Detours en route to a total synthesis of (+)-cassiol

Article abstract of DOI:10.1016/S0957-4166(03)00082-X

A synthesis of the antiulcerogenic compound (+)-cassiol 1b has been achieved in 43% yield starting with lactol (S)-2 and sulfone 26. This short and efficient synthesis features the one-pot Julia olefination reaction of the sodium anion of (S)-2 with 26, through the key intermediate (-)-9. This synthesis has been developed as a result of exploratory experiments including different olefination reactions on 2. An attempt to synthesize the intermediate 9 by an intramolecular aldol condensation approach of the open chain precursor 4 is also described.

Full text of DOI:10.1016/S0957-4166(03)00082-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 717–725
Detours en route to a total synthesis of (+)-cassiol
Mar´ıa I. Colombo, Juan Zinczuk, Mar´ıa L. Bohn and Edmundo A. Ru´veda*
Instituto de Qu´ımica Orga´nica de S´ıntesis (CONICET-UNR), Facultad de Ciencias Bioqu´ımicas y Farmace´uticas, Suipacha 531,
2000, Rosario, Argentina
Received 3 December 2002; accepted 10 January 2003
Abstract—A synthesis of the antiulcerogenic compound (+)-cassiol 1b has been achieved in 43% yield starting with lactol (S)-2 and
sulfone 26. This short and efficient synthesis features the one-pot Julia olefination reaction of the sodium anion of (S)-2 with 26,
through the key intermediate (−)-9. This synthesis has been developed as a result of exploratory experiments including different
olefination reactions on 2. An attempt to synthesize the intermediate 9 by an intramolecular aldol condensation approach of the
open chain precursor 4 is also described. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
As depicted retrosynthetically in Scheme 1, three main
strategies were used for the synthesis of (+)-cassiol.
As the result of a pharmacological analysis of the
aqueous extract of the dried stem bark of Cinnamomum
cassia Blume, one of the constituents of the traditional
Chinese prescription ‘goreisan’ (‘kennan keihi’ in
Japanese) that displayed potent serotonin-induced
antiulcerogenic activity in rats, Fukaya et al. isolated
the glucoside (−)-cassioside 1a, whose enzymatic
hydrolysis afforded the aglycone (+)-cassiol 1b, exhibit-
ing more potent antiulcer activity than cassioside itself.1
Scheme 1.
A careful analysis of the structure of (+)-cassiol 1b
reveals a rather simple molecular framework that
accommodates a functionalized cyclohexenone moiety
with the (S)-C-4 quaternary stereocenter and a 2-eth-
enyl-1,3-propanediol side chain which is connected at
C-3.
The strategy involving disconnection a, based on the
assembly of a chiral and adequately functionalized
cyclohexenone/cyclohexanone intermediate, and its
coupling with a side chain precursor, was used by
several research groups.3–9 Disconnection bb% involves a
chiral Diels–Alder cycloaddition reaction,10 and discon-
nection c, a cycloisomerization in an ene type fashion.11
A comparative analysis of the approaches to cassiol
indicates that the sequence reported by Corey et al.10 in
which the key step is a catalyzed enantioselective Diels–
Alder reaction is, by far, the most efficient with respect
to the number of synthetic steps and the overall yield
(40%). It is worthwhile mentioning in connection with
this, that the glucoside (−)-cassioside 1a has also been
synthesized. In fact, Boeckman et al.12 obtained the
The structural features and pharmacological activity of
cassiol have aroused the interest of synthetic organic
chemists and several valuable contributions to its syn-
thesis have appeared in the literature in recent years.2
* Corresponding author. Tel.: 54-3414370477; fax: 54-3414370477;
e-mail: eruveda@fbioyf.unr.edu.ar
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00082-X

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M. I. Colombo et al. / Tetrahedron: Asymmetry 14 (2003) 717–725
natural product following a sequence that includes an
asymmetric Diels–Alder reaction and the glycosidation
of an advanced intermediate. To the best of our knowl-
edge, this is the only synthesis of (−)-1a so far reported.
Recently, as part of our project on the preparation of
key intermediates for the synthesis of natural products,
we have reported an efficient chemical resolution of
lactol 2a.13 The availability of both enantiomers
together with our interest on the use of the sequence
involving a Michael addition followed by an aldol
condensation in synthesis, prompted us to study two
alternative routes toward (+)-1b that had not previously
been explored: an intramolecular aldol condensation of
the open chain substrate 4 already carrying the side
chain present in cassiol and a convergent approach via
olefination reaction of 2a with a precursor of the side
chain (3) (Scheme 2).14
Scheme 3. Reagents and conditions: (a) (triphenylphospho-
ranylidene) acetaldehyde, PhH, reflux; (b) methyl propionate,
THF, LDA, −78°C; (c) PDC, CH2Cl2, 24 h; (d) EVK, EtOH,
NaOH.
able experimentation we found that the treatment of 4
with 4% aqueous potassium hydroxide in refluxing
methanol afforded 9 in only 9% yield, together with
56% of the unexpected compound 10 (Scheme 4). The
structure and stereochemistry of the exocyclic double
bond of 9 and the structure of 10 were defined by
1
analysis of their H and 13C NMR spectra.
Scheme 4. Reagents and conditions: (a) 4% KOH (aq),
MeOH, reflux.
Scheme 2.
The intramolecular aldol condensation approach has
been used previously with varied success for the synthe-
sis of the cyclohehexenone present in the trisporic
acids.15–18 The olefination approach has, in turn, also
been used for their synthesis via Wittig reaction of the
racemic lactol 2a with appropriate phosphoranes.19
Furthermore, the structure of 10 was confirmed by H,H
and H,C COSY correlations and NOE experiments.
Undoubtedly, the isolation of 10 indicates that the
condensation step had occurred through the alternative
enolate 11. This is probably due to the poorly elec-
trophilic character of the a,b-unsaturated carbonyl
group together with the steric hindrance imposed by the
neighboring neopentyl carbon in 4. This could also be
the reason why this approach gave low yields in most
syntheses of the trisporic acids.
Although the antiulcerogenic activity of 1b is probably
due to the presence of a cyclohexenone moiety in the
molecule,20 the proposed synthetic sequences, if success-
fully developed, would allow the preparation of (+)-
and (−)-cassiol and side chain analogues, in order to
elucidate the role of these features in the pharmacolog-
ical activity.
The results of our attempts to transform these ideas
into reality are the basis of this report.
2. Results and discussion
Our first choice for the synthesis of 1b through the
olefination approach was to use a simple Wittig reac-
tion and the necessary reagent 13 was expected to be
easily prepared by treatment of the known bromide
1222 with triphenylphosphine. However, all of our
attempts to prepare 13 were unsuccessful and the treat-
For the synthesis of 4, we followed the sequence
described in Scheme 3, starting with the known alde-
hyde 5.21
Unfortunately, the conversion of 4 into 9 in acceptable
yields was more difficult than expected. After consider-

M. I. Colombo et al. / Tetrahedron: Asymmetry 14 (2003) 717–725
719
ment of bromide 12 with triphenylphosphine under the
usual conditions led to extensive cleavage of the pro-
tecting group.† The same result was obtained using a
variety of hydroxyl protecting groups under several
different reaction conditions.23
Several attempts to improve the yield of 18 (longer
reaction times, higher temperatures, order of addition
of reagents, etc.) were unsuccessful, however, careful
analysis of the reaction mixture allowed us to identify
additional products, including 19, 20 and 21a, the
formation of which deserve some comments.
The formation of 19 is readily explained through the
reaction of unchanged starting material 2 with diazo-
methane during the work-up of the reaction and, the
simultaneous formation of an alcohol and of a car-
boxylic acid, identified as the lactone 20 and the
dimethyl ester 21b, suggested that under the olefination
reaction conditions, 2 would undergo a Cannizzaro-
type reaction giving 20 and 21a.
In view of these difficulties, we decided to apply the
one-pot reaction recently reported by Julia et al.24 and
successfully used by Kociensky et al. in the synthesis of
several natural products.25,26
The 2-benzothiazolylsulfone 17, that was selected as the
most adequate reaction partner, was prepared starting
with the known ester 14a,21 as shown in Scheme 5, in
which the protecting group has been changed to the
butyraldehyde acetal, which is more resistant to depro-
tection than the acetone ketal present in 14a.23
However, if a solution of 2 in THF was first treated
with equimolar sodium hydride and then added to the
anion of the benzothiazolylsulfone 17, the coupling
product 18 is obtained in ca. 78% yield, exclusively as
the E-isomer, without formation of the side products.‡
We believe that under these conditions the carboxylate
of 2b predominates over the anion of 2a, allowing in
this way the rapid attack of the lithiated benzothia-
zolylsulfone to the carbonyl of the free aldehyde, lead-
ing to the coupling product. To the best of our
knowledge, this is the first example of a Julia one-pot
olefination reaction using a lactol in its anionic form as
the reaction partner. We believe that this observation
could extend the usefulness of this important reaction.
Scheme 5. Reagents and conditions: (a) 6N HCl, MeOH,
20°C; (b) CH3(CH2)2CHO, TsOH, hexane, reflux; (c) LAH,
Et2O, 20°C; (d) MsCl, Et3N, 0°C; (e) 2-mercaptobenzothia-
zole, KOH, EtOH, 20°C; (f) ammonium molybdate, H2O2,
0–20°C.
We have found that by the addition of lactol 2 to the
anion of 17, generated with LDA in THF at −80°C, the
desired product 18 was obtained in only 18% yield after
treatment of the crude product with excess diazo-
methane and purification by column chromatography
With compound 18 in hand, we turned our attention to
the closing steps in the sequence towards cassiol. We
envisioned that by reduction of 18 to a diol, followed
by selective oxidation of the allylic alcohol and depro-
tection would furnish 1b.
1
(Scheme 6). The H and 13C NMR spectral data are in
excellent agreement with the proposed structure and
stereochemistry for 18.
Reduction of 18 with LAH in Et2O gave a 1.7:1 mix-
ture of diols in good yield. The diols were then sepa-
rated and analyzed by 1H NMR spectroscopy. The
minor diol was shown to be the pseudoaxial allylic
alcohol 22a and, the major one, was identified as the
pseudoequatorial allylic alcohol 22b. Our first choice
for the oxidation of the mixture of allylic alcohols was
to use manganese dioxide. We noted, however, that 22b
Scheme 6. Reagents and conditions: (a) LDA, THF, −80°C,
17, 1 h, 2, −80–15°C; (b) CH2N2, Et2O.
† The easy cleavage of this ketal is probably due to the simultaneous
presence of phosphonium and bromide ions in the reaction medium.
‡ We thank Professor S. V. Ley (Cambridge) for this helpful sugges-
tion.

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M. I. Colombo et al. / Tetrahedron: Asymmetry 14 (2003) 717–725
lyzed intramolecular conjugate addition, as shown in
25, is in competition with the hydrolysis of the
butyraldehyde acetal. That is, we have paid the price of
planning the sequence with a resistant protecting group.
was oxidized faster than 22a to give 22c. This observa-
tion was confirmed with the individual epimers. Diol
22a, even after 16 h, gave a low yield of 22c while
unidentified products were detected in the reaction mix-
ture (TLC).
With the information obtained in the exploratory
experiments described above, we were able to develop
an efficient synthetic sequence to 1b that could also be
used for the synthesis of (+)-cassiol.
The sulfone 26, carrying the more labile diol protecting
group and prepared following a sequence very similar
to that described for 17 (Scheme 5), when coupled with
2, indeed afforded 9 in 78% yield.
To improve the yield of 22c, we decided to study the
oxidation of the epimeric allylic alcohols with DDQ
under the conditions described by Burn et al.27 In spite
of the fact that under these conditions we obtained 22c
in a reasonable yield, a careful analysis of the reaction
mixture allowed us to isolate a less polar compound in
32% yield.
To avoid the problems detected in the sequence of
reduction and oxidation of 18, we decided to protect
the ketonic carbonyl group of 9 leaving the car-
bomethoxyl group free for reduction. On treatment
with TBDMSOTf and Et3N, 9 was transformed into
the silyl enol ether 27a which, on reduction with
DIBALH at −78°C afforded 27b. By deprotection with
TBAF 27b gave the known ketone 28,10 which, upon
treatment with aqueous HCl in methanol at 20°C gave
1b in good overall yield (Scheme 7).
On the basis of its 1H and 13C NMR spectroscopic
data, structure 23 was assigned to this compound. The
formation of 23 was also detected working with the
individual epimers.
We assume that the formation of 23 has occurred
through an acid-catalyzed SN1 type process, due to the
low pKa of the hydroquinone generated in the reaction
mixture.28
Scheme 7. Reagents and conditions: (a) TBDMSOTf, Et3N,
CH2Cl2, 0°C then 20°C, 1 h; (b) DIBALH, THF, −78°C, 1 h;
(c) TBAF, THF, 20°C, 1 h; (d) 6N HCl, MeOH, 20°C, 1 h.
Attempts to hydrolyze the protecting group of 22c to
give 1b also led us to problems. In fact, only unreacted
starting material was detected (TLC) by treatment of
22c with aqueous HCl in a solution of methanol at
20°C for several hours. However, after 40 min at reflux,
a mixture of 1b (42% yield) together with an unexpected
product (35% yield), was obtained. The spectral data of
1b were coincident with those reported in the literature1
and the structure of the unknown product was estab-
lished as 24 by analysis of its 1H and 13C NMR spectra.
Apparently, the formation of 24, through an acid-cata-
Finally, starting with (S)-2 and following the sequence
used for racemic cassiol, (+)-1b was obtained in 43%
overall yield. Its spectroscopic properties and specific
rotation value matched those of naturally derived cas-
siol. The sequence with the optically active compounds
was carried out without isolation and purification of
the intermediates 27a, 27b and 28, requiring only chro-
matographic purification of (−)-9 and of (+)-1b.
The synthesis of (+)-1b described in this report, featur-
ing an excellent approach for the olefination of lactols,
is short and efficient and uses simple reactions that
allow good reproducibility and material throughput.
3. Experimental
Melting points are uncorrected. IR spectra were mea-
1
sured in a Bruker FT-IFS25 spectrometer. The H and

M. I. Colombo et al. / Tetrahedron: Asymmetry 14 (2003) 717–725
721
13C NMR spectra were recorded on a Bruker AC 200
spectrometer for CDCl3 solutions (except where noted)
with Me4Si as internal standard. For the 2D, COSY
and NOE experiments Bruker standard software was
employed. Column chromatography was performed on
silica gel 60 H, slurry packed, run under low pressure of
nitrogen and employing increasing amounts of EtOAc
in hexane as solvent. Analytical TLC was carried out
using Kieselgel Merck GF254 with thickness 0.20 mm.
The homogeneity of all intermediates prior to the high
resolution mass spectral determination was carefully
verified by TLC. Reactions were routinely run under a
dry nitrogen atmosphere with magnetic stirring. All
chemicals were used as purchased or purified according
to standard procedures. The enantiomeric purities were
afforded 8 as a colorless oil (273 mg, 74%), which
showed to be a mixture of the keto and enol forms.
1H NMR (keto form) l: 6.84 (dd, J=15.9 and 7.9
Hz, 1H), 6.32 (d, J=15.9 Hz, 1H), 3.78 (m, 5H), 3.73
(s, 3H), 2.65 (m, 1H), 1.45 (s, 3H), 1.43 (s, 3H), 1.38
(d, J=7.1 Hz, 3H), signals of the enol form were also
detected. 13C NMR (keto form) l: 194.28 (CO)
170.73 (CO), 144.61 (d), 129.02 (d), 97.80 (s), 62.83
(t, two carbons), 52.25 (q), 50.64 (d), 37.84 (d), 25.83
(q), 21.40 (q), 12.69 (q), signals of the enol form were
also detected.
3.1.3. Preparation of diketo ester 4. To a stirred solu-
tion of the b-ketoester 8 (332 mg, 1.30 mmol) in
EtOH (4 mL) was added 1 M aqueous NaOH (0.1
mL). To the resulting solution ethyl vinyl ketone
(0.15 mL, 1.48 mmol) in EtOH (1.2 mL) was added
dropwise (30 min). After 4 h at 20°C the solvent was
evaporated, the residue dissolved in Et2O, the organic
phase was washed with brine, dried (Na2SO4) and
evaporated to give essentially pure 4 as an oil (392
1
established via H NMR analysis employing the shift
reagent tris(3-[heptafluoropropyl-hydroxymethylene]-d-
camphorato) europium(III) derivative [Eu(hfc)3.
3.1. Preparation of compounds 9 and 10
Starting with the known aldehyde 5,21 and following
the conditions described by Boeckman et al.12 the
enal 6 was obtained in 79%, as a yellowish oil. 1H
NMR l: 9.53 (d, J=7.7 Hz, 1H), 6.85 (dd, J=15.9
and 7.8 Hz, 1H), 6.20 (ddd, J=15.9, 7.7 and 1.1 Hz,
1H), 4.05 (dd, J=11.8 and 4.3 Hz, 2H), 3.80 (dd,
J=11.8 and 7.2 Hz, 2H), 2.67 (m, 1H), 1.45 (s, 6H).
mg, 89%). H NMR l: 6.85 (dd, J=15.0 and 7.5 Hz,
1
1H), 6.30 (d, J=15.0 Hz, 1H), 4.0–3.6 (m, 4H), 3.70
(s, 3H), 2.75–2.55 (m, 1H), 2.40 (q, J=7.3 Hz, 2H),
2.55–2.30 (m, 1H), 2.30–1.90 (m, 2H), 1.43 (s, 3H),
1.42 (s, 3H), 1.34 (s, 3H), 1.04 (t, J=7.3 Hz, 3H).
13C NMR l: 209.91 (CO), 195.23 (CO), 173.09 (CO),
144.56 (d), 126.20 (d), 97.79 (s), 62.89 (t, two car-
bons), 57.37 (s), 52.34 (q), 37.87 (d), 37.04 (t), 35.78
(t), 28.31 (t), 26.00 (q), 21.32 (q), 19.13 (q), 7.65 (q).
3.1.1. Preparation of hydroxy ester 7. To a stirred
solution of diisopropylamine (0.54 mL, 3.89 mmol) in
THF (3 mL) at −30°C was added dropwise n-BuLi
(2.85 mL, 3.89 mmol). The reaction was stirred for 15
min and cooled to −80°C. A solution of methyl pro-
pionate (0.37 mL, 3.88 mmol) in THF (2 mL) was
added dropwise so that the internal reaction tempera-
ture remained below −78°C. When the addition of the
methyl propionate was complete, the reaction was
stirred for 50 min at −78°C. A solution of aldehyde 6
(0.60 g, 3.5 mmol) in THF (3 mL) was then added
via cannula. The reaction was stirred for 5 min and
quenched by the addition of saturated aqueous
NH4Cl and extracted with Et2O. The combined
organic extracts were washed with brine, dried
(Na2SO4), and evaporated. The residue (1.05 g) was
chromatographed to yield 7 as an oily solid mixture
of diastereoisomers (0.58 g, 64%). 1H NMR l: 5.56
(m, 2H), 4.35 (br s, 0.4H), 4.15 (br s, 0.6H), 3.9–3.6
(m, 4H), 3.71 and 3.70 (s, 3H), 2.75 (m, 1H), 2.60–
2.45 (m, 1H), 1.44 (s, 3H), 1.41 (s, 3H), 1.16 and 1.15
(d, 3H) 13C NMR l: 175.63 (CO), 175.41 (CO),
132.55 (d), 131.96 (d), 129.41 (d), 128.66 (d), 97.43
(s), 74.04 (d), 72.50 (d), 63.85 (t, two carbons), 51.61
(q), 45.18 (d), 44.63 (d), 37.53 (d), 27.45 (q), 27.27
(q), 20.13 (q), 19.96 (q), 13.79 (q), 11.24 (q).
3.1.4. Preparation of a,b-unsaturated ketone 9. To a
stirred solution of compound 4 (198 mg, 0.60 mmol)
in MeOH (8 mL) an aqueous 4% solution of KOH
(0.28 mL) was added. The solution was heated at
reflux for 7 h, until the TLC spot for the starting
material had disappeared. The mixture was cooled
and poured into brine. The aqueous phase was
extracted with Et2O, the combined organic extracts
were washed with brine, dried (Na2SO4) and evapo-
rated. The residue (128 mg) was chromatographed
yielding 9 (17.2 mg, 9%) and 10 (85.6 mg, 56%).
Compound 9 crystallized on standing, mp 74.5–
1
75.5°C. IR (KBr) 1728, 1664, 1634 cm−1. H NMR l:
6.27 (d, J=16.4, 1H), 5.67 (dd, J=16.4 and 8.2 Hz,
1H), 3.95–3.85 (m, 2H), 3.80–3.60 (m, 2H), 3.68 (s,
3H), 2.60–2.30 (m, 4H), 1.95 (m, 1H), 1.87 (s, 3H),
1.47 (s, 3H), 1.43 (s, 3H), 1.42 (s, 3H). 13C NMR l:
197.78 (CO), 175.85 (CO), 151.69 (s), 133.92 (d),
132.41 (s), 128.86 (d), 97.62 (s), 63.66 (t, two car-
bons), 52.22 (q), 46.78 (s), 39.33 (d), 34.05 (t), 33.39
(t), 26.59 (q), 22.66 (q), 20.92 (q), 12.39 (q). HRMS
calcd for C18H26O5 (M+): 322.1780, found: 322.1784.
1
Compound 10: IR (neat) 1610, 1666 cm−1. H NMR
l: 5.76 (br s, 1H), 4.40 (s, 2H), 4.08 (s, 2H), 2.50–
2.30 (m, 3H), 2.26 (q, J=7.7 Hz, 2H), 2.15–1.95 (m,
1H), 1.80–1.55 (m, 1H), 1.44 (s, 6H), 1.13 (d, J=6.8
Hz, 3H), 1.07 (t, J=7.7 Hz, 3H). 13C NMR l: 200.16
(CO), 162.82 (s), 136.04 (s), 129.57 (s), 116.06 (d),
98.58 (s), 64.46 (t), 61.03 (t), 40.94 (d), 30.07 (t),
28.75 (t), 28.50 (t), 23.91 (q), 23.78 (q), 15.42 (q),
11.52 (q). HRMS calcd for C16H24O3 (M+): 264.1725,
found: 264.1727.
3.1.2. Preparation of keto ester 8. To a stirred solu-
tion of 7 (366 mg, 1.4 mmol) in anhydrous redistilled
CH2Cl2 (30 mL) was added finely powdered PDC (1.2
g, 3.2 mmol). After 24 h, Celite was added, and the
mixture was stirred for a further 20 min and filtered
through a column of silica gel 60H with copious
washings (EtOAc). Concentration of the filtrate

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M. I. Colombo et al. / Tetrahedron: Asymmetry 14 (2003) 717–725
3.2. Preparation of sulfone 17
cooled to 0°C and a solution of 15c (279 mg, 1.17
mmol) in EtOH (5.4 mL) was gradually added. The
mixture was stirred for 68 h at 20°C and the solvent
evaporated, the residue was taken up in H2O and the
aqueous phase extracted with CH2Cl2. The combined
organic extracts were washed with H2O, dried (Na2SO4)
and evaporated. The residue (337 mg) was chro-
matographed affording pure 16 (218 mg, 56% for two
3.2.1. Preparation of diol 14b. To a solution of 14a21
(2.50 g, 13.3 mmol) in MeOH (18.3 mL) was added 6N
aqueous HCl (1.15 mL). After 12 h at 20°C excess of
solid NaHCO3 was added and the resulting mixture was
stirred for 30 min. The solvent was then evaporated and
the residue was taken up in Me2CO. The resulting
slurry was filtered through a short pad of silica gel,
washed copiously with EtOAc and the filtrate evapo-
1
steps), recrystallized from EtOH, mp 56.6–57.6°C. H
NMR l: 7.88–7.72 (m, 2H), 7.42–7.26 (m, 2H), 4.45 (t,
J=6.0 and 4.0 Hz, 1H), 4.25 (dd, J=12.0 and 4.0 Hz,
2H), 3.48 (t, J=12.0 Hz, 2H), 3.15 (d, J=8.0 Hz, 2H),
2.49 (m, 1H), 1.60–1.30 (m, 4H), 0.91 (t, J=8.0 Hz,
3H). 13C NMR l: 165.45 (s), 152.78 (s), 135.02 (s),
125.84 (d), 124.15 (d), 121.33 (d), 120.75 (d), 101.89 (d),
70.57 (t, two carbons), 36.55 (t), 34.08 (d), 30.95 (t),
27.06 (t), 13.75 (q).
1
rated to yield 14b (1.76 g). H NMR l: 4.23 (q, J=7.1
Hz, 2H), 4.10–3.90 (m, 4H), 2.80–2.65 (m, 1H), 1.30 (t,
J=7.1 Hz, 3H). This product was used in the next step
without further purification.
3.2.2. Preparation of acetal 15a. To a solution of crude
14b (1.76 g) and butyraldehyde (1.28 g, 17.7 mmol) in
hexane (13 mL) p-toluenesulfonic acid monohydrate
(420 mg, 2.2 mmol) was added. The flask was fitted
with a Dean–Stark trap connected to a reflux condenser
and the mixture was heated under reflux for 4 h. The
mixture was cooled and anhydrous NaOAc (356 mg,
4.33 mmol) was added. After stirring for 45 min, the
mixture was taken up in Et2O, washed with H2O, dried
(Na2SO4) and evaporated. The yellowish oily residue
was purified by distillation to give 15a (1.2 g, 45% for
3.2.6. Preparation of 2-benzothiazolylsulfone 17. To a
solution of 16 (100 mg, 0.32 mmol) in anhydrous EtOH
(3 mL) at 0°C ammonium molybdate (37 mg, 0.16
mmol) and 28% aqueous H2O2 (0.3 mL) were added.
After stirring at 0°C for 3 h and at 20°C for 48 h, the
majority of the EtOH was evaporated, H2O (10 mL)
was added and the mixture was extracted with CH2Cl2.
The combined organic extracts were washed succes-
sively with 5% aqueous H2SO4, saturated aqueous
NaHCO3 solution, H2O and brine, dried (Na2SO4) and
evaporated to give a residue (113 mg) which was chro-
matographed to yield the sulfone 17 (103 mg, 93%), mp
114.6–115°C from Et2O. IR (KBr) 1470, 1410, 1340,
980 cm−1. 1H NMR l: 8.25–8.15 (m, 1H), 8.05–7.95 (m,
1H), 7.70–7.55 (m, 2H), 4.44 (t, J=5.0 Hz, 1H), 4.27
(dd, J=11.8 and 4.5 Hz, 2H), 3.48 (t, J=11.5 Hz, 2H),
3.26 (d, J=8.0 Hz, 2H), 2.80–2.60 (m, 1H), 1.60–1.25
(m, 4H), 0.90 (t, J=6.0 Hz, 3H). 13C NMR l: 165.24
(s), 152.24 (s), 136.39 (s), 128.00 (d), 127.55 (d), 125.14
(d), 122.15 (d), 101.89 (d), 69.88 (t, two carbons), 52.91
(t), 36.36 (t), 29.42 (d), 16.88 (t), 13.63 (q). Anal. calcd
for C15H19NO4S2: C, 52.77; H, 5.61; N, 4.10, S, 18.78.
Found: C, 52.81; H, 5.65; N, 4.16; S, 18.78%.
1
two steps) as a colorless oil. H NMR l: 4.44 (t, J=5.0
Hz, 1H), 4.28 (dd, J=11.9 and 5.0 Hz, 2H), 4.13 (q,
J=7.0 Hz, 2H). 3.75 (t, J=11.5 Hz, 2H), 3.05–2.87 (m,
1H), 1.65–1.20 (m, 4H), 1.25 (t, J=7.1 Hz, 3H), 0.91 (t,
J=7.1 Hz, 3H).
3.2.3. Preparation of alcohol 15b. To a stirred mixture
of LAH (160 mg, 4.21 mmol) in anhydrous Et2O (28
mL) at 0°C was gradually added a solution of 15a (905
mg, 4.48 mmol) also in anhydrous Et2O (9 mL). After
stirring at 20°C for 40 min the reaction mixture was
quenched by addition of H2O (0.16 mL), 10% aqueous
NaOH (0.32 mL) and saturated KF (0.5 mL). After
stirring for 20 min, the mixture was filtered and the
filtrate evaporated to give 15b as a colorless oil (715
1
mg, 100%). H NMR l: 4.44 (t, J=5.0 Hz, 1H), 4.15
(dd, J=11.7 and 4.6 Hz, 2H), 3.51 (d, J=18.5 Hz, 2H).
3.46 (d, J=11.4 Hz, 2H), 2.35–2.13 (m, 1H), 1.65–1.20
(m, 4H), 0.92 (t, J=7.2 Hz, 3H).
3.3. Preparation of diene 18 by Julia olefination reac-
tion of 17 and 2
A solution of n-BuLi in hexane (1.65 M, 0.6 mL, 1
mmol) was added to a solution of diisopropylamine
(0.15 mL, 1.08 mmol) in anhydrous THF (2 mL) at
−80°C. After warming up to 0°C and stirred for 30 min,
this solution was slowly added to a solution of 17 (341
mg, 1 mmol) in anhydrous THF (6 mL) at −80°C.
Stirring was continued for 1 h after which a solution of
2 (100 mg, 0.51 mmol) in anhydrous THF (4 mL)
cooled at −80°C was added. The mixture was allowed
to warm to 15°C and then poured into brine and
extracted with Et2O. The aqueous phase, after acidifica-
tion with 0.5N aqueous HCl (pH 4) was extracted with
Et2O and the combined organic extracts were dried
(Na2SO4) and evaporated. The residue was dissolved in
Et2O, treated with an excess of ethereal diazomethane
and the solvent evaporated. The residue was chro-
matographed to yield 18 (30.8 mg, 18%), 19 (18.8 mg,
20%) and a 1:1 inseparable mixture of 20 and 21b (18
3.2.4. Preparation of mesylate 15c. To a stirred solution
of 15b (200 mg, 1.25 mmol) in Et3N (0.37 mL) at 0°C
methanesulfonyl chloride (0.2 mL, 2.5 mmol) was grad-
ually added. The mixture was stirred for 4 h at 0°C.
After addition of H2O (3 mL), the solution was made
alkaline with Et3N and extracted with Et2O. The com-
bined organic extracts were dried (Na2SO4) and evapo-
1
rated to give 15c (279 mg, 94%) as an oil. H NMR l:
4.41 (t, J=5.0 Hz, 1H), 4.15 (dd, J=11.7 and 4.6 Hz,
2H), 4.02 (d, J=6.0 Hz, 2H), 3.65–3.45 (m, 2H), 3.02
(s, 3H), 2.60–2.35 (m, 1H), 1.65–1.20 (m, 4H), 0.92 (t,
J=7.2 Hz, 3H).
3.2.5. Preparation of 2-benzothiazolylsulfide 16. To a
mixture of 2-mercaptobenzothiazole (215 mg, 1.29
mmol) in EtOH (1.8 mL) solid KOH (83 mg, 1.48
mmol) was added. The resulting orange solution was

M. I. Colombo et al. / Tetrahedron: Asymmetry 14 (2003) 717–725
723
mg). Compound 18 is a colorless oil. IR (neat) 1720,
filtered through a silica gel pad with copious washings
with EtOAc, the filtrate was evaporated to give a
mixture of diastereoisomeric diols as a colorless oil
(233.2 mg, 82%). The residue was chromatographed to
yield the more polar diol 22a (56.6 mg, 19.7%) and the
less polar diol 22b (98.3 mg, 35%). Diol 22a: IR (neat)
1
1660, 1629 cm−1. H NMR l: 6.22 (d, J=16.5 Hz, 1H),
5.38 (dd, J=16.2 and 8.1 Hz, 1H), 4.45 (t, J=5.0 Hz,
1H), 4.09–3.90 (m, 2H), 3.67 (s, 3H), 3.50 (ddd, 2H),
2.80–2.50 (m, 1H), 2.60–2.30 (m, 3H), 2.00–1.90 (m,
1H), 1.85 (s, 3H), 1.70–1.30 (m, 4H), 1.47 (s, 3H), 0.92
(t, J=7.2 Hz, 3H). 13C NMR l: 197.70 (CO), 175.75
(CO), 151.42 (s), 132.60 (s), 132.13 (d), 129.49 (d),
101.77 (d), 70.40 (t, two carbons), 52.21 (q), 46.78 (s),
39.43 (d), 36.71 (t), 34.06 (t), 33.42 (t), 22.71 (q), 17.17
(t), 13.83 (q), 12.43 (q): HRMS calcd for C19H28O5
1
3569, 1670 cm−1. H NMR l: 5.94 (dq, J=16.1 and 1.1
Hz, 1H), 5.14 (dd, J=16.1 and 7.8 Hz, 1H), 4.46 (t,
J=5.1 Hz, 1H), 4.07 (dd, J=11.5 and 4.7 Hz, 2H), 3.94
(br t, W1/2=5.8 Hz, 1H), 3.54 (d, J=10.7 Hz, 1H), 3.52
(t, J=10.7 Hz, 2H), 3.23 (d, J=10.7 Hz, 1H), 2.90–2.65
(m, 1H), 1.80 (s, 3H), 2.10–1.20 (m, 9H), 0.93 (t, J=7.2
Hz, 3H), 0.90 (s, 3H). 13C NMR l: 136.63 (s), 133.43
(s), 130.25 (d), 129.56 (d), 101.63 (d), 70.79 (t, two
carbons), 69.30 (t), 68.66 (d), 39.60 (s), 38.69 (d), 36.68
(t), 27.44 (t), 27.17 (t), 21.45 (q), 19.03 (q), 17.12 (t),
13.75 (q). HRMS calcd for C18H30O4 (M+): 310.2144,
found: 310.2148.
1
(M+): 336.1937, found: 336.1935. The H NMR spec-
trum of compound 20 is coincident with that reported
by White et al.,19 l: 4.98 (br s, 2H), 2.64–2.56 (m, 2H),
2.24–2.00 (m, 2H), 1.74 (br s, 3H), 1.50 (s, 3H). Com-
1
pounds 19 and 21b were identified by analysis of the H
NMR spectrum of the mixture and comparison with
the spectra of the pure compounds independently pre-
pared. The 1H NMR spectrum of compound 19 is
coincident with that reported by Secrist et al.,29 l: 10.30
(s, 1H), 3.67 (s, 3H), 2.70–1.90 (m, 4H), 2.22 (s, 3H),
1
Diol 22b: IR (neat) 3405, 1650 cm−1. H NMR l: 5.94
(dq, J=16.1 and 1.0 Hz, 1H), 5.12 (dd, J=16.1 and 7.8
Hz, 1H), 4.46 (t, J=5.0 Hz, 1H), 4.07 (dd, J=11.6 and
4.8 Hz, 2H), 4.07 (m, 1H), 3.51 (t, J=11.6 Hz, 2H),
3.51 (d, J=10.8 Hz, 1H), 3.25 (d, J=10.8 Hz, 1H),
2.80–2.60 (m, 1H), 2.10–1.20 (m, 9H), 1.78 (s, 3H), 0.96
(s, 3H), 0.93 (t, J=7.2 Hz, 3H). 13C NMR l: 136.68 (s),
134.16 (s), 130.36 (d), 129.73 (d), 101.63 (d), 70.78 (t,
two carbons), 69.81 (d), 68.98 (t), 39.63 (s), 38.67 (d),
36.69 (t), 28.94 (t), 28.24 (t), 22.83 (q), 17.67 (q), 17.11
(t), 13.74 (q). HRMS calcd for C18H30O4 (M+):
310.2144, found: 310.2149.
1
1.50 (s, 3H). Compound 21b: H NMR l: 3.81 (s, 3H),
3.73 (s, 3H), 2.60 (m, 2H), 2.45–2.05 (m, 2H), 1.93 (s,
3H), 1.52 (s, 3H). 13C NMR l: 197.66 (CO), 174.18
(CO), 167.55 (CO), 146.13 (s), 136.54 (s), 52.42 (q),
52.16 (q), 45.60 (s), 33.57 (t), 33.51 (t), 22.75 (q), 13.04
(q).
3.4. Improved preparation of 18
A solution of n-BuLi in hexane (2.1 mmol) was added
to a stirred solution of diisopropylamine (0.29 mL, 2
mmol) in anhydrous THF (4 mL) at −30°C. After
stirred for 30 min, this solution was slowly added to a
solution of 17 (650 mg, 1.9 mmol) in anhydrous THF
(13 mL) at −80°C. Stirring was continued for 1 h after
which a solution of 2 (186.2 mg, 0.95 mmol) in anhy-
drous THF (8 mL) that was treated with NaH (76 mg,
60% dispersion in mineral oil, 1.9 mmol) and cooled at
−80°C was added. The mixture was allowed to warm to
−10°C and kept at this temperature for 12 h. The
mixture was then poured into Et2O and extracted with
H2O. The aqueous phase, after acidification with 0.5N
aqueous HCl (pH 4) was extracted with Et2O and the
combined organic extracts were washed with brine,
dried (Na2SO4) and treated with an excess of an ethe-
real solution of diazomethane. When the reaction was
complete (TLC) a few drops of AcOH were added and
the solvent was evaporated. The residue was chro-
matographed to yield the desired coupling product (250
mg, 78%) as an oil. The 1H NMR and 13C NMR of this
product are coincident with those described above for
18.
3.6. Oxidation of diols 22a and 22b
3.6.1. Method (a) with MnO2. To a well stirred suspen-
sion of activated MnO2 (750 mg, 8.6 mmol) in CH2Cl2
(10 mL) was added a solution of the mixture of diols
22a and 22b (76 mg, 0.24 mmol) in CH2Cl2 (2 mL).
After 18 h of stirring at 20°C, the solvent was evapo-
rated and the residue was taken up with EtOAc and
filtered through a silica gel pad with copious washings.
The filtrate was evaporated and the residue was chro-
matographed to give 22c (38 mg, 50%) and the more
polar diol 22a (22 mg, 29%). (b) With DDQ: to a
stirred solution of the mixture of diols 22a and 22b
(58.4 mg, 0.19 mmol) in toluene (9 mL) DDQ (99.8 mg,
0.44 mmol) was added and the mixture was heated at
70°C. After 24 h (TLC) the mixture was filtered and the
residue was washed with benzene and the filtrate evapo-
rated. The residue was chromatographed to yield 22c,
as an oil, (28.0 mg, 47%) and 23 (18 mg, 32%) also an
oil. Enone 22c: IR (neat) 3500, 1663 cm−1. H NMR l:
1
6.14 (dt, J=16.3 and 1.1 Hz, 1H), 5.25 (dd, J=16.3
and 7.9 Hz, 1H), 4.46 (t, J=4.9 Hz, 1H), 4.09 (dd,
J=11.6 and 4.8 Hz, 2H) 3.67 (d, J=10.8 Hz, 1H), 3.55
(t, J=11.5 Hz, 2H), 3.41 (d, J=10.8 Hz, 1H), 2.95–2.70
(m, 1H), 2.58–2.50 (m, 1H), 2.30–2.20 (m, 1H), 1.77 (d,
J=1.1 Hz, 3H), 1.76–1.60 (m, 4H), 1.55–1.30 (m, 2H),
1.07 (s, 3H), 0.92 (t, J=7.2 Hz, 3H). 13C NMR l:
198.80 (CO), 156.65 (s), 132.56 (s), 132.19 (d), 129.02
(d), 101.72 (d), 70.45 (t, two carbons), 68.90 (t), 40.45
(s), 38.87 (d), 36.62 (t), 33.60 (t), 31.37 (t), 21.30 (q),
17.06 (t), 13.70 (q), 13.42 (q). HRMS calcd for
3.5. Preparation of diols 22a and 22b
To a stirred mixture of LAH (650 mg, 17 mmol) in
anhydrous Et2O (28 mL) at 0°C was gradually added a
solution of 18 (305 mg, 0.91 mmol) also in anhydrous
Et2O (24 mL). After stirring at 20°C for 30 min (TLC)
the reaction mixture was quenched by addition of H2O
(0.7 mL), 10% aqueous NaOH (1.4 mL) and saturated
KF (2.1 mL). After stirring for 20 min, the mixture was

724
M. I. Colombo et al. / Tetrahedron: Asymmetry 14 (2003) 717–725
C18H28O4 (M+): 308.1988, found: 308.1986. Compound
23: IR (neat) 1722 cm−1. 1H NMR l: 5.95 (d br t, J=16.0
Hz, 1H), 5.18 (dd, J=16.0 and 5.2 Hz, 1H), 4.47 (t,
J=5.1 Hz, 1H), 4.15–4.03 (m, 3H) 3.56–3.44 (m, 3H),
3.05 (dd, J=7.2 and 3.2 Hz, 1H), 2.85–2.65 (m, 1H), 1.80
(s, 3H), 1.04 (s, 3H), 0.93 (t, J=7.2 Hz, 3H). 13C NMR
l: 136.96 (s), 135.38 (s) 128.81 (d), 126.68 (d), 101.59 (d),
72.84 (t), 71.89 (d), 70.96 (t), 38.95 (d), 36.71 (s), 35.84
(t), 30.14 (t), 26.11 (t), 19.41 (q), 17.11 (t), 16.68 (q), 13.73
(q). HRMS calcd for C18H29O3 (MH+): 293.2117, found:
293.2122.
was added freshly distilled (KOH) Et3N (0.10 mL) and
TBDMSOTf (0.11 mL, 0.48 mmol) in CH2Cl2 (1 mL).
After 1 h at 20°C (TLC) the mixture was poured into
aqueous saturated NaHCO3 and extracted with CH2Cl2.
The combined organic phases were dried (Na2SO4) and
evaporated to give a residue (83.8 mg) that was chro-
matographed through a silica gel column with elution by
hexane:EtOAc:Et3N (95:5:1) to give pure 27a (42.3 mg,
70%). 1H NMR (benzene-d6) l: 6.43 (d, J=16.3 Hz, 1H),
5.72 (dd, J=16.3 and 8.3 Hz, 1H), 5.08 (dd, J=5.9 and
3.6 Hz, 1H), 4.11–3.75 (m, 4H), 3.59 (s, 3H), 3.27 (dd,
J=16.2 and 3.6 Hz, 1H), 2.75–2.57 (m, 1H), 2.24 (dd,
J=16.2. and 5.2 Hz, 1H), 2.13 (s, 3H), 1.72 (s, 6H), 1.55
(s, 3H), 1.21 (s, 9H), 0.36 (s, 3H), 0.34 (s, 3H). 13C NMR
(benzene-d6) l: 178.39 (CO), 150.52 (s), 135.62 (s), 130.36
(d), 130.30 (s), 129.18 (d), 100.21 (d), 96.24 (s), 65.17 (t),
64.99 (t), 52.27 (q), 48.14 (s), 40.56 (d), 35.45 (t), 28.40
(q), 26.63 (q, three carbons), 21.66 (q), 21.34 (q), 19.04
(s), 14.62 (q), −3.72 (q), −3.88 (q).
3.7. Preparation of cassiol
To a stirred solution of 22c (29.8 mg, 0.097 mmol) in
MeOH (5 mL) was added a 6N aqueous HCl and heated
at reflux. After 40 min (TLC) solid NaHCO3 was added
and the stirring was continued for 15 min, the solvent
was evaporated and the residue in Me2CO was filtered
through a silica gel pad with copious washings, the
filtrate was evaporated and the residue was chro-
matographed to yield 1b (10.4 mg, 42%) and 24 (8.6 mg,
3.8.2. Reduction of enol ether 27a to alcohol 27b. To a
stirred solution of ester 27a (42.3 mg, 0.097 mmol) in
THF (5 mL) at −78°C was added DIBALH 1 M in
toluene (1.0 mL, 1 mmol). After 1 h (TLC) the reaction
was quenched by the addition of H2O (0.04 mL), 10%
aqueous NaOH (0.11 mL) and saturated KF (0.60 mL).
After stirring for 20 min, the mixture was filtered through
a silica gel pad with copious washings with EtOAc and
the filtrate evaporated to give pure 27b (33.3 mg, 85%)
1
35%). Cassiol 1b: IR (neat) 3368, 1644, 1594 cm−1. H
NMR (D2O, 200 MHz) l: 6.28 (d, J=16.3 Hz, 1H), 5.67
(dd, J=16.3 and 8.4 Hz, 1H), 3.76 (d, J=11.4 Hz, 1H),
3.75 (dd, A part of ABX, J=11.5 and 5.9 Hz, 2H), 3.66
(dd, B part of ABX, J=11.1 and 7.0 Hz, 2H), 3.43 (d,
J=11.5 Hz, 1H), 2.71–2.55 (m, 3H), 2.17 (ddd, J=13.4,
9.8 and 6.0 Hz, 1H), 1.81 (d, J=0.9 Hz, 3H), 1.74 (ddd,
J=13.6, 6.1 and 6.1 Hz, 1H), 1.12 (s, 3H). The signals
at l 3.75 and l 3.66 simplify into an AB quartet upon
1
as an oil. H NMR (benzene-d6) l: 5.91 (d, J=16.3 Hz,
1
irradiation at l 2.67. This H NMR spectrum is coinci-
1H), 5.22 (dd, J=16.3 and 7.7 Hz, 1H), 4.88 (t, J=4.7
Hz, 1H), 3.78 (dd, J=9.4 and 4.8 Hz, 2H), 3.64–3.52 (m,
2H), 3.52 (d, J=10.6 Hz, 1H), 3.20 (d, J=10.6 Hz, 1H),
2.52 (dd, J=16.7 and 4.8 Hz, 1H), 2.45–2.30 (m, 1H),
1.92 (dd, J=16.7 and 4.8 Hz, 1H), 1.92 (s, 3H), 1.48 (s,
3H), 1.34 (s, 3H), 1.00 (s, 9H), 0.96 (s, 3H), 0.17 (s, 3H),
0.00 (s, 3H). 13C NMR (benzene-d6) l: 150.43 (s), 138.93
(s), 132.54 (d), 130.50 (d), 129.88 (s), 100.79 (d), 98.36 (s),
68.21 (t), 65.03 (t), 64.93 (t), 40.33 (d), 39.83 (s), 32.95
(t), 28.08 (d), 26.70 (q, three carbons), 22.17 (q), 21.73
(q), 19.09 (s), 15.99 (q), −3.72 (q, two carbons).
dent with that reported by Fukaya et al.1 for (+)-1b at
250 MHz. Compound 24: IR (neat) 3402, 1656 cm−1. 1H
NMR l: 4.30 (ddd, J=9.7, 6.9 and 2.5 Hz, 1H),
3.93–3.70 (m, 4H), 3.40 (s, 2H), 2.83–2.47 (m, 5H)
1.90–1.33 (m, 4H), 1.76 (s, 3H), 1.33 (s, 3H). 13C NMR
l: 198.02 (CO), 156.71 (s) 130.96 (s), 73.01 (t), 72.50 (d),
63.37 (t), 62.59 (t), 42.04 (d), 36.89 (s), 33.25 (t), 32.32
(t), 26.91 (t), 21.92 (q), 10.68 (q). HRMS calcd for
C14H23O3 (MH+): 255.1596, found: 255.1585.
3.8. New preparation of cassiol 1b
3.8.3. Preparation of enone 28. To a stirred solution of
27b (33.3 mg) in THF (2 mL) at 20°C, TBAF 1 M in THF
(0.25 mL, 0.25 mmol) was added. After 1 h (TLC) the
mixture was poured into brine and extracted with Et2O,
the organic extracts were dried (Na2SO4) and evaporated
to give a residue (28.6 mg) that was chromatographed
through a silica gel column to give pure 28 (17.5 mg,
73%). IR (neat) 3462, 1654, 1607 cm−1. 1H NMR l: 6.21
(dt, J=16.3 and 1.1 Hz, 1H), 5.57 (dd, J=16.3 and 7.6
Hz, 1H), 3.96 (dd, J=12.0 and 4.7 Hz, 2H), 3.85–3.75
(m, 2H), 3.71 (d, J=11.0 Hz, 1H), 3.42 (d, J=11.0 Hz,
1H), 2.65–2.50 (m, 3H), 2.32–2.15 (m, 1H), 1.81 (d,
J=1.0 Hz, 3H), 1.76–1.63 (m, 1H), 1.44 (s, 6H), 1.11 (s,
3H). 13C NMR l: 199.17 (CO), 157.34 (s), 134.07 (d),
132.40 (s), 128.54 (d), 97.73 (s), 68.98 (t), 63.72 (t), 63.59
(t), 40.62 (s), 38.46 (d), 33.69 (t), 31.45 (t), 25.97 (q), 21.53
(q), 21.30 (q), 13.50 (q). These data are coincident with
those reported by Corey et al.10 for the optically active
product.
Sulfone 26: mp 112.8–113.3°C from Et2O. IR (KBr)
1
1465, 1325, 1140, 1040 cm−1. H NMR l: 8.24–8.20 (m,
1H), 8.10–8.00 (m, 1H), 7.66–7.60 (m, 2H), 4.12 (dd,
J=12.0 and 3.5 Hz, 2H), 3.81 (dd, J=12.0 and 4.6 Hz,
2H), 3.76 (d, J=6.1 Hz, 2H), 2.41 (m, 1H), 1.43 (s, 3H),
1.39 (s, 3H). 13C NMR l: 165.68 (s), 152.40 (s), 136.49
(s), 127.98 (d), 127.57 (d), 125.27 (d), 122.20 (d), 98.25
(s), 63.09 (t, two carbons), 54.30 (t), 29.45 (d), 25.75 (q),
21.56 (q). Anal. calcd for C14H17NO4S2: C, 51.36; H,
5.23; N, 4.28, S, 19.58. Found: C, 51.16; H, 5.23; N, 4.35;
S, 19.56%.
Ester 9 was prepared in 78% yield following a sequence
1
very similar to that described for 18. The H and 13C
NMR of this product are coincident with those described
above for 9.
3.8.1. Preparation of enol ether 27a. To a stirred solution
of ester 9 (45.3 mg, 0.14 mmol) in CH2Cl2 (2 mL) at 0°C

M. I. Colombo et al. / Tetrahedron: Asymmetry 14 (2003) 717–725
725
3.8.4. Deprotection of 28. A solution 28 (17.5 mg, 0.059
mmol) in MeOH (2.0 mL) was treated with a 6N aqueous
solution of HCl (0.1 mL) at 20°C and stirred for 1 h. The
resulting solution was treated with excess solid NaHCO3.
The suspension was stirred for 15 min and concentrated
under a nitrogen current. The residue was dissolved in
Me2CO and filtered through a silica gel pad, with copious
washings. The filtrate was evaporated and the residue
(47.8 mg) was chromatographed with EtOAc:Me2CO
(7:3) to afford pure 1b (13.5 mg, 90%).
2. For a review on the synthetic approaches to cassiol until
1998, see: Colombo, M. I.; Ru´veda, E. A. J. Braz. Chem.
Soc. 1998, 9, 303–312.
3. Takemoto, T.; Fukaya, C.; Yokoyama, K. Tetrahedron
Lett. 1989, 30, 723–724.
4. Uno, T.; Watanabe, H.; Mori, K. Tetrahedron 1990, 46,
5563–5566.
5. Taber, D. F.; Meagly, R. P.; Doren, D. J. J. Org. Chem.
1996, 61, 5723–5728.
6. Irie, O.; Fujiwara, Y.; Nemoto, H.; Shishido, K. Tetra-
hedron Lett. 1996, 37, 9229–9232.
7. Maiti, S.; Achari, B.; Banerjee, A. K. Synlett 1998,
129–130.
3.9. Preparation of (+)-1b
8. Miyaoka, H.; Kajiwara, Y.; Hara, M.; Suma, A.;
Yamada, Y. Tetrahedron: Asymmetry 1999, 10, 3189–
3196.
9. Momose, T.; Toyooka, N.; Nishio, M.; Shinoda, H.;
Fujii, H.; Yanagino, H. Heterocycles 1999, 51, 1321–
1343.
10. Corey, E. J.; Guzman-Perez, A.; Luh, T.-P. J. Am. Chem.
Soc. 1994, 116, 3611–3612.
11. Trost, B. M.; Li, Y. J. Am. Chem. Soc. 1996, 118,
6625–6633.
Starting with (S)-2 and following the sequence used for
racemic cassiol, (+)-1b was obtained in 43% overall yield.
This sequence was carried out without isolation and
purification of the intermediates 27a, 27b and 28, requir-
ing only chromatographic purification of (−)-9 and of
(+)-1b.
1
Compound (−)-9: colorless oil; the H and 13C NMR
spectra of this product are coincident with those
described for the racemic product; [h]2D7 −25.32 (c 3,
CHCl3), ee 97%, the enantiomeric purity was established
12. Boeckman, R. J., Jr.; Liu, Y. J. Org. Chem. 1996, 61,
7984–7985.
1
by H NMR. (+)-Cassiol 1b: colorless oil, [h]3D0 8.34 (c
0.35, MeOH) (lit.1 [h]D 8.6 (c 0.25, MeOH). The 1H NMR
spectrum (200 MHz) of this compound is coincident with
that described above for the racemic product and with
that reported by Fukaya et al.1 for (+)-1b at 250 MHz.
1H NMR (D2O, 500 MHz) l 6.28 (dt, J=16.3 and 1.0
Hz, 1H), 5.67 (dd, J=16.2 and 8.4 Hz, 1H), 3.76 (d,
J=11.4 Hz, 1H), 3.745 (dd, J=11.2 and 5.9 Hz, 1H),
3.740 (dd, J=11.2 and 5.9 Hz, 1H), 3.670 (dd, J=11.2
and 7.1 Hz, 1H), 3.666 (dd, J=11.2 and 7.1 Hz, 1H), 3.43
(d, J=11.4 Hz, 1H), 2.68–2.52 (m, 3H), 2.17 (ddd,
J=13.5, 10.4 and 5.3 Hz, 1H), 1.81 (d, J=0.9 Hz, 3H),
1.75 (ddd, J=13.5, 6.6 and 5.8 Hz, 1H), 1.12 (s, 3H). This
1H NMR spectrum is essentially identical with that
reported by Corey et al.10 for synthetic (+)-1b at 500
MHz. 13C NMR (D2O, 50 MHz) l 207.12 (s), 164.87 (s),
139.17 (d), 134.35 (s), 131.37 (d), 70.44 (t), 64.55 (t, two
carbons), 50.30 (d), 43.18 (s), 35.89 (t), 33.28 (t), 23.02
(q), 15.63 (q). These data are coincident with those
reported by Corey et al.10 for (+)-1b at 100 MHz.
13. Bacigaluppo, J. A.; Colombo, M. I.; Preite, M. D.;
Zinczuk, J.; Ru´veda, E. A. Tetrahedron: Asymmetry 1996,
7, 1041–1057.
14. A part of this work has been published in a preliminary
form: Colombo, M. I.; Zinczuk, J.; Mischne, M. P.;
Ru´veda, E. A. Tetrahedron: Asymmetry 2001, 12, 1251–
1253.
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Fried, J. H. Chem. Commun. 1971, 292–293.
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3115–3118.
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1985, 50, 5233–5244.
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Acknowledgements
We thank Drs. Manuel Gonza´lez-Sierra and Gerardo
Burton for 1H NMR spectra determinations and Dr. Jose´
A. Bacigaluppo for his contributions to some aspects of
this project. This work was supported by Consejo
Nacional de Investigaciones Cient´ıficas y Te´cnicas
(CONICET), Universidad Nacional de Rosario (UNR)
and Agencia Nacional de Promocio´n Cient´ıfica y Tecno-
lo´gica.
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1996, 652–666.
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