A convenient catalytic asymmetric conjugate addition reaction to enones using alkylzirconium reagents

Article abstract of DOI:10.1055/s-0033-1339485

Alkylzirconium reagents undergo highly enantioselective copper-catalysed 1,4-addition reaction to cyclic enones. These reactions use alkylmetal species generated in situ from alkenes and the Schwartz reagent, and do not require premade organometallic reag

Full text of DOI:10.1055/s-0033-1339485

Journal of
Synthetic Organic
Chemistry
SYNTHESIS
REPRINT
With compliments of the Author
Thieme

2662▌
PRACTICAL SYNTHETIC PROCEDURES
pAracCticaol snynvtheetniciperoncetduCresatalytic Asymmetric Conjugate Addition Reaction to Enones
Using Alkylzirconium Reagents
Addition of Alkylzirconium Reagents to Enones
Rebecca M. Maksymowicz, Mireia Sidera, Philippe M. C. Roth, Stephen P. Fletcher*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road,
Oxford, OX1 3TA, UK
Fax +44(1865)285002; E-mail: stephen.fletcher@chem.ox.ac.uk
PSP
Received: 24.06.2013; Accepted after revision: 03.07.2013
No256
Abstract: Alkylzirconium reagents undergo highly enantioselective copper-catalysed 1,4-addition reaction to cyclic enones. These reac-
tions use alkylmetal species generated in situ from alkenes and the Schwartz reagent, and do not require premade organometallic reagents.
The reactions have been performed on practical synthetic scales (2.5 mmol) and a scale-up to 10 mmol is demonstrated. The reactions pro-
ceed at room temperature, in a variety of solvents, and tolerate many functional groups.
Key words: alkenes, asymmetric catalysis, copper, Michael addition, Schwartz reagent
R2
catalyst
H
hydro-
R1
X
metallation
R1
R1
X
ACA
M
H–M
R2
TfO
O
O
Ph
Cu
Cp2ZrHCl, CH2Cl2
O
O
+
P
N
complex A (10 mol%)
Et2O, TMSCl
r.t.
Ph
10 mmol scale
63%, 91% ee
1.46 g
complex A
Scheme 1 Hydrometallation–asymmetric conjugate addition of alkenes (HM-ACA)
Conjugate additions are important C–C bond-forming lents.5 This methodology involves a tandem hydrometal-
reactions.1 Asymmetric variations of these reactions are lation-asymmetric conjugate addition (HM-ACA)
highly desirable, and a wide range of methods has been sequence (Scheme 1). The initial stage utilises the
developed.2 Copper-catalysed asymmetric conjugate Schwartz reagent in a hydrometallation reaction of an al-
addition has received tremendous attention over the last kene to generate a nucleophile in situ.6 When combined
20 years3 and a number of procedures now allow use of with a copper-ligand precatalyst these nucleophiles add to
catalytic amounts of chiral nonracemic species to obtain enones in an asymmetric 1,4-addition. The approach has
excellent enantioselectivities. These reactions typically advantages over the use of premade organometallics, such
require use of reactive premade organometallic nucleo- as the ability to perform these reactions at room tempera-
philes, in the form of Grignards, dialkylzincs, trialkyl- ture, which is important for industrial or large-scale chem-
aluminums, or alkyllithiums.2,3 Despite the excellent istry.4 Perhaps most importantly, the reaction offers the
results obtained in these systems, the use of premade or- opportunity to add alkenes containing a range of function-
ganometallic reagents is not ideal. For example, cryogenic al groups, providing a handle to enable further elabora-
temperatures are often required in order to obtain high tion, which is an important element for synthesis.
levels of enantioselectivity and large scales are potentially
problematic.4
Scope and Limitations
We have recently reported a new approach to catalytic
asymmetric conjugate addition where cheap, readily
Previous optimisation of the HM-ACA reaction to form
available alkenes are employed as alkylmetal equiva-
tertiary centres5a (Scheme 2, a) led to conditions involving
a commercially available and easily prepared phosphora-
midite ligand7 A and copper triflate benzene complex.
Due to the sensitive nature of the copper triflate benzene
complex, we found it convenient to pre-complex these
SYNTHESIS 2013, 45, 2662–2668
Advanced online publication: 24.07.2013
DOI: 10.1055/s-0033-1339485; Art ID: SS-2013-Z0433-PSP
© Georg Thieme Verlag Stuttgart · New York
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0
3
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7
8
8
1
1
4
3
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X
Synthesis 2000, No. X, x–xx ISSN 0039-7881 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Addition of Alkylzirconium Reagents to Enones
2663
O
a) Addition to cyclic enones
O
n
Cp2ZrHCl
R1
R2 R2
R1
Cp2ZrHCl
n
R1
complex A (10 mol%)
CH2Cl2
TMSCl, Et2O
R1 = alkyl or
functionalised group
n = 0, 1, 2
R
2 = H, Me, Ph
R2 R2
r.t.
up to 96% ee
b) Synthesis of complex
(CuOTf)2·PhH
Ph
TfO
Ph
O
O
P
N
Cu
Ph
O
P
A
O
CH2Cl2
Ph
complex A
Scheme 2 (a) Optimal conditions for the HM-ACA reaction; (b) synthesis of air-stable complex A
materials to form a relatively stable catalyst complex, In Table 2 the ability to add more functionalised alkenes
which can be stored under argon at ambient temperature is demonstrated, which is a key advantage in our method.
for at least one month, and weighed and handled in air The ability to use functionalised alkenes provides the op-
(Scheme 2, b). When complex A is combined with diethyl portunity to add a handle for extending the complexity of
ether and CH2Cl2 as a co-solvent, along with 5 equivalents the resulting compounds.
of TMSCl, the best results were achieved. We were
Enone coupling partners of varying ring sizes, such as
pleased to discover that the reaction tolerates a diverse
five-, six-, and seven-membered rings were used (Table 2,
range of solvents, both halogenated, nonhalogenated, po-
entries 2, 3, and 4, respectively), all providing high enan-
lar and nonpolar,5a which offers the potential to perform
tioselectivities. The lower yield with the five-membered
the reaction with compounds that may not be soluble (or
ring (entry 2) is characteristic of these reactions, and the
be compatible) with the limited solvent range typical for
low yield is believed to result from the zirconium enolate
comparable procedures with premade organometallics.
undergoing further 1,4-addition and polymerisation type
Here, we show these procedures are applicable to scale-up reactions.3d,8,9
with a variety of cycloalkenones and alkene substrates on
We previously reported the HM-ACA to form a naturally
a 2.5 mmol scale. Additionally, along with substrates that
occurring liverwort5b and here this procedure is scaled up
have been previously reported by us on a 0.4 mmol
with complex A to obtain 330 mg of (+)-(R)-2a the unnat-
scale,5a,b the procedure can be extended to the use of gas-
ural enantiomer of the natural product (Table 2, entry 1),
eous alkenes (Table 1). It is possible to reduce the amount
with outstanding (95% ee) enantioselectivity and good
of alkene and zirconium used in these reactions from our
yield. Alkenes containing halogens (entry 5), internal al-
previously reported conditions (2.5 equiv alkene, 2 equiv
kynes (entry 6), and protected alcohols (entry 7) were
Cp2ZrHCl)5 to 1.7 equivalents of alkene and 1.5 equiva-
used, which all provide pleasing enantioselectivities and
lents of Cp2ZrHCl while maintaining good yields and en-
good yields. These reactions were performed comfortably
on 5 mmol and 10 mmol scales (Scheme 3) without ad-
antioselectivities.
Table 1 illustrates the ability to take simple alkenes and versely affecting the yield or enantioselectivity.
add them in the HM-ACA with uniformly high enantiose-
lectivities. In the case of these alkenes, which are gases,
the reactions are performed under a balloon atmosphere of
the relevant gas. Linear (Table 1, entries 1, 2, 3, and 5) and
branched alkenes (entry 4) can be added. We are pleased
to report that these reactions all go to completion within
3–18 hours, are performed at room temperature, and no
special addition procedures (such as dropwise addition of
the substrate) are required.
O
O
Cp2ZrHCl, CH2Cl2
+
Ph
complex A (10 mol%)
Et2O, TMSCl
r.t.
Ph
3a
0.4 mmol:5a 0.05 g (59%), 90% ee
5.0 mmol: 0.74 g (64%), 90% ee
10.0 mmol: 1.46 g (63%), 91% ee
Scheme 3 Effect of scale-up on yield and enantioselectivity
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2662–2668

2664
R. M. Maksymowicz et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 HM-ACA with Gaseous Alkenesa
Petroleum ether (PE) refers to light petroleum boiling in the range
40–60 °C. Analytical TLC was performed on precoated glass-
backed plates (Silica Gel 60 F254; Merck), and visualised using a
combination of UV light (254 nm) and aq ceric ammonium molyb-
date (CAM), aq basic KMnO4 stains or vanillin solution. Flash col-
umn chromatography was carried out using Apollo Scientific silica
gel 60 (0.040–0.063 nm), Merck 60 A silica gel, VWR (40–63 μm)
silica gel, and Sigma Aldrich silica gel. Unless stated otherwise, so-
lution NMR spectra were recorded at r.t. 1H and 13C nuclear mag-
netic resonance experiments were carried out using Bruker DPX-
200 (200/50 MHz), DPX-400 (400/100 MHz), DQX-400 (400/100
MHz), or AVC-500 (500/125 MHz) spectrometers. Chemical shifts
are reported in ppm from the residual solvent peak. Low-resolution
mass spectra were recorded using a Walters LCT premier XE. High-
resolution mass spectra (EI and ESI) were recorded using a Bruker
MicroTOF spectrometer by the internal service at the University of
Oxford. IR measurements (neat, thin film) were carried out using a
Bruker Tensor 27 FT-IR with internal calibration in the range 4000–
600 cm–1. Optical rotations were recorded using a PerkinElmer 241
polarimeter. For detailed information on materials and methods, see
the Supporting Information (SI).
O
O
Cp2ZrHCl, CH2Cl2
+
R1
complex A (10 mol%)
R1
Et2O, TMSCl
r.t.
R2 R2
R2 R2
2.5 mmol scale
Entry
Substrate Product
Yield
ee
Isolated
(%)b
(%)c mass
O
1
67
88d 0.26 g
1a
O
2
3
4
66
71
87
86d 0.30 g
87d 0.28 g
87d 0.43 g
Catalytic Asymmetric Conjugate Addition of Gaseous Alkenes
Using Complex A; General Procedure 1
Two round-bottomed flasks (one 25 mL and the other 10 mL) were
flame dried under vacuum and allowed to cool before being purged
with argon. In the 10 mL flask, Cp2ZrHCl (970 mg, 3.75 mmol, 1.5
equiv) was stirred in CH2Cl2 (2.5 mL) at r.t. while a balloon of the
relevant gaseous alkene was bubbled through the solution for 1 min
before being left under the relevant gaseous alkene atmosphere. Af-
ter stirring for about 15 min, a clear yellow homogeneous solution
was formed. During this time, complex A (188.0 mg, 0.25 mmol,
0.10 equiv) was weighed in air and placed into the purged 25 mL
flask followed by the addition of Et2O (12.5 mL) to afford a clear
colourless solution (sometimes a white precipitate was observed).
After stirring the complex for 5 min, the hydrozirconated yellow so-
lution was added dropwise. The resulting dark mixture was allowed
to stir for an additional 10 min before the cyclic enone (2.5 mmol,
1.0 equiv) and TMSCl (1.6 mL, 12.5 mmol, 5.0 equiv) were added
dropwise via syringe. The reaction mixture was stirred until com-
plete consumption of the starting material (TLC monitoring; EtO-
Ac–PE, 1:9). The reaction was quenched by the addition of Et2O
(ca. 13 mL) and then NH4Cl (1 M aq, ca. 5 mL). The mixture was
partitioned between the organic and aqueous phases, and the aque-
ous phase was extracted with Et2O (3 × 20 mL). The combined or-
ganic phases were washed with sat. aq NaHCO3 (ca. 20 mL), dried
(MgSO4), filtered, and concentrated in vacuo to give an oil. Flash
column chromatography of the residue (SiO2, EtOAc–PE) gave the
desired cyclic ketone.
1b
O
1c
O
1d
O
5
74
95e 0.51 g
Ph Ph
1e
a Conditions: alkene (balloon atmosphere), Cp2ZrHCl (1.5 equiv),
enone (1 equiv), complex A (0.1 equiv), TMSCl (5 equiv).
b Isolated yield.
Catalytic Asymmetric Conjugate Addition of Alkenes Using
Complex A; General Procedure 2
c Absolute configurations known, determined, or assigned by analogy.
d Determined by derivatisation and 13C NMR spectroscopy.
e Determined by HPLC.
Two round-bottomed flasks (one 25 mL and the other 10 mL) were
flame dried under vacuum and allowed to cool before being purged
with argon. In the 10 mL flask, Cp2ZrHCl (970 mg, 3.75 mmol, 1.5
equiv) was added to a stirred solution of alkene (4.25 mmol, 1.7
equiv) in CH2Cl2 (1.9 mL) at r.t. under an argon atmosphere. After
stirring for about 40 min, a clear yellow homogeneous solution was
formed. During this time, complex A (188.0 mg, 0.25 mmol, 0.10
equiv) was weighed in air and placed into the purged 25 mL flask
followed by the addition of Et2O (12.5 mL) to afford a clear colour-
less solution (sometimes a white precipitate was observed). After
stirring the complex for 5 min, the hydrozirconated yellow solution
was added dropwise. The resulting dark mixture was allowed to stir
for an additional 10 min before the cyclic enone (2.5 mmol, 1.0
equiv) and TMSCl (1.6 mL, 12.5 mmol, 5.0 equiv) were added
dropwise via syringe. The reaction mixture was stirred until com-
plete consumption of starting material (TLC monitoring; EtOAc–
PE, 1:9). The reaction was quenched by the addition of Et2O (ca. 13
mL) and then 1 M aq NH4Cl (ca. 5 mL). The mixture was parti-
Summary
In summary, we have reported a procedure for the catalyt-
ic asymmetric conjugate addition of alkyl groups to
enones that does not require use of premade organometal-
lic reagents. Our method involves the formation of nu-
cleophiles in situ from alkenes and is compatible with a
wide range of functional groups. These reactions proceed
at room temperature or 0 °C in a range of solvents and ap-
pear easy to scale up while maintaining good yields and
high enantioselectivities.
Synthesis 2013, 45, 2662–2668
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Addition of Alkylzirconium Reagents to Enones
2665
Table 2 HM-ACA with Functionalised Alkenesa
O
O
Cp2ZrHCl, CH2Cl2
+
R1
complex A (10 mol%)
Et2O, TMSCl
r.t.
n
n
R1
R2 R2
R2 R2
2.5 mmol scale
Entry
Substrate
Product
Yield (%)b
ee (%)c
Isolated mass
O
1d
57
95e
0.33 g
MeO
OMe
2a
O
2d
32
65
90e
0.17 g
0.40 g
Ph
2b
O
3
92e
Ph
2c
O
4
67
52
47
87e
90f
80e
0.43 g
0.32 g
0.32 g
Ph
2d
O
5
Cl
Cl
2e
O
6g
2f
O
OTBS
OTBS
7
82h
90e
0.87 g
Cl
Cl
2g
a Conditions: alkene (1.7 equiv), Cp2ZrHCl (1.5 equiv), enone (1 equiv), complex A (0.1 equiv), TMSCl (5 equiv).
b Isolated yield.
c Absolute configurations known, determined, or assigned by analogy (see Supporting Information).
d Reaction performed at 0 °C.
e Determined by HPLC.
f Determined by derivatisation and 13C NMR spectroscopy.
g Reaction heated at hydrometallation stage.
h Isolated as a 1:1 mixture of diastereomers.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2662–2668

2666
R. M. Maksymowicz et al.
PRACTICAL SYNTHETIC PROCEDURES
tioned between the organic and aqueous phases, and the aqueous
phase extracted with Et2O (3 × 20 mL). The combined organic
phases were washed with sat. aq NaHCO3 (ca. 20 mL), dried
(MgSO4), filtered, and concentrated in vacuo to give an oil. Flash
column chromatography of the residue (SiO2, EtOAc–PE) gave the
desired cyclic ketone.
(+)-(S)-3-Isopentyl-4,4-dimethylcyclohexanone (1d)
Prepared according to general procedure 1, using a balloon of 3-
methylbut-1-ene and 4,4-dimethylcyclohexenone (0.33 mL, 2.5
mmol, 1 equiv) with purification by flash chromatography (1:9
Et2O–hexane) as a colourless oil (425 mg, 2.16 mmol, 87%) giving
87% ee, determined by integration of the diastereomeric mixture of
the corresponding (+)-(R,R)-DPEN derivative by 13C NMR spectro-
scopic analysis (see SI); [α]20589 +22.58 (c 0.84, CHCl3).
(+)-(R)-3-Butylcyclohexanone (1a)
Prepared according to general procedure 1, using a balloon of but-
1-ene and 2-cyclohexenone (0.24 mL, 2.5 mmol, 1 equiv) with pu-
rification by flash chromatography (1:9 Et2O–hexane) as a colour-
less oil (258 mg, 1.67 mmol, 67%) giving 88% ee, determined by
integration of the diastereomeric mixture of the corresponding
(+)-(R,R)-DPEN derivative by 13C NMR spectroscopic analysis
(see SI); [α]20589 +12.10 (c 1.06, CHCl3).
IR (ATR): 1468, 1716, 2869, 2956 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.46–2.37 (m, 2 H), 2.30–2.24 (m,
1 H), 2.04 (dd, J = 14.7, 12.2, 1 H), 1.74–1.69 (m, 1 H), 1.63–1.41
(m, 4 H), 1.25–1.14 (m, 1 H), 1.09–0.96 (m, 2 H), 1.03 (s, 3 H), 1.00
(s, 3 H), 0.88 (d, J = 6.6 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.4, 47.1, 43.0, 40.5, 38.3, 36.8,
32.9, 28.7, 28.3, 28.0, 23.0, 22.1, 19.5.
Characterisation data (1H, 13C, IR, MS) were consistent with those
reported in the literature.10
HRMS (ESI): m/z calcd for C13H24O + Na [M + Na]+: 219.1719;
found: 219.1726.
IR (ATR): 1449, 1713, 2859, 2927 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.45–2.40 (m, 1 H), 2.39–2.32 (m,
1 H), 2.30–2.22 (m, 1 H), 2.08–1.97 (m, 2 H), 1.93–1.87 (m, 1 H),
1.81–1.72 (m, 1 H), 1.70–1.59 (m, 1 H), 1.37–1.28 (m, 7 H), 0.91–
0.88 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.2, 48.2, 41.5, 39.1, 36.3, 31.3,
28.8, 25.3, 22.7, 14.0.
(+)-(S)-3-Ethyl-4,4-diphenylcyclohexanone (1e)
Prepared according to general procedure 1, using a balloon of eth-
ylene and 4,4-diphenylcyclohexenone (620 mg, 2.5 mmol, 1 equiv)
with purification by flash chromatography (1:9 Et2O–hexane) as a
colourless oil (514 mg, 1.85 mmol, 74%) giving 95% ee as deter-
mined by HPLC analysis; [α]20589 +211.5 (c 0.70, CHCl3).
HPLC: Chiralpak® IC; flow: 1.0 mL/min; hexane–i-PrOH (98:2),
λ = 210 nm; major enantiomer (+)-(S)-3-ethyl-4,4-diphenylcyclo-
hexanone, tR = 7.98 min; minor enantiomer (–)-(R)-3-ethyl-4,4-di-
phenylcyclohexanone, tR = 8.91 min].
MS (ESI): m/z (%) = 155.2 ([M + H]+, 100).
(+)-(S)-3-Butyl-4,4-dimethylcyclohexanone (1b)
Prepared according to general procedure 1, using a balloon of but-
1-ene and 4,4-dimethylcyclohexenone (0.33 mL, 2.5 mmol, 1
equiv) with purification by flash chromatography (1:9 Et2O–
hexane) as a colourless oil (300 mg, 1.65 mmol, 66%) giving 86%
ee, determined by integration of the diastereomeric mixture of the
corresponding (+)-(R,R)-DPEN derivative by 13C NMR spectro-
scopic analysis (see SI); [α]20589 +23.82.10 (c 1.02, CHCl3).
IR (ATR): 1496, 1598, 1713, 3052 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.52 (m, 2 H), 7.36 (t, J = 7.8 Hz,
2 H), 7.29–7.19 (m, 5 H), 7.14–7.10 (m, 1 H), 3.01–2.93 (m, 2 H),
2.84–2.79 (m, 1 H), 2.62 (td, J = 13.6, 4.7 Hz, 1 H), 2.52 (dt,
J = 14.7, 2.7 Hz, 1 H), 2.43–2.27 (m, 2 H), 1.24–1.05 (m, 2 H), 0.88
(t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 211.5, 146.7, 145.0, 128.9 (2 C),
128.41 (2 C), 126.7 (2 C), 126.4 (2 C), 126.2, 125.7, 48.8, 45.2,
41.5, 38.3, 30.1, 22.6, 12.6.
Characterisation data (1H, 13C) were consistent with those reported
in the literature.10
IR (ATR): 1468, 1715, 2860, 2957 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.45–2.37 (m, 2 H), 2.30–2.24 (m,
1 H), 2.05 (dd, J = 14.7, 11.0 Hz, 1 H), 1.74–1.69 (m, 1 H), 1.63–
1.45 (m, 3 H), 1.39–1.20 (m, 3 H), 1.16–1.05 (m, 2 H), 1.03 (s, 3 H),
0.99 (s, 3 H), 0.89 (t, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.5, 48.8, 42.9, 40.5, 38.3, 32.8,
30.2, 29.7, 28.7, 22.8, 19.5, 14.0.
HRMS (ESI): m/z calcd for C20H22O + Na [M + Na]+: 301.1563;
found: 301.1573.
(+)-(R)-3-(4-Methoxyphenethyl)cyclohexanone (2a)
Prepared according to general procedure 2, using 4-methoxystyrene
(0.57 mL, 4.25 mmol, 1 equiv) and 2-cyclohexenone (0.24 mL, 2.5
mmol, 1 equiv) and cooled down to 0 °C after addition of the hydro-
zirconated alkene to the solution of complex A. Purification by flash
chromatography (8:92 → 1:9 EtOAc–PE; Note: the column had to
be run quickly as the compound is sensitive to silica gel) afforded a
colourless oil (329 mg, 1.42 mmol, 57%) giving 95% ee as deter-
mined by HPLC analysis; [α]20589 +8.84 (c 1.12, CHCl3).
MS (ESI): m/z (%) = 205.2 ([M + Na]+, 100).
(+)-(S)-3-Ethyl-4,4-dimethylcyclohexanone (1c)
Prepared according to general procedure 1, using a balloon of eth-
ylene and 4,4-dimethylcyclohexenone (0.33 mL, 2.5 mmol, 1
equiv) with purification by flash chromatography (1:9 Et2O–
hexane) as a colourless oil (275 mg, 1.78 mmol, 71%) giving 87%
ee, determined by integration of the diastereomeric mixture of the
corresponding (+)-(R,R)-DPEN derivative by 13C NMR spectro-
scopic analysis (see SI); [α]20589 +16.85 (c 0.92, CHCl3).
HPLC: Chiralpak® IB; flow: 1 mL/min; hexane–i-PrOH (98:2);
λ = 210 nm; major enantiomer (+)-(R)-3-(4-methoxyphenethyl)cy-
clohexanone, tR = 11.2 min; minor enantiomer (–)-(S)-3-(4-meth-
oxyphenethyl)cyclohexanone, tR = 12.4 min.
Characterisation data (1H, 13C) were consistent with those reported
Characterisation data (1H, 13C, IR, MS) were consistent with those
for the corresponding racemic compound.10
reported in the literature.5b
IR (ATR): 1468, 1715, 2869, 2961 cm–1.
IR (ATR): 1036, 1245, 1512, 1710, 2933 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.48–2.37 (m, 2 H), 2.30–2.23 (m,
1 H), 2.02 (dd, J = 16.4, 12.5 Hz, 1 H), 1.73–1.55 (m, 3 H), 1.43–
1.36 (m, 1 H), 1.06–0.95 (m, 1 H), 1.03 (s, 3 H), 0.99 (s, 3 H), 0.87
(t, J = 8.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.4, 48.8, 42.3, 40.5, 38.3, 32.9,
28.7, 23.3, 19.5, 12.2.
1H NMR (400 MHz, CDCl3): δ = 1.32–1.45 (m, 1 H), 1.55–1.73 (m,
3 H), 1.75–1.87 (m, 1 H), 1.91–2.00 (m, 1 H), 2.01–2.11 (m, 2 H),
2.28 (dddd, J = 14.2, 12.0, 6.0, 1.0 Hz, 1 H), 2.33–2.41 (m, 1 H),
2.49 (ddt, J = 13.8, 4.0, 1.9, 1.9 Hz, 1 H), 2.58 (t, J = 8.0 Hz, 2 H),
3.79 (s, 3 H), 6.83 (d, J = 8.7 Hz, 2 H), 7.09 (d, J = 8.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 25.1, 31.2, 32.0, 38.4, 38.6, 41.5,
48.0, 55.2, 113.8 (2 C), 129.1 (2 C), 134.0, 157.7, 211.8.
MS (ESI): m/z (%) = 177.1 ([M + Na]+, 100).
Synthesis 2013, 45, 2662–2668
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Addition of Alkylzirconium Reagents to Enones
2667
HRMS (ESI): m/z calcd for C15H20O2 + Na [M + Na]+: 255.1356;
found: 255.1349.
Characterisation data (1H, 13C, IR, MS) were consistent with those
reported in the literature.5a
IR (ATR): 698, 1711, 2858, 2932 cm–1.
(+)-(R)-3-(4-Phenylbutyl)cyclopentanone (2b)
1H NMR (400 MHz, CDCl3): δ = 1.00 (s, 3 H), 1.03 (s, 3 H), 1.04–
1.11 (m, 1 H), 1.12–1.25 (m, 1 H), 1.36–1.52 (m, 2 H), 1.52–1.66
(m, 4 H), 1.68–1.77 (m, 1 H), 1.97–2.11 (m, 1 H), 2.21–2.33 (m, 1
H), 2.35–2.48 (m, 2 H), 2.56–2.65 (m, 2 H), 7.14–7.22 (m, 3 H),
7.24–7.34 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 19.5, 27.1, 28.7, 30.4, 31.5, 32.8,
35.9, 38.3, 40.5, 42.88, 46.7, 125.7, 128.3 (s, 2 C), 128.4 (s, 2 C),
142.5, 212.3.
Prepared according to general procedure 2, using 4-phenylbut-1-
ene (0.64 mL, 4.25 mmol, 1 equiv) and 2-cyclopentenone (0.20 mL,
2.5 mmol, 1 equiv) and cooled down to 0 °C after addition of the hy-
drozirconated alkene to the solution of complex A. Purification by
flash chromatography (1:19 EtOAc–PE) afforded a yellow oil (170
mg, 0.79 mmol, 32%) giving 90% ee as determined by HPLC anal-
ysis; [α]20589 +76.73 (c 1.07, CHCl3).
HPLC: Chiralpak® IC; flow: 1.5 mL/min; hexane–i-PrOH (99:1);
λ = 210 nm; major enantiomer (+)-(R)-3-(4-phenylbutyl)cyclopen-
tanone, tR = 23.15 min; minor enantiomer (–)-(S)-3-(4-phenylbu-
tyl)cyclopentanone, tR = 25.15 min.
HRMS (EI): m/z calcd for C18H26O [M]+: 258.1984; found:
258.1984.
Characterisation data (1H, 13C, IR, MS) were consistent with those
(+)-(S)-3-(6-Chlorohexyl)-4,4-dimethylcyclohexanone (2e)
Prepared according to general procedure 2, using 6-chlorohex-1-
ene (0.56 mL, 4.25 mmol, 1 equiv) and 4,4-dimethylcyclohexenone
(0.33 mL, 2.5 mmol, 1 equiv) with purification by flash chromatog-
raphy (35:65 → 1:1 CH2Cl2–PE) afforded a colourless oil (316 mg,
1.29 mmol, 52%) giving 90% ee, determined by integration of the
diastereomeric mixture of the corresponding (+)-(R,R)-DPEN de-
rivative by 13C NMR spectroscopic analysis (see SI); [α]20589 +14.63
(c 1.08, CHCl3).
reported in the literature.5a
IR (ATR): 699, 1158, 1740, 2927 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.31–1.56 (m, 5 H), 1.65 (dt,
J = 15.15, 7.53 Hz, 2 H), 1.79 (app dd, J = 18.01, 9.64 Hz, 1 H),
2.07–2.22 (m, 3 H), 2.23–2.44 (m, 2 H), 2.63 (t, J = 7.30 Hz, 2 H),
7.15–7.22 (m, 3 H), 7.27–7.33 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 27.5, 29.5, 31.5, 35.5, 35.8, 37.1,
38.5, 45.3, 125.7, 128.3 (2 C), 128.4 (2 C), 142.5, 219.9.
IR (ATR): 1213, 1229, 1366, 1739, 2970 cm–1.
HRMS (ESI): m/z calcd for C15H20O + Na [M + Na]+: 239.1406;
found: 239.1404.
1H NMR (400 MHz, CDCl3): δ = 0.98 (s, 3 H), 1.01 (s, 3 H), 1.07–
1.18 (m, 1 H), 1.18–1.45 (m, 6 H), 1.45–1.55 (m, 2 H), 1.59 (dd,
J = 13.2, 4.9 Hz, 1 H), 1.65–1.71 (m, 1 H), 1.72–1.80 (m, 2 H), 2.03
(dd, J = 14.5, 12.3 Hz, 1 H), 2.20–2.29 (m, 1 H), 2.32–2.46 (m, 2
H), 3.51 (t, J = 6.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 19.5, 26.8, 27.3, 28.7, 29.0, 30.4,
32.5, 32.9, 38.3, 40.5, 42.9, 45.1, 46.8, 212.2.
(+)-(R)-3-(4-Phenylbutyl)cycloheptanone (2c)
Prepared according to general procedure 2, using 4-phenylbut-1-
ene (0.64 mL, 4.25 mmol, 1.7 equiv) and 2-cycloheptenone (0.28
mL, 2.5 mmol, 1 equiv) with purification by flash chromatography
(1:19 EtOAc–PE) as a light yellow oil (397 mg, 1.62 mmol, 65%)
giving 92% ee as determined by HPLC analysis; [α]20589 +29.28 (c
1.18, CHCl3).
HRMS (ESI): m/z calcd for C14H25ClO + Na [M + Na]+: 267.1486;
found: 267.1503.
HPLC: Chiralpak® IB; flow: 1.5 mL/min; hexane–i-PrOH
(99.4:0.6); λ = 210 nm; major enantiomer (+)-(R)-3-(4-phenylbu-
tyl)cycloheptanone, tR = 10.95 min; minor enantiomer (–)-(S)-3-(4-
phenylbutyl)cycloheptanone, tR = 12.29 min.
(+)-(S)-3-(5-Phenylpent-4-yn-1-yl)-4,4-dimethylcyclohexanone
(2f)
Prepared according to general procedure 2, using pent-4-en-1-yn-1-
ylbenzene (0.65 mL, 4.25 mmol, 1 equiv) and 4,4-dimethylcyclo-
hexenone (0.33 mL, 2.5 mmol, 1 equiv) with purification by flash
chromatography (3:97 → 5:95 EtOAc–PE) as a colourless oil (315
mg, 1.17 mmol, 47%) giving 80% ee as determined by HPLC anal-
ysis; [α]20589 +20.91 (c 1.10, CHCl3).
Characterisation data (1H, 13C, IR, MS) were consistent with those
reported in the literature.5a
IR (ATR): 699, 1453, 1699, 2855, 2927 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.19–1.51 (m, 6 H), 1.52–1.74 (m,
4 H), 1.80–1.98 (m, 3 H), 2.34–2.43 (app dd, J = 10.43, 14.22 Hz 1
H), 2.43–2.52 (m, 3 H), 2.62 (t, J = 7.60 Hz, 2 H), 7.14–7.22 (m, 3
H), 7.25–7.33 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 24.4, 26.6, 28.5, 31.5, 35.9, 36.0,
36.9, 37.1, 43.91, 49.93, 125.7, 128.3(2 C), 128.4 (2 C), 142.6,
214.6.
HPLC: Chiralpak® AY-H; flow: 1.2 mL/min; hexane–i-PrOH
(96:4); λ = 254 nm; major enantiomer (+)-(S)-3-(5-phenylpent-4-
yn-1-yl)-4,4-dimethylcyclohexanone, tR = 11.13 min; minor enan-
tiomer (–)-(R)-3-(5-phenylpent-4-yn-1-yl)-4,4-dimethylcyclohexa-
none, tR = 16.50 min.
Characterisation data (1H, 13C, IR, MS) were consistent with those
reported in the literature.5a
HRMS (ESI): m/z calcd for C17H24O + Na [M + Na]+: 267.1719;
found: 267.1717.
IR (ATR): 692, 757, 1367, 1490, 1713, 2955 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.03 (s, 3 H), 1.07 (s, 3 H), 1.13–
1.28 (m, 1 H), 1.46 (ddq, J = 12.91, 9.91, 6.48, 6.48, 6.48 Hz, 1 H),
1.51–1.59 (m, 1 H), 1.63 (dd, J = 13.24, 4.73 Hz, 1 H), 1.66–1.76
(m, 2 H), 1.76–1.83 (m, 1 H), 2.10 (ddd, J = 14.82, 12.14, 0.79 Hz,
1 H), 2.25–2.33 (m, 1 H), 2.37–2.44 (m, 3 H), 2.44–2.48 (m, 1 H),
7.27–7.31 (m, 3 H), 7.36–7.42 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 19.4, 19.5, 26.6, 28.7, 29.8, 32.9,
38.3, 40.4, 42.9, 46.4, 81.0, 89.7, 123.9, 127.5, 128.2 (2 C), 131.5
(2 C), 212.0.
(+)-(S)-3-(4-Phenylbutyl)-4,4-dimethylcyclohexanone (2d)
Prepared according to general procedure 2, using 4-phenylbut-1-
ene (0.64 mL, 4.25 mmol, 1 equiv) and 4,4-dimethylcyclohexenone
(0.33 mL, 2.5 mmol, 1 equiv) with purification by flash chromatog-
raphy (1:19 EtOAc–PE) as a white solid (431 mg, 1.67 mmol, 67%)
giving 87% ee as determined by HPLC analysis; mp 27–29 °C;
[α]20589 +17.09 (c 1.17, CHCl3).
HPLC: Chiralpak® IB; flow: 1.0 mL/min; hexane–i-PrOH
(99.4:0.6); λ = 210 nm; major enantiomer (+)-(S)-3-(4-phenylbu-
tyl)-4,4-dimethylcyclohexanone, tR = 10.995 min; minor enantio-
mer (–)-(R)-3-(4-phenylbutyl)-4,4-dimethylcyclohexanone, tR =
11.95 min.
HRMS (ESI): m/z calcd for C19H24O + Na [M + Na]+: 291.1719;
found: 291.1721.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2662–2668

2668
R. M. Maksymowicz et al.
PRACTICAL SYNTHETIC PROCEDURES
(+)-(3S)-3-{4-[(tert-Butyldimethylsilyl)oxy]-4-(4-chlorophe-
nyl)butyl}-4,4-dimethylcyclohexanone (2g)
13C NMR (100 MHz, CDCl3): δ = 25.3, 26.3, 31.3, 31.4, 35.8, 36.4,
39.0, 41.5, 48.2, 125.6, 128.1 (2 C), 128.3 (2 C), 142.5, 212.0.
Prepared according to general procedure 2, using tert-butyl[(1-(4-
chlorophenyl)but-3-en-1-yl)oxy]dimethylsilane (1.26 g, 4.25
mmol, 1.7 equiv) and 4,4-dimethylcyclohexenone (0.33 mL, 2.5
mmol, 1 equiv) with purification by flash chromatography (3:97
EtOAc–PE) as a colourless oil (867 mg, 2.05 mmol, 82%) giving
90% ee, determined by integration of the diastereomeric mixture of
the corresponding (+)-(R,R)-DPEN derivative by 13C NMR spectro-
scopic analysis (see SI); [α]20589 +7.31 (c 1.04, CHCl3).
HRMS (EI): m/z calcd for C16H22O [M]+: 230.1671; found:
230.1675.
Acknowledgment
We gratefully acknowledge financial support from the EPSRC
(EP/H003711/1, a Career Acceleration Fellowship to S.P.F.) and
the Oxford University Press John Fell Fund. B. Odell (NMR) is
thanked for generous technical assistance.
Characterisation data (1H, 13C, IR, MS) were consistent with those
reported in the literature.5a
IR (ATR): 859, 1089, 1715, 2954 cm–1.
1H NMR (400 MHz, CDCl3): δ = –0.15 (s, 3 H), 0.02 (s, 3 H), 0.88
(s, 9 H), 0.97 (s, 3 H), 1.00 (d, J = 2.78 Hz, 3 H), 1.08–1.24 (m, 1
H), 1.25–1.40 (m, 1 H), 1.40–1.55 (m, 3 H), 1.56–1.63 (m, 2 H),
1.63–1.74 (m, 2 H), 2.01 (br t, J = 13.40, 13.40 Hz, 1 H), 2.21–2.30
(m, 1 H), 2.33–2.46 (m, 2 H), 4.59 (q, J = 6.15 Hz, 1 H), 7.18–7.24
(m, 2 H), 7.25–7.30 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = –5.0, –4.7, 18.1, 19.4, 23.3, 25.8
(3 C), 28.7, 30.5, 32.8, 38.2, 40.4, 41.0, 42.8, 46.7, 74.2, 127.1 (2
C), 128.2 (2 C), 132.4, 144.2, 212.2.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
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HPLC: Chiralpak® IC; flow: 1.5 mL/min; hexane–i-PrOH (99:1);
λ = 210 nm; major enantiomer (+)-(R)-3-(4-phenylbutyl)cyclohex-
anone, tR = 19.9 min; minor enantiomer (–)-(S)-3-(4-phenylbu-
tyl)cyclohexanone, tR = 21.8 min.
Characterisation data (1H, 13C, IR, MS) were consistent with those
reported in the literature.5a
IR (ATR): 700, 749, 1453, 1711, 2856, 2929 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.26–1.45 (m, 5 H), 1.55–1.70 (m,
3 H), 1.71–1.83 (m, 1 H), 1.84–1.94 (m, 1 H), 1.95–2.09 (m, 2 H),
2.21–2.31 (m, 1 H), 2.32–2.39 (m, 1 H), 2.39–2.47 (m, 1 H), 2.61 (t,
J = 7.60 Hz, 2 H), 7.13–7.23 (m, 3 H), 7.25–7.33 (m, 2 H).
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Synthesis 2013, 45, 2662–2668
© Georg Thieme Verlag Stuttgart · New York