A multigram, catalytic and enantioselective synthesis of optically active 4-methyl-2-cyclohexen-1-one: A useful chiral building block

Article abstract of DOI:10.1055/s-2001-11445

The first catalytic asymmetric synthesis of both (R)-(+)- and (S)-(-)-4-methyl-2-cyclohexen-1-one and a new and improved synthesis of both enantiomers of (1S,4S)-(-) and (1R,4R)-(+)-4-methyl-2-cyclohexen-1-o1 was developed on a multigram scale. The key step of this approach is the asymmetric catalyzed addition of Me₂Zn (S_N2′-pathway) to racemic 1,3-cyclohexadiene monoepoxide. This step has been optimized as for as enantio- and regioselectivities, and work-up procedures. The striking ligand accelerated catalysis exhibited by the chiral copper complex of the 2,2′-binaphthyl-based phosphoramidite, herein reported, permitted a very low catalyst loading (0.6 mol%).

Full text of DOI:10.1055/s-2001-11445

PAPER
483
A Multigram, Catalytic and Enantioselective Synthesis of Optically Active
4-Methyl-2-cyclohexen-1-one: a Useful Chiral Building Block
Fabio Bertozzi,a Paolo Crotti,a Ben L. Feringa,*b Franco Macchia,a Mauro Pineschi*a
aDipartimento di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
Fax +3905043321; E-mail: pineschi@farm.unipi.it
bDepartment of Organic and Molecular Inorganic Chemistry, University of Groningen, Nijenborgh 4, NL 9747, AG Groningen,
The Netherlands
Received 9 October 2000; revised 24 October 2000
ene-based enantio-enriched building blocks. Optically
pure (R)-(+)- and (S)-( )-4-methyl-2-cyclohexen-1-one
(1) are synthetically useful building blocks for the prepa-
ration of a vast array of natural products including ( )-mi-
Abstract: The first catalytic asymmetric synthesis of both (R)-(+)-
and (S)-( )-4-methyl-2-cyclohexen-1-one and a new and improved
synthesis of both enantiomers of (1S,4S)-( ) and (1R,4R)-(+)-4-me-
thyl-2-cyclohexen-1-ol was developed on a multigram scale. The
key step of this approach is the asymmetric catalyzed addition of crocionin 2,2 pseudopterosin A,3 tetronasin4 (Scheme 1).
Me2Zn (SN2'-pathway) to racemic 1,3-cyclohexadiene monoep-
Also enantio-enriched (88% ee) (1S, 4S)-4-methyl-2-cy-
oxide. This step has been optimized as for as enantio- and regiose-
clohexenol (2) has recently been used as a key building
lectivities, and work-up procedures. The striking ligand accelerated
block for the synthesis of the homochiral cyclohexane
portion of tetronomycin.5 Several synthetic preparations
of optically active 1 have been reported, all of which em-
ployed a "chiral pool approach" from (R)-(+)-pulegone2,6
or (S)-(+)-carvone7 or conventional racemate resolution
methods.8 These procedures are often long and tedious
and the overall yields obtained are generally quite low.
Hiroi et al. reported the asymmetric synthesis of optically
active 4-substituted-2-cyclohexenones by the use of sto-
ichiometric chiral organoselenium compounds, but only
with a modest 26% ee.9 We hypothesized that a straight-
forward synthesis of both enantiomers of 1 and 2 on a
multigram scale could be simply performed by means of
our catalytic kinetic resolution (CKR) procedure.
catalysis exhibited by the chiral copper complex of the 2,2'-binaph-
thyl-based phosphoramidite, herein reported, permitted a very low
catalyst loading (0.6 mol%).
Key words: enantiomer resolution, scale-up, catalysis, organozinc
reagent, copper
In the endeavour of natural product total synthesis and the
development of efficient routes to new pharmaceuticals,
there is a constant need for small chiral non-racemic mol-
ecules as starting material. In the course of our studies on
the catalytic enantioselective addition of dialkyl zinc re-
agents to vinyl oxiranes,1 we realized the potential of our
approach for a possible large-scale synthesis of cyclohex-
O
ref. 2
O
microcionin 2
H
ref. 4
R
R
CO2Me
(R)-1
ref. 5
R'
H
tetronasin
(cyclohexane portion)
OH
OH
tetronomycin
(cyclohexane portion)
(1S, 4S)-2
OH
HO
O
ref. 3
H
(S)-1
pseudopterosin A
(aglycone)
Scheme 1
Synthesis 2001, No. 3, 483–486 ISSN 0039-7881 © Thieme Stuttgart · New York

484
F. Bertozzi et al.
PAPER
PDC
93% ee
CH2Cl2
20 h r.t.
OH
O
(R)-1
(1R, 4R)-2
Me2Zn/ toluene
+
0.3 mol% Cu(OTf)2
O
0.6 mol% (R,R,R)-4
PDC
Me2Zn / toluene
(±)-3
-78 °C 30 min
0.3 mol% Cu(OTf)2
CH2Cl2
20 h r.t.
O
0.6 mol% (S,S,S)-4
OH
Ph
O
(S)-1
CH3
CH3
(1S, 2R)-3
O
-78 °C 40 min
(1S, 4S)-2
P
N
O
94% ee
Ph
(R,R,R)-4
Scheme 2
We herein report the first catalytic enantioselective ap- epoxide 3 an attractive option (i.e., so-called "double
proach to optically active 1 by means of a very simple and CKR").15 The toluene solution containing enantio-en-
efficient procedure. The key step of our procedure is the riched epoxide (1S,2R)-3, recovered in the kinetic resolu-
asymmetric addition of Me2Zn to racemic 1,3-cyclohexa- tion protocol, was directly used in "double CKR" by
diene monoepoxide (3)10 catalyzed by the chiral copper treatment with Me2Zn in the presence of catalytic amounts
complex of Binol-derived phosphoramidite (R,R,R)-4 of enantiomeric chiral ligand (S,S,S)-4. Under these cir-
(Scheme 2). The striking ligand accelerated catalysis11 ex- cumstances, the (1S,2R)-3 enantiomer, in which the start-
hibited by copper complexes of phosphoramidites12 per- ing material is enriched, is now the faster-reacting
mitted a very low catalyst loading (< 1 mol%), and a enantiomer and consequently the opposite (1S,4S)-2 SN2
careful screening of the most suitable chiral ligand permit- adduct with 94% ee was obtained (50% yield) with com-
ted an optimization of the key step of our approach for a plete (>98%) regioselectivity (see Scheme 2 and experi-
multigram-scale reaction. The regio- and enantioselectiv- mental section). Subsequent PDC oxidation gave (S)-1
ity of the catalyzed addition of Me2Zn to 1,3-cyclohexadi- with 94% ee (85% yield). As expected, a direct synthesis
ene monoepoxide (3) was dependent on the extent of of (1S,4S)-2 was also accomplished with the catalyzed ad-
conversion of the racemic starting material.13
dition reaction of Me2Zn to racemic 3 by the use of a cop-
per complex of ligand (S,S,S)-4 (0.6 mol%) as the chiral
catalyst in a multigram-scale reaction. In this case, the re-
action was stopped at 42% conversion after 15 minutes of
reaction time at 78 °C. Usual work-up afforded (1S,4S)-
( )-2 (36% yield, 86% yield based on the reacted ep-
oxide) with a slight increase in both enantio- and regiose-
lectivity (94% ee and SN2 / SN2 = 97:3).
We found a satisfactory compromise between yield and
selectivity (both regio- and enantioselectivity) stopping
the reaction at 46% conversion (calculated by GC analysis
with an internal standard). After filtration of the reaction
mixture, in order to remove all inorganic substances, the
organic solution was distilled under reduced pressure
(100 mmHg) to afford a toluene solution containing the
unreacted epoxide (1S,2R)-3 (Scheme 2). The crude resi- In summary, the present work describes the first catalytic
due was subsequently distilled (1.5 mmHg) to afford asymmetric synthesis of both (R)-(+)- and (S)-( )-4-me-
(1R,4R)-2 (41% yield, 89% yield based on the reacted ep- thyl-2-cyclohexen-1-one (1) and a new and improved syn-
oxide) with a SN2 /SN2 regioselectivity of 96:4 and 93% thesis of both enantiomers of 4-methyl-2-cyclohexenol
ee (values calculated by chiral GC and 1H NMR analysis (2). Compared with other multistep syntheses of 1, our
on the distillate). A smooth PDC oxidation14 of (1R,4R)-2 two-step procedure is simple and starts from commercial-
afforded the desired compound (R)-1 with 93% ee and ly cheap and readily available reagents. An attractive fea-
85% yield (75% overall for two steps). It should be men- ture of this approach is represented by the simple work-up
tioned that the chiral ligand (R,R,R)-4 was recovered pure procedures based on filtration and distillation, which qual-
in approximately 40% yield in the distillation residue after ifies the procedure for further scale-up. As a large number
simple filtration over a pad of silica gel, and re-used for of dialkylzinc reagents are available by standard meth-
another reaction without any loss of catalytic activity.
ods,16 it is reasonable to assume that other optically active
4-alkyl-2-cyclohexenones (and 4-alkyl-2-cyclohexenols)
can be synthesized by this procedure, allowing a novel,
The ease of preparation of both enantiomers of the chiral
ligand 4 makes further CKR of enantiomerically enriched
Synthesis 2001, No. 3, 483–486 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active 4-Methyl-2-cyclohexen-1-one
485
time 40 min). Extraction with Et2O and evaporation of the dried
(MgSO4) organic phase gave a crude product, which was purified
by chromatography (SiO2, hexanes/EtOAc, 85:15) to afford pure
(1S,4S)-2 (0.40 g, approx. 46% yield). The enantiomeric excess
(94%) was determined by chiral GC as described above.
easy and practical multigram-scale synthesis of this inter-
esting class of compounds by the use of minimal amounts
of Binol-derived phosphoramidites.
All reactions were conducted in flame-dried glassware with mag-
netic stirring under an Ar atm. Toluene was distilled from sodium/
benzophenone ketyl and stored under Ar. Me2Zn (2.0 M solution in
toluene) and 1,3-cyclohexadiene were purchased from Aldrich.
Enantiomeric excesses were determined on a Perkin Elmer 8420
apparatus (FI detector) using a Chrompak fused silica 50 m 0.25
mm column coated with CP-Cyclodextrin-B-236-M-19. In all cas-
es, the injector and detector temperature was 250 °C and a 0.9 mL/
min He flow was employed. Conversions were determined on a HP-
5890 instrument equipped with a HP-5 capillary column (30 m X
0.25 mm). For other experimental details, see ref. 1b.
(4R)-4-Methyl-2-cyclohexenone (1); Typical Procedure for the
PDC Oxidation of Allylic Alcohol 2
To a solution of (1R,4R)-2 (2.18 g, 19.5 mmol) in anhyd CH2Cl2
(26 mL) was added in two portions PDC (11.0 g, 29 mmol) at 0 °C
and the mixture obtained was stirred at r.t. After 20 h, the reaction
mixture was diluted with of hexanes/Et2O(20 mL, 75:25 mixture)
and directly filtered through a short pad of SiO2. Flash chromatog-
raphy (hexanes with 15% EtOAc) afforded pure (R)-1 (1.823 g,
85%) as a liquid. The enantiomeric excess ( 93% ee, not complete
baseline separation) was determined by chiral GC, isothermal
90 °C, tR 26.00 ( ), tR 26.28 (+).
[ ]D23 = +110° (c 1.4, EtOH) {Lit.8
EtOH)}.
[
23 = +117° (c 0.0372,
(1R,4R)-(+)-4-Methyl-2-cyclohexen-1-ol (2); Typical Procedure
for the Enantioselective Conjugate Addition Reaction of Me2Zn
to (±)-3
A solution of Cu(OTf)2 (54.3 mg, 0.15 mmol) and (R,R,R)-4
(0.160 g, 0.3 mmol) in anhyd toluene (30 mL) was stirred for 40
min. The colorless solution was cooled to 78 °C and (±)-3 (4.80 g,
50 mmol) in anhyd toluene (5 mL) and isopropylbenzene (1.80 g as
the internal standard) were added. Then a solution of Me2Zn in tol-
uene (2.0 M, 11.4 mL) was added dropwise to the cooled ( 78 °C)
reaction mixture over a period of 7 min. The reaction was monitored
D
1H NMR:
=
(m, 1H), 5.89 (dd, 1H, J = 10.1, 2.3 Hz),
1.65 2.55 (m, 5H), 1.11 (d, 3H, J = 7.3 Hz).
13C NMR: = 199.60, 156.14, 128.55, 36.77, 31.01, 30.79, 20.10.
Anal. Calcd. for C7H10O: C, 76.33; H, 9.15. Found : C, 76.30; H,
9.10.
by GC and quenched with H2O (15 mL) after 30 min (46% conver- Acknowledgement
sion). The slight yellow suspension obtained was vigorously stirred
This work was partly supported by the Consiglio Nazionale delle
for 1 h at r.t. The precipitate was filtered through a glass sintered
Buchner washing with the minimal amount of CH2Cl2 (3 8 mL).
The organic layer was separated and the dried (MgSO4). The organ-
ic phase was distilled with a Vigreux column under reduced pres-
sure (100 mmHg), thus obtaining a toluene solution (total volume
35 mL)containing the enantio-enriched unreacted epoxide (1S,2R)-
3. The remaining liquid was distilled at 1.5 mmHg (43 45 °C) to
give (1R,4R)-2 (2.296 g, 41%), as a colorless liquid (contaminated
with 4% regioisomeric alcohol). The enantiomeric excess (93%)
was determined by chiral GC, isothermal 104 °C: tR18.91 ( ); tR
19.75 (+).
Ricerche (CNR) and by the University of Pisa. One of us (P.C.) gra-
tefully acknowledges Merck for generous financial support derived
from the 2000 ADP Chemistry Award. We thank Dr. R. Olsson
(Acadia Pharmaceuticals, Glostrup, Denmark) for helpful discussi-
ons.
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(1S,4S)-( )-4-Methyl-2-cyclohexen-1-ol (2)
Following the typical procedure, the reaction of (±)-3 (6.0 g,
62.5 mmol) and Me2Zn (14.0 mL) in the presence of Cu(OTf)2 (67.9
mg, 0.187 mmol) and (S,S,S)-4 (0.20 g, 0.375 mmol) was quenched
with H2O (16 mL) after 15 min reaction time at 78 °C (42% con-
version). Fractional distillation afforded (1S,4S)-2 (2.53 g, 36%) as
a colorless liquid (contaminated with 3% regioisomeric alcohol).
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"Double CKR" Method
A solution of Cu(OTf)2 (16.7 mg, 0.046 mmol) and (S,S,S)-4
(50 mg, 0.093 mmol) in anhyd toluene (7 mL) was stirred for 40
min. The colorless solution was cooled to 78 °C and a solution of
the epoxide (1S,2R)-3 (19 mL deriving from the fractional distilla-
tion, approx. 7.7 mmol) and isopropylbenzene (0.30 g as the inter-
nal standard) were added. Then a solution of Me2Zn in toluene (2.0
M, 3.1 mL) was added dropwise to the cooled ( 78 °C) reaction
mixture over a period of 5 min. The reaction was monitored by GC
and quenched with H2O (6 mL) at approx. 63% conversion (reaction
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Synthesis 2001, No. 3, 483–486 ISSN 0039-7881 © Thieme Stuttgart · New York

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PAPER
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1437-210X,E;2001,0,03,0483,0486,ftx,en;Z09200SS.pdf
Synthesis 2001, No. 3, 483–486 ISSN 0039-7881 © Thieme Stuttgart · New York