An efficient protocol for the enantioselective preparation of a key polyfunctionalized cyclohexane. New access to (R)- and (S)-4-hydroxy-2- cyclohexenone and (R)- and (S)-trans-cyclohex-2-ene-1,4-diol

Article abstract of DOI:10.1021/jo800107h

(Chemical Equation Presented) Starting from very accessible raw materials such as p-methoxyphenol, ethylene glycol, and thiophenol, a protocol has been developed to prepare multigram quantities of the polyfunctionalized cyclohexane (±)-7. A highly efficie

Full text of DOI:10.1021/jo800107h

An Efficient Protocol for the Enantioselective Preparation of a Key
Polyfunctionalized Cyclohexane. New Access to (R)- and
(S)-4-Hydroxy-2-cyclohexenone and (R)- and
(S)-trans-Cyclohex-2-ene-1,4-diol
Pau Bayón, Georgina Marjanet, Gladis Toribio, Ramon Alibés, Pere de March,
Marta Figueredo,* and Josep Font
UniVersitat Autònoma de Barcelona, Departament de Química, 08193 Bellaterra, Spain
marta.figueredo@uab.es
ReceiVed January 28, 2008
Starting from very accessible raw materials such as p-methoxyphenol, ethylene glycol, and thiophenol,
a protocol has been developed to prepare multigram quantities of the polyfunctionalized cyclohexane
(()-7. A highly efficient resolution of (()-7 has been achieved through enantioselective acetylation
catalyzed by Candida antarctica lipase B. Straightforward and enantioselective syntheses of 4-hydroxy-
2-cyclohexenone, 1, trans-cyclohex-2-ene-1,4-diol, 2, and their O-protected derivatives 18 and 19 have
been readily accomplished from 7.
Introduction
biological activities and the challenge of binding oxygen atoms
to a carbocycle in a regio- and stereoselective manner. However,
in spite of the considerable efforts devoted to this endeavor,
much work is still needed in this area. In particular, there is a
need for chiral raw materials, sufficiently available in enantio-
merically pure form, with the necessary versatility to handle
the structural diversity occurring among the pursued polyoxy-
genated cyclohexanes. In this scenario, the functional motif of
R,ꢀ-cyclohexenone makes its chiral derivatives very attractive
precursors to these targets. In particular, 4-hydroxy-2-cyclo-
hexenone, 1, has been used as a building block in the synthesis
of several bioactive compounds such as the anticholesterol
agents compactin and ML-236A,7 the immunosuppressant FK-
506,8 the marine sesquiterpene 10-isothiocyanatoguaia-6-ene,9
the structurally related metabolites (+)-epiepoformin, (+)-
epiepoxydon, and (+)-bromoxone,10 the antifungal and antibiotic
A great number of compounds isolated from natural sources
present a cyclohexane core as the main structural feature. Among
them, those possessing diverse oxygen-based substituents such
as conduritols,1 conduramines,2 inositols,3 cyclohexene epox-
ides,4 gabosines,5 and other carbasugars6 have deserved the
special attention of synthetic chemists because of their diverse
(1) (a) Balci, M.; Sütbeyaz, Y.; Seçen, H. Tetrahedron 1990, 46, 3715. (b)
Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J. Chem. ReV. 1996,
96, 1195. (c) Gueltekin, M. S.; Celik, M.; Balci, M. Curr. Org. Chem. 2004, 8,
1159. (d) Rassu, G.; Auzzas, L.; Battistini, L.; Casiraghi, G. Mini-ReV. Org.
Chem. 2004, 1, 343.
(2) (a) Vogel, P. Chimia 2001, 55, 359. (b) Łysek, R.; Vogel, P. Tetrahedron
2006, 62, 2733.
(3) Potter, B. V. L. Nat. Prod. Rep. 1990, 7, 1.
(4) (a) Marco-Contelles, J. Eur. J. Org. Chem. 2001, 1607. (b) Marco-
Contelles, J.; Molina, M. T.; Anjum, S. Chem. ReV. 2004, 104, 2857.
(5) (a) Bach, G.; Breiding-Mack, S.; Grabley, S.; Hammann, P.; Hütter, K.;
Thiericke, R.; Uhr, H.; Wink, J.; Zeeck, A. Liebigs Ann. Chem. 1993, 241. (b)
See also references in: Alibés, R.; Bayón, P.; de March, P.; Figueredo, M.; Font,
J.; Marjanet, G. Org. Lett. 2006, 8, 1617.
(7) Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc. 1989, 111, 2599.
(8) Jones, A. B.; Yamaguchi, M.; Patten, A.; Danishefsky, S. J.; Ragan, J. A.;
Smith, D. B.; Schreiber, S. L. J. Org. Chem. 1989, 54, 17.
(6) Arjona, O.; Gómez, A. M.; López, J. C.; Plumet, J Chem. ReV. 2007,
107, 1919.
(9) Iwasawa, N.; Funahashi, M.; Narasaka, K. Chem. Lett. 1994, 1697.
3486 J. Org. Chem. 2008, 73, 3486–3491
10.1021/jo800107h CCC: $40.75 2008 American Chemical Society
Published on Web 03/26/2008

Polyfunctionalized Cyclohexanes
CHART 1
multigram availability. Moreover, we also planned to direct the
synthesis to a suitably protected derivative of 1, in order to
circumvent some practical problems associated to its isolation,
related to its volatility and high solubility in water. In this article
we describe a new, more practical preparation of either
enantiomer of 1, as well as a new enantioselective synthesis of
trans-cyclohexene-1,4-diol, 2, that improves our previously
reported one.18 A monoprotected derivative of 2 has been used
as an intermediate for the synthesis of petasins16j and cyclo-
hexane prostanoids.19
Results and Discussion
Scale-up of the Preparation of the Racemic Starting
Material (()-3. One of our synthetic sequences previously
developed for the preparation of ketones (+)- and (-)-1
(Scheme 1) was completed in four chemical steps and 54% total
yield starting from (-)-and (+)-3, respectively. Compound 3
can be visualized as a chiral derivative of p-benzoquinone in
which one of the carbonyl groups is protected as ethylene ketal
and one of the double bonds has been masked by addition of
thiophenol.14 Starting from ketone (-)-3, we also synthesized
diol (-)-2 and its monosilyl derivative (-)-11 in 27% and 35%
yield, respectively.18 The main drawback of these syntheses was
that the separated enantiomers of 3 were only available by
chromatographic resolution of the racemate on a limited scale
of several hundred miligrams.15b,c An additional weakness came
from the laborious chromatographic separation involved in the
isolation protocol of (()-3, which is prepared by conjugate
addition of thiophenol to ketal 13 under thermodynamic control,
being therefore obtained along with the diaddition products cis-
and trans-14 and some unreacted 13 (Scheme 2). With the aim
of skipping these problems, a thorough reexamination of all the
procedures formerly established was undertaken.
Accordingly to literature precedents, we originally prepared
the p-benzoquinone monoketal 13 from 3,3,6,6-tetramethoxy-
1,4-cyclohexadiene by transketalization with ethylene glycol,20
followed by ketal monohydrolysis.21 In the present work, we
have used a slight modification22 of the more convenient method
recently reported by Wong and co-workers,23 consisting of the
treatment of p-methoxyphenol, 12, with phenyliodonium bis-
(trifluoroacetate) (PIFA) and ethylene glycol in dichloromethane.
This reaction can be performed on a multigram scale and the
product purified by crystallization or filtration through a small
path of silica gel. In our previously established procedure,
compound (()-3 was prepared by reaction of thiophenol with
ketal 13 (1.8 equiv) in the presence of lithium hydroxide in
chloroform at reflux temperature and isolated from the crude
product mixture by column chromatography. This chromato-
graphic purification prevented the scaling up of the process that
otherwise could be run with large quantities of reactants without
problems. Therefore, we decided to explore the possibility of
separating the monoaddition product (()-3 from the mixture
by fractional crystallization. Thus, the relative solubility of each
(+)-apiosporamide,11 the fungal metabolite diversonol,12 and
the bacterial DNA primase inhibitor Sch 64230513 (some of
these compounds are depicted in Chart 1). In these syntheses,
the relative configuration of the stereogenic centers of the prod-
ucts is induced by the stereogenic center at C-4 of ketone 1.
In an earlier publication, we reported two alternative prepara-
tions of optically active 1,14 starting from chiral synthetic
equivalents of p-benzoquinone previously developed in our
laboratories.15 Other syntheses of (+)- and (-)-1 (or O-protected
derivatives of them) have also been described in the literature,16
many of which involve multistep sequences with low overall
yields or poor enantioselectivities. Besides one of our own
approaches,14 only the syntheses described by Demir and
Sesenoglu16k and by Bräse and co-workers16o give access to
both (+)- and (-)-1, although resolution protocols for racemic
1 have also been described.16n,17
To further extend the use of (R)- or (S)-1 as precursors to
more sophisticated molecules with multiple stereocenters, we
judged convenient to search for a new synthetic approach to
the enantiomers of 1, which was easy to scale, avoiding tedious
chromatographic separations that are a severe limitation for
(10) Tachihara, T.; Kitahara, T. Tetrahedron 2003, 59, 1773.
(11) Williams, D. R.; Kammler, D. C.; Donnell, A. F.; Goundry, W. R. F.
Angew. Chem., Int. Ed. 2005, 44, 6715.
(12) Nising, C. F.; Ohnemüller, U. K.; Bräse, S. Angew. Chem., Int. Ed.
2006, 45, 307.
(13) (a) Wilson, E. M.; Traumer, D. Org. Lett. 2007, 9, 1327. (b) García-
Fontanet, J.; Carda, M.; Marco, J. A. Tetrahedron 2007, 63, 12131.
(14) de March, P.; Escoda, M.; Figueredo, M.; Font, J.; García-García, E.;
Rodríguez, S. Tetrahedron: Asymmetry 2000, 11, 4473.
(15) (a) de March, P.; Escoda, M.; Figueredo, M.; Font, J.; Álvarez-Larena,
A.; Piniella, J. F. J. Org. Chem. 1995, 60, 3895. (b) de March, P.; Escoda, M.;
Figueredo, M.; Font, J. Tetrahedron Lett. 1995, 36, 8665. (c) de March, P.;
Escoda, M.; Figueredo, M.; Font, J.; Medrano, J. An. Quim. Int. Ed. 1997, 93,
81.
(16) (a) Trost, B. M.; Romero, A. G. J. Org. Chem. 1986, 51, 2332. (b)
Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.; Danishefsky, S. J. J.
Org. Chem. 1989, 54, 3738. (c) Carreño, M. C.; García-Ruano, J. L.; Garrido,
M.; Ruiz, M. P.; Solladié, G. Tetrahedron Lett. 1990, 31, 6653. (d) Brünjes, R.;
Tilstam, U.; Winterfeldt, E. Chem. Ber. 1991, 124, 1677. (e) Kazlauskas, R. J.;
Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56,
2656. (f) Essig, S.; Scheffold, R. Chimia 1991, 45, 30. (g) Chang, S.; Heid,
R. M.; Jacobsen, E. N. Tetrahedron Lett. 1994, 35, 669. (h) Marchand, A. P.;
Xing, D.; Wang, Y.; Bott, S. G. Tetrahedron: Asymmetry 1995, 6, 2709. (i)
Gebauer, O.; Brückner, R. Liebigs Ann. 1996, 1559. (j) Witschel, M. C.;
Bestmann, H. J. Synthesis 1997, 107. (k) Demir, A. S.; Sesenoglu, O Org. Lett.
2002, 4, 2021. (l) Fudickar, W.; Vorndran, K.; Linker, T. Tetrahedron 2006,
62, 10639. (m) Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 12658. (n) Bickley, J. F.; Evans, P.; Meek, A.; Morgan, B. S.; Roberts,
S. M. Tetrahedron: Asymmetry 2006, 17, 355. (o) Nising, C. F.; Ohnemüller,
U. K.; Bräse, S. Synthesis 2006, 16, 2643.
(18) Alibés, R.; de March, P.; Figueredo, M.; Font, J.; Marjanet, G.
Tetrahedron: Asymmetry 2004, 15, 1151.
(19) López-Pelegrín, J. A.; Janda, K. D. Chem. Eur. J. 2000, 6, 1917.
(20) Capparelli, M. P.; Swenton, J. S. J. Org. Chem. 1987, 52, 5360.
(21) Heller, J. E.; Dreiding, A. S.; O’Connor, B. R.; Simmons, H. E.;
Buchanan, G. L.; Raphael, R. A.; Taylor, R. HelV. Chim. Acta 1973, 56, 272.
(22) The same product yield is obtained using a 0.3 M solution of PIFA
(instead of 0.1 M), saving a considerable volume of anhydrous dichloromethane.
(23) Trân-Huu-Dâu, M.-E.; Wartchow, R.; Winterfeldt, E.; Wong, Y.-S.
Chem. Eur. J. 2001, 7, 2349.
(17) (a) Suzuki, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 2001, 66,
1494. (b) Morgan, B. S.; Hoenner, D.; Evans, P.; Roberts, S. M Tetrahedron:
Asymmetry 2004, 15, 2807.
J. Org. Chem. Vol. 73, No. 9, 2008 3487

Bayón et al.
SCHEME 1. Former Syntheses of Hydroxyenone (+)-114 and Enediol (-)-218 Starting from (-)-3
SCHEME 2. Preparation of (()-3 from p-Methoxyphenol,
12
SCHEME 3. Enzymatic Resolution of (()-7
TABLE 1. Qualitative Solubility of Compounds 3, 13, cis-14, and
trans-14 in Different Solvents at Room and Boiling Temperaturesa
soluble than the monoaddition product 3 in 2-propanol at room
temperature. Thus, crystallization of the crude reaction material
from 2-propanol, followed by one or two recrystallizations from
the same solvent, allows the isolation of pure (()-3 in 60–70%
overall yield from thiophenol. Following this protocol, quantities
over 4 g of (()-3 have been obtained from a single operation.
Since the conjugate addition of thiophenol to ketal 13 is a
reversible process, the crystallization residue can be easily
recycled.
Enzymatic Resolution of (()-7. Once a practical methodol-
ogy for accessing (()-3 in substantial amounts had been
established, our following challenge was to find an easily
scalable mode to resolve its racemate, as an alternative to the
previously employed chiral liquid chromatography on cellulose
triacetate.15b,c Since the enantioselective reduction of ketone
(()-3 to the alcohol (+)- or (-)-7 met with failure, we turned
out our attention to the resolution of the racemate (()-7, easily
prepared from (()-3 by reduction with NaBH4.14
3
13
cis-14
trans-14
rt bt
solvent
pentane
rt
bt
rt
bt
rt
bt
i
i
i
s
s
s
s
s
i
i
i
i
i
i
i
i
i
s
i
s
s
s
i
i
i
i
i
i
s
i
s
s
s
i
δ
δ
i
i
i
i
s
i
s
s
s
i
i
i
i
i
hexane
s
ib
s
s
s
s
s
s
ib
s
s
s
s
ib
ib
s
s
s
s
s
s
s
s
s
s
s
cyclohexane
ib
s
i
iPr2O
s
s
s
s
s
s
s
δ
s
s
s
tBuOMe
toluene
s
s
s
i
δ
δ
s
s
i
CH2Cl2
acetonitrile
iPrOH
EtOH
H2O
i
δ
δ
δ
δ
iPrOH/ H2O
EtOH/ H2O
acetonitrile/ H2O
i
i
i
δ
δ
i
i
i
a If 25 mg of the pure compound is completely dissolved in 0.25 mL
of the solvent at room temperature (rt) or boiling temperature (bt) the
experiment is labeled as s (soluble); if dilution up to 0.75 mL leads to
total dissolution, the experiment is labeled as δ (partially soluble); if
some solid still remains, the experiment is labeled as i (insoluble).
b Insoluble oily material is observed.
On the basis of a closely related literature precedent,17b we
investigated the enzyme-catalyzed enantioselective acetylation
of (()-7 (Scheme 3). The initial experiments were performed
with quantities of around 1 g of racemic substrate following
the reported conditions. Accordingly, an 18 mM solution of
(()-7 in diisopropyl ether was treated with vinyl acetate (6 mol
per mol of racemic 7) in the presence of lipase acrylic resin
from Candida antarctica (CALB) (2 g per g of racemic 7) at
32 °C (Scheme 3).24
of the four compounds ((()-3, 13, cis-14, and trans-14) present
in the crude reaction product in a series of solvents was
qualitatively examined (Table 1).
It was observed that the four compounds show low solubility
in apolar solvents and are quite soluble in polar aprotic solvents.
Fortunately, a distinct behavior was found in polar protic
solvents, where the diaddition compounds cis- and trans-14 are
poorly soluble compared to 3 and 13, but the most remarkable
observation was that the unreacted ketal 13 is noticeably more
By 1H NMR and CHPLC analyses of aliquot samples (Table
2), it was observed that, after 15 min of reaction, almost 50%
of the starting racemate was already acetylated and the ee of
(24) A preliminary description of this reaction was included in ref 5b.
3488 J. Org. Chem. Vol. 73, No. 9, 2008

Polyfunctionalized Cyclohexanes
TABLE 2. Evolution of the CALB-Catalyzed Reaction of (()-7
SCHEME 4. Syntheses of 4-Hydroxy-2-cyclohexenone, 1, Its
Silyl-Protected Derivative 18, trans-Cyclohex-2-ene-1,4-diol,
2, and Its Silyl-Protected Derivative 11
with Vinyl Acetate in Diisopropyl Ether
ee of
ee of
entry
time
(+)-7/(-)-15a
(+)-7b (%)
(-)-15b (%)
1
2
3
4
5
6
7
8
15 min
30 min
45 min
1 h
1 h 15 min
1 h 30 min
2 h 30 min
24 h
1:0.9
1:1.3
1:1.4
1:1.4
1:1.6
1:1.7
1:1.8
1:2.7
91
99
99
99
99
99
99
40
95
93
91
89
85
83
71
13
a The reaction evolution was monitorized by GC (“cross linked”
dimethyl silicone, from 200 to 260 °C, gradient ) 6 °C/min), and the
product ratio was determined by 1H NMR. A GC peak relation of 7/15
)
1:1.1 corresponds to an equimolar mixture. b The ee’s were
determined by CHPLC (CHIRACEL OD, 0.7 mL/min, hexane/PrOH
4:1).
TABLE 3. Evolution of the ee’s in the CALB-Catalyzed
Enantioselective Acetylation of (()-7a
ee of
(+)-7c (%)
ee of
min, the alcohol was recovered without any loss of diastereo-
meric purity. An analogous reference experiment was performed
with a sample of racemic acetate (()-15, and after 90 min,
CHPLC analysis of the recovered material showed three peaks,
corresponding to the acetate (-)-15 (27%), the alcohol (-)-7
(24%), and the acetate (+)-15 (48%). Consequently, the lower
than expected ee of the residual alcohol was attributed to partial
hydrolysis of the formed acetate. In an attempt to minimize this
undesired hydrolysis reaction, the concentration of enzyme was
further reduced to a weight proportion (()-7/CALB ) 1:0.06.
Reference experiments showed that, at this lower enzyme
concentration, the hydrolysis of the acetate (-)-15 is consider-
ably slower. Under these new conditions, it took 3 h 20 min to
complete the enantioselective acetylation, with ee values of 93%
for both (+)-7 and (-)-15. The procedure was then scaled up
to 5 g of starting substrate and, after 3.5 h of reaction, the
residual alcohol (+)-7 (81% ee) and the acetate (-)-15 (95%
ee) were isolated in 46% and 45% yield, respectively. These
compounds are easily separable by a fast column chromatog-
raphy on silica gel. Methanolysis of the acetate (-)-15 furnished
the corresponding alcohol (-)-7. Enantiomerically pure alcohols
(+)- or (-)-7 can be readily obtained by crystallization from
dichloromethane/pentane.
Synthesis of 4-Hydroxy-2-cyclohexenone, 1, and trans-
Cyclohex-2-ene-1,4-diol, 2. Having a convenient methodology
for the supply of both enantiomers of alcohol 7 in substantial
amounts, our previous syntheses of hydroxyenone 1 and enediol
2 (Scheme 1) were re-examined. First, our syntheses were
continued from this point to the final compounds in racemic
fashion. The two transformations required for the conversion
of 7 into 1 were ketal hydrolysis and hydrodesulfuration
(Scheme 4). The hydrolysis of the ketal in 7 had been previously
accomplished, but the reduction of the carbon-sulfur bond on
the corresponding ketone was unsuccessful.14 In former experi-
ments, the desulfurated ketal 16 had been detected as a minor
product in reaction mixtures of reduction of 7 with Bu3SnH/
AIBN in toluene. Now, we have investigated this reaction in
more detail and, after extensive experimentation, we have found
that the hydrodesulfuration of 7 can be cleanly accomplished
in multigram scale and 81–83% yield if the AIBN is slowly
and continuously added to the reaction medium and the Bu3SnH
is added in portions each 30 min to a total amount of 10 equiv.
Hydrolysis of the desulfurated ketal 16 by treatment with
time
(min)
entry
(+)-7/(-)-15b
(calcd ee, %)d
(-)-15c (%)
1
2
3
4
5
6
30
40
50
60
90
1:0.38
1:0.57
1:0.76
1:0.96
1:1.15
1:1.21
24 (43)
40 (56)
56 (75)
73 (98)
95
100
100
97
95
92
105
93
89
a [(()-7]0
) 72 mM; weight proportion (()-7/CALB ) 1:0.25.
b Ratio determined by 1H NMR. c The ee’s were determined by CHPLC
(CHIRACEL OD, 0.7 mL/min, hexane/iPrOH 4:1). d Calculated ee value
considering the conversion and assuming that the only process occurring
was the acetylation of (-)-7.
the remaining alcohol (+)-7 was 91% (entry 1). Prolonged
reaction time increased the ee of (+)-7 to 99%, with this value
being maintained for at least 2.5 h (entries 2–7). During this
time, the proportion of acetate (-)-15 increased slowly and its
enantiomeric purity diminished in a percentage consistent with
the slower acetylation of the less reactive enantiomer (+)-7. It
was also observed (entry 8) that, after 1 day under the reaction
conditions, the enantiomeric purity of the residual alcohol
decreased notably, a fact that we tentatively attributed to an
enzyme-catalyzed transesterification process. Since the enantio-
selective acetylation was quite fast, we investigated the pos-
sibility of diminishing the proportion of enzyme and found that
a weight ratio of (()-7/CALB ) 1:0.25 was enough to complete
the process in around 3 h. It was also proved that the enzyme
can be reused at least up to four consecutive times without a
significant loss of ee’s. Next, additional experiments were
performed starting from 9, 36, and 72 mM solutions of (()-7
and maintaining the same (()-7/vinyl acetate/enzyme ratio. It
was observed that the reaction rate increased with the substrate
concentration, without any enzyme inhibition being detected.
Therefore, the reaction evolution was studied in more detail at
an initial substrate concentration of 72 mM (Table 3).
At this higher initial concentration of (()-7, the ee of the
residual alcohol (+)-7 increased more slowly than expected
(entries 1–4), indicating that, simultaneously to the enantiose-
lective acetylation, at least another competitive process was
occurring that diminished the ee of the residual alcohol.
Epimerization of the remaining alcohol (+)-7 in the reaction
medium was discarded because, after submitting a sample of
enantiomerically pure (+)-7 to the reaction conditions for 90
J. Org. Chem. Vol. 73, No. 9, 2008 3489

Bayón et al.
J ) 12.8, 9.3 Hz, 1H); 1.68 (dd, J ) 8.2, 0.6 Hz, 1H). Enantiomeric
purities were determined by CHPLC (hexane/2-propanol, 4:1): (-)-
15 (11 min); (-)-7 (15 min); (+)-15 (51 min); (+)-7 (59 min).
(8S,10R)-10-Phenylthio-1,4-dioxaspiro[4.5]dec-6-en-8-ol,
(-)-7. To a solution of acetate (-)-15(980 mg, 3.2 mmol) in MeOH
(11 mL) was added NaMeO (173 mg, 3.2 mmol), and the mixture
was stirred at room temperature for 0.5 h. Then, the solvent was
removed under reduced pressure, and the residue was diluted in
water and slightly acidified with 2% HCl. The aqueous solution
was extracted with CH2Cl2 (3 × 35 mL), the combined organic
extracts were dried over anhydrous MgSO4 and the solvent was
evaporated under vacuum. Purification of the residue by flash
chromatography (CH2Cl2/Et2O, 9:1) furnished alcohol (-)-7 (770
mg, 2.9 mmol, 92% yield, 96% ee) as a white solid, mp 87–88 °C.
1,4-Dioxaspiro[4.5]dec-6-en-8-ol, 16. To a boiling solution of
alcohol (()-7 (1.25 g, 4.7 mmol) in anhydrous toluene (48 mL)
under nitrogen were initially added Bu3SnH (2.5 mL, 9.4 mmol,
dropwise addition) and a small quantity of AIBN. Then, a solution
of AIBN (2.44 g, 14.8 mmol) in toluene (96 mL) was added
continuously during 4 h, and additional portions of Bu3SnH (1.25
mL, 4.7 mmol) were added every 30 min. After that time, the
solvent was evaporated under vacuum and the residue was purified
by flash chromatography (CH2Cl2 to CH2Cl2/Et2O, 10:3), providing
unreacted (()-7 (120 mg, 0.45 mmol, 9.6%) and alcohol (()-1616l
(595 mg, 3.8 mmol, 81%) as an oil: Rf ) 0.14 (CH2Cl2/Et2O, 10:
montmorillonite K-10 in dichloromethane furnishes the target
enone 1 in 62% yield. To avoid losses of material due to the
volatility of this ketone, the formation of the TBDMS derivative
17 before ketal hydrolysis results advantageous. This protocol
leads to the more convenient protected ketone 18 in 84% total
yield from 16. Treatment of this ketone with DIBAL-H in THF
at -78 °C furnished an easily separable mixture of the trans
alcohol 11 and the cis isomer 19 in 72% and 26% isolated yield,
respectively. Desilylation of 11 was readily accomplished to
deliver the corresponding diol 2. Starting from (-)-7, and
following identical pathways, the syntheses of (S)-1,14 [R]D )
-92 (c 0.50, CHCl3), (S)-18,10 [R]D ) -100 (c 0.16, CH2Cl2),
(1S,4S)-11,18 [R]D ) -96 (c 0.96, CHCl3), and (1S,4S)-2,18 [R]D
) -112 (c 0.25, CHCl3), were also completed without any loss
of enantiomeric purity.
Conclusions
In summary, we have developed a very convenient protocol
for the preparation of multigram quantities of either enantiomer
of the polyfunctionalized cyclohexane 7, starting from very
accessible raw materials such as p-methoxyphenol, ethylene
glycol, and thiophenol. A highly efficient, enantioselective
acetylation catalyzed by C. antarctica lipase B has been used
to perform the key resolution of racemic 7. Starting from 7, the
syntheses of 4-hydroxy-2-cyclohexenone, 1, and trans-cyclohex-
2-ene-1,4-diol, 2, have been completed in two and five chemical
steps and 50% and 44% total yield, respectively. Their corre-
sponding O-protected derivatives 18 and 11, which are more
convenient for synthetic purposes, have also been prepared from
7 through three- and four-step sequences and 68% and 49%
yields, respectively. Starting from the readily available enan-
tiomers (+)- or (-)-7, the same synthetic sequences can be
applied to prepare either antipode of the former products,
without any loss of enantiomeric purity. Work is in progress to
exploit these compounds as precursors to several bioactive
polyoxygenated cyclohexanes.
1
3); H NMR (360 MHz, CDCl3) δ 5.95 (ddd, J ) 10.1, 2.8, 1.1
Hz, 1H), 5.63 (dt, J ) 10.1, 1.5 Hz, 1H), 4.22 (m, 1H), 3.96 (m,
4H), 2.12 (m, 1H), 1.95 (m, 1H), 1.75 (m, 2H). The same reaction
starting from (8S,10R)-7 furnished (S)-16, [R]D ) -38 (c 1.64,
CHCl3) (lit.10 [R]D ) -40.5 (c 1.24, CHCl3)).
8-tert-Butyldimethylsilyloxy-1,4-dioxaspiro[4.5]dec-6-ene,
17. To a solution of alcohol (()-16 (763 mg, 4.9 mmol) in CH2Cl2
(34 mL) at 0 °C under N2 was added TBDMS-imidazole (1.3 mL,
6.7 mmol) dropwise, and the reaction mixture was heated at the
reflux temperature for 20 h. After that time, water (3 mL) was
added, and the resulting suspension was acidified with 2 M HCl.
The organic layer was separated, the aqueous one extracted with
CH2Cl2 (3 × 10 mL), and the combined organic extracts were dried
over anhydrous MgSO4. The solvent was evaporated under reduced
pressure, and the residue was purified by flash chromatography
(CH2Cl2/Et2O, 9:1) to provide silyl ether (()-17 (1.20 g, 4.4 mmol,
1
91% yield) as a colorless oil: Rf ) 0.66 (CH2Cl2/Et2O, 9:1); H
NMR (360 MHz, CDCl3) δ 5.84 (ddd, J ) 10.1, 2.6, 0.9 Hz, 1H),
5.55 (dt, J ) 10.1, 1.5 Hz, 1H), 4.21 (m, 1H), 3.96 (m, 4H), 1.95
(m, 2H), 1.75 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H). The same reaction
starting from (S)-16 furnished (S)-17, [R]D ) -47 (c 2.40, CHCl3)
(lit.10 [R]D ) -54.9 (c 0.70, CHCl3)).
4-Hydroxy-2-cyclohexenone, 1. Montmollironite K-10 (383 mg)
was added to a solution of acetal (()-16 (45 mg, 0.29 mmol) in
CH2Cl2 (3.4 mL), and the mixture was stirred at room temperature
for 2 h. Then, it was filtered and the solvent removed under vacuum
to furnish an oily residue, which was purified by flash chromatog-
raphy in Baker silica gel (hexanes/EtOAc, from 7:4 to 1:1) to
provide (()-114 (20 mg, 0.18 mmol, 62%) as an oil: Rf ) 0.4
(EtOAc); 1H NMR (360 MHz, CDCl3) δ 6.93 (ddd, J ) 10.2, 2.4,
1.6 Hz, 1H), 5.97 (dt, J ) 10.2, 2.0, 1.0 Hz, 1H), 4.57 (m, 1H),
2.60 (dt, J ) 17.0, 4.3 Hz, 1H), 2.38 (m, 2H), 1.95 (m, 1H). The
same reaction starting from (S)-16 furnished (S)-1, [R]D ) -92 (c
0.50, CHCl3) (lit.14 [R]D ) -92.3 (c 1.30, CH2Cl2)).
4-tert-Butyldimethylsilyloxy-2-cyclohexenone, 18. Montmol-
lironite K-10 (5.81 g) was added to a solution of acetal (()-17
(1.18 g, 4.4 mmol) in CH2Cl2 (50 mL), and the mixture was stirred
at room temperature for 1 h. Then, it was filtered and the solvent
removed under vacuum to furnish an oily residue, which was
purified by flash chromatography in Baker silica gel (CH2Cl2/Et2O,
10:3) to provide (()-18 (905 mg, 4.0 mmol, 92%) as an oil: Rf )
0.66 (CH2Cl2/Et2O, 10:3); 1H NMR (360 MHz, CDCl3) δ 6.83 (ddd,
J ) 10.2, 2.4, 1.7 Hz, 1H), 5.92 (ddd, J ) 10.2, 2.0, 1.1 Hz, 1H),
4.53 (ddt, J ) 9.0, 4.5, 2.4 Hz, 1H), 2.57 (dtd, J ) 17.1, 4.5, 1.1
Experimental Section
General Procedures. See the Supporting Information for details.
Resolution of (()-7: (8R,10S)-10-Phenylthio-1,4-dioxaspi-
ro[4.5]dec-6-en-8-ol, (+)-7, and (8S,10R)-10-Phenylthio-1,4-
dioxaspiro[4.5]dec-6-en-8-yl Acetate, (-)-15. Alcohol (()-7 (5.00
g, 18.9 mmol) was placed in a 500 mL reactor provided with
mechanical stirrer and dissolved in iPr2O (275 mL), and the solution
was warmed to 32 °C. Then, lipase acrylic resin from C. antarctica
(287 mg) and vinyl acetate (10.5 mL, 113.9 mmol) were added.
The reaction evolution was monitored by TLC (CH2Cl2/Et2O, 9:1)
and GC analyses. Enzyme removal was carried out by simple
filtration, and the solvents were evaporated under vacuum. Purifica-
tion of the residue by flash chromatography (CH2Cl2 to CH2Cl2/
Et2O, 9:1) furnished (-)-1524 (2.62 g, 8.6 mmol, 45% yield, 95%
ee) and (+)-718,24 (2.32 g, 8.8 mmol, 46% yield, 81% ee).
Enantiomerically pure (+)-7 (1.86 g, 80% yield, >99% ee) was
obtained by crystallization from CH2Cl2/pentane. (-)-15: Rf ) 0.72
1
(CH2Cl2/Et2O, 9:1); H NMR (250 MHz, CDCl3) δ 7.48 (m, 2H),
7.27 (m, 3H), 5.80 (dt, J ) 10.2, 1.6 Hz, 1H), 5.74 (dd, J ) 10.2,
1.5 Hz, 1H), 5.31 (ddt, J ) 10.0, 5.9, 1.5 Hz, 1H), 4.14 (m, 4H),
3.47 (dd, J ) 13.8, 3.3 Hz, 1H), 2.48 (dddd, J ) 12.7, 5.9, 3.2, 1.4
Hz, 1H), 2.12 (ddd, J ) 13.8, 12.7, 10.0 Hz, 1H), 2.01 (s, 3H).
(+)-7: Rf ) 0.30 (CH2Cl2/Et2O, 9:1); 1H NMR (250 MHz, CDCl3)
δ 7.49 (m, 2H), 7.28 (m, 3H), 5.91 (dt, J ) 10.1, 1.8 Hz, 1H);
5.66 (dd, J ) 10.1, 1.9 Hz, 1H); 4.23 (m, 5H); 3.43 (dd, J ) 12.8,
3.1 Hz, 1H); 2.46 (dddd, J ) 5.6, 3.1, 2.8, 1.5 Hz, 1H); 2.00 (dt,
3490 J. Org. Chem. Vol. 73, No. 9, 2008

Polyfunctionalized Cyclohexanes
Hz, 1H), 2.35 (ddd, J ) 17.1, 12.8, 4.5 Hz, 1H), 2.21 (m, 1H),
2.02 (ddd, J ) 12.8, 9.1, 4.5 Hz, 1H), 0.92 (s, 9H), 0.12 (s, 6H).
-95 (c 0.95, CHCl3)) and (1R,4S)-19, [R]D ) -30 (c 0.40, EtOH)
(lit.25 for the enantiomer [R]D ) +34 (c 1.58, EtOH)).
trans-Cyclohex-2-ene-1,4-diol, 2. To a solution of silyl ether
(()-11 (334 mg, 1.5 mmol) in THF (2.9 mL) at room temperature
was added TBAF (1 M in THF, 2.9 mL, 2.9 mmol), and the mixture
was stirred for 14 h. Then, the solvent was evaporated under reduced
pressure and the residue was purified by flash chromatography
(CHCl3/MeOH, 30:1) to provide (()-218,26 (151 mg, 1.3 mmol,
The same reaction starting from (S)-17 furnished (S)-18, [R]D
)
-100 (c 0.16, CH2Cl2) (lit.16n [R]D ) -109.6 (c 1.46, CH2Cl2)).
trans-4-tert-Butyldimethylsilyloxy-2-cyclohexenol, 11. To a
solution of (()-18 (505 mg, 2.2 mmol) in THF (30 mL) at -78 °C
was added DIBAL-H (1 M THF, 9 mL, 9.0 mmol) dropwise, and
the mixture was stirred for 50 min, quenched with MeOH (30 mL),
and allowed to warm to room temperature. After 1 h of additional
stirring, the mixture was filtered through a Celite pad and the solvent
was evaporated. The residue so obtained was purified by flash
chromatography (hexanes/EtOAc, from 20:1 to 12:1) to provide
(()-117 (365 mg, 1.6 mmol, 72%) and (()-1925 (135 mg, 0.6 mmol,
26%). (()-11: oil; Rf ) 0.38 (hexanes/EtOAc, 7:3); 1HNMR (360
MHz, CDCl3) δ 5.71 (m, 2H), 4.26 (m, 2H), 2.12 (m, 1H), 2.00
(m, 1H), 1.54 (m, 1H), 1.46 (m, 1H), 0.89 (s, 9H), 0.08 (s, 3H),
0.07 (s, 3H). (()-19: oil; Rf ) 0.44 (hexanes/EtOAc, 7:3); 1H NMR
(250 MHz, CDCl3) δ 5.75 (m, 2H), 4.12 (m, 1H), 4.08 (m, 1H),
1.72 (m, 2H), 1.47 (d, J ) 7.6 Hz, 1H), 1.29 (m, 2H), 0.89 (s, 9H),
0.08 (s, 3H), 0.07 (s, 3H). The same reaction starting from (S)-18
1
90%) as a white solid: Rf ) 0.30 (EtOAc); H NMR (360 MHz,
CDCl3) δ 5.81 (s, 2H), 4.27 (bt, 2H), 2.14 (m, 2H), 1.50 (m, 2H).
The same reaction starting from (1S,4S)-11 furnished (1S,4S)-2,
[R]D ) -112 (c 0.25, CHCl3) (lit.27 for the enantiomer [R]D
+144.7 (c 0.15, CHCl3)).
)
Acknowledgment. We acknowledge financial support from
DGI(projectCTQ2004-2539)andCIRIT(project2001SGR00178)
and grants from DGR (G.M.) and MECD (G.T.). We also
acknowledge Prof. Josep López-Santín and Dr. Gloria Caminal
for helpful discussions on the enzymatic resolution work.
Supporting Information Available: General experimental
procedures, preparation of compounds 13, (()-3, and (()-7,
1H NMR spectra of compounds 1-3, 7, 11, 13, (-)-15, and
16-19, CHPLC of 2, 7, 11, and 15, and CGC of compound 1.
This material is available free of charge via the Internet at
http://pubs.acs.org.
furnished (1S,4S)-11, [R]D ) -96 (c 0.96, CHCl3) (lit.18 [R]D
)
(25) Gatti, R. G. P.; Larsson, A. L. E.; Bäckvall, J.-E. J. Chem. Soc., Perkin
Trans. 1 1997, 577.
(26) Bäckvall, J.-E.; Byström, S. E.; Nordberg, R. E. J. Org. Chem. 1984,
49, 4619.
(27) Sanfilippo, C.; Patti, A.; Nicolosi, G. Tetrahedron: Asymmetry 2000,
11, 3269.
JO800107H
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