A new catalyst for a Pd catalyzed Alder ene reaction. A total synthesis of (+)-cassiol

Article abstract of DOI:10.1021/ja960642f

The scope of the palladium catalyzed cycloisomerization of enynes in an Alder ene type fashion that led to a new catalytic system was explored in the context of a synthetic strategy to the antiulcerogenic agent (+)-cassiol. In a model study, the effect of

Full text of DOI:10.1021/ja960642f

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J. Am. Chem. Soc. 1996, 118, 6625-6633
6625
A New Catalyst for a Pd Catalyzed Alder Ene Reaction. A
Total Synthesis of (+)-Cassiol
Barry M. Trost* and Yong Li
Contribution from the Department of Chemistry, Stanford UniVersity, Stanford, California 94305
ReceiVed February 27, 1996X
Abstract: The scope of the palladium catalyzed cycloisomerization of enynes in an Alder ene type fashion that led
to a new catalytic system was explored in the context of a synthetic strategy to the antiulcerogenic agent (+)-cassiol.
In a model study, the effect of six-membered ring formation, the presence of a carbonyl group in the tether, and the
steric hindrance of the alkene conspire to prevent the cycloisomerization under the “standard” conditions. Two
variables proved key in the development of a new catalytic system that has proven to be effective, the absence of
traditional ligands and the choice of acid. An effective synthesis of (+)-cassiol was accomplished in which this new
reaction played a key. A lipase served to introduce the chirality, and a palladium(0) catalyzed reaction was important
in elaborating a side chain. The final adjustment of oxidation level made advantageous use of a platinum catalyzed
enone hydrosilyation.
The Pd catalyzed Alder ene-type reaction constitutes a
The cycloisomerization step involves two significant meth-
odological issuessthe compatibility of a carbonyl group in the
tether and the formation of a six-membered ring, especially
considering the steric congestion associated with the quarternary
carbon adjacent to the alkene requiring the intramolecular
carbapalladation step occurring at a neopentyl center. Early
work questioned the compatibility of a carbonyl group in the
tether. Fortunately, in the context of a chokol C synthesis,
although the presence of the carbonyl group proved nontrivial,
the feasibility for cyclopentanone construction was established
(eq 1).1e In this paper, we record our observations on the
feasibility of the cycloisomerization for cyclohexanone synthesis,
the development of a new catalyst system, and the applicability
of this process to help create a synthetic strategy to (+)-cassiol.
potentially powerful ring forming process.1 While five-
membered ring formation occurs smoothly with a broad array
of substrates, six-membered ring formation appears less general,
presumably because the higher entropy of cyclization to the six-
membered ring allowed competing noncyclization reactions to
predominate.2 We therefore embarked on a program to examine
the scope and limitations of the six-membered ring forming
reaction in the context of a synthesis of (+)-cassiol 1, a potent
antiulcerogenic agent. Chinese cinnamon has long been used
in traditional Chinese medicine as a diaphoretic, an antipyretic,
and an analgesic. An aqueous extract from Cinnamomi Cortex
(the dried stem bark of Cinnamomum cassia Blume) was
reported to have potent antiulcerogenic activity.3 The active
ingredient proved to be cassioside (2) whose enzymatic hy-
drolysis product, cassiol (1), proved to be even more potent.4
The attractiveness of this interesting biological target which
has been the subject of three syntheses to date5 was the
simplicity of the strategy outlined in Scheme 1 emanating from
the employment of two Pd catalyzed reactionssallylic alkyla-
tion6 and cycloisomerization.1,2 By factoring the problem to a
differentially dialkylated malonate as starting material, asym-
metry could be introduced by an enzymatic hydrolysis which
simultaneously chemodifferentiates the two esters in order to
facilitate elaboration of one to the highly functional side chain
of cassiol.7
A Model Study. The design of a meaningful model system
required many of the structural issues of cassiol that would
impact the effectiveness of the reaction, notably the steric
hindrance. For this reason, the enyne 3 as illustrated in Scheme
2 was chosen. The 1,1-bishydroxymethyl segment was intro-
duced using Pd(0) catalyzed allylic alkylation. Notably, both
the regioselectivity and alkene geometry were completely
controlled in this process. The polarity of the diol resulting
from reduction of the diester with LAH made the workup of
this reaction critical. Best results involved sequential addition
of water, 10% aqueous sodium hydroxide, and finally saturated
aqueous potassium fluoride. The addition of fluoride was
necessary to liberate the diol from the aluminum salts which,
by using this reagent, became quite granular and easily removed
by filtration. This workup should prove generally useful for
such polar products. Chemoselective hydroboration was readily
accomplished with disiamylborane.8 The remaining steps were
uneventful. The model substrate was available in eight steps
X Abstract published in AdVance ACS Abstracts, July 1, 1996.
(1) (a) Trost, B. M. Acc. Chem. Res. 1990, 23, 34. (b) Trost, B. M.;
Edstrom, E. D. Angew. Chem., Int. Ed. Engl. 1990, 29, 520. (c) Trost, B.
M.; Tasker, A. S.; Ru¨hter, G.; Brandes, A.; J. Am. Chem. Soc. 1991, 113,
670. (d) Trost, B. M.; Hipskind, P. A. Tetrahedron Lett. 1992, 33, 4541.
(e) Trost, B. M.; Phan, L. T. Tetrahedron Lett. 1993, 34, 4735. (f) Trost,
B. M.; Krische, M. J. J. Am. Chem. Soc. 1996, 118, 233.
(2) Trost, B. M.; Pedregal, C. J. Am. Chem. Soc. 1992, 114, 7292. Trost,
B. M.; Tanoury, G. J.; Lautens, M.; Chan, C.; MacPherson, D. T. J. Am.
Chem. Soc. 1994, 116, 4255. Trost, B. M.; Romero, D. L.; Rise, F. J. Am.
Chem. Soc. 1994, 116, 4268.
(3) Tanaka, S.; Akira, T.; Tabata, M. Yakugaku Zasshi 1984, 104, 601.
Tanaka, S.; Akira, T.; Tabata, M. Planta Medica 1986, 440.
(4) Shiraga, Y.; Okano, K.; Akira, T.; Fukaya, C.; Yokoyama, K.; Tanaka,
S.; Fukui, H.; Tabata, M. Tetrahedron 1988, 44, 4703.
(5) Takemoto, T.; Fukaya, C.; Yokoyama, K. Tetrahedron Lett. 1989,
30, 723. Uno, T.; Watanabe, H.; Mori, K. Tetrahedron 1990, 46, 5563.
Corey, E. J.; Guzman-Perez, A.; Loh, T.-P. J. Am. Chem. Soc. 1994, 116,
3611.
(7) For reviews, see: Ohno, M.; Otsuka, M. Org. Reactions 1989, 37,
1. Enzyme Catalysis in Organic Synthesis; Drauz, K., Waldmann, H., Eds.,
VCH Verlagsgesellschaft mbH: Weinheim, 1995; Chapter B.1, pp 165-
270.
(6) For a review, see: Godleski, S. A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon
Press: Oxford, 1991; Vol. 4, Chapter 3.3, pp 585-682.
(8) Leopold, E. J. Org. Syn. 1986, 64, 164.
S0002-7863(96)00642-7 CCC: $12 00 © 1996 American Chemical Society

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6626 J. Am. Chem. Soc., Vol. 118, No. 28, 1996
Trost and Li
Scheme 1. A Retrosynthetic Analysis of (+)-Cassiol
Scheme 2a
a (a) CH2dCHMgBr, THF, 0 °C, then Ac2O, room temperature. (b) CH2(CO2CH3)2, NaH, 2 mol% (η3-C3H5PdCl)2, 12 mol% Ph3P, THF, room
temperature. (c) (i) LAH, THF, reflux; (ii) CH3C(OCH3)2CH3, CH3COCH3, CSA, room temperature. (d) [(CH3)2CHCH(CH3)]2BH, THF, 0 °C, then
NaOH, H2O2, room temperature. (e) PDC, CH2Cl2, room temperature. (f) TMS-CtCH, n-C4H9Li, THF, -78 °C. (g) PDC, CH2Cl2, room temperature
in 30% overall yield from 2,2-dimethyl-4-pentenal, the thermal
adduct of allyl alcohol and isobutyraldehyde.9
coordination sites on the metal while prolonging catalyst
lifetime, we focused efforts on performing the reaction in the
absence of ligands (entries 2 and 7-15). The first sign of a
trace of product occurred when the slightly stronger acid,
benzoic acid (pKa 4.19), replaced acetic acid (pKa 4.75) (entry
10 vs 8). Using a bis-benzoic acid further increased the yield
(entry 12) still requiring elevated temperatures (entry 11 vs 12).
This trend suggested that shifting the equilibrium of eq 3 to the
right helped increase the efficacy of the reaction. Stronger
Subjecting 3 to our preferred catalyst system, N,N-bisben-
zylideneethylenediamine (BBEDA), (dba)3Pd‚CHCl3 (dba )
dibenzylideneacetone, 4), and acetic acid in 1,2-dichloroethane
(DCE) at 60 °C 10 gave none of the desired cyclization product
5 (eq 2).
acids should do so, however, previous experiences demonstrated
too strong an acid caused decomposition. In seeking a balance,
we turned to formic acid not only because of its somewhat
higher acidity (pK 3.75) but also because it might prevent
deleterious reactions that could be attributed to Pd(2+) catalysts
(other than those of the type shown in eq 3) by reducing any
such Pd(2+) complexes back to Pd(0). Indeed, with formic
acid, the reaction now proceeded at room temperature (entry
13) but still somewhat slowly since somewhat higher temper-
atures did improve the yield (entry 14). Solvent choice played
a significant role since switching to DCE (entry 15) from toluene
gave the best result at room temperature. The structure of the
product of the cycloisomerization is readily apparent from its
spectroscopic properties. In the IR spectrum, the loss of the
This failure led to a search for an effective catalyst system,
a part of which is summarized in Table 1. As a perusal of the
overall table reveals, the reaction appears plagued with low
reactivity leading to recovered starting material or, if forced, to
decomposition. Since it appears the reaction requires the
substrate to function as a bidentate ligand to palladium,
facilitating this coordination might increase this rate. We
concluded that we required boosting the reaction rate so as to
perform the reaction in as short a time period as possible to
avoid product decomposition. Since the presence of ligands
(entries 1,3-5) normally retards the rate by competing for
(9) Salomon, R. G.; Ghosh, S. Org. Syn. 1984, 62, 125.

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A Total Synthesis of (+)-Cassiol
Table 1. Catalyst Search for Cyclization of Enyne 3
J. Am. Chem. Soc., Vol. 118, No. 28, 1996 6627
entry
Pd sourcea
ligand
acid
solv
temp °Cb,f
resultc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pd(OAc)2
Pd(OAc)2
BBEDAd
none
none
none
DCEe
60
80
60
60
60
80
rt
60
rt
60
rt
S. M. + dec
S. M. + dec
dec
S. M. + dec
S. M. + dec
Dec.
S. M. + dec
S. M. + dec
S. M. + dec
5 (trace)
S. M. + dec
5 (20%)
5 (40%)
5 (50%)
C6D6
4
4
4
4
4
4
4
4
4
4
4
4
4
BBEDAd
HOAc
HOAc
HOAc
HCO2H
HOAc
HOAc
PhCO2H
PhCO2H
DCEe
)
(o-CH3C6H4 3
Ph3P
(o-CH3C6H4)3P
none
none
none
none
none
none
P
DCEe
DCEe
DCEe
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
DCEe
1,1′-binaphthyl-2,2′-dicarboxylic acid
1,1′-binaphthyl-2,2′-dicarboxylic acid
HCO2H
HCO2H
HCO2H
60
rt
60
rt
none
none
none
5 (68%)
a 4 ) (dba)3Pd2‚CHCl3. Reactions run with 4 mol% of Pd source. b Bath temperature. c S.M. ) starting material, dec ) decomposition. d BBEDA
) N,N′-bis(benzylidene)ethylenediamine. e DCE ) 1,2-dichloroethane. f Room temperature ) rt.
Scheme 3. The Cyclization Substrate for a (+)-Cassiol Synthesisa
a (a) 5% NaH, THF, room temperature. (b) PLE, phosphate buffer, pH 7, room temperature; 75% for two steps. (c) HOBT, DCC, THF, 0 °C,
then NaBH4, 64%. (d) DMSO, ClCOCOCl, CH2Cl2, (C2H5)3N, -78 °C to room temperature. (e) CH2dCHMgBr, THF, -78 °C, then Ac2O; 76%
for two steps. (f) CH2(CO2CH3)2, NaH, 2% (η3-C3H5PdCl)2, 12% Ph3P, THF, 80%. (g) NaBH4, THF-C2H5OH (10:1), 90%. (h) TBDMS-Cl,
imidazole, DMF, 80 °C, 94%. (i) TMSCtCLi, BF3‚ether, 74%.
alkyne stretching vibration at 2156 cm-1 for 3 and the presence
of bands for a conjugated cyclohexanone (1684, 1596 cm-1
of the requisite alkynone.1e The conjugate addition of dimethyl
methylmalonate to N,N-dimethylacrylamide did not proceed in
methanol nor was catalyzed by Ni(acac)2.12 Use of stoichio-
metric amounts of strong base under nonprotic conditions gave
oligomerization. Good results arose by use of only a catalytic
amount of sodium hydride in the presence of a slight excess of
the Michael donor. Since the NMR spectrum of the material
upon workup showed it was virtually pure adduct 6, it was
subjected to enzymatic desymmetrization without any purifica-
tion.
)
support the presence of the functional groups of 5. The 1H and
13C NMR data indicate a single isomer. The Z-geometry of
the trisubstituted double bond, suggested by the proposed
mechanism, was supported by the olefinic H appearing at δ
5.77 (d, J ) 1.8 Hz). The E-geometry of the disubstituted
alkene is clearly indicated by the coupling pattern of the olefinic
H (δ 5.50, ddd, J ) 15.5, 8.6, 0.9 Hz, 1H and δ 5.21, dd, J )
15.5, 7.8 Hz, 1H).
A Synthesis of (+)-Cassiol. With the realization of the
model cycloisomerization (eq 2), the stage was set for a synthesis
of (+)-cassiol. Scheme 3 outlines the synthesis of the cycliza-
tion substrate. We envisioned introduction of the absolute
stereochemistry by an enzymatic desymmetrization of a dialky-
lated malonate.1,11 The choice of the Michael acceptor for the
malonate was influenced by the effectiveness of addition of an
alkynyllithium to a N,N-dimethyl carboxamide for the synthesis
Among the various enzymes, pig liver esterase (PLE) has
been used most extensively for the desymmetrization of
disubstituted malonates.11 Virtually all of the examples involve
(11) Bjo¨rkling, F.; Boutelje, J.; Gatenbeck, S.; Hult, K.; Norin, T.;
Szmulik, P. Tetrahedron 1985, 41, 1347. Luyten, M.; Mu¨ller, S.; Herzog,
B.; Keese, R. HelV. Chim. Acta 1987, 70, 1250. Toone, E. J.; Jones, J. B.
Tetrahedron: Asym. 1991, 2, 1041.
(12) Nelson, J. H.; Howells, P. N.; De Lullo, G. C.; Landen, G. L.; Henry,
R. A. J. Org. Chem. 1980, 45, 1246. Trost, B. M.; Quayle, P. J. Am. Chem.
Soc. 1984, 106, 2469.
(10) Trost, B. M.; Jebaratnam, D. J. Tetrahedron Lett. 1987, 28, 1611.

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6628 J. Am. Chem. Soc., Vol. 118, No. 28, 1996
Trost and Li
two different alkyl groups with enantioselectivities varying over
a wide range. The effect of one of the two substituents being
polar has been mixed as shown in eq 4.13 These results make
any predictions for the malonate 6 quite tenuous. Based upon
the model put forth by Jones et.al.,14 we felt that our substituent,
if not too sterically bulky for the hydrophilic pocket occupied
Chemoselective ester reduction to triol 11 occurs with sodium
(not lithium) borohydride in a 10:1 THF:ethanol mixture.13 The
polarity of the product required minimization of water during
workup. In this regard, the best protocol involved addition of
methanol and acidification to pH 3 with amberlyst 15 followed
by simple filtration, evaporation in Vacuo, and column chro-
matography. On large scale, the quantity of amberlyst 15
required for the acidification makes the use of 1 N hydrochloric
acid more convenient, but the yield drops from 90% to 60-
70% as a result. Conversion of the amide 12 to the alkynyl
ketone 13 requires addition of boron trifluoride to promote loss
of the dimethylamino group rather than the alkynyl moiety
during breakdown of the tetrahedral intermediate. The cycliza-
tion precursor was available in 18% overall yield in nine steps.
With the requisite enyne in hand, the key cycloisomerization
was attempted. Applying the “ligandless” conditions with
formic acid as in the model series proceeded even better (83%
yield) to give a 3:1 diastereomeric mixture (eq 6). Because
the diastereoselectivity was irrelevant to the target, establishment
by the hydroxymethyl group in eq 4, would favor the S
enantiomer 7 but may give low ee. Since chemoselective
manipulation of either the acid or ester should be possible, either
enantiomer was acceptable. In the event, PLE catalyzed
hydrolysis proceeded nearly quantitatively (75% overall yield
from dimethyl methylmalonate) to give the (-) enantiomer. The
ee was established by conversion of the acid 7 to the amide
with (S)-R-methylbenzylamine using diphenyl chlorophosphate
(eq 5) which proceeded in >95% isolated yields and analysis
(6)
of the relative stereochemistry was not pursued. Simple steric
considerations suggest 14a may be the major diastereomer.
Double bond migration and desilylation of 14 are required
to complete the synthesis of (+)-cassiol. Numerous acid and
transition metal catalyzed processes were investigated to no
avail. In one experiment with the model substrate 5, aqueous
hydrochloric acid appeared to achieve both transformations, but
these conditions failed with the cassiol precursor 14 and could
not be reproduced in the model series. Desilylation also proved
troublesome. The usual fluoride methods normally left 14
untouched or decomposed. A Michael initiated desilylation as
outlined in eq 7 wherein the nucleophile would also be a group
of the diastereomeric ratio by capillary gas chromatography. It
proved to be 66% ee. Variation of buffer or pH had little effect,
whereas addition of organic solvents decreased the ee. Use of
different enzymes like Candida cylindracea lipase (CCL)15a and
porcine pancreas lipase (PPL)15 prove inferior. Fortunately, it
was possible to crystallize the racemate from the major
enantiomer. One recrystallization from ethyl acetate-ether gave
7 of 92% ee from the mother liquor . The absolute configuration
was tentatively assigned as S as depicted but was not confirmed
until completion of the synthesis.
Chemoselective reduction of the carboxylic acid with borane
leads to ester rather than carboxylic acid reduction.16 On the
other hand, chemoselective reduction of the acid was nicely
accomplished via a protocol developed for our synthesis of
merulidial1d involving activation of the carboxylic acid as its
3-hydroxybenztriazole derivative and in situ reduction with
sodium borohydride to 8. Oxidation with chromium based
reagents or the Dess-Martin periodinane seemed plagued with
cleavage. The Moffatt-Swern method however proved satis-
factory to produce aldehyde 9a. Addition of freshly prepared
vinylmagnesium bromide and in situ capping with acetic
anhydride provided the substrate 9b for the first Pd catalyzed
reaction which proceeded with excellent regioselectivity and
geometrical control as in the model series to form triester 10.
that can stabilize an adjacent carbanion did not come to fruition.
A variation on this theme did succeed as outlined in Scheme 4.
Conjugate reduction with triethylsilane catalyzed by Karstedt’s
platinum17 catalyst generated the enol silyl ether 15. Hydride
abstraction of the bis-allylic hydrogen with DDQ gave the net
double bond migrated product 16. Complete O and C desily-
lation with TBAF gave (+)-cassiol whose spectral properties
are in complete agreement with those previously recorded. The
sequence was performed without purification of either 15 or
16 and gave a 42% overall yield for the three steps.
(13) Fukuyama, T.; Xu, L. J. Am. Chem. Soc. 1993, 115, 8449.
(14) Toone, E. J.; Werth, M. J.; Jones, J. B. J. Am. Chem. Soc. 1990,
112, 4946.
(15) (a) Kitazume, T.; Sato, T.; Ishikawa, N. Chem. Lett. 1984, 1811;
(b) Kitazume, T.; Sato, T.; Kobayashi, T.; Tain Lin, T. J. Org. Chem. 1986,
51, 1003.

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A Total Synthesis of (+)-Cassiol
Scheme 4. Final Stage of Synthesis of (+)-Cassiola
J. Am. Chem. Soc., Vol. 118, No. 28, 1996 6629
a (a) (C2H5)3SiH, {[CH2dCHSi(CH3)2]2O}2Pt, PhCH3, 70 °C. (b) DDQ, CH2Cl2, room temperature. (c) TBAF, THF, room temperature; 42%
overall for three steps.
Scheme 5. A Mechanistic Rationale for the Cycloisomerization
Conclusions
self-condensation dominates. Thus, the silylalkyne obviates
such problems.
The palladium catalyzed enyne cyclization represents an
attractive strategy for ring construction. With the development
of a new catalyst system, a so-called “ligandless” palladium
catalyst in the presence of formic acid, a previously difficultly
attainable ring system now becomes readily available. Ap-
plication of this new catalyst system to other programs currently
underway suggests it is generally effective. The fact that the
reaction proceeds well even at room temperature is promising
for high chemoselectivity. While five- and six-membered ring
formation appears generally secure by this methodology, exten-
sion to other ring sizes must await further work. The nature of
the tether substituents is broadened to include the carbonyl
group. In this case where the carbonyl group is conjugated with
the alkyne, the latter cannot be terminal (i.e., bearing H) since
Scheme 5 outlines the proposed mechanism of the Pd(0)/H+
version of the cycloisomerization.2 The effectiveness of formic
acid may be associated with helping to make the equilibrium
between the precatalyst Pd(0) complex and the catalytically
active HPd+ species shift toward the latter (eq 3). In comparison
to acetic acid, the higher acidity of formic acid should favor
protonation. While stronger acids may further shift the equi-
librium in the direction of HPd+, lower chemoselectivity is
experienced. The choice of acid must be a compromise between
these two orthogonal effects. We suggest the key to the
efficiency of the cycloisomerization is associated with the ability
of the substrate to function as a bidentate ligand to palladium
as in 17. Thus, it is not surprising that a three atom tether which

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6630 J. Am. Chem. Soc., Vol. 118, No. 28, 1996
Trost and Li
Francisco on a Kratos MS-90 instrument with an ionizing current of
98 mA and an ionizing voltage of 70 eV. Microanalyses were
performed by M-H-W Laboratories, Phoenix, AZ.
leads to five membered ring formation is almost universally
successful. Increasing tether length makes this bis-coordination
less favorable. In such circumstances, reducing the presence
of alternative ligands in the reaction medium then makes the
palladium sufficiently coordinatively unsaturated it still recog-
nizes the substrate as a bidentate ligand in which any strain in
functioning as such is overcome by the enhanced bonding
energy. Furthermore, the absence of bulky ligands coordinated
to palladium also will decrease any unfavorable steric interac-
tions especially in substrates like 3 and 13 which have neopentyl
type alkenes. The higher reactivity of alkynes in cis-syn
additions of palladium species leads to 18 whose intramolecular
carbapalladation sets the diastereoselectivity of the reaction. The
bulkiness of the siloxymethyl group should favor 18a going to
19a over 18b going to 19bsaccounting for the modest diaste-
reoselectivity observed. While this stereochemical issue was
inconsequential for the current objective, the observed selectivity
is a promising beginning in those applications where such
control is needed. The efficacy of the palladium catalyzed
cycloisomerization compared to thermal Alder ene reactions is
apparent in this case since FVT at 500 °C generated only a
trace of product. Of course, access to 1,3-dienes, not accessible
by thermal methods, constitutes another important benefit of
the palladium catalyzed process.1,2
Preparation of 3-Acetoxy-4,4-dimethyl-1,6-heptadiene. To 2,2-
dimethyl-4-pentenal (11.22 g, 100 mmol) in dry THF (100 mL) at 0
°C was added dropwise a THF solution of vinylmagnesium bromide
(1 M, 120 mL, 120 mmol). The mixture was stirred for 15 min at 0
°C and 1 h at room temperature. It was cooled to 0 °C, and acetic
anhydride (28.3 mL, 300 mmol) was then introduced. The reaction
was allowed to proceed for 30 min at 0 °C and for 12 h at room
temperature. Water was added, and the resultant mixture was extracted
with diethyl ether. The ethereal solution was washed (1 × NaHCO3,
3 × H2O), dried (MgSO4), and evaporated in Vacuo. The residue was
vacuum distilled (71-79 °C/18 mmHg) to afford the title compound
(17.3 g, 95%) as a colorless liquid: IR (thin film) 3074, 2971, 1743,
1639, 1469, 1239 cm-1 1H NMR (200 MHz, CDCl3) δ 5.7-5.9 (m,
.
2H), 5.26 (m, 1H), 5.18-5.22 (m, 1H), 5.0-5.1 (m, 3H), 2.09 (s, 3H),
2.08 (m, 2H), 0.92 (s, 3H), 0.89 (s, 3H). 13C NMR (50 MHz, CDCl3)
δ 170.1, 134.4, 133.2, 118.3, 117.6, 80.6, 43.2, 36.9, 23.0, 22.7, 21.0.
Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.28; H,
10.15.
Preparation of Methyl (4E)-6,6-Dimethyl-2-(methoxycarbonyl)-
4,8-nonadienoate. Dry THF (350 mL) was added to sodium hydride
(6.68 g of 60% dispersion in mineral oil, 167 mmol), washed with dry
hexanes (50 mL) twice, at which time dimethyl malonate (20 mL, 175
mmol) was slowly added by syringe at room temperature. The resulting
sodium malonate THF solution was cannulated into a solution of π-
allylpalladium chloride dimer (150 mg, 0.41 mmol), triphenylphosphine
(1.29 g, 1.64 mmol), the above acetate (15.2 g, 83.5 mmol), and dry
THF (50 mL) also at room temperature. The reaction mixture was
then heated at reflux for 6 h, cooled, quenched with water (400 mL),
and extracted with diethyl ether (2 × 400 mL). The organic layer was
washed (2 × H2O, 1 × brine), dried over MgSO4, and evaporated.
The residue was vacuum distilled (90-100 °C/0.5 mmHg) to obtain
the title compound (13.59 g, 64%) as a colorless liquid. Performing
this reaction on a 5.92 mmol scale of allyl acetate gave a 78% yield of
the title compound: IR (thin film) 3074, 2959, 1741, 1638, 1439, 1344,
The lipase technology to desymmetrize disubstituted mal-
onates has been extended to a propionamide substituent. Using
the Jones model, this substituent occupies the same hydrophilic
pocket as a hydroxymethyl group meaning that pocket is capable
of accommodating somewhat larger groups than his model
depicts. No attempt was made to vary the amide substituent to
further enhance the ee, a prospect that would be worthwhile to
pursue.
The platinum catalyzed hydrosilylation of 14 highlights the
effectiveness of this process. The unreactivity of the Michael
system present in 14 toward many donors demonstrates the
advantage of the transition metal catalyzed methodology. The
ultimate result of these developments is an effective synthetic
strategy to (+)-cassiol and analogues. More generally, a
promising strategy for the synthesis of cyclohexanones and
cyclohexenones has been demonstrated.
1233 cm-1 1H NMR (300 MHz, CDCl3) δ 5.8-5.6 (m, 1H), 5.50 (d,
.
J ) 15.6, 1H), 5.25 (dt, J ) 15.6, 7.0, 1H), 4.9-5.02 (m, 2H), 3.72 (s,
6H), 3.41 (t, J ) 7.6, 1H), 2.59 (td, J ) 7.3, 1.1, 2H), 1.98 (d, J ) 7.4,
2H), 0.93 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 169.5, 143.5, 135.5,
121.2, 116.8, 52.3, 52.0, 47.1, 35.7, 32.0, 26.8. HRMS calcd for
C14H22O4 (M+): 254.15189. Found: 254.1523.
Preparation of 2,2-Dimethyl-5-[(2′E)-4′,4′-dimethyl-2′,6′-hepta-
dienyl]-1,3-dioxane. LAH (8.1 g, 213 mmol) was carefully added to
150 mL of dry THF at 0 °C and then heated to reflux for 40 min.
After the suspension was cooled to 0 °C, the above malonate (13.45 g,
52.88 mmol) in 50 mL of THF was added by syringe over 40 min.
After heating at reflux for 15 h, the reaction mixture was then cooled
to rt and magnetic stirring was replaced with mechanical stirring. After
addition of 150 mL of THF, the reaction was worked up by slow
addition of water (8.1 mL), followed by 10% aqueous sodium hydroxide
(16 mL) and saturated potassium fluoride solution (25 mL). The white
solid, removed by filtration, was thoroughly washed with methylene
chloride. The combined organic layers were dried over Na2SO4 and
evaporated in Vacuo to yield crude diol (12.2 g) as a colorless liquid
which was directly used for the next step without further purification.
1H NMR (300 MHz, CDCl3) δ 5.66-5.81 (m, 1H), 5.46 (d, J ) 15.6,
1H), 5.29 (dt, J ) 15.6, 6.9, 1H), 4.94-5.04 (m, 2H), 3.80 (dd, J )
10.8, 4.0, 2H), 3.67 (dd, J ) 10.7, 7.4, 2H), 1.96-2.06 (m, 4H), 1.78-
1.94 (m, 1H), 0.97 (s, 6H).
Experimental Section
Reactions were generally conducted under a positive pressure of dry
nitrogen within glassware which had been flame-dried under a stream
of nitrogen. Reaction flasks were sealed with red rubber septa and
were, unless otherwise mentioned, magnetically stirred. Anhydrous
solvents and reaction mixtures were transferred by oven-dried syringe
or cannula. Flash chromatography employed ICN silica gel (Kiesselgel
60, 230-400 mesh). Analytical TLC was performed with 0.2 mm
coated commercial silica gel plates (E. Merck, DC-Plastikfolien,
Kieselgel 60 F254). 1H NMR spectra were obtained and recorded from
Gemini GEM-200 (200 MHz), Gemini GEM-300 (300 MHz), or Varian
XL-400 (400 MHz) instrument, in ppm from residual CDCl3 (7.26
ppm), residual C6D6 (7.15 ppm), or from an internal t-BuOH standard
(1.27 ppm) in D2O. 13C NMR spectra were recorded on a Gemini
GEM-200 (50 MHz) or a Gemini GEM-300 (75 MHz) or a Varian
XL-400 (100 MHz) instrument. Chemical shifts are reported in δ units,
parts per million from the central peak of CDCl3 (δ ) 77.0), or C6D6
(128.0) as an internal reference, or from an internal t-BuOH standard
(32.10, 72.25) in D2O. IR spectra were obtained using a Nicolet 205
FT-IR spectromer. Melting points were determined using Thomas-
Hoover oil bath apparatus and were not corrected. Analytical gas
chromatography was performed on a Varian 3700 gas chromatograph
using a 25 m × 0.25 mm polydimethylsiloxane column from Alltech.
Mass spectral analyses were performed by the NIH Mass Spectral
Facility at the School of Pharmacy, University of California-San
To the mixture of the above crude diol (12.2 g, 52.88 mmol) and
dimethoxypropane (30 mL, 244 mmol) in reagent grade acetone (50
mL) was added a catalytic amount of camphorsulfonic acid (200 mg,
0.86 mmol) at room temperature. After stirring 2 h at room temperature,
anhydrous Na2CO3 was added, and the mixture was stirred for 4 h at
room temperature. It was filtered through a silica gel plug and vacuum
distilled (85-96 °C/2.5 mmHg) to afford the titled acetonide (11.17 g,
(16) Fadel, A.; Canet, J.-L.; Salaun, J. Tetrahedron Lett. 1989, 30, 6687.
(17) Johnson, C. R.; Raheja, R. K. J. Org. Chem. 1994, 59, 2287. The
catalyst was purchased from United Chemical Technolgy, Bristol, PA, as
a 2-3% solution in xylene.

+
+
A Total Synthesis of (+)-Cassiol
J. Am. Chem. Soc., Vol. 118, No. 28, 1996 6631
89% for two steps) as a colorless liquid. IR (thin film) 3075, 2961,
µl, 0.1 mmol) was added to a solution of Pd2dba3‚CHCl3 and 4 (2 mg,
0.002 mmol) in 1,2-dichloroethane (0.5 mL) at room temperature. The
reaction was stirred at room temperature for 9 h. Celite was then added,
and the mixture was filtered through a silica plug. Purification by flash
chromatography (3% diethyl ether in hexane) afforded the cyclized
ketone 5 (24 mg, 68%) as a colorless liquid. IR (thin film) 2995, 2869,
1637, 1456, 1198, 1071 cm-1 1H NMR (300 MHz, CDCl3) δ 5.65-
.
5.8 (m, 1H), 5.43 (d, J ) 15.6, 1H), 5.21 (dt, J ) 15.6, 6.7, 1H), 4.93-
5.03 (m, 2H), 3.84 (dd, J ) 11.6, 4.5, 2H), 3.57 (dd, J ) 11.9, 9.0,
2H), 2.01 (d, J ) 7.3, 2H), 1.8-1.95 (m, 3H), 1.43 (s, 3H), 1.41 (s,
3H), 0.96 (s, 6H). 13C NMR (50 MHz, CDCl3) δ 142.2, 135.6, 122.4,
116.7, 97.7, 64.6, 47.4, 35.8, 34.3, 32.1, 27.3, 27.1, 20.7. HRMS calcd
for C15H26O2 (M+): 238.1933. Found: 238.1941.
1684, 1596, 1451, 1390, 1373, 1247, 1197, 1073 cm-1
.
1H NMR (400
MHz, CDCl3) δ 5.77 (d, J ) 1.8, 1H), 5.5 (ddd, J ) 15.5, 8.6, 0.9,
1H), 5.21 (dd, J ) 15.4, 7.8, 1H), 3.84 (dd, J ) 12.0, 4.9, 2H), 3.72
(m, 2H), 2.76 (bro d, J ) 8.5, 1H), 2.6 (m, 1H), 2.45 (t, J ) 7.2, 2H),
1.6-1.8 (m, 2H), 1.45 (s, 3H), 1.42 (s, 3H), 0.99 (s, 3H), 0.93 (s, 3H),
0.09 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 203.0, 153.5, 142.5, 131.5,
130.1, 97.5, 64.3, 59.9, 38.3, 37.1, 35.9, 33.8, 28.7, 27.6, 23.3, 20.4,
-0.4. HRMS calcd for C20H34O3Si (M+): 350.2277. Found: 350.2269.
Preparation of (S)-4-(N′,N′-Dimethylaminocarbonyl)-2-(meth-
oxycarbonyl)-2-methylbutanoic Acid (7). To a suspension of sodium
hydride (0.5 g of 60% dispersion in mineral oil, 12.5 mmol, washed
with 35 mL pentane) in THF (150 mL) was added dimethyl methyl-
malonate (33.9 mL, 255 mmol) at room temperature. The mixture was
stirred at room temperature for 30 min, and N,N-dimethylacrylamide
(24.7 g, 250 mmol) in THF (120 mL) was added dropwise. After 2 h
stirring, ethyl acetate (300 mL) was added. The solution was washed
(NH4Cl, H2O, brine), dried (MgSO4), and evaporated in situ to give
the Michael adduct 6 (47.5 g, 194 mmol) as a colorless liquid. 1H
NMR (300 MHz, CDCl3) δ 3.73 (s, 6H), 3.01 (s, 3H), 2.94 (s, 3H),
2.29-2.39 (m, 2H), 2.17-2.26 (m, 2H), 1.45 (s, 3H).
Preparation of 2,2-Dimethyl-5-[(2′E)-4′,4′-dimethyl-7′-hydroxy-
2′-heptenyl]-1,3-dioxane. 2-Methyl-2-butene (7.1 mL, 67 mmol)) was
added to a THF solution of borane (1 M, 30 mL, 30 mmol) at -30 °C.
The mixture was stirred at 0 °C for 2 h and then transferred to a THF
solution (20 mL) of the above diene (4.77 g, 20 mmol) at 0 °C. The
reaction was allowed to proceed for 1.5 h at 0 °C and then for 15 h at
room temperature. After cooling to -10 °C, 10% aqueous sodium
hydroxide (11 mL) followed by 30% aqueous hydrogen peroxide (11
mL, slow addition) was added, and the resultant mixture was stirred
for 5 h at room temperature. The ethereal layer obtained by extraction
was washed (2 × NH4Cl, 1 × H2O, 1 × brine), dried (MgSO4), and
evaporated in Vacuo. The residue was vacuum distilled (170-200 °C/2
mmHg) to give the title alcohol (4.77 g, 93%) as a colorless liquid. IR
(thin film) 3420, 2950, 1656, 1455, 1371, 1198 cm-1 1H NMR (300
.
MHz, CDCl3) δ 5.38 (d, J ) 15.6, 1H), 5.2 (dt, J ) 15.6, 6.8, 1H),
3.83 (dd, J ) 12.0, 4.3, 2H), 3.51-3.61 (m, 4H), 1.8-1.95 (m, 3H),
1.35-1.45 (m, 2H), 1.41 (s, 3H), 1.39 (s, 3H), 1.24-1.32 (m, 2H),
0.95 (s, 6H). 13C NMR (50 MHz, CDCl3) δ 142.3, 122.3, 97.7, 64.4,
63.2, 38.8, 35.4, 34.2, 32.0, 28.0, 27.2, 27.0, 20.7. HRMS calcd for
C15H28O3(M+): 256.2038. Found: 256.2018.
PLE (2000 units) was added to diester 6 (47.5 g, 194 mmol) in 0.03
M pH 7 phosphate buffer (1.5l) at room temperature. The pH of the
solution was maintained at 7 by addition of 1 M aqueous sodium
hydroxide through a pH-stat. More PLE, total 4000 units, was added
as the reaction proceeded. The hydrolysis was stopped after 1 equiv
of base was consumed (194 mL, in 9 days). The reaction mixture was
frozen at -78 °C and then just thawed at which point a saturating
amount of sodium chloride was added. The resulting solution had its
pH adjusted to 13, was washed with ethyl acetate (2 × 50 mL), and
was then acidified to pH 2 with 6 N aqueous hydrochloric acid.
Extraction with ethyl acetate (2 × 1 mL) followed by evaporation of
the dried (MgSO4) ethyl acetate extracts yielded monoester acid 7 (43.4
g, 75.2%. 66% ee) as a white solid. Recrystallization was performed
with ethyl acetate and diethyl ether. Racemic mixtures were crystallized
out, and the mother liquor was enriched to provide pure 7 with 92%
Preparation of 2,2-Dimethyl-5-[(2′E)-4′,4′-dimethyl-7′-oxo-2′-hep-
tenyl]-1,3-dioxane. A mixture of the above alcohol (86.8 mg, 0.338
mmol) and PDC (191 mg, 0.508 mmol) in methylene chloride (4 mL)
was stirred for 22 h at room temperature. Diethyl ether (10 ml) and
anhydrous MgSO4 was then added, and stirring was continued for 2 h.
The solution was passed through a silica plug. Removal of solvents
in Vacuo afforded the title aldehyde (78.3 mg, 91%) as a colorless liquid.
IR (thin film) 2993, 2961, 2863, 2712, 1456, 1370, 1198 cm-1 1H
.
NMR (300 MHz, CDCl3) δ 9.75 (t, J ) 1.4, 1H), 5.19-5.39 (m, 2H),
3.85 (dd, J ) 1.20, 4.5, 2H), 3.57 (dd, J ) 12.0, 8.8, 2H), 2.33 (td, J
) 8.0, 1.5, 2H), 1.94 (t, J ) 6.3, 2H), 1.8-1.9 (m, 1H), 1.60 (t, J )
7.9, 2H), 1.43 (s, 3H), 1.41 (s, 3H), 0.98 (s, 6H). 13C NMR (75 MHz,
CDCl3) δ 202.5, 141.0, 123.6, 97.6, 64.4, 39.8, 35.3, 34.1, 31.9, 27.0,
26.8, 20.8. HRMS calcd for C14H23O3 (M+ - CH3): 239.1647
Found: 239.1638.
ee; mp 104-105 °C, [R]25 ) -1.69° (c 2.45, CD3OD). IR (KBr)
D
3430, 2925, 1731, 1669, 1463, 1259 cm-1 1H NMR (300 MHz, CDCl3)
.
δ 3.74 (s, 3H), 3.08 (s, 3H), 2.96 (s, 3H), 2.38-2.6 (m, 2H), 2.1-2.28
(m, 2H), 1.48 (s, 3H). 13C NMR (100 MHz, CD3OD): δ 175.0, 174.7,
174.2, 54.2, 52.9, 37.7, 35.8, 32.4, 29.8, 20.7. Anal. Calcd for
C10H17O5N: C, 51.94; H, 7.41; N, 6.06. Found: C, 52.12; H, 7.44; N,
6.21.
Preparation of 2,2-dimethyl-5-[(2′E)-4′,4′-dimethyl-7′-oxo-9′-tri-
methylsilyl-2′-nonen-8′-ynyl]-1,3-dioxane (3). To a trimethylsily-
lacetylene (74.8 mg, 0.762 mmol) solution in THF (0.5 mL) was added
dropwise n-butyllithium in hexanes (1.55 M, 0.448 mL, 0.694 mmol)
at -78 °C. After 30 min stirring, the above aldehyde (85 mg, 0.334
mmol) in THF (0.5 ml) was slowly added by syringe at -78 °C. The
reaction was then allowed to slowly warm to room temperature,
quenched with saturated ammonium chloride solution, and extracted
with diethyl ether. The resultant ethereal solution was washed (1 ×
water, 2 × brine), dried over MgSO4, and evaporated in Vacuo to yield
the corresponding alkynol (101.3 mg, 85%) as a slightly yellow liquid
which was directly used for oxidation without purification.
Determination of Enantiomeric Excess. To a solution of acid 7
(5.0 mg, 0.021 mmol), [R]25 ) -1.69 (c 2.45, CDCl3), and triethy-
D
lamine (9.0 µl, 0.07 mmol) in methylene chloride (0.5 mL) was added
diphenyl chlorophosphate (6.1 µl, 0.027 mmol). After stirring at 0 °C
for 15 min and at room temperature for 3 h, (S-R-methylbenzylamine
(4.6 µl, 0.032 mmol) was added, and the reaction was stirred at room
temperature overnight. Ethyl acetate (5 mL) was added, and the
resulting organic layer was washed (1 × H2O, 2 × NaHCO3, 1 × brine),
and dried (MgSO4). Purification by silica gel chromatography (4%
MeOH in CH2Cl2) afforded amide (7.0 mg, 97%) as a colorless syrup
for which GC analysis shows 92% de. IR (thin film) 3323, 3010, 2978,
The above alcohol (74 mg, 0.21 mmol) and PDC (118 mg, 0.315
mmol) in dry methylene chloride (1 mL) was stirred at room
temperature for 40 h. Diethyl ether (8 mL) and MgSO4 were then
added, and the resultant mixture was stirred for 2 h. The solution was
filtered through a Celite plug and evaporated in Vacuo, and the residue
was purified on silica gel (4:1, hexanes-diethyl ether) to afford ketone
3 (47 mg, 64%) as a colorless liquid. IR (thin film) 2963, 2156, 1681,
2943, 1736, 1635, 1530, 1454, 1405, 1262, 1117 cm-1 1H NMR (400
.
MHz, CDCl3) δ 7.48 (d, J ) 7.2, 1H), 7.33-7.30 (m, 5H), 5.08 (dq,
J ) 6.2, 1H), 3.75 (s, 3H), 2.88 (s, 3H), 2.76 (s, 3H), 2.22-2.0 (m,
4H), 1.48 (d, J ) 7.3, 3H), 1.47 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 175.4, 171.8, 169.9, 143.6, 128.6, 127.2, 126.0, 52.9, 52.7, 49.2, 37.0,
35.4, 33.2, 29.0, 22.0, 21.6 HRMS calcd for C18H26O4N2 (M+):
334.1893. Found: 334.1899.
Preparation of (S)-N,N-Dimethyl-5-hydroxy-4-(methoxycarbo-
nyl)-4-methyl pentanamide (8). A mixture of acid 7 (14.0 g, 60.6
mmol) and hydroxybenzotriazole hydrate (20 g, 118 mmol) in dry THF
(250 mL) to which was added DCC (18.7 g, 90.8 mmol) at 0 °C was
stirred at room temperature for 6 h. The mixture was filtered through
Celite and washed with THF. The combined THF solution was cooled
1455, 1369, 1253, 1198 cm-1 1H NMR (300 MHz, CDCl3) δ 5.35 (d,
.
J ) 15.7, 1H), 5.25 (dt, J ) 15.6, 6.4, 1H), 3.85 (dd, J ) 12.0, 4.4,
2H), 3.58 (dd, J ) 12.0, 8.8, 2H), 2.46 (t, J ) 8.0, 2H), 1.95 (t, J )
6.7, 2H), 1.8-1.92 (m, 1H), 1.63 (t, J ) 8.0, 2H), 1.43 (s, 3H), 1.41
(s, 3H), 0.98 (s, 6H), 0.25 (s, 9H). 13C NMR (50 MHz, CDCl3) δ
188.0, 141.2, 123.5, 102.0, 97.8, 97.6, 64.5, 41.3, 36.0, 35.4, 34.3, 32.1,
27.2, 27.0, 20.9, -0.8. Anal. Calcd for C20H34O3Si: C, 68.52; H,
9.98. Found: C, 68.60; H, 10.06.
Cycloisomerization of 3. Preparation of 5. Enyne 3 (35 mg, 0.1
mmol) in 1,2-dichloroethane (0.5 mL) followed by formic acid (3.5

+
+
6632 J. Am. Chem. Soc., Vol. 118, No. 28, 1996
Trost and Li
to 0 °C, and sodium borohydride (4.6 g, 121 mmol) was slowly added
after which stirring was continued at 0 °C for an additional 1.5 h. The
reaction was then quenched with 1 N aqueous hydrochloric acid (3
mL, solution pH ) 3) and water. The THF was removed in Vacuo. A
white solid was removed by filtration and washed with water. The
combined aqueous layers were saturated with sodium chloride and
extracted with ethyl acetate. After drying over MgSO4, purification
by flash chromatography (3% MeOH in CH2Cl2) afforded hydroxy ester
8 (8.36 g, 64%) as a colorless liquid; [R]25D ) -4.22 (c 2.08, CDCl3).
1 mmol) was added slowly to the triester 10 (35 mg, 0.098 mmol) in
a solution of 10:1 THF:EtOH (2 mL). After heating at 80 °C for 2
days, the reaction was diluted with methanol (10 mL), and its pH was
adjusted with Amberlyst 15:4. Filtration, evaporation in Vacuo and
purification on silica gel (5% MeOH in CH2Cl2 and then 10% MeOH
in CH2Cl2) afforded triol 11 (24 mg, 90%) as a colorless syrup; [R]25
D
) +1.0 (c 0.5, MeOH). Note: There are cases when palladium black
appeared upon addition of sodium borohydride. In such cases, the
reaction must be worked up with water to remove palladium or very
low yields are observed. IR (thin film) 3375, 2925, 1623, 1513, 1403,
IR (thin film) 3410, 2951, 1737, 1645, 1505, 1403 cm-1 1H NMR
.
(400 MHz, CDCl3) δ 3.70 (s, 3H), 3.59 (d, J ) 11.7, 1H), 3.55 (d, J
) 11.7, 1H), 3.01 (s, 3H), 2.95 (s, 3H), 2.34 (br t, J ) 7.3, 2H), 1.91-
2.04 (m, 2H), 1.20 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 176.9,
173.0, 66.3, 51.9, 47.7, 37.2, 35.7, 29.3, 28.3, 20.5. HRMS calcd for
C10H19O4N (M+): 217.1314. Found: 217.1311.
1038 cm-1 1H NMR (400 MHz, CDCl3) δ 5.36-5.47 (m, 2H), 3.6-
.
3.8 (m, 4H), 3.30 (s, 2H), 3.01 (s, 3H), 2.94 (s, 3H), 2.2-2.32 (m,
2H), 2.04-2.1 (m, 2H), 1.6-1.85 (m, 3H), 0.98 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 174.1, 137.3, 127.5, 69.5, 64.3, 64.1, 42.4, 41.0,
37.4, 35.7, 31.9, 31.7, 28.1, 21.0. Anal. Calcd for C14H27O4N: C,
61.51; H, 9.95; N, 5.12. Found: C, 61.43; H, 10.08; N, 5.10.
Method B. Sodium borohydride (0.52 g, 13.7 mmol) was added
slowly to the triester 10 (0.662 g, 1.85 mmol) in 10:1 THF:ethanol (10
mL). After 15 h at 60 °C, it was quenched with water, and the pH
was adjusted to 2 with aqueous 2 N hydrochloric acid. It was
thoroughly extracted with 5:2 chloroform:ethanol, and the organic layers
were dried (Na2SO4) and evaporated in Vacuo to give after purification
on silica gel as above triol 11 (0.316 g, 63%).
Preparation of (4S)-N,N-dimethyl-5-acetoxy-4-(methoxycarbo-
nyl)-4-methyl-5-heptenamide (9b). To a methylene chloride (10 mL)
solution of oxalyl chloride (0.44 mL, 5.04 mmol) was slowly added
DMSO (0.72 mL, 10.1 mmol) in methylene chloride (3 mL) at -78
°C. After 10 min stirring, alcohol 8 (0.731 g, 3.37 mmol) in methylene
chloride (5 mL) was slowly added at the same temperature. The
reaction mixture was stirred at -78 °C for 30 min at which point
triethylamine (2.4 mL, 17.2 mmol) was introduced. The reaction
temperature was kept at -78 °C for 1 h and then allowed to warm to
room temperature. The reaction was quenched with water, dried over
MgSO4, and evaporated to give the crude aldehyde (0.672 g) as a
liquid: 1H NMR (300 MHz, CDCl3) δ 9.68 (s, 1H), 3.74 (s, 3H), 2.97
(s, 3H), 2.91 (s, 3H), 2.05-2.35 (m, 4H), 1.32 (s, 3H).
Preparation of (4S,5E)-N,N-Dimethyl-4,8-bis(tert-butyldimeth-
ylsiloxymethyl)-9-(tert-butyldimethylsiloxy)-4-methyl-5-nonena-
mide (12). The mixture of the triol 11 (100 mg, 0.366 mmol),
imidazole (177 mg, 2.6 mmol), and TBDMSCl (200 mg, 1.3 mmol) in
dry DMF (5 mL) was kept at 70 °C overnight. It was then partitioned
between diethyl ether and water. The ethereal solution was washed
thoroughly with water, dried (MgSO4), and evaporated. Purification
on silica gel (diethyl ether) afforded 19 (214 mg, 94%) as a colorless
liquid; [R]25D ) -1.5˚ (c 1.0, CDCl3). IR (thin film) 2954, 2858, 1657,
To the crude aldehyde in dry THF (6 mL) was added vinylmagne-
sium bromide (1 M in THF, 4.68 mmol) slowly at -78 °C. After 2 h
stirring, acetic anhydride (1.2 mL, 12.7 mmol) was introduced slowly.
The reaction mixture was kept at -78 °C for 30 min and at room
temperature for 8 h. Ethyl acetate (100 mL) was added. The reaction
mixture was washed (2 × NaHCO3, 2 × H2O, 1 × brine), dried
(MgSO4), and evaporated in Vacuo. The residue was chromatographed
on silica gel (CH2Cl2, then 2% MeOH in CH2Cl2) to afford the allylic
acetate 9b (0.733 g, 76% over two steps) as a mixture of two
diastereomers in a ratio of 1.4 to 1. IR (thin film) 2995, 2946, 1740,
1520, 1467, 1394, 1254, 1090 cm-1 1H NMR (400 MHz, CDCl3) δ
.
5.30-5.40 (m, 2H), 3.53 (d, J ) 5.6, 4H), 3.35 (d, J ) 9.5, 1H), 3.29
(d, J ) 9.5, 1H), 2.98 (s, 3H), 2.93 (s, 3H), 2.18-2.26 (m, 2H), 2.01
(t, J ) 6.3, 2H), 1.6-1.72 (m, 3H), 0.95 (s, 3H), 0.883 (s, 18H), 0.877
(s,. 9H), 0.025 (s, 12H), 0.014 (s, 6H). 13C NMR (100 MHz, CDCl3)
δ 173.7, 137.0, 127.2, 70.9, 62.5, 62.3, 43.9, 40.7, 37.3, 35.4, 32.6,
31.3, 28.8, 25.9, 21.0, 18.3, -5.4, -5.5. Anal. Calcd for C32H69O4-
NSi3: C, 62.38; H, 11.29; N, 2.27. Found: C, 62.50; H, 11.24; N,
2.23.
1650, 1646, 1400, 1236 cm-1 1H NMR (400 MHz, CDCl3) major
.
isomer, δ 5.70-5.8 (m, 1H), 5.54 (d, J ) 6.5, 1H), 5.22-5.36 (m,
2H), 3.68 (s, 3H), 2.98 (s, 3H), 2.94 (s, 3H), 2.2-2.31 (m, 2H), 2.08
(s, 3H), 1.7-1.9 (m, 2H), 1.19 (s, 3H); minor isomer, 5.7-5.81 (m,
1H), 5.54 (d, J ) 6.5, 1H), 5.22-5.36 (m, 2H), 3.67 (s, 3H), 2.98 (s,
3H), 2.94 (s, 3H), 2.2-2.31 (m, 2H), 2.03 (s, 3H), 1.7-1.9 (m, 2H),
1.22 (s, 3H). 13C NMR (100 MHz, CDCl3) major isomer, δ 174.5,
172.1, 169.7, 132.3, 119.1, 77.6, 51.9, 49.4, 37.1, 35.4, 30.7, 28.5, 20.9,
17.3; minor isomer, 174.8, 171.9, 169.5, 131.4, 120.1, 78.1, 51.9, 49.3,
37.1, 35.4, 30.7, 28.2, 20.9, 16.3. Anal. Calcd for C14H23O5N: C,
58.93; H, 8.12; N, 4.91. Found: C, 58.71; H, 8.16; N, 4.76.
Preparation of (6S,7E)-(6,10)-Bis(tert-butyldimethylsiloxymethyl)-
11-(tert-butyldimethylsiloxy)-6-methyl-1-trimethylsilyl-7-undecen-
1-yn-3-one (13). To trimethylsilylacetylene (126 µL, 0.89 mmol) in
THF (2 mL) was added n-butyllithium (1.49 M, 0.77 mmol) at -78
°C. After 5 min, boron trifloride etherate (96 µL, 0.78 mmol) was
added slowly, and, after another 15 min, amide 12 (344 mg, 0.558
mmol) in THF (3 mL) was added. After 2 h stirring, more boron
trifloride etherate (100 µL) was added, followed by addition of acetic
acid (100 µL) at -78 °C. The reaction was then allowed to warm to
-20 °C and was quenched with saturated aqueous ammonium chloride
solution. Extraction with diethyl ether, drying over MgSO4, and
evaporation in Vacuo gave, after purification on silica gel (3% ether in
hexanes) enyne 13 (276 mg, 74%) as a colorless liquid; [R]25D ) -2.6
(c 0.8 in hexanes). IR (thin film) 2957, 2858, 2154, 1681, 1472, 1253,
Preparation of (4S,5E)-N,N-Dimethyl-4,8-bis(methoxycarbonyl)-
9-methoxy-4-methyl-9-oxo-5-nonenamide (10). Dimethyl malonate
(0.44 mL, 3.85 mmol) was added to a THF (10 mL) suspension of
sodium hydride (3.43 mmol) at room temperature. After 10 min
stirring, it was cannulated into a THF (2 mL) solution of π-allylpal-
ladium chloride dimer (18 mg, 0.049 mmol) and triphenylphosphine
(103 mg, 0.393 mmol). After the solution was stirred for 20 min, allylic
acetate 9b (0.544 g, 1.91 mmol) in THF (3 mL) was added. The
reaction was kept at 70 °C for overnight. Most THF was removed
under vacuum, and the residue was dissolved in ethyl acetate (100 mL).
The ethyl acetate solution was washed (1 × NH4Cl, 1 × H2O, 1 ×
brine), dried (MgSO4), and evaporated in Vacuo. Flash chromatography
(2% MeOH in CH2Cl2) of the residue gave triester 10 (0.549 g, 80%)
1094, 837 cm-1 1H NMR (400 MHz, CDCl3) δ 5.40-5.25 (m, 2H),
.
3.54 (d, J ) 5.4, 4H), 3.31 (q, J ) 9.5, 2H), 2.48 (t, J ) 8.1, 2H), 2.02
(t, J ) 6.4, 2H), 1.87-1.6 (m, 3H), 0.94 (s, 3H), 0.89 (s, 27H), 0.24
(s, 9H), 0.03 (s, 12H), 0.02 (s, 6H). 13C NMR (50 MHz, CDCl3) δ
188.3, 136.5, 127.6, 102.1, 97.3, 70.8, 62.4, 46.8, 41.0, 40.6, 31.3, 31.2,
25.9, 21.0, 18.3, -0.7, -5.5, -5.4. HRMS calcd for C31H63O4Si4 (M+
- C4H9): 611.3804. Found: 611.3794.
as an oil; [R]25 ) -3.2 (c 0.5, CDCl3). IR (thin film) 2954, 1750,
D
1732, 1664, 1566, 1457, 1437, 1400, 1233, 1113 cm-1 1H NMR (400
.
Preparation of 14. A toluene (1 mL) solution of Pd2dba3‚CHCl3,
4 (6.6 mg, 0.0064 mmol), formic acid (12 µL, 0.32 mmol), and enyne
13 (107 mg, 0.16 mmol) was stirred at room temperature for 35 h.
Direct purification on silica gel (3% diethyl ether in hexanes) yielded
14 (89 mg, 83%) as an inseparable mixture of two diastereomers in a
ratio of 3:1 as a colorless liquid. IR (thin film) 2955, 2858, 1690,
MHz, CDCl3) δ 5.71 (d, J ) 15.7, 1H), 5.47 (dt, J ) 15.7, 7.1, 1H),
3.70 (s, 6H), 3.65 (s, 3H), 3.41 (t, J ) 7.5, 1H), 2.97 (s, 3H), 2.91 (s,
3H), 2.61 (t, J ) 7.2, 2H), 2.22-2.18 (m, 2H), 2.02-1.8 (m, 2H),
1.24 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.8, 172.3, 169.1, 136.3,
125.1, 52.4, 52.0, 51.6, 47.3, 37.1, 35.4, 34.1, 31.8, 28.7, 21.6. Anal.
Calcd for C17H27O7N: C, 57.13; H, 7.61; N, 3.92. Found: C, 57.33;
H, 7.47; N, 4.06.
1583, 1470, 1254, 1095, 837 cm-1
.
1H NMR (300 MHz, CDCl3) major
δ 5.85 (d, J ) 1.7, 1H); 5.40 (t, J ) 7.8, 2H); 3.7-3.6 (m, 1H); 3.63
(d, J ) 4.7, 2H); 3.55 (dd, J ) 9.7, 5.5, 1H); 3.42 (d, J ) 9.3, 1H);
3.26 (d, J ) 9.4, 1H); 3.17 (dd, J ) 7.7, 1.6, 1H); 2.5-2.4 (m, 2H);
Preparation of (4S,5E)-N,N-Dimethyl-4,8-bis(hydroxymethyl)-9-
hydroxy-4-methyl-5-nonenamide (11). Sodium borohydride (37 mg,

+
+
A Total Synthesis of (+)-Cassiol
2.4-2.3 (m, 1H); 2.05-1.9 (m, 1H); 1.67-1.57 (m, 1H); 0.88 (s, 27H);
J. Am. Chem. Soc., Vol. 118, No. 28, 1996 6633
TBAF (30 µL 1 M in THF, 0.03 mmol) was added to a THF (0.5
mL) solution of 16. After overnight stirring, it was loaded on silica
gel and eluted (5% MeOH in CH2Cl2) to yield cassiol (1.5 mg, 42%);
0.84 (s, 3H); 0.09 (s, 9H), 0.04 (s, 6H); 0.03 (s, 6H); 0.01 (s, 6H). 13
C
NMR (75 MHz, C6D6) major δ 201.3, 154.3, 124.7, 133.3, 130.2, 70.0,
63.5, 54.1, 48.5, 38.8, 36.7, 30.9, 26.2, 26.1, 19.0, 18.6, 18.5, 0.07,
-5.2, -5.3, -5.4, -5.5. HRMS calcd for C31H63O4Si4 (M+ - C4H9):
611.380. Found: 611.3757.
Preparation of (S)-2,4-Dimethyl-3-[(1′E)-4′-hydroxy-3′-hydroxy-
methyl-1′-butenyl]-2-cyclohexen-1-one [(+)-Cassiol] (1). Karstedt’s
catalyst17 (25 µL) was added to triethylsilane (20 µL, 0.12 mmol) in
toluene (0.2 mL) at room temperature. After the solution was stirred
for 10 min, enone 14 (9.1 mg, 0.014 mmol) in toluene (0.3 mL) was
added. The reaction mixture was kept at 70 °C for overnight,
evaporated in Vacuo, and passed through a florisil plug (rinsed with
hexanes then 1% ether in hexanes) to give the crude triethylsilyl ether
15 (7.5 mg, 0.0096 mmol).
DDQ (5 mg, 0.022 mmol) was added to a methylene chloride (0.4
mL) solution of 15 at room temperature. After overnight stirring, the
reaction was quenched with aqueous saturated sodium bicarbonate
solution and extracted with diethyl ether. After washing (2 × NaHCO3,
1 × brine) and drying (MgSO4), the ethereal solution was evaporated
in Vacuo, and the residue was passed through a silica gel plug (3%
ether in hexanes) to give enone 16 (4.1 mg, 0.0061 mmol).
[R]25 ) +16.1 (c 0.15 in MeOH). IR (thin film) 3376, 2927, 2874,
D
1648, 1589, 1462, 1357, 1038 cm-1 1H NMR (400 MHz, D2O) δ
.
6.30 (d, J ) 16.2, 1H); 5.69 (dd, J ) 16.3, 8.5, 1H); 3.80 (d, J ) 11.6,
1H); 3.76 (ddd, J ) 11.1, 6.0, 2.0, 2H); 3.68 (ddd, J ) 11.1, 7.1, 1.3,
2H); 3.49 (d, J ) 11.5, 1H); 2.4-2.5 (m, 3H); 2.25-2.15 (m, 1H);
1.83 (s, 3H); 1.82-1.7 (m, 1H); 1.14 (s, 3H); 13C NMR (100 MHz,
D2O) δ 207.1, 164.7, 139.0, 134.2, 131.2, 70.4, 64.5, 50.1, 43.1, 35.8,
33.2, 22.9, 15.4. HRMS calcd for C14H22O4 (M+): 254.1518. Found:
254.1519.
Acknowledgment. We thank the National Institutes of
Health, General Medical Sciences Institute, for their generous
support of our programs. Mass spectra were recorded by the
Mass Spectrometry Facility of the University of California-San
Francisco. Johnson Matthey Alfa Aesar generously provided a
loan of palladium salts.
JA960642F