Studies directed to the synthesis of the unusual cardiotoxic agent kalmanol. Enantioselective construction of the advanced tetracyclic 7-oxy-5,6-dideoxy congener

Article abstract of DOI:10.1021/ja9533454

The first synthesis of a highly functionalized B-homo-C-nor grayanotoxin closely related to kalmanol is reported. An enantiocontrolled route to the diquinane sector was first developed from (4R)-(+)-tert-butyldimethylsiloxycyclopentenone by taking advantage of the Michael acceptor properties of this enone and an α,β-unsaturated ester subsequently derived from it, viz., 4 → 7 → 8. These experiments formed the basis for more advanced substitution of the bicyclo[3.3.0]octane core. In fact, ready access was gained to the α-hydroxy esters 24-27. In these advanced intermediates, it is imperative that the acetyl and carbomethoxy groups bear a trans 1,3-relationship. The neighboring OR substituent should preferably be larger than methoxy in order to guarantee 100% facial selectivity during the ensuing capture by 1 (as its lithiated derivative). This condensation leads unidirectionally to tricyclic lactones represented by 30 and 31 and sets the stage for implementation of sequential Tebbe olefination and Claisen rearrangement. This pivotal two-step process gives rise directly to the targeted tetracyclic framework. The further oxygenation of 35 can be accomplished in a highly stereoselective manner to give 3. The characteristics of the [3.3] sigmatropic event that results in ring expansion plays a significant role in defining absolute configuration at key carbon centers which would otherwise be difficult to establish unequivocally. A total of 25 synthetic steps was involved.

Full text of DOI:10.1021/ja9533454

J. Am. Chem. Soc. 1996, 118, 727-740
727
Studies Directed to the Synthesis of the Unusual Cardiotoxic
Agent Kalmanol. Enantioselective Construction of the
Advanced Tetracyclic 7-Oxy-5,6-dideoxy Congener
Stephane Borrelly and Leo A. Paquette*
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity,
Columbus, Ohio 43210
ReceiVed October 2, 1995X
Abstract: The first synthesis of a highly functionalized B-homo-C-nor grayanotoxin closely related to kalmanol is
reported. An enantiocontrolled route to the diquinane sector was first developed from (4R)-(+)-tert-butyldimeth-
ylsiloxycyclopentenone by taking advantage of the Michael acceptor properties of this enone and an R,â-unsaturated
ester subsequently derived from it, Viz., 4 f 7 f 8. These experiments formed the basis for more advanced substitution
of the bicyclo[3.3.0]octane core. In fact, ready access was gained to the R-hydroxy esters 24-27. In these advanced
intermediates, it is imperative that the acetyl and carbomethoxy groups bear a trans 1,3-relationship. The neighboring
OR substituent should preferably be larger than methoxy in order to guarantee 100% facial selectivity during the
ensuing capture by 1 (as its lithiated derivative). This condensation leads unidirectionally to tricyclic lactones
represented by 30 and 31 and sets the stage for implementation of sequential Tebbe olefination and Claisen
rearrangement. This pivotal two-step process gives rise directly to the targeted tetracyclic framework. The further
oxygenation of 35 can be accomplished in a highly stereoselective manner to give 3. The characteristics of the [3.3]
sigmatropic event that results in ring expansion plays a significant role in defining absolute configuration at key
carbon centers which would otherwise be difficult to establish unequivocally. A total of 25 synthetic steps was
involved.
The grayanotoxins are noted for their ability to open sodium
channels easily and to maintain them in that condition longer
than normal.1 Their ineffectiveness on the sodium permeability
of inexcitable cells or excitable cells having no sodium currents
has focused attention on the existence of a receptor in a strongly
hydrophobic region. The structures of these toxins cause them
to be lipid-soluble and to gain ready access to the boundaries
between membrane lipids and the membrane-crossing segments
of the sodium channel.2,3 Once the sodium channels are
distorted, a large depolarization results, and both gating and
permeation are strongly affected.4 As a result, the strong
preference for sodium ions is lessened, such that the ionic
selectivity of a channel may actually be altered. The resultant
impact on nerve impulses is therefore very significant.
The grayanotoxin diterpenes possess a unique tetracyclic
framework which is densely populated with hydroxyl groups.5
The functionalities essential for biological activity have been
determined to reside on the A and B rings. The active binding
site at or near the sodium channel may therefore possess a
configuration that extends a hydrophobic anchor to this array
of hydroxyl groups.6
Given this historical backdrop, the isolation and characteriza-
tion in 1989 of kalmanol, a new diterpenoid type having a highly
oxygenated B-homo-C-nor grayanoid framework,7 was certain
to be accompanied by many questions surrounding its biological
activity. Kalmanol is indeed pharmacologically active and is
cardiotoxic as a consequence of its ability to increase the
permeability of sodium ions in excitable membranes as do the
grayanotoxins. Preliminary evaluation has suggested that kal-
manol may be less active than grayanotoxin I. A more complete
evaluation must, however, await the procurement of more
material.
Consequently, kalmanol and analogs thereof merit consider-
ation as synthetic targets. Since the biosynthetic origin of
kalmanol may consist in Wagner-Meerwein rearrangement of
a grayanotoxin precursor with ring contraction,7 it is likely that
these molecules share a common absolute configuration. Early
efforts targeted toward kalmanol have resulted in the acquisition
of both enantiomers of cyclopentenyl bromide 1 by means of
an unprecedented tandem reaction sequence.8 The advanced
X Abstract published in AdVance ACS Abstracts, January 15, 1996.
(1) Ku, D. D.; Akera, T.; Frank, M.; Brody, T. M.; Iwasa, J. J.
Pharmacol. Exp. Ther. 1977, 200, 363.
(2) Keynes, R. D. Sci. Am. 1979, 126-135.
(3) Hille, B. Ionic Channels of Excitable Membranes, 2nd ed.; Sinauer
Assoc.: Sunderland, MA, 1992.
(4) Ulbricht, W. Erg. Physiol. Biol. Chem. Exp. Pharmakol. 1969, 61,
18.
(5) (a) Iwasa, J.; Kumazawa, Z.; Nakajima, M. Chem. Ind. 1961, 511.
(b) Fushiya, S.; Hikino, H.; Takemoto, T. Tetrahedron Lett. 1974, 2, 183.
(6) Masutani, T.; Seyama, I.; Narahashi, T.; Iwasa, W. J. Pharmacol.
Exp. Ther. 1981, 217, 812.
diquinane building block 2 has also been made available by
(7) Burke, J. W.; Doskotch, R. W.; Ni, C.-Z.; Clardy, J. J. Am. Chem.
Soc. 1989, 111, 5831.
(8) Borrelly, S.; Paquette, L. A. J. Org. Chem. 1993, 58, 2175.
0002-7863/96/1518-0727$12.00/0 © 1996 American Chemical Society

728 J. Am. Chem. Soc., Vol. 118, No. 4, 1996
Borrelly and Paquette
proper adaptation of Pauson-Khand technology.9 Although the
route to 2 proved to be diastereoselective, several complications
associated with regiocontrol were uncovered, and the prelimi-
nary study involved racemic compounds. Herein, we report an
alternate enantioselective route to a key bicyclic intermediate
related to 2, demonstrate the feasibility of a Tebbe-Claisen
sequence for assembling the entire kalmanol backbone and detail
the manageability of introducing most of the requisite func-
tionality. As indicated in the title, the insights gained from this
experimentation have resulted in acquisition of 7-oxy-5,6-
dideoxykalmanol (3).10
Scheme 1
Discussion of Results
Enantiocontrolled Route to the Diquinane Subunit. An
earlier reported provocative observation was the relative ease
with which ester A undergoes epimerization to C under mildly
basic conditions.9 Although simple configurational inversion
R to the acetyl functionality could be operational, the ring
fragmentation-intramolecular Michael addition made possible
by the 1,5-relationship of the two carbonyls was viewed to be
cyclization with formation of a 60:25:15 mixture of diastereo-
mers 8-10. The elevated stereoselectivity of this process can
be attributed to chelation control in an aprotic solvent (see D)
under the terms previously defined by Stork.15 The major
consequence of the involvement of D is predominant R
introduction of the acetyl group at C-9. Treatment of the
mixture with a catalytic amount of potassium carbonate in
methanol resulted in the conversion of 10 into 8 and made
possible the facile chromatographic separation of 8 from 9. The
stereochemical assignments to both diastereomers were cor-
roborated by NOE analysis (see Experimental Section). No
means was found to isolate 10 in a pure state and therefore to
confirm its structure spectroscopically. Nevertheless, it is very
unlikely that it is the â,â isomer because of the substantive strain
inherent in this diquinane (MM2 calculations9).
kinetically viable. Analysis of the structural features of B led
to the decision to explore this mechanistic option directly via
the known (4R)-(+)-tert-butyldimethylsiloxycyclopentenone
(4).11 Copper-catalyzed 1,4-addition of the Grignard reagent
derived from 5-bromo-2-pentanone ethylene ketal12 in the
presence of chlorotrimethylsilane provided the silyl enol ether
5a (Scheme 1). Rapid filtration of this sensitive intermediate
through glass wool, direct regeneration of the enolate anion with
methyllithium, and O-triflation13 afforded 5b in 91% overall
yield. In order to maximize the efficiency of this conversion,
it was necessary to maintain the reaction temperature below
-10 °C in order to skirt the irreversible elimination of tert-
butyldimethylsilanol made possible by enolate equilibration.
Carbomethoxylation of 5b under 1 atm of CO in DMF14
afforded 6 (87%), controlled hydrolysis of which provided 7
efficiently. Brief treatment of this keto ester with 0.5 equiv of
potassium tert-butoxide in benzene resulted in the anticipated
As the means for increasing the level of substitution in the
diquinane fragment, we came to favor initial concomitant ketone
protection and hydroxyl deprotection by reaction of the 8/9
mixture with equal proportions of trimethyl orthoformate and
methanol under acidic conditions (Scheme 2). Subsequent
perruthenate oxidation16 of 11 gave rise to 12 (86%). Neither
transformation impacted on the 2.3:1 (R/â) distribution. An
earlier trial run with pure 8 had indicated that loss of stereo-
(9) Paquette, L. A.; Borrelly, S. J. Org. Chem. In press.
(10) Borrelly, S. Ph.D. Dissertation, The Ohio State University, 1995.
(11) Paquette, L. A.; Earle, M. J.; Smith, G. F. Org. Synth. 1995, 73,
36.
(12) Ponaras, A. A. Tetrahedron Lett. 1976, 36, 3105.
(13) Ritter, K. Synthesis 1993, 737.
(14) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 109.
(15) Stork, G.; Winkler, J. D.; Saccomano, N. A. Tetrahedron Lett. 1983,
24, 465.
(16) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13.

Synthesis of the Cardiotoxic Agent Kalmanol
J. Am. Chem. Soc., Vol. 118, No. 4, 1996 729
Scheme 2
Scheme 3
process, a 50% optimized yield of the sensitive 15 could be
realized. It was interesting to find that the subsequent palla-
dium-mediated hydrogenolysis of this alkenyl oxirane exhibited
a pronounced dependency on the phosphine ligand employed.
Ammonium formate was used as the hydride source according
to Tsuji.19 When reduction was conducted in the presence of
tributylphosphine, a separable 13:1 mixture of 16 and 17 was
obtained in 91% yield. Recourse instead to triphenylphosphine
redirected matters so that 17 was the only product formed with
equal efficiency. The impressive regioselectivity of these
processes is believed to arise as a consequence of the varied
steric bulk in the π-allylpalladium intermediate. When the
ligand is (n-Bu)3P, reductive elimination via hydride delivery
to the exocyclic terminus (see K) is kinetically favored and
chemical integrity should not be expected. This was not a point
of particular concern, however, in light of impending introduc-
tion of unsaturation adjacent to the carbomethoxy substituent.
Having secured 12, we soon recognized that mono-O-
silylation to produce 18 was not to accommodate expedient
conversion to the unsaturated keto ester 13. Quite unexpectedly,
the action of N-bromosuccinimide on 18 followed by the
addition of triethylamine effected conversion to a 1:1 mixture
of 13 and the R-hydroxy ketone 19. Control experiments
established that the oxygenation process was not the end result
of the capture of molecular O2. As illustrated in Scheme 3, the
present suspicion is that 19 arises by SN2′ substitution17 of the
allylic bromine in H, which is generated in turn by eliminative
ring opening within bromonium ion G. Alternatively, the
possibility exists that oxyallyl cation I captures water regiose-
lectively.18
The electron-deficient double bond in 13 proved highly
receptive to alkaline peroxidation and furnished uniquely the
R-isomer 14 (78%). In contrast, the olefination of 14 was a
problematical step. Extensive decomposition was observed with
organometallic reagents. With the more conventional Wittig
delivers the more thermodynamically stable product. On the
other hand, the presence of large phenyl groups on phosphorus
likely skews the complex to position the palladium center more
into the environment of the exocyclic terminus such that hydride
delivery to the ring carbon (as in J) now operates exclusively.
Ideally, both 16 and 17 would serve as useful precursors to
the tertiary carbinol at C-16. Since the regioselective ring
(17) (a) Paquette, L. A.; Stirling, C. J. M. Tetrahedron 1992, 48, 7392.
(b) Magid, R. M. Tetrahedron 1980, 36, 1901.
(18) For other examples of cine substitution in oxyallyl cations,
consult: (a) Hassner, A.; Naidorf-Meir, S.; Gottlieb, H. E. J. Org. Chem.
1993, 58, 5699. (b) Hassner, A.; Naidorf-Meir, S.; Gottlieb, H. E.
Tetrahedron Lett. 1990, 31, 2181. (c) Hoffmann, H. M. R. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 1.
(19) Oshima, M.; Hirayushi, Y.; Shimizu, I.; Nisar, N.; Tsuji, J. J. Am.
Chem. Soc. 1989, 111, 6280.

730 J. Am. Chem. Soc., Vol. 118, No. 4, 1996
Borrelly and Paquette
Scheme 4
Scheme 5
opening of terminal oxiranes is well documented,20 the projected
course of the epoxidation and reduction of 17 was not cause
for concern. In contrast, the existing situation in 16 was not
clear. Consequently, a preliminary scrutiny of this question was
put in motion with 16 as the test case (Scheme 4). The
formation of intermediates 20-22 was uneventful as expected.
Satisfyingly, the exposure of 22 to Red-Al proceeded by initial
rapid reduction of the carbomethoxy group to the primary
alcohol and ensuing regiocontrolled internal hydride delivery21
(see L) to cleave the oxirane ring and give rise to 23 as the
sole product (94%). In light of these results, this methodology
or a closely related one was deemed attractive as the means for
introducing the 16-hydroxyl substituent after elaboration of the
B-ring.
Tebbe-Claisen Technology. Elaboration of the Complete
Tetracyclic Ring System. At this stage, the plan called for
conjoining of the A-ring synthon 1 with either 16 or 17 as the
means for constructing the cyclooctanoid B ring and assembling
the complete framework of the target. Control of the stereo-
chemical course of the 1,2-carbonyl addition was, of course,
mandated since this event has obvious implications on the
particular transition state to be adopted during the projected [3.3]
sigmatropic transition state. Since little precedence was avail-
able, thorough experimental analysis of this strategic connectiv-
ity was first planned.
Beyond this, deployment of a Tebbe-Claisen sequence
ultimately requires olefination of the ester carbonyl already
resident in 16 and 17. Since the nature of the substituent
positioned R to this functionality could impact on the central
Claisen rearrangement step, the O-substituted derivatives 24-
27 were prepared for direct evaluation.
Following halogen-metal exchange in 1 with tert-butyl-
lithium, the organometallic reagent was added first to 27 in THF
at -78 °C. This inverse addition resulted in the formation of
hydroxy ester 28; only trace amounts of lactone 29 were seen.
In contrast, comparable processing of 25 and 26 led directly to
the fully cyclized lactones 30 and 31, respectively, in excellent
yield (Scheme 5). A similar experiment involving ent-1 and
24 led again predominantly to the hydroxy ester, Viz. 32. The
conversion of 28 and 32 to their respective lactones 29 and 33
was accomplished smoothly by sequential saponification and
brief treatment of the resulting hydroxy acids with Mukaiyama’s
reagent.22 The overall yields from the keto esters were 85-
95%.
1H NMR analysis revealed that a strong bias for stereose-
lective nucleophilic addition was operational in all four cases.
In fact, a single isomer was formed in each instance except for
32 where a 10:1 ratio of diastereomers was produced. NOE
studies performed on each of the conformationally rigid lactones
provided convincing evidence that all belonged to the same
(20) For example: Quartucci, J.; Rickborn, B. J. Org. Chem. 1964, 29,
3165.
(21) Viti, S. M. Tetrahedron Lett. 1982, 44, 4541.
(22) (a) Mukaiyama, T.; Angew. Chem., Int. Ed. Engl. 1979, 18, 707.
(b) Mukaiyama, T.; Ushui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975,
1045. (c) Mukaiyama, T.; Toda, H.; Kobayashi, S. Chem. Lett. 1976, 13.

Synthesis of the Cardiotoxic Agent Kalmanol
J. Am. Chem. Soc., Vol. 118, No. 4, 1996 731
The highly stereocontrolled course of lactone formation was
a most welcomed development which set the stage admirably
for examination of the projected ring expansion. This central,
convergent element of our strategy, shown to be highly workable
in other synthetic contexts,23,24 requires not only successful
methenylation of 30-32 but also an ability on the part of the
resulting enol ethers to participate in [3.3] sigmatropy via a
suitable chair-like transition state.
To this end, 33 was initially treated with the Tebbe reagent25
and pyridine in a 1:1 mixture of CH2Cl2 and THF at -40 °C,
and the exocyclic enol ether so produced26 was purified by rapid
filtration through a plug of basic alumina and heated in
p-cymene at 120-130 °C for 2 h. Smooth conversion to 34
(as a 10:1 isomeric mixture) was observed (68% for the two
steps, Scheme 6). In the same fashion, both 31 and 30 were
readily transformed into 35 and 36, respectively, in 86% overall
yield. The exceptionally low temperature and short reaction
times required for these conversions suggest that strain relief
within the bridged diquinane components operates at the rate-
determining transition states and provides a useful driving force
for facilitating the electronic reorganization.
Numerous examples24 have established that the Claisen ring
expansion is controlled by an overriding thermodynamic prefer-
ence for setting a Z double bond in the 4-cylcooctenone ring
via a chair-like transition state if at all possible. From among
the two geometries available to 31, for example, the choices
are to orient the cyclopentenyl unit as in N or O. In the first
instance, a chair-like alignment shall develop, a Z double bond
will be generated, and H-5 will be projected to the R-face.
Option O, on the other hand, requires a boat-like geometry,
results in the evolution of an E double bond, and fixes H-5 in
a â-orientation. In addition, O suffers from steric compression
between the exocyclic methylene group and the OTBS sub-
stituent. On the basis of these many factors, transition state N
should be kinetically favored by a wide margin and apparently
is. The relative stereochemistry resident in 35 follows from
NOE studies performed on diepoxide 38 (see Experimental
Section).
Figure 1. The four possible nucleophilic trajectories associated with
26 and 27.
stereochemical subset. Consequently, both 1 and ent-1 exhibit
the same facial selectivity, indicating that the configuration of
the OTBS-substituted carbon has little, if any, effect on the
product distribution. Similarly, the exo or endo positioning of
the double bond in ring D has no impact on selectivity,
presumably as a result of its relatively remote location relative
to the reaction center. Four transition state arrangements emerge
as potential candidates for that which is of lower energy under
these circumstances (Figure 1). Without doubt, the trajectories
associated with M-1 and M-2 can be quickly dismissed on the
basis of the high steric demands for nucleophilic attack. The
geometry associated with M-3 brings into play nonbonded steric
compression between the methyl ketone and the R group situated
on the protected C-8 hydroxyl. This state of affairs is minimized
significantly in M-4. On this basis, we favor the M-4 trajectory,
which satisfyingly corresponds to the experimental results.
According to this model, the greater the size of R, the more
elevated should be the stereoselectivity of nucleophilic capture.
The observed diastereomeric ratios do indeed give evidence of
being linked to the bulkiness of the R group. The remarkably
high levels of stereoselectivity appear therefore to be linked to
the restricted spatial orientation of the methyl ketone functional-
ity, which in turn is dictated by the level of steric congestion
provided by R.
Functionalization of the Backbone. The ready formation
of 35 permitted its exploitation as a precursor to 3. The requisite
Scheme 6

732 J. Am. Chem. Soc., Vol. 118, No. 4, 1996
Borrelly and Paquette
Scheme 7
series of transformations, summarized in Scheme 7, began with
the generation of hydroxy ketone 37 and its conversion to
diepoxide 38. These efficient steps straightforwardly introduced
requisite oxygen atoms at both C-10 and C-16 in concurrent
fashion. Furthermore, the facial selectivity of peracid attack
was established by NOE methods to be as desired. Whereas
reaction at the C-1/C-10 double bond was 100% R-stereose-
lective, the partitioning at the exocyclic C-16 site was R-selective
to the extent of 87%.
Submission of 38 to perruthenate oxidation in the presence
of triethylamine prompted conversion to enolate anion P, setting
in place the opportunity for â-elimination and establishment of
the proper stereochemistry for the tertiary carbinol functionality
resident at C-10. With arrival at 39, the stage was set for
saturation of the enone by catalytic hydrogenation over Pd/C.
In line with precedent,27 a cis A/B ring junction was thereby
established. The pair of ketone carbonyls in 40 differ ap-
preciably in their steric screening. Advantage was taken of this
feature to accomplish controlled reduction to 41 with 1 equiv
of lithium triethylborohydride in cold CH2Cl2 solution. To
demonstrate beyond reasonable doubt that the global structural
features of 41 have been properly assigned, a detailed NOE
analysis of this keto diol was carried out (see Experimental
Section).
The action of excess tert-butyldimethylsilyl triflate and
imidazole on 41 (under DMAP catalysis) served to make 42
available. The doubly-protected diol 43 was produced to a level
of only 4%. One’s ability to accomplish protection of the
tertiary hydroxyl rests only on the choice of silylating agent.
The conversion of 42 to 44 proceeded quite well when recourse
was made to excess potassium hexamethyldisilazide and chlo-
rotrimethylsilane. Note that silyl enol ether formation was not
realized concurrently. This experiment, in fact, provided the
first hint of how difficult it would be to develop sp2 character
at C-6.10
Next to be addressed was removal of the benzyl protecting
group. Much to our delight, treatment of 45 with lithium in
liquid ammonia resulted in concomitant cleavage of the benzyl
ether and the oxirane ring. Subsequent oxidation of (-)-46 with
the Dess-Martin periodinane28 proceeded without complication
to deliver (+)-3 (93%).
Summary
Recourse to a Tebbe-Claisen reaction sequence provides a
very concise route to the B-homo-C-nor grayanoid framework
found uniquely in kalmanol. The diquinane subunit that forms
the C/D sector of the tetracyclic ring system is conveniently
assembled from the chiral building block 4 by 1,4-addition, Pd-
(II)-catalyzed carbonylation, and intramolecular aldol cycliza-
tion. Since it is crucial that the diquinane be adequately
functionalized, particularly in connection with a 1,3-exo-acetyl/
endo-carbomethoxy pattern, some preliminary chemical trans-
formations required implementation. Some of the key lessons
learned include (i) a strong diastereofacial bias exists during
the 1,2-addition of metalated 1 and its enantiomer to 24-27,
such that lactonization often operates spontaneously; (ii) the
Claisen ring expansion proceeds via a chair-like transition state,
thereby generating a 4-cyclooctenone B-ring in which desirable
R stereochemistry is set at C-5 with high fidelity; (iii) the
introduction of hydroxyl groups at C-3, C-8, C-10, and C-15
(23) (a) Kinney, W. A; Coghlan, M. J.; Paquette, L. A. J. Am. Chem.
Soc. 1984, 106, 6868; 1985, 107, 7352. (b) Kang, H.-J.; Paquette, L. A. J.
Am. Chem. Soc. 1990, 112, 3252. (c) Paquette, L. A.; Kang, H.-J. J. Am.
Chem. Soc. 1991, 113, 2610. (d) Friedrich, D.; Paquette, L. A. J. Org. Chem.
1991, 56, 3831. (e) Paquette, L. A.; Wang, T.-Z.; Pinard, E. J. Am. Chem.
Soc. 1995, 117, 1455. (f) He, W.; Pinard, E.; Paquette, L. A. HelV. Chim.
Acta 1995, 78, 391.
(24) Paquette, L. A. In Stereocontrolled Organic Synthesis; Trost, B.
M., Ed.; Blackwell Scientific Publications: Oxford, England, 1994; pp 313-
336.
(25) (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.
(26) Schore, N. E. Org. React. 1991, 40, 1.
(27) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757 and
relevant references cited therein.
(28) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.

Synthesis of the Cardiotoxic Agent Kalmanol
J. Am. Chem. Soc., Vol. 118, No. 4, 1996 733
(elution with 2.5:1 hexanes-ether) gave 1.44 g (87%) of 6 as a colorless
oil: IR (neat, cm-1) 3020-2900, 2900-2760, 1720, 1630, 1440, 1360,
can be efficiently achieved in a minimum number of steps with
proper stereochemistry; and (iv) application of the Dess-Martin
periodinane to oxidation of a 1,2-diol for the purpose of
elaborating an acyloin proceeds without evidence of carbon-
carbon bond cleavage.
It can be stated with considerable assurance that the geom-
etries adopted by such molecules as 3 and 44 are not conducive
to enolization R to the carbonyl.
Finally, the total synthesis of 3 was accomplished from 4 in
25 steps and 1.6% overall yield. It is hoped that the lessons
learned in this series of experiments can be successfully applied
to the acquisition of kalmanol and bioactive analogs thereof.
1
1250, 1110, 830, 770; H NMR (300 MHz, CDCl3) δ 6.66 (m, 1H),
4.09 (m, 1H), 3.94-3.88 (m, 4H), 3.71 (s, 3H), 2.86-2.78 (m, 1H),
2.64 (m, 1H), 2.47-2.38 (m, 1H), 1.73-1.61 (m, 2H), 1.50-1.25 (m,
4H), 1.29 (s, 3H), 0.86 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3)
ppm 165.5, 144.8, 132.8, 109.8, 77.9, 64.6, 55.3, 51.4, 40.6, 39.3, 32.4,
25.8, 23.8, 22.1, 17.9, -4.5, -4.8; HRMS m/z calcd for C20H36O5Si
384.2332, obsd 384.2332; [R]20D -45.6 (c 0.38, CH2Cl2). Anal. Calcd
for C20H36O5Si: C, 62.46; H, 9.44. Found: C, 62.58; H, 9.49.
Methyl (3R,4R)-4-(tert-Butyldimethylsiloxy)-3-(4-oxopentyl)-1-
cyclopentene-1-carboxylate (7). A magnetically stirred solution of 6
(1.5 g, 3.9 mmol) in anhydrous acetone (30 mL) was stirred at room
temperature in the presence of a catalytic amount of p-toluenesulfonic
acid for 36 h, quenched by the addition of a few drops of triethylamine,
and concentrated. The residue was purified by silica gel chromatog-
raphy (elution with 1.5:1 hexanes-ether) to give 1.13 g (85%) of 7 as
a colorless oil: IR (neat, cm-1) 3020-2890, 2760, 1715, 1625, 1430,
1350, 1250, 1100, 1060, 830, 770; 1H NMR (300 MHz, CDCl3) δ 6.61
(m, 1H), 4.07 (m, 1H), 3.68 (s, 3H), 2.79-2.76 (m, 1H), 2.64-2.60
(m, 1H), 2.44-2.37 (m, 3H), 2.09 (s, 3H), 1.64-1.55 (m, 2H), 1.46-
1.39 (m, 1H), 1.35-1.27 (m, 1H), 0.84 (s, 9H), 0.02 (s, 6H); 13C NMR
(75 MHz, CDCl3) ppm 208.3, 165.3, 144.2, 133.0, 77.8, 54.9, 51.4,
43.4, 40.6, 31.5, 29.8, 25.7, 17.9, -4.5, -4.9; HRMS m/z [M+] calcd
for C18H32O4Si 340.2070, obsd 340.2064; [R]20D -47.7 (c 2.7, CHCl3).
Methyl (1S,3R,3aR,6S,6aR)-6-Acetyl-3-(tert-butyldimethylsiloxy)-
octahydro-1-pentalenecarboxylate (8) and Methyl (1R,3R,3aR,6S,
6aR)-6-Acetyl-3-(tert-butyldimethylsiloxy)octahydro-1-pentalenecar-
boxylate (9). To a nitrogen-blanketed solution of 7 (1 g, 2.94 mmol)
in dry benzene (55 mL) was added potassium tert-butoxide (165 mg,
0.5 equiv) in one portion. The reaction mixture was stirred for 10 min
at room temperature and quenched by the addition of saturated NH4Cl
solution (30 mL). The organic phase was separated, dried, and
concentrated. The residue was dissolved in 20 mL of dry MeOH and
stirred in the presence of a catalytic amount of K2CO3 overnight.
Solvent evaporation and purification of the residue by silica gel
chromatography (elution with 2:1 hexanes-ether) gave a 2.3:1 mixture
of 8 and 9 (920 mg, 92%): HRMS m/z [M+] calcd for C18H32O4Si
340.2070, obsd 340.2076. Anal. Calcd for C18H32O4Si: C, 63.49; H,
9.47. Found: C, 63.35; H, 9.41.
Experimental Section
General Procedure. All manipulations were performed under a
nitrogen atmosphere. Solvents were dried over 4 Å molecular sieves
before distillation. Benzene, ether, THF, and toluene were distilled
from sodium or sodium/benzophenone ketyl. Chlorotrimethylsilane,
CH2Cl2, diisopropylamine, DMSO, DMF, dioxane, acetonitrile, HMPA,
and triethylamine were each distilled from CaH2. Melting points are
uncorrected. Exact mass measurements were recorded on Kratos MS-
30 or VG-70-2505 mass spectrometers at The Ohio State University
Chemical Instrumentation Center. Elemental analyses were performed
at the Scandinavian Microanalytical Laboratory, Herlev, Denmark. The
chromatographic separations were carried out either under flash
conditions on Fluka silica gel H or by gravity on Woelm silica gel
63-200. The organic extracts were dried over anhydrous Na2SO4. All
reagents were reagent grade and purified where necessary.
(3R,4R)-4-(tert-Butyldimethylsiloxy)-3-[3-(2-methyl-1,3-dioxolan-
2-yl)propyl]-1-cyclopenten-1-yl Trifluoromethanesulfonate (5b). The
Grignard reagent was prepared from a suspension of 5-bromo-2-
pentanone ethylene ketal (14.8 g, 3 equiv) and magnesium turnings
(4.3 g, 2.25 equiv) in dry THF (120 mL) according to precedent.12
The resulting gray-green solution was transferred to a precooled (-78
°C) suspension of CuBr‚Me2S complex (2.2 g, 0.15 equiv) and dry
HMPA (13 mL) in dry THF (60 mL). The resulting slurry was stirred
at -78 °C for an additional hour and a precooled (-78 °C) solution of
4 (5 g, 0.0236 mol) and trimethylchlorosilane (30 mL, 10 equiv) in
dry THF (70 mL) was transferred Via cannula over 5 min. The reaction
mixture was stirred at the same temperature for an additional hour and
was quenched with dry triethylamine (100 mL) in hexanes (250 mL),
warmed to room temperature, and concentrated by rotary evaporation
to leave a black residue which was taken up in 10% Et3N in hexanes
and filtered through glass wool. The colorless oily 5a obtained after
concentration to dryness (9 g, 99%) was dissolved in dry THF (300
mL). The resulting solution was cooled to -20 °C, treated with 1.4
M MeLi (21.5 mL, 1.3 equiv) solution in ether, stirred at the same
temperature for 0.5 h before the addition of a N-phenyltrifluo-
romethanesulfonimide (13 g, 1.5 equiv) solution in dry THF (100 mL),
agitated at the same temperature overnight, quenched with 10% NaOH
solution (100 mL), and diluted with hexanes (300 mL). The organic
layer was dried, and the residue obtained after concentration was
purified by silica gel chromatography (elution with 5:1 hexanes-ether)
to give 9.49 g (91%) of 5b as a colorless oil: IR (neat, cm-1) 3010-
For 8: IR (neat, cm-1) 2950, 2880, 1730, 1710, 1430, 1360, 1250,
1
1160, 1100, 830, 770; H NMR (300 MHz, C6D6) 3.81 (br d, J ) 3.7
Hz, 1H), 3.42-3.34 (m, 2H), 3.38 (s, 3H), 2.60 (m, 1H), 2.42 (br q, J
) 4.4 Hz, 1H), 1.99-1.90 (m, 1H), 1.89 (s, 3H), 1.88-1.78 (m, 1H),
1.75 (m, 1H), 1 68, m, 1H), 1.21 (m, 1H), 0.96 (s, 9H), 0.81 (m, 1H),
0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz, C6D6) ppm 207.3, 174.5,
78.1, 55.4, 54.5, 50.8, 46.5, 44.7, 36.7, 32.6, 31.5, 28.6, 26.0, 18.2,
-4.7, -4.8; [R]20 -10.5 (c 1.95, CH2Cl2).
D
For 9: IR (neat, cm-1) 2950, 2880, 1730, 1710, 1430, 1360, 1250,
1
1160, 1100, 830, 770; H NMR (300 MHz, C6D6) δ 3.61 (q, J ) 5.1
Hz, 1H), 3.37 (s, 3H), 3.16 (m, 1H), 2.38 (m, 1H), 2.24 (m, 1H), 2.18
(m, 1H), 2.04 (m, 1H), 1.93 (m, 1H), 1.81 (s, 3H), 1.73-1.60 (m, 2H),
1.41 (m, 1H), 1.08 (m, 1H), 0.92 (s, 9H), 0.00 (s, 6H); 13C NMR (75
MHz, CDCl3) ppm 309.7, 174.7, 78.8, 59.3, 52.4, 51.7, 48.2, 47.2, 39.1,
30.0, 29.3, 28.4, 25.7, 17.9, -4.7, -4.8; [R]20D -14.8 (c 0.8, CH2Cl2).
Methyl (1S,3R,3aR,6R,6aR)-6-(1,1-Dimethyloxyethyl)octahydro-
3-hydroxy-1-pentalenecarboxylate (11). To a solution of 8 (400 mg,
1.176 mmol) in dry methanol (15 mL) was added trimethyl orthoformate
(2 mL, 15 equiv) followed by a catalytic amount of p-toluenesulfonic
acid. The mixture was stirred for 8 h, at which time a few drops of
pyridine were added. Concentration by rotary evaporation followed
by silica gel chromatography (elution with 1:3 hexanes-ether) afforded
11 (297 mg, 93%) as a colorless oil: IR (neat, cm-1) 3600-3100, 2865,
1715, 1430, 1375, 1250, 1150, 840; 1H NMR (300 MHz, C6D6) δ 3.79
(m, 1H), 3.36 (s, 3H), 3.01 (s, 3H), 2.98 (s, 3H), 2.95 (m, 1H), 2.78
(d, J ) 6.9 Hz, 1H), 2.47 (dq, J ) 3.0, 8.8 Hz, 1H), 2.00-191 (m,
3H), 1.75 (m, 1H), 1.57 (m, 1H), 1.26 (m, 1H), 1.14 (s, 3H), 0.94 (m,
1H); 13C NMR (75 MHz, C6D6) ppm 177.9, 103.7, 79.3, 54.4, 52.7,
51.5, 50.0, 48.6, 47.9, 47.5, 38.7, 30.8, 29.6, 17.7; HRMS m/z [M+]
calcd for C14H24O5 257.1389, obsd 257.1421; [R]20D +21.9 (c 0.7, CH2-
Cl2).
1
2900, 2895, 1425, 1380, 1220, 1150, 1085, 840, 785; H NMR (300
MHz, C6D6) δ 5.22 (br s, 1H), 3.81 (m, 1H), 3.53 (s, 4H), 2.52-2.32
(m, 3H), 1.63-1.58 (m, 2H), 1.43-1.33 (m, 2H), 1.27 (s, 3H), 1.24
(m, 1H), 1.11 (m, 1H), 0.89 (s, 9H), -0.028 (s, 3H), -0.075 (s, 3H);
13C NMR (75 MHz, C6D6) ppm 144.1, 119.3, 117.3, 117.1 (q, JCF
)
318.45 Hz, CF3), 107.8, 73.6, 62.6, 49.7, 39.0, 37.7, 31.3, 23.8, 22.0,
20.0, 16.0, -6.6, -6.9; HRMS m/z [M+ - t-Bu] calcd for C19H33O6F3-
Si 397.1294, obsd 397.1119; [R]20 -36.1 (c 3.2, CHCl3).
D
Methyl (3R,4R)-4-(tert-Butyldimethylsiloxy)-3-[3-(2-methyl-1,3-
dioxolan-2-yl)propyl]-1-cyclopentene-1-carboxylate (6). A nitrogen-
blanketed, magnetically stirred solution of 5b (1.9 g, 4.3 mmol),
triethylamine (1.2 mL, 2 equiv), methanol (8.6 mL, 5 equiv), tri-
phenylphosphine (110 mg, 0.1 equiv), and palladium acetate (41 mg,
4% mol) in dry DMF (15 mL) was flushed with carbon monoxide for
5 min, kept under 1 atm of carbon monoxide for 3 h, diluted with
ether(100 mL), washed with saturated NH4Cl solution (2 × 20 mL),
and dried. Purification of the residue by silica gel chromatography
Methyl (1S,3aR,6R,6aR)-6-(1,1-Dimethyloxyethyl)octahydro-3-
oxo-1-pentalenecarboxylate (12). A mixture of 11 (950 mg, 3.49

734 J. Am. Chem. Soc., Vol. 118, No. 4, 1996
Borrelly and Paquette
1380, 1270, 1240, 1100, 860, 815, 740; 1H NMR (300 MHz, C6D6) δ
3.31 (s, 3H), 2.97-2.95 (m, 1H), 2.96 (s, 3H), 2.89 (s, 3H), 2.67 (m,
1H), 2.65-2.49 (m, 2H), 2.22 (dd, J ) 18.4, 8.5 Hz, 1H), 1.98 (q, J )
7.8 Hz, 1H), 1.68-1.60 (m, 2H), 1.55-1.50 (m, 1H), 1.48-1.29 (m,
1H), 1.00 (s, 3H); 13C NMR (75 MHz, C6D6) ppm 216.9, 175.2, 103.4,
52.1, 51.4, 50.5, 47.9, 47.6, 44.0, 40.5, 28.3, 27.7, 17.6; HRMS m/z
[M+] calcd for C14H22O5 270.1467, obsd 270.1448; [R]20 -49.2 (c
D
0.7, CH2Cl2). Anal. Calcd for C14H22O5: C, 62.20; H, 8.20. Found:
C, 62.24; H, 8.17.
Methyl (3aR,6R,6aR)-6-(1,1-Dimethoxyethyl)-3,3a,4,5,6,6a-hexahy-
dro-3-oxo-1-pentalenecarboxylate (13). To a cold (-78 °C) solution
of 12 (as a 2.3:1 isomer mixture, 91 mg, 0.34 mmol) and trimethyl-
chlorosilane (0.22 mL, 5 equiv) in dry THF (10 mL) was added a 0.1
M LDA solution (8 mL, 2.6 equiv) in THF. The reaction mixture was
stirred for 10 min before being quenched by the addition of triethyl-
amine (1 mL) in hexanes (5 mL), allowed to warm up to room
temperature, and concentrated. Filtration through a plug of glass wool
followed by concentration to dryness afforded 109 mg (94%) of the
corresponding silyl enol ether as a colorless oil, which was directly
dissolved in dry THF (20 mL) and cooled to -78 °C. Propylene oxide
(0.24 mL, 10 equiv) followed by N-bromosuccinimide (68 mg, 1.3
equiv) was added, and the reaction mixture was allowed to warm up
to room temperature over 1 h. Et3N (0.48 mL, 10 equiv) was added,
and the resulting solution was stirred overnight, quenched with saturated
NaHCO3 solution (10 mL), and extracted with ether (2 × 20 mL).
Drying and concentration of the organic layers afforded a residue which
was purified by silica gel chromatography to give 13 (78 mg, 86%) as
a colorless solid, mp 101-102 °C (from 1:2 pentane-ether): IR
1
(CHCl3, cm-1) 2970, 2815, 1715, 1600, 1430, 1380, 850; H NMR
(300 MHz, C6D6) δ 6.36 (d, J ) 1.3 Hz, 1H), 3.34 (s, 3H), 3.29 (m,
1H), 2.99 (s, 3H), 2.88 (s, 3H), 2.57 (m, 1H), 2.05 (q, J ) 5.9 Hz,
1H), 1.79-1.72 (m, 2H), 1.48-1.39 (m, 2H), 1.09 (s, 3H); 13C NMR
(75 MHz, C6D6) ppm 210.2, 166.2, 165.3, 135.3, 102.8, 53.4, 51.4,
50.6, 48.7, 48.1, 47.9, 28.5, 27.1, 17.9; HRMS m/z [M+] calcd for
C14H20O5 268.1311, obsd 268.1311; [R]20 -47.9 (c 0.61, CH2Cl2).
D
Anal. Calcd for C14H20O5: C, 59.15; H, 7.10. Found: C, 59.16; H,
7.15.
Methyl (1S,2S,3aR,6R,6aS)-6-(1,1-Dimethoxyethyl)-2,3-epoxyoc-
tahydro-3-oxo-1-pentalenecarboxylate (14). To a cold (-10 °C)
solution of 13 (180 mg, 0.68 mmol) in CH2Cl2 (10 mL) and methanol
(4 mL) was added 30% H2O2 (0.9 mL, 5 equiv) followed by 1 N NaOH
solution (0.78 mL, 1.3 equiv). The resulting solution was warmed to
10 °C over 2 h, at which time saturated brine (20 mL) and CH2Cl2 (20
mL) were introduced. The separated organic layer was dried and
concentrated. The residue was purified by silica gel chromatography
(elution with 1:1 hexanes-ether) to give 14 (150 mg, 78%) as a
colorless solid, mp 101-102 °C: IR (neat, cm-1) 2975, 2890, 1730,
1
1440, 1375, 1160, 1035, 870; H NMR (300 MHz, C6D6) δ 3.53 (s,
1H), 3.32 (s, 3H), 2.93 (t, J ) 7.6 Hz, 1H), 2.88 (s, 3H), 2.85 (s, 3H),
2.46 (m, 2H), 1.81 (m, 1H), 1.36-1.33 (m, 3H), 0.94 (s, 3H); 13C NMR
(75 MHz, C6D6) ppm 208.8, 165.8, 103.1, 66.8, 59.3, 51.7, 49.5, 48.0,
47.5, 46.1, 45.5, 27.9, 25.9, 17.2; HRMS m/z [M+ - CH3] calcd for
C14H20O6 269.1025, obsd 269.1017; [R]20D +5.1 (c 0.17, CH2Cl2). Anal.
Calcd for C14H20O6: C, 59.15; H, 7.10. Found: C, 59.16; H, 7.15.
Methyl (1S,2S,3aR,6R,6aS)-6-(1,1-Dimethoxyethyl)-2,3-epoxyoc-
tahydro-3-methylene-1-pentalenecarboxylate (15). A nitrogen-
blanketed suspension of methyltriphenylphosphonium bromide (190 mg,
1.5 equiv) in dry THF (20 mL) was treated with 1.3 M n-butyllithium
in hexanes (0.39 mL, 1.4 equiv), stirred for 0.5 h at room temperature,
and cooled to -78 °C. A cold (-78 °C) solution of 14 (100 mg, 0.354
mmol) in dry THF (20 mL) was added via cannula to the Wittig reagent.
The resulting mixture was allowed to warm to room temperature over
3 h, stirred for an additional 3 h, quenched with saturated brine (30
mL), and diluted with ether (70 mL). The separated organic layer was
dried and concentrated to afford a residue which was purified by silica
gel chromatography (elution with 1.5:1 hexanes-ether) to give 15 as
mmol), N-methylmorpholine N-oxide (740 mg, 1.81 equiv), 4 Å
molecular sieves (500 mg), and a catalytic amount of N-methylmor-
pholine was slurried in dry CH2Cl2 (60 mL) and stirred for 15 min
before the addition of tetrapropylammoniumperruthenate (30 mg, 2.5%
mol). The resulting mixture was stirred overnight, filtered through a
small plug of Celite, and concentrated to leave a residue which was
purified by silica gel chromatography (elution with 1:1 hexanes-ether).
There was obtained 820 mg (86%) of 12 as a colorless solid, mp 94
°C (from hexanes): IR (CHCl3, cm-1) 3020-2860, 2840, 1740, 1440,
a colorless solid (49.6 mg, 50%), mp 62-63 °C: IR (CH2Cl2, cm-1
)
3035, 2980, 2890, 1735, 1655, 1445, 1375, 1155, 1040, 870; 1H NMR
(300 MHz, C6D6) δ 5.08 (d, J ) 2.6 Hz, 1H), 4.81 (d, J ) 2 Hz, 1H),
3.85 (s, 1H), 3.43 (s, 3H), 2.94 (s, 3H), 2.93 (s, 3H), 2.86 (m, 1H),
2.76-2.63 (m, 2H), 1.61-1.40 (m, 4H), 1.01 (s, 3H); 13C NMR (75
MHz, C6D6) ppm 167.5, 151.0, 110.9, 103.7, 68.3, 64.5, 51.4, 49.8,

Synthesis of the Cardiotoxic Agent Kalmanol
J. Am. Chem. Soc., Vol. 118, No. 4, 1996 735
48.1, 47.5, 45.9, 44.3, 29.4, 27.6, 17.2; HRMS m/z [M+] calcd for
282.1467, obsd 282.1461; [R]20 -9.1 (c 0.6, CH2Cl2). Anal. Calcd
D
C15H22O5 282.1467, obsd 282.1478; [R]20 -47.5 (c 0.12, CH2Cl2).
for C15H22O5: C, 63.36; H, 8.51. Found: C, 63.38; H, 8.60.
D
Methyl (1R,3aR,6R,6aR)-6-(1,1-Dimethyloxyethyl)-1,3a,4,5,6,6a-
hexahydro-1-hydroxy-3-methyl-1-pentalenecarboxylate (16). A so-
lution of 15 (325 mg, 1.15 mmol), ammonium formate (148 mg, 2
equiv), Pd2(dba)3‚CHCl3 (61 mg, 5% mol), and tributylphosphine (30
µL, 5% mol) in dry dioxane was refluxed for 1 h, cooled to room
temperature, filtered through a plug of Celite, and concentrated to
dryness. Purification of the residue by silica gel chromatography
(elution with 1:4 hexanes-ether) afforded a 13:1 mixture of 16 and
17 (297 mg, 91%).
Methyl (1R,2R,3S,3aR,6R,6aR)-2,3-Epoxyoctahydro-1-hydroxy-
3-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-1-pentalenecarboxylate (21).
To a slurry of 20 (61 mg, 0.216 mmol) and sodium carbonate (54 mg,
3 equiv) in dry CH2Cl2 (10 mL) was added 95% m-chloroperbenzoic
acid (75 mg, 2 equiv) in batches over 2 h. The reaction mixture was
stirred for 2 h and quenched by the addition of a saturated aqueous
solution of sodium sulfite (10 mL). The organic layer was dried and
concentrated. The residue was purified by silica gel chromatography
(elution with 1:4 hexanes-ethyl acetate) to give 21 (54 mg, 84%) as
a colorless oil: IR (neat, cm-1) 3500-3100, 2995, 2980, 2860, 1745,
For 16: IR (neat, cm-1) 3700-3200, 2975, 2840, 1730, 1650, 1475,
1420, 1275, 1200, 905; 1H NMR (300 MHz, C6D6) δ 5.31 (d, J ) 1.3
Hz, 1H), 3.85 (s, 1H), 3.08 (s, 3H), 3.06 (m, 1H), 3.04 (s, 3H), 3.03 (s,
3H), 2.87 (dd, J ) 8.07, 6.28 Hz, 1H), 2.57 (q, J ) 7 Hz, 1H), 1.78-
1.54 (m, 3H), 1.57 (s, 3H), 1.44 (m, 1H), 1.14 (s, 3H); 13C NMR (75
MHz, C6D6) ppm 175.8, 149.0, 127.0, 103.8, 88.6, 60.3, 54.6, 51.7,
47.9, 47.5, 46.1, 29.5, 29.2, 17.7, 15.1; HRMS m/z [M+] calcd for
1
1450, 1380, 1240, 1100, 1045; H NMR (300 MHz, CDCl3) δ 3.96-
3.89 (m, 4H), 3.80 (s, 3H), 3.43 (s, 3H), 3.20 (br s, 1H), 2.70 (m, 1H),
2.37 (dd, J ) 5.6, 9.45 Hz, 1H), 1.84 (m, 2H), 1.69 (m, 1H), 1.52-
1.45 (m, 2H), 1.43 (s, 3H), 1.21 (s, 3H); 13C NMR (75 MHz, CDCl3)
ppm 173.7, 110.4, 85.5, 68.4, 67.3, 64.7, 55.5, 52.3, 51.5, 51.4, 30.5,
28, 22.1, 15.6; HRMS m/z [M+] calcd for C15H22O6 298.1416, obsd
C15H24O5 284.1624, obsd 284.1627; [R]20 -18.6 (c 0.25, CH2Cl2).
298.1423; [R]20 -17.4 (c 0.3, CH2Cl2).
D
D
Anal. Calcd for C15H24O5: C, 63.36; H, 8.51. Found: C, 63.38; H,
8.60.
Methyl (1R,2S,3S,3aR,6R,6aR)-2,3-Epoxyoctahydro-1-methoxy-
3-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-1-pentalenecarboxylate (22).
To a nitrogen-blanketed solution of 21 (650 mg, 2.18 mmol) in dry
DMF (10 mL) was added sodium hydride (157 mg, 3 equiv) followed
by methyl iodide (0.34 mL, 2.5 equiv). The resulting solution was
stirred for 15 min at room temperature and quenched with saturated
brine (5 mL). The organic phase was extracted with ether (2 × 25
mL) and was dried. The residue obtained after concentration by rotary
evaporation was purified by silica gel chromatography (elution with
1:1 hexanes-ether) to give 22 (632 mg, 93%) as a colorless oil: IR
(neat, cm-1) 3000-2940, 2875, 1725, 1440, 1375, 1255, 1175, 1100;
1H NMR (300 MHz, C6D6) δ 3.58-3.51 (m, 4H), 3.42 (s, 1H), 3.30
(s, 3H), 3.29 (s, 3H), 2.85 (dd, J ) 9.12, 5.4 Hz, 1H), 2.67 (q, J ) 9.5
Hz, 1H), 2.23 (m, 1H), 1.83 (m, 1H), 1.59-1.44 (m, 3H), 1.40 (s, 3H),
1.30 (s, 3H); 13C NMR (75 MHz, C6D6) ppm 172.4, 111.2, 91.9, 67.3,
65.1, 65.0, 64.9, 55.9, 54.5, 51.7, 51.5, 51.0, 29.5, 28.4, 23.7, 16.0;
Methyl (1S,3aR,6R,6aR)-6-(1,1-Dimethoxyethyl)octahydro-1-hy-
droxy-3-methylene-1-pentalenecarboxylate (17). A solution of 15
(400 mg, 1.41 mmol), ammonium formate (177.6 mg, 2 equiv), Pd2-
(dba)3‚CHCl3 (75 mg, 5% mol), and triphenylphosphine (15 mg, 5%
mol) in dry dioxane was refluxed for 1 h, cooled to room temperature,
filtered through a plug of Celite, and concentrated to dryness.
Purification of the residue by silica gel chromatography (elution with
1:4 hexanes-ether) afforded 17 as a colorless oil (356 mg, 91%): 1H
NMR (300 MHz, C6D6) δ 4.97 (br t, J ) 1 Hz, 1H), 4.91 (br t, J ) 1
Hz, 1H), 3.40 (s, 3H), 3.30 (br s, 1H), 3.28 (m, 1H), 3.11 (dq, J )
12.3, 2.5 Hz, 1H), 2.92 (s, 3H), 2.91 (s, 3H), 2.64 (br d, J ) 12.4 Hz,
1H), 2.59 (m, 1H), 2.41 (br t, J ) 6.3 Hz, 1H), 1.69-1.51 (m, 3H),
1.49-1.47 (m, 1H), 0.99 (s, 3H); 13C NMR (75 MHz, C6D6) ppm 174.9,
154.1, 106.9, 104.3, 83.6, 60.4, 51.7, 50.2, 48.1, 47.3, 44.2, 43.9, 33.2,
27.5, 17.3; HRMS m/z [M+] calcd for C15H24O5 284.1623, found
HRMS m/z [M+] calcd for C16H24O6 312.1573, obsd 312.1592; [R]20
-14.8 (c 1.04, CH2Cl2).
D
284.1627; [R]20 -25.4 (c 0.4, CH2Cl2). Anal. Calcd for C15H24O5:
D
C, 63.36; H, 8.51. Found: C, 63.38; H, 8.60.
(1R,2S,3S,3aR,6R,6aR)-3-(tert-Butyldimethylsiloxy)octahydro-1-
methoxy-3-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-1-pentalen-1′-ol (23).
To a cold (-10 °C) solution of 22 (33 mg, 0.106 mmol) in dry THF
(6 mL) was added 3.4 M Red-Al in toluene (0.1 mL, 3 equiv). The
resulting solution was heated to reflux, treated with 3.4 M Red-Al (3
× 0.1 mL) over 24 h, cooled to -10 °C, and quenched with 20%
Rochelle’s salt solution (1 mL). The organic phase was extracted with
CH2Cl2 (2 × 20 mL) and dried. Concentration and purification of the
residue by silica gel chromatography (elution with 25:1 dichlo-
romethane-methanol) afforded 23 as a colorless oil (28.5 mg, 94%):
IR (neat, cm-1) 3540-3020, 2960-2860, 1450, 1370, 1080; 1H NMR
(300 MHz, C6D6) δ 4.16-3.80 (br s, 1H), 3.62 (br d, J ) 13.2 Hz,
1H), 3.50-3.31 (m, 6H), 3.16 (s, 3H), 2.75-2.68 (m, 2H), 2.07 (m,
1H), 1.69 (dt, J ) 14.2, 1.6 Hz, 1H), 1.66-1.44 (m, 3H), 1.24 (s, 3H),
1.07 (s, 3H), 1.02 (d, J ) 14.3 Hz, 1H); 13C NMR (75 MHz, C6D6)
ppm 111.6, 90.3, 79.1, 64.6, 64.4, 61.9, 60.0, 52.1, 50.6, 49.8, 41.9,
31.1, 31.0, 22.7, 22.4; HRMS m/z [M+] calcd for C15H26O6 255.1596,
Methyl (1S,3aS,6R,6aR)-6-(1,1-Diethoxyethyl)octahydro-3a-hy-
droxy-3-oxo-1-pentalenecarboxylate (19). For 19: mp 95 °C; IR
(KBr, cm-1) 3600-3130, 2920, 2830, 1720, 1380, 1310, 1100, 1030,
1
840; H NMR (300 MHz, C6D6) δ 3.33 (s, 3H), 3.08 (s, 1H), 2.97 (s,
3H), 2.95 (s, 3H), 2.68-2.47 (m, 3H), 2.31-2.22 (m, 2H), 1.83 (m,
1H), 1.63 (m, 2H), 1.44 (m, 1H), 1.24 (s, 3H); 13C NMR (75 MHz,
C6D6) ppm 214.6, 174.8, 103.6, 87.8, 55.0, 52.0, 51.6, 48.2, 47.8, 44.3,
39.4, 36.2, 27.7, 17.8; HRMS m/z [M+] calcd for C14H22O6 286.1416,
obsd 286.1403; [R]20 -26 (c 0.62, CH2Cl2).
D
obsd 255.1606; [R]20 -25.4 (c 0.9, CH2Cl2)
D
Methyl (1S,3aR,6R,6aR)-6-Oxo-1,3a,4,5,6,6a-hexahydro-1-(meth-
oxy)-3-methyl-1-pentalenecarboxylate (24). To a solution of 20 (274
mg, 0.97 mmol) and methyl iodide (0.12 mL, 2 equiv) in dry DMF (7
mL) was added sodium hydride (70 mg, 3 equiv). The mixture was
stirred for 15 min at room temperature, quenched with saturated brine
(2 mL), and diluted with ether (20 mL). The organic phase was
concentrated by rotary evaporation, the residue was dissolved in acetone
(10 mL), and a crystal of p-toluenesulfonic acid was added. Stirring
was maintained for 10 min prior to quenching with 2 drops of
triethylamine. Concentration and purification of the residue by silica
gel chromatography (elution with 1:1.5 hexanes-ether) afforded 24
(227.5 mg, 93%) as a colorless oil: IR (neat, cm-1) 2975, 2880, 1745,
Methyl (1R,3aR,6R,6aR)-6-(2-Methyl-1,3-dioxolan)-1,3a,4,5,6,6a-
hexahydro-1-hydroxy-3-methyl-1-pentalenecarboxylate (20). Ester
16 (100 mg, 0.354 mmol) was dissolved in a 1:1 mixture of
dimethoxypropane and ethylene glycol (5 mL total), and a crystal of
p-TsOH was added. This was stirred for 10 min, at which time it was
diluted with ether, washed with water (3 × 5 mL), and dried. The
residue obtained after concentration was purified by silica gel chro-
matography (elution with 1:4 hexanes-ether) to give 20 (100 mg, 98%)
as a colorless oil: IR (neat, cm-1) 3700-3100, 2995, 2940, 1735, 1450,
1380, 1245, 1110, 1000, 920; 1H NMR (300 MHz, C6D6) δ 5.16 (br s,
1H), 3.93-3.89 (m, 4H), 3.76 (s, 3H), 3.17 (q, J ) 8.3 Hz, 1H), 2.76
(t, J ) 8.2 Hz, 1H), 2.18 (m, 1H), 1.90-1.79 (m, 2H), 1.74 (br s, 1H),
1.64-1.53 (m, 1H), 1.38-126 (m, 1H), 1.23 (s, 3H); 13C NMR (75
MHz, C6D6) ppm 176.1, 149.2, 126.7, 88.4, 65, 64.6, 59, 54.6, 51.8,
50.3, 30.9, 30.0, 23.5, 15.1; HRMS m/z [M+] calcd for C15H22O5
1
1725, 1650, 1440, 1360, 1080; H NMR (300 MHz, C6D6) δ 5.64 (br
s, 1H), 3.45 (s, 3H), 3.31 (t, J ) 7 Hz, 1H), 3.14 (s, 3H), 3.07 (m, 1H),
2.55 (q, J ) 7 Hz, 1H), 1.92 (s, 3H), 1.61-1.47 (m, 3H), 1.51 (br s,
3H), 1.24 (m, 1H); 13C NMR (75 MHz, C6D6) ppm 207.3, 172.5, 151.2,
123.9, 93.8, 55.5, 54.7, 53, 52.1, 51.1, 30.6, 28.2, 27.8, 14.7; HRMS
m/z [M+ - CH3] calcd for C13H17O4 232.1127, obsd 232.1117; [R]20
D

736 J. Am. Chem. Soc., Vol. 118, No. 4, 1996
Borrelly and Paquette
+13.6 (c 0.14, CH2Cl2). Anal. Calcd for C14H20O4: C, 66.64; H, 7.99.
Found: C, 66.56; H, 8.19.
1650, 1420, 1345, 1230, 1095; 1H NMR (300 MHz, C6D6) δ 5.93 (dq,
J ) 18, 5.3 Hz, 1H), 5.32 (br s, 1H), 5.25 (dq, J ) 18, 1.8 Hz, 1H),
4.96 (br s, 1H), 4.88 (br s, 1H), 3.98 (t, J ) 6.5 Hz, 1H), 3.82 (m, 2H),
3.36 (s, 3H), 3.32 (m, 1H), 3.18 (m, 1H), 3.02 (dq, J ) 15, 1.6 Hz,
1H), 2.72 (br d, J ) 14.4 Hz, 1H), 2.50 (dd, J ) 14.4, 6.2 Hz, 1H),
2.33 (ddd, J ) 14.4, 6.3, 2.1 Hz, 1H), 2.15 (m, 1H), 1.87 (m, 1H),
1.66-1.54 (m, 3H), 1.20 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H), 0.97 (s,
9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz, C6D6) ppm 173.3,
154.2, 145.8, 135.7, 132.8, 115.6, 106.8, 90.8, 81.1, 75.0, 66.8, 56.0,
51.1, 50.9, 48.2, 47.0, 41.1, 40.8, 34.5, 28.9, 27.2, 27.0, 26.9, 26.0,
21.0, 18.3, -4.34, -4.8; HRMS m/z [M+ + H+] calcd for C29H48O5Si
Methyl (1S,3aR,6R,6aR)-1-(Benzyloxy)-1,3a,4,5,6,6a-hexahydro-
3-methyl-6-oxo-1-pentalenecarboxylate (25) and Methyl (1S,3aR,6R,
6aR)-6-Oxo-octahydro-1-(benzyloxy)-3-methylene-1-pentalenecar-
boxylate (26). A nitrogen-blanketed solution of either 16 or 17 (142
mg, 0.5 mmol), benzyl bromide (120 µL, 2 equiv) and a catalytic
amount of tetrabutylammonium iodide in dry DMF (5 mL) was treated
with sodium hydride (18 mg, 1.5 equiv). The resulting mixture was
stirred for 15 min, diluted with ether (20 mL), and quenched with
saturated brine (10 mL). Concentration of the organic layer gave a
residue which was dissolved in dry acetone (10 mL), and the resulting
solution was stirred in the presence of a catalytic amount of p-
toluenesulfonic acid for 5 min, quenched with 2 drops of triethylamine,
and concentrated by rotary evaporation. Purification of the residue by
silica gel chromatography (elution with 1:1 hexanes-ether) afforded
either 25 or 26 (158 mg, 98%) as colorless oils.
504.3271, obsd 504.3286; [R]20 -75.1 (c 0.25, CH2Cl2).
D
(3S,3aR,5aR,7aR,7bR)-7a-(Allyloxy)-3-[(4S)-4-(tert-butyldimeth-
ylsiloxy)-3,3-dimethyl-1-cyclopenten-1-yl]-3-methylene-3,6-pentane-
leno[1,6-cd]pyran-1(3H)-one (29). To a solution of 28 (85 mg, 0.305
mmol) in THF (8 mL), methanol (3 mL), and water (3 mL) was added
5 N KOH (0.6 mL, 10 equiv). After being stirred overnight, the reaction
mixture was cooled to 0 °C, carefully quenched with saturated NH4Cl
solution (10 mL), and diluted with CH2Cl2 (40 mL). The aqueous layer
was extracted with CH2Cl2 (2 × 20 mL), and the combined organic
extracts were dried and concentrated to afford a white solid which was
dissolved in dry CH2Cl2 (10 mL) and treated with 2-chloro-1-
methylpyridinium iodide (310 mg, 3 equiv) and triethylamine (0.4 mL,
6 equiv). The resulting bright yellow solution was stirred for 10 min
at room temperature and quenched with saturated NH4Cl solution (3
mL). The organic extract was dried and concentrated, and the residue
was purified by silica gel chromatography (elution with 1:1 hexanes-
For 25: IR (neat, cm-1) 3030, 2960, 2890, 1745, 1735, 1480, 1390,
1
1095; H NMR (300 MHz, C6D6) δ 7.37-7.35 (m, 2H), 7.17-7.03
(m, 3H), 5.64 (br s, 1H), 4.43 (d, J ) 11.2 Hz, 1H), 4.38 (d, J ) 11.2
Hz, 1H), 3.37 (s, 3H), 3.36 (m, 1H), 3.02 (m, 1H), 2.54 (q, J ) 6.9
Hz, 1H), 1.85 (s, 3H), 1.55-1.45 (m, 3H), 1.46 (br s, 3H), 1.41-1.19
(m, 1H); 13C NMR (75 MHz, C6D6) ppm 207.3, 172.6, 151.4, 139.4,
128.3, 127.9, 127.5, 124.4, 93.7, 67.3, 55.7, 54.7, 53.0, 51.2, 30.6, 28.2,
27.9, 14.8; HRMS m/z [M+ - C2H3O2] calcd for C20H24O4 269.1541,
obsd 269.1537.
For 26: IR (neat, cm-1) 3030, 2960, 2890, 1745, 1735, 1480, 1390,
1095; 1H NMR (300 MHz, C6D6) δ 7.34 (br d, J ) 7.2 Hz, 2H), 7.18-
7.07 (m, 3H), 4.90 (br s, 1H), 4.82 (br s, 1H), 4.40 (d, J ) 11.2 Hz,
1H), 4.35 (d, J ) 11.2 Hz, 1H), 3.34 (s, 3H), 3.30 (dt, J ) 8.4, 1.8 Hz,
1H), 3.09 (m, 1H), 2.90 (dq, J ) 16.8, 2.4 Hz, 1H), 2.77 (br d, J ) 7.3
Hz, 1H), 2.57 (q, J ) 8 Hz, 1H), 1.81 (m, 1H), 1.80 (s, 3H), 1.58 (m,
1H), 1.42-1.20 (m, 2H); 13C NMR (75 MHz, C6D6) ppm 207.0, 172.7,
154.0, 139.0, 128.3, 127.8, 127.6, 107.7, 89.0, 67.4, 55.8, 54.7, 51.4,
48.3, 39.3, 33.7, 31.3, 28.3; HRMS m/z [M+ - C2H3O2] calcd for
ether) to afford 29 (75 mg, 86%) as a colorless oil: IR (neat, cm-1
)
3045, 3005, 2970, 1795, 1415, 1360, 1310, 1270, 1240, 1200, 1055,
1
1015, 740; H NMR (300 MHz, C6D6) δ 5.98 (dq, J ) 18.1, 5.3 Hz,
1H), 5.68 (br s, 1H), 5.28 (dq, J ) 18.1, 1.8 Hz, 1H), 5.04 (dq, J )
9.3, 1.7 Hz, 1H), 4.88 (br s, 1H), 4.83 (br s, 1H), 4.23 (m, 2H), 3.86
(t, J ) 6.5 Hz, 1H), 3.00 (br d, J ) 18.3 Hz, 1H), 2.92 (m, 1H), 2.86
(dq, J ) 18.3, 2.5 Hz, 1H), 2.46 (dd, J ) 14.4, 8.3 Hz, 1H), 2.35 (dd,
J ) 14.4, 6.3 Hz, 1H), 2.30 (ddd, J ) 14.4, 6.3, 2.1 Hz, 1H), 1.91 (m,
1H), 1.55-1.28 (m, 4H), 1.24 (s, 3H), 1.23 (m, 1H), 0.98 (s, 3H), 0.94
(s, 9H), 0.89 (s, 3H), 0.02 (s, 3H), 0.008 (s, 3H); 13C NMR (75 MHz,
C6D6) ppm 171.7, 154.9, 140.4, 137.4, 135.6, 115.6, 109.3, 86.1, 86.0,
81.0, 66.9, 51.3, 51.2, 47.0, 45.1, 44.3, 41.8, 32.9, 28.3, 26.8, 26.2,
25.9, 21.1, 18.2, -4.5, -4.8; HRMS m/z [M+] calcd for C28H43O4Si
C18H21O2 269.1541, obsd 269.1537; [R]20 -60.5 (c 0.83, CH2Cl2).
D
Anal. Calcd for C20H24O4 C, 73.19; H, 7.42. Found: C, 73.08; H,
7.42.
Methyl (1S,3aR,6R,6aR)-6-Oxo-octahydro-1-(allyloxy)-3-meth-
ylene-1-pentalenecarboxylate (27). To a nitrogen-blanketed solution
of 17 (56 mg, 0.197 mmol) and a catalytic amount of tetrabutylam-
monium iodide in dry DMF (4 mL) was successively added sodium
hydride (12 mg, 2.5 equiv) and allyl bromide (34 µL, 2 equiv). The
reaction mixture was stirred for 10 min before being quenched with
5% HCl solution (10 mL) and diluted with ether (15 mL). The
separated organic phase was dried and concentrated to afford a residue
which was purified by silica gel chromatography (elution with 1:1
hexanes-ether) to give 27 (50.4 mg, 92%) as a colorless oil: IR (neat,
cm-1) 3010, 2985, 1755, 1680, 1475, 1405, 1295, 1205, 1080, 975,
471.2931, obsd 471.2956; [R]20 -115 (c 0.95, CH2Cl2).
D
1
905; H NMR (300 MHz, C6D6) δ 5.87 (dq, J ) 18.3, 5.2 Hz, 1H),
5.20 (dq, J ) 18.3, 1.9 Hz, 1H), 5.00 (dq, J ) 9.5, 1.7 Hz, 1H), 4.88
(br s, 1H), 4.81 (br s, 1H), 3.84 (br d, J ) 1 Hz, 1H), 3.82 (br d, J )
1 Hz, 1H), 3.34 (s, 3H), 3.26 (dt, J ) 8.05, 1.1 Hz, 1H), 3.12 (m, 1H),
2.87 (dq, J ) 16.7, 2.5 Hz, 1H), 2.62 (br d, J ) 16.7 Hz, 1H), 2.55 (q,
J ) 8.5 Hz, 1H), 1.80 (m, 1H), 1.79 (s, 3H), 1.58 (m, 1H), 1.41-1.19
(m, 2H); 13C NMR (75 MHz, C6D6) ppm 206.7, 172.4, 153.7, 135.2,
115.4, 107.3, 88.6, 66.2, 55.4, 54.4, 51.1, 48.0, 39.2, 33.4, 31.0, 28.1;
HRMS m/z [M+] calcd for C16H22O4 278.1518, obsd 278.1499; [R]20
-148.8 (c 0.66, CH2Cl2).
D
(3S,3aR,5aR,7aR,7bR)-7a-(Benzyloxy)-3-[(4S)-4-(tert-butyldime-
thylsiloxy)-3,3-dimethyl-1-cyclopenten-1-yl]-3a,4,5,5a,7b-hexahydro-
3,6-pentaneleno[1,6-cd]pyran-1(3H)-one (30) and (3S,3aR,5aR,7aR,
7bR)-7a-(Benzyloxy)-3-[(4S)-4-(tert-butyldimethylsiloxy)-3,3-dimethyl-
1-cyclopenten-1-yl]-3-methylene-3,6-pentaneleno[1,6-cd]pyran-1(3H)-
one (31). A cold (-78 °C), argon-blanketed, magnetically stirred
solution of 1 (93 mg, 1.15 equiv) in dry THF (5 mL) was treated
dropwise with 1.7 M tert-butyllithium (0.39 mL, 2.16 equiv) in pentane,
stirred at this temperature for an additional 15 min, and rapidly added
Via cannula to a precooled (-78 °C) solution of 25 or 26 (87 mg, 0.267
mmol) in dry THF (5 mL). The resulting reaction mixture was stirred
for 1 h at the same temperature, allowed to warm to room temperature
over 2 h, quenched with saturated NH4Cl solution (5 mL), and diluted
with ether (20 mL). The organic phase was dried and concentrated,
Methyl (1R,3aR,6R,6aR)-1-(Methoxy)-6-[(1S)-1-[(4S)-4-(tert-bu-
tyldimethylsiloxy)-3,3-dimethyl-1-cyclopenten-1-yl]-1-hydroxyethyl]-
3-methylene-1-pentalenecarboxylate (28). A cold (-78 °C), argon-
blanketed, magnetically stirred solution of 1 (93 mg, 1.15 equiv) in
dry THF (15 mL) was treated dropwise 1.7 M tert-butyllithium in
pentane (0.36 mL, 2.3 equiv), stirred at -78 °C for an additional 15
min, and rapidly transferred Via cannula to a precooled (-78 °C)
solution of 27 (74 mg, 0.266 mmol) in dry THF (10 mL). The reaction
mixture was stirred for 1 h at -78 °C, allowed to warm to room
temperature during 3 h, quenched with saturated NH4Cl solution (10
mL), and diluted with ether (50 mL). The organic phase was dried
and concentrated. The residue was purified by silica gel chromatog-
raphy (elution with 2:1 hexanes-ether) to afford 91.6 mg (70%) of 28
as a colorless oil: IR (neat, cm-1) 3700-3100, 3060, 2940, 2860, 1700,

Synthesis of the Cardiotoxic Agent Kalmanol
J. Am. Chem. Soc., Vol. 118, No. 4, 1996 737
and the residue was purified by silica gel chromatography (elution with
5:1 hexanes-ether) to afford 127 mg (88%) of either 30 or 31 as
colorless oils.
1,3a,4,5,6,6a-hexahydro-3-methyl-1-pentalenecarboxylate (32). A
cold (-78 °C), argon-blanketed, magnetically stirred solution of ent-1
(361 mg, 1.1 equiv) in dry THF (15 mL) was treated dropwise with
1.7 M tert-butyllithium in pentane (1.4 mL, 2.2 equiv), stirred at -78
°C for an additional 15 min and rapidly transferred Via cannula to a
precooled (-78 °C) solution of 24 (255 mg, 1.08 mmol) in dry THF
(10 mL). The resulting reaction mixture was stirred for 1 h at this
temperature, allowed to warm to room temperature over 3 h, quenched
with saturated NH4Cl solution (10 mL), and diluted with ether (50 mL).
The organic phase was dried and concentrated, and the residue was
purified by silica gel chromatography (elution with 2:1 hexanes-ether)
to afford 32 (310 mg, 60%, 92% based on recovered 24) as a 10:1
mixture of diastereomers: IR (neat, cm-1) 3700-3180, 3060, 3010-
2800, 1730, 1650, 1420, 1345, 1295, 1170, 1045, 1010; 1H NMR (300
MHz, C6D6) δ 5.53 (t, J ) 1.3 Hz, 1H), 5.32 (s, 1H), 3.96 (t, J ) 6.9
Hz, 1H), 3.42 (s, 3H), 3.28-3.21 (m, 1H), 3.18 (s, 3H), 3.03 (q, J )
7 Hz, 1H), 2.57 (dd, J ) 15.18, 6.9 Hz, 1H), 2.37 (ddd, J ) 15.24,
8.86, 1.9 Hz, 1H), 2.00 (m, 1H), 1.79 (m, 1H), 1.68-1.57 (m, 2H),
1.55 (br s, 1H), 1.47-1.17 (m, 2H), 1.35 (s, 3H), 1.16 (m, 1H), 1.09
(s, 3H), 1.06 (s, 3H), 0.97 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR
(75 MHz, C6D6) ppm 173.1, 150.8, 145.4, 132.5, 123.4, 96.0, 80.8,
74.1, 55.6, 55.0, 52.2, 50.6, 49.7, 46.8, 40.5, 29.9, 29.0, 27.6, 26.7,
25.8, 20.9, 18.0, 15.1, -4.7, -5.1; HRMS m/z [M+ - C2H3O2] calcd
for C25H43O3Si 419.2981, obsd 419.2999.
For 30: IR (neat, cm-1) 3020, 2975, 2880, 1720, 1450, 1370, 1245,
1
1115, 830; H NMR (300 MHz, C6D6) δ 7.41-7.36 (m, 2H), 7.35-
7.06 (m, 3H), 5.65 (br s, 1H), 5.60 (br s, 1H), 5.13 (d, J ) 11.4 Hz,
1H), 4.71 (d, J ) 11.4 Hz, 1H), 3.93 (t, J )6.9 Hz, 1H), 2.84 (m, 1H),
2.79-2.40 (m, 2H), 2.37 (dd, J ) 8.56, 6.6 Hz, 1H), 1.57-1.44 (m,
3H), 1.41 (s, 3H), 1.34-1.26 (m, 3H), 1.15 (m, 1H), 1.05 (s, 3H), 0.94
(s, 12H), 0.92 (m, 1H), 0.01 (s, 3H), 0.00 (s, 3H); 13C NMR (75 MHz,
C6D6) ppm 170.5, 153.9, 139.9, 139.2, 137.1, 128.5, 128.3, 127.8, 127.7,
127.3, 124.4, 90.2, 85.7, 80.9, 67.5, 51.9, 51.6, 49.7, 47.2, 41.8, 29.8,
27.1, 27.0, 26.4, 26.0, 21.1, 18.2, 14.4, -4.4, -4.8; HRMS m/z [M+]
calcd for C32H46O4Si 522.3165, obsd 522.3203; [R]20 +3.6 (c 0.98,
D
CH2Cl2).
(3S,3aR,5aR,7aS,7bS)-7a-(Methoxy)-3-[(4S)-4-(tert-butyldimeth-
ylsiloxy)-3,3-dimethyl-1-cyclopenten-1-yl]-3a,4,5,5a,7b-hexahydro-
3,6-pentaneleno[1,6-cd]pyran-1(3H)-one (33). A solution of 32 (74
mg, 0.155 mmol) in THF (8 mL), methanol (3 mL), and water (3 mL)
was treated with 5 N KOH (0.3 mL, 10 equiv), stirred overnight, cooled
to 0 °C, carefully quenched with saturated NH4Cl solution (10 mL),
and diluted with CH2Cl2 (40 mL). The aqueous layer was extracted
with CH2Cl2 (2 × 20 mL), and the combined organic extracts were
dried and concentrated to afford a white solid which was dissolved in
dry CH2Cl2 (10 mL) and treated with 2-chloro-1-methylpyridinium
iodide (160 mg, 3 equiv) followed by triethylamine (0.2 mL, 6 equiv).
The resulting bright yellow solution was stirred for 10 min at room
temperature and quenched with saturated NH4Cl solution (3 mL). The
organic extract was dried and concentrated. The residue was purified
by silica gel chromatography (elution with 1:1 hexanes-ether) to afford
33 (10:1 mixture of diastereomers) (59 mg, 85%) as a colorless solid,
mp 102-103 °C: IR (neat, cm-1) 3030, 2915, 2820, 1770, 1410, 1345,
1295, 1260, 1170, 1010, 720; 1H NMR (300 MHz, C6D6) δ 5.57 (br s,
1H), 5.49 (br s, 1H), 3.93 (t, J ) 6.2 Hz, 1H), 3.52 (s, 3H), 2.85 (m,
1H), 2.64-2.40 (m, 3H), 1.59-1.42 (m, 3H), 1.41 (br t, J ) 1.2 Hz,
3H), 1.27 (s, 3H), 1.26 (m, 1H), 1.15-1.02 (m, 1H), 1.05 (s, 3H), 0.99
(s, 3H), 0.97 (s, 9H), 0.06 (s, 3H), 0.035 (s, 3H); 13C NMR (75 MHz,
C6D6) ppm 170.2, 153.9, 139.2, 136.8, 123.9, 89.8, 85.8, 80.5, 52.9,
51.8, 51.6, 49.6, 47.9, 42.5, 29.8, 27.7, 27.1, 26.6, 26.0, 21.2, 18.3,
14.4, -4.5, -4.9; HRMS m/z [M+] calcd for C26H42O4Si 447.2931,
obsd 447.2900. Anal. Calcd for C26H42O4Si: C, 69.91; H, 9.48.
Found: C, 70.11; H, 9.52.
For 31: IR (neat, cm-1) 3020, 2975, 2880, 1720, 1450, 1370, 1245,
1
1115, 830; H NMR (300 MHz, C6D6) δ 7.56-7.54 (d, J ) 7.2 Hz,
2H), 7.27-7.12 (m, 3H), 5.80 (br s, 1H), 4.92 (m, 2H), 4.85 (d, J )
9.2 Hz, 1H), 4.78 (d, J ) 9.2 Hz, 1H), 3.91 (t, J ) 6.6 Hz, 1H), 3.15-
2.95 (m, 3H), 2.62 (dd, J ) 12.4, 7.4 Hz, 1H), 2.44-2.33 (m, 2H),
2.04 (m, 1H), 1.66-1.35 (m, 3H), 1.34 (s, 3H), 1.32 (m, 1H), 1.03 (s,
3H), 0.99 (s, 9H), 0.94 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR
(75 MHz, C6D6) ppm 171.9, 154.8, 140.5, 139.1, 137.5, 128.3, 127.7,
127.6, 109.5, 86.3, 86.1, 80.9, 67.9, 51.2, 50.9, 46.9, 45.1, 44.6, 41.8,
32.9, 28.4, 26.7, 26.1, 25.9, 21.2, 18.2, -4.5, -4.9; HRMS m/z [M+]
calcd for C32H46O4Si: 522.3165, obsd 522.3203; [R]20D -72.8(c 1.78,
CH2Cl2). Anal. Calcd for C32H46O4Si: C, 73.52; H, 8.87. Found: C,
73.52; H, 8.98.
Methyl (1R,3aR,6R,6aR)-1-(Methoxy)-6-[(1S)-1-[(4S)-4-(tert-bu-
tyldimethylsiloxy)-3,3-dimethyl-1-cyclopenten-1-yl]-1-hydroxyethyl]-

738 J. Am. Chem. Soc., Vol. 118, No. 4, 1996
Borrelly and Paquette
(2aR,4aR,6aR,8S,10aR,10bR)-8-(tert-Butyldimethylsiloxy)-2,2a,
4a,6,6a,7,8,9,10a,10b-decahydro-4a-(methoxy)-3,7,7,10-tetra-
methylcyclopenta[5,6]cycloocta[1,2,3-cd]pentalen-5(1H)-one (34). A
sample of 33 (25 mg, 0.056 mmol) and pyridine (2 drops) was dissolved
in dry THF (3 mL) and dry CH2Cl2 (3 mL) under N2, cooled to -40
°C, and treated dropwise with 0.83 M Tebbe reagent in toluene (0.17
mL, 2.5 equiv). The solution was warmed to room temperature during
0.5 h, stirred for 1 h, cooled to -60 °C, and quenched with 10% KOH
solution (1 mL). A 5% triethylamine solution in ether was added, and
the mixture was filtered through a pad of basic alumina (activity I).
Concentration to dryness left a residue which was dissolved in dry
p-cymene (8 mL) and heated at 130 °C for 90 min. Purification by
silica gel chromatography (elution with 8:1 hexanes-ether) afforded
34 (10:1 mixture of diastereomers) (17 mg, 68%) as a colorless oil:
IR (neat, cm-1) 3100-3000, 2990, 2890, 1715, 1430, 1380, 1260, 1115,
815; 1H NMR (300 MHz, C6D6) δ 5.48 (br s, 1H), 3.89 (t, J ) 6.4 Hz,
1H), 3.61 (m, 1H), 3.08 (m, 1H), 3.06 (s, 3H), 2.97 (s, 1H), 2.94 (d, J
) 2.7 Hz, 1H), 2.61 (m, 1H), 2.52 (m, 1H), 2.19 (m, 1H), 1.93 (m,
1H), 1.55 (br s, 3H), 1.51 (br s, 3H), 1.49 (m, 1H), 1.45-1.12 (m,
2H), 1.10 (s, 3H), 1.08-1.01 (m, 1H), 0.97 (s, 9H), 0.93 (s, 3H), 0.059
(s, 3H), 0.049 (s, 3H); 13C NMR (75 MHz, C6D6) ppm 211.7, 151.7,
136.6, 130.0, 122.3, 96.2, 79.6, 57.3, 53.6, 51.8, 47.8, 46.4, 45.8, 44.8,
42.2, 35.5, 28.6, 26.1, 21.4, 19.5, 18.3, 14.5, -4.4, -4.9; HRMS m/z
[M+] calcd for C27H44O3Si 444.3060, obsd 444.3062.
purified by silica gel chromatography (elution with 1:1.5 hexanes-
ether) to afford 37 (35.5 mg, 91%) as a colorless oil: IR (neat, cm-1
)
3700-3100, 2995, 2985, 1720, 1510, 1385, 1265, 1125; 1H NMR (300
MHz, C6D6) δ 7.27-7.18 (m, 2H), 7.16-7.04 (m, 3H), 4.93 (br d, J
) 0.9 Hz, 1H), 4.88 (br d, J ) 0.9 Hz, 1H), 4.45 (d, J ) 9.7 Hz, 1H),
4.00 (d, J ) 9.7 Hz, 1H), 3.85 (br d, J ) 12.4 Hz, 1H), 3.54 (t, J ) 8.4
Hz, 1H), 3.43 (br d, J ) 17.4 Hz, 1H), 3.24-3.14 (m, 2H), 2.81 (dd,
J ) 12.9 Hz, 1H), 2.64-2.51 (m, 2H), 2.16-2.00 (m, 3H), 1.91-1.79
(m, 2H), 1.44 (s, 3H), 1.40-1.24 (m, 1H), 1.23-0.93 (m, 1H), 0.92-
0.88 (m, 1H), 0.91 (s, 3H), 0.76 (s, 3H); 13C NMR (75 MHz, C6D6)
ppm 210.7, 154.3, 138.7, 133.5, 130.5, 128.5, 128.2, 127.8, 127.2,
106.8, 94.0, 75.9, 67.3, 57.6, 49.5, 48.8, 46.1, 44.3, 39.9, 35.3, 35.2,
32.1, 21.9, 21.8, 21.3; HRMS m/z [M+] calcd for C27H34O3 406.2508,
obsd 406.2475.
(2aR,3R,4aS,6aS,8R,9aS,10R,10aR,10bR)-4a-(Benzyloxy)-9a,10-
epoxytetradecahydro-8-hydroxy-7,7,10-trimethylspiro[cyclopenta-
[5,6]cycloocta[1,2,3-cd]pentalene-3(5H),2′-oxiran]one (38). To a
slurry of 37 (40 mg, 0.098 mmol) and NaHCO3 (66 mg, 8 equiv) in
dry CH2Cl2 (5 mL) was added 90% m-chloroperbenzoic acid (59 mg,
3.5 equiv) in one portion. The reaction mixture was stirred at room
temperature for 4 h and quenched by addition of a 10% NaHSO3
solution (5 mL). The separated organic layer was dried and concen-
trated to leave a residue which was purified by silica gel chromatog-
raphy (elution with 1:3 hexanes-ether) to afford 38 (37 mg, 86%) as
a 6.5:1 mixture of diastereomers, mp 154-157 °C: IR (CHCl3, cm-1
)
(2aR,4aS,6aR,8R,10aR,10bR)-4a-(Benzyloxy)-8-(tert-butyldimeth-
ylsiloxy)-2,2a,3,4,4a,6,6a,7,8,9,10a,10b-dodecahydro-7,7,10-trimethyl-
3-methylenecyclopenta[5,6]cycloocta[1,2,3-cd]pentalen-5(1H)-one (35)
and (2aR,4aS,6aR,8R,10aR,10bR)-8-(tert-Butyldimethylsiloxy)-2,2a,
4a,6,6a,7,8,9,10a,10b-decahydro-4a-(benzyloxy)-3,7,7,10-tetra-
methylcyclopenta[5,6]cycloocta[1,2,3-cd]pentalen-5(1H)-one (36). A
solution of either 31 or 30 (372 mg, 0.71 mmol) and pyridine (2 drops)
in dry THF (10 mL) and dry CH2Cl2 (10 mL) was prepared under N2.
The mixture was cooled to -40 °C and 0.4 M Tebbe reagent (2.7 mL,
1.5 equiv) in toluene was added dropwise. The solution was warmed
to room temperature over 0.5 h and stirred at the same temperature for
1 h. At this time, the reaction mixture was cooled to -60 °C and
quenched with 10% KOH solution (2 mL). A 5% triethylamine solution
in ether was added, and the mixture was filtered through a pad of basic
alumina (activity I). Concentration to dryness left a residue which was
dissolved in dry p-cymene (8 mL) and heated to 130 °C for 90 min.
Purification by silica gel chromatography (elution with 8:1 hexanes-
ether) afforded 35 or 36 (315 mg, 85%), respectively.
3690-3100, 3030, 2950, 2860, 1700, 1655, 1425, 1370, 1260, 1100;
1H NMR (300 MHz, C6D6) δ 7.35-7.18 (m, 2H), 7.17-7.05 (m, 3H),
4.77 (d, J ) 10.9 Hz, 1H), 3.88 (d, J ) 10.9 Hz, 1H), 3.58 (m, 1H),
3.05 (m, 1H), 2.85 (d, J ) 15.7 Hz, 1H), 2.79 (m, 1H), 2.75 (dd, J )
13.9, 4.1 Hz, 1H), 2.43-2.30 (m, 4H), 2.11 (t, J ) 14 Hz, 1H), 1.74-
1.26 (m, 6H), 1.20 (s, 3H), 1.06 (s, 3H), 1.03 (m, 1H), 0.98 (m, 1H),
0.74 (s, 3H); 13C NMR (75 MHz, C6D6) ppm 210.9, 128.3, 127.7, 127.6,
127.5, 126.7, 93.7, 76.1, 72.6, 67.1, 66.0, 61.6, 53.3, 49.0, 48.7, 46.8,
45.6, 45.1, 41.6, 40.5, 33.6, 31.3, 29.0, 21.9, 21.7; HRMS m/z [M+]
calcd for C27H34O5 438.2406, obsd 438.2402.
For 35 (9.5:1 mixture of diastereomers): IR (neat, cm-1) 2950, 2930,
1
2850, 1700, 1460, 1350, 1240, 1100; H NMR (300 MHz, C6D6) δ
7.39-7.21 (m, 2H), 7.19-7.08 (m, 3H), 5.49 (br s, 1H), 4.43 (d, J )
11.3 Hz, 1H), 4.21 (d, J ) 11.3 Hz, 1H), 3.96 (br d, J ) 12.4 Hz, 1H),
3.76 (t, J ) 8.5 Hz, 1H), 3.09-3.01 (m, 2H), 2.96 (dd, J ) 12.9, 3.3
Hz, 1H), 2.62 (dd, J ) 16.6, 8 Hz, 1H), 2.26-2.12 (m, 3H), 1.91 (m,
1H), 1.56 (br s, 3H), 1.49 (m, 1H), 1.44 (br s, 3H), 1.31-1.08 (m,
2H), 1.05 (s, 3H), 0.95 (s, 9H), 0.87 (s, 3H), -0.07 (s, 6H); 13C NMR
(75 MHz, C6D6) ppm 211, 152.3, 139.5, 134.1, 129.9, 128.5, 127.7,
127.4, 122.5, 96.0, 76.8, 66.6, 57.1, 53.6, 47.9, 45.5, 44.7, 44.1, 40.1,
35.5, 26.0, 25.7, 22.5, 22.4, 21.4, 18.2, 14.5, -4.3, -4.9; HRMS m/z
[M+] calcd for C33H48O3Si 520.3373, obsd 520.3377. Anal. Calcd
for C33H48O3Si: C, 76.10; H, 9.29. Found: C, 76.20; H, 9.55.
For 36: IR (neat, cm-1) 2950, 2930, 2850, 1705, 1460, 1360, 1240,
1
1150; H NMR (300 MHz, C6D6) δ 7.27-7.24 (m, 2H), 7.18-7.09
(m, 3H), 4.92 (d, J ) 1 Hz, 1H), 4.87 (d, J ) 1 Hz, 1H), 4.45 (d, J )
11.7 Hz, 1H), 4.00 (d, J ) 11.7 Hz, 1H), 3.87 (m, 1H), 3.72 (t, J )
8.5 Hz, 1H), 3.41 (m, 1H), 3.74-3.63 (m, 2H), 2.79 (dd, J ) 13.2, 4.1
Hz, 1H), 2.59-2.54 (m, 2H), 2.25-1.79 (series of m, 5H), 1.42 (br s,
3H), 1.17-0.98 (m, 2H), 0.95 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), -0.32
(s, 6H); 13C NMR (75 MHz, C6D6) ppm 210.6, 154.4, 138.7, 133.5,
130.4, 128.5, 128.3, 127.2, 106.9, 94.0, 76.5, 67.3, 57.7, 49.6, 48.8,
45.6, 44.7, 44.3, 40.2, 35.4, 35.2, 32.0, 26.0, 22.3, 22.2, 21.4, -4.3,
-4.9; HRMS m/z [M+] calcd for C33H48O3Si 520.3373, obsd 520.3377;
(2aR,3R,4aS,6aR,10R,10aR,10bS)-4a-(Benzyloxy)-2a,4,4a,6a,7,
10,10a,10b-octacahydro-7,7,10-trimethyl-10-hydroxyspiro[cyclopenta-
[5,6]cycloocta[1,2,3-cd]pentalene-3(1H),2′-oxirane]-5,8(2H,6H)-di-
one (39). A mixture of 38 (60 mg, 0.137 mmol), 97% N-meth-
ylmorpholine N-oxide (25 mg, 1.5 equiv), powdered 4 Å molecular
sieves (50 mg), and a catalytic amount of N-methylmorpholine was
stirred in dry CH2Cl2 (5 mL) for 15 min before the addition of
tetrapropylammonium perruthenate (1.5 mg, 3% mol). The reaction
mixture was stirred at room temperature for 30 min and triethylamine
[R]20 +72.5 (c 1.06, CH2Cl2).
D
(2aR,4aS,6aR,8R,10aR,10bR)-4a-(Benzyloxy)-8-hydroxy-
2,2a,3,4,4a,6,6a,7,8,9,10a,10b-dodecahydro-7,7,10-trimethyl-3-
methylenecyclopenta[5,6]cycloocta[1,2,3-cd]pentalen-5(1H)-one (37).
A solution of 35 (50 mg, 0.096 mmol) in THF (5 mL) was treated
with a 1 M TBAF solution in THF (0.15 mL, 1.5 equiv). The reaction
mixture was stirred overnight and concentrated. The residue was

Synthesis of the Cardiotoxic Agent Kalmanol
J. Am. Chem. Soc., Vol. 118, No. 4, 1996 739
(0.2 mL, 10 equiv) was added. After 1 h of stirring, the solvent was
removed, and the residue was taken up in ether and filtered through a
small plug of Celite. Purification by silica gel chromatography (elution
with 1:6 hexanes-ether) afforded 39 (50 mg, 84%) as a colorless solid,
mp 189-191 °C: IR (CHCl3, cm-1) 3690-3100, 3030, 2950, 2860,
1
1700, 1655, 1425, 1370, 1260, 1100; H NMR (300 MHz, C6D6) δ
7.39 (br d, J ) 7.2 Hz, 1H), 7.18-7.05 (m, 3H), 5.70 (s, 1H), 4.64 (d,
J ) 10.7 Hz, 1H), 3.85 (d, J ) 10.7 Hz, 1H), 3.68 (dd, J ) 14.3, 6.6
Hz, 1H), 3.27 (br t, J ) 9.9 Hz, 1H), 3.06 (m, 1H), 2.60 (q, J ) 9.5
Hz, 1H), 2.48-2.38 (m, 4H), 2.12 (dd, J ) 14.3, 3.6 Hz, 1H), 1.73 (br
d, J ) 15.6 Hz, 1H), 1.43-0.81 (series of m, 5H), 1.29 (s, 3H), 1.02
(s, 3H), 0.95 (s, 3H); 13C NMR (75 MHz, C6D6) ppm 211.0, 209.5,
183.7, 138.4, 128.7, 128.6, 128.4, 128.2, 127.9, 127.7, 93.5, 72.4, 67.6,
66.6, 54.2, 52.6, 50.3, 49.4, 48.5, 46.2, 37.5, 32.6, 30.8, 29.7, 29.5,
28.6, 20.2; HRMS m/z [M+] calcd for C27H32O5 436.2249, obsd
436.2243; [R]20 -23.5 (c 0.71, CH2Cl2).
D
(2aR,3R,4aS,6aR,8S,9aR,10S,10aR,10bS)-4a-(Benzyloxy)-2a,4,
4a,6a,7,10,10a,10b-octahydro-7,7,10-trimethyl-10-hydroxyspiro-
[cyclopenta[5,6]cycloocta[1,2,3-cd]pentalene-3(1H),2′-oxirane]-5,8-
(2H,6H)-dione (40). A solution of 39 (10 mg, 0.023 mmol) and 10%
Pd/C (1 mg, 2.5% mol) in dry ethyl acetate (3 mL) was blanketed with
H2 and stirred under 1 atm of H2 for 15 min. Removal of the catalyst
by filtration through a small plug of Celite (elution with ether) followed
by concentration to dryness afforded 40 (9.2 mg, 92%) as a colorless
solid, mp 74-76 °C: IR (CHCl3, cm-1) 3700-3100, 2960, 2885, 1735,
1
1470, 1380, 1255, 1095, 1005, 830, 785; H NMR (300 MHz, C6D6)
δ 7.31 (br d, J ) 7.2 Hz, 1H), 7.11-7.02 (m, 3 H), 4.78 (d, J ) 10.9
Hz, 1 H), 3.84 (d, J ) 10.9 Hz, 1 H), 3.46 (t, J ) 8.2 Hz, 1 H), 3.15
(m, 1 H), 3.04 (d, J ) 15.5 Hz, 1H), 2.81 (dd, J ) 12.6, 3.3 Hz, 1 H),
2.51 (dd, J ) 14.4, 2.7 Hz, 1 H), 2.48 (br s, 1 H), 2.45 (m, 1 H), 2.38
(dd, J ) 10.5, 9.6 Hz, 1 H), 2.06 (t, J ) 12.8 Hz, 1 H), 1.72 (br d, J
) 15.5 Hz, 1 H), 1.66-1.42 (m, 5 H), 1.27 (m, 1 H), 1.04 (s, 3 H),
0.92 (m, 1 H), 0.74 (s, 3 H), 0.72 (s, 3 H); 13C NMR (75 MHz, C6D6)
ppm 219.2, 213.2, 138.3, 128.4, 128.3, 128.2, 128.1, 127.8, 95.1, 72.2,
68.0, 65.6, 54.6, 51.7, 51.5, 49.1, 47.9, 45.8, 45.3, 40.7, 38.4, 33.4,
31.4, 29.4, 28.3, 25.1, 20.0; HRMS m/z [M+] calcd for C27H34O5
For 42: oil; IR (neat, cm-1) 3700-3100, 2960, 2930, 2890, 1700,
1
1615, 1450, 1270, 1170; H NMR (300 MHz, CDCl3) δ 7.41 (br d, J
438.2406, obsd 438.2391; [R]20 +69.1 (c 0.16, CH2Cl2).
D
) 6.7 Hz, 1H), 7.33-7.24 (m, 3H), 4.78 (d, J ) 9.1 Hz, 1H), 4.05 (d,
J ) 9.1 Hz, 1H), 3.57 (m, 1H), 3.31 (m, 2H), 2.95 (d, J ) 15.6 Hz,
1H), 2.78 (m, 3H), 2.44 (q, J ) 9.6 Hz, 1H), 2.12 (m, 1H), 1.97 (m,
1H), 1.86-1.74 (series of m, 4H), 1.56-1.51 (m, 2H), 1.20 (m, 1H),
1.10 (s, 3H), 0.92 (s, 9H), 0.85 (m, 1H), 0.74 (s, 3H), 0.74 (s, 3H),
0.068 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) ppm 215.4,
138.0, 128.1, 127.3, 94.9, 80.9, 71.9, 67.6, 66.0, 54.3, 52.6, 51.9, 51.5,
47.3, 46.4, 43.4, 40.6, 36.0, 33.3, 31.5, 29.6, 29.1, 26.1, 22.4, 22.0,
18.3, -4.6, -4.8; HRMS m/z [M+] calcd for C33H50O5Si 554.3427,
(2aR,3R,4aS,6aR,8S,9aR,10S,10aR,10bS)-4a-(Benzyloxy)-2a,4,
4a,6a,7,10,10a,10b-octahydro-7,7,10-trimethyl-10-hydroxyspiro-
[cyclopenta[5,6]cycloocta[1,2,3-cd]pentalene-3(1H),2′-oxirane]-5-
(2H,6H)-one (41). To a cold (-78 °C), magnetically stirred solution
of 40 (10 mg, 0.023 mmol) in dry CH2Cl2 (2 mL) was added 1 M
Superhydride in THF (25 µL, 1 equiv). After 10 min, the reaction
mixture was quenched with Rochelle’s salt solution (0.5 mL) and
allowed to warm to room temperature. The separated organic layer
was dried, and the residue obtained after concentration was purified
by silica gel chromatography (elution with 1.5:1 ethyl acetate-hexanes)
to afford 41 (9 mg, 90%) as a colorless solid, mp 80-81 °C: IR (KBr,
cm-1) 3700-3100, 2910, 2880, 1695, 1440, 1410, 1100; 1H NMR (300
MHz, CDCl3) δ 7.41 (br d, J ) 6.8 Hz, 1H), 7.35-7.25 (m, 3H), 4.77
(d, J ) 10.9 Hz, 1H), 4.02 (d, J ) 10.9 Hz, 1H), 3.53 (d, J ) 3.6 Hz,
1H), 3.31 (t, J ) 8.5 Hz, 1H), 2.91 (d, J ) 15.6 Hz, 1H), 2.86-2.76
(m, 4H), 2.42 (q, J ) 9.6 Hz, 1H), 2.19 (m, 1H), 2.04 (m, 1H), 1.98-
1.79 (series of m, 5H), 1.77-1.50 (m, 3H), 1.28-1.21 (m, 2H), 1.16
(s, 3H), 0.86 (m, 1H), 0.82 (s, 3H), 0.67 (s, 3H); 13C NMR (75 MHz,
C6D6) ppm 215.4, 137.8, 128.2, 127.5, 127.4, 94.8, 80.3, 72.9, 67.8,
65.9, 54.3, 52.5, 51.7, 51.4, 47.5, 46.2, 43.1, 40.8, 35.4, 33.0, 31.7,
29.5, 29.4, 22.4, 21.2; HRMS m/z [M+] calcd for C27H36O5 440.2563,
obsd 554.3427; [R]20 +30.3 (c 0.52, CH2Cl2).
D
For 43: mp 154 °C; IR (neat, cm-1) 3100-3000, 2980, 2950, 2860,
1
1700, 1460, 1375, 1250, 1120, 1060, 1000, 840, 770; H NMR (300
MHz, CDCl3) δ 7.32-7.27 (m, 5H), 4.87 (d, J ) 11.4 Hz, 1H), 4.03
(d, J ) 11.4 Hz, 1H), 3.67 (m, 2H), 3.54 (d, J ) 3.2 Hz, 1H), 3.37 (s,
1H), 3.31 (t, J ) 8.4 Hz, 1H), 2.74 (m, 2H), 2.54 (dd, J ) 2.5, 14 Hz,
1H), 2.37 (d, J ) 13.9 Hz, 1H), 2.25 (m, 1H), 2.20-2.06 (m, 2H),
1.96-1.68 (m, 3H), 1.61-1.35 (m, 2H), 1.08 (s, 3H), 0.92 (s, 9H),
0.911 (s, 9H), 0.87 (m, 1H), 0.59 (s, 3H), 0.56 (s, 3H), 0.94-0.63 (3
s, 12 H); 13C NMR (75 MHz, CDCl3) ppm 213.8, 136.6, 128.4, 127.8,
127.0, 96.2, 81.3, 80.8, 71.7, 68.1, 57.0, 54.1, 53.5, 52.0, 49.5, 47.6,
43.9, 40.3, 35.7, 35.2, 31.5, 29.0, 28.6, 26.0, 25.6, 21.9, 21.6, 18.3,
-3.6, -4.6, -4.8; HRMS m/z [M+ - Bn] calcd for C32H57O5Si2
obsd 440.2565; [R]20 +42.3 (c 0.4, CH2Cl2).
577.3745, obsd 577.3748; [R]20 +29.5 (c 0.88, CH2Cl2).
D
D
(2aR,3R,4aS,6aR,8S,9aR,10S,10aR,10bS)-4a-(Benzyloxy)-8-(tert-
butyldimethylsiloxy)tetradecahydro-10-(tert-butyldimethylsiloxy)-
7,7-hydroxytrimethylspiro[cyclopenta[5,6]cycloocta[1,2,3-cd]pentalene-
3(5H),2′-oxiran]-5-one (42) and (2aR,3R,4aS,6aR,8S,9aR,10S,10aR,
10bS)-4a-(Benzyloxy)-8-(tert-butyldimethylsiloxy)tetradecahydro-
3,10-(tert-butyldimethylsiloxy)-7,10-trimethylspiro[cyclopenta[5,6]-
cycloocta[1,2,3-cd]pentalene-3(5H),2′-oxiran]-5-one (43). Diol 41 (55
mg, 0,125 mmol) in dry DMF (5 mL) was treated with imidazole (42.5
mg, 5 equiv) and TBSOTf (375 µL, 5 equiv) in the presence of a
catalytic amount of DMAP. The reaction mixture was stirred for 0.5
h before dropwise addition of saturated NH4Cl solution (3 mL). The
organic phase was extracted with ether, dried, and concentrated.
Purification of the residue by silica gel chromatography (elution with
1.5:1 hexanes-ether) afforded 42 (55 mg, 93%) and 43 (3 mg, 4%).
(2aR,3R,4aS,6aR,8S,9aR,10S,10aR,10bS)-4a-(Benzyloxy)-8-(tri-
methylsiloxy)-10-(tert-butyldimethylsiloxy)-7,10-trimethylspiro-
[cyclopenta[5,6]cycloocta[1,2,3-cd]pentalene-3(5H),2′-oxiran]-5-
one (44). A cold (-78 °C), magnetically stirred, N2-blanketed solution
of 42 (8 mg, 0.0145 mmol) in dry THF (5 mL) was successively treated
with 0.5 M potassium hexamethyldisilazide (0.6 mL, 20 equiv) in
toluene followed by trimethylsilyl triflate (30 µL, 10 equiv). The
resulting reaction mixture was gradually warmed to room temperature
over 1 h, at which time it was treated with 10% Et3N in ether (10 mL)
and quenched with saturated NaHCO3 solution (5 mL). The separated
organic layer was dried and concentrated, and the residue was purified
by silica gel chromatography (elution with 1.5:1 hexanes-ether) to
afford 44 (7.6 mg, 83%) as a colorless oil: IR (CHCl3, cm-1) 3100-
3000, 2980, 2880, 1700, 1455, 1375, 1255, 1115, 1065, 1000, 840,

740 J. Am. Chem. Soc., Vol. 118, No. 4, 1996
Borrelly and Paquette
1
775; H NMR (300 MHz, C6D6) δ 7.39 (d, J ) 7.3 Hz, 2H), 7.17-
added, and the resulting solution was quenched by the addition of
saturated NH4Cl solution (2 mL). The separated organic layer was
dried and concentrated, and the residue was purified by silica gel
chromatography (elution with 1:1.75 hexanes-ethyl acetate) to afford
7.02 (m, 3H), 4.89 (d, J ) 9.4 Hz, 1H), 3.97 (d, J ) 9.4 Hz, 1H), 3.56
(dd, J ) 7.1, 10.3 Hz, 1H), 3.47 (t, J ) 8.5 Hz, 1H), 3.05 (d, J ) 15.6
Hz, 1H), 3.01-2.93 (m, 2H), 2.45 (s, 2H), 2.35 (q, J ) 9.4 Hz, 1H),
1.78 (dd, J ) 6.7, 7.6 Hz, 1H), 1.87-1.67 (m, 3H), 1.55-1.44 (m,
4H), 1.41-1.22 (m, 3H), 1.16 (s, 3H), 0.99 (s, 9H), 0.95 (s, 3H), 0.93
(m, 2H), 0.78 (s, 3H), 0.11 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H); 13C
NMR (75 MHz, C6D6) ppm 214.5, 138.7, 128.4, 128.2, 127.9, 127.5,
127.4, 95.2, 78.2, 77.2, 68.1, 65.5, 55.3, 53.2, 52.0, 51.7, 47.2, 45.7,
43.8, 40.4, 35.8, 33.9, 31.3, 29.6, 27.1, 26.2, 23.5, 23.3, 18.3, 3.4, -4.1,
-4.8; HRMS m/z [M+] calcd for C36H60O5Si2 628.3979, obsd 628.3947;
46 (8.5 mg, 35%) as a colorless solid, mp 212 °C: IR (CHCl3, cm-1
)
3720-3100, 2960, 2860, 1465, 1380, 1265, 1115, 1055; 1H NMR (300
MHz, CDCl3) δ 4.19 (d, J ) 5.9 Hz, 1H), 3.60 (m, 1H), 3.06-3.01
(m, 2H), 2.56 (br q, J ) 7.6 Hz, 1H), 2.52-2.32 (m, 2H), 2.26-2.14
(m, 3H), 2.12-1.51 (series of m, 7H), 1.54-1.38 (m, 2H), 1.29 (s,
3H), 1.28 (m, 1H), 1.14 (s, 3H), 0.95 (s, 3H), 0.93 (s, 9H), 0.92 (m,
1H), 0.75 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3)
ppm 83.8, 81.4, 80.5, 74.8, 72.6, 60.1, 53.2, 52.6, 48.8, 48.3, 47.9,
40.4, 36.4, 35.0, 31.1,29.4, 26.1, 25.6, 24.1, 22.8, 22.5, 18.5, -4.6,
-4.65; HRMS m/z [M+ - H2O] calcd for C26H46O4Si 450.3165,
[R]20 +34.1 (c 0.24, CH2Cl2).
D
(2aR,3R,4aS,5S,6aR,8S,9aR,10S,10aR,10bS)-4a-(Benzyloxy)-8-
(tert-butyldimethylsiloxy)tetradecahydro-3,10-(tert-butyldimethyl-
siloxy)-5-hydroxy-7,10-trimethylspiro[cyclopenta[5,6]cycloocta[1,2,3-
cd]pentalene-3(5H),2′-oxirane] (45). To a cold (-78 °C) solution of
42 (9 mg, 0.016 mmol) in dry CH2Cl2 (2 mL) was added 1 M
Superhydride solution in THF (80 µL, 5 equiv). The reaction mixture
was allowed to warm to room temperature and quenched by addition
of saturated Rochelle’s salt solution (0.5 mL). The separated organic
layer was dried and concentrated to afford a residue which was purified
by silica gel chromatography (elution with 1:1 hexanes-ether). There
was obtained 7.6 mg (85%) of 45 as a colorless solid, mp 153 °C: IR
(KBr, cm-1) 3700-3060, 2960, 2860, 1455, 1410, 1375, 1250, 1115,
1040; 1H NMR (300 MHz, CDCl3) δ 7.38 (br d, J ) 7 Hz, 1H), 7.31-
7.20 (m, 3H), 4.67 (d, J ) 10.8 Hz, 1H), 4.48 (m, 1H), 4.34 (d, J )
9.1 Hz, 1H), 3.59 (m, 1H), 3.42 (s, 1H), 3.18 (t, J ) 8.8 Hz, 1H), 3.01
(m, 1H), 2.88 (d, J ) 14.9 Hz, 1H), 2.76 (s, 2H), 2.50 (m, 1H), 2.36
(m, 1H), 2.13-2.08 (m, 2H), 1.89-1.43 (series of m, 6H), 1.27 (m,
2H), 1.17 (s, 3H), 0.92 (s, 9H), 0.86 (s, 3H), 0.73 (s, 3H), 0.1 (s, 3H),
0.09 (s, 3H); 13C NMR (75 MHz, CDCl3) ppm 139.4, 128.0, 127.5,
127.0, 87.9, 81.1, 72.8, 71.2, 66.2, 64.5, 52.3, 51.8, 49.3, 47.7, 46.9,
40.1, 36.7, 36.5, 35.0, 31.3, 29.9, 29.7, 26.1, 23.0, 22.6, 18.4, -4.6,
-4.7; HRMS m/z [M+] calcd for C33H52O5Si 556.3584, obsd.556.3594;
obsd.450.3156 [R]20 -21 (c 0.2, CH2Cl2).
D
(2aR,3R,4aS,6aR,8S,9aR,10S,10aR,10bR)-8-(tert-Butyldimethyl-
siloxy)tetradecahydro-3,4a,10-trihydroxy-3,7,7,10-tetramethylspiro-
[cyclopenta[5,6]cycloocta[1,2,3-cd]pentalen-5(1H)-one (3). A solu-
tion of 46 (2.8 mg, 6 × 10-3 mmol) and pyridine (1 drop) in dry CH2-
Cl2 (2 mL) was treated with the Dess-Martin periodinane reagent (3.4
mg, 1.3 equiv). After 10 min of stirring, the reaction mixture was
quenched by addition of saturated NaHCO3 solution (0.5 mL). The
organic layer was dried, and the residue obtained after concentration
to dryness was purified by silica gel chromatography (elution with 1:2
hexanes-ether) to give 3 (2.6 mg, 93%) as a highly crystalline solid,
mp 156 °C: IR (CHCl3, cm-1) 3720-3100, 2960, 2860, 1465, 1380,
1
1265, 1115, 1055; H NMR (300 MHz, CDCl3) δ 3.64 (dd, J ) 0.7,
3.9 Hz, 1H), 3.44 (br s, 1H), 3.03 (t, J ) 2.8 Hz, 1H), 2.9 (dd, J ) 2.8,
12.8 Hz, 1H), 2.79 (m, 1H), 2.49 (d, J ) 14.4 Hz, 1H), 2.40 (m, 1H),
2.16 (dt, J ) 0.7, 2.4 Hz, 1H), 1.91 (t, J ) 12.5 Hz, 1.86-1.37 (series
of m, 6H), 1.31 (s, 3H), 1.26 (br s, 2H), 1.07 (s, 3H), 1.02 (s, 3H),
0.93 (s, 9H), 0.89-0.74 (m, 2H), 0.72 (s, 3H), 0.11 (s, 6H); 13C NMR
(75 MHz, CDCl3) ppm 213.8, 89.5, 81.8, 81.3, 71.8, 59.4, 56.6, 53.2,
52.4, 47.6, 44.9, 42.4, 40.8, 35.9, 31.4, 29.1, 28.9, 26.1, 23.9, 22.4,
22.0, 18.4, -4.6, -4.7; HRMS m/z [M+] calcd for C26H48O5Si
[R]20 -27.2 (c 0.18, CH2Cl2).
D
(2aR,3R,4aS,5S,6aR,8S,9aR,10S,10aR,10bR)-8-(tert-Butyldimeth-
ylsiloxy)tetradecahydro-3,4a,10-trihydroxy-3,7,7,10-tetramethyl-
[cyclopenta[5,6]cycloocta[1,2,3-cd]pentalene-3,4a,5,10(1H)-tetrol (46).
Dry NH3 (20 mL) was condensed in a 50 mL two-necked round-
bottomed flask at -78 °C. Lithium pieces (3 mg, 8 equiv) were added
portionwise over 10 min during which time the solution turned deep
blue. The solution was stirred for an additional 20 min and 45 (30
mg, 0.054 mmol) dissolved in ether (5 mL) was rapidly introduced Via
cannula. The reaction mixture was gradually warmed to -33 °C and
kept at that temperature for 0.5 h. At this time, ether (10 mL) was
466.3114, obsd 466.3110 [R]20 +30.9 (c 0.39, CH2Cl2).
D
Acknowledgment. S.B. served as a Presidential Fellow
during 1994-1995. This work was financially supported by
the National Institutes of Health (Grant GM-30827) and the Eli
Lilly Company. We thank Dr. Kurt Loening for his assistance
with nomenclature.
JA9533454