An efficient stereoselective synthesis of stypodiol and epistypodiol

Article abstract of DOI:10.1021/jo980311g

An efficient synthesis of stypodiol (1) and its epimer at C-14, epistypodiol (2), was accomplished starting from (S)-(+)-carvone (7). The synthesis of both epimeric compounds proceeds through common intermediates using an IMDA reaction, a sonochemical Barbier reaction, and an acid- catalyzed quinol-tertiary alcohol cyclization as key synthetic steps.

Full text of DOI:10.1021/jo980311g

5100
J . Org. Chem. 1998, 63, 5100-5106
An Efficien t Ster eoselective Syn th esis of Styp od iol a n d
Ep istyp od iol
Antonio Abad,*,† Consuelo Agullo´, Manuel Arno´, Ana C. Cun˜at, Benjam´ın Meseguer, and
Ramo´n J . Zaragoza´
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad de Valencia, C/ Dr. Moliner 50,
E-46100 Burjassot, Valencia, Spain
Received February 19, 1998
An efficient synthesis of stypodiol (1) and its epimer at C-14, epistypodiol (2), was accomplished
starting from (S)-(+)-carvone (7). The synthesis of both epimeric compounds proceeds through
common intermediates using an IMDA reaction, a sonochemical Barbier reaction, and an acid-
catalyzed quinol-tertiary alcohol cyclization as key synthetic steps.
In tr od u ction
Stypodiol (1), epistypodiol (2), and stypotriol (3) are
secondary diterpene metabolites identified as the major
compounds excreted by the tropical brown algae Sty-
popodium zonale (Lamouroux) Papenfuss.1 These com-
pounds display diverse biological properties, particularly
toxic and strong narcotic and hyperactive effects upon
the reef-dwelling fish, Eupomacentrus leucostictus.1a,b,2
The nonnatural but related o-quinone stypoldione (4),
rapidly formed by air oxidation of stypotriol (3), has also
been found to show pronounced cytotoxic properties and
to inhibit cell division in marine embryos and in mam-
malian cell cultures, through a mechanism that appears
to inhibit polymerization of tubulin into microtubes.3 This
interesting biological activity together with their novel
structures has made these compounds desirable targets
for synthesis and for structure-activity studies.
both epimeric spirobenzofuran compounds, stypodiol (1)
and epistypodiol (2), through common intermediates.7
Two successful syntheses of stypoldione (4), via stypo-
diol (1), have been reported.4,5 In addition, stypotriol (3)
has also been prepared by reduction of stypoldione (4).1b
To date, however, the synthesis of epistypodiol (2) has
never been achieved and no chemical methods have been
found to relate it to stypodiol (1), although it could be
likely that both epimers might be interconverted through
a carbocation such as 5, which has been considered as a
common intermediate in their biosynthesis.6 Herein we
describe a very efficient and stereoselective synthesis of
Resu lts a n d Discu ssion
The synthesis of stypodiol (1), our initial target in this
work, commences with the preparation of the enantio-
merically pure tricyclic intermediate 6 (Scheme 1), which
represents the ABC ring system of 1. This compound has
the necessary functionality already present for further
elaboration of rings A and C, and in particular, the
carbonyl group could be utilized for introducing the
spirobenzofuranyl unit (DE rings) of the target com-
pound. The preparation of 6 is effected using (S)-(+)-
carvone (7) as a C-ring synthon which is incorporated into
the tricyclic framework following a C f ABC annulation
strategy, using an intramolecular Diels-Alder (IMDA)
reaction as the key step.8
† Phone: 34-6-3864509. Fax: 34-6-3864328. E-mail: Antonio.Abad@
uv.es.
(1) (a) Gerwick, W. H.; Fenical, W.; Fritsch, N.; Clardy, J . Tetrahe-
dron Lett. 1979, 145. (b) Gerwick, W. H.; Fenical, W. J . Org. Chem.
1981, 46, 22. (c) Rovirosa, J .; Sepu´lveda, M.; Quezada, E.; San-Martin,
A. Phytochemistry 1992, 31, 2679.
(2) (a) Gerwick, W.; Fenical, W.; Norris, J . Phytochemistry 1985, 24,
1279. (b) Gerwick, W. H.; Whatley, G. J . J . Chem. Ecol. 1989, 15, 677.
(3) (a) White, S. J .; J acobs, R. S. Mol. Pharmacol. 1983, 24, 500. (b)
J acobs, R.; Culver, P.; Langdon, R.; O’Brien, T.; White, S. Tetrahedron
1985, 41, 981. (c) O’Brien, E. T.; Asai, D. J .; J acobs, R. S.; Wilson, L.
Mol. Pharmacol. 1989, 35, 635.
The synthesis of key intermediate 6 is summarized in
Scheme 2. The known methyl carvone 8,9 which was
(4) (a) Mori, K.; Koga, Y. Bioorg. Med. Chem. Lett. 1992, 2, 391. (b)
Mori, K.; Koga, Y. Liebigs Ann. Chem. 1991, 769. (c) Mori, K.; Koga,
Y. Liebigs Ann. Chem. 1995, 1755. (d) Falck, J . R.; Chandrasekhar,
S.; Manna, S.; Chiu, C.-C., S. J . Am. Chem. Soc. 1993, 115, 11606.
(5) For related synthetic work, see: (a) Begley, M. J .; Fish, P. V.;
Pattenden, G. J . Chem. Soc., Perkin Trans. 1 1990, 2263. (b) Fish, P.
V.; Pattenden, G.; Hodgson, S. T. Tetrahedron Lett. 1988, 29, 3857. (c)
Spanevello, R. A.; Gonzalez-Sierra, M.; Ru´veda, E. A. Synth. Commun.
1986, 16, 749.
(6) (a) Gonzalez, A. G.; Alvarez, M. A.; Mart´ın, J . D.; Norte, M.;
Pe´rez, C.; Rovirosa, J . Tetrahedron 1982, 38, 719. (b) Kato, T.;
Kumanireng, A. S.; Ichinose, I.; Kitahara, Y.; Kaminuna, Y., Kato, Y.
Chem. Lett. 1975, 335. (c) Gonzalez, A. G.; Mart´ın, J . D.; Rodriguez,
M. L. Tetrahedron Lett. 1973, 3657.
(7) The preparation of stypodiol (1) and its conversion into stypoldi-
one (4) was published previously as a preliminary communication:
Abad, A.; Agullo´, C.; Arno´. M.; Cun˜at, A. C.; Meseguer, B.; Zaragoza´,
R. J . Synlett 1996, 913.
S0022-3263(98)00311-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/09/1998

Stereoselective Synthesis of Stypodiol and Epistypodiol
J . Org. Chem., Vol. 63, No. 15, 1998 5101
Sch em e 1
Sch em e 3
Sch em e 2
Heating a solution of 13 in toluene and a small amount
of propylene oxide in a sealed tube at 190 °C for 7 days
afforded the trans-anti-trans fused adduct 6 in 97%
yield after column chromatography. In the absence of
propylene oxide as proton scavenger, partial isomeriza-
tion of the double bond was observed and a chromatog-
raphycally inseparable 1:1 mixture of the adduct 6 and
its ∆2,3-isomer12 was obtained. The stereochemistry of
6, the only identifiable stereoisomer formed in the IMDA
reaction, was confirmed by a detailed spectroscopic
analysis effected on the diketone 14, formed by hydrolysis
of the tert-butyldimethylsilyl moiety of 6. Of particular
significance was the enhancement observed at the signals
corresponding to the axial hydrogens at C-6, C-4, C-2,
and C-11 and the axial methyl group at C-8 upon
irradiation of the 10â-Me at δ 1.16, in a NOE experiment.
In the same way, irradiation of the 8â-Me signal at δ 1.06
gave NOE enhancement for H-6â, H-7â, H-11â, and 10â-
Me. The overall yield for the preparation of the key
tricyclic intermediate 6 from carvone was 52% (six steps).
With the tricyclic enone 6 readily at hand, we turned
our attention to the required modification of the A-ring
functionality and introduction of the spirobenzofuranyl
unit. Toward this end, the enone 6 was transformed into
compound 15 (Scheme 3). First the tricyclic ketone 6 was
submitted to Simmons-Smith cyclopropanation condi-
tions to stereoselectively cyclopropanate the ring A double
bond, necessary for the introduction of the geminal
dimethyl group at C-4 in the natural compound. An NOE
enhancement observed between the R hydrogen atom of
the methylene group of the cyclopropane ring at δ 0.21
and the axial hydrogen atoms at C-5 and C-1 supported
the stereochemistry assigned to the cyclopropane ring.
The reduction of the enone 15 using sodium tellurium
hydride13 prepared a mixture of epimeric ketones which
was transformed into the saturated ketone 16 by sodium
methoxide equilibration.14 This ketone, obtained in 85%
obtained as a mixture of epimers by methylation of the
kinetic enolate of 7 with methyl iodide in an improved
86% yield, was deprotonated at low temperature with
LDA and treated with 3-iodopropanaldehyde diethyl
acetal10 to afford diastereoselectively compound 9 in an
excellent 80% yield. Removal of the acetal protecting
group with pyridinium p-toluenesulfonate (PPTS) in
aqueous acetone provided the aldehyde 10 in 92% yield.
Homologation of aldehyde 10 with the R-phosphonate
carbanion generated from diethyl 2-oxobutane-3-phos-
phonate11 and NaH in THF at room temperature gave
the desired (E)-enone 11 in 86% yield after column
chromatography, together with the corresponding (Z)-
isomer 12 in 5% yield. The synthesis of the IMDA
precursor 13 was completed in nearly quantitative yield
by treatment of enone 11 with TBDMS triflate and
triethylamine in dichloromethane at -78 °C.
(8) The route followed for the preparation of 6 parallels one described
previously by us for the preparation of a related system, see: Abad,
A.; Agullo´, C.; Arno´, M.; Cun˜at, A. C.; Meseguer, B.; Zaragoza´, R. J .
Synlett 1994, 733.
(9) Cory, R. M.; Renneboog, R. M. J . Org. Chem. 1984, 49, 3898.
(10) Larson, G. L.; Klesse, R. J . Org. Chem. 1985, 50, 3627.
(11) Corbel, B.; Medinger, L.; Haelters, J . P.; Sturtz, G. Synthesis
1985, 1048.
(12) The numbering system as given in structure 15 (see Scheme
3) will be followed throughout the text of this paper for all polycyclic
compounds (diterpene and steroid numbering). Systematic Chemical
Abstracts names are used for title compounds in the Experimental
Section.
(13) Yamashita, M.; Tanaka, Y.; Arita, A.; Nishida, M. J . Org. Chem.
1994, 59, 3500.

5102 J . Org. Chem., Vol. 63, No. 15, 1998
Abad et al.
Sch em e 4
overall yield from enone 6, was the optimal precursor for
the spiroannulation.
place in THF at low temperature and must be attributed
to the higher steric requirements of the benzylic orga-
nometallic reagent.
Our strategy for the construction of the spirobenzofu-
ran unit of stypodiol (1) from 16 was based on the
preparation of a hydroquinone tertiary alcohol moiety (as
in compound 21, Scheme 4), which was expected to
undergo a stereoselective cyclization process to afford the
desired portion (DE rings) of the natural compound.
Thus, we attempted the coupling of the ketone 16 with
the C7-aromatic part 17,15 by addition of the correspond-
ing benzylic organometallic derivative of 17 to the car-
bonyl group of 16. Despite many attempts, we were
initially not able to produce the desired tertiary alcohol.
For instance, treatment of 16 with the lithium16 or
magnesium17 reagent derived from 17 always afforded
the unreacted ketone 16 together with the cross-coupling
product of 17 and the protonated organometalic species
(17, X ) H). Other alternative procedures implying
traditional Barbier reaction conditions,16a SmI2-promoted
coupling,18 or organocerium reagents19 also failed to give
any addition product.
Fortunately and after some experimentation, it was
found that this decisive step could be promoted by
sonication.20 Thus, treatment of ketone 16 with the
benzyl chloride 17 and lithium in THF at 0 °C under
sonication in a 150 W cleaning bath afforded a 3:7
mixture of epimeric tertiary alcohols 18 and 19, respec-
tively, in 70% combined yield together with 2-5% of the
unreacted starting material. These two alcohols were
easily separated by flash chromatography, and their
stereochemistries were assigned by intramolecular NOE
studies. In particular, irradiation of the Me-8â of the less
polar isomer 18 at δ 0.96 gave NOE enhancements for
the benzylic hydrogens at δ 2.83 and 2.94, the aromatic
hydrogens at δ 6.71 and 6.77, and the Me-Ar group at δ
2.24, which strongly supported the â disposition of the
benzylic moiety in this isomer. Contrarily, irradiation
of the same methyl group of the more polar isomer 19
gave an NOE enhancement to 14-OH at δ 3.35, which
indicated the R orientation of the benzylic unit in this
epimer.
The 3:7 ratio of 18 and 19 obtained from the above
sonochemical Barbier reaction was somewhat disappoint-
ing and contrary to our initial expectations.21 However,
the availability of both epimeric tertiary alcohols allowed
us to independently study the construction of the spirodi-
hydrofuran unit from each epimer, to gain some insight
into the mechanism operating in this process, and to
complete finally the synthesis not only of stypodiol (1)
but also of its epimer epistypodiol (2).
These disappointing results contrast with the easy
addition of other nucleophilic reagents to the carbonyl
group of 16, for example, smooth and clean â-stereose-
lective addition of vinylmagnesium bromide and dimeth-
ylsulfonium methylide to the carbonyl group of 16 takes
(14) Reduction of the conjugated double bond could also be effected
by catalytic hydrogenation (H2, Pd/C, or Rh/Al2O3) without affecting
the cyclopropane ring but in slightly lower yield since partial reduction
(ca. 10%) of the carbonyl group also occurs.
(15) Prepared in 60-70% overall yield from 1-bromo-2,5-bis-
(methoxymethoxy)-3-methylbenzene as described in the Supporting
Information.
We started by treating the minor alcohol 18, with the
hydroxyl group axially disposed, with hydrochloric acid
in MeOH at room temperature to remove the methoxy-
methyl (MOM) and tert-butyldimethylsilyl (TBDMS)
(16) The organolithium compound was prepared by the reaction of
benzyl mesylate 17 (X ) OMs) or benzyl thioether 17 (X ) SPh) with
lithium/naphthalene, see: (a) Guijarro, D.; Manchen˜o, B.; Yus, M.
Tetrahedron 1992, 48, 4593. (b) Screttas, C. G.; Micha-Screttas, M. J .
Org. Chem. 1978, 43, 1064.
(17) Generated from 17 (X ) Cl) and [Mg(anthracene)(THF)3], see:
(a) Gallagher, M. J .; Harvey, S.; Raston, C. L.; Sue, R. E. J . Chem.
Soc., Chem. Commun. 1988, 289. (b) Bogdanovie´, B.; J anke, N.;
Kinzelmann, H. G. Chem. Ber. 1990, 123, 1507.
(18) Souppe, J .; Namy, J . L.; Kagan, H. B. Tetrahedron Lett. 1982,
23, 3497.
(19) Imanoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita,
T.; Hatanaka, Y.; Yokoyama, M. J . Org. Chem. 1984, 49, 3904.
(20) (a) Luche, J . L.; Damiano, J . C. J . Am. Chem. Soc. 1980, 102,
7927. (b) Einhorn, C.; Einhorn, J .; Luche, J . L. Synthesis 1989, 787.
(21) A completely opposite stereochemical result was obtained in
the addition of other organometallic species to the carbonyl group of
16. Meseguer, B. Ph.D. Thesis, Universidad de Valencia, February
1997.

Stereoselective Synthesis of Stypodiol and Epistypodiol
J . Org. Chem., Vol. 63, No. 15, 1998 5103
protecting groups (Scheme 4). Not unexpectedly, partial
acid-induced ring cleavage of the cyclopropane moiety of
the initially formed cyclopropanol 20 also occurred under
these conditions, affording after 2 h a mixture of cyclo-
propanol 20 and ketone 21. Although both compounds
could be easily separated by chromatography, the sepa-
ration proved to be unnecessary because subsequent
exposure of the mixture to catalytic p-toluenesulfonic acid
(PTSA) in refluxing chloroform for 1.30 h completed the
cleavage of the cyclopropanol and resulted in simulta-
neous cyclization to produce solely the desired spirodi-
hydrofuran 22 in an excellent 72% overall yield for the
whole process. It is interesting to note that prolonging
the hydrochloric acid treatment of 18 for 2 days, under
the conditions mentioned above, also led to the spirodi-
hydrofuran 22 as the only identifiable product, albeit in
considerably lower yield.22
Similarly, the reaction of the major equatorial alcohol
19 with hydrochloric acid in MeOH at room temperature
for 2 h afforded a mixture of cyclopropanol 23 and ketone
24. Exposure of this mixture to catalytic PTSA in
chloroform at reflux resulted in smooth cyclization to
produce exclusively the spirodihydrofuran 25 in 75%
overall yield for the two steps. One interesting observa-
tion was that prolonged treatment of 19 with hydrochloric
acid in MeOH did not yield, in contrast to the axial
alcohol 18, the corresponding spirodihydrofuran, ketone
24 being the main product identified in the reaction
mixture after several days of stirring at room tempera-
ture.
Although the formation of the equatorial alcohol 19 as
the major isomer in the above sonochemical Barbier
reaction allowed us to obtain 25, direct precursor of
epistypodiol (2), in acceptable global yield from the
tricyclic ketone 16 (ca. 37% overall yield), the formation
of the axial alcohol 18 as the minor isomer limited the
global yield obtained for the conversion of ketone 16 into
22, direct precursor of stypodiol (1). This situation
prompted us to explore alternative ways for increasing
the production of 22 from 16. An obvious way of
achieving this objective was to find a procedure to
transform the alcohol 19 (or the correspondent phenols
23 or 24) into 22.23 After several unsuccessful trials,24
a
simple solution was found. Heating at reflux the mixture
of cyclopropanol 23 and ketone 24 in hydrochloric acid
and methanol for 15 h led to an 85:15 mixture of 22 and
25, respectively, from which the desired spirodihydrofu-
ran 22 could be easily separated by chromatography. In
practice, the conversion of alcohol 19 into 22 could be
effected without isolation of intermediates 23 and 24,
since its treatment with hydrochloric acid in methanol,
first stirring at room temperature for 2 h and then
heating at reflux for another additional 15 h, afforded
the above-mentioned mixture of 22 and its epimer at
C-14. From this mixture the spirodihydrofuran 22 was
obtained in 68% yield after column chromatography.
Thus, the global yield for the conversion of the tricyclic
ketone 16 into 22, via both epimeric tertiary alcohols,
was 48%.25
The results obtained in the above cyclization reactions
deserve some mechanistic considerations. Evidently, a
carbonium ion similar to that proposed as intermediate
in the biosynthesis of stypodiol (1) and epistypodiol (2)
(e.g., 5, R ) O, vide supra) is a discrete intermediate in
the reaction of both epimeric alcohols when hydrochloric
acid in MeOH at reflux is used to promote the cyclization
(Scheme 5). For the same reasons discussed by
Pattenden5a for a related monocyclic system, this car-
bonium ion experiences preferential nucleophilic R-attack
by the phenolic hydroxyl group to afford the spirodihy-
drofuran 22. On the contrary, the stereochemical out-
come followed by the cyclization reaction catalyzed by
PTSA in refluxing chloroform, in which cyclization occurs
without affecting the stereochemical integrity of the
carbinol center, excludes the participation of such a
cationic intermediate. In this case, a plausible mecha-
nism could involve as key step the nucleophilic addition
of the tertiary hydroxyl group to the keto tautomeric form
of the phenolic moiety.
Both epimeric spirodihydrofurans 22 and 25 showed
1H and 13C NMR spectroscopic data which were super-
imposable on all of the signals associated with the CDE
ring portions of the corresponding natural products
stypodiol (1) and epistypodiol (2), respectively. A sig-
nificant difference in the chemical shift of the angular
methyl group at C-8 of both compounds is observed in
their 1H NMR spectra; this methyl group resonates at
0.25 ppm downfield in 25 compared with 22 (1.18 and
0.93 ppm in 25 and 22, respectively), due to the gauche
interaction with the equatorial oxygen atom in the
former. Also in agreement with the assigned stereo-
chemistry to both epimers, the signal for the benzylic
carbon atom in the 13C NMR spectrum of 25 is quite
shifted upfield relative to that of 22 (∆δ -4.4 ppm) due
to the cooperative γ interaction with C-7, C-9, and C-12.
(22) The use of an oxygen-free atmosphere and a high-quality
hydrochloric acid in this prolonged acid treatment was essential to
reproduce this result. We obtained the best result with Aldrich HCl,
37 wt % in water, 99.999%. Treatment of 18 in MeOH for 2 days with
the habitual hydrochloric acid used in the laboratory led to a different
compound that was presumed to be the ketone i. Further support for
the structure assigned to i was obtained after its reduction to the
alcohol ii (NaBH4, CH2Cl2-MeOH, -10 °C) and comparison of the
spectroscopic data of this with that of stypodiol (1). Both compounds
had nearly superimposable 1H NMR spectra with the exception of the
signal attributed to the aromatic moiety. Thus, compound ii showed
only an aromatic hydrogen and the signal corresponding to Me-Ar was
moved 0.1 ppm downfield with respect the same signal of 1 [1H NMR
of ii (CDCl3, 200 MHz): δ 6.60 (s, 1H), 3.20 (m, 1H), 3.19 (d, J ) 16.5
Hz), 2.74 (d, J ) 16.5 Hz, 1H), 2.24 (s, 3H), 0.91 (s, 6H), 0.83 (s, 3H),
0.74 (s, 3H), 0.64 (d, J ) 6.5 Hz, 3H)]. Conclusive evidence of the
presence of the chlorine atom in ii was obtained from its HRMS (calcd
for C27H39ClO3 446.2588, found 446.2607).
Completion of the synthesis of stypodiol (1) only
required stereoselective reduction of the carbonyl group
of 22. This end was readily achieved in 86% yield by
(23) The possible epimerization of the spirodihydrofuran 25 to 22
was also attempted. Several acidic (e.g., PTSA/C6H6, reflux; PTSA,
THF/H2O, 150 °C; AcOH/HBr, reflux; HCl/MeOH, reflux) and basic
conditions (e.g., KOH, MeOH, reflux) were assayed without success.
For experimental conditions and related isomerizations, see: (a)
Reference 6a. (b) Paquette, L. A.; Ezquerra, J .; He, W. J . Org. Chem.
1995, 60, 1435. (c) Gonza´lez, A. G.; Alvarez, M. A.; Darias, J .; Mart´ın,
J . D. J . Chem. Soc., Perkin Trans. 1 1973, 2637.
(24) These included some attempts for forcing the formation of a
carbonium ion at C-14, via transformation of the OH into a better
leaving group, that could react with the MOM ether moiety. Examples
of formation of cyclic ethers by a related process are known, see: Ziegler,
F. E.; Wallace, O. B. J . Org. Chem. 1995, 60, 3626.
(25) As expected, treatment of the axial alcohol 18, or even the
mixture of 18 and 19, under the same conditions as used for 19 also
led to a similar mixture of the epimeric spirodihydrofurans 22 and
25.

5104 J . Org. Chem., Vol. 63, No. 15, 1998
Abad et al.
rotations were determined using a 5 cm path length cell. [R]D
Sch em e 5
values are given in units of 10-1 deg cm2 g-1. IR spectra were
1
measured as KBr pellets or liquid films. All H spectra were
recorded at 300 or 400 MHz, and all 13C at 75 MHz. The signal
of the deuterated solvent (CDCl3) was taken as the reference
1
(the singlet at δ 7.24 for H and the triplet centered at δC 77.00
for 13C NMR data). Complete assignment of most of the
products was made on the basis of a combination of homo-
nuclear COSY, DEPT, and inverse-detected heteronuclear
multiple quantum coherence (HMQC) experiments. In all
compounds NMR assignments are given with respect to the
numbering scheme shown in structures 11 and 15 for mono-
cyclic and polycyclic systems, respectively. Mass spectra were
obtained by electron impact (EI) at 70 eV. Column chroma-
tography refers to flash chromatography and was performed
on Merck silica gel 60, 230-400 mesh. Silica gel 60 (Macherey
Nagel, 0.015-0.04 mm) was used for medium-pressure liquid
chromatography (MPLC). All reaction were carried out under
an inert atmosphere of dry argon using oven-dried glassware
and freshly distilled and dried solvents. The ampules used
for the Diels-Alder reactions were previously treated during
at least 48 h with a 5% solution of 1,1,1,3,3,3-hexamethyl-
disilazane in ether, washed with acetone, and dried at 120 °C
overnight. Unless stated otherwise, reaction mixtures were
worked up by addition of water and extraction with the
appropriated solvent (indicated), the organic extracts being
washed with water and brine and dried using anhydrous
sodium sulfate. Evaporation was performed under reduced
pressure.
(5R,6R)-6-(3,3-Dieth oxyp r op yl)-2,6-d im eth yl-5-(1-m eth -
yleth en yl)-2-cycloh exen -1-on e (9). To a solution of LDA
in THF (0.8 M solution; 4.9 mL, 3.92 mmol) at -78 °C was
slowly added (ca. 1 h) a solution of methyl carvone (8; mixture
of epimers at C-6) (500 mg, 3.05 mmol) and HMPA (0.848 mL,
4.88 mmol) in THF (4 mL). After the reaction mixture had
been allowed to warm to room temperature and then stirred
at this temperature for 1 h, it was cooled to -78 °C and treated
with 3-iodopropanaldehyde diethyl acetal (1.18 g, 4.57 mmol).
The reaction mixture was then slowly allowed to warm to room
temperature during 3 h, poured into a cooled saturated
aqueous NH4Cl solution, and extracted with a 1:1 mixture of
hexanes-ethyl ether. Workup afforded an oily residue, which
was purified by MPLC, using 95:5 hexane-ethyl acetate as
eluent, to give the ketone ketal 9 (709 mg, 80%) as a colorless
oil: [R]21D +25 (c 7.3, CHCl3); IR (film) 3070, 2990-2800, 1668,
treatment of 22 with NaBH4 at low temperature. The
spectral and physical data of 1 were identical with those
previously reported for the natural compound.1b Simi-
larly, reduction of ketone 25 under the same conditions
as for 22 afforded epistypodiol (2) in 90% yield. The
spectral data (1H and 13C NMR, IR, and MS) of 2 were
also identical with those of the natural product.1b,26
In conclusion, we have completed the stereoselective
synthesis of stypodiol (1) and epistypodiol (2) from (S)-
(+)-carvone (7), via the tricyclic ketone 6, in 13 synthetic
steps and in ca. 20% and 14% overall yields, respectively.
A relevant step of the synthesis of both epimeric spirodi-
hydrofurans is the acid-catalyzed cyclization of the
quinol-tertiary alcohol 19 (and also of the axial epimer
18). In the case of 19, the stereochemical outcome of this
process depends on the acid conditions used. It can take
place with inversion or retention of the configuration at
C-14 to afford the pentacyclic framework of stypodiol (1)
or epistypodiol (2), respectively. The synthesis of 1
represents a considerable improvement, in both number
of steps and overall yield, with respect to previous
syntheses described for this product while the synthesis
of 2 constitutes the first synthesis of this natural
compound.27
1
1376, 1063, 897 cm-1; H NMR (CDCl3) δ 6.51 (1 H, m, H-3),
4.72 (1 H, s, H-2′′), 4.67 (1 H, s, H′-2′′), 4.37 (1 H, dd, J ) 5.5,
5.0, H-3′), 3.56 (2 H, m, OCH2CH3), 3.41 (2 H, m, OCH′2CH3),
2.66 (1 H, dd, J ) 6.0, 6.0, H-5), 2.56 (1 H, m, H-4), 2.25 (1 H,
m, H′-4), 1.71 (3 H, m, Me-2), 1.59 (3 H, s, Me-1′′), 1.14 (6 H,
two overlapped t, J ) 6.5, 2 × OCH2CH3), 0.97 (3 H, s, Me-6);
MS (EI) m/z 294 (M+, 5), 249 (7), 202 (25), 187 (20), 85 (100);
HRMS C18H30O3 requires 294.2195, found 294.2192.
3-[(1R,6R)-1,3-Dim et h yl-6-(1-m et h ylet h en yl)-2-oxo-3-
cycloh exen yl]-1-p r op a n a l (10). PPTS (306 mg, 1.2 mmol)
was added to a solution of ketal 9 (588 mg, 1.98 mmol) in 4%
aqueous acetone (40 mL), and the resulting mixture was
heated at reflux for 1 h and then poured into water. Extraction
of the resulting mixture with ether and workup of the extract
afforded a residue, which was purified by MPLC, using 9:1
hexanes-ethyl acetate as eluent, to afford aldehyde 10 (402
Exp er im en ta l Section
Gen er a l. All melting points were determined using a
Kofler hot-stage apparatus and are uncorrected. Optical
mg, 92%) as an oil: [R]21 +20 (c 4.25, CHCl3); IR (film) 3070,
D
(26) The specific rotation of the synthetic product, an amorphous
solid, was [R]19D +4.5 (c 0.44, CHCl3), while the literature value of the
natural compound, an oil, was [R]D -4.5 (c 1.35, CHCl3). We believe
that the difference in the value of the specific rotation of synthetic
and natural epistypodiol (2) should be attributable to a different degree
of purity of both samples, since this compound (and also 1) decomposes
on exposure to air and is difficult to keep in a high degree of purity.
The pertinence of 1 and 2, both isolated from the same natural source,
to different enantiomeric series seems improbable. Unfortunately, the
specific rotation of 2 has only be described on one occasion. Its
corresponding diacetate, prepared by us by treatment of 2 with excess
pyridine and acetic anhydride at rt for 48 h, had [R]D -7.9 (c 0.76,
CHCl3).
3040, 2724, 1724, 1665, 997, 900 cm-1; 1H NMR (CDCl3) δ 9.7
(1 H, s, CHO), 6.58 (1 H, m, H-3), 4.8 (1 H, s, H-2′′), 4.71 (1 H,
s, H′-2′′), 2.65 (1 H, dd, J ) 6.0, 6.0, H-5), 2.25-2.6 (4 H, m,
H-4 and H-2′), 1.85 (2H, m, H-1′), 1.72 (3 H, m, Me-2), 1.62 (3
H, s, Me-1′′), 1.00 (3 H, s, Me-6); MS (EI) m/z 220 (M+, 2), 163
(35), 123 (25), 109 (20), 93 (20), 82 (100); HRMS C14H20O2
requires 220.1463, found 220.1459.
(5R,6R)-2,6-Dim eth yl-5-(1-m eth yleth en yl)-6-[(E)-4-m eth -
yl-5-oxo-3-h exen yl]-2-cycloh exen -1-on e (11). To a stirred
slurry of prewashed NaH (55% dispersion oil; 113 mg, 2.60
mmol) in THF (12 mL) at 0 °C was added, dropwise via
syringe, diethyl 2-oxobutane-3-phosphonate (557 mg, 0.49 mL,
2.68 mmol) during 45 min. After hydrogen evolution had
(27) Although not described here, we have also prepared stypoldione
(4) by oxidation of stypodiol (1) with Fremy’s salt (see preliminary
communication7).

Stereoselective Synthesis of Stypodiol and Epistypodiol
J . Org. Chem., Vol. 63, No. 15, 1998 5105
ceased, the mixture was warmed to room temperature and
stirred for 10 min. To the resulting mixture was added a
solution in THF (4 mL) of the aldehyde 10 (190 mg, 0.87
mmol). After being stirred at room temperature for 30 min,
the mixture was treated with a saturated aqueous NH4Cl
solution and poured into water. Extraction with ethyl ether
and workup as usual afforded an oil, which was purified by
chromatography, using 85:15 hexanes-ethyl acetate as eluent,
to give the (Z)-olefin 12 (11.6 mg, 5%) followed by the (E)-olefin
11 (203 mg, 86%).
80%) as a white solid: mp 164-165 °C (from ether); [R]25D +48
(c 3.27, CHCl3); IR (film) 1706, 1670 cm-1; 1H NMR (CDCl3) δ
6.62 (1 H, m, H-12), 2.42 (1 H, ddd, J ) 14.5, 14.5, 7.0, H-2â),
2.32 (3 H, m, H-2R, 2H-11), 2.28 (1 H, dq, J ) 12.5, 6.0, H-4),
1.99 (1 H, ddd, J ) 13.0, 9.5, 2.5, H-1â), 1.95 (1 H, ddd, J )
14.0, 3.0, 3.0, H-7â), 1.72 (3 H, m, Me-13), 1.55 (1 H, dd, J )
10.0, 5.6, H-9), 1.16 (3 H, s, Me-10), 1.06 (3 H, s, Me-8), 0.99
(3 H, d, J ) 7.0, Me-4).
[1a S-(1a r,1bâ,3a r,7a â,7br,9a r)]-9a -[(ter t-Bu tyld im eth -
ylsilyl)oxy]-1,1a ,1b ,2,3,3a ,7,7a ,7b ,8,9,9a -d od eca h yd r o-
1a ,3a ,5,7b-tetr a m eth yl-4H-cyclop r op a [a ]p h en a n th r en -4-
on e (15). A solution of compound 6 (159 mg, 0.41 mmol) in
dry toluene (6 mL) was treated with diethylzinc (2.5 mL of 1
M in hexane, 2.46 mmol). Diiodomethane (0.39 mL, 4.9 mmol)
was introduced dropwise, and the mixture was stirred for 2
h, poured into a saturated aqueous NH4Cl solution, and
extracted with ether. Workup as usual gave a residue, which
was purified by chromatography, using 97.5:2.5 hexanes-ethyl
acetate as eluent, to afford cyclopropane 15 as a white solid
(151 mg, 92%): mp 138-139 °C (from methanol); [R]25D +62 (c
Compound 11, an oil: [R]24 +51 (c 2.10, CHCl3); IR (film)
D
3071, 1666, 1639, 1371, 1279, 1084, 897 cm-1; 1H NMR (CDCl3)
δ 6.60 (1 H, m, H-3), 6.56 (1 H, ddd, J ) 8.0, 8.0, 1.5, H-3′),
4.83 (1 H, m, H-2′′), 4.76 (1 H, br s, H′-2′′), 2.75 (1 H, dd, J )
7.5, 7.5, H-5), 2.55 (1 H, m, H-4), 2.38 (1 H, H’-4), 2.28 (3 H, s,
H-6′), 1.77 (3 H, m, Me-2), 1.73 (3 H, m, Me-4′), 1.67 (3 H, s,
Me-1′′), 1.06 (3 H, s, Me-6); MS (EI) m/z 274 (M+, 2), 247 (2),
206 (2), 177 (3), 164 (100); HRMS calcd for C18H26O2 274.1933,
found 274.1934.
Compound 12, an oil: IR (film) 3071, 3030, 1686, 1665, 1369,
1
895 cm-1; H NMR (CDCl3) δ 6.56 (1 H, m, H-3), 5.63 (1 H,
6.0, CHCl3); IR (KBr) 3080, 3050, 1660, 1200, 1010, 840 cm-1
;
ddd, J ) 7.0, 3.0, H-3′), 4.77 (1 H, m, H-2′′), 4.72 (1 H, br s,
H′-2′′), 2.73 (1 H, dd, J ) 5.0, 5.0, H-5), 2.62 (1 H, m, H-4),
2.31 (1 H, H′-4), 2.23 (3 H, s, H-6′), 1.90 (3 H, m, Me-4′), 1.76
(3 H, s, Me-2), 1.63 (3 H, s, Me-1′′), 1.02 (3 H, s, Me-6); MS
(EI) m/z 274 (M+, 7), 247 (1), 231 (2), 206 (3), 177 (6), 164 (100);
HRMS calcd for C18H26O2 274.1933, found 274.1931.
1H NMR (CDCl3) δ 6.61 (1 H, m, H-12), 1.70 (3 H, m, Me-13),
1.63 (1 H, dd, J ) 12.5, 7.5, H-9), 1.03 and 1.02 (3 H each,
each s, Me-4 and Me-8), 0.91 (3 H, s, Me-10), 0.83 (9 H, s, Me3-
CSi), 0.53 (1 H, ddd, J ) 14.0, 14.0, 6.5, H-1R), 0.49 (1 H, d, J
) 4.5, H-18â), 0.21 (1 H, d, J ) 4.5, H-18R), 0.08 and 0.02 (3H
each, each s, Me2Si); MS (EI) m/z 403 (M+ + 1, 10), 402 (M+,
40), 346 (25), 345 (90), 317 (5), 288 (7), 253 (12), 211 (100);
HRMS calcd for C25H42O2Si 402.2954, found 402.2954.
(5R,6R)-6-[(3E)-5-[(ter t-Bu tyldim eth ylsilyl)oxy]-4-m eth -
yl-3,5-h exa d ien yl]-2,6-d im eth yl-5-(1-m eth yleth en yl)-2-cy-
cloh exen -1-on e (13). Enone 11 (171 mg, 0.63 mmol) in dry
CH2Cl2 (7 mL) was cooled to -78 °C and treated sequentially
with triethylamine (0.26 mL, 1.88 mmol) and tert-butyldi-
methylsilyl triflate (0.21 mL, 0.94 mmol). After 1 h at -78
°C, the reaction mixture was quenched with a 5% aqueous
NaHCO3 solution and poured into water and the mixture was
extracted with ether. Workup as usual furnished an oily
residue which was purified by MPLC on silica gel, using 95:5
hexanes-ethyl acetate as eluent, to give compound 13 as a
colorless oil (237 mg, 98%): [R]25D +28 (c 1.94, C6H6); IR (film)
1a S -(1a r,1b â,3a r,5â,7a â,7b r,9a r)]-9a -[(t er t -Bu t yld i-
m eth ylsilyl)oxy] tetr a d eca h yd r o-1a ,3a ,5,7b-tetr a m eth yl-
4H-cyclop r op a [a ]p h en a n th r en -4-on e (16). A mixture of
powdered tellurium (148 mg, 2.76 mmol), anhydrous ethanol
(4 mL), and NaBH4 (104 mg, 1.16 mmol) was heated and
stirred under argon at 80 °C. After 30 min the mixture was
cooled to room temperature and a solution of enone 15 (117
mg, 0.29 mmol) in a 3:1 mixture of ethanol-pentane (3 mL)
was added. After refluxing for about 1.5 h, the mixture was
cooled and filtered through a short pad of silica gel, eluting
with 9:1 hexanes-ether. Evaporation of the solvent afforded
1
3075, 1669, 1593, 1298, 1012, 836, 780 cm-1; H NMR (C6D6)
δ 6.29 (1 H, dd, J ) 7.5, 7.5, H-3′), 5.92 (1 H, s, H-3), 4.72 (1
H, s, H-2′′), 4.65 (1 H, s, H′-2′′), 4.48 (1 H, s, H-6′), 4.36 (1 H,
s, H′-6′), 2.50 (1 H, dd, J ) 6.0, 6.0, H-5), 1.88 (1 H, m, H-4),
1.77 (3 H, m, Me-2), 1.76 (3 H, s, Me-4′), 1.50 (3 H, s, Me-1′′),
1.06 (3 H, s, Me-1), 1.01 (9 H, s, Me3CSi), 0.17 (6 H, s, Me2Si);
MS (EI) m/z 388 (M+, 5), 331 (4), 226 (21), 225 (100), 199 (3),
164 (62); HRMS calcd for C24H40O2Si 388.2798, found 388.2799.
[4a R-(4a r,4bâ,8a r,10a â)]-7-[(ter t-Bu tyld im eth ylsilyl)-
oxy]-2,4b,8,10a -tetr a m eth yl-4a ,4b,5,6,8a ,9,10,10a -octa h y-
d r o-1(4H)-p h en a n th r en on e (6). A toluene solution (10 mL)
of 13 (205 mg, 0.53 mmol) and a small amount of propylene
oxide (2 drops) was sealed in a tube under argon and heated
at 190-195 °C during 168 h. After cooling, the tube was
opened and the solvent removed in vacuo to give an oily
residue. This was purified by chromatography, using 9:1
hexanes-ethyl acetate 9:1 as eluent, to give enone 6 as a white
a mixture of C-13 epimeric methyl ketones (116 mg).
A
solution of this mixture in THF (1.5 mL) was treated with 5%
NaOMe in MeOH (4 mL). The reaction mixture was stirred
for 1 h and poured into water. Extraction with CH2Cl2 and
workup as usual afforded a residue, which was purified by
chromatography, using 99:1 hexanes-ethyl acetate as eluent,
to give the ketone 16 (108 mg, 92%) as a white solid: mp 144-
143 °C (from methanol); [R]25 +40 (c 2.87, CHCl3); IR (KBr)
D
1
1705, 1250, 1185, 825 cm-1; H NMR (CDCl3) δ 2.64 (1 H, m,
H-13), 2.08 (1H, m, H-1â), 2.04 (1H, m, H-2R), 1.90 (1 H, ddd,
J ) 13.5, 13.5, 7.5, H-2â), 1.15 (3 H, s, Me-8), 1.02 (3 H, s,
Me-4), 0.93 (3 H, d, J ) 7.0, Me-13), 0.87 (3 H, s, Me-10), 0.83
(9 H, s, Me3CSi), 0.51 (1 H, ddd, J ) 13.5, 13.5, 6.0, H-1R),
0.48 (1 H, d, J ) 5.0, H-18â), 0.20 (1 H, d, J ) 5.0, H-18R),
0.08 and 0.02 (3 H each, each s, Me2Si); MS (EI) m/z 405 (M+
+ 1, 6), 404 (M+, 25), 348 (12), 347 (47), 255 (15), 212 (17),
211 (100); HRMS calcd for C25H44O2Si 404.3111, found 404.3111.
solid (199 mg, 97%): mp 140-141 °C (from pentane); [R]24
D
+32 (c 0.75, C6H6); IR (film) 1670, 1256, 1199, 838, 778 cm-1
;
1H NMR (C6D6) δ 6.13 (1 H, m, H-12), 1.84 (3 H, m, Me-13),
1.63 (3 H, br s, Me-4), 1.03 (9 H, s, Me3CSi), 0.95 (3 H, s, Me-
8), 0.73 (3 H, s, Me-10), 0.13 (6 H, s, Me2Si); MS (EI) m/z 389
(M+ + 1, 30), 388 (M+, 100), 373 (35), 331 (35), 274 (15), 237
(23), 197 (7); HRMS calcd for C24H40O2Si 388.2798, found
388.2788.
1 a S -(1 a r,1 b â,3 a r,4 r,5 â,7 a â,7 b r,9 a r)]-9 a -[(t e r t -
Bu tyld im eth ylsilyl)oxy]-4-[[2,5-bis(m eth oxym eth oxy)-3-
m eth ylph en yl]m eth yl]tetr a deca h yd r o-1a ,3a ,5,7b-tetr a m -
eth yl-1H-cyclop r op a [a ]p h en a n th r en -4-ol (18) a n d 1a S-
(1a r,1bâ,3a r,4â, 5â,7a â,7br,9a r)]-9a -[(ter t-bu tyld im eth yl-
silyl)oxy]-4-[[2,5-bis(m eth oxym eth oxy)-3-m eth ylp h en yl]-
m eth yl]tetr a d eca h yd r o-1a ,3a ,5,7b-tetr a m eth yl-1H-cyclo-
p r op a [a ]p h en a n th r en -4-ol (19). A mixture of ketone 16
(120 mg, 0.29 mmol), benzyl chloride 17 (X ) Cl) (161 mg, 0.61
mmol), lithium (20 mg, 2.9 mmol), and THF (8.8 mL) was
sonicated in a cleaning bath (150 W) for 1 h between 0 and 5
°C. After this time the reaction mixture was quenched by
addition of a saturated aqueous NH4Cl solution (2 mL) and
poured into water. Extraction with CH2Cl2 and workup as
usual gave an oily residue that was purified by MPLC eluting
with 96:4 hexanes-ethyl acetate, to afford the unreacted
ketone 16 (3.3 mg, 3%) and the epimeric alcohols 18 and 19.
[4a R-(4a r,4b â,8â,8a r,10a â)]-4a ,4b ,5,6,7,8,8a ,9,10,10a -
d eca h yd r o-2,4b ,8,10a -t et r a m et h yl-7-oxo-1(4H )-p h en a n -
th r en on e (14). In the same manner as above, a solution of
13 (195 mg, 0.50 mmol) in toluene (10 mL) was heated at 190-
195 °C for 168 h. The residue obtained after evaporation of
the solvent was dissolved in 4% aqueous acetone (16 mL),
PTSA (20 mg, 0.1 mmol) was added, and the resulting mixture
was heated at reflux for 1 h and then poured into water.
Extraction with ether and workup of the extract afforded a
residue, which was purified by chromatography, using 8:2
hexanes-ethyl acetate as eluent, to give diketone 14 (110 mg,

5106 J . Org. Chem., Vol. 63, No. 15, 1998
Abad et al.
18 (axial alcohol; less polar isomer): 39 mg (21%); an oil;
P r ep a r a tion of Sp ir od ih yd r ofu r a n 22 fr om Alcoh ol 19.
A solution of alcohol 19 (32 mg, 0.05 mmol) in MeOH (4 mL)
under an atmosphere of argon was treated with hydrochloric
acid (0.3 mL, 37 wt % in water) and stirred at room temper-
ature for 1.5 h. After this time, the reaction mixture was
refluxed overnight (ca. 15 h), cooled to room temperature,
treated with a 5% aqueous NaHCO3 solution, and poured into
water. Workup using ether as extract gave an oil that was
purified by chromatography (8:2 hexanes-ethyl acetate, as
eluent) to give spirodihydrofurans 22 (14 mg, 68%), which was
identical with the compound obtained from alcohol 18 (see
above), and 25 (2.5 mg, 12%).
[R]22 +19 (c 0.95, CHCl3); IR (film) 3500, 3055, 1590, 1460,
D
1150, 1030, 830, 770 cm-1; H NMR (CDCl3) δ 6.77 (1 H, d, J
1
) 2.5, H-Ar), 6.71 (1 H, d, J ) 2.5, H′-Ar), 5.08 (2 H, s,
OCH2O), 4.90 (2 H, dd, J ) 5.5, OCH′2O), 3.57 (3 H, s, MeO),
3.44 (3 H, s, Me′O), 2.94 and 2.83 (1 H each, AB system, J )
14.5, CH2-Ar), 2.24 (3 H, s, Me-Ar), 1.08 (3 H, s, Me-4), 0.96 (3
H, s, Me-8), 0.82 (9 H, s, Me3CSi), 0.76 (3 H, d, J ) 7.0, Me-
13), 0.75 (3 H, s, Me-10), 0.41 (1 H, d, J ) 5.0, H-18â), 0.18 (1
H, d, J ) 5.0, H-18R), 0.07 and 0.01 (3H each, each s, Me2Si);
MS (EI) m/z 630 (M+, 2), 568 (5), 466 (2), 405 (15), 295 (2),
255 (12), 227 (12), 226 (100); HRMS calcd for C37H62O6Si
630.4316, found 630.4320.
(3â,5r,13r)-14,17-Epoxy-4,4,8-tr im eth yl-16,24-cyclo-13,17-
secoch ola -16,20(22),23-t r ien e-3,23-d iol (St yp od iol, 1).
NaBH4 (7.8 mg, 0.21 mmol) was slowly added to a solution of
ketone 22 (18 mg, 0.042 mmol) in a 1:1 mixture of CH2Cl2-
MeOH (4.5 mL) at -60 °C. The reaction mixture was stirred
for 1 h from -60 to -10 °C; then acetone (0.1 mL, 1.37 mmol)
was added and the mixture allowed to warm to room temper-
ature. Water was added, and the mixture was extracted with
CH2Cl2. Usual workup followed by column chromatography
of the residue on silica gel, using 6:4 hexanes-ethyl acetate
as eluent, afforded (-)-stypodiol (1) (15.5 mg, 86%) as a solid:
mp 260-265 °C (dec) (from CHCl3); [R]21D -7.6 (c 0.59, CHCl3)
(lit.1b [R] D -3.1); IR (film) 3420, 3010-2800, 1475, 1370, 1225,
19 (equatorial alcohol; more polar isomer): 91 mg (49%);
an oil; [R]20 +22 (c 2.0, CHCl3); IR (film) 3490, 3050, 1695,
D
1590, 1150, 1035, 830, 770, 730 cm-1; 1H NMR (CDCl3) δ 6.78
(1 H, d, J ) 2.5, H-Ar), 6.70 (1 H, d, J ) 2.5, H′-Ar), 5.07 (2 H,
s, OCH2O), 4.89 (2 H, br s, OCH′2O), 3.58 (3 H, s, MeO), 3.44
(3 H, s, Me′O), 3.35 (1 H, br s, OH), 3.05 and 2.87 (1 H each,
AB system, J ) 14.5, CH2-Ar), 2.24 (3 H, s, Me-Ar), 1.06 (3 H,
s, Me-4), 0.99 (3 H, s, Me-8), 0.84 (9 H, s, Me3CSi), 0.79 (3 H,
s, Me-10), 0.66 (3 H, d, J ) 7.0, Me-13), 0.46 (1 H, d, J ) 5.0,
H-18â), 0.21 (1 H, d, J ) 5.0, H-18R), 0.09 and 0.03 (3H each,
each s, Me2Si); MS (EI) m/z 630 (M+, 7), 568 (9), 466 (4), 436
(3), 405 (13), 296 (2), 255 (12), 227 (12), 226 (100); HRMS calcd
for C37H62O6Si 630.4316, found 630.4329.
1
1020 cm-1; H NMR (CDCl3) δ 6.39 (1 H, s, H-Ar), 6.37 (1 H,
(5r,13r)-14,17-Ep oxy-23-h yd r oxy-4,4,8-tr im eth yl-16,24-
cyclo-13,17-secoch ola -16,20(22),23-tr ien -3-on e (22). To a
stirred solution of alcohol 18 (38 mg, 0.06 mmol) in MeOH (4
mL) was added hydrochloric acid (0.3 mL, 37 wt % in water)
under an argon atmosphere. After the mixture was stirred
for 2.5 h at room temperature, the reaction was quenched with
5% aqueous NaHCO3 solution and stirred until CO2 evolution
ceased. Water was added, and the mixture was worked up to
give an oil, a mixture of cyclopropanol 20 and ketone 21. A
solution of this oil and PTSA (1 mg, 0.005 mmol) in chloroform
(4 mL) was heated at reflux during 1.5 h. The reaction mixture
was treated with a 5% aqueous NaHCO3 solution, poured into
water, and then worked up using ether to extract. Purification
by chromatography, using 8:2 hexanes-ethyl acetate as eluent,
afforded the spirodihydrofuran 22 (18 mg, 72% overall for the
s, H′-Ar), 4.18 (1 H, br s, OH), 3.22 (1 H, dd, J ) 11.0, 5.5,
H-3), 3.18 and 2.73 (1 H each, AB system, J ) 16, CH2-Ar),
2.15 (3 H, s, Me-Ar), 0.93 (3 H, s, Me-8), 0.92 (3 H, s, Me-10),
0.84 (3 H, s, Me-4â), 0.75 (3 H, s, Me-4R), 0.66 (3 H, d, J )
6.5, Me-13); MS (EI) m/z 413 (M+ + 1, 27), 412 (M+, 100), 328
(2), 275 (4), 257 (25), 215 (4), 189 (5); HRMS calcd for C27H40O3
412.2977, found 412.2974.
(3â,5r,13r,14â)-14,17-Ep oxy-4,4,8-tr im eth yl-16,24-cyclo-
13,17-secoch ola -16,20(22),23-tr ien e-3,23-d iol (Ep istyp o-
d iol, 2). Following the same procedure used to prepare 1 from
22, the ketone 25 (15 mg, 0.035 mmol) was converted to (+)-
epistypodiol (2) (13.5 mg, 90%) as an amorphous solid that
could not be induced to crystallize: [R]25 +4.5 (c 0.35, CHCl3)
D
[lit.1b -4.5]; IR (film) 3460, 3010-2800, 1475, 1375, 1230, 1015
1
cm-1; H NMR (CDCl3) δ 6.44 (1 H, s, H-Ar), 6.35 (1 H, s, H′-
two steps) as an amorphous solid: [R]21 +12 (c 1.18, CHCl3);
Ar), 4.35 (1 H, br s, OH), 3.18 (1 H, dd, J ) 11.0, 5.0, H-3),
3.06 and 2.91 (1 H each, AB system, J ) 17, CH2-Ar), 2.11 (3
H, s, Me-Ar), 1.14 (3 H, s, Me-8), 0.91 (3 H, s, Me-10), 0.85 (3
H, s, Me-4â), 0.74 (3 H, s, Me-4R), 0.70 (3 H, d, J ) 6.5, Me-
13); MS (EI) m/z 413 (M+ + 1, 31), 412 (M+, 100), 395 (8), 379
(5), 351 (2), 276 (7), 257 (50), 215 (4), 189 (8); HRMS calcd for
D
IR (film) 3390, 3015, 1695, 1475, 1230, 1130, 845, 820 cm-1
;
1H NMR (CDCl3) δ 6.39 (1 H, s, H-Ar), 6.37 (1 H, s, H′-Ar),
4.23 (1 H, br s, OH), 3.18 and 2.75 (1 H each, AB system, J )
16, CH2-Ar), 2.50 (2 H, m, H-2), 2.14 (3 H, s, Me-Ar), 1.02 (3
H, s, Me-4â), 1.00 (3 H, s, Me-10), 0.95 (3 H, s, Me-4R), 0.93 (3
H, s, Me-8), 0.67 (3 H, d, J ) 6.5, Me-13); MS (EI) m/z 411
(M+ + 1, 32), 410 (M+, 100), 273 (31); HRMS calcd for C27H38O3
410.2821, found 410.2827.
C
27H40O3 412.2977, found 412.2974.
Ack n ow led gm en t. Financial support from DGYCT
(5r,13r14â)-14,17-E p oxy-23-h yd r oxy-4,4,8-t r im et h yl-
16,24-cyclo-13,17-secoch ola -16,20(22),23-tr ien -3-on e (25).
This compound was prepared by successive treatment of 19
(38 mg, 0.06 mmol) with HCl/MeOH/rt (1.5 h) and PTSA/
CHCl3/reflux (2.5 h), as described above for the synthesis of
22. Chromatography of the crude product, using 8:2 hexanes-
ethyl acetate as eluent, yielded 25 (18.5 mg, 75%) as an
(Grant PB95-1088) is gratefully acknowledged. B.M.
thanks Conselleria d’Educacio´ i Cie`ncia de la Generali-
tat Valenciana for a grant.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 1, 2, 6, 8-11, 13-19, 22, and 25 tables of 13C NMR
data of compounds 8-13 (Table 1) and 1, 2, 6, 14-16, 18, 19,
22, and 25 (Table 2), and spectroscopic data and experimental
procedures for the preparation of 3-iodopropanaldehyde diethyl
acetal and compound 17 (X ) Cl) from 1-bromo-2,5-bis-
(methoxymethoxy)-3-methylbenzene (21 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
amorphous solid: [R]19 +31 (c 1.18, CHCl3); IR (film) 3460,
D
3010, 1695, 1470, 1230, 845, 725 cm-1; 1H NMR (CDCl3) δ 6.45
(1 H, s, H-Ar), 6.35 (1 H, s, H′-Ar), 4.3 (1 H, br s, OH), 3.05
and 2.92 (1 H each, AB system, J ) 16.5, CH2-Ar), 2.52 (1 H,
ddd, J ) 15.5, 10.5, 7.5, H-2â), 2.37 (1 H, ddd, J ) 16.5, 7.0,
4.0, H-2R), 2.11 (3 H, s, Me-Ar), 1.18 (3 H, s, Me-8), 1.02 (3 H,
s, Me-4â), 1.00 (3 H, s, Me-10), 0.97 (3 H, s, Me-4R), 0.71 (3 H,
d, J ) 6.5, Me-13); MS (EI) m/z 411 (M+ + 1, 27), 410 (M+,
100), 273 (26), 231 (2), 205 (4); HRMS calcd for C27H38O3
410.2821, found 410.2828.
J O980311G