Cyclohexenone construction by intramolecular alkylidene C-H insertion: Synthesis of (+)-cassiol

Article abstract of DOI:10.1021/jo960973a

We report new procedures for stereoselective cyclopentene and cyclohexenone construction employing the alkylidene carbene C-H insertion reaction. Described are diastereoselective insertion into methylene and enantiospecific insertion into methine C-H bonds. The latter case leads directly to the enantioselective synthesis of (+)-cassiol (1).

Full text of DOI:10.1021/jo960973a

J . Org. Chem. 1996, 61, 5723-5728
5723
Articles
Cycloh exen on e Con str u ction by In tr a m olecu la r Alk ylid en e C-H
In ser tion : Syn th esis of (+)-Ca ssiol
Douglass F. Taber,* Robert P. Meagley, and Douglas J . Doren
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
Received May 28, 1996X
We report new procedures for stereoselective cyclopentene and cyclohexenone construction employing
the alkylidene carbene C-H insertion reaction. Described are diastereoselective insertion into
methylene and enantiospecific insertion into methine C-H bonds. The latter case leads directly
to the enantioselective synthesis of (+)-cassiol (1).
In tr od u ction
Ba ck gr ou n d : Th e Tr a n sition Sta te for C-H
In ser tion by Alk ylid en e Ca r ben e
The stereospecific construction of functionalized five-
and six-membered carbocycles continues to challenge
practitioners of organic synthesis. The work of Gilbert1a,b
and later of Ohira1c,d suggested that the intramolecular
C-H insertion of an alkylidene carbene1 could offer a
general method for converting acyclic ternary stereogenic
centers into cyclic quaternary centers of defined absolute
configuration. We detail here our exploration of several
procedures for generating alkylidene carbenes from
ketones and our delineation of experimentally effective
protocols for effecting these cyclizations. The utility of
this approach is illustrated by an expeditious synthesis
of (+)-cassiol (1), a potent antiulcerant isolated from
Cinnimomum cassia, from the enantiomerically pure
ketone 3 via the cyclopentene 2.2
From a theoretical standpoint, the alkylidene carbene
is an interesting species, bearing both similarities to
alkyl carbenoids and significant differences. Ab initio
calcuculations3a,c employing a 6-31G** basis set on 4
indicate that this is a singlet carbene, which is essential-
ly sp hydridized: the HOMO extends linearly, as with
an alkyne, and the p orbital is empty, making the
LUMO. Experimental evidence for a singlet state may
be found in earlier work by Gilbert and Ohira who have
confirmed that C-H insertion into a stereochemically
defined methine proceeded with retention of absolute
configuration.1
A key issue that had not been resolved was one of
diastereoselectivity. Alkyl carbenoids are known to effect
C-H insertion to form cyclopentanes with significant
diastereoselectivity.4 We postulated that though more
reactive the alkylidene carbene could show a similar
diastereomeric preference. The transition state geometry
for the C-H insertion may be represented as a half chair.
In this example, the phenyl substituent lies in a
pseudoequatorial position. The methyl group adjacent
to the phenyl group may either be pseudoequatorial or
pseudoaxial. In each case only one of the two possible
methylene C-H bond molecular orbitals is periplanar
with and therefore can overlap with the empty orbital of
the alkylidene carbene. The case where the methyl group
is pseudoaxial leads to the syn diastereomer, and the case
where the methyl group is pseudoequatorial leads to the
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) For alkylidene carbene generation using dimethyl (diazomethyl)-
phosphonate, see: (a) Gilbert, J . C.; Giamalva, D. H.; Weersooriya, U.
J . Org. Chem 1983, 48, 5251. (b) Gilbert, J . C.; Giamalva, D. H.; Baze,
M. E. J . Org. Chem 1985, 50, 2557. For alkylidene carbene generation
and cyclization using (trimethylsilyl)diazomethane, see: (c) Ohira, S.;
Okai, K.; Moritani, T. J . Chem. Soc., Chem. Commun. 1992, 721. (d)
Ohira, S.; Sawamoto, T.; Yamato, M. Tetrahedron Lett. 1995, 36, 1537.
For our initial reports of the work described in full here, see: (e) Taber,
D. F.; Meagley, R. P. Tetrahedron Lett. 1994, 35, 7909. (f) Taber, D.
F.; Walter, R.; Meagley, R. P. J . Org. Chem. 1994, 59, 6014. (g) Taber,
D. F.; Sahli, A.; Yu, H.; Meagley, R. P. J . Org. Chem. 1995, 60, 6571.
For leading references to alternative strategies for the generation and
subsequent C-H insertion reactions of alkylidene carbenes, see: (h)
Karpf, M.; Dreiding, A. S. Helv. Chim. Acta 1979, 62, 852. (i) Ochiai,
M.; Uemura, K.; Masaki, Y. J . Am. Chem. Soc. 1993, 115, 2528. (j)
Williamson, B. L.; Tykwinski, R. R.; Stang, P. J . J . Am. Chem. Soc.
1994, 116, 93.
(3) (a) Geometries were optimized at the Hartree-Fock level
(restricted for the singlet, unrestricted for the triplet) with the 6-31G**
basis set. Single-point energies were calculated at the MP2 (frozen
core) level. Hybridization was analyzed by the natural bond orbital
method. (b) Molecular mechanics calculations were carried out using
the program Mechanics, implemented on a Tektronix CAChe worksta-
tion interfaced with a Silicon Graphics Indigo workstation. This code
is based on the MM2 molecular mechanics code of Allinger, with
extensions provided by the CAChe group. (c) For a detailed analysis
of the electronic structure of alkylidenes (vinylidenes) and of the
rearrangement to the corresponding alkyne, see: Gallo, M. M.;
Hamilton, T. P.; Schaefer, H. F., III. J . Am. Chem. Soc. 1990, 112,
8714.
(2) For the three previous preparations of (+)-cassiol, see: (a) Corey,
E. J .; Guzman-Perez, A.; Loh, T. J . Am. Chem. Soc. 1994, 116, 3611.
(b) Uno, T.; Watanabe, H.; Mori, K. Tetrahedron 1990, 46, 5563. (c)
Takemoto, T.; Fukaya, C.; Yokoyama, K. Tetrahedron Lett. 1989, 30,
723. Note added in proof: After this work was accepted for publication
a fourth synthesis of (+)-cassiol appeared. Trost, B. M.; Li, Y. J . Am.
Chem. Soc. 1996, 118, 6625.
S0022-3263(96)00973-5 CCC: $12.00 © 1996 American Chemical Society

5724 J . Org. Chem., Vol. 61, No. 17, 1996
Taber et al.
it was also determined that the system would not tolerate
hexane, either as a solvent for the commercial (trimeth-
ylsilyl)diazomethane or as a solvent for the base (i.e.,
n-butyllithium). We therefore employed methyllithium,
available as a salt free solution in diethyl ether, and
carefully distilled the (trimethylsilyl)diazomethane away
from the hexane solvent.7 Treatment of the DME solu-
tion of (trimethylsilyl)diazomethane with methyllithium
at -78 °C resulted in a slurry of [(trimethylsilyl)-
diazomethyl] lithium that efficiently converted 4 to a
4.4:1 mixture of 5 and 6.
anti diastereomer. A molecular mechanics3b simulation
of this system with an MM2 force field and a “weak bond”
between the alkylidene carbon and the target H indicates
that at the point of commitment the syn transition state
lies 1.5 kcal/mol higher in energy than the anti transition
state, largely due to 1,3 diaxial interactions with the
methyl group. On the basis of this model, we predicted
that the anti product would be the major diastereomer
formed in the reaction.
In tr a m olecu la r Alk ylid en e In ser tion : Meth in e
In ser tion
In support of our continuing studies toward the syn-
thesis of taxol, we next investigated the preparation of
enone 14, a possible taxol A-ring synthon.1f Crucial to
this effort is the conversion of ketone 12 to cyclopentene
13 via the kinetically favorable alkylidene carbene me-
thine insertion reaction. Having accomplished the C-H
insertion into the electronically deactivated methylene
of 9, we expected that application of our methodology to
this system would pose little difficulty, for in addition to
being a methine the target C-H bond is further activated
for carbene insertion by R-oxygenation.4b Indeed, upon
treatment with [(trimethylsilyl)diazomethyl]lithium, 12
was transformed efficiently into 13.
Alk ylid en e Ca r ben e Gen er a tion by Wa y of th e
Cu m u la ted Dia zoa lk en e
To test the above hypothesis, we prepared ketone 9
from 4-(4-(N,N-dimethylamino)phenyl)-3-buten-2-one,5 by
copper-mediated conjugate addition of ethylmagnesium
bromide. We expected that this would be a challenging
substrate to cyclize, as the inherently slower rate for
methylene compared to methine insertion would be
exacerbated by inductive electron withdrawal by the
adjacent aromatic ring. Thus, alternative pathways
could intervene.1a
We first explored procedures that would convert ke-
tones into alkylidene carbenes directly. The use of the
anion of dimethyl (diazomethyl)phosphonate to effect this
transformation was pioneered by Gilbert.1a,b This re-
agent is not commercially available but can be prepared
from dimethyl (phthalimidomethyl)phosphonate in two
steps. We have found Ohira’s substitution of (trimeth-
ylsilyl)diazomethane in this reaction to be more conve-
nient, since this reagent is commercially available.1c-f
We initially observed that the Ohira procedure, as
published, was not effective for the C-H insertion into
deactivated methine and methylene bonds. Selection of
the solvent system proved to be critical to success.6 It
was crucial to employ DME for smooth insertion into the
inherently less reactive methylene C-H bonds. Further,
(4) For reviews of diastereoselectivity in Rh-mediated C-H insertion
reactions, see: (a) Doyle, M. P.; Dyatkin, A. B.; Roos, G. H. P.; Canas,
F.; Pierson, D. A.; van Basten, A.; Muler, P.; Polleux, P. J . Am. Chem.
Soc. 1994, 116, 4507. (b) Wang, P.; Adams, J . J . Am. Chem. Soc. 1994,
116, 3296. (c) Doyle, M. In Homogeneous Transition Metal Catalysis
in Organic Synthesis; Moser, W. R., Slocum, D. W., Eds.; ACS Advanced
Chemistry Series 230; American Chemical Society: Washington, DC,
1992; Chapter 30. (d) Taber, D. F. Comprehensive Organic Synthesis,
Vol. 3; Pattenden, G., Ed.; Pergamon Press: Oxford, 1991; p 1045. For
more recent references, see: (e) Taber, D. F.; You, K. K. J . Am. Chem.
Soc. 1995, 117, 5759. (f) Taber, D. F.; You, K. K., Rheingold, A. L. J .
Am. Chem. Soc. 1996, 118, 547.
In tr a m olecu la r Alk ylid en e In ser tion :
Ch lor om eth ylen a tion /Elim in a tion
The efficiency of the cyclization of 12 to 13 suggested
that this could be a good system with which to explore
an alternative route1g to alkylidene carbenes, conversion
(7) The commercial material also contains impurities that we were
unable to remove by distillation.
(8) (a) Wittig, G.; Schlosser, M. Chem. Ber. 1961, 94, 1373. (b)
Ketley, A. D.; Berlin, A. J .; Gorman, E.; Fisher, L. P. J . Org. Chem.
1966, 31, 305.
(5) Matsui, M.; Oji, A.; Hiramatsu, K.; Shibata, K.; Muramatsu, H.
J . Chem. Soc., Perkin Trans. 2 1992, 201.
(6) (a) Gilbert, J . C.; Blackburn, B. K. J . Org. Chem. 1986, 51, 3656.
(b) Gilbert, J . C.; Giamalva, D. H. J . Org. Chem. 1992, 557, 4185.

Synthesis of (+)-Cassiol
J . Org. Chem., Vol. 61, No. 17, 1996 5725
Sch em e 2
of 12 to the vinyl chloride 14 followed by R-elimination,
and subsequent C-H insertion to give 13.
Treatment of the ketone 12 with (chloromethylene)-
triphenylphosphorane (prepared by the action of sodium
bis(trimethylsilylamide) upon (chloromethyl)triphenylphos-
phonium chloride in THF) gives 14 as 50/50 mixture of
the E and Z vinyl chlorides. We found that the selection
of an appropriate base was critical for eliciting R-elimina-
tion and subsequent C-H insertion by the alkylidene
carbene. Both sodium hydride and potassium tert-
butoxide proved to be ineffective. When LDA was used,
cyclization was complicated by reduction of the alkylidene
carbene to a simple alkene.10 However, when either
sodium or potassium bis(trimethylsilylamide) was used,
the exclusive product was 13 in high yield. Thus, in
systems for which C-H insertion is facile, chlorometh-
ylenation/R-elimination can take the place of treatment
with (trimethylsilyl)diazomethane.11
ylmagnesium bromide followed by hydrolysis gave a
crude mixture of the diastereomeric secondary alcohols
which was oxidized under Swern conditions to give the
requisite ketone 3.
At this point we were ready to attempt cyclization.
First we employed our modification of the Ohira cycliza-
tion, with the lithium derivative of (trimethylsilyl)-
diazomethane.1e,f The cyclization was so efficient in this
case that we could use n-butyllithium as the base, with
the accompanying hexane solvent.
We then turned our attention to the alternative vinyl
chloride cyclization procedure. Treatment of 3 with a
THF solution of (chloromethylene)triphenylphosphorane
gave an excellent yield of a 1:1 mixture of the Z and E
vinyl chlorides. Treatment of this mixture with excess
potassium bis(trimethylsilyl)amide in ether resulted in
the formation of 2 in high yield, underscoring the utility
of this procedure for generating alkylidene carbenes.
In ser tion in a Dea ctiva ted Meth in e: Tota l
Syn th esis of (+)-Ca ssiol
With the methodology proven successful in the two
extreme cases, we turned our attention to C-H insertion
into a deactivated methine, in the context of the total
synthesis of the antiulcerant (+)-cassiol (1). Our ap-
proach to 1 used a convergent strategy (Scheme 1). The
first task was to create a synthon for the 2,4-dimethyl-
4-(hydroxymethyl)-2-cyclohexenone ring that forms the
core of the molecule. A synthon that would become the
2-ethenyl-1,3-propanediol side chain was also required.
For the enone synthon, we employed the vinylogous ester
15. This was to be coupled with the lithio derivative of
the side chain synthon 2,2-dimethyl-5-(2-bromoethenyl)-
1,3-dioxane (16) to give (+)-cassiol after hydrolysis. The
alcohol 15 was to be elaborated from the cyclopentene 2,
the expected product from the reaction of ketone 3 with
[(trimethylsilyl)diazomethyl]lithium.
With cyclopentene in hand we carried on through
ozonolysis, MacDonald oxidation12 to the methyl ester 19,
and Claisen cyclization to the desired cyclohexanedione
(Scheme 3). We found this vinylogous acid to be unstable,
with a room temperature halflife in solution of only a few
days, thus complicating its esterification. We solved this
problem by effecting esterification with 2-diazopropane13a
to generate a 4:1 mixture of regioisomers of the vinylo-
gous ester 2013b directly from the crude dione. The
regioisomers were readily separable by column chroma-
tography. It is noteworthy that (trimethylsilyl)diazo-
methane gave a 1:1 mixture of the two methyl ether
regioisomers. Catalytic hydrogenation with 10% Pd-C
at 20 °C cleanly gave the alcohol 15.
Sch em e 1
(9) For earlier reports of 1,5 C-H insertion by alkylidene carbenes
generated from vinyl halides, see: (a) Erickson, K. L.; Wolinsky, J . J .
Am. Chem. Soc. 1965, 87, 1143. (b) Wolinsky, J .; Clark, G. W. J . Org.
Chem. 1976, 41, 745. (c) Fisher, R. H.; Baumann, M.; Koebrich, G.
Tetrahedron Lett. 1974, 1207.
(10) Creary, X. J . Am. Chem. Soc. 1977, 99, 7632.
(11) Treatment of the chloromethylene derivative of 9 with KHMDS
in diethyl ether resulted in a complex mixture of products, including
small amounts of both 10 and 11, and also the alkyne resulting from
1,2 methyl shift.
(12) MacDonald, C. E.; Nice, L. E.; Shaw, A. A.; Nestor, N. B.
Tetrahedron Lett. 1993, 34, 2741.
(13) (a) For the preparation of 2-diazopropane, see: Andrews, S. D.;
Day, A. C.; Raymond, P.; Whiting, M. C. Org. Synth. 1970, 50, 27. (b)
For the use of 2-diazopropane to esterify vinylogous acids, see: Solas,
D.; Wolinsky, J . J . Org. Chem., 1983, 48, 670.
In the event, we prepared enantiomerically pure 3
from (-)-norcitronellol (17) (Scheme 2), available from
geraniol following our published procedure.4e Benzyl
protection of 17 gave an ether (18) which after selective
ozonolysis gave the aldehyde. Homologation with eth-

5726 J . Org. Chem., Vol. 61, No. 17, 1996
Taber et al.
Sch em e 3
general cyclopentene synthesis originally adumbrated by
Gilbert1a,b and Ohira.1c,d
.
Exp er im en ta l Section
Gen er a l. 1H NMR and 13C NMR spectra were obtained as
solutions in deuteriochloroform (CDCl3). 13C multiplicities
were determined with the aid of a J VERT pulse sequence,
differentiating the signals for methyl and methine carbons as
“d” from methylene and quaternary carbons as “u”. The
infrared (IR) spectra were determined as neat oils. Mass
spectra (MS) were obtained at an ionizing potential of 15 eV.
Substances for which C, H analyses are not reported were
purified as specified and gave spectroscopic data consistent
with being >95% the assigned structure. Optical rotations
were determined as solutions in dichloromethane unless
otherwise noted. Rf values indicated refer to thin layer
chromatography (TLC) on 2.5 × 10 cm, 250 µm analytical
plates coated with silica gel GF, unless otherwise noted, and
developed in the solvent system indicated. Column chroma-
tography was carried out following the procedure described
by Taber.17 The solvent mixtures used are volume/volume
mixtures. All glassware was flame dried under a dry nitrogen
stream immediately before use. Tetrahydrofuran (THF), di-
ethyl ether, and 1,2-dimethoxyethane (DME) were distilled
from sodium metal/benzophenone ketyl under dry nitrogen.
Dichloromethane (CH2Cl2) and toluene were distilled from
calcium hydride under dry nitrogen. All reaction mixtures
were stirred magnetically, unless otherwise noted.
Sch em e 4
(S)-(-)-2,6-Dim eth yl-7-(ph en ylm eth oxy)-2-h epten e (18).
To a mixture of 28 mL of DME and 1.46 g of NaH (60% oil
dispersion, 36.6 mmol, 1.3 equiv) was added a solution of 17
(4.00 g, 28.2 mmol) in DME (28 mL) dropwise over 2 min at
rt. After the solution was stirred for 10 min, benzyl bromide
(4.0 mL, 33.8 mmol, 1.2 equiv) was added at rt. The mixture
was stirred for 75 min at rt while gas was evolved. After being
heated to reflux for 3 min, the mixture was stirred for 15 h at
rt. The reaction was quenched with 0.5 mL of 35% aqueous
HCl followed by 5 g of Na2SO4 and then concentrated and
chromatographed to give 6.21 g (27.8 mmol, 95% yield) of 18:
TLC Rf(10% ethyl acetate/petroleum ether) ) 0.90, bp0.25 (bath)
) 100-105 °C. [R]D ) 3.1° (c ) 79.2 CH2Cl2). 1H NMR (δ):
7.30 (m, 5H), 5.10 (bt, J ) 7.1 Hz, 1 H), 4.49 (s, 2H), 3.34 (m,
2H), 1.99 (t, J ) 7.3 Hz, 2H), 1.83 (m, 1H), 1.68 (s, 3H), 1.59
(s, 3H), 1.49 (m, 1H), 1.14 (m, 1H), 0.94 (d, J ) 6.8 Hz, 3 H).
13C NMR (δ): u, 138.8, 131.2, 75.9, 73.0, 33.8, 25.4; d, 128.3,
127.5, 127.3, 127.0, 124.8, 33.1, 25.7, 17.6, 17.1. IR: 2913,
2854, 1496, 1453, 1376, 1098, 1028, 820, 734, 697. Anal.
Calcd for C16H24O: C, 82.70; H, 10.41. Found: C, 82.84; H,
10.41. MS (m/z, %): 232 (15), 141 (14), 123 (55), 91 (100), 81
(29), 69 (28), 55 (12). HRMS: calcd for C16H24O 232.182716,
found 232.183394.
The side chain synthon we developed was 2,2-dimethyl-
5-(2-bromoethenyl)-1,3-dioxane (16), readily prepared in
five steps from commercial diethyl allylmalonate (Scheme
4). First the diester was reduced to the diol14 with
LiAlH4; then the allyl group was isomerized with
RhCl3‚nH2O and the diol was protected as the acetonide.
Ozonolysis of the olefin gave an aldehyde15 which was
condensed with (bromomethylene)triphenylphosphorane
to form 16 as an approximately equal E/Z mixture.
We lithiated 16 using tert-butyllithium and added the
resulting anion to 15. The intermediate alkoxide was
unravelled with aqueous acid to give (+)-cassiol, identical
(S)-6-Meth yl-7-(p h en ylm eth oxy)-3-h ep ta n on e (3).
mixture of 18 (3.00 g, 12.9 mmol), Sudan III (1 mg as an
indicator), and 30 mL of CH2Cl2 was chilled to -78 °C.
A
A
steady stream of 6% O3 in O2 (dried by passing through a -78
°C trap) was bubbled through the solution until the red color
of the indicator faded to pale yellow. The solution was sparged
with N2 for 2 min to remove the residual O3, then was treated
with triphenylphosphine (3.72 g, 14.2 mmol, 1.1 equiv) and
allowed to stir and come up to rt. The solution was concen-
trated to a thick yellow oil, presumably a mixture of (S)-1-
(phenylmethoxy)-2-methylpentanal, TLC, Rf(10% ethyl acetate
in petroleum ether) ) 0.75, and triphenylphosphine oxide, TLC
Rf(10% ethyl acetate in petroleum ether) ) 0.00. This mixture
was then redissolved in THF (30 mL) and chilled to 0 °C. To
this mixture was added ethylmagnesium bromide (1.5 M in
THF, 35 mL, 51 mmol, 4.0 equiv) over 5 min, resulting in a
clear red solution. The ice bath was removed, and the mixture
was allowed to warm to rt over 10 min. The mixture was
1
(TLC, H, 13C NMR, and MS) with the natural product.
Con clu sion
It is apparent that conversion of a ketone to the
homologous cyclopentene via the intermediate alkylidene
carbene can be achieved efficiently by employing [(tri-
methylsilyl)diazomethyl]lithium or by homologation to
the chlorovinyl derivative followed by base treatment. We
believe that the method outlined here represents a
significant step16 toward reducing to practicality the
(14) Sells, T. B.; Nair, V. Tetrahedron 1994, 50, 117.
(15) Bates, H. A.; Farina, J .; Tong, M. J . Org. Chem. 1986, 51,
2637.
(16) Since the inception of our work, several alternative procedures
for the generation and cyclization of alkylidene carbenes have been
put forward. For leading references, see: (a) Tykwinski, R. R.; Stang,
P. J .; Persky, N. E. Tetrahedron Lett. 1994, 35, 23. (b) Kunishima,
M.; Hikoi, K.; Tani, S.; Kato, A. Tetrahedron Lett. 1994, 35, 7253. (c)
Kim, S.; Cho, C. M. Tetrahedron Lett. 1994, 35, 8405. (d) Schildknegt,
K.; Bohnstedt, A. C.; Feldman, K. S.; Sambandam, A. J . Am. Chem.
Soc. 1995, 117, 7544. (e) Ohira, S.; Sawamoto, T.; Yamato, M.
Tetrahedron Lett. 1995, 36, 1537.
(17) Taber, D. F. J . Org. Chem 1982, 47, 1351.

Synthesis of (+)-Cassiol
J . Org. Chem., Vol. 61, No. 17, 1996 5727
partitioned between 3% aqueous HCl and ethyl acetate. The
combined organic extract was dried (Na2SO4), concentrated,
and chromatographed to give the diasteromeric secondary
alcohols, (6S,3S)- and (6S,3R)-6-methyl-7-(phenylmethoxy)-3-
haptanol (2.57 g, 84% yield), TLC Rf(10% ethyl acetate/
petroleum ether) ) 0.25.
Dimethyl sulfoxide (5 M in CH2Cl2, 4.4 mL, 22 mmol, 2.2
equiv) was added over 5 min to a mixture of CH2Cl2 (11.5 mL)
and oxalyl chloride (2 M in CH2Cl2, 5.5 mL, 11 mmol, 1.1 equiv)
at -78 °C. After an additional 30 min, the secondary alcohol
(2.36 g, 10 mmol, in 10 mL of CH2Cl2) was added over 12 min.
After an additional 7.5 h, 6.4 mL of triethylamine (46 mmol,
4.6 equiv) was added and the mixture was allowed to warm
to rt overnight. The mixture was partitioned between ethyl
acetate and, sequentially, water, 5% aqueous HCl, and satu-
rated aqueous NaHCO3. The combined organic extract was
dried (Na2SO4), concentrated, and chromatographed to give 3
(1.79 g, 65% yield from 18): TLC Rf(10% ethyl acetate/
A mixture of 22 (398 mg, 1.52 mmol) in acetonitrile (7.6 mL),
methanol (2.0 mL, 50 mmol, 33 equiv), and powdered 4 Å
molecular sieves (1.3 g) was stirred 0.5 h at rt. Acetic acid
(0.52 mL, 9.12 mmol, 6 equiv) and Ca(OCl)2 (0.652 g, 4.56
mmol, 3 equiv) were added, and the mixture was stirred for
3.0 h with the exclusion of light. Powdered Na2S2O8 (0.377 g,
5 equiv) was added, and the mixture was stirred 20 min at rt.
The mixture was filtered through silica gel to give 16 (365 mg,
61% yield from 2): [R]D ) 1.0° (c ) 25.1, CH2Cl2). 1H NMR
(δ): 7.25 (m, 5H), 4.42 (s, 2H), 3.59 (s, 2H), 3.50 (d, J ) 8.1
Hz, 1H), 3.41 (d, J ) 8.1 Hz, 1H), 2.36 (m, 4H), 1.80 (m, 2H),
1.12 (s, 3H), 0.96 (t, J ) 7.5 Hz, 3H). 13C NMR (δ): u, 210.7,
175.9, 138.2, 75.2, 73.2, 46.5, 37.4, 35.8, 29.4; d, 128.2, 127.4,
110.2, 51.7, 20.0, 7.8. IR (cm-1): 2978, 2359, 2338, 1735, 1715,
1454, 1376, 1102, 806, 741, 699. MS (m/z, %): 292 (2), 277
(87), 185 (14), 139 (7), 125 (12), 105 (100), 91 (62), 77 (22).
HRMS: calcd for C17H24O4 292.167460, found 292.165948.
(S )-2,6-D i m e t h y l-3-(1-m e t h y le t h o x y )-6[(p h e n y l-
m et h oxy)m et h yl]-2-cycloh exen on e (20a ) a n d (S)-2,4-
Dim eth yl-3-(1-m eth yleth oxy)-4-[(ph en ylm eth oxy)m eth yl]-
2-cycloh exen on e (20b). Under dry conditions, KHMDS (120
mg, 0.57 mmol, 1.5 equiv) was added as a dry powder to a
mixture of 19 (111 mg, 0.38 mmol) and DME (1.5 mL). After
9.5 h at rt, TLC analysis showed conversion to the desired
dione, TLC Rf ) 0.19 (30% ethyl acetate/petroleum ether). The
mixture was partitioned between ethyl acetate and saturated
aqueous NH4Cl (adjusted to pH ) 7.0 by the addition of 10%
aqueous HCl). The combined organic extract was dried (Na2-
SO4), chilled to 0°, and then treated with 2-diazopropane1 (1.5
M in Et2O, 8 mL, 12 mmol, 32 equiv). After 8 h at rt, the
mixture was concentrated and chromatographed to give 69 mg
of 20a (59 % from 19), TLC Rf ) 0.55 (7% CH2Cl2/7% MTBE/
petroleum ether) and 17 mg of 20b (15 % from 19), TLC Rf )
0.30 (7% CH2Cl2/7% MTBE/petroleum ether).
petroleum ether) ) 0.50, bp0.25 (bath) ) 105-110 °C. [R]D
)
-2.15° (c ) 52.2, CH2Cl2). 1H NMR (δ): 7.30 (m, 5H) 4.49 (s,
2H), 3.29 (dd, J ) 1.8, 6.0 Hz, 2H), 2.41 (m, 4H), 1.74 (m, 2H),
1.42 (m, 1H), 0.98 (t, J ) 7.3 Hz, 3H), 0.93 (d, J ) 6.6 Hz,
3H). 13C NMR (δ): u, 212.1, 138.5, 75.7, 72.8, 39.0, 36.1, 27.5;
d, 129.2, 128.2, 127.5, 127.3, 127.2, 32.1, 15.5, 9.5. IR (cm-1):
2931, 2872, 1713, 1455, 1414, 1367, 1102, 738, 697. MS (m/z,
%): 234 (0.28), 143 (28), 128 (24), 127 (26), 107 (24), 99 (23),
97 (12), 91 (100), 85 (40), 73 (12), 65 (21), 57 (83). HRMS:
calcd for C15H22O2 234.161980, found 234.16253.
(S)-1-Eth yl-3-m eth yl-3[(p h en ylm eth oxy)m eth yl]cyclo-
p en ten e (2) (via (Tr im eth ylsilyl)d ia zom eth a n e). A solu-
tion of n-butyllithium in hexane (2.16 M, 0.4 mL, 0.86 mmol,
1.8 equiv) was added to (trimethylsilyl)diazomethane (4.18 M
in hexane, 0.2 mL, 0.88 mmol, 1.8 equiv) and DME (3.6 mL)
at -68 °C. After 5 min, a solution of 3 (111 mg, 0.48 mmol)
in DME (0.2 mL) was added. After 23 min between -53 and
-68 °C, the mixture was partitioned between 10% aqueous
HCl and 14% ethyl acetate/petroleum ether. The combined
organic extract was dried (Na2SO4), concentrated, and chro-
matographed to give 2 (90 mg, 82% yield from 3): TLC, Rf(7%
ethyl acetate/petroleum ether) ) 0.86, bp0.25 (bath) ) 100-
110 °C. [R]D ) -38.7° (c ) 1.6, EtOH). 1H NMR (δ): 7.32 (m,
5H), 5.20 (bs, 1H), 4.57 (s, 2H), 3.27 (s, 2H), 2.31 (dt, J ) 0.7,
7.2 Hz, 2H), 2.08 (dq, J ) 1.0, 7.5 Hz, 2H), 1.92 (dt, J ) 7.2,
12.7 Hz, 1H), 1.60 (m, 1H), 1.11 (s, 3H), 1.07 (t, J ) 7.4 Hz,
3H). 13C NMR (δ): u, 146.1, 139.0, 78.4, 75.5, 73.2, 73.0, 49.6,
34.7, 34.1, 24.2; d, 129.2, 128.2, 127.5, 127.3, 127.2, 24.1, 12.3.
IR (cm-1): 3030, 2964, 2845, 1496, 1454, 1367, 1205, 1098,
1029, 845. Anal. Calcd for C16H22O: C, 83.43; H, 9.63.
Found: C, 83.62; H, 9.44. MS (m/z, %): 230 (2), 199 (9), 122
(7), 109 (100), 91 (79), 81 (35), 67 (53), 55 (25). HRMS: calcd
for C16H22O 230.167066, found 230.168383.
(S)-1-Eth yl-3-m eth yl-3-[(p h en ylm eth oxy)m eth yl]cyclo-
p en ten e (2) (via ch lor om eth ylen a tion ). A solution of
sodium bis(trimethylsilyl)amide in THF (1.0 M, 17.3 mL) was
added to a suspension of (chloromethyl)triphenylphosphonium
chloride (6.54 g, 17.9 mmol, 3 equiv) and THF (11 mL) at 0
°C. The mixture was then chilled to -78 °C, and a solution of
3 (1.40 g, 5.98 mmol, 1 equiv) in THF (6 mL) was added. After
12 h at rt the mixture was filtered through silica gel to give a
1:1 mixture of the E and Z vinyl chlorides (1.48 g, 5.75 mmol,
97% yield from 3).
To the mixed vinyl chlorides (1.48 g, 5.75 mmol) and diethyl
ether (225 mL) within a drybox was added potassium bis-
(trimethylsilyl)amide (4.49 g, 22.5 mmol, 4 equiv) as a dry
powder over 15 min. After 12 h, the mixture was partitioned
between saturated aqueous NaHCO3 and 2% ethyl acetate in
petroleum ether. The combined organic extract was dried (Na2-
SO4), concentrated, and chromatographed to give 2 (1.23 g,
89% from 3) identical to the cyclopentene prepared with
(trimethylsilyl)diazomethane.
Meth yl (S)-2-Meth yl-5-oxo-2-[(p h en ylm eth oxy)m eth yl]-
h ep ta n oa te (19). Following the procedure for converting 18
to 3, 2 was ozonized to the crude keto aldehyde. The mixture
was concentrated and chromatographed to give 22 (0.503 g,
1.92 mmol, 74% yield).
20a : [R]D ) 19.9° (c ) 19.3, CH2Cl2). 1H NMR (δ): 7.15
(m, 5H), 4.36 (m, 3H), 3.50 (d, J ) 8.9 Hz, 1H), 3.16 (d, J )
8.9 Hz, 1H), 2.36 (m, 2H), 2.15 (m, 1H), 1.79 (m, 4H), 1.12 (d,
J ) 6.1 Hz, 3H), 1.08 (d, J ) 6.1 Hz, 3H), 0.93 (s, 3H). 13C
NMR (δ): u, 201.2, 169.2, 138.3, 115.4, 75.4, 73.4, 44.2, 29.9,
22.5; d, 128.3, 127.3, 126.5, 69.8, 22.6, 20.1, 8.0. IR (cm-1):
2977, 1724, 1615, 1380, 1358, 1239, 1155, 1057, 971, 865, 747,
700. MS (m/z, %): 302 (0.04), 196 (6), 211 (5), 168 (22), 139
(24), 126 (23), 113 (5), 111 (5), 98 (19), 91 (100), 83 (15), 57
(13). HRMS: calcd for C19H26O3 302.188195, found 302.189387.
20b. 1H NMR (δ): 7.28 (m, 5H), 4.68 (m, 1H), 4.47 (s, 2H),
3.61 (d, J ) 8.7 Hz, 1H), 3.25 (d, J ) 8.7 Hz, 1H), 2.51 (m,
1H), 2.35 (m, 1H), 2.14 (m, 1H), 1.78 (s, 3H), 1.63 (m, 1H),
1.23 (d, J ) 6.1 Hz, 3H), 1.20 (d, J ) 6.0 Hz, 3H), 1.10 (s, 3H).
13C NMR (δ): u, 200.2, 174.5, 138.3, 117.3, 75.9, 73.1, 41.7,
33.6, 30.6; d, 128.2, 127.4, 127.2, 73.8, 22.7, 21.4, 10.8. IR
(cm-1): 2978, 2872, 1726, 1658, 1602, 1453, 1376, 1300, 1178,
1102, 1029, 751, 699. MS (m/z, %): 302 (0.65), 274 (7), 230
(5), 196 (4), 181 (6), 139 (23), 125 (5), 105 (67), 91 (100), 83
(30), 77 (15), 57 (6). HRMS: calcd for C19H26O3 302.188195,
found 302.189948.
(S)-4-(Hydr oxym eth yl)-2,4-dim eth yl-3-(1-m eth yleth oxy)-
2-cycloh exen on e (15). A 5 mL reactivial equipped with a
gas inlet adapter was charged with 20a (99 mg, 0.328 mmol)
and ethanol (1.5 mL). To this was added 10% Pd-C (10 mg,
9 wt %), and the vial was purged with and stirred under H2
for 78 min with monitoring by TLC. The mixture was then
filtered through Florisil, concentrated, and chromaographed
to give 15 (56 mg, 81% yield, TLC Rf ) 0.55 (33% MTBE/33%
CH2Cl2/33% petroleum ether). [R]D ) -45.0° (c ) 4.8, CH2-
Cl2). 1H NMR: 4.51 (m, J ) 6.1 Hz, 1H), 3.48 (bs, 2H), 3.23
(bs, 1H), 2.55-2.54 (t, J ) 1.9 Hz, 2H), 1.91 (m, 1H), 1.61 (s,
3H), 1.53 (m, 1H), 1.24 (d, J ) 6.0 Hz, 6H), 1.07 (s, 3H). 13C
NMR (δ): u, 205.0, 170.0, 114.8, 69.6, 43.7, 29.6, 22.3; d, 70.3,
23.1, 23.0, 18.8, 7.7. IR (cm-1): 3422, 2933, 1716, 1615, 1456,
1381, 1236, 1111, 1028, 943, 668. MS (m/z, %): 212 (18), 182
(10), 170 (18), 152 (30), 140 (31), 139 (24), 137 (11), 125 (15),
113 (4), 111 (8), 98 (100), 85 (22), 83 (62), 82 (40), 71 (33), 70
(35), 69 (43), 67 (11), 57 (57). HRMS: calcd for C12H20O3
212.141245, found 212.143461.
2,2-Dim eth yl-1,3-d ioxa n e-5-ca r boxa ld eh yd e (21). 2-(2-
Propenyl)-1,3-propanediol14 (41.0 g, 353 mmol) and rhodum

5728 J . Org. Chem., Vol. 61, No. 17, 1996
Taber et al.
trichloride hydrate (216.4 mg, 0.4 mol %) were stirred and
heated to 120 °C for 108 h to give crude 2-(1-propenyl)-1,3-
propanediol (41.2 g, 85% yield).
mixture of 16 (250 mg, 1.15 mmol, 4 equiv) and ether (2.7 mL)
at -78 °C. The mixture was allowed to warm to 0 °C; then a
solution of 15 (60 mg, 0.28 mmol) in ether (0.3 mL) was added
and rinsed in with ether (2 × 0.7 mL). After 48 h at rt the
mixture was warmed to reflux for 2 min and then partitioned
between ethyl acetate and saturated aqueous NaHCO3 (buff-
ered to pH ) 8 with NH4Cl). The combined organic extract
was then dried (Na2SO4 and NaHCO3) and concentrated.
The crude 2-(1-propenyl)-1,3-propanediol (41.2 g, 353 mmol,
1 equiv) and 2,2-dimethoxypropane (110 mL, 1.06 mol, 3 equiv)
were treated with camphorsulfonic acid (100 mg). A simple
still equipped with vacuum takeoff was attached, and the
mixture was distilled (21-90 °C, 760 mmHg) to remove
acetone, methanol, and excess 2,2-dimethoxypropane; then the
pressure was reduced and distillation was continued to give
2,2-dimethyl-5-(1-propenyl)-1,3-dioxane, bp18 (bath) ) 90-145
°C (41.84 g, 76% yield).
Following the procedure for converting 18 to 3, 2,2-dimethyl-
5-(1-propenyl)-1,3-dioxane (29.6 g, 190 mmol) was ozonized to
the crude aldehyde 21. After 1 h at rt the solution was
concentrated (Caution: sufficient time must be given for this
ozonide to be reduced before concentration to prevent rapid
exothermic reaction and potential explosive decomposition) and
distilled to give 21, bp19 (bath) ) 104-108 °C (17.96 g, 125
mmol, 78% yield) which was identical to material produced
by Bates.15 1H NMR: 9.89 (s, 1H), 4.23 (m, 4H), 2.38 (m, 1H),
1.48 (s, 3H), 1.37 (s, 3H).
2,2-Dim eth yl-5-(2-br om o-1-eth en yl)-1,3-d ioxa n e (16). A
solution of sodium bis(trimethylsilyl)amide (1.0 M in THF, 67
mL, 1.3 equiv) was added to a suspension of (bromomethyl)-
triphenylphosphonium bromide (29.0 g, 66.5 mmol, 1.3 equiv)
in THF (70 mL) at -78 °C. After 30 min, a solution of 21 (7.43
g, 51.6 mmol) in THF (20 mL) was added and the mixture was
stirred and warmed to 0 °C. After 2 h the mixture was
partitioned between saturated aqueous NaHCO3 and diethyl
ether. The combined extract was filtered through silica gel
to give an oil which was distilled to give 16 (bp3.0 (bath) ) 80-
100 °C, 6.7 g, 61% yield) as a 1:1 mixture of the E and Z vinyl
bromides. 1H NMR (δ): 6.33-6.05 (m, 2H), 4.07-3.83 (m, 2H),
3.76-3.68 (m, 2H), 3.01-2.94 (m, 0.5H), 2.78-2.54 (m, 0.5H),
1.45 (s, 6H). 13C NMR (δ): u, 97.8, 97.7, 63.3, 62.6; d, 134.5,
131.9, 110.0, 107.6, 38.9, 36.4, 26.7, 25.1, 22.6, 20.9. IR (cm-1):
2993, 2866, 1731, 1619, 1454, 1372, 1261, 1198, 1135, 1078,
937, 832, 792, 708, 518, 481, 456, 472. MS (m/z, %): 207 (43),
204 (44), 191 (14), 190 (13), 134 (93), 131 (100). HRMS: calcd
for C7H10O2Br 206.984270, found 206.983579.
The residue was redissolved in MTBE (5 mL) and treated
with 5 mL of 10% aqueous HCl. After 2.5 h, solid NaHCO3
(2.0 g) was added. The phases were separated, and the salts
were washed with EtOAc. The combined organic extract was
concentrated and chromatographed to give 1 (48 mg, 60%
yield). [R]D ) 9.1° (c ) 4.5, MeOH). 1H NMR (400 MHz, D2O,
δ): 6.09 (d, J ) 16.3 Hz, 1H), 5.48 (dd, J ) 8.4, 16.3 Hz, 1H),
3.67-3.27 (m, 5H), 3.24 (d, J ) 11.5 Hz, 1H), 2.49-2.34 (m,
2H), 2.02-1.95 (m, 1H), 1.66-1.53 (m, 4H), 0.93 (s, 3H); (400
MHz, CDCl3, δ) 6.23 (d, J ) 16.3, 1H), 5.61-5.55 (dd, J ) 8.1,
16.3, 1H), 3.79-3.72 (m, 4H), 3.67 (d, J ) 11.4, 1H), 3.37 (d,
J ) 11.4, 1H), 2.66-2.61 (m, 1H), 2.56-2.45 (m, 2H), 2.40-
2.22 (m, 1H), 2.21-2.15 (m, 1H), 1.81 (s, 3H), 1.12 (s, 3H). 13
C
NMR (101 MHz, D2O, δ uncorrected): u, 204.9, 162.6, 132.1,
68.2, 62.3, 40.9, 33.6, 31.0; d, 136.9, 129.1, 48.1, 20.7, 13.4;
(101 MHz, CDCl3, δ) u, 199.5, 158.3, 131.8, 69.5, 63.8, 40.8,
33.8, 31.9; d, 135.1, 129.4, 47.5, 20.9, 13.5. IR (cm-1): 3394,
2925, 1732, 1652, 1616, 1456, 1380, 1260, 1110, 1032, 802, 739.
These data were identical (1H and 13C NMR in D2O) with those
reported2a for 1.
Ack n ow led gm en t. We thank C. Fukaya for provid-
ing spectral data of cassoiside as isolated in his labora-
tory. We also thank S. Ohira for his advice. Finally,
we are grateful to the NIH (GM 46762) for financial
support.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for all new compounds (17 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for information.
(+)-Ca ssiol (1). A solution of tert-butyllithium (1.34 mL,
1.73 M in hexane, 2.26 mmol, 8.0 equiv) was added to a
J O960973A