Chemoenzymatic synthesis of chiral enones from aromatic compounds

Article abstract of DOI:10.1016/S0957-4166(02)00682-1

A series of chiral enones was successfully synthesized from chemoenzymatically produced chiral diols. These chiral enones are highly functionalized synthons, which can be used in the total synthesis of natural products such as forskolin and avermectins.

Full text of DOI:10.1016/S0957-4166(02)00682-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2453–2459
Chemoenzymatic synthesis of chiral enones from aromatic
compounds
Valeria Schapiro,a Gabriel Cavalli,a Gustavo A. Seoane,a,* Ricardo Facciob and
Alvaro W. Mombru´b
aDepartamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad de la Repu´blica, General Flores 2124,
Montevideo, Uruguay
bLaboratorio de Cristalograf´ıa, Facultad de Qu´ımica, Universidad de la Repu´blica, General Flores 2124, Montevideo, Uruguay
Received 18 September 2002; accepted 27 September 2002
Abstract—A series of chiral enones was successfully synthesized from chemoenzymatically produced chiral diols. These chiral
enones are highly functionalized synthons, which can be used in the total synthesis of natural products such as forskolin and
avermectins. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
a,b-Unsaturated ketones are among the most versatile
building blocks in organic synthesis. Indeed, several
natural products have been synthesized using enones as
basic scaffolds.1–5 Chiral enones are particularly inter-
esting since they can be used in non-racemic total
syntheses. Herein, we disclose the chemoenzymatic syn-
thesis of chiral a,b-unsaturated ketones as highly func-
tionalized intermediates for natural products synthesis
starting from monosubstituted aromatic compounds.
2.1. Methylcyclohexadienediol-derived enones
Toluene-derived diene diol 1 is being studied in our
laboratory as a potential starting material in the asym-
metric synthesis of forskolin and its derivatives.12 The
proposed construction of the skeleton starts from an
enone as a precursor of ring B. A tandem Michael–
aldol addition sequence allows for the closure of ring
A, and further olefination and cyclization give ring C of
forskolin (Scheme 1).
These simple aromatics were converted to chiral cyclo-
hexadienediols through whole-cell oxidation using
Pseudomonas putida F39/D.6–8 These compounds have
been used extensively in organic synthesis due to their
high functionality and enantiomeric purity.9 Several
aromatic compounds, possessing either electron-with-
drawing or -donating groups have been used in the
microbial oxidation. In particular, the efficient prepara-
tion of an enone from the cyclohexadienediol derived
from anisol10,11 constitutes one of the first synthetic
applications of this diol.
Enone 5, which contains all the required stereogenic
centers of ring B in the correct arrangement, was
obtained from toluene, via diol 1, via a simple synthetic
sequence (Scheme 2). Non-selective protection of 1
proceeded in high yields to give acetonide 2a and
acetate 2b, which were then dihydroxylated via catalytic
osmylation.
For both the acetate and the acetonide, the reaction
occurred primarily on the more electron-rich double
* Corresponding author. Tel.: (598)(2) 924 4066; fax: (598)(2) 924
1906; e-mail: gseoane@bilbo.edu.uy
Scheme 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00682-1

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V. Schapiro et al. / Tetrahedron: Asymmetry 13 (2002) 2453–2459
Scheme 2. Reagents and conditions: (i) P. putida F39/D; (ii) 2,2-dimethoxypropane (solvent), p-TsOH (catalytic), rt, 80% of 2a,
or acetic anhydride (solvent), NEt3 (2.2 equiv.), DMAP (catalytic), 90% of 2b; (iii) OsO4 (catalytic), NMO (1.1 equiv.),
acetone/water (1/1), 55% for R=C(Me)2, 42% for R=Ac; (iv) Dess–Martin (1.5 equiv.), CH2Cl2, rt, overnight, 75% for
R=C(Me)2, 60% for R=Ac; (v) for 4a: Dowex 50, MeOH/H2O (1/5), 50°C, 86%.
bond, in 65% yield.13 Then, the secondary alcohol in
diols 3 was oxidized with Dess–Martin periodinane14 to
furnish the corresponding enones, 4a and 4b, in accept-
able yields. Subsequently, the hydroxy groups could be
conveniently deprotected to yield enone 5 with the
chiral enones on its own turn. However, to obtain the
correct stereoselectivity in the closure of ring A from
enone 5 via the Michael–aldol addition sequence, selec-
tive protection of the diol system in 1 is required. The
selective protection of the diol functionality was per-
formed using the bulky silylating agent chlorothexyl-
trimethylsilane (Cl-THS)15 that reacted with the less
hindered hydroxy group. Following the previously
described methodology, the corresponding enones 9
were obtained in acceptable yields (Scheme 3).
correct regio- and stereochemistry of ring
B of
forskolin. Enone 4a was deprotected easily using an
acidic ion-exchange resin to give trihydroxyenone 5,
whose structure has been confirmed by X-ray analysis,
as shown in Fig. 1. In this way, this compound was
obtained in 36% overall yield from diol 1 through a
short and efficient sequence.
Attempts to desilylate 9a (using Bu4NF/THF and HF/
py) resulted in partial migration of the acetate group,
producing a mixture of monoacetylated dihydroxy-
enones. However, 9a could be deacetylated to afford 10
in moderate yields, while 9b was conveniently desily-
lated yielding enone 11 (Scheme 4). The use of enone 11
in the construction of the A–B ring system of forskolin
is currently under study and will be published in due
course.
Conversely, acetylated enone 4b could not be success-
fully deprotected: It decomposed under basic deprotec-
tion conditions (K2CO3/MeOH and DBU/toluene), and
was not hydrolyzed under enzymatic conditions, using
Candida cylindracea lipase, in a pH 7.6 buffer, at 36°C,
for 5 days.
The use of non-selective protecting groups described
above to obtain enone 5 allow us ready access to
simpler intermediates in order to evaluate the success of
the synthetic approach, and may also produce useful
In summary, starting from diol 1 a set of differentially
protected enones, resulting in mono-, di- and trihydroxy-
enones, was prepared.
2.2. Methoxycyclohexadienediol-derived enone
Microbial dihydroxylation of anisol produces methoxy-
cyclohexadienediol 12, which is an unstable metabolite
that decomposes to aromatic products even under mild
conditions.10 In order to make this diol synthetically
useful we intended to control its reactivity by perform-
ing a Diels–Alder reaction in which 12 was treated with
the Cookson dienophile.16 The expected cycloaddition
adduct was not observed. Instead, enone 13 was iso-
lated in 90% yield, as shown in Scheme 5. We propose
a Diels–Alder reaction followed by collapse of the
adduct to the enone to account for the formation of 13.
The absolute stereochemistry at C4 in enone 13 was not
unambiguously confirmed, but, as free diols generate
endo-syn adducts,10,17,18 the most probable configura-
tion is S, which is in agreement with observed spectro-
scopic data.
Figure 1.

V. Schapiro et al. / Tetrahedron: Asymmetry 13 (2002) 2453–2459
2455
Scheme 3. Reagents and conditions: (i) THSCl (1.1 equiv.), imidazole (2.2 equiv.), DMF, 0°C, 85%; (ii) acetic anhydride (solvent),
NEt3 (1.2 equiv.), DMAP (catalytic), 0°C, 80% or chloromethylmethyl ether (1 equiv.), DIPEA (1.1 equiv.), CH2Cl2, 0°C“rt,
80%; (iii) OsO4 (catalytic), NMO (1.1 equiv.), acetone/water (1/1), 70% for R=Ac, 52% for R=MOM; (iv) Dess–Martin (1.5
equiv.), CH2Cl2, rt, overnight, 75% for R=Ac, 80% for R=MOM.
Finally, 14 was reacted via catalytic osmium tetraoxide
dihydroxylation producing 1513 and via bromohydrin
synthesis producing 17.24 Two different enones, 16 and
18, were then synthesized by oxidation of the allylic
alcohols with Dess–Martin periodinane14 (MnO2 gave
no reaction after 15 days) in moderate to good yields as
shown in Scheme 6. In the case of the diol 15, equimo-
lar addition of oxidizing agent resulted in extremely
poor yields of 16, while increasing the amounts of
Dess–Martin reagent caused overoxidation to the corre-
sponding diketone. The best results were obtained using
Scheme 4. Reagents and conditions: (i) K2CO3 (2.5 equiv.),
MeOH, rt, 35%; (ii) Bu4NF (1.2 equiv.), THF, 0°C“rt, 52%.
2 equivalents of oxidizing agent, resulting in 45% iso-
lated yield, the remainder being diketone (30%) and
unreacted starting material, which could be recycled.
On the other hand, the bromoketone 18 was obtained
in good yield and debrominated25 with Zn/NH4Cl in
moderate yield to give the corresponding enone 19.
2.3. Chlorocyclohexadienediol-derived enones
Enones 16, 18, and 19 are highly functionalized inter-
The dienic system in chlorocyclohexadienediol reacts
with electrophiles preferentially at the distal alkene
mediates with interesting synthetic potential for the
preparation of natural products. In particular, enone 19
moiety to produce compounds such as 15 and 17, as
can be used as a building block for the synthesis of
opposed to the previous cases (Scheme 6).9 These com-
avermectines. The chlorinated a,b-unsaturated ketone
pounds can be used as precursors to a,b-unsaturated
system can also be further functionalized by conjugate
ketones, 16, 18, and 19. In these enones, the chlorinated
substitution reactions.26
system offers new possibilities of functionalization
through conjugate substitution of the chlorine atom by
nucleophiles.
3. Conclusions
To produce the desired enones, chlorocyclohexadiene-
A series of highly functionalized, polyoxygenated chiral
diol was prepared through microbial oxidation of
enones, 4, 5, 9–11, 13, 16, 18, and 19, with potential
chlorobenzene and then quantitatively protected as the
applications as synthetic intermediates have been suc-
corresponding acetonide 14.13 Functionalization of 14
cessfully synthesized via simple reactions. The reported
synthetic sequences are short and allow the rapid
preparation of these synthons in multigram quantities.
through the distal alkene was attempted via hydrobora-
tion–oxidation using catecholborane19,20 (no reaction
observed)
and
oxymercuration–demercuration21
(decomposition to aromatic products occurred).
Harsher methods (such as HBr addition with or with-
out phase transfer agents) resulted in deprotection of
the diol system followed by aromatization. Attempts to
synthesize 17 via Wacker oxidation22 resulted in decom-
position through Diels–Alder dimerization23 of the
starting acetonide with no oxidation observed.
4. Experimental
4.1. General
All non-hydrolytic reactions were carried out in a nitro-
gen atmosphere with standard techniques for the

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V. Schapiro et al. / Tetrahedron: Asymmetry 13 (2002) 2453–2459
Scheme 5. Reagents and conditions: (i) P. putida F39/D; (ii) CH2Cl2, 0°C, 1 h, 90%.
Scheme 6. Reagents and conditions: (i) P. putida F39/D then 2,2-dimethoxypropane, p-TsOH (cat.), rt, 90%; (ii) OsO4 (catalytic),
NMO (1.1 equiv.), acetone/water (1/1), reflux, overnight, 80%; (iii) NBS (1.1 equiv.), water, DME, 0°C, darkness, 1 h, 70%; (iv)
Dess–Martin periodinane (1.1 equiv.), CH2Cl2, rt, overnight, 45%; (v) Dess–Martin periodinane (1.1 equiv.), CH2Cl2, rt,
overnight, 75%; (vi) Zn (1.1 equiv.), NH4Cl (30% in water), rt, 10 min, 50%.
4.2. (1S,2R)-1-(Dimethylthexylsilyl)oxy-2-O-
exclusion of air. All solvents were distilled prior to use.
Melting points were determined on a Gallenkamp capil-
lary melting point apparatus and are uncorrected. Mass
spectra were recorded on a Shimadzu GC–MS QP 1100
EX instrument using the electron-impact mode (70 eV)
or chemical ionization (if indicated) or on a Finnigan
MATQSQ spectrometer. Infrared spectra were recorded
either on neat samples (KBr disks) or in solution (with
solvent substraction) on Perkin–Elmer 1310 or Bomem,
Hartmann & Braun FTIR spectrometers. Proton NMR
spectra were obtained on Bruker Avance DPX-400,
Bruker AC-200, or Varian XL-100 instruments. Carbon
NMR were obtained on Bruker Avance DPX-400 at 100
MHz. Proton chemical shifts (l) are reported in ppm
downfield from tetramethylsilane as an internal reference
(0.0 ppm), and carbon chemical shifts are reported in
ppm relative to the center line of the CDCl3 triplet (77.0
ppm). Combustion analyses were performed in a Fisons
EA 1108 CHNS-O analyser. X-Ray studies were done on
a AFC75-Rigaku single-crystal diffractometer, over
recrystallized samples. Optical rotations were measured
on a Perkin–Elmer 241 polarimeter using a 2 mL cell. [h]D
values are given in units of 10−1 deg cm2 g−1.
methoxymethyl-3-methyl-3,5-cyclohexadien-2-ol, 7b
To a solution of monosilylated diol 615 (2 g, 7.5 mmol)
in CH2Cl2 (30 mL) at 0°C was added diisopropylethyl-
amine (1.1 g, 8.3 mmol) and chloromethylmethyl ether
(0.6 g, 7.5 mmol). After 20 h of stirring the solvent was
evaporated and the residue was dissolved in Et2O. The
ethereal solution was neutralized with saturated aqueous
NaHCO3, washed with 10% aqueous CuSO4 (3×), and
with brine (2×), and dried over MgSO4, and filtered, and
then the solvent was evaporated to yield 7b (1.8 g, 80%).
Due to the instability of this compound no further
1
attempts were made towards its purification. H NMR
(400 MHz, CDCl3): l 0.17 (s, 3H), 0.18 (s, 3H), 0.90 (m,
12H), 1.62 (m, 1H), 1.96 (s, 3H), 3.37 (s, 3H), 3.74 (d,
J=5.4 Hz, 1H), 4.54 (m, 1H), 4.66 (d, J=6.8 Hz, 1H),
4.94 (d, J=6.8 Hz, 1H), 5.72 (d, J=9.4 Hz, 1H), 5.82 (s,
1H), 5.87 (m, 1H).
4.3. (1S,2S,3S,4S)-4-(Dimethylthexylsilyl)oxy-3-O-
methoxymethyl-2-methyl-5-cyclohexen-1,2,3-triol, 8b
To a stirred solution of 7b (1.7 g, 5.4 mmol) in a 1/1
mixture of acetone/water (20 mL) was added N-methyl-
morpholine-N-oxide (0.77 g, 6.5 mmol) and a catalytic
amount of OsO4 at rt. The mixture was protected
from light and stirred for 6 h. The acetone was then
evaporated and the residue dissolved in EtOAc. The
organic solution was successively washed with saturated
aqueous NaHSO3 (1×) and 10% aqueous CuSO4. The
Diols 1, 12 and 14 were obtained by fermentation of the
corresponding arenes.27 Analytical TLC was performed
on silica gel 60F-254 plates and visualized with UV light
(254 nm) and/or p-anisaldehyde in acidic ethanolic
solution. Flash column chromatography was performed
using silica gel (Kieselgel 60, EM Reagents, 200–400
mesh).

V. Schapiro et al. / Tetrahedron: Asymmetry 13 (2002) 2453–2459
2457
combined aqueous layers were then extracted with
EtOAc (2×) and the combined organic layers were
washed with brine (1×), and dried over MgSO4. Evapo-
ration of the solvent gave a yellow oil, which was
chromatographed (silica gel, EtOAc/hexanes: 20/80)
4.7. (2R,3S,4S)-3-Acetoxy-4-(dimethylthexylsilyl)oxy-2-
hydroxy-2-methyl-5-cyclohexen-1-one, 9a
Yield: 75%; [h]D25=+80.7 (c 0.15, CHCl3); 1H NMR
(100 MHz, CDCl3): l 0.13 (s, 6H), 0.86 (m, 12H), 1.42
(s, 3H), 1.48–1.80 (m, 1H), 2.14 (s, 3H), 3.48 (broad s,
1H), 4.78 (t, J=6.0 Hz, 1H), 5.18 (d, J=5.0 Hz, 1H),
6.10 (d, J=5.0 Hz, 1H), 6.75 (dd, J=11.0, 5.0 Hz, 1H);
MS (EI, 20 eV) m/z, (%): 257 (1), 197 (100), 169 (29),
153 (71), 139 (5) 117 (30), 95 (13), 75 (41), 73 (28), 43
(37).
1
yielding 8b (0.98 g, 52%). H NMR (400 MHz, CDCl3):
l 0.13 (d, J=2.3 Hz, 3H), 0.16 (d, J=4.8 Hz, 3H),
0.84–0.90 (m, 12H), 1.38 (d, J=10.6 Hz, 3H), 1.64 (m,
1H), 3.01 (s, 1H), 3.32 (s, 1H), 3.34 (s, 3H), 3.77 (d,
J=3.6 Hz, 1H), 4.12 (m, 1H), 4.55 (m, 1H), 4.71 (d,
J=6.8 Hz, 1H), 4.86 (d, J=6.8 Hz, 1H), 5.53–5.71 (m,
2H); 13C NMR (100 MHz, CDCl3): l −2.5, −2.3, 18.9,
19.0, 20.5, 20.6, 23.7, 25.4, 34.3, 56.5, 69.0, 71.2, 128.5,
129.3, 131.3. Due to the instability of this compound it
was not possible to obtain other characterization data.
4.8. (2R,3S,4S)-4-(Dimethylthexylsilyl)oxy-3-O-
methoxymethyl-2,3-dihydroxy-2-methyl-5-cyclohexen-1-
one, 9b
Yield: 80%; [h]2D5=+108.8 (c 6.1, acetone); 1H NMR
(400 MHz, CDCl3): l 0.17 (s, 3H), 0.19 (s, 3H), 0.85 (s,
6H), 0.86 (d, J=1.9 Hz, 3H), 0.88 (d, J=1.9 Hz, 3H),
1.45 (s, 3H), 1.63 (m, 1H), 3.43 (s, 3H), 3.85 (d, J=4.3,
1H), 4.59 (t, J=4.6 Hz, 1H), 4.79 (d, J=6.5 Hz, 1H),
4.89 (d, J=6.5 Hz, 1H), 6.06 (d, J=10.1 Hz, 1H), 6.78
(dd, J=10.1, 4.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3): l −2.2, −2.3, 18.9, 19.0, 20.5, 20.6, 23.2, 25.5,
34.4, 56.5, 67.1, 97.4, 127.0, 147.8, 199.1 Due to the
instability of this compound it was not possible to
obtain other characterization data.
4.4. General procedure for Dess–Martin oxidation
To a solution of the corresponding alcohol (diols 3a,13
3b,13 8a,13 8b, 1513 or bromohydrin 1724) in CH2Cl2 was
added a solution of Dess–Martin reagent (1.5 equiv.).
After stirring overnight at rt, the CH2Cl2 was evapo-
rated and the residue partitioned between Et2O and
saturated aqueous NaHCO3. Then Na2S2O3 (7 equiv.)
was added and the mixture was stirred to dissolve the
solid. After phase separation, the aqueous layer was
extracted with Et2O (3×) and the combined organic
extracts were washed with saturated aqueous NaHCO3
until no more CO2 evolved, and then with brine. The
organic layer was dried over MgSO4, filtered, and the
solvent was evaporated to give a residue, which was
purified by chromatography (silica gel, EtOAc/
hexanes).
4.9. (4S,5S,6S)-3-Chloro-4,5-isopropylidenedioxy-6-
hydroycyclohex-2-en-1-one, 16
Yield: 45%; [h]2D5=−33.1 (c 0.16, acetone); 1H NMR
(400 MHz, CDCl3): l 1.48 (s, 3H), 1.59 (s, 3H), 3.60
(broad s, 1H), 4.33 (d, J=7.4 Hz, 1H), 4.43 (dd, J=7.4,
6.3 Hz, 1H), 4.85 (d, J=6.2 Hz, 1H), 6.41 (s, 1H); 13C
NMR (100 MHz, CDCl3): l 26.4, 28.2, 74.7 76.1, 78.9,
112.6, 127.8, 152.3, 194.9; MS (EI, 70 eV) m/z (%): 205
(3), 203 (10), 163 (2.5), 161 (7); IR (KBr): 3420, 3050,
2980, 2870, 1700, 1620, 1365 (d), 1240, 1220, 1160,
1120, 1070 cm−1.
4.5. (2R,3S,4S)-3,4-Isopropylidenedioxy-2-hydroxy-2-
methyl-5-cyclohexen-1-one, 4a
Yield: 75%; mp 72.0–73.0°C; [h]2D5=+110.8 (c 0.11,
1
CHCl3); H NMR (400 MHz, CDCl3): l 1.42 (s, 3H),
1.44 (s, 3H), 1.45 (s, 3H), 3.11 (s, 1H), 4.42 (dd, J=6.0,
1.0 Hz, 1H), 4.86 (m, 1H), 6.11 (dd, J=10.2, 1.2 Hz,
1H), 6.76 (ddd, J=10.2, 3.2, 1.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): l 23.0, 26.4, 27.4, 72.0, 74.5, 80.8,
111.6, 127.3, 144.3, 199.2; MS (CI, CH4) m/z (%): 199
((M+1)+, 17), 198 (M+, 4), 183 (16), 169 (5), 141 (70),
123 (100), 115 (51), 114 (11), 113 (13), 97 (58), 95 (59),
81 (10), 59 (16), 43 (61); IR (KBr): 3410, 2980, 2920,
2880, 1675, 1380 (d), 1225, 1040, 1060 cm−1. Anal. calcd
for C10H14O4: C, 60.60; H, 7.11. Found: C, 60.26; H,
7.34%.
4.10. (4S,5S,6S)-6-Bromo-3-chloro-4,5-isopropylidene-
dioxycyclohex-2-en-1-one, 18
Yield: 75%; [h]D20=−69.3 (c 0.15, CH2Cl2); 1H NMR
(400 MHz, CDCl3): l 1.35 (s, 3H), 1.39 (s, 3H), 4.40 (s,
1H), 4.76 (s, 2H), 6.23 (s, 1H); 13C NMR (100 MHz,
CDCl3): l 27.2, 27.8, 41.9, 74.3, 78.3, 113.3, 125.5,
154.6, 187.4; EM (EI, 70 eV) m/z (%): 269 (9), 267 (19),
265 (11), 227 (2), 225 (7), 223 (6); IR (KBr): 2990, 2940,
1685, 1610, 1375 (d), 1340, 1290, 1230, 1150, 1070 cm−1.
4.6. (2R,3S,4S)-3,4-Diacetoxy-2-hydroxy-2-methyl-5-
cyclohexen-1-one, 4b
4.11. (2R,3S,4S)-2-Methyl-2,3,4-trihydroxy-5-cyclo-
hexen-1-one, 5
1
Yield: 60%; [h]2D5=+123.7 (c 0.19, CHCl3); H NMR
(100 MHz, CDCl3): l 1.46 (s, 3H), 2.10 (s, 3H), 2.12 (s,
3H), 4.78 (s, 1H), 5.42 (d, J=4.0 Hz, 1H), 6.00 (ddd,
J=4.0, 4.0, 1.0 Hz, 1H), 6.26 (dd, J=10.0, 1.0 Hz, 1H),
6.82 (dd, J=10.0, 4.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): l 21.0, 21.1, 21.9, 66.4, 73.5, 75.1, 129.4, 143.4,
170.2, 198.6; MS (CI, CH4) m/z (%): 139 (11), 97 (36),
84 (21), 74 (17), 43 (100); IR (KBr): 3447, 2924, 1750,
1696, 1372, 1283 cm−1. Anal. calcd for C11H14O6: C,
54.54; H, 5.83. Found: C, 54.24; H, 5.85%.
Enone 4a (200 mg, 1 mmol) was dissolved in MeOH (2
mL). Water (10 mL) and catalytic amounts of acidic
resin DOWEX 50 WX8-200 were added, and the reac-
tion mixture was heated at 50°C for 12 h. The resin was
filtered off and EtOAc was added in order to evaporate
water by vacuum azeotropic distillation. The residue
was chromatographed (silica gel, EtOAc) yielding
enone 5 (137 mg, 86%); mp 139.0–141.5°C; [h]2D5=

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V. Schapiro et al. / Tetrahedron: Asymmetry 13 (2002) 2453–2459
1
+175.4 (c 0.7, MeOH); H NMR (400 MHz, CD3OD):
l 1.36 (s, 3H), 3.93 (dd, J=3.7, 2.0 Hz, 1H), 4.77 (m,
1H), 5.93 (dd, J=10.4, 2.2 Hz, 1H), 6.75 (dt, J=10.4,
2.2 Hz, 1H); 13C NMR (100 MHz, CD3OD): l 20.1,
66.7, 75.2, 77.3, 126.6, 149.3, 199.4; MS (CI, CH4) m/z
(%): 159 ((M+1)+, 26), 141 (40), 123 (100), 113 (20), 95
(99); IR (KBr): 3350, 2920, 2880, 1680, 1445, 1370,
1290, 1150, 1090, 1045 cm−1. Anal. calcd for C7H10O4:
C, 53.20; H, 6.33. Found: C, 53.15; H, 6.54%.
(silica gel, EtOAc/hexanes: 80/20) yielding enone 13
(580 mg, 90%); mp 159–162°C; [h]2D0=−37.0 (c 0.54,
MeOH); 1H NMR (400 MHz, CD3OD): l 4.43 (d,
J=2.6 Hz, 1H), 4.59 (dd, J=5.5, 2.6 Hz, 1H), 4.88 (s,
1H), 5.37 (dd, J=5.5, 2.9 Hz, 1H), 6.18 (dd, J=10.2,
2.9 Hz, 1H), 6.89 (dt, J=10.2, 1.8 Hz, 1H), 7.47 (m,
5H); 13C NMR (100 MHz, CDCl3): l 56.8, 75.4, 75.5,
126.1, 128.2, 128.8, 128.8, 131.6, 144.0, 153.2, 153.5,
198.0; MS (CI, CH4) m/z (%): 302 ((M−1)+, 0.9), 286
(100), 245 (39), 213 (79), 152 (28), 126 (32), 125 (21),
120 (29), 94 (63); HRMS calcd for C14H11N3O4 (M+−
H2O): 285.0746. Found: 285.0676; IR (KBr): 3400,
1740, 1650, 1480, 1420, 1280, 1260, 1120 cm−1.
Crystallographic data (excluding structure factors) for
enone 5 have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication
numbers CCDC 182304. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
4.15. (4S,5S)-3-Chloro-4,5-isopropylidenedioxycyclohex-
2-en-1-one, 19
To a solution of enone 18 (0.18 g, 0.64 mmol) in THF
(0.5 mL) was added aqueous 30% NH4Cl (10 mL) and
Zn dust (45 mg, 0.69 mmol). The mixture was stirred at
rt and after 10 min was extracted with EtOAc (3×10
mL). The combined organic extracts were washed with
brine (3×10 ml), dried over MgSO4, and the solvent was
evaporated. The residue was chromatographed (silica
gel, EtOAc/hexanes: 20/80) yielding enone 19 as a clear
oil (65 mg, 50%); [h]2D0=−33.1 (c 0.16, CH2Cl2); 1H
NMR (400 MHz, CDCl3): l 1.41 (s, 3H), 1.42 (s, 3H),
2.72 (dd, J=17.6, 3 Hz, 1H), 2.97 (dd, J=17.4, 2.5 Hz,
1H), 4.70 (m, 2H), 6.28 (s, 1H); 13C NMR (100 MHz,
CDCl3): l 26.8, 27.9, 39.0, 73.4, 74.9, 111.2, 128.8,
155.7, 193.2; MS (EI, 70 eV) m/z (%): 189 (14), 187
(43), 147 (18), 145 (55); IR (KBr): 2990, 2920, 1685,
1610, 1500, 1375 (d), 1300, 1220, 1110 cm−1.
4.12. (2R,3S,4S)-2,3-Dihydroxy-4-(dimethylthexylsilyl)-
oxy-2-methyl-5-cyclohexen-1-one, 10
To a solution of enone 9a (50 mg, 0.15 mmol) in
MeOH (5 mL) was added K2CO3 (52 mg, 0.375 mmol)
at rt. After stirring for 3 h, the MeOH was evaporated
and the residue was dissolved in EtOAc. The organic
layer was washed with brine (2×), dried over MgSO4,
and the solvent was evaporated. The residue was chro-
matographed (silica gel, EtOAc/hexanes: 30/70) yield-
ing enone 10 (15 mg, 35%). [h]2D5=+106.6 (c 0.43,
1
acetone); H NMR (100 MHz, CDCl3): l 0.20 (s, 3H),
0.90 (m, 12H), 1.42 (s, 3H), 1.50–1.90 (m, 1H), 3.42 (s,
2H), 4.65 (dd, J=8.0, 4.0 Hz, 1H), 4.90 (m, 1H), 6.12
(d, J=2.0 Hz, 1H), 6.75 (ddd, J=11.0, 4.0, 2.0 Hz,
1H).
4.13. (2R,3S,4S)-2-Methyl-3-O-methoxymethyl-2,3,4-
trihydroxy-5-cyclohexen-1-one 11
Acknowledgements
To a stirred solution of enone 9b (200 mg, 0.58 mmol)
in anhydrous THF (15 mL) was added Bu4NF (0.8 mL
of a 1 M solution in THF) at 0°C and the reaction was
allowed to warm to rt. After 5 h the solvent was
evaporated and the residue was dissolved in EtOAc.
This solution was washed with brine (2×), dried over
MgSO4, and the solvent was evaporated to give a
residue which was chromatographed (silica gel, EtOAc/
hexanes: 60/40) yielding enone 11 (61 mg, 52%); [h]2D5=
Support of this work by Universidad de la Repu´blica
(Uruguay) and PEDECIBA (UN-Project URU/97/016)
is gratefully acknowledged. The authors thank Mrs.
Gladys Garc´ıa for the production of diols and Prof. T.
Hudlicky for providing the cultures of P. putida F39/D.
Gabriel Cavalli thanks CONICYT (Uruguay) for a
scholarship.
1
+63.7 (c 6.0, acetone); H NMR (400 MHz, CDCl3): l
1.45 (s, 3H), 3.17 (broad s, 2H), 3.46 (s, 3H), 3.90 (d,
J=4.6 Hz, 1H), 4.65 (t, J=4.6 Hz, 1H), 4.82 (d, J=6.5
Hz, 1H), 4.94 (d, J=6.5 Hz, 1H), 6.16 (dd, J=10.2, 0.7
Hz, 1H), 6.92 (dd, J=10.2, 4.6 Hz, 1H). Due to the
instability of this compound it was not possible to
obtain other characterization data.
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