1 C not observed); MS
stirred for 6 h, recooled to -20 °C, and treated sequentially with water
(0.2 mL), 20% NaOH solution (0.2 mL), and 30% hydrogen peroxide
(0.2 mL) prior to overnight stirring at 20 °C. The products were
extracted into ethyl acetate, washed with brine, and concentrated.
Chromatography of the residue on silica gel (elution with 10:1 hexanes-
ethyl acetate) afforded 5 mg (60%) of 55 as a 1:1 mixture of epimers.
1
For one epimer: IR (neat, cm-1) 1462, 1037; H NMR (300 MHz,
C6D6) (one epimer) δ 4.68 (d, J ) 6.7 Hz, 1 H), 4.40 (d, J ) 6.7 Hz,
1 H), 3.68 (dd, J ) 10.2, 2.7 Hz, 1 H), 3.33-3.24 (m, 2 H), 3.22 (s,
3 H), 2.52-2.48 (m, 1 H), 2.30-2.20 (m, 2 H), 2.18-1.95 (m, 2 H),
1.60-1.01 (series of m, 15 H), 0.98 (d, J ) 7.2 Hz, 3 H), 0.96 (d, J )
7.1 Hz, 3 H), 0.91 (d, J ) 7.1 Hz, 3 H), 0.74 (s, 3 H); 13C NMR (75
MHz, C6D6) ppm 95.0, 79.3, 68.5, 55.5, 47.7, 45.6, 45.0, 43.7, 43.2,
41.6, 40.6, 36.3, 30.2, 29.4, 26.4, 23.7, 23.2, 22.2, 21.4, 15.7; MS m/z
(M+) calcd 352.2977, obsd 352.2973.
m/z (M+) calcd 334.2871, obsd 334.2880; [R]20 +137.3 (c 0.63,
D
EtOAc).
(1R,3aR,4S,6S,6aS,7S,9aR,10aS)-Tetradecahydro-6-hydroxy-7-
isopropyl-1,9a-dimethyldicyclopenta[a,d]cyclooctene-4-methanol 4-Ac-
etate (57) and (1R,3aR,4R,6S,6aS,7S,9aR,10aS)-Tetradecahydro-6-
hydroxy-7-isopropyl-1,9a-dimethyldicyclopenta[a,d]cyclooctene-4-
methanol 4-Acetate (58). A solution of 55 (4.6 mg, 0.013 mmol) in
2.5% hydrochloric acid/methanol (2 mL) was refluxed for 1 h, cooled,
neutralized with saturated NaHCO3 solution, and extracted with ethyl
acetate. The combined organic layers were washed with brine, dried,
and concentrated to leave a pair of diols which were taken up in
CH2Cl2 (1 mL) containing pyridine (0.1 mL). This solution was treated
with acetic anhydride (3.2 mg, 0.031 mmol) and stirred overnight at
room temperature under N2. After solvent removal, the residue was
subjected to flash chromatography on silica gel (elution with 20:1
hexanes-ethyl acetate) to give 2.0 mg (43%) of 57 and 2.1 mg (46%)
of 58.
(1R,3aR,4S,5R,6R,6aS,7S,9aR,10aS)-4,5-Epoxytetradecahydro-7-
isopropyl-6-(methoxymethoxy)-1,4,9a-trimethyldicyclopenta[a,d]cy-
clo-octene (52). To a solution of 50 (10 mg, 0.03 mmol) in CH2Cl2
(1 mL) was added NaHCO3 (12.6 mg, 0.15 mmol) followed by MCPBA
(23 mg of 90% purity, 0.12 mmol). The reaction mixture was stirred
for 3 h, diluted with ether, washed with water and brine, dried, and
concentrated. Flash chromatography of the residue on silica gel (elution
with 30:1 hexanes-ethyl acetate) gave 52 (9 mg, 85%) as a colorless
1
oil: IR (neat, cm-1) 1036; H NMR (300 MHz, C6D6) δ 5.20 (d, J )
7.0 Hz, 1 H), 4.67 (d, J ) 7 Hz, 1 H), 4.25 (dd, J ) 10.5, 6.1 Hz, 1
H), 3.34 (s, 3 H), 2.81 (d, J ) 6.1 Hz, 1 H), 2.68-2.55 (m, 2 H),
2.18-2.10 (m, 1 H), 2.05-1.99 (m, 1 H), 1.80-1.14 (series of m, 12
H), 1.10 (s, 3 H), 1.01 (d, J ) 7.0 Hz, 3 H), 0.95 (d, J ) 6.8 Hz, 3 H),
0.88 (d, J ) 6.9 Hz, 3 H), 0.87 (s, 3 H); 13C NMR (75 MHz, C6D6)
ppm 95.7, 75.6, 62.9, 62.1, 55.9, 50.7, 48.4, 47.4, 45.5, 43.2, 40.7,
40.2, 39.1, 34.8, 29.9, 25.8, 24.4, 23.1, 21.9, 21.6, 18.4, 15.6; MS m/z
1
For 57: IR (neat, cm-1) 3495, 1741, 1460, 1243, 1041; H NMR
(M+) calcd 350.2820, obsd 350.2793; [R]25 +125 (c 0.67, EtOAc).
(300 MHz, C6D6) δ 3.94 (dd, J ) 10.5, 6.5 Hz, 1 H), 3.78 (dd, J )
10.5, 8.5 Hz, 1 H), 3.63-3.58 (m, 1 H), 2.65-2.50 (m, 1 H), 2.48-
2.40 (m, 1 H), 2.30-2.06 (m, 3 H), 1.90-0.86 (series of m, 15 H),
1.66 (s, 3 H), 0.98 (d, J ) 7 Hz, 3 H), 0.92 (d, J ) 6.8 Hz, 3 H), 0.87
(d, J ) 7 Hz, 3 H), 0.74 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 73.1,
69.6, 48.2, 46.5, 44.9, 43.6, 43.2, 43.0, 41.1, 40.6, 32.4, 31.8, 30.1,
30.0, 29.5, 23.1, 23.0, 22.4, 21.2, 20.5, 15.6 (CdO not observed due
to low S/N); MS m/z (M+) calcd 349.2743, obsd 349.2714.
D
(1R,3aR,4R,6S,6aS,7S,9aR,10aS)-Tetradecahydro-7-isopropyl-6-
(methoxymethoxy)-1,4,9a-trimethyldicyclopenta[a,d]cycloocten-4-
ol (53). A suspension of 52 (10 mg, 0.03 mmol) and lithium aluminum
hydride (20 mg, 0.53 mmol) in dry THF (4 mL) was refluxed under
N2 for 10 days. After being cooled to -78 °C, the reaction mixture
was quenched with ethyl acetate and water and then extracted with
ether. The usual workup and silica gel chromatography (elution with
3:1 hexanes-ethyl acetate) furnished 8 mg (80%) of 53 as a colorless
1
For 58: IR (neat, cm-1) 3410, 1736, 1460; H NMR (300 MHz,
1
gum: IR (neat, cm-1) 3548, 1462, 1383, 1032; H NMR (300 MHz,
C6D6) δ 4.38 (dd, J ) 10.8, 8.1 Hz, 1 H), 3.95 (dd, J ) 10.8, 4.0 Hz,
1 H), 2.52-2.40 (m, 1 H), 2.38-2.30 (m, 1 H), 2.08-1.94 (m, 4 H),
1.85-0.90 (series of m, 15 H), 1.69 (s, 3 H), 0.96 (d, J ) 7.7 Hz, 3
H), 0.94 (d, J ) 7.0 Hz, 3 H), 0.86 (d, J ) 7.7 Hz, 3 H), 0.80 (s, 3 H);
13C NMR (75 MHz, C6D6) ppm 74.2, 69.6, 50.5, 49.4, 45.9, 43.6, 42.1,
41.1, 40.5, 39.3, 39.2, 36.5, 34.6, 33.9, 29.5, 22.9, 22.2, 21.1, 20.6,
18.5, 15.7 (CdO not observed due to low S/N); MS m/z (M+-H) calcd
349.2743, obsd 349.2780.
C6D6) δ 4.45 (d, J ) 6.4 Hz, 1 H), 4.32 (d, J ) 6.4 Hz, 1 H), 3.60
(ddd, J ) 10.2, 4.6, 2.1 Hz, 1 H), 3.11 (s, 3 H), 3.10-2.95 (m, 2 H),
2.42 (t, J ) 10.0 Hz, 1 H), 2.21-1.05 (series of m, 16 H), 1.10 (s, 3
H), 0.92 (d, J ) 6.7 Hz, 3 H), 0.91 (d, J ) 7.0 Hz, 1 H), 0.87 (d, J )
6.0 Hz, 3 H), 0.73 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 96.7, 82.6,
75.2, 56.1, 52.0, 49.8, 48.8, 46.2, 43.7, 42.3, 40.7, 39.9, 39.5, 32.8,
29.1, 27.5, 26.2, 22.9, 22.2, 21.3, 19.9, 15.5; MS m/z (M+) calcd
334.2872, obsd 334.2907; [R]25 -64.6 (c 1.00, CH2Cl2).
D
(2aR,4aS,6R,6aR,9R,9aS,10aR,10bS)-Tetradecahydro-3,3,9,10a-
tetramethyl-2H-4-oxacyclopenta[5,6]cycloocta[1,2,3-cd]pentalene-
6-methanol Acetate (59). A solution of 58 (1.4 mg, 0.004 mmol),
iodine (1.5 mg, 0.006 mmol), and iodobenzene diacetate (2.0 mg, 0.0062
mmol) in cyclohexane (1 mL) was irradiated with a 600 W tungsten
filament lamp at 50 °C for 2 h. The reaction mixture was poured into
water and extracted with ether. The organic layer was washed with
sodium thiosulfate solution and brine prior to drying and concentration.
Flash chromatography of the residue on silica gel (elution with 10:1
(1R,3aR,6S,6aS,7S,9aR,10aS)-Tetradecahydro-7-isopropyl-6-(meth-
oxymethoxy)-1,9a-dimethyl-4-methylenedicyclopenta[a,d]cy-
clooctene (54). A solution of 53 (10.6 mg, 0.03 mmol) and Martin’s
sulfurane (80 mg, 0.12 mmol) in benzene (3 mL) was heated at 50 °C
under N2 for 2 h, cooled, quenched with saturated NaHCO3 solution,
and extracted with ether. The combined organic layers were washed
with brine, dried, and evaporated. Flash chromatography of the residue
on silica gel (elution with 99:1 hexanes-ethyl acetate) gave 8.6 mg
(86%) of 54 as a colorless oil: IR (neat, cm-1) 1462, 1375, 1260, 1037;
1H NMR (300 MHz, C6D6) δ 5.05 (br s, 1 H), 4.93 (br s, 1 H), 4.62 (d,
J ) 6.8 Hz, 1 H), 4.46 (d, J ) 6.8 Hz, 1 H), 3.58 (dt, J ) 8.0, 2.6 Hz,
1 H), 3.20 (s, 3 H), 2.84-2.75 (m, 1 H), 2.62-2.56 (m, 1 H), 2.45-
2.38 (m, 1 H), 2.34-2.18 (m, 2 H), 1.85-1.00 (series of m, 13 H),
hexanes-ethyl acetate) provided 1.3 mg (93%) of 59: IR (neat, cm-1
)
1742, 1242; 1H NMR (300 MHz, C6D6) δ 4.08 (dd, J ) 10.7, 3.7 Hz,
1 H), 3.78 (dd, J ) 10.6, 7.4 Hz, 1 H), 3.60 (dt, J ) 10.3, 4.7 Hz, 1
H), 2.47 (ddd, J ) 13.7, 10.6, 8.2 Hz, 1 H), 2.36 (dd, J ) 12.9, 5.1
Hz, 1 H), 2.07 (dd, J ) 13.7, 10.3 Hz, 1 H), 1.90 (dt, J ) 12.6, 4.8
Hz, 1 H), 1.83-0.80 (series of m, 14 H), 1.64 (s, 3 H), 1.33 (s, 3 H),
1.15 (s, 3 H), 0.92 (d, J ) 6.9 Hz, 3H), 0.86 (s, 3 H); 13C NMR (125
MHz, C6D6) ppm 73.9, 69.2, 61.3, 58.0, 47.4, 46.4, 44.0, 43.1, 43.0,
42.4, 36.6, 34.2, 32.5, 30.1, 30.0, 29.9, 24.8, 24.5, 21.2, 20.4, 20.1
(CdO not observed due to low S/N); MS m/z (M+) calcd 348.2664,
obsd 348.2653.
0.98 (d, J ) 7.0 Hz, 3 H), 0.91 (d, J ) 6.7 Hz, 6 H), 0.83 (s, 3 H); 13
C
NMR (75 MHz, C6D6) ppm 148.1, 115.5, 95.6, 78.8, 55.4, 50.0, 49.4,
46.1, 45.3, 43.7, 43.4, 42.7, 40.5, 39.3, 33.3, 32.4, 30.1, 23.2, 23.1,
21.3, 20.0, 15.8; MS m/z (M+) calcd 334.2871, obsd 334.2863.
(1R,3aR,6S,6aS,7S,9aR,10aS)-Tetradecahydro-7-isopropyl-6-(meth-
oxymethoxy)-1,9a-dimethyldicyclopenta[a,d]cyclooctene-4-metha-
nol (55). To a suspension of 54 (8.0 mg, 0.024 mmol) and lithium
borohydride (0.9 mg, 0.04 mmol) in THF (1.5 mL) at -20 °C under
N2 was added borane-THF complex (96 µL of 1 M in THF, 0.096
mmol). The mixture was allowed to warm slowly to room temperature,
(2aR,4aS,6S,6aR,9R,9aS,10aR,10bS)-Tetradecahydro-3,3,9,10a-
tetramethyl-2H-4-oxacyclopenta[5,6]cycloocta[1,2,3-cd]pentalene-
6-methanol Acetate (60). A 2.0 mg (0.0057 mmol) sample of 57 was
reacted analogously with iodine (2.2 mg, 0.0086 mmol) and iodoben-

8450 J. Am. Chem. Soc., Vol. 119, No. 36, 1997
Paquette et al.
zene diacetate (2.8 mg, 0.0088 mmol) in cyclohexane (1 mL). There
H), 2.46 (ddd, J ) 14.0, 11.3, 7.6 Hz, 1 H), 2.02 (dd, J ) 13.6, 10.2
Hz, 1 H), 2.00-1.90 (m, 1 H), 1.85-1.20 (series of m, 12 H), 1.25 (s,
3 H), 1.17 (s, 3 H), 1.00 (d, J ) 6.5 Hz, 3 H), 0.88 (s, 3 H); 13C NMR
(125 MHz, C6D6) ppm 146.3, 114.7, 78.0, 74.8, 59.6, 57.5, 51.0, 48.4,
44.2, 43.9, 43.3, 41.5, 36.6, 34.7, 34.1, 29.2, 24.3, 24.0, 20.2, 19.2;
was isolated 1.9 mg (95%) of 60: IR (neat, cm-1) 1742, 1462, 1371,
1
1232; H NMR (500 MHz, C6D6) δ 4.20 (m, 2 H), 3.98 (m, 1 H),
2.58-2.50 (m, 1 H), 2.36-2.28 (m, 2 H), 2.07 (dd, J ) 13.6, 10.5 Hz,
1 H), 2.00-1.96 (m, 1 H), 1.80-0.90 (series of m, 13 H), 1.73 (s, 3
H), 1.38 (s, 3 H), 1.22 (s, 3 H), 0.96 (d, J ) 6.6 Hz, 3 H), 0.94 (s, 3
H); 13C NMR (125 MHz, C6D6) ppm (all peaks are broadened due to
slow conformational dynamics; the visible peaks are cited) 170.2, 77.1,
71.3, 44.5, 44.1, 42.4, 36.7, 30.1, 29.7, 24.4, 24.0, 20.4, 20.3; MS m/z
(M+) calcd 348.2664, obsd 348.2675.
MS m/z (M+) calcd 288.2455, obsd 288.2459; [R]25 +72.4 (c 0.04,
D
hexanes).
Acknowledgment. Generous financial support was provided
by the National Institutes of Health and Eli Lilly and Company.
Fellowships to D.F. by the Wigner-Stiftung der Technischen
Universita¨t Berlin (1989-1990) and the Deutsche Forschungs-
gemeinschaft (1990-1991) and to P.B.S. from the National
Institues of Health (CA63780) are gratefully acknowledged.
Dedicated to Professor Dieter Seebach on the occasion of his
60th birthday.
(+)-Epoxydictymene (1). A solution of 60 (1.5 mg, 0.0043 mmol)
in 2.5% hydrochloric acid/methanol (1 mL) was heated at reflux for 1
h, cooled, neutralized with saturated NaHCO3 solution, and extracted
with ethyl acetate. The organic phase was washed with brine, dried,
and concentrated to leave alcohol 61 which was dissolved in THF (0.5
mL) containing o-nitrophenyl selenocyanate (9 mg, 0.04 mmol). The
resulting solution was treated with tributylphosphine (8 mg, 0.04 mmol)
in THF (0.5 mL) and stirred under N2 for 2 h. The THF was
evaporated, the residue was taken up in ether and filtered, and the filtrate
was evaporated. The selenide was dissolved in THF (0.5 mL) and
treated at 0 °C with 0.25 mL of THF and 0.25 mL of 30% hydrogen
peroxide. After 2 h of stirring at 0 °C, the reaction mixture was diluted
with ether, washed with saturated NaHSO3 solution, dried, and
concentrated. Purification of the residue by flash chromatography on
silica gel (elution with 20:1 hexanes-ethyl acetate) gave 1.0 mg (80%)
of (+)-1: IR (neat, cm-1) 1462, 1280, 1135, 1090; 1H NMR (300 MHz,
C6D6) δ 4.97 (s, 1 H), 4.80 (s, 1 H), 3.56 (dt, J ) 9.7, 6.5 Hz, 1 H),
2.84 (dd, J ) 11.6, 6.6 Hz, 1 H), 2.62 (ddd, J ) 12.1, 9.9, 7.1 Hz, 1
Supporting Information Available: Detailed synthetic
procedures and spectroscopic data for compounds 16-25 and
51, along with crystallographic experimental details, bond
lengths, bond lengths involving the hydrogen atoms, bond
angles, positional parameters and B(eq) values, and anisotropic
displacement parameters for 46 (23 pages). See any current
masthead page for ordering and Internet access instructions.
JA971526V