A catalytic route to acyclic chiral building blocks: Applications of the catalytic asymmetric conjugate addition of organozinc reagents to cyclic enones

Article abstract of DOI:10.1560/NHK0-C8JE-27G9-NUB3

Through the Cu-phosphoramidite-catalyzed asymmetric conjugate addition a number of chiral cyclic enones are available with high ee. Here we report the sequential conjugate addition to these enones as a route towards multisubstituted chiral cyclic ketones.

Full text of DOI:10.1560/NHK0-C8JE-27G9-NUB3

A Catalytic Route to Acyclic Chiral Building Blocks: Applications of the Catalytic
Asymmetric Conjugate Addition of Organozinc Reagents to Cyclic Enones
RICHARD B.C. JAGT, ROSALINDE IMBOS, ROBERT NAASZ, ADRIAAN J. MINNAARD, AND BEN L. FERINGA*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
(Received 25 December 2001)
Abstract. Through the Cu-phosphoramidite-catalyzed asymmetric conjugate
addition a number of chiral cyclic enones are available with high ee. Here we report
the sequential conjugate addition to these enones as a route towards multisubstituted
chiral cyclic ketones. A subsequent Baeyer–Villiger oxidation followed by ring-
opening results in various linear synthons containing multiple stereocenters. This
procedure represents a short, catalytic, and highly enantioselective route to a variety
of acyclic chiral building blocks.
INTRODUCTION
Recently, we realized the first catalytic 1,4-addition
of organometallic reagents to enones with complete
stereocontrol.9 The asymmetric conjugate addition of
dialkylzinc reagents to various cyclic enones, using a
Cu-phosphoramidite complex as catalyst, proceeds with
high yields and excellent ee’s of >96% (Scheme 2).
Shortly after these findings, two routes to chiral
cyclohexenones were developed in our laboratories.
The Cu(OTf)2-L*-1 catalyst proved to be very efficient
for kinetic resolutions of racemic 5-substituted cyclo-
hexenones, providing the starting compounds 1a,1b,
and 1c with ee’s >99%, >99%, and 89%, respectively10
(Scheme 3a). Furthermore, not only cyclic enones, but
also cyclohexadienone monoketals are excellent sub-
strates for the asymmetric conjugate addition,11 yielding
the corresponding chiral cyclohexenones with >99% ee
(Scheme 3b).
Herein we report the use of these easily accessible
chiral cyclohexenones 1a–c, as well as the use of enantio-
merically pure (ee > 99%) 6-methyl-cycloheptenone 8
(available through asymmetric conjugate addition to
cycloheptadienone) in the synthesis of linear building
blocks containing 2 stereocenters. The route involves an
asymmetric Cu(OTf)2-L*-1-catalyzed conjugate addi-
Author to whom correspondence should be addressed. E-mail:
B.L.Feringa@chem.rug.nl
Acyclic chiral building blocks play a major role in or-
ganic synthesis, as is particularly evident in total synthe-
sis of macrolide antibiotics1 and pheromones.2 Linear
fragments containing methyl-substituted stereogenic
centers are especially of interest. Two general routes to
obtain these linear building blocks in enantiomerically
pure form comprise a synthesis starting from a precursor
from the chiral pool, and methodology based on a chiral
auxiliary in the crucial steps where the asymmetry is
introduced.3
Alternatively, catalytic methods might be employed
to generate acyclic chiral building blocks. Recent ap-
proaches include, among other methods, catalytic
enantioselective (Mukaiyama) aldol reaction,4 isomer-
ization,5 hydrogenation,6 and allylic substitution.7
The use of cyclic substrates in catalytic asymmetric
transformations has the distinct advantage of limited
conformational flexibility and, as a consequence, usu-
ally strongly enhanced stereocontrol.8 Catalytic 1,4-ad-
dition to 5-substituted-cyclohexenones, readily acces-
sible through kinetic resolution or asymmetric conju-
gate addition, provides trans-3,5-disubstituted cyclo-
hexenones. Subsequent ring-opening of the chiral cyclic
products allows the formation of the desired acyclic build-
ing blocks, with multiple stereocenters (see Scheme 1).
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2001 pp. 221–229

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Scheme 1. (a) kinetic resolution, (b) conjugate addition, (c) ring opening.
Scheme 2. Asymmetric conjugate addition of dialkylzinc reagents to cycloalkenones catalyzed by a Cu(OTf)2/ L*-1 complex.
Scheme 3. Catalytic asymmetric route to chiral cyclohexenones using the Cu/L*-1-catalyzed conjugate addition of R2Zn
reagents.
EXPERIMENTAL
tion of Me2Zn to create the second stereocenter, fol-
lowed by a Baeyer–Villiger oxidation and subsequent
ring-opening by transesterification (See Scheme 4 (i)).
Furthermore, the chiral cyclohexenone-monoketals 2a
and 2b provide, through a similar sequence, a method to
obtain linear building blocks with three stereocenters
(see Scheme 4 (ii)).
General Procedure for the Conjugate Addition of
Dialkylzinc to Cyclic Enones Employing a Chiral Catalyst
Derived from Cu(OTf)2 and L*-1
A solution of 2.5 mol% Cu(OTf)2 and 5 mol% of
L*-1 in 5 mL of freshly distilled toluene was stirred under a
nitrogen atmosphere at ambient temperature for 1 h, after
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223
Scheme 4. General schemes for chiral linear building blocks, starting from (i) cycloalkenones leading to linear fragments
containing 2 stereogenic centers, (ii) cyclohexenone monoacetals, yielding acyclic building block containing 3 stereogenic
centers. Conditions: (a) trans-selective conjugate addition, (b) (1) Baeyer–Villiger oxidation, (2) transesterification, (c) trans-
selective conjugate addition, (d) (1) Wittig reaction, (2) reduction, (e) (1) Baeyer–Villiger oxidation, (2) transesterification.
which the enone was added. The mixture was cooled to –25 °C trans adduct. [α]D = –8.2° (c = 1.0, CHCl3). (Reported: [α]D =
and 1.2 equiv of R2Zn in toluene was added. Stirring was –12.28° (c 1.18, CHCl3)12) 1H NMR δ 0.92 (d, J = 6.6 Hz, 6H),
continued at –25 °C for 16 h. Conversion was determined by 1.54 (t, J = 5.7 Hz, 2H), 1.98 (m, 2H), 2.23 (m, 2H), 2.33 (d,
TLC. After complete conversion, the reaction mixture was J = 8.4 Hz, 1H), 2.36 (d, J = 3.7 Hz, 1H). 13C NMR: δ 20.79
poured into 50 mL of 2N NaOH and extracted three times with (q), 29.54 (d), 39.45 (t), 48.70 (t), 212.11 (s). NMR data were
diethyl ether (100 mL). The combined organic layers were in accordance with data published previously.13 CIMS (M+1)
washed with brine (50 mL) and dried on Na2SO4, filtered, and 127, (M+18) 144. Ee determination: GC Chiraldex B-TA,
the solvent evaporated to yield the crude 1,4-adduct.
30 m × 0.25 mm, He-flow = 1.0 mL/min, Ti = 75 °C for
10 min, Tf = 150 °C, rate 10 °C/min, rt 14.4 (3S, 5S), 14.6 (3R,
5R) min.
General Procedure for the Baeyer–Villiger Oxidation of Di-
and Tri-substituted Cyclohexanones 3a–3c and 14a–b
A suspension of 3.90 mmol mCPBA and NaHCO3
(3.90 mmol) in 50 mL of freshly distilled dichloromethane was
stirred under a nitrogen atmosphere at ambient temperature for
1 h, after which 1.3 mmol of di- or tri-substituted cyclo-
hexanone was added. Stirring was continued for 16 h, during
which a precipitate was formed. Conversion was shown to be
complete by TLC. The reaction mixture was washed with 10%
NaHSO3, saturated NaHCO3, and brine. The last three steps
were repeated until the brine layer tested negative on perox-
ides. Subsequently, the organic layer was dried with Na2SO4,
filtered, and the solvent evaporated. The resulting crude prod-
ucts were purified by column chromatography (SiO2, hexane/
Et2O = 4/1).
(–)-3-Isopropyl-5-methylcyclohexanone (3b)
Isolated yield 75% after purification by column chroma-
tography (SiO2, hexane/Et2O = 4/1). 1H NMR shows no cis
adduct. [α]D = –49.6° (c = 1.0, CHCl3). 1H NMR: δ 0.84 (d, J =
7.0 Hz, 6H), 0.91 (d, J = 7.0 Hz, 3H), 1.55 (m, 2H), 1.72 (m,
2H), 2.06 (m, 2H), 2.32 (m, 3H). 13C NMR: δ 19.76 (q), 19.91
(q), 20.18 (q), 29.60(d), 31.40 (d), 34.79 (t), 40.40 (d), 44.88
(t), 48.34 (t), 212.65 (s). CIMS (M+1) 155, (M+18) 172. Ee
determination: GC Chiraldex B-TA, 30 m × 0.25 mm, He-flow
= 1.0 mL/min, Ti = 90 °C for 10 min, Tf = 150 °C, rate 10 °C/
min, rt 19.0, 19.3 min.
(–)-3-Methyl-5-phenylcyclohexanone (3c)
Isolated yield 78% after purification by column chroma-
tography (SiO2, hexane/Et2O = 4/1). 1H NMR shows no cis
adduct. [α]D = –32.3° (c = 0.9, CHCl3). 1H NMR: δ 0.97 (d, J =
7.0 Hz, 3H), 1.81 (m, 1H), 1.99–2.27 (m, 3H), 2.54 (m, 3H),
3.33 (m, 1H), 7.18 (m, 3H), 7.27 (m, 2H). 13C NMR: δ 20.20
(q), 29.16 (d), 39.21 (t), 39.44 (d), 47.06 (t), 48.34 (t), 126.40
(d), 126.85 (d), 128.48 (d), 144.23 (s), 211.48 (s). CIMS
(M+1) 189, (M+18) 206.
General Procedure for the Ring-opening of Multi-substituted
Lactones
The lactones (0.25 mmol) were dissolved in 10 mL of
methanol and treated with an excess of NaOMe for 16 h at
ambient temperature. Conversion was shown to be complete
by TLC. The reaction mixture was poured into 25 mL of water
and extracted three times with diethyl ether (50 mL). The
combined organic layers were washed with brine (25 mL) and
dried on Na2SO4, filtered, and the solvent evaporated to yield
the product.
(4R,6R)-Dimethyl-2-oxepanone (4a)
1
Isolated yield 70%. [α]D = –31.9° (c = 1.1, CHCl3). H
NMR: δ 0.91 (d, J = 7.3 Hz, 3H), 0.98 (d, J = 7.0, 3H), 1.55
(m, 3H), 2.03 (m, 1H), 2.46 (dd, J = 13.7, 8.6 Hz, 1H), 2.61
(3R,5R)-3,5-Dimethylcyclohexanone (3a)
Isolated yield 68% after purification by column chroma- (dd, J = 13.7, 2.0 Hz, 1H), 3.93 (dd, J = 12.8, 7.3 Hz, 1H),
1
tography (SiO2, pentane/Et2O = 4/1). H NMR shows >99% 4.09 (d, J = 12.8 Hz, 1H). 13C NMR: δ 16.75 (q), 20.46(q),
Jagt et al. / A Catalytic Route to Acyclic Chiral Building Blocks

224
25.72 (d), 30.25 (d), 41.04 (t), 43.84 (t), 73.46 (t), 174.72 (s). 126.56 (d), 126.88 (d), 127.43 (d), 128.09 (d), 128.51 (d), 128.70
CIMS (M+1) 143, (M+18) 160. Ee determination: GC (d), 141.36 (s), 143.38 (s), 172.73 (s), 173.25 (s). CIMS (M+1)
Chiraldex B-TA, 30 m × 0.25 mm, He-flow = 1.0 mL/min, Ti = 237, (M+18) 254. De determination: GC HP-5, 30 m × 0.25 mm,
125 °C for 10 min, Tf = 180 °C, rate 10 °C/min, rt 14.9 (4S, 6S), He-flow = 1.3 mL/min, Ti = 75 °C for 1 min, Tf = 300 °C, rate
15.5 (4R, 6R) min.
10 °C/min, rt 14.2, 14.5 min. Ee determination major diastere-
omer: HPLC OD, Heptane/IPA = 97.5/2.5, rt 15.6, 16.9 min.
6-Isopropyl-4-methyl-2-oxepanone and 4-isopropyl-6-
methyl-2-oxepanone (4b/5b)
(S)-6-Methyl-2-cyclohepten-1-one (8)
Isolated yield 81%. Ratio 4b/5b = 56/44 1H NMR: δ 0.86
(m), 1.37 (m), 1.54 (m), 1.73 (m), 1.99 (m), 2.48 (m), 3.01 (dd,
J = 12.6, 6.8 Hz), 4.08 (m). 13C NMR: δ 16.25 (q), 19.53 (q),
19.57 (q), 19.94 (q), 20.92 (q), 25.59 (d), 27.67 (d), 30.26 (d),
31.30 (d), 36.36 (d), 37.56 (t), 38.63 (t), 39.00 (t), 41.15 (t),
41.53 (d), 71.13 (t), 73.10 (t), 174.70 (s), 175.15 (s). CIMS
(M+1) 171, (M+18) 188. Ee and de determinations: GC
Chiraldex B-TA, 30 m × 0.25 mm, He-flow = 1.0 mL/min, Ti =
100 °C for 10 min, Tf = 170 °C, rate 10 °C/min, rt 28.7, 29.0,
30.1, 30.3 min.
Isolated yield 76% (after column chromatography (SiO2,
pentane/Et2O = 4/1). [α]D = –46.3° (c = 1.1, CHCl3) (literature:
[α]D = –59° (c = 1.0, CHCl3), [α]D = + 64.6° (c = 1.3, CHCl3,
R enantiomer). 1H NMR: δ 0.91 (d, J = 6.6 Hz, 3H), 1.42 (m,
1H), 1.81 (m, 1H), 1.99 (m, 1H), 2.41 (m, 3H), 2,57 (dd,
J = 14.5, 4.6 Hz, 1H), 5.88 (d, J = 12.1 Hz, 1H), 6.53 (m, 1H).
13C NMR: δ 21.87 (q), 28.20 (t), 28.36 (d), 34.72 (t), 51.24 (t),
132.56 (d), 147.29 (d), 202.91 (s). CIMS (M+1) 125, (M+18)
142. Ee determination: GC Chiraldex B-TA, 30 m × 0.25 mm,
He-flow = 1.0 mL/min, Ti = 75 °C for 10 min, Tf = 150 °C, rate
10 °C/min, rt 17.1 (S), 17.2 (R) min.
4-Methyl-6-phenyl-2-oxepanone and 6-methyl-4-phenyl-2-
oxepanone (4c/5c)
(–)trans-(3S,6S)-Dimethylcycloheptanone (9)
Isolated yield 79% after purification by column chroma-
Isolated yield 68%. Ratio 4c/5c = 70/30. mp 132–133 °C.
1H NMR: δ 1.09 (d, J = 7.0 Hz), 1.10 (d, J = 7.3 Hz), 1.61 (m),
4.46 (m), 2.58–3.13 (m), 4.10–4.41 (m), 7.02–7.30 (m).
13C NMR: δ 14.81 (q), 17.95 (q), 26.51 (d), 31.35 (d), 35.41
(d), 40.25 (t), 40.81 (d), 40.93 (t), 42.72 (t), 43.55 (t), 72.40 (t),
73.15 (t), 126.36 (d), 126.68 (d), 126.97 (d), 128.67 (d),
128.79 (d), 141.96 (s), 145.05 (s), 174.10 (s), 174.26 (s).
CIMS (M+1) 205, (M+18) 222. De determination: GC CP
57 CB, 5 m × 0.25 mm, He-flow = 1.0 mL/min, Ti = 75 °C for
10 min, Tf = 250 °C, rate 10 °C/min, rt 19.6, 19.8 min.
1
tography (SiO2, pentane/Et2O = 4/1). H NMR shows no cis
adduct. [α]D = –50.0° (c = 1.0, CHCl3). 1H NMR: δ 0.94 (d, J =
6.6 Hz, 6H), 1.20 (m, 2H), 1.66 (m, 4H), 2.32 (m, 4H).
13C NMR: δ 24.15 (q), 31.58 (d), 38.28 (t), 52.23 (t), 213.56 (s).
CIMS (M+1) 141, (M+18) 158. Ee determination: GC
Chiraldex B-TA, 30 m × 0.25 mm, He-flow = 1.0 mL/min, Ti =
75 °C for 10 min, Tf = 150 °C, rate 10 °C/min, rt 15.5, 15.6 min.
(–)-4,7-Dimethyl-2-oxocanone (10)
A mixture of 1.14 mL of acetic anhydride and 0.9 mL of
30% H2O2 (aq) in 10 mL of freshly distilled dichloromethane
was stirred under a nitrogen atmosphere at 0 °C for 1 h, after
which 9.2 mmol of maleic anhydride was added. The mixture
was heated to reflux, after which 0.64 mmol of 3,6-
dimethylcycloheptanone (9) was added. After 16 h, 1H NMR
showed 87% conversion. The reaction mixture was extracted
with 10% NaHSO3, 2N NaOH, and brine. The last three steps
were repeated until the brine layer tested negative on perox-
ides. The organic layer was dried with Na2SO4, filtered, and
the solvent evaporated. The resulting crude product was puri-
fied by column chromatography (SiO2, hexane/Et2O = 4/1).
65% isolated yield. [α]D = –4.6° (c = 1.0, CHCl3). 1H NMR: δ
0.90 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H), 1.10 (m,
2H), 1.75 (m, 3H), 1.91 (m, 1H), 2.22 (dd, J = 12.1, 9.9 Hz,
1H), 2.48 (dd, J = 12.1, 4.0 Hz, 1H), 4.01 (dd, J = 12.3, 5.5 Hz,
1H), 4.27 (dd, J = 12.1, 3.7 Hz, 1H). 13C NMR: δ 18.26 (q),
23.23 (q), 31.05 (t), 33.57 (t), 35.50 (d), 36.46 (d), 36.46 (t),
38.67 (t), 175.42 (s). CIMS (M+1) 157, (M+18) 174.
(+)-Methyl 6-hydroxy-3,5-dimethylhexanoate (6a)
Isolated yield 91% (colorless oil). [α]D = +19.4° (c = 1.1,
1
CHCl3). H NMR: δ 0.84 (d, J = 3.7 Hz, 3H), 0.87 (d, J =
3.7 Hz, 3H), 1.03 (m, 1H), 1.20 (m, 1H), 1.65 (m, 2H), 2.01
(m, 1H), 2.11 (dd, J = 14.6, 7.3 Hz, 1H), 2.37 (dd, J = 14.7,
6.6 Hz, 1H), 3.39 (m, 2H), 3.60 (s, 3H).13C NMR: δ 16.13 (q),
19.37 (q), 27.56 (d), 33.13 (d), 40.17 (t), 42.38 (t), 51.40 (q),
68.68 (t), 173.61 (s). CIMS (M+1) 175, (M+18) 192.
Methyl 6-hydroxy-5-isopropyl-3-methylhexanoate (6b′) and
Methyl 6-hydroxy-3-isopropyl-5-methylhexanoate (6b)
Isolated yield 81% (colorless oil). 1H NMR: δ 0.74 (d, J =
6.6 Hz), 0.87 (m), 1.15 (m), 1.34 (m), 1.55–1.91 (m), 2.00 (m),
2.27 (m), 3.31–3.57 (m), 3.59 (s). 13C NMR: δ 16.91 (q), 17.38
(q), 19.06 (q), 19.21 (q), 19.71 (q), 20.46 (q), 27.69 (d), 28.39
(d), 29.18 (d), 33.24 (d), 35.02 (t), 35.25 (t), 35.73 (t), 37.77
(d), 41.53 (t), 43.73 (d), 51.38 (q), 51.46 (q), 63.88 (t), 68.21
(t), 173.78 (s), 174.54 (s). CIMS (M+1) 203, (M+18) 220.
(–)-Methyl 7-hydroxy-3,6-dimethylheptanoate (11)
Methyl 6-hydroxy-3-methyl-5-phenylhexanoate (6c′) and
Methyl 6-hydroxy-5-methyl-3-phenylhexanoate (6c)
Isolated yield 70% (oil). [α]D = –5.8° (c = 1.2, CHCl3).
1H NMR: δ 8.54 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H),
1.09 (m, 1H), 1.22 (m, 3H), 1.34 (m, 1H), 1.52 (s, 1H), 1.89
(m, 1H), 2.09 (dd, J = 14.7, 7.7 Hz, 1H), 2.25 (dd, J = 11.8, 6.4
Hz, 1H), 3.41 (m, 2H), 3.61 (s, 3H).13C NMR: δ 16.43 (q), 19.64
(q), 30.19 (t), 30.51 (d), 33.76 (t), 35.79 (q), 41.62 (t), 51.39 (d),
68.26 (t), 216.07 (s). CIMS (M+1) 189, (M+18) 206.
1
Isolated yield 73% (oil). H NMR: δ 0.85 (m), 1.03–1.51
(m), 1.81 (m), 2.15 (m), 2.54 (dd, J = 7.7, 4.0 Hz), 2.84 (m),
3.17 (m), 3.28 (d, J = 5.9 Hz), 3.52 (s), 3.56 (s), 3.62 (m),
3.67–4.96 (s), 7.02–7.37 (m). 13C NMR: δ 15.76 (q), 19.07 (q),
27.51 (d), 33.21 (d), 38.25 (t), 39.15 (t), 39.42 (d), 42.19 (t),
42.53 (t), 46.06 (d), 51.34 (q), 51.48 (q), 68.18 (t), 68.56 (t),
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(+)-trans-3,5-Dimethyl-4,4-dimethoxycyclohexanone (12a)
(d), 111.99 (t), 142.75 (s), 215.03 (s). CIMS (M+1) 167,
Colorless oil, 65% isolated yield after purification by col- (M+18) 184.
umn chromatography (SiO2, hexane/EtOAc = 10/1). [α]D
=
(–)-trans-2,6-Dimethyl-4-methylcyclohexanone (14a)
+15.4° (c = 1.3, CHCl3). 1H NMR shows >99% trans adduct.
1H NMR: δ 0.98 (d, J = 7.0 Hz, 6H), 2.19 (m, 2H), 2.30 (m,
2H), 2.44 (td, J = 18.7, J = 4.8, J = 1.5 Hz, 2H), 3.30 (s, 6H).
13C NMR: δ 15.94 (q), 35.81 (d), 45.70 (t), 49.89 (q), 101.26
(s), 210.98 (s). CIMS (M+1) 187, (M+18) 204.
A mixture of 2,6-dimethyl-4-methylenecyclohexanone
13a (1.70 mmol), ethyl acetate (40 mL), PtO2 (0.12 mmol),
and activated carbon (13 mmol) was stirred under 1 atm of H2
for 16 h. Conversion was shown to be complete by TLC. The
reaction mixture was filtered over Celite, the filtrate was con-
centrated, and the resulting crude product was purified by
column chromatography (SiO2, hexane/Et2O = 4/1). 53% iso-
lated yield. [α]D = -88.3° (c = 1.2, CHCl3).1H NMR: δ 0.90 (d,
J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.04 (q, J = 12.7 Hz,
1H), 1.30 (d, J = 7.3 Hz, 3H), 1.47 (m, 1H), 1.70 (m,1H), 1.91
(m, 1H), 2.11 (m, 1H), 2.53 (m, 2H). 13C NMR: δ 14.56 (q),
17.83 (q), 21.39 (q), 26.23 (d), 39.81 (d), 41.64 (t), 43.97 (d),
44.08 (t), 217.26 (s). CIMS (M+1) 141, (M+18) 158.
(+)-trans-3,5-Diethyl-4,4-dimethoxycyclohexanone (12b)
Oil, 77% isolated yield after purification by column chro-
1
matography (SiO2, hexane/EtOAc = 10/1). H NMR shows
>98% trans adduct. [α]D = +20.3° (c = 1.2, CHCl3). 1H NMR:
δ 0.84 (t, J = 7.3 Hz, 6H), 1.01 (m, 2H), 1.75 (m,4H), 1.95 (m,
2H), 2.10 (dd, J = 5.0, 1.0 Hz, 2H), 3.26 (s, 6H). 13C NMR: δ
12.69 (q), 22.48 (t), 42.06 (d), 43.89 (t), 49.80 (q), 101.46 (s),
211.34 (s). CIMS (M+1) 215, (M+18) 232.
(–)-trans-2,6-Dimethyl-4-methylenecyclohexanone (13a)
A suspension of triphenylmethylphosphonium iodide
(3.8 mmol) in 20 mL of freshly distilled THF was stirred under
a nitrogen atmosphere at 0 °C. nBuLi (3.8 mmol, 1.6 M in
hexanes) was added dropwise, resulting in a yellow solution.
The 3,5-dialkyl-4,4-dimethoxycyclohexanone 12a (2.55 mmol)
was added and the reaction mixture was stirred for 16 h at
ambient temperature, during which a precipitate was formed.
Conversion was shown to be complete by TLC. 50 mL of 10%
(–)-trans-2,6-Diethyl-4-methylcyclohexanone (14b)
A mixture of 2,6-diethyl-4-methylenecyclohexanone 13b
(1.70 mmol), ethyl acetate (40 mL), PtO2 (0.12 mmol), and
activated charcoal powder (13 mmol) was stirred under 1 atm
of H2 for 16 h.16 Full conversion was determined by TLC. The
reaction mixture was filtered over Celite, the filtrate was con-
centrated, and the resulting crude product was purified by
column chromatography (SiO2, hexane/Et2O = 4/1). 82% iso-
lated yield. [α]D = –84.7° (c = 1.1, CHCl3). 1H NMR: δ 0.90
(m, 9H), 1.04 (q, J = 7.0 Hz, 1H), 1.13 (m, 1H), 1.42 (m, 2H),
1.66 (m, 3H), 1.99 (m, 2H), 2.24 (m, 2H). 13C NMR: δ 11.60
(q), 11.88 (q), 21.49 (q), 22.04 (t), 25.10 (t), 26.85 (d), 40.00
(t), 41.77 (t), 47.19 (d), 52.16 (d), 216.61 (s). CIMS (M+1)
169, (M+18) 186.
1
citric acid (aq) was added. After 5 h, H NMR showed that
deprotection of the ketone was complete and no epimerization
had occurred. The aqueous layer was extracted three times
with diethyl ether (100 mL), the combined organic layers were
washed with brine (50 mL) and dried on Na2SO4, filtered, and
the solvent evaporated. The product was purified by column
chromatography (SiO2, hexane/Et2O = 4/1). Oil, 87% isolated
yield. [α]D = -164.1° (c = 0.41, CHCl3). 1H NMR: δ 1.04 (d,
J = 3.3 Hz, 6H), 2.15 (m, 2H), 2.56 (m, 4H), 4.84 (s, 2H).
13C NMR: δ 15.97 (q), 41.43 (t), 42.71 (d), 111.97 (t), 142.38
(s, 215.85 (s). CIMS (M+1) 156, (M+18) 139.
3,5,7-Trimethyl-2-oxepanone (15a, 16a)
1
Oil, 92% isolated yield. H NMR major diastereomer: δ
1.91 (d, J = 15.6 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H), 1.36 (d, J =
7.81 Hz, 3H), 1.20–1.70 (m, 3H), 1.85 (m, 1H), 2.03 (m, 1H),
3.08 (m, 1H), 4.65 (m, 1H). 13C NMR major diastereomer: δ
14.62 (q), 22.76 (q), 23.06 (q), 28.27 (d), 37.31 (t), 40.68 (d),
44.81 (t), 74.96 (d), 176.78 (s). CIMS (M+1), (M+18). de
determination: GC HP-5, 30 m × 0.25 mm, He-flow = 1.3 mL/
min, Ti = 75 °C for 10 min, Tf = 200 °C, rate 10 °C/min, rt 18.5,
18.7 min.
(–)-trans-2,6-Diethyl-4-methylenecyclohexanone (13b)
A suspension of triphenylmethylphosphonium iodide
(3.8 mmol) in 20 mL of freshly distilled THF was stirred under
a nitrogen atmosphere at 0 °C. 3.8 mmol of nBuLi (1.6 M in
hexanes) was added dropwise, upon which a yellow solution
formed. The 3,5-dialkyl-4,4-dimethoxycyclohexanone 12b
(2.55 mmol) was added and the reaction mixture was stirred
for 16 h at ambient temperature, during which a precipitate
was formed. Complete conversion was determined by TLC.
50 mL of 10% citric acid (aq) was added and after 5 h,
1H NMR showed that deprotection of the ketone was complete
and no epimerization had occurred. The aqueous layer was
extracted three times with diethyl ether (100 mL), the com-
bined organic layers were washed with brine (50 mL) and
dried on Na2SO4, filtered, and the solvent evaporated. The
products were purified by column chromatography (SiO2, hex-
3,7-Diethyl-5-methyl-2-oxepanone (15b, 16b)
1
Oil, 72% isolated yield. H NMR major diastereomer: δ
0.95 (m, 9H), 1.20–1.95 (m, 9H), 2.80 (m, 1H), 4.32 (m, 1H).
13C NMR major diastereomer: δ 9.76 (q), 12.15 (q), 21.98 (q),
23.09 (t), 28.71 (t), 29.83 (d), 35.47 (t), 42.68 (t), 48.71 (d),
79.67 (d), 176.42 (s). CIMS (M+1) 185, (M+18) 202. De
determination: GC HP-5, 30 m × 0.25 mm, He-flow = 1.3 mL/
min, Ti = 75 °C for 10 min, Tf = 200 °C, rate 10 °C/min, rt 18.5,
18.6 min. Ee determination major diasteroisomer: GC CP
Cyclodex CB, 25 m × 0.25 mm, He-flow = 1.0 mL/min, Ti =
50 °C for 5 min, Tf = 160 °C, rate 5 °C/min, rt 26.5, 26.7 min.
ane/Et2O = 4/1). 88% isolated yield. [α]D = –59.1° (c = 0.89,
1
CHCl3). H NMR: δ 0.86 (t, J = 7.4 Hz, 6H), 1.33 (m, 2H), Methyl 6-hydroxy-2,4-dimethylheptanoate (17a)
1.60 (m, 2H), 2.26 (m, 4H), 2.57 (dd, J = 12.9, 5.4 Hz, 2H),
4.86 (s, 2H). 13C NMR: δ 11.45 (q), 23.49 (t), 39.61 (t), 50.20 (d, J = 6.2 Hz, 3H), 0.87-1.34 (m, 2H), 1.06 (d, J =7.0 Hz, 3H),
Oil, 86% isolated yield. 1H NMR major diastereomer: δ 0.83
Jagt et al. / A Catalytic Route to Acyclic Chiral Building Blocks

226
yields with >99% trans selectivity (1H and 13C NMR
spectra showed no cis-product), with retention of ee
(Scheme 5).
1.12 (d, J = 6.2 Hz, 3H), 1.37-1.80 (m, 3H), 1.97 (s, 1H), 2.48
(m, 1H), 3.60 (s, 3H), 3.84 (m, 1H). 13C NMR major diastere-
omer: δ 17.00 (q), 19.14 (q), 24.37 (q), 27.26 (d), 37.07 (d),
41.52 (t), 46.63 (t), 51.54 (q), 65.59 (d), 177.56 (s). CIMS
(M+1) 189, (M+18) 206. De determination: GC HP-5, 30 m ×
0.25 mm, He-flow = 1.3 mL/min, Ti = 50 °C for 10 min, Tf =
250 °C, rate 10 °C/min, rt 14.2, 14.5 min.
Treatment of the symmetrical cyclohexanone 3a
with mCPBA afforded, due to C2 symmetry in 3, the
lactone 4a as a single diastereomer with 99% ee. The
Baeyer–Villiger reaction with nonsymmetrical cyclo-
hexanones 3b and 3c would provide a mixture of two
regioisomers if there was no side-selectivity. Indeed, for
the iPr-substituted cyclohexanone 3b the regio-
selectivity was poor, giving products 4b and 5b as a
mixture of two regioisomers in a ratio of 56:44. For the
phenyl-substituted cyclohexanone 3c, the regio-
selectivity improved to 70:30. Based on NMR analysis,
structure 4c was assigned to the major regioisomer.
The ring-opening of the lactones using MeOH/
NaOMe proceeded smoothly, and linear building block
6a17 (comprizing a 1,3-arrangement of stereocenters)
was obtained in high yield (91%). The linear hydroxy-
Methyl 2-ethyl-6-hydroxy-4-methyloctanoate (17b)
1
Oil, 72% isolated yield. H NMR major diastereomer: δ
0.83 (t, J = 7.32 Hz, 3H), 0.88 (t, J = 7.32 Hz, 3H), 1.05–1.64
(m, 13H), 2.26 (m, 1H), 3.53 (m, 1H), 3.62 (s, 3H). 13C NMR
major diastereomer: δ 9.94 (q), 11.78 (q), 19.65 (q), 25.67 (t),
27.53 (d), 31.15 (t), 40.22 (t), 43.94 (t), 44.94 (d), 51.37 (q),
70.82 (d), 177.01 (s). CIMS (M+1) 217, (M+18) 234. De
determination: GC HP-5, 30 m × 0.25 mm, He-flow = 1.3 mL/
min, Ti = 50 °C for 10 min, Tf = 250 °C, rate 10 °C/min, rt 16.4,
16.6 min.
RESULTS AND DISCUSSION
Optically active cyclohexenones 1a–c are easily acces- esters 6b and 6c were formed as a mixture of the two
sible through the kinetic resolution procedure (see isomers.
Scheme 3a)10 employing chiral ligand L*-1.
No separation of enantiomers could be found on any
Cyclohexenones 1a–c were subjected to a subse- chiral GC or HPLC column for acyclic synthons 6a–6c.
quent catalytic enantioselective conjugate addition. The However, the Baeyer–Villiger/saponification procedure
enantiomer of the ligand (L*-1) was chosen in such a is unlikely to give any epimerization for these com-
way that the chiral catalyst provided the trans-diadduct, pounds, so the ee’s of the products 6a–6c are likely to be
i.e., the second stereogenic center would be of the same equal to the ee’s of starting compounds (i.e., >99%,
handedness as the first, leading to R,R-disubstituted >99%, and 89%, respectively).
cyclohexanones. Products 3a–c were formed in good
The conjugate addition of Me2Zn to cyclohepta-
Scheme 5. Reaction conditions: (a) Me2Zn, 1.4 equiv, toluene, L*-1 (5 mol%), Cu(OTf)2 (2.5 mol%), (b) mCPBA, NaHCO3,
CH2Cl2, (c) NaOMe, MeOH.
Israel Journal of Chemistry
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227
using MeOH/NaOMe proceeded smoothly, and linear
building block 11 (comprising a 1,4-arrangement of
stereocenters) was obtained in good yield (70%).
The chiral cyclohexenone monoacetals 2a and 2b,
obtained through catalytic enantioselective conjugate
addition of dialkylzinc reagents to cyclohexadienones
(see Scheme 3b) provide a way of synthesizing linear
building blocks with three stereocenters in a 2,4,6-array.
The bisadduct 12b of Et2Zn to 4,4-dimethoxycyclo-
hexadienone was previously reported11 to be, selectively,
the trans isomer when, in both conjugate addition-steps
in the sequential conjugate addition, the (S, R, R)-enanti-
omer of ligand L*-1 was used for the preparation of the
catalyst. Since in natural products, linear fragments with
methyl substituents occur more frequently than those
with ethyl substituents, it would be interesting to know
if Me2Zn would behave in a similar way. Indeed, start-
ing from the enantiomerically pure monoadduct 2a, also
trans-bisadduct 12a was formed selectively (based on
Scheme 6. Reaction conditions: (a) Me2Zn, 1.4 equiv, toluene,
L*-1 (5 mol%), Cu(OTf)2 (2.5 mol%), (b) Me2Zn, 1.4 equiv,
toluene, L*-1 (5 mol%), Cu(OTf)2 (2.5 mol%), (c) H2O2, ma-
leic anhydride, acetic anhydride, CH2Cl2, (d) NaOMe, MeOH.
dienone 7,18 catalyzed by L*-1/Cu(OTf)2, affords
3-methyl cycloheptenone 8 in good yield and with
>99% ee. A conjugate addition of Me2CuLi to racemic
methyl cycloheptenone 8 has been reported to give the
product as a 1:1 mixture of the cis:trans disubstituted
product. However, a second conjugate addition of
Me2Zn to 8 using the same L*-1/Cu(OTf)2 catalyst lead
to the selective formation of the trans-disubstituted
cyclo-heptanone 9, with retention of ee (see Scheme 6,
no cis-product was identified by 1H and 13C NMR spec-
troscopy).
Lactonization of cycloheptanone 9 with mCPBA
proved to be difficult (<10% conversion after refluxing
the mixture for 5 d), presumably due to unfavorable
seven- to eight-membered ring enlargement.20 Fortu-
nately, by using the more powerful H2O2/maleic anhy-
dride method reported by Bidd et al.21 we were able to
isolate product 10 in 65% yield. Ring-opening of 10
13
1H and C NMR) through a Cu/L*-1-catalyzed conju-
gate addition of Me2Zn (see Scheme 7).
A Wittig reaction of 12a and 12b with CH3PPh3I
followed by mild hydrolysis of the acetal in the presence
of citric acid (10%) smoothly gave 13a and 13b. Based
on 1H and 13C NMR, it was established that no epimeri-
zation occurs. However, reduction of the methylene
groups in the presence of Pd/C and H2 afforded, not the
desired cyclohexanones 14a and 14b, but isomers of the
starting compound (1H NMR indicates that the exocyclic
alkene isomerized to the endocyclic alkene). We were
pleased to see that reduction of the methylene group in
the presence of PtO2/C16 was successful, giving 14a and
14b in satisfactory yields. No epimerization of the C-2
1
and C-6 centers was observed (based on H and 13C
NMR, as no cis-2,6-dialkyl signals were seen).
Scheme 7. Reaction conditions: (a) R2Zn, 1.4 equiv, toluene, L*-1 (5 mol%), Cu(OTf)2 (2.5 mol%), (b) (1) CH3PPh3I, nBuLi,
THF, (2) 10% citric acid, (c) PtO2/C, H2, EtOAc (d) mCPBA, NaHCO3, CH2Cl2, (e) NaOMe, MeOH.
Jagt et al. / A Catalytic Route to Acyclic Chiral Building Blocks

228
The C-4 methyl substituent in these 2,4,6-trisubsti- 79% (15a) and in 85% (15b), respectively. Unequivocal
tuted cyclohexanones is positioned on the C2-axis, and assignment of major isomers was not possible so far,
therefore compounds 14a and 14b contain only 2 despite the fact that extensive NMR experiments have
stereocenters (at C-2 and C-6), but after a Baeyer– been performed.
Villiger reaction C-4 in lactones 15a,b and 16a,b is also
Ring-opening proceeds smoothly, and the linear
a stereocenter. The Baeyer–Villiger is expected to pro- building blocks, 17a and 17b, with three stereocenters at
ceed with some regioselectivity; the reaction has prefer- positions 2, 4, and 6, are obtained, together with small
ence for oxygen insertion between the carbonyl and the amounts of the C4 epimers.
adjacent carbon atom bearing an axial methyl group.22,23
In our case, tri-substituted cyclohexanone 14a will be
CONCLUSIONS
preferentially in chair-conformation I with two equatorial
By using chiral cyclohexenones, which are easily acces-
and one axial oriented methyl substituent (Scheme 8).
sible through the kinetic resolutions based on the asym-
This conformation will be lower in energy than the alter-
metric Cu/L*-1-catalyzed conjugate additions, it is pos-
native chair conformation II, which contains two axial
sible to obtain, through a subsequent catalytic conjugate
methyl groups. Oxygen insertion during the Baeyer–
addition/ring-opening approach, linear building blocks
Villiger oxidation will be at the side that contains the
axial methyl leading to 15a or 16a, respectively.22 As-
suming that there is not a large energy difference for
these two oxygen insertion pathways, we expect 15a to
be the major regioisomer. For the tri-substituted cyclo-
hexanone 14b, similar reasoning might indicate that 15b
would be formed preferentially (see Scheme 8). Starting
from 14a and 14b, the major regioisomer is formed in
6a–c with two stereocenters (at C3 and C5) in satisfac-
tory yields and with ee’s of >99%, >99%, and 89%,
respectively. Linear building block 11 (with two stereo-
centers at C3 and C6) is easily formed in 4 steps (>99% ee)
from 2,6-cycloheptadien-2-one through a sequential
asymmetric Cu/L*-1-catalyzed conjugate addition of
Me2Zn (yielding the trans di-adduct 9 in 99% ee), fol-
lowed by subsequent lactonization and ring-opening.
Trans-selective sequential Cu/L*-1-catalyzed asym-
metric conjugate additions of dialkylzinc reagents to
4,4-dimethoxycyclohexadienone, followed by a Wittig
reaction, reduction of the formed olefinic bond, lactoni-
zation, and ring-opening, results in linear building blocks
17a and 17b, which contain three stereocenters (at C2,
C4, and C6) in good yield and excellent ee’s (>99%).
In conclusion, we have demonstrated the versatility
of sequential catalytic 1,4-addition, Baeyer–Villiger
oxidation/ring-opening in new catalytic, diastereo-, and
enantioselective routes to acyclic chiral synthons.
Acknowledgment. We thank Mr. M.B. van Gelder for carrying
out HPLC and GC measurements and Dr. R. Hulst for per-
forming the NMR measurements. Financial support from the
Dutch Foundation for Scientific Research (NWO-CW) is
gratefully acknowledged.
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