Asymmetric synthesis of the diterpenoid marine toxin (+)-acetoxycrenulide

Article abstract of DOI:10.1021/ja9533609

An enantioselective route to the marine toxin (+)-acetoxycrenulide is described. The early stages of the synthesis feature the conversion of (R)-citronellol into a butenolide whose sole stereogenic center is provided by the terpenic alcohol. Three contiguous chiral carbon atoms are subsequently set in the requisite absolute configuration by conjugate addition of an enantiopure allylphosphonamide reagent. The resulting product is transformed during several steps into a primary selenoxide whose thermal activation in dimethylacetamide at 220°C promotes sequential 1,2-elimination and Claisen rearrangement. The cyclooctenone core of the target is formed in this step. The final stages of the synthesis involve a series of fully stereoselective reactions including Simmons-Smith cyclopropanation and controlled Dibal-H reduction. The naturally occurring dextrorotatory enantiomer of acetoxycrenulide was ultimately acquired.

Full text of DOI:10.1021/ja9533609

J. Am. Chem. Soc. 1996, 118, 1309-1318
1309
Asymmetric Synthesis of the Diterpenoid Marine Toxin
(+)-Acetoxycrenulide
Ting-Zhong Wang, Emmanuel Pinard, and Leo A. Paquette*
Contribution from EVans Chemical Laboratories, The Ohio State UniVersity,
Columbus, Ohio 43210
ReceiVed October 2, 1995X
Abstract: An enantioselective route to the marine toxin (+)-acetoxycrenulide is described. The early stages of the
synthesis feature the conversion of (R)-citronellol into a butenolide whose sole stereogenic center is provided by the
terpenic alcohol. Three contiguous chiral carbon atoms are subsequently set in the requisite absolute configuration
by conjugate addition of an enantiopure allylphosphonamide reagent. The resulting product is transformed during
several steps into a primary selenoxide whose thermal activation in dimethylacetamide at 220 °C promotes sequential
1,2-elimination and Claisen rearrangement. The cyclooctenone core of the target is formed in this step. The final
stages of the synthesis involve a series of fully stereoselective reactions including Simmons-Smith cyclopropanation
and controlled Dibal-H reduction. The naturally occurring dextrorotatory enantiomer of acetoxycrenulide was
ultimately acquired.
Acetoxycrenulide (1a),1 the most prominent member of a
limited group of structurally unusual diterpenes that includes
pachylactone,2 several crenuacetals,3 crenuladial,4 and a 17-
acetoxy derivative,5 was first isolated independently by Fenical6
and Sims7 in 1983 from small brown seaweeds of the family
Dictyotaceae and from the sea hare Aplysia Vaccaria known to
feed on this algae. Acetoxycrenulide is recognized to be highly
toxic to herbivorous reef-dwelling fish at very low concentra-
tions (10 µg/mL). A. Vaccaria presumably concentrates 1a as
a chemical defense mechanism to ward off potential predation
in its natural habitat.6,7 The structure of 1a was originally
assigned on the basis of detailed spectroscopic analysis and
ultimately confirmed by X-ray crystallographic analysis of a
closely related derivative. The substance is a regular diterpenoid
possessing an unprecedented bicyclo[6.1.0]nonane framework
to which is appended R,â-unsaturated γ-lactone and acetoxyl
functionalities. The stereogenic center in the alkenyl side chain
is of the R configuration.
Evidence has recently been provided by Guella and Pietra
that the crenulatan skeleton present in 1a may originate from
the photoisomerization of xenicane diterpenes by the sun at low
tide.8 These workers showed that irradiation of 2 in either
CHCl3 or CH3OH results in conversion to 1b. Although the
mechanistic details of this interesting intramolecular rearrange-
ment are lacking, the possibility has been established that the
final step in crenulide biosynthesis may not be enzymatic but
solar-induced.
Synthetic Plan
As a consequence of the unusual structural features and
biological properties of 1a, its enantioselective total synthesis
was undertaken. The end game was designed to showcase the
capacity of the Claisen rearrangement for direct elaboration of
the cyclooctanoid core in properly stereocontrolled fashion.9
Thus, 3 was set as an advanced objective (Scheme 1). It was
anticipated that the rigidly locked, twisted tublike ground-state
conformation of 3 would constitute a reliable template for
stereocontrolled cyclopropanation from the open â-face, for 1,2-
reduction of the ketone carbonyl to set the hydroxyl cis to the
three-membered ring, and for introduction of the butenolide
double bond by organoselenium-based methodology. Our
earlier studies in this area revealed the key fact that the side
chain had to be incorporated prior to arrival at 3. Most relevant
X Abstract published in AdVance ACS Abstracts, February 1, 1996.
(1) Preliminary communication: Paquette, L. A.; Wang, T.-Z.; Pinard,
E. J. Am. Chem. Soc. 1995, 117, 1455.
(2) Ishitsuka, M.; Kusumi, T.; Kakisawa, H.; Kawakami, Y.; Nagai, Y.;
Sato, T. Tetrahedron Lett. 1983, 24, 5117.
(3) Kusumi, T.; Muanza-Nkongolo, D.; Goya, M.; Ishitsuka, M.; Iwashita,
T.; Kakisawa, H. J. Org. Chem. 1986, 51, 384.
(4) Tringali, C.; Oriente, G.; Piattelli, M.; Geraci, C.; Nicolosi, G.;
Breitmaier, E. Can. J. Chem. 1988, 66, 2799.
(5) Ko¨nig, G. M.; Wright, A. D.; Sticker, O. Tetrahedron 1991, 47, 1399.
(6) Sun, H. H.; McEnroe, F. J.; Fenical, W. J. Org. Chem. 1983, 48,
1903.
(7) Midland, S. L.; Wing, R. M.; Sims, J. J. J. Org. Chem. 1983, 48,
1906.
(8) Guella, G.; Pietra, F. J. Chem. Soc., Chem. Commun. 1993, 1539.
(9) Paquette, L. A. In Stereocontrolled Organic Synthesis; Trost, B. M.,
Ed.; Blackwell Scientific Publications: Oxford, England, 1994; pp 313-
336.
0002-7863/96/1518-1309$12.00/0 © 1996 American Chemical Society

1310 J. Am. Chem. Soc., Vol. 118, No. 6, 1996
Wang et al.
Scheme 1
absolute configurations at sites a and b very reliably and without
concern for the configurational characteristics at position c. The
present paper details the successful realization of this plan and
presents additional peripheral observations recorded along the
way.1
Results and Discussion
Setting the Contiguous Stereocenters in a Lactone of Type
7. From the outset, (R)-citronellol (10a) was regarded to be
the appropriate natural source of the alkenyl side chain in 1a.
Material of 96.3% ee13 was sequentially acetylated, ozonolyzed,
and subjected to reduction with the borane-dimethyl sulfide
complex to afford the monoesterified diol 11a in quantitative
yield (Scheme 2). Equally efficient was the silylation of 11a
with tert-butyldiphenylsilyl chloride and ensuing hydrolytic
removal of the acetate functionality. Oxidation of the primary
hydroxyl site in 11c followed by esterification with diazo-
methane furnished 12b.
From the retrosynthetic perspective, 12b was considered to
be an ideal intermediate for the elaboration of 15. Two routes
to this butenolide were evaluated. In the first, 12b was
C-allylated, and 13 so formed was ozonolyzed and directly
reduced with sodium borohydride. Spontaneous cyclization
occurred to deliver the γ-lactone 14, which in turn was trans-
formed into 15 by means of R-selenenylation and oxidation.
We came to favor this route in view of its efficiency (80% for
12b f 14, 87% for 14 f 15) and the ease with which it could
be scaled up. These features were not found in the second
approach, which was modeled on an earlier report by Yao and
Wu.14 The aldol condensation leading to 16a could not be
accomplished with >62% efficiency. A similar complication
surfaced in the acid-catalyzed cyclization of 16b to 17. After
rather tedious chromatographic purification, this lactone could
be secured in only 60% yield. Most unsatisfactory of all was
â-elimination of the protected hydroxyl group in 17 to give 15
(44%). While this alternative was certainly interesting and
served to deliver an end product identical in all respects with
that produced earlier, it was not as practical and was abandoned.
Attention was now directed to the homologation of 15 with
total absolute control over the two new stereogenic centers being
in this connection were the observations that 8 could not be
made to enter into alkylation chemistry10 and that 9 was not
amenable to epimerization R to the ketone carbonyl (the side
chain in 9 is projected axially).11 Models suggest that the
requisite enolization is not facile because an R-proton is not
properly stereoaligned with either flanking π-system. The
carbocyclic framework in both examples is evidently quite rigid.
Since a cyclopropanation step constitutes an integral part of
the synthetic plan, it is not realistic to expect the 6-methyl-5-
hepten-2-yl side chain to survive intact because of the inherently
greater reactivity of its double bond.12 Consequently, a â-tert-
butyldiphenylsiloxy group at R has been utilized as a satisfactory
surrogate.
The cyclooctenone ring in 3 was expected to be made
available by thermal activation of 4. Should a chairlike [3.3]
sigmatropic transition state be adopted as expected, it is required
that the propenyl substituent possess an E configuration in order
to properly set the configuration of the secondary methyl group
in 3. Arrival at 4 was anticipated by an aldol reaction with
crotonaldehyde followed by acid-catalyzed cyclization and
selenoxide elimination.
(12) This conclusion is supported by trial experiments performed on 9
(Pinard, E., 1993). Thus, Simmons-Smith cyclopropanation of 9 with
diethylzinc (1.2 equiv) and diiodomethane (8 equiv) in benzene at 20 °C
gave mixtures of 9, a, b, and c. The product distribution was dependent,
of course, on the timing of the quench but most often approximated 15:
15:35:35. Treatment of 9 with 2 equiv of diethylzinc provided c as the
only detectable product (70% isolated). No cyclopropanation was observed
with CH2N2/Pd(OAc)2 or Me3Al/CH2I2. Although 9 could be regioselec-
tively transformed into epoxide d and diol e (as 1:1 diastereomeric mixtures)
with controlled amounts of MCPBA and OsO4/pyridine, and these
intermediates could be stereoselectively cyclopropanated as in f, no means
was found for ultimate removal of the oxygen atoms from the side chain.
The three contiguous stereogenic centers in hydroxy acetal
6 were to be set in its cyclic precursor 7. In an earlier phase of
this investigation, the stereogenicity present at position c in the
side chain was used as the point of reference for correlating
the absolute stereochemistry of the other chiral centers. How-
ever, this protocol ultimately would lead to a diastereomer of
1a.11 Consequently, a different stratagem is required to set the
(10) (a) Ezquerra, J.; He, W.; Paquette, L. A. Tetrahedron Lett. 1990,
31, 6979. (b) Paquette, L. A.; Ezquerra, J.; He, W. J. Org. Chem. 1995,
60, 1435.
(11) He, W.; Pinard, E.; Paquette, L. A. HelV. Chim. Acta 1995, 78,
391.
(13) (R)-Citronellol of this optical purity was generously provided to us
by Dr. Susumu Akutagawa of the Takasago Research Institute (Tokyo),
whom we thank.
(14) Yao, Z.-J.; Wu, Y.-L. Tetrahedron Lett. 1994, 35, 157.

Asymmetric Synthesis of (+)-Acetoxycrenulide
J. Am. Chem. Soc., Vol. 118, No. 6, 1996 1311
Scheme 2a
Scheme 3a
a (a) n-BuLi, THF, -78 °C, 15; (b) O3, CH2Cl2-CH3OH, -78 °C,
Me2S; (c) HC(OCH3)3, (TsOH), CH3OH; (d) (i-Bu)2AlH, CH2Cl2, -78
°C; (e) (C6H5)3PCH3+Br-, KN(SiMe3)2, THF, 0 °C f room temper-
ature.
key Claisen rearrangement, 21 was reduced to the lactol and
treated with methylenetriphenylphosphorane. As will become
apparent below, this maneuver also sets the stage for ready
elaboration of that γ-lactone unit that constitutes ring A of
acetoxycrenulide.
Implementation of the Claisen Rearrangement. Mild
acidic hydrolysis of 22 resulted in intramolecular nucleophilic
attack on the liberated aldehyde by the neighboring hydroxyl
substituent. The resultant colorless oily lactol was uneventfully
oxidized to 23. In the setting of Scheme 4, 23 is recognized to
possess an enolizable center exploitable for the introduction of
an additional carbon chain at CR complementary to that existing
at Câ. The issue of the oxidation level at Câ could not be
deferred,16 and consequently 23 was ozonolyzed to produce the
nor-aldehyde, which was condensed with (phenylseleno)-
methyllithium17 to afford 24. It was interesting to find that 24
was a single diastereomer, presumably as a consequence of
adherence by the nucleophile to a Cram-like transition-state
trajectory. This finding was more a matter of convenience than
of substance since the stereogenic carbinol center developed in
this process was soon to be eliminated.18 Due to the impending
aldol condensation, the hydroxyl group in 24 had to be
temporarily protected in a base-insensitive manner. Exposure
of this intermediate to 2-methoxypropene in the presence of
phosphorus oxychloride19 proved serviceable, giving rise to the
acetal in 96% yield. Predictably,10,11 the anion of the protected
lactone underwent condensation with (E)-crotonaldehyde pre-
dominantly from its less sterically encumbered surface. Another
potential problem, that of generating a 1:1 mixture epimeric at
the carbinol center, turned out not to pose any serious difficul-
ties, nor was the finding that some deprotection of the
a (a) Ac2O, py, CH2Cl2, 0 °C; (b) O3, CH2Cl2, -78 °C, BH3‚SMe2,
0 °C; (c) TBDPSCl, Et3N, CH2Cl2; (d) K2CO3, CH3OH; (e) PDC, 4 Å
molecular sieves, CH2Cl2; (f) NaClO2, NaH2PO4, t-BuOH, H2O; (g)
CH2N2, Et2O; (h) LDA, THF, -78 °C, CH2dCHCH2Br, THF, HMPA;
(i) O3, CH2Cl2, -78 °C, Ph3P, room temperature; (j) NaBH4, CH3OH,
H3O+; (k) KN(SiMe3)2, THF, PhSeCl, H2O2, py, CH2Cl2, 0 °C f room
temperature; (l) LDA, OHCCH2OTHP, THF, -78 °C; (m) MOMCl,
(i-Pr)2NEt, CH2Cl2, 0 °C; (n) 10% H2SO4, THF; (o) DBU, THF, C6H6,
70 °C.
introduced. It soon became clear that the reagent selected for
participation in the conjugate addition must have the intrinsic
ability to ensure a high degree of organization in the associated
transition state and thereby guarantee the stereochemical
outcome. Few reagents do this well. Among these, we came
to favor the R-allylphosphonamide 18 recently described by
Hanessian et al.15 The high-level capacity exerted by 18 on
the facial selectivity of C-allylation essentially guarantees that
the configuration at site a in 19 be R. The usual thermodynamic
advantage of positioning large vicinal groups trans to each other
on a five-membered ring serves to fix the configuration at site
b. The consequences of this asymmetric Michael addition is
that 19 is formed as the only detectable product (Scheme 3).
This important intermediate harbors stereogenic centers properly
defined for advancing to 1a.
Ozonolysis of 19 reflected removal of the chiral auxiliary
with formation of aldehyde 20. The latter was subjected to the
action of trimethyl orthoformate in the presence of a catalytic
quantity of acid, thereby delivering acetal 21 without loss of
stereochemical integrity. In preparation for deployment of the
(16) Aldol condensations of 21 with (E)-crotonaldehyde gave a mixture
of two epimeric alcohols, neither of which could be induced to undergo
cyclization during attempted generation of a phenylselenonium ion. For
example, N-(phenylseleno)phthalimide and p-toluenesulfonic acid left the
alcohols unchanged, while benzeneselenenyl chloride induced quite rapid
decomposition.
(15) (a) Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve´, Y.; Beaudouin,
S. J. Org. Chem. 1993, 58, 5032. (b) Hanessian, S.; Gomtsyan, A.
Tetrahedron Lett. 1994, 35, 7509.
(17) Seebach, D.; Peleties, N. Chem. Ber. 1972, 105, 511.

1312 J. Am. Chem. Soc., Vol. 118, No. 6, 1996
Wang et al.
preexisting hydrolylic center a concern, since it was to be
removed in the very next maneuver. Nonetheless, we were
moved to suppress this side reaction, a feat that was easily
accomplished by adding a small amount of triethylamine to the
drying solution (MgSO4) and the chromatography solvent
system. When these guidelines were adopted, good yields of
25 were realized.
Scheme 4a
By heating the inseparable 1:1 aldol mixture with a catalytic
amount of p-toluenesulfonic acid in benzene, closure to the
tetrahydropyran 26 could be effected. Although the primary
product was invariably the â-crotyl epimer 26a, the ratio of
26a:26b was seen to vary as a function of reaction time. This
result did not occasion surprise, since independent resubmission
of 26b to the reaction conditions returned a 4:1 mixture of 26a:
26b. This ratio appears to be a good approximation of the
thermodynamic equilibrium. The interconversion is believed
to proceed by acid-catalyzed retro-Michael opening of the
tetrahydropyran ring followed by proton-induced readdition from
one face of the conjugated diene π-surface or the other. The
stereochemistry unique to 26a,b was established by NOE
experiments, the more important details of which are sum-
marized in formulas A and B.
a (a) 5% HCl, THF; (b) PDC, 4 Å molecular sieves, CH2Cl2; (c) O3,
CH2Cl2, -78 °C, (C6H5)3P; (d) (C6H5Se)2CH2, n-BuLi, THF, -78 °C;
(e) CH2dC(OCH3)CH3, POCl3; (f) LDA, THF, (E)-CH3CHdCHCHO,
-78 °C; (g) (TsOH), C6H6, ∆; (h) NaIO4, NaHCO3, CH3OH, H2O; (i)
(C2H5)3N, CH3CH2OCHdCH2, CH3CON(CH3)2, 220 °C, sealed tube.
The cyclooctenone segment of acetoxycrenulide was about
to be fashioned from 26a. The trans nature of the ring fusion
(18) In model studies performed on the less substituted aldehyde i (He,
W. Ph.D. Dissertation, The Ohio State University, Columbus, OH, 1991),
other approaches to the substitution plan present in 24 were found to be
more problematic. Since nucleophilic organotitanium reagents are recog-
nized to exhibit excellent selectivity for aldehydes and ketones, it was
expected that exposure of i to (PhSeCH2)Ti(Oi-Pr)3 would result in smooth
1,2-addition to the side chain. However, admixture of i with this reagent,
prepared from PhSeCH2Li and ClTi(Oi-Pr)3 as detailed by Reetz (Reetz,
M. T. Top. Curr. Chem. 1982, 106, 1), led only to the recovery of unchanged
aldehyde. When recourse was made instead to (PhSeCH2)ClTi(Oi-Pr)2,
generated in situ from PhSeCH2Li, Ti(Oi-Pr)4, and TiCl4, high selectivity
was observed with resultant production of ii and iii in isolated yields of
33% and 43%, respectively, following chromatographic separation. Chemose-
lective addition was also realized with SmI2/CH2I2 (Tabuchi, T.; Inanaga,
J.; Yamaguchi, M. Tetrahedron Lett. 1986, 27, 3891. Girard, P.; Namy, J.
L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693), but an inseparable
mixture of stereoisomeric hydroxy iodides iv was produced in low (44%)
yield. Although iv should in principle be amenable to conversion into ii
and iii by exposure to PhSeNa (Grieco, P. A.; Noguez, J. A.; Masaki, Y.
Tetrahedron Lett. 1975, 4213. Sharpless, K. B.; Lauer, R. F. J. Am. Chem.
Soc. 1973, 95, 2697. Miyoshi, N.; Kondo, K.; Murai, S.; Sonada, N. Chem.
Lett. 1979, 909), this transformation has not been attempted. Evidently,
the stereoselectivity encountered in the production of 24 is a direct
consequence of the neighboring stereogenic center.
and the E stereochemistry of the crotyl double bond are of
central importance for controlling proper introduction of the ring
unsaturation and secondary methyl group. Following the oxi-
dation of this advanced intermediate with sodium periodate, the
stage was set for concurrent selenoxide elimination and Claisen
rearrangement. Application of those conditions found to be con-
veniently workable during model studies, viz. diethylamine-
buffered mesitylene at 162 °C, only brought on extensive
decomposition. The reluctance of 27 to engage as readily in
[3.3] sigmatropy was not unanticipated. For reasons alluded
to before, the examples studied earlier were either free of the
side chain or carried it into the chairlike transition state in an
equatorial disposition. The scenario for 27 is one in which the
large pendant chain must be projected axially as depicted in
28. Although the energetic costs associated with the desired
conversion to 29 were certain to be higher, the manner in which
this factor had to be dealt with experimentally was approached
empirically.
Since it seemed that the polar characteristics of Claisen
transition states might be better accommodated by performing
the rearrangement in a polar aprotic solvent, the response of
the selenoxide to being heated in dimethylformamide at 220
°C was next examined. As before, diethylamine was also added
to neutralize the electrophilic PhSeOH liberated during the
generation of 27 and to guard against unwanted processes
induced from that direction. These conditions led predominantly
to 30. A small amount of 29 was detected, and the combined
yield was disappointingly low. When recourse was made
(19) Kluge, A. F.; Untch, K. G.; Field, J. H. J. Am. Chem. Soc. 1972,
94, 7827.

Asymmetric Synthesis of (+)-Acetoxycrenulide
J. Am. Chem. Soc., Vol. 118, No. 6, 1996 1313
Scheme 5a
Although it was hoped that the ketone carbonyl could be
reduced chemoselectively, this was found not to be possible
because of its significant steric screening. The first indication
of sluggish reactivity surfaced when 31 was treated with sodium
borohydride in methanol. Above room temperature, only
conversion to the triol was observed.22 The conclusion that the
lactone ring was being reduced first was supported by a number
of observations, including the fact that keto lactol was produced
cleanly following exposure to 1 equiv of Dibal-H at -78 °C.22
In the end, advantage was taken of this reactivity ordering by
treating 31 with 2 equiv of Dibal-H to give the hydroxy lactol
35 as an inseparable mixture of epimers. Without purification,
a (a) CH2T2, (C2H5)2Zn, C6H6, room temperature; (b) (i-Bu)2AlH (2
equiv), CH2Cl2, -78 °C; (c) Ag2CO3-Celite, C6H6, ∆; (d) KN(SiMe3)2,
THF, -78 °C, PhSeCl, NaIO4, NaHCO3, CH3OH, H2O; (e) Ac2O,
DMAP, CH2Cl2; (f) py‚HF, CH3CN, H2O; (g) PDC, 4 Å molecular
sieves, CH2Cl2; (h) (CH3)2CdP(C6H5)3, THF, -78 °C f room
temperature.
the overreduced product was oxidized chemoselectively with
Fetizon reagent to deliver 32 in 87% overall yield. The
configuration of the carbinol carbon in 32, anticipated to be S
on the basis of steric approach control, was corroborated by
NOE experiments (see D).
instead to a tertiary amine (specifically triethylamine) as buffer,
less conjugation materialized (29:30 ) 1:1), but considerable
decomposition, was again noted. It seemed possible that the
vinyl ether functionality in 27 was the most sensitive component
of this intermediate. Consequently, to ward off any possible
attack at this site by a reactive selenium species, the system
was next provided with an excess of ethyl vinyl ether that should
prove more available and more reactive. When this innovation
was implemented, the combined yield of 29 and 30 rose to 53%.
Finally, the replacement of DMF by N,N-dimethylacetamide as
solvent was met with a significant reduction in the proportion
of conjugated isomer formed. These highly favorable conditions
afforded 29 in 55% yield and 30 in only 7% yield and were
adapted to the production of reasonable quantities of the desired
cyclooctenone. The stereochemical assignment to 30 was
confirmed by means of the NOE method as shown in C.
Without protection of the hydroxyl group, 32 was treated
sequentially with 2 equiv of potassium hexamethyldisilazide and
benzeneselenyl chloride. Upon direct oxidation of the resulting
selenides with sodium periodate, the unsaturated lactone 33a
was obtained as a colorless, crystalline, dextrorotatory ([R]25
D
+28.8) solid in 87% yield. Acetylation of this substance gave
rise to 33b and completed elaboration of the fully functionalized
cyclooctanoid core.
Modification of the side chain was accomplished convention-
ally and without difficulty (Scheme 5). It is noteworthy,
however, that the advanced intermediates 33a-c and 34, as well
1
as acetoxycrenulide (1a), itself, exhibit line-broadened H and
13C NMR spectra at ambient temperature. In each case,
warming of the solution to 60 °C caused nicely resolved signals
to appear. Evidently, the introduction of a double bond into
the medium ring is accompanied by a modest heightening of
the barriers to conformational interconversion.
The synthetic acetoxycrenulide obtained in this manner
proved to be spectroscopically identical with the natural material
by direct comparison with spectra provided to us by Professor
James Sims. The optical rotation of our sample, construed to
be 96.3% ee in view of its direct link to 10a, was [R]23D +20.1
(c 1.8, CHCl3). This value is in excellent agreement with the
[R]D value of +21.5 reported by Tringali and co-workers who
obtained their material by manganese dioxide oxidation of diol
37 derived in turn from optically pure crenuladial (36). The
optical rotations given by Fenical (+13) and Sims (+13.6)
are of considerably smaller magnitude although comparable in
sign.
Completion of the Synthesis. For maximum conciseness,
29 was first subjected to the Simmons-Smith cyclopropanation
reaction.20 Since this substrate is believed to adopt a conforma-
tion that uniquely exposes the â-face of its double bond, efficient
conversion to 31 was expected and realized (Scheme 5). The
information gained from the model studies10,11 proved relevant
in this instance (92% yield). Although 31 could be readily
desilylated with pyridinium fluoride in aqueous acetonitrile,
experiments involving the pyridinium dichromate oxidation of
this alcohol revealed the derived aldehyde to be quite labile.21
As a result, attempts to perform a Wittig reaction on this
intermediate were to no avail. For these reasons, the sequence
of steps was inverted.
Experimental Section
Melting points were determined in open capillaries with a Thomas-
Hoover apparatus and are uncorrected. Infrared spectra were recorded
on a Perkin-Elmer Model 1320 instrument. 1H NMR spectra were
recorded at 300 MHz and 13C NMR spectra at 75 MHz on a Bruker
AC-300 instrument as denoted. Mass spectra were recorded at The
Ohio State University Chemical Instrument Center. Elemental analyses
(20) Sawada, S.; Inoue, Y. Bull. Chem. Soc. Jpn. 1969, 42, 2669.
(21) The possibility is real that intramolecular aldolization is the root
cause of this instability. This aspect of the problem was not investigated.
(22) Wang, T.-Z. Unpublished observations from this laboratory.

1314 J. Am. Chem. Soc., Vol. 118, No. 6, 1996
Wang et al.
3.46, CHCl3). Anal. Calcd for C25H36O3Si: C, 72.77; H, 8.79.
Found: C, 73.15; H, 8.93.
(3R)-6-(tert-Butyldiphenylsiloxy)-3-methyl-1-hexanol (11c).
A
mixture of 11b (4.48 g, 0.01 mol) and K2CO3 (4.5 g, 0.033 mol) in
methanol (50 mL) and water (50 mL) was heated at reflux for 4 h,
cooled to 0 °C, and neutralized with concentrated HCl. The aqueous
phase was extracted with CH2Cl2 (3×), and the combined organic layers
were dried and concentrated to provide 11c (4.0 g, 100%) as a colorless
oil which was used without further purification. A small sample was
1
flash distilled for analysis: IR (CHCl3, cm-1) 3600; H NMR (300
MHz, CDCl3) δ 7.69-7.66 (m, 4 H), 7.42-7.35 (m, 6 H), 3.71-3.60
(m, 4 H), 1.64-1.50 (m, 4 H), 1.47-1.30 (m, 2 H), 1.26-1.10 (m, 2
H), 1.05 (s, 9 H), 0.88 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 135.5, 134.1, 129.5, 127.6, 64.2, 61.1, 39.8, 33.0, 29.9,
were performed by Scandinavian Microanalytical Laboratory, Herlev,
Denmark. All solvents were predried by standard methods. All
reactions involving nonaqueous solutions were performed under an inert
atmosphere. Unless otherwise indicated, all separations were carried
out under flash chromatography conditions on silica gel 60 (230-400
mesh, 60 Å) using the indicated solvents. The organic extracts were
dried over anhydrous magnesium sulfate. The purity of all compounds
was shown to be g95% by high-field 1H NMR analysis. Optical
rotations are based on concentrations of g/100 mL.
29.2, 26.9, 19.6, 19.2; [R]20 +2.4 (c 3.1, CHCl3). Anal. Calcd for
D
C23H34O2Si: C, 74.54; H, 9.25. Found: C, 74.78; H, 9.51.
(3R)-6-(tert-Butyldiphenylsiloxy)-3-methylhexanoic Acid (12a).
To a solution of 11c (20.0 g, 54.1 mmol) in CH2Cl2 (400 mL) was
added 4 Å molecular sieves (27 g) and pyridinium dichromate (27.0 g,
71.8 mmol). The mixture was stirred at room temperature for 1 h,
diluted with ether (1 L), and filtered through a Celite pad. The filtrate
was concentrated to leave a deeply colored material which was eluted
through a short column of silica gel to remove residual chromium salts
(elution with 25% ethyl acetate in hexanes). The yellowish aldehyde
so obtained (17.5 g) was dissolved in tert-butyl alcohol (500 mL)
containing 2-methyl-2-butene (80 mL). With cooling in ice water, this
mixture was treated during 10 min with a solution of NaClO2 (35.0 g,
0.38 mol) and NaH2PO4‚H2O (37.0 g, 0.27 mol) in water (260 mL)
and stirred at room temperature for 6 h. Most of the tert-butyl alcohol
was removed on a rotary evaporator. The residual material was diluted
with water (300 mL), acidified to pH 2 with 5% HCl, and extracted
with ethyl acetate. The combined organic phases were washed with
brine, dried, and evaporated. Chromatography of the residue on silica
gel (elution with 25% ethyl acetate in hexanes) gave 14.5 g (70%) of
(3R)-3,7-Dimethyl-6-octen-1-ol Acetate (10b). A solution of (R)-
citronellol (5.0 g, 0.03 mol, 96.3% ee) in CH2Cl2 (150 mL) was cooled
to 0 °C and successively treated with pyridine (10.3 mL, 0.13 mol),
DMAP (390 mg, 3.2 mmol), and acetic anhydride (9 mL, 0.1 mol).
After 45 min of stirring at this temperature, the reaction mixture was
diluted with CH2Cl2 and washed in turn with 1 N HCl, water, saturated
NaHCO3 solution, and brine prior to drying and solvent evaporation.
The residue was distilled in vacuo in a Kugelrohr apparatus to provide
10b (6.34 g, 100%) as a faintly yellow oil which was used without
further purification: IR (CHCl3, cm-1) 1745; 1H NMR (300 MHz,
CDCl3) δ 5.09 (m, 1H), 4.16-4.03 (m, 2 H), 2.25-1.82 (m, 2 H),
2.04 (s, 3 H), 1.73-1.12 (series of m, 5 H), 1.68 (s, 3 H), 1.60 (s, 3
H), 0.92 (d, J ) 6.4 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 170.9,
131.1, 124.5, 62.9, 36.9, 35.4, 29.4, 25.6, 25.3, 20.9, 19.2, 17.5; MS
12a as a colorless oil which was directly esterified: IR (CHCl3, cm-1
)
m/z (M+ - HOAc) calcd 138.1409, obsd 138.1424; [R]20 +3.7 (c
D
3550, 1720; 1H NMR (300 MHz, CDCl3) δ 7.68-7.66 (m, 4 H), 7.42-
7.35 (m, 6 H), 3.66 (t, J ) 6.3 Hz, 2 H), 2.34 (dd, J ) 5.8, 15.0 Hz,
1 H), 2.15 (dd, J ) 8.1, 15.0 Hz, 1 H), 2.00-1.93 (m, 1 H), 1.63-
1.54 (m, 2 H), 1.52-1.33 (m, 1 H), 1.31-1.19 (m, 2 H), 1.06 (s, 9 H),
0.97 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 179.6,
135.6, 134.0, 129.5, 127.6, 63.9, 41.5, 32.8, 29.9 (2 C), 26.9, 19.6,
3.29, CHCl3).
(3R)-3-Methyl-1,6-hexanediol 1-Acetate (11a). Ozone was bubbled
into a solution of 10b (25.0 g, 0.13 mol) in CH2Cl2 (150 mL) at -78
°C for 2 h, and the resulting blue reaction mixture was deoxygenated
with N2 for 10 min until decoloration. At -78 °C, borane-dimethyl
sulfide complex (50 mL, 0.5 mol) was introduced dropwise, the
colorless mixture was carefully warmed to 0 °C, and stirring was
maintained at this temperature for 3 h prior to the slow addition of 1
N HCl (250 mL). After 45 min of vigorous stirring, the aqueous layer
was separated and extracted with CH2Cl2 (3×). The combined organic
layers were washed successively with saturated NaHCO3 solution,
saturated NH4Cl solution, and brine and concentrated in vacuo to
provide 11a (22.0 g, 100%) as a colorless oil which was used without
purification. A small sample was flash distilled for analysis: IR
(CHCl3, cm-1) 3400, 1730; 1H NMR (300 MHz, CDCl3) δ 4.16-4.02
(m, 2 H), 3.61 (t, J ) 6.5 Hz, 2 H), 2.02 (s, 3 H), 1.70-1.32 (series of
m, 6 H), 1.25-1.13 (m, 1 H), 0.91 (d, J ) 6.2 Hz, 3 H); 13C NMR (75
MHz, CDCl3) ppm 171.2, 62.9, 62.8, 35.4, 32.7, 30.0, 29.6. 20.9, 19.3;
19.2; [R]20 +3.4 (c 3.85, CHCl3).
D
Methyl (3R)-6-(tert-Butyldiphenylsiloxy)-3-methylhexanoate (12b).
A solution of 12a (18.0 g, 46.8 mmol) in ether (300 mL) was cooled
to 0 °C and treated with an ethereal solution containing excess
diazomethane (prepared from N-methylnitrosourea). The yellow solu-
tion was left to stand at room temperature for 1 h, and the excess reagent
was destroyed with acetic acid. The ether solution was washed with
saturated NaHCO3 solution and brine, dried, and evaporated. Chro-
matography of the residue on silica gel (elution with 4% ethyl acetate
in hexanes) furnished 15.3 g (82%) of the ester as a viscous, colorless
1
oil: IR (CHCl3, cm-1) 1731; H NMR (300 MHz, CDCl3) δ 7.72-
7.63 (m, 4 H), 7.48-7.34 (m, 6 H), 3.67 (t, J ) 5.9 Hz, 2 H), 3.66 (s,
3 H), 2.32 (dd, J ) 14.5, 6.0 Hz, 1 H), 2.12 (dd, J ) 14.5, 8.0 Hz, 1
H), 1.97 (m, 1 H), 1.65-1.07 (series of m, 4 H), 1.05 (s, 9 H), 0.94 (d,
J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 173.6, 135.6, 134.1,
129.5, 127.6, 64.0, 51.3, 41.6, 32.8, 30.2, 30.0, 26.9, 19.7, 19.2; MS
m/z (M+) calcd 398.2277, obsd 398.2253; [R]23D +2.9 (c 2.32, CHCl3).
Anal. Calcd for C24H34O3Si: C, 72.32; H, 8.60. Found: C, 72.29; H,
8.59.
Methyl (3R)-2-Allyl-6-(tert-butyldiphenylsiloxy)-3-methylhex-
anoate (13). To a solution of lithium diisopropylamide [prepared from
4.54 mL (32.4 mmol) of diisopropylamine and n-butyllithium (18.6
mL of 1.6 M, 29.8 mmol) in 100 mL of dry THF at -78 °C] was
added a solution of 12b (9.10 g, 22.9 mmol) in 30 mL of dry THF
over 10 min. After 70 min of stirring, HMPA (9 mL) was added
followed by allyl bromide (10 mL, excess). The reaction mixture was
stirred for 2 h at -78 °C and warmed to 0 °C, the reaction was quenched
with saturated NH4Cl solution, and the mixture was extracted with ether.
The combined organic layers were washed with brine, dried, and
evaporated to leave a colorless liquid which was used directly in the
next step. A small aliquot was chromatographed on silica gel (elution
MS m/z (M+ + H) calcd 175.1334, obsd 175.1353; [R]20 +4.5 (c
D
1.30, CHCl3). Anal. Calcd for C9H18O3: C, 62.04; H, 10.41. Found:
C, 62.02; H, 10.59.
(3R)-6-(tert-Butyldiphenylsiloxy)-3-methyl-1-hexanol Acetate (11b).
A solution of tert-butyldiphenylsilyl chloride (85.4 g, 0.31 mol), DMAP
(3.5 g, 29 mmol), and triethylamine (50 mL, 0.36 mol) in CH2Cl2 (200
mL) cooled to 0 °C was treated dropwise with alcohol 11a (50.0 g,
0.29 mol). The reaction mixture was stirred overnight at room
temperature, diluted with CH2Cl2, washed successively with 1 N HCl,
saturated NaHCO3 solution, saturated NH4Cl solution, and brine, and
then dried. Solvent removal provided 11b (118.0 g, 100%) as a
colorless oil which was used without further purification. A small
1
sample was flash distilled for analysis: IR (CHCl3, cm-1) 1750; H
NMR (300 MHz, CDCl3) δ 7.69-7.44 (m, 4 H), 7.42-7.34 (m, 6 H),
4.11-4.06 (m, 2 H), 3.65 (t, J ) 6.5 Hz, 2 H), 2.03 (s, 3 H), 1.68-
1.34 (series of m, 6 H), 1.26-1.19 (m, 1 H), 1.05 (s, 9 H), 0.89 (d, J
) 6.4 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 171.1, 135.5, 134.1,
129.5, 127.6, 64.1, 63.0, 35.4, 32.9, 29.8, 29.6, 26.9, 20.9, 19.4, 19.2;
MS m/z (M+ - H) calcd 411.2356, obsd 411.2315; [R]20 +2.6 (c
D

Asymmetric Synthesis of (+)-Acetoxycrenulide
J. Am. Chem. Soc., Vol. 118, No. 6, 1996 1315
with 4% ethyl acetate in hexanes) for spectroscopic and analytical
purposes: IR (CHCl3, cm-1) 1728; 1H NMR (300 MHz, CDCl3) δ
7.73-7.60 (m, 4 H), 7.45-7.33 (m, 6 H), 5.74 (m, 1 H), 5.08-4.98
(m, 2 H), 3.68-3.64 (m, 2 H), 2.40-2.17 (series of m, 3 H), 1.80-
1.31 (series of m, 6 H), 1.27-1.12 (m, 2 H), 1.06 (s, 4.5 H), 1.05 (s,
4.5 H), 0.91 (d, J ) 6.2 Hz, 1.5 H), 0.89 (d, J ) 6.2 Hz, 1.5 H); 13C
NMR (75 MHz, CDCl3) ppm 175.4, 175.2, 136.1, 136.0, 135.6, 134.1,
129.5, 127.6, 127.5, 116.4, 116.3, 64.0, 51.1, 51.0, 50.5, 34.9, 34.1,
32.9, 30.7, 30.4, 30.2, 29.9, 26.9, 19.2, 16.7, 16.6; MS m/z (M+) calcd
438.2590, obsd 438.2573. Anal. Calcd for C27H38O3Si: C, 73.93; H,
8.73. Found: C, 73.95; H, 8.71.
(62%) of 16a as a mixture of diastereomeric aldols (1H NMR analysis),
which were directly protected.
The above isomeric mixture (100 mg, 0.18 mmol) dissolved in CH2-
Cl2 (1 mL) and cooled to 0 °C was treated in turn with diisopropyl-
ethylamine (0.16 mL, 0.90 mmol) and chloromethyl methyl ether (60
µL, 0.78 mmol). After 40 min, the reaction mixture was allowed to
warm to room temperature, stirred for 12 h, diluted with ether, and
washed with saturated NaHCO3 solution and brine. After drying and
solvent evaporation, the residue was chromatographed on silica gel
(elution with 20% ethyl acetate in hexanes) to give 96 mg (89%) of
16b.
3-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-methylbutyl]dihydro-2(3H)-
furanone (14). Ester 13 produced above was dissolved in CH2Cl2 (200
mL), cooled to -78 °C, and ozonolyzed until a blue color was sustained
(ca. 45 min). The excess ozone was removed by bubbling N2 through
the system for 10 min, at which point triphenylphosphine (12.0 g, 45.8
mmol) was introduced and the mixture was kept at room temperature
overnight. Solvent evaporation afforded an orange oil which was
dissolved in methanol (100 mL), cooled to -10 °C, and treated with
NaBH4 (2.6 g, 76 mmol) in small portions. After 30 min of stirring,
the mixture was warmed to room temperature for 6 h, acidified to pH
3 with 5% HCl, and extracted with ethyl acetate. The combined organic
phases were washed with dilute NaHCO3 solution and brine, dried,
and evaporated. Chromatography of the residue on silica gel (elution
with 15% ethyl acetate in hexanes) gave 6.53 g of lactone. Continued
elution with 50% ethyl acetate in hexanes furnished 1.2 g of uncyclized
methyl ester which was treated with K2CO3 in methanol to give an
additional 1.0 g of 14 (total overall yield from 12b of 80%): IR (CHCl3,
cm-1) 1766; 1H NMR (300 MHz, CDCl3) δ 7.68-7.65 (m, 4 H), 7.46-
7.35 (m, 6 H), 4.34-4.12 (m, 2 H), 3.70-3.63 (m, 2 H), 2.62-2.46
(m, 1 H), 2.24-1.93 (m, 3 H), 1.66-1.21 (m, 4 H), 1.06 (s, 9 H), 1.02
(d, J ) 6.8 Hz, 1.5 H), 0.87 (d, J ) 6.8 Hz, 1.5 H); 13C NMR (75
MHz, CDCl3) ppm 178.9, 178.5, 135.5, 134.0, 129.6, 129.5, 127.6,
66.4, 66.3, 63.9, 63.8, 44.6, 43.6, 33.0, 32.1, 31.1, 30.2, 29.3, 26.9,
24.9, 22.9, 19.2, 17.4, 15.3; MS m/z (M+) calcd 410.2277, obsd
410.2247. Anal. Calcd for C25H34O3Si: C, 73.13; H, 8.35. Found:
C, 73.10; H, 8.39.
A 90 mg (0.15 mmol) sample of 16b in THF (2.5 mL) was treated
with 1 mL of 10% H2SO4 solution, stirred for 24 h, diluted with ether,
washed with saturated NaHCO3 solution and brine, dried, and evapo-
rated. Chromatographic purification of the residue on silica gel (elution
with 20% ethyl acetate in hexanes) furnished 17 as a colorless oil (41
mg, 60%): 1H NMR (300 MHz, CDCl3) δ 7.66 (m, 4 H), 7.41 (m, 6
H), 4.62 (s, 2 H), 4.38 (m, 1 H), 4.26 (m, 1 H), 4.17 (m, 1 H), 3.68 (m,
2 H), 3.35 (s, 3 H), 2.66 (t, J ) 4.5 Hz, 1 H), 2.11 (m, 1 H), 1.69-
1.35 (m, 4 H), 1.06 (s, 9 H), 0.93 (d, J ) 6.9 H, 3 H); 13C NMR (75
MHz, CDCl3) ppm (major isomer) 177.0, 135.5, 133.9, 129.6, 127.6,
95.9, 74.4, 72.3, 63.8, 55.9, 50.9, 32.4, 30.7, 30.2, 26.9, 19.2, 16.4;
MS m/z (M+) calcd 470.2488, obsd 470.2514.
Conversion of 17 to 15. A solution of 17 (40 mg, 0.085 mmol) in
benzene (1.5 mL) was treated with DBU (70 µL, 0.42 mmol), heated
at 70 °C for 9 h, and concentrated. The yellow residue was subjected
to silica gel chromatography (elution with 20% ethyl acetate in hexanes)
to afford 15 mg (44%) of 15, which proved spectroscopically identical
with the material obtained above.
(3S,4S)-3-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-methylbutyl]dihy-
dro-4-[(E)-3-(octahydro-1,3-dimethyl-2H-1,3,2-benzodiazaphosphol-
2-yl)allyl]-2(3H)-furanone P-Oxide (19). A cold (-78 °C), magneti-
cally stirred solution of 18 (2.04 g, 8.9 mmol) in dry THF (65 mL)
was treated with n-butyllithium (6.0 mL of 1.6 M in hexanes, 9.6 mmol).
After 3 min, a solution of 15 (3.65 g, 8.9 mmol) in the same solvent
(45 mL) at -78 °C was introduced via a cannula. The mixture was
stirred for 30 min before the reaction was quenched with saturated NH4-
Cl solution and the mixture extracted with ethyl acetate. The combined
organic phases were washed with brine, dried, and evaporated.
Chromatography on silica gel (elution with 6% methanol in ethyl
acetate) returned 400 mg of unreacted 15 and afforded 4.1 g (81%
based on recovered starting material) of 19, a viscous colorless oil:
3-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-methylbutyl]-2(5H)-fura-
none (15). To a solution of potassium hexamethyldisilazide (38.2 mL
of 0.5 M in toluene, 19.1 mmol) in anhydrous THF (120 mL) cooled
to -78 °C was added 14 (6.50 g, 15.9 mmol) dissolved in 36 mL of
THF. After 1 h, a solution of benzeneselenenyl chloride (3.70 g, 19.2
mmol) in THF (16 mL) was introduced, and the reaction mixture was
stirred for 30 min before the reaction was quenched with saturated NH4-
Cl solution and the mixture extracted with ether. The combined organic
phases were washed with brine, dried, and concentrated to leave 11.0
g of an orange liquid which was dissolved in CH2Cl2 (200 mL) at 0
°C. Pyridine (7.5 mL) and 30% hydrogen peroxide (11.5 mL) were
added in sequence, and the mixture was warmed to room temperature
for 20 min prior to dilution with ether. The separated organic layer
was washed with saturated NaHSO3 solution, 5% HCl, saturated
NaHCO3 solution, and brine prior to drying and concentration.
Chromatography of the residue on silica gel (elution with 20% ethyl
acetate in hexanes) afforded 5.7 g (87%) of the oily lactone 15: IR
(CHCl3, cm-1) 1753; 1H NMR (300 MHz, CDCl3) δ 7.68-7.64 (m, 4
H), 7.44-7.34 (m, 6 H), 7.01 (dd, J ) 2.9, 1.6 Hz, 1 H), 4.74 (t, J )
1.6 Hz, 2 H), 3.67 (m, 2 H), 2.60 (m, 1 H), 1.72-1.50 (series of m, 4
H), 1.15 (d, J ) 6.9 Hz, 3 H), 1.05 (s, 9 H); 13C NMR (75 MHz,
CDCl3) ppm 173.7, 143.0, 139.3, 135.6, 134.0, 129.6, 127.6, 69.9, 63.8,
31.2, 30.4, 30.1, 26.9, 19.2, 19.0; MS m/z (M+) calcd 408.2121, obsd
1
IR (neat, cm-1) 1780, 1630; H NMR (300 MHz, CDCl3) δ 7.64 (m,
4 H), 7.38 (m, 6 H), 6.54 (m, 1 H), 5.54 (dd, J ) 20.8, 16.6 Hz, 1 H),
4.28 (dd, J ) 9.2, 7.4 Hz, 1 H), 3.85 (dd, J ) 9.2, 5.8 Hz, 1 H), 3.64
(t, J ) 6.1 Hz, 2 H), 2.74 (m, 1 H), 2.48 (d, J ) 10.8 Hz, 3 H), 2.44
(d, J ) 10.2 Hz, 3 H), 2.38-2.19 (m, 3 H), 2.02-1.80 (m, 4 H), 1.63-
1.05 (series of m, 11 H), 1.03 (s, 9 H), 0.98 (d, J ) 6.9 Hz, 3 H); 13
C
NMR (75 MHz, CDCl3) ppm 177.5, 148.0 (d, J ) 3.1 Hz), 135.4, 133.9,
129.5, 127.5, 123.3 (d, J ) 150.4 Hz), 70.8, 64.5 (d, J ) 7.3 Hz),
63.74, 63.69, 50.1, 38.3 (d, J ) 19.5 Hz), 36.9, 33.3, 30.4, 29.9, 28.7,
28.5, 28.1, 28.0, 26.8, 24.2, 24.1, 19.1, 16.7; MS m/z (M+) calcd
636.3511, obsd 636.3474; [R]23 -20.7 (c 1.7, CHCl3).
D
(3S,4S)-4-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-methylbutyl]tet-
rahydro-5-oxo-3-furanacetaldehyde (20). Ozone was bubbled through
a solution of 19 (6.0 g, 9.4 mmol) in CH2Cl2 (200 mL) and methanol
(50 mL) at -78 °C until a blue color was sustained. Excess ozone
was removed by a flow of N2. Dimethyl sulfide (18 mL) was added,
and the mixture was warmed to room temperature for 1.5 h prior to
being extracted with ether. The combined ethereal phases were washed
with brine (2×), dried, and evaporated. Chromatography of the residue
on silica gel (elution with 30% ethyl acetate in hexanes) provided 3.36
408.2140; [R]22 -6.7 (c 1.56, CHCl3). Anal. Calcd for C25H32O3-
D
Si: C, 73.49; H, 7.89. Found: C, 73.55; H, 7.99.
1
3-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-methylbutyl]dihydro-4-
(methoxymethoxy)-2(3H)-furanone (17). To a cold (-78 °C) solution
of lithium diisopropylamide (1.4 mL of 0.3 M in THF) was added 12b
(130 mg, 0.33 mmol) dissolved in 0.8 mL of THF. After 1 h, a solution
of OHCCH2OTHP (71 mg, 0.49 mmol) in 0.5 mL of THF was
introduced, and the reaction mixture was stirred for 30 min before the
reaction was quenched with saturated NH4Cl solution and the mixture
extracted with ether. The combined ethereal layers were washed with
brine, dried, and concentrated. The residue was chromatographed on
silica gel (elution with 25% ethyl acetate in hexanes) to give 110 mg
g (79%) of 20 as a colorless oil: IR (CHCl3, cm-1) 1772, 1724; H
NMR (300 MHz, CDCl3) δ 9.75 (s, 1 H), 7.68-7.65 (m, 4 H), 7.43-
7.36 (m, 6 H), 4.52 (dd, J ) 9.4, 7.7 Hz, 1 H), 3.77 (dd, J ) 9.4, 6.7
Hz, 1 H), 3.67 (t, J ) 5.9 Hz, 2 H), 2.83-2.76 (m, 2 H), 2.59 (dd, J
) 19.4, 10.2 Hz, 1 H), 2.20 (dd, J ) 7.5, 3.8 Hz, 1 H), 1.65-1.44 (m,
5 H), 1.05 (s, 9 H), 1.00 (d, J ) 6.9 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 199.2, 177.0, 135.6, 134.0, 129.6, 127.6, 71.2, 63.8, 49.7,
48.0, 33.1, 32.4, 30.4, 30.0, 26.9, 19.2, 16.9; MS m/z (M+ + 1) calcd
453.2461, obsd 453.2466; [R]20D -26.0 (c 1.3, CHCl3). Anal. Calcd
for C27H36O4Si: C, 71.71; H, 8.02. Found: C, 71.51; H, 8.03.

1316 J. Am. Chem. Soc., Vol. 118, No. 6, 1996
Wang et al.
(3S,4S)-4-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-methylbutyl]tet-
temperature for 6 h, diluted with ether (60 mL), filtered through a short
path of silica gel, and concentrated. The residue was chromatographed
on silica gel (elution with 15% ethyl acetate in hexanes) to give 777
rahydro-5-oxo-3-furanacetaldehyde 3-(Dimethyl acetal) (21).
A
solution of 19 (3.36 g, 7.4 mmol) in trimethyl orthoformate (30 mL)
and methanol (12 mL) was stirred with p-toluenesulfonic acid mono-
hydrate (105 mg, 0.55 mmol) for 10 min. Solid NaHCO3 was
introduced, the mixture was extracted with ether, and the combined
extracts were washed with brine and dried prior to concentration. The
residue was purified by silica gel chromatography (elution with 25%
ethyl acetate in hexanes) to give 3.31 g (90%) of 21 as a colorless oil:
1
mg (97%) of 23 as a colorless oil: IR (neat, cm-1) 1785; H NMR
(300 MHz, CDCl3) δ 7.66 (m, 4 H), 7.41 (m, 6 H), 5.53 (dt, J ) 17.0,
10.0 Hz, 1 H), 5.13 (dd, J ) 10.3, 1.8 Hz, 1 H), 5.03 (dd, J ) 17.0,
1.8 Hz, 1 H), 4.27 (dd, J ) 9.0, 7.8 Hz, 1 H), 3.86 (t, J ) 9.0 Hz, 1
H), 3.65 (t, J ) 6.5 Hz, 2 H), 2.65 (m, 2 H), 2.12 (dd, J ) 17.0, 10.0
Hz, 1 H), 1.94 (m, 1 H), 1.60-1.15 (series of m, 5 H), 1.06 (s, 9 H),
0.82 (d, J ) 6.8 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 176.8,
135.6, 134.9, 134.0, 129.6, 127.6, 118.5, 72.4, 63.9, 51.8, 37.0, 34.1,
33.1, 31.3, 30.0, 26.9, 19.2, 14.5; MS m/z (M+ - H) calcd 449.2512,
1
IR (CHCl3, cm-1) 1780, 1595, 1435; H NMR (300 MHz, C6D6) δ
7.78 (m, 4 H), 7.24 (m, 6 H), 3.98 (m, 2 H), 3.65 (t, J ) 6.0 Hz, 2 H),
3.39 (t, J ) 8.7 Hz, 1 H), 2.99 (s, 3 H), 2.98 (s, 3 H), 2.14 (m, 1 H),
1.82 (dd, J ) 9.5, 3.0 Hz, 1 H), 1.66-1.49 (m, 7 H), 1.18 (s, 9 H),
0.84 (d, J ) 6.7 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 176.5,
136.0, 134.4, 129.9, 128.0, 103.2, 71.2, 64.2, 53.2, 52.4, 49.7, 36.2,
34.7, 32.7, 31.0, 30.4, 27.1, 19.5, 16.3; MS m/z (M+ - H) calcd
497.2723, obsd 497.2704; [R]25D -6.4 (c 1.36, CHCl3). Anal. Calcd
for C29H42O5Si: C, 69.84; H, 8.49. Found: C, 69.85; H, 8.51.
(3S,4S,5R)-8-(tert-Butyldiphenylsiloxy)-3-(hydroxymethyl)-5-methyl-
4-vinyloctanal Dimethyl Acetal (22). A cold (-78 °C), magnetically
stirred solution of 21 (3.31 g, 6.65 mmol) in CH2Cl2 (50 mL) was treated
with Dibal-H (8.0 mL of 1.0 M in hexanes, 8.0 mmol) and stirred for
25 min, and the reaction was quenched with saturated NH4Cl solution.
Saturated Rochelle’s salt solution was introduced, and the resultant
mixture was stirred for 15 min and extracted with ether. The combined
organic phases were washed with brine (2×), dried, and evaporated.
Chromatography of the residue on silica gel (elution with 40% ethyl
acetate in hexanes) afforded 3.21 g (97%) of the lactol as a colorless,
obsd 449.2480; [R]20 -2.8 (c 1.7, benzene). Anal. Calcd for
D
C28H38O3Si: C, 74.62; H, 8.50. Found: C, 74.58; H, 8.42.
(4S)-4-[(1S,2R)-5-(tert-Butyldiphenylsiloxyl)-1-[(1S)-1-hydroxy-
2-(phenylselenyl)ethyl]-2-methylpentyl]dihydro-2(3H)-furanone (24).
Into a solution of 23 (655 mg, 1.47 mmol) in CH2Cl2 (25 mL) at -78
°C was bubbled ozone until a blue color persisted. Following the
introduction of an N2 stream for 15 min, triphenylphosphine (1.0 g,
3.8 mmol) was introduced, and the mixture was warmed to room
temperature for 5 h prior to dilution with ether. The organic phase
was washed with brine, dried, and evaporated to leave a residue,
chromatography of which on silica gel (elution with 25% ethyl acetate
in hexanes) gave 570 mg (87%) of the aldehyde as a colorless oil: IR
1
(neat, cm-1) 1790, 1730; H NMR (300 MHz, CDCl3) δ 9.73 (d, J )
1.0 Hz, 1 H), 7.65 (m, 4 H), 7.41 (m, 6 H), 4.62 (dd, J ) 9.3, 7.9 Hz,
1 H), 3.79 (t, J ) 9.0 Hz, 1 H), 3.71 (t, J ) 5.6 Hz, 2 H), 2.93 (m, 1
H), 2.51 (dd, J ) 17.3, 8.6 Hz, 1 H), 2.13 (dd, J ) 17.3, 10.4 Hz, 1
H), 1.83-1.44 (series of m, 6 H), 1.07 (s, 9 H), 0.92 (d, J ) 6.9 Hz,
3 H); 13C NMR 75 MHz, CDCl3) ppm 203.1, 175.7, 135.5, 133.8, 129.7,
127.7, 72.4, 63.4, 59.3, 33.7, 33.4, 32.3, 31.7, 30.5, 26.9, 19.2, 15.9;
1
oily mixture of epimers: IR (neat, cm-1) 3435; H NMR (300 MHz,
C6D6) δ (major isomer) 7.96 (m, 4 H), 7.39 (m, 6 H), 5.31 (t, J ) 2.7
Hz, 1 H), 4.33 (t, J ) 5.5 Hz, 1 H), 4.26 (t, J ) 8.0 Hz, 1 H), 3.94 (t,
J ) 8.8 Hz, 1 H), 3.81 (t, J ) 6.3 Hz, 2 H), 3.21 (s, 6 H), 2.57 (d, J
) 6.7 Hz, 1 H), 2.01-1.66 (series of m, 9 H), 1.34 (s, 9 H), 0.97 (d,
J ) 6.7 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm (major isomer) 136.0,
134.5, 129.9, 127.9, 103.9, 101.0, 72.5, 64.4, 58.1, 52.7, 52.1, 38.7,
36.6, 33.8, 31.6, 30.8, 27.1, 19.5, 16.5; MS m/z (M+ - H2O) calcd
482.2852, obsd 482.2854.
MS m/z (M+ - H) calcd 451.2304, obsd 451.2333; [R]23 -44.3 (c
D
1.45, CHCl3). Anal. Calcd for C27H36O4Si: C, 71.64; H, 8.02.
Found: C, 71.38; H, 7.88.
To a solution of bis(phenylseleno)methane (192 mg, 0.59 mmol) in
THF (15 mL) at -78 °C was added n-butyllithium (0.41 mL of 1.6 M
in hexanes, 0.65 mmol). After 40 min of stirring, the anion solution
was transferred via cannula to a solution of the above aldehyde (221
mg, 0.49 mmol) in THF (20 mL) at -78 °C. The reaction mixture
was stirred for 40 min, the reaction quenched with saturated NH4Cl
solution, and the mixture extracted with ether. The combined ethereal
layers were washed with brine, dried, and evaporated. The residue
was purified by chromatography on silica gel (elution with 25% ethyl
acetate in hexanes) to give 245 mg (80%) of 24 as a colorless oil: IR
A suspension of methyltriphenylphosphonium bromide (10.6 g, 29.7
mmol) in dry THF (200 mL) at 0 °C was treated with potassium
hexamethyldisilazide (56 mL of 0.5 M in toluene, 28.0 mmol). After
30 min, the resulting yellow solution was treated with the above lactol
(4.73 g, 9.5 mmol) in 50 mL of the same solvent. The reaction mixture
was warmed to room temperature for 4.5 h, the reaction was quenched
with saturated NH4Cl solution, and the mixture was diluted with ether,
washed with brine, dried, and concentrated. Chromatography of the
residue on silica gel (elution with 25% ethyl acetate in hexanes)
provided 4.1 g (80%) of 22 as a colorless oil: IR (neat, cm-1) 3490,
1
(neat, cm-1) 3500, 1785; H NMR (300 MHz, CDCl3) δ 7.65 (m, 4
H), 7.47 (m, 2 H), 7.42 (m, 6 H), 7.22 (m, 3 H), 4.47 (t, J ) 8.2 Hz,
1 H), 3.96 (t, J ) 9.2 Hz, 1 H), 3.61 (m, 1 H), 3.57 (t, J ) 6.5 Hz, 2
H), 3.02 (dd, J ) 12.8, 3.1 Hz, 1 H), 2.88 (m, 1 H), 2.74 (dd, J )
12.8, 10.3 Hz, 1 H), 2.47 (m, 2 H), 2.17 (dd, J ) 7.0, 1.6 Hz, 1 H),
1.47 (m, 6 H), 1.05 (s, 9 H), 0.82 (d, J ) 6.9 Hz, 3 H); 13C NMR (75
MHz, CDCl3) ppm 176.7, 135.5, 133.9, 133.4, 129.7, 129.3, 128.3,
127.8, 127.6, 73.1, 67.8, 63.7, 50.3, 38.3, 35.6, 34.4, 34.3, 31.0, 30.7,
1
1640; H NMR (300 MHz, CDCl3) δ 7.80 (m, 4 H), 7.24 (m, 6 H),
5.44 (dt, J ) 17.0, 10.2 Hz, 1 H), 4.99 (dd, J ) 10.2, 2.4 Hz, 1 H),
4.91 (dd, J ) 17.0, 2.4 Hz, 1 H), 4.50 (br t, 1 H), 3.66 (t, J ) 6.5 Hz,
2 H), 3.63 (m, 1 H), 3.47 (br d, J ) 11.0 Hz, 1 H), 3.13 (s, 3 H), 3.12
(s, 3 H), 1.92 (m, 1 H), 1.79 (m, 4 H), 1.58 (m, 3 H), 1.43 (m, 1 H),
1.19 (s, 9 H), 0.76 (d, J ) 6.8 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 138.5, 136.0, 134.5, 129.9, 128.1, 117.0, 103.9, 64.6, 63.4, 52.8,
26.9, 19.2, 15.7; MS m/z (M+) calcd 624.2174, obsd 624.2186; [R]23
+13.5 (c 1.0, CHCl3).
D
52.1, 50.7, 37.8, 33.2, 32.7, 31.8, 30.4, 27.1, 19.5, 15.7; [R]23 +6.1
D
(3aS,4R,6S,7aR)-7-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-methylbu-
tyl]hexahydro-6-[(phenylselenyl)methyl]-4-[(E)-1-propenyl]-3H-
furo[3,4-c]pyran-3-ene (26). A solution of 24 (80 mg, 0.13 mmol)
in 2-methoxypropene (2 mL) was treated with 1 drop of phosphorus
oxychloride and stirred at room temperature for 2.5 h, the reaction was
quenched with a few drops of triethylamine, and the mixture was passed
down a short column of silica gel packed with 20% ethyl acetate in
hexanes containing 2% triethylamine. The eluate was concentrated and
the residue purified by chromatography on silica gel (elution with 15%
ethyl acetate in hexanes, 3% in (C2H5)3N) to provide 85 mg (96%) of
the acetal as a colorless oil: IR (neat, cm-1) 1780; 1H NMR (300 MHz,
CDCl3) δ 7.68 (m, 4 H), 7.50 (m, 2 H), 7.42 (m, 6 H), 7.22 (m, 3 H),
4.44 (t, J ) 8.1 Hz, 1 H), 4.00 (dd, J ) 10.2, 8.7 Hz, 1 H), 3.98 (m,
1 H), 3.65 (t, J ) 6.4 Hz, 2 H), 3.43 (dd, J ) 12.6, 3.4 Hz, 1 H), 3.24
(s, 3 H), 2.87 (m, 2 H), 2.47 (dd, J ) 17.0, 8.0 Hz, 1 H), 2.18 (dd, J
) 17.0, 12.2 Hz, 1 H), 1.86 (m, 1 H), 1.70-1.33 (series of m, 3 H),
1.31 (s, 3 H), 1.29 (s, 3 H), 1.22 (m, 2 H), 1.07 (s, 9 H), 0.83 (d, J )
6.8 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 176.8, 135.6, 133.9,
(c 1.3, benzene). Anal. Calcd for C30H46O4Si: C, 72.24; H, 9.30.
Found: C, 72.21; H, 9.32.
(4S)-4-[(1S)-1-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-methylbutyl]-
allyl]dihydro-2(3H)-furanone (23). A solution of 22 (1.55 g, 3.1
mmol) in THF (60 mL) ws stirred with 5% HCl (7 mL) for 7 h, diluted
with ether, and washed with saturated NaHCO3 solution and brine. The
organic phase was dried, concentrated, and chromatographed on silica
gel (elution with 25% ethyl acetate in hexanes) to give 1.1 g (78%) of
1
the lactol as a colorless oil: IR (neat, cm-1) 3420, 1640; H NMR
(300 MHz, C6D6) δ (major isomer) 7.79 (m, 4 H), 7.23 (m, 6 H), 5.35
(m, 2 H), 4.82 (m, 2 H), 4.09 (t, J ) 8.2 Hz, 1 H), 3.64 (t, J ) 6.5 Hz,
2 H), 3.45 (t, J ) 8.3 Hz, 1 H), 2.49 (m, 1 H), 1.93 (m, 1 H), 1.84 (dd,
J ) 12.3, 7.1 Hz, 1 H), 1.62-1.20 (series of m, 7 H), 1.19 (s, 9 H),
0.66 (d, J ) 6.8 Hz, 3 H).
A solution of the above lactol (0.89 g, 1.77 mmol) in CH2Cl2 (30
mL) was treated with 1.0 g of 4 Å molecular sieves and 1.00 g (2.66
mmol) of pyridinium dichromate. The mixture was stirred at room

Asymmetric Synthesis of (+)-Acetoxycrenulide
J. Am. Chem. Soc., Vol. 118, No. 6, 1996 1317
133.0, 129.9, 129.6, 129.2, 127.6, 127.2, 101.5, 73.3, 70.4, 63.8, 49.0,
47.7, 36.0, 34.3, 34.0, 33.1, 31.8, 30.7, 26.9, 25.5, 24.6, 19.2, 15.8;
4.28 (s, 1 H), 4.25 (d, J ) 3.0 Hz, 1 H), 3.67 (t, J ) 5.7 Hz, 2 H), 2.83
(dd, J ) 14.0, 9.4 Hz, 1 H), 2.65 (dd, J ) 11.4, 6.9 Hz, 1 H), 2.56-
2.24 (series of m, 4 H), 1.81 (m, 1 H), 1.57 (m, 2 H), 1.43 (m, 1 H),
1.20 (d, J ) 6.4 Hz, 3 H), 1.11 (m, 1 H), 1.05 (s, 9 H), 0.79 (d, J )
6.4 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 215.1, 175.3, 140.5,
135.5, 133.8, 129.7, 127.7, 123.6, 67.9, 63.6, 56.8, 54.8, 44.2, 39.4,
32.6, 30.7, 29.8, 28.9, 26.9, 22.9, 19.2, 17.9; MS m/z (M+ - H) calcd
517.2774, obsd 517.2745; [R]23D -17.5 (c 1.5, CHCl3). Anal. Calcd
for C32H42O4Si: C, 74.09; H, 8.16. Found: C, 74.25; H, 8.46.
MS m/z (M+) calcd 696.2749, obsd 696.2754; [R]23 -7.5 (c 1.0,
D
CHCl3).
To a solution of lithium diisopropylamide [prepared from 0.47 mL
(3.4 mmol) of diisopropylamine and n-butyllithium (2.2 mL of 1.55
M in hexanes, 3.4 mmol) in 25 mL of THF] at -78 °C was added a
solution of the above acetal (1.8 g, 2.6 mmol) in 13 mL of THF. The
reaction mixture was stirred at this temperature for 1 h, treated with a
solution of crotonaldehyde (640 mg, 9.1 mmol) in THF (4 mL), and
stirred for an additional 20 min. The reaction was quenched with
saturated NH4Cl solution and the mixture extracted with ether. The
combined organic phases were washed with brine, dried over magne-
sium sulfate (triethylamine and NaHCO3 were added to inhibit
deprotection), and concentrated. The residue was chromatographed on
silica gel (elution with 30% ethyl acetate in hexanes containing 3%
triethylamine) to furnish 1.8 g (91%) of 25 as an inseparable aldol
mixture.
The aldols were dissolved in benzene (400 mL), treated with
p-toluenesulfonic acid (55 mg, 0.29 mmol), and heated under a Dean-
Stark trap with removal of water for 7 h. The benzene was evaporated,
and the residue was subjected to silica gel chromatography (elution
with 10% ethyl acetate in hexanes) to afford 785 mg (49%) of 26a
and 230 mg (14%) of 26b.
1
30: colorless oil; IR (neat, cm-1) 1770, 1710, 1685; H NMR (300
MHz, CDCl3) δ 7.67 (m, 4 H), 7.40 (m, 6 H), 6.78 (ddd, J ) 10.2, 8.6,
3.2 Hz, 1 H), 4.59 (t, J ) 8.9 Hz, 1 H), 4.33 (t, J ) 8.4 Hz, 1 H), 3.69
(t, J ) 5.9 Hz, 2 H), 3.29 (m, 2 H), 2.61 (dt, J ) 13.1, 10.5 Hz, 1 H),
2.41 (dd, J ) 10.6, 5.5 Hz, 1 H), 2.30 (m, 1 H), 2.24 (t, J ) 8.8 Hz,
1 H), 1.78 (m, 2 H), 1.61 (m, 2 H), 1.46 (m, 1 H), 1.26 (m, 1 H), 1.14
(d, J ) 6.7 Hz, 3 H), 1.06 (s, 9 H), 0.87 (d, J ) 9.5 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) ppm 215.0, 171.0, 137.1, 135.5, 133.8, 130.0,
129.7, 127.7, 66.6, 63.7, 57.1, 54.1, 38.5, 34.1, 33.9, 30.3, 28.8, 28.6,
26.9, 24.1, 19.2, 17.7; MS m/z (M+ - H) calcd 517.2774, obsd
517.2780; [R]23 -51.4 (c 2.0, CHCl3).
D
(3aR,4S,7R,7aS,8aS,8bR)-4-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-
methylbutyl]octahydro-7-methyl-1H-cyclopropa[3,4]cycloocta[1,2-
c]furan-1,5(2H)-dione (31). A solution of 29 (252 mg, 0.48 mmol)
in benzene (20 mL) was treated with diethylzinc (0.95 mL of 1.1 M in
toluene, 1.0 mmol) and diiodomethane (0.5 mL, 5.8 mmol). The
reaction mixture was stirred at room temperature for 1.5 h, the reaction
quenched with saturated NH4Cl solution (25 mL), and the mixture
diluted with ether. The separated organic phase was washed with brine,
dried, and concentrated. Chromatography of the residue on silica gel
(elution with 15% ethyl acetate in hexanes) provided 240 mg (92%)
26a: colorless oil; IR (neat, cm-1) 1765; 1H NMR (300 MHz, CDCl3)
δ 7.65 (m, 4 H), 7.51 (m, 2 H), 7.41 (m, 6 H), 7.25 (m, 3 H), 5.86 (m,
1 H), 5.62 (m, 1 H), 4.23 (dd, J ) 8.3, 6.5 Hz, 1 H), 4.13 (m, 2 H),
4.00 (dd, J ) 11.4, 8.4 Hz, 1 H), 3.63 (m, 2 H), 3.25 (dd, J ) 12.3,
6.7 Hz, 1 H), 3.08 (dd, J ) 12.3, 8.0 Hz, 1 H), 2.61 (m, 1 H), 2.28
(dd, J ) 14.5, 10.0 Hz, 1 H), 1.89 (m, 1 H), 1.75 (d, J ) 6.5 Hz, 3 H),
1.65-1.09 (series of m, 5 H), 1.06 (s, 9 H), 0.92 (d, J ) 6.8 Hz, 3 H);
13C NMR (75 MHz, CDCl3) ppm 173.9, 135.5, 133.8, 133.1, 129.6,
129.4, 129.1, 128.2, 127.7, 127.6, 127.3, 73.0, 70.9, 69.3, 63.7, 42.7,
41.0, 39.6, 33.9, 30.8, 30.4, 26.9, 19.1, 17.9, 17.2; MS m/z (M+) calcd
1
of 31 as a colorless oil; IR (neat, cm-1) 1790, 1705; H NMR (300
MHz, CDCl3) δ 7.66 (m, 4 H), 7.40 (m, 6 H), 4.25 (m, 1 H), 4.13 (dd,
J ) 11.1, 8.6 Hz, 1 H), 3.69 (t, J ) 5.8 Hz, 2 H), 3.05 (dd, J ) 11.3,
6.6 Hz, 1 H), 2.59-2.38 (m, 2 H), 2.25 (d, J ) 10.2 Hz, 1 H), 1.82-
1.39 (series of m, 5 H), 1.21 (d, J ) 2.3 Hz, 3 H), 1.16 (m, 2 H), 1.06
(s, 9 H), 1.01 (m, 1 H), 0.85 (d, J ) 6.3 Hz, 3 H), 0.80 (m, 2 H), 0.28
(dd, J ) 10.7, 5.3 Hz, 1 H); 13C NMR (75 MHz, CDCl3) ppm 217.6,
176.6, 135.5, 133.8, 129.7, 127.6, 67.6, 63.6, 55.5, 55.1, 44.3, 43.7,
35.1, 33.1, 29.9, 28.9, 26.8, 23.1, 20.4, 19.1, 18.2, 13.8, 9.5; MS m/z
676.2487, obsd 676.2496; [R]23 +4.8 (c 1.87, CHCl3).
D
26b: colorless oil; IR (neat, cm-1) 1765; 1H NMR (300 MHz, CDCl3)
δ 7.64 (m, 4 H), 7.53 (m, 2 H), 7.39 (m, 6 H), 7.22 (m, 3 H), 5.87
(ddq, J ) 15.2, 6.3, 1.2 Hz, 1 H), 5.58 (ddq, J ) 15.2, 6.1, 1.6 Hz, 1
H), 4.60 (t, J ) 6.0 Hz, 1 H), 4.31 (dd, J ) 8.5, 6.7 Hz, 1 H), 4.03 (dd,
J ) 12.0, 8.5 Hz, 1 H), 3.62 (m, 3 H), 3.18 (dd, J ) 12.5, 3.4 Hz, 1
H), 3.02 (dd, J ) 12.5, 7.0 Hz, 1 H), 2.84 (m, 2 H), 1.98 (m, 1 H),
1.72 (d, J ) 6.5 Hz, 3 H), 1.67-1.08 (series of m, 5 H), 1.06 (s, 9 H),
0.87 (d, J ) 6.9 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm 173.7,
135.5, 133.80, 133.77, 133.3, 130.0, 129.7, 129.0, 127.7, 127.0, 126.0,
74.6, 72.9, 68.8, 63.6, 44.3, 41.4, 35.8, 34.5, 32.6, 31.9, 30.8, 26.9,
19.2, 17.9, 17.7; MS m/z (M+) calcd 676.2487, obsd 676.2481.
Equilibration of 26b with 26a. A solution of 26b (340 mg, 0.5
mmol) in benzene (80 mL) was refluxed for 4 h in the presence of
p-toluenesulfonic acid (15 mg, 0.08 mmol). The same chromatographic
separation as described above led to the isolation of 205 mg (60%) of
26a and the return of 50 mg (15%) of 26b.
(M+) calcd 532.3009, obsd 532.3003; [R]23 +8.6 (c 1.86, CHCl3).
D
Anal. Calcd for C33H44O4Si: C, 74.39; H, 8.32. Found: C, 74.67; H,
8.66.
(3aR,4S,5R,7R,7aS,8aS,8bR)-4-[(1R)-4-(tert-Butyldiphenylsiloxy)-
1-methylbutyl]decahydro-5-hydroxy-7-methyl-1H-cyclopropa[3,4]-
cycloocta[1,2-c]furan-1-one (32). A solution of 31 (285 mg, 0.54
mmol) in CH2Cl2 (12 mL) cooled to -78 °C was treated with Dibal-H
(1.6 mL of 1.0 M in hexanes, 1.6 mmol) and stirred for 15 min. The
reaction was quenched with saturated NH4Cl solution, and the mixture
was acidified with 5% HCl to pH 3 and extracted with ethyl acetate.
The combined organic extracts were dried and evaporated, and the
residual oil was filtered through a short column of silica gel (elution
with 50% ethyl acetate in hexanes) to give 260 mg (91%) of a 2:1
stereoisomeric mixture of hydroxy lactols (1H NMR analysis). This
material was dissolved in benzene (90 mL), treated with silver carbonate
on Celite (3.0 g, ca. 10 equiv), stirred at the reflux temperature for 10
min, cooled, and filtered through a small pad of silica gel (elution with
30% ethyl acetate in hexanes). Lactone 32 was obtained in quantitative
(3aR,4S,7R,9aR)-4-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-methylbu-
tyl]-3a,4,7,9a-tetrahydro-7-methylcycloocta[c]furan-1,5(3H,6H)-di-
one (29) and (3aR,4S,7S)-4-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-
methylbutyl]-3a,4,7,8-tetrahydro-7-methylcycloocta[c]furan-
1,5(3H,6H)-dione (30). Into a solution of 26a (213 mg, 0.32 mmol)
in methanol (15 mL) and water (1.5 mL) was introduced sodium
periodate (86 mg, 0.4 mmol) and sodium bicarbonate (40 mg, 0.5
mmol). The mixture was stirred for 30 min, and the resulting white
suspension was diluted with water to a total volume of 200 mL prior
to extraction with CH2Cl2 (3 × 80 mL). The combined organic phases
were washed with water, dried, and evaporated to leave the selenoxide
which was divided into two equal portions. Each lot was dissolved in
9 mL of dimethylacetamide, transferred into a pressure tube, and treated
with ethyl vinyl ether (0.75 mL) and triethylamine (0.25 mL). The
sealed tubes were heated at 220 °C in a Wood’s metal bath for 20
min, cooled, diluted with water, and extracted with ether. The combined
organic phases were washed with brine, dried, and concentrated.
Chromatography of the residue on silica gel (elution with 15% ethyl
acetate in hexanes) gave 92 mg (55%) of 29 and 12 mg (7%) of 30.
29: colorless oil; IR (neat, cm-1) 1785, 1700; 1H NMR (300 MHz,
CDCl3) δ 7.64 (m, 4 H), 7.40 (m, 6 H), 5.83 (m, 1 H), 5.65 (m, 1 H),
1
yield as a colorless oil: IR (neat, cm-1) 3520, 1770; H NMR (300
MHz, CDCl3) δ 7.65 (m, 4 H), 7.40 (m, 6 H), 4.47 (dd, J ) 11.5, 7.7
Hz, 1 H), 4.23 (t, J ) 7.2 Hz, 1 H), 4.17 (m, 1 H), 3.68 (m, 2 H), 2.65
(dd, J ) 13.5, 9.9 Hz, 1 H), 2.35 (m, 1 H), 2.07 (dd, J ) 6.0, 3.3 Hz,
1 H), 1.77 (dd, J ) 13.8, 6.1 Hz, 1 H), 1.63-1.12 (series of m, 8 H),
1.09 (d, J ) 6.6 Hz, 3 H), 1.06 (s, 9 H), 1.00 (m, 1 H), 0.92 (d, J )
6.7 Hz, 3 H), 0.63 (m, 2 H), 0.24 (q, J ) 5.1 Hz, 1 H); 13C NMR (75
MHz, CDCl3) ppm 179.1, 135.5, 133.9, 129.6, 127.6, 71.4, 70.6, 63.8,
47.5, 47.3, 44.7, 43.6, 36.8, 31.6, 30.7, 29.8, 26.8, 23.5, 20.8, 19.2,
16.9, 14.2, 9.2; MS m/z (M+ - C4H8) calcd 478.2508, obsd 478.2494;
[R]23 +29.3 (c 2.17, CHCl3).
D
(4S,5R,7R,7aS,8aS)-4-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-meth-
ylbutyl]-3,4,5,6,7,7a,8,8a-octahydro-5-hydroxy-7-methyl-1H-
cyclopropa[3,4]cycloocta[1,2-c]furan-1-one (33a). A solution of 32
(107 mg, 0.20 mmol) in THF (5 mL) at -78 °C was treated with

1318 J. Am. Chem. Soc., Vol. 118, No. 6, 1996
Wang et al.
potassium hexamethyldisilazide (0.96 mL of 0.5 M in toluene, 0.48
mmol), stirred for 1 h, and treated with benzeneselenenyl chloride (92
mg, 0.48 mmol) dissolved in 0.8 mL of THF. The mixture was stirred
for 15 min before the reaction was quenched with saturated NH4Cl
solution and the mixture extracted with ether. The combined organic
phases were washed with saturated NaHCO3 solution and brine, dried,
and evaporated to leave a residue which was purified by chromatog-
raphy on silica gel (elution with 20% ethyl acetate in hexanes). There
was obtained 104 mg (83% based on recovered 32) of a 2:1 mixture
(1H NMR analysis) of selenides and 10 mg of unreacted 32.
6 h. The mixture was then diluted with water and extracted with ethyl
acetate. The combined organic extracts were washed with 5% HCl,
saturated NaHCO3 solution, and brine prior to drying and solvent
evaporation. Chromatography of the residue gel (elution with 90%
ethyl acetate in hexanes) afforded 77 mg (87%) of 33c as a colorless
1
oil: IR (neat, cm-1) 3495, 1770, 1740, 1665; H NMR (300 MHz,
CDCl3) δ 5.44 (br s, 1 H), 4.83 (dd, J ) 17.2, 2.3 Hz, 1 H), 4.76 (dd,
J ) 17.2, 2.8 Hz, 1 H), 3.61 (m, 2 H), 3.20 (d, J ) 8.1 Hz, 1 H), 2.01
(s, 3 H), 1.90 (dd, J ) 14.8, 4.3 Hz, 1 H), 1.82-1.22 (series of m, 7
H), 1.12 (m, 3 H), 0.99 (d, J ) 6.7 Hz, 3 H), 0.96 (d, J ) 6.7 Hz, 3
H), 0.92 (m, 1 H), 0.34 (q, J ) 5.2 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) ppm 174.0, 169.6, 166.1, 128.9, 72.3, 71.4, 62.4, 47.6, 43.9,
33.2, 31.8, 30.2, 29.3, 25.9, 23.2, 21.1, 17.1, 10.3, 8.4; MS m/z (M+)
The above selenides (104 mg, 0.15 mmol) were dissolved in
methanol (10 mL) and water (0.65 mL), treated with sodium periodate
(104 mg, 0.48 mmol) and sodium bicarbonate (52 mg, 0.62 mmol),
stirred for 1 h, diluted with water, and extracted with ethyl acetate.
The combined organic extracts were washed with brine, dried, and
evaporated. Chromatographic purification of the residue (silica gel,
elution with 30% ethyl acetate in hexanes) afforded 33a (70 mg, 87%)
as a white solid: mp 141-142 °C; IR (CHCl3, cm-1) 3640, 1755, 1660;
1H NMR (300 MHz, CDCl3) δ 7.64 (m, 4 H), 7.40 (m, 6 H), 4.97 (dd,
J ) 17.3, 2.5 Hz, 1 H), 4.67 (dd, J ) 17.3, 2.8 Hz, 1 H), 4.32 (br s,
1 H), 3.64 (m, 2 H), 3.08 (d, J ) 8.2 Hz, 1 H), 1.87 (m, 1 H), 1.72 (m,
3 H), 1.50 (m, 4 H), 1.25 (m, 2 H), 1.04 (s, 9 H), 1.01 (d, J ) 7.0 Hz,
3 H), 0.99 (d, J ) 6.5 Hz, 3 H), 0.96 (m, 2 H), 0.35 (q, J ) 5.2 Hz,
1 H); 13C NMR (75 MHz, CDCl3) ppm 174.8, 168.8, 135.5, 133.8,
129.6, 127.9, 127.6, 72.3, 69.8, 63.7, 48.8, 48.4, 33.1, 31.8, 30.2, 28.3,
26.8, 26.0, 23.7, 19.1, 17.4, 10.0, 8.1; MS m/z (M+) calcd 432.3009,
calcd 336.1939, obsd 336.1938; [R]23 +41.9 (c 1.0, CHCl3).
D
(rR,4S,5R,7R,7aS,8aS)-3,4,5,6,7,7a,8,8a-Octahydro-5-hydroxy-
γ,7-dimethyl-oxo-1H-cyclopropa[3,4]cycloocta[1,2-c]furan-4-bu-
tyraldehyde Acetate (34). A solution of 33c (55 mg, 0.16 mmol) in
CH2Cl2 (5 mL) was treated with pyridinium dichromate (80 mg, 0.21
mmol) and 4 Å molecular sieves (80 mg), stirred at room temperature
for 80 min, diluted with ether (10 mL), and filtered through a short
column of silica gel. There was obtained 44 mg (80%) of 34 as a
colorless oil: IR (neat, cm-1) 1775, 1750, 1735, 1670; 1H NMR (300
MHz, CDCl3) δ 5.45 (br s, 1 H), 4.85 (m, 2 H), 3.18 (d, J ) 8.1 Hz,
1 H), 2.52 (m, 2 H), 2.02 (s, 3 H), 1.91-1.60 (series of m, 5 H), 1.47
(m, 1 H), 1.31 (m, 1 H), 1.04 (m, 3 H), 0.98 (d, J ) 6.7 Hz, 3 H), 0.96
(d, J ) 6.7 Hz, 3 H), 0.35 (dd, J ) 10.7, 5.2 Hz, 1 H); 13C NMR (75
MHz, CDCl3) ppm 200.7, 173.7, 169.6, 165.3, 129.2, 72.1, 71.2, 47.7,
43.9, 41.3, 32.8, 29.3, 27.6, 25.9, 23.2, 21.1, 16.7, 10.4, 8.4; MS m/z
obsd 532.3010; [R]23 +28.8 (c 1.67, CHCl3). Anal. Calcd for
D
C33H44O4Si: C, 74.39; H, 8.32. Found: C, 74.00; H, 8.32.
(4S,5R,7R,7aS,8aS)-4-[(1R)-4-(tert-Butyldiphenylsiloxy)-1-meth-
ylbutyl]-3,4,5,6,7,7a,8,8a-octahydro-5-hydroxy-7-methyl-1H-
cyclopropa[3,4]cycloocta[1,2-c]furan-1-one Acetate (33b). A solu-
tion of 33a (171 mg, 0.32 mmol) in CH2Cl2 (10 mL) was treated with
acetic anhydride (0.28 mL, excess) and DMAP (70 mg, 0.57 mmol).
The reaction mixture was stirred at room temperature for 1 h, diluted
with ether (20 mL), washed with saturated NaHCO3 solution and brine,
dried, and evaporated. Chromatography of the residue on silica gel
(elution with 20% ethyl acetate in hexanes) gave 183 mg (99%) of
(M+) calcd 334.1758, obsd 334.1769; [R]23 +43.3° (c 1.5, CHCl3).
D
Acetoxycrenulide (1a). A suspension of vacuum-dried isopropyl-
triphenyl phosphonium bromide (50 mg, 0.13 mmol) in cold (0 °C)
THF (2 mL) was treated with n-butyllithium (0.10 mL of 1.5 M in
hexanes, 0.15 mmol), and an oranged-colored solution resulted. This
solution was cooled to -78 °C, treated with 34 (28 mg, 0.084 mmol)
dissolved in THF (1 mL), stirred for 5 min at -78 °C, and warmed to
room temperature for 10 min. The reaction was quenched with
saturated NH4Cl solution and the mixture extracted with ether. The
combined organic layers were dried and concentrated to leave a residue
which was chromatographed on silica gel (elution with 25% ethyl
acetate in hexanes). There was isolated 23 mg (79%) of 1a, which
1
33b as a colorless oil: IR (neat, cm-1) 1765, 1740, 1670; H NMR
(300 MHz, CDCl3) δ 7.64 (m, 4 H), 7.40 (m, 6 H), 5.44 (br s, 1 H),
4.76 (dd, J ) 17.0, 2.4 Hz, 1 H), 4.67 (dd, J ) 17.0, 2.7 Hz, 1 H),
3.62 (m, 2 H), 3.15 (d, J ) 8.3 Hz, 1 H), 2.01 (s, 3H), 1.91 (dd, J )
15.4, 4.4 Hz, 1 H), 1.81-1.06 (series of m, 9 H), 1.03 (s, 9 H), 0.97
(d, J ) 6.6 Hz, 6 H), 0.93 (m, 1 H), 0.37 (q, J ) 5.2 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) ppm 174.2, 169.8, 166.8, 135.5, 133.7, 129.6,
128.7, 127.6, 72.0, 71.4, 63.6, 47.3, 43.9, 32.9, 31.9, 30.0, 29.0, 26.8,
25.9, 23.4, 21.3, 19.1, 17.0, 10.1, 8.2; MS m/z (M+ - H) calcd
573.3036, obsd 573.3027; [R]23D +21.0 (c 1.9, CHCl3). Anal. Calcd
for C35H46O5Si: C, 73.13; H, 8.07. Found: C, 73.51; H, 8.33.
(4S,5R,7R,7aS,8aS)-3,4,5,6,7,7a,8,8a-Octahydro-5-hydroxy-4-[(1R)-
4-hydroxy-1-methylbutyl]-7-methyl-1H-cyclopropa[3,4]cycloocta-
[1,2-c]furan-1-one 5-Acetate (33c). A solution of 33b (153 mg, 0.27
mmol) in CH3CN (8 mL) was treated with pyridinium fluoride solution
[prepared by adding 1 mL of 48% HF to a mixture of CH3CN (1 mL)
and pyridine (2.4 mL) at 0 °C] in three equal aliquots of 0.33 mL over
1
exhibits a H NMR spectrum identical with those of natural acetoxy-
crenulide:6,7 13C NMR (75 MHz, CDCl3, 60 °C) ppm 173.9, 169.6, 166.2,
132.4, 128.8, 123.6, 72.4, 71.4, 47.5, 43.9, 35.7, 32.9, 29.3, 25.9, 25.5
(2 C), 23.3, 21.1, 17.6, 17.1, 10.4, 8.4; [R]23 +20.1 (c 1.8, CHCl3).
D
The highest reported optical rotation for 1a is +21.5.4
Acknowledgment. This work was generously supported by
the National Institutes of Health (Grant GM-30827). We thank
Professor James Sims (University of California, Riverside) for
providing the IR and 1H NMR spectra of acetoxycrenulide and
Dr. Susumu Akutagawa (Takasago Research Institute, Tokyo)
for a generous sample of (R)-citronellol.
JA9533609