Organocatalytic dynamic kinetic resolution via conjugate addition: Synthesis of chiral trans-2,5-dialkylcyclohexanones

Article abstract of DOI:10.1039/c2ob26597d

A novel strategy of initiating an organocatalysed dynamic kinetic resolution (dr up to 99:1 and er up to 94:6) for the synthesis of chiral trans-2,5-dialkylcyclohexanones by an asymmetric conjugate addition of dimethyl malonate on to 6-substituted cyclohexenones is reported.

Full text of DOI:10.1039/c2ob26597d

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PAPER
Organocatalytic dynamic kinetic resolution via conjugate addition: synthesis
of chiral trans-2,5-dialkylcyclohexanones†
Ganesh Pandey,*a Priyanka A. Adatea and Vedavati G. Puranikb
Received 9th April 2012, Accepted 24th August 2012
DOI: 10.1039/c2ob26597d
A novel strategy of initiating an organocatalysed dynamic kinetic resolution (dr up to 99 : 1 and er up to
94 : 6) for the synthesis of chiral trans-2,5-dialkylcyclohexanones by an asymmetric conjugate addition of
dimethyl malonate on to 6-substituted cyclohexenones is reported.
the methodologies pertaining to the syntheses of the molecules
Introduction
displaying 2,5-disubstituted cyclohexanone core structure have
relied either on chiral pool6 approach utilizing menthone, dihydro-
In the last few years asymmetric conjugate addition has emerged
as one of the most powerful C–C bond forming strategies and
many ligands and catalysts are designed to affect this important
reaction.1 Transition metals in combination with chiral ligands
have been successfully demonstrated to catalyze asymmetric
conjugate addition of stabilized as well as non-stabilized carb-
anions.2 The versatility of this reaction has been amply demon-
strated utilizing wide spectrum of donor–acceptor combinations.
Of all donor and acceptor pairs used, the conjugate adduct
obtained between cyclohexenone and dimethylmalonate pair is
known to have maximum synthetic utility as this has served as
a starting material for building complex molecular entities.3
Sibasaki et al. have employed a BINOL–heterobimetallic complex
to catalyze this conjugate addition reaction even up to a kilogram
scale4 with excellent enantioselectivity. Recently, several organo-
catalysts have also been developed to catalyse this reaction with
excellent yields and enantioselectivity5 but it is limited to only
those with simple non-substituted cyclohexenones. To the best of
our knowledge conjugate addition on substituted cyclohexenones
using organocatalysts has still remained unexplored.
carvone, isopulegone or kinetic resolution of racemic substituted
cyclohexenones. In this paper, we would like to disclose our
success in initiating dynamic kinetic resolution processes during
organocatalyzed conjugate addition of dialkyl malonate on
racemic 6-alkyl cyclohexenone producing trans-2,5-dialkyl
cyclohexanone with good to excellent enantioselectivity.
Results and discussion
Initially, as per our planning, we attempted the synthesis of
chiral trans-2,5-dialkylcyclohexanones via asymmetric conjugate
addition of dimethyl malonate on racemic 6-alkyl substituted
cyclohexenone (1) in the presence of organocatalyst IIa (readily
available in the group), but to our surprise, no reaction occurred.
We also evaluated the same reaction using chiral 6-alkyl cyclo-
hexenone using achiral secondary amine (pyrrolidine and piper-
idine); however, here too the complete starting material was
recovered. Interestingly the recovered starting material (1) was
found to be optically inactive (racemised). This unexpected
observed racemisation was tentatively rationalized by implicating
iminium/enamine tautomerization as shown in Scheme 1. This
racemisation phenomenon led us to envision that in the presence
of a chiral amine catalyst and a base, the rate of iminium ions (3
and 4) formation may vary7 leading to either one of the enriched
iminium ion diastereomer preferentially, which on conjugate
addition with malonate would produce enantiomerically enriched
5 stereoselectively. Furthermore, fast equilibration of slower
forming diastereomer 3 through tautomerization may set in a
dynamic kinetic resolution (DKR) processes as shown in
Scheme 1. To our knowledge dynamic kinetic resolution of
6-substituted cyclohexenone via organocatalytic conjugate addition
is not studied so far.8 Based on this hypothesis, we first scanned
different catalysts (Fig. 1) under various reaction conditions to
optimize the conjugate addition of dimethyl malonate on to
enone 69 (Table 1). Stirring a solution of 6 (1 mmol, 1.0 equiv.)
Considering the importance of 2,5-dialkylcyclohexanone moi-
eties as versatile building blocks for the synthesis of many
complex structures with pharmacological importance6 and our
requirement of a scalable synthesis of chiral trans-2,5-dialkyl-
cyclohexanone for an ongoing project, we envisioned its synthesis
via organocatalysed conjugate addition of malonate on 6-alkyl
cyclohexenones. It may be appropriate to mention that most of
aDivision of Organic Chemistry, National Chemical Laboratory, Pune-
411 008, India. E-mail: gp.pandey@ncl.res.in; Fax: +91 20 2590-2628;
Tel: +91 20 2590-2281
bCentre for Material Characterization, National Chemical Laboratory,
Pune-411 008, India. E-mail: vg.puranikncl.res.in
†Electronic supplementary information (ESI) available: NMR and
HPLC spectra of all new compounds. CCDC 861580. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob26597d
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Table 1 Scanning of different catalyst for DKR studiesa
Sr. no.
Catalyst
Solvent
Conversionb %
drc
erd
1
2
3
4
5
6
7
8
9
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
NR
NR
NR
NR
NR
50
5
70
5
—
—
—
—
—
—
—
—
IIa
IIb
III
IV
V
VI
V
—
—
85 : 15
65 : 35
87 : 13
49 : 51
93 : 7
47 : 53
94 : 6
92 : 8
VII
CH2Cl2
a Enone (1 mmol), catalyst (10 mol%), dimethyl malonate (1.5 mmol),
piperidine (1 mmol), solvent 3 mL, 5 days, RT (25 °C). b Conversion
monitored by GC. c Diastereomeric ratio determined either by HPLC or
NMR. d Enantiomeric excess determined by chiral stationary phase
HPLC. NR = no reaction.
Scheme 1 DKR Hypothesis.
Fig. 2 Relative stereochemistry of 6A confirmation using NMR.
Fig. 3 ORTEP diagrams of trans-6A.
Fig. 1 Catalyst evaluated.
It may be worth mentioning that there are very few methods
known in the literature for the synthesis of chiral 2,5-disubsti-
tuted cyclohexanone. For example, Tamioka et al. have demon-
strated asymmetric conjugate addition of either arylboronic acid
or dialkylzinc on racemic 6-alkyl cyclohexenone in the presence
in dichloromethane with catalyst V10 (10 mol%) and piperidine
(1.0 equiv., as an additive) gave 6A as an exclusive product with
50% conversion. Chiral stationary phase HPLC analysis of 6A
indicated it to be an enantiomerically enriched diastereomeric
mixture (dr = 85 : 15, er = 93 : 7) (Table 1, entry 6). We were
delighted to find recovered 6 to be racemic (analysed using
Kromasil 5-Amycoat, mobile phase i-PrOH–petroleum ether
5 : 95, 1.0 mL min−1, wavelength: 220 nm) thus, supporting our
hypothesis. Furthermore, DKR using recovered 6 gave identical
results indicating its probable reuse. The relative stereochemistry
of 2,5-dialkyl substituent of major and minor diastereomers (iso-
lated by preparative HPLC column: Kromasil RP-8, acetonitrile–
H2O = 35 : 65, wavelength: 220 nm) were confirmed as trans-6A
and cis-6A, respectively, by extensive 2D NMR studies (Fig. 2).
Relative and absolute stereochemistry of the major diastereomer
of 6A was further confirmed as trans (14R, 15R) using X-ray
crystallographic analysis under Cu radiations (λ = 1.5418)
(Fig. 3).11 At this point, we do not exactly understand the origin
of trans stereoselectivity12 in this reaction but believe that
addition is somehow directed by tetrazole moiety from only one
face of the enone moiety possibly due to combined effects of
electronic and steric factors.13
14
of chiral amidophosphane-[RhCl(C2H4)]2 and chiral amido-
phosphane-copper(I) complex15 as catalysts, respectively, and
corresponding conjugate addition products were obtained in 1 : 1
diastereomeric mixtures which were eventually epimerized to
thermodynamically more stable trans-2,5-dialkyl cyclohexa-
nones (ee up to 99%) using a strong base. Luo et al.16 have syn-
thesized chiral cis-2,5-disubstituted cyclohexanones (dr = 1 : 99)
via kinetic resolution of 3-substituted cyclohexanone by α-alkyl-
ation using pyrrolidine derived functionalized chiral ionic liquids
in low to moderate enantioselectivity (ee = 69–84%).
In order to improve the enantioselectivity and diastereoselec-
tivity further, we evaluated primary amine based catalyst VII,17
derived from cinchona alkaloid, but the results were not very
exciting as 6A was formed only with 5% conversion (no conju-
gate adduct was observed in the absence of a base) and without
any diastereoselectivity, however, the enantioselectivity (er =
92 : 8) obtained was excellent. To improve the enantioselectivity
and diastereoselectivity further, different solvent and base com-
binations were scanned (Table 2). From the results of solvent
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Table 2 Base and solvent studiesa
Sr. no.
Solvent
Base
Conversionb %
drc
erd (major diastereomer)
1
2
3
4
5
6
MeCN
THF
PhCH3
EtOH
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
—
NEt3
DBU
Pyrrolidine
K2CO3
Pyridine
4
NR
NR
NR
3
10
70
NR
NR
NR
20
60
2 : 1
—
—
—
ND
—
—
—
ND
12 : 88
94 : 6
—
—
—
DMF
—
DMSO
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
1 : 5
85 : 15
—
—
—
3 : 1
87 : 13
—
7
8e
9
10
11
12
13
14
60 : 40
72 : 28
—
NR
SM decompose
—
—
a Enone (1.0 mmol), catalyst V (10 mol%), dimethylmalonate (1.5 mmol), base (1.0 mmol), solvent (3 mL), 5 days, RT (25 °C). b Determined by GC
analysis. c Diastereomeric ratio determined either by HPLC or NMR. d Enantiomeric excess determined by chiral stationary phase HPLC and
mentioned only for major diastereomer. e No catalyst used. NR = no reaction, ND = not determined. THF = tetrahydrofuran, DMF =
dimethylformamide, DMSO = dimethylsulfoxide.
scanning, it was observed that DKR works well in chlorinated
hydrocarbon solvents. Use of chloroform as a solvent improved
conversion to 70% compared to dichloromethane. This obser-
vation can be correlated with Guttmans acceptor number18 (AN)
(AN of acetonitrile 18.9, DMSO 19.3, CH2Cl2 20.4, CHCl3
23.1), as a solvent with higher AN is known to enhance the reac-
tivity of the intermediate iminium cation. Among the different
solvent and bases19 tried, chloroform and piperidine combination
was found to be the best giving better conversion and stereo-
selectivity. The bulk scale (up to 20.0 g of 6) DKR gave 6Awith
almost same enantioselectivity and diastereoselectivity (dr =
70 : 30, er = 94 : 6).
Without any catalyst or base additive, no background reaction
was observed (Table 2, entry 8) (Table 2, entry 9). Other variants
for reaction were also evaluated systematically to improve the
yield and selectivity. For example, increasing the malonate
concentration (3 equiv.) did not improve reaction conversion
rather made purification of 6A difficult. Surprisingly, reaction
at lower temperature (10 °C) did not improve enantioselectivity
(dr = 87 : 13, er = 94 : 6) rather just decreased the rate of
reaction.
Next, we studied the substituent effect at the 6th position of
the cyclohexenones.21 It was observed that 11 having sterically
bulky TBS group on the alkyl chain at the 6th position improved
the conversion slightly but decreased diastereoselectivity (dr =
60 : 40) and enantioselectivity (er = 90 : 10) as compared to 6.
Excellent conversions (92–95%) were obtained with enones
without any substitution at the 4th position (e.g. 8, 12–14). Gen-
erally better enantiomeric ratios were observed using diethyl
malonate as a nucleophile in comparison to dimethyl malonate
(Table 4, entries 2 and 3; 4 and 5; Table 3, entry 2 and Table 4,
entry 7). A considerable decrease in diastereoselectivity was
noticed with the reaction of 6-methyl cyclohexenone (13) and
diethyl malonate in comparison to dimethyl malonate (Table 4,
entries 4, 5). The stereochemistry of cycloadduct 13A was
confirmed as usual by 2D NMR studies. Conjugate addition of
2-nitropropane on to 13 gave corresponding conjugate adduct
(13C) in excellent diastereoselectivity (dr = 94 : 6) and enantio-
selectivity (er = 88 : 12) (Table 4, entry 9). Surprisingly, no
conjugate addition occurred with piperitone (15) while
aliphatic enone 16 gave very low diastereoselectivity and
enantioselectivity (Table 4, entries 11, 12).
Having standardized the DKR reaction, we next studied the
reaction with other enones of different ring sizes using dimethyl
malonate as the donor (Table 3). For example, 5-allylcyclopente-
none (7) underwent conjugate addition with good conversion
(80%) but with low stereoselectivity (dr = 82 : 18, er = 66 : 34)
as compared to its 6-membered congener (8). 2,5-trans Stereo-
chemistry of 8A was confirmed by extensive 2D NMR studies.
Surprisingly, 9 did not undergo DKR under our standard reaction
conditions.20 In contrast, 10 underwent conjugate addition (60%
conversion) with poor diastereoselectivity (60 : 40) but without
any enantioselectivity (52.15 : 47.85) (Table 3, entry 3).
Conclusions
In summary, we have developed a conceptually new strategy of
initiating a DKR reaction for preparing chiral trans-2,5-dialkyl-
cyclohexanones by organocatalyzed asymmetric conjugate
addition of dimethyl malonate on to 6-substituted cyclohexe-
nones. Application of this methodology for the synthesis of
complex terpenes is in progress and will be disclosed in the near
future.
8262 | Org. Biomol. Chem., 2012, 10, 8260–8267
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Table 3 Studies on effect of ring size of enones on DKRa
Sr. no.
1
Starting enone
Michael donore
A
Yieldsb %
80
Drc
erd Major (Minor)
66 : 34 (41 : 59)
82 : 18
2
3
A
A
92
99 : 1
87 : 13
NR
—
—
4
A
70
60 : 40
50.4 : 49.6 (52.2 : 47.8)
a Enone (1 mmol), catalyst V (10 mol%), malonate (1.5 mmol), piperidine (1 mmol), CHCl3 (3 mL), 5 days, RT (25 °C). b Isolated yields
on purification. c Diastereomeric ratio determined either by HPLC or NMR. d Enantiomeric excess determined by chiral stationary phase HPLC.
e A = dimethylmalonate, B = diethylmalonate.
of triplet; td, triplet of doublet; m, multiplet). 13C NMR spectra
Experimental
were recorded on Bruker AV-400 and Bruker DRX 500 instru-
ments operating at 100 MHz and 125 MHz respectively. 13C
General
NMR chemical shifts are reported in ppm relative to the central
line of CDCl3 (δ 77.0). HPLC were performed on Shimadzu
All moisture-sensitive reactions were performed under an atmos-
phere of argon and glasswares were dried in an oven at 125 °C
Class-VP V6.12 SP5 with UV detector. Electro spray ionization
prior to use. Dry tetrahydrofuran (THF) was obtained by passing
(ESI) mass spectrometry (MS) experiments were performed on a
commercially available pre-dried, oxygen-free formulations
Finnigan Mat-1020 spectrometer. Elemental analyses were deter-
through activated neutral alumina columns and dried by distilla-
mined at Central Elemental Analysis Facility division at National
tion over sodium/benzophenone. All the solvents and bases used
Chemical Laboratory. Optical rotations were measured on a
were distilled prior to use. Solvents used for chromatography
JASCO P-1020 polarimeter. High resolution mass (HR-ESI-MS)
were distilled at respective boiling points using known pro-
cedures. All commercial reagents were obtained from Sigma-
Aldrich Chemical Co and S. D. Fine Chemical Co. India. Reac-
spectra was recorded on a Thermo scientific make Q-exactive
model spectrometer using electrospray ionization. Racemic
samples of Michael adduct were prepared using an equivalent
tions were monitored by thin layer chromatography (TLC,
amount of lithium perchlorate and catalytic amount of triethyl-
0.25 mm E. Merck silica gel plates, 60F254) and visualized by
amine in dry CH2Cl2 as solvent.
using UV light, ethanolic solution of phosphomolybdic acid and
iodine. Column chromatography was performed on silica gel
60–120/100–200/230–400 mesh obtained from S. D. Fine
Chemical Co. India or SRL India. Typical syringe and cannula
General procedure for DKR reaction
techniques were used to transfer air and moisture sensitive
reagents. All melting points were uncorrected in degree Celsius
and were recorded on a Thermonik melting point apparatus. IR
spectra were recorded on a Perkin-Elmer infrared spectrometer
model 599-B and model 1620 FT-IR. 1H NMR spectra were
recorded on Bruker AC-200, Bruker AV-400 and Bruker
DRX500 instruments using deuteriated solvent. Chemical shifts
are reported in ppm. Proton coupling constants (J) are reported
as absolute values in Hz and multiplicity (bs, broadened; s,
singlet; d, doublet; t, triplet; dd, doublet of doublet; dt, doublet
To a stirred suspension of 6-substituted enones (0.2 mmol) and
catalyst (10 mol%) in CHCl3 (2 mL) was added dialkylmalonate
(0.3 mmol) and piperidine (0.2 mmol) at room temperature. The
progress of the reaction was monitored by thin layer chromato-
graphy and gas chromatography. After 5 days of stirring when
no further conversion was noticed, the reaction was quenched
with water. The aqueous phase was extracted with CH2Cl2 (3 ×
10 mL). The combined organic phase was dried over anhydrous
Na2SO4, concentrated in vacuum, purified by flash column
chromatography to obtain conjugate addition product.
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Table 4 Generalization of substrate scope for DKRa
Sr. no.
1
Starting enone
Michael donore
A
Conversionb%
80
drc
erd Major (Minor)
60 : 40
90 : 10 (81 : 19)
2
3
A
B
95
95
85 : 15
96 : 4
84 : 16 (86 : 14)
90 : 10
4
5
A
B
95
95
99 : 1
42 : 58
79 : 21
88 : 12 (87 : 13)
6
7
C
B
75
90
94 : 6
91 : 9
88 : 12
91 : 9 (89 : 11)
8
B
95
75 : 25
88 : 12 (87 : 13)
9
10
A
C
NR
NR
—
—
—
—
11
12
A
B
40
35
50.2 : 49.8
78 : 22
52 : 48 (51 : 49)
50.5 : 49.5 (92.1 : 7.9)
a Enone (1 mmol), catalyst V (10 mol%), malonate (1.5 mmol), piperidine (1 mmol), CHCl3 (3 mL), 5 days, RT (25 °C). b Isolated yields on
purification. c Diastereomeric ratio determined either by HPLC or NMR. d Enantiomeric excess determined by chiral stationary phase HPLC. NR = no
reaction. e A = dimethylmalonate, B = diethylmalonate, C = 2-nitropropane.
55.91, H 6.85; HRMS-ESI (m/z): [M + H]+ calcd for C18H27O9,
Dimethyl-2-(9-(3-ethoxy-3-oxopropyl)-8-oxo-1,4-dioxaspiro-
[4.5]decan-6-yl)malonate (6A). Pale yellow solid, M.P.
=
387.1650; found, 387.1654. HPLC: major diastereomer: τR
=
81.9 °C; [α]2D5: +19.12 (c = 1.9, CHCl3, 70% de, 88% ee); IR
70.01 min (major enantiomer), τR = 64.2 min (minor enantio-
mer); minor diastereomer: τR = 53.15 min (major enantiomer);
τR = 44.03 min (minor enantiomer); (Chromasil OJ-H, i-propa-
nol–petroleum ether 20 : 80, 0.5 mL min−1, 220 nm).
1
νmax (CHCl3): 2982, 2955, 2903, 1732, 1435, 1155; H NMR
(500 MHz, CDCl3) δ ppm: 1.23 (t, J = 5.0 Hz, 3 H), 1.47–1.60
(m, 2 H), 2.03 (dd, J = 14.8, 7.2 Hz, 1 H), 2.11 (dd, J = 13.4,
5.8 Hz, 1 H), 2.25–2.43 (m, 2 H), 2.50 (dd, J = 13.9, 4.7 Hz,
1 H), 2.63 (dd, J = 12.8, 7.0 Hz, 1 H), 2.69–2.78 (m, 1 H), 2.99
(ddd, J = 13.9, 7.0, 4.7 Hz, 1 H), 3.68 (d, J = 7.3 Hz, 1 H), 3.70
(s, 3 H), 3.72 (s, 3 H), 3.9–4.1 (m, 4 H), 4.1–4.1 (m, 2 H); 13C
NMR (126 MHz, CDCl3) δ ppm (only for major diastereomer):
14.2, 23.9, 31.7, 39.0, 41.4, 44.4, 45.4, 50.6, 52.4, 52.6, 60.3,
64.7, 65.0, 107.8, 168.3, 168.4, 173.3, 208.5. m/z (%): 425.28
(M + K, 41), 409.29 (M + Na, 100), 237 (50), 221 (47). Elemen-
tal analysis calcd (%) for C18H26O9: C 55.95, H 6.78; found: C
Data for trans 6A. 1H NMR (500 MHz, CDCl3) δ ppm: 1.24
(t, J = 7.02 Hz, 3 H), 1.49–1.60 (m, 2 H), 2.04 (dq, J = 14.27,
7.25 Hz, 1 H), 2.12 (dd, J = 13.43, 5.80 Hz, 1 H), 2.31 (dt, J =
15.87, 7.63 Hz, 1 H), 2.35–2.44 (m, 1 H), 2.51 (dd, J = 14.04,
4.58 Hz, 1 H), 2.64 (dd, J = 13.12, 6.71 Hz, 1 H), 2.75 (t, J =
13.89 Hz, 1 H), 2.96–3.03 (m, 1 H), 3.69 (d, J = 7.02 Hz, 1 H),
3.73 (s, 3 H), 3.71 (s, 3 H), 3.98–4.07 (m, 4 H), 4.11 (q, J =
7.22 Hz, 2 H). 13C NMR (125 MHz, CDCl3) δ ppm: 14.2, 23.9,
8264 | Org. Biomol. Chem., 2012, 10, 8260–8267
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31.9, 39.0, 41.4, 44.4, 45.1, 50.8, 52.4, 52.8, 60.3, 64.6, 65.0,
107.9, 166.3, 166.4, 173.3, 206.5.
49.5, 57.0, 61.5, 116.4, 136.2, 167.7, 167.8, 209.7. m/z (%):
319.93 (M + Na, 25), 318.99 (100), 296.99 (M + H, 32), 161.83
(33), 160.5 (100), 136.56 (100), 132.82 (31). Elemental analysis
calcd (%) for C16H24O5: C 64.84, H 8.16; found: C 65.10, H
8.07; HRMS-ESI (m/z): [M + Na]+ calcd for C16H24O5Na,
Data for cis 6A. 1H NMR (500 MHz, CDCl3) δ ppm:
1.24–1.27 (t, 3 H), 1.61 (d, J = 6.71 Hz, 1 H), 1.90–1.98 (m,
1 H), 2.01–2.16 (m, 2 H), 2.30–2.37 (m, 2 H), 2.42 (dd, J =
15.26, 5.80 Hz, 1 H), 2.67 (dd, J = 10.83, 6.26 Hz, 1 H),
2.75–2.84 (m, 1 H), 2.98–3.10 (m, 1 H), 3.43 (d, J = 9.46 Hz,
1 H), 3.74 (s, 3 H), 3.72 (s, 3 H), 3.92–4.09 (m, 4 H), 4.10–4.17
(m, 2 H). 13C NMR (126 MHz, CDCl3) δ ppm: 14.2, 24.7, 31.7,
37.7, 40.7, 43.2, 45.9, 51.9, 52.7, 60.4, 64.7, 64.8, 107.9, 168.1,
168.5, 173.2, 209.6.
319.1516; found, 319.1524. HPLC: major diastereomer: τR
=
38.183 min (major enantiomer), τR = 42.85 min (minor enantio-
mer); minor diastereomer: τR = 51.342 min (major enantiomer);
τR = 47.617 min (minor enantiomer); (Chiralcel OJ-H, petroleum
ether–i-propanol 99.5 : 0.5, 0.5 mL min−1, 230 nm).
Dimethyl 2-(4-allyl-3-oxocyclooctyl) malonate (10A). Colour-
less liquid, IR ν
(CHCl3): 2932, 1751, 1735, 1701, 1437,
max
1
Dimethyl-2-(4-allyl-3-oxocyclopentyl)malonate (7A). Colour-
less liquid, [α]2D5: +29.01 (c = 1.2, CHCl3, 64% de, 32% ee); IR
νmax (CHCl3): 2956, 1735, 1437, 1223, 1156; 1H NMR
(400 MHz, CDCl3) δ ppm: 1.27–1.38 (m, 1 H), 1.96 (dd, J =
18.70, 11.67 Hz, 1 H), 2.03–2.19 (m, 1 H), 2.25–2.44 (m, 2 H),
2.44–2.63 (m, 2 H), 2.71–2.84 (m, 0.77 H), 2.9–2.96 (m, 0.19
H), 3.30–3.39 (d, J = 10.04, 1 H), 3.74 (s, 3 H), 3.77 (s, 3 H),
4.93–5.12 (m, 2 H), 5.63–5.78 (m, 1 H); 13C NMR (101 MHz,
CDCl3) δ ppm (only for major diastereomer): 33.4, 33.6, 34.1,
42.8, 49.3, 52.6, 56.2, 116.81, 135.3, 168.4, 168.5, 216.8; m/z
(%): 277 (M + Na, 100), 240 (12), 195 (8); Elemental analysis
calcd (%) for C13H18O5: C 61.40, H 7.14; found: C 61.68, H
6.95; HRMS-ESI (m/z): [M + Na]+ calcd for C13H18O5Na,
1195, 1157; H NMR (400 MHz, CDCl3) δ ppm: 1.34–1.46 (m,
2 H), 1.50–1.63 (m, 3 H), 1.64–1.83 (m, 4 H), 2.05–2.14 (m,
1 H), 2.24–2.48 (m, 3 H), 2.75–2.85 (m, 1 H), 2.90–3.02 (m,
1 H), 3.35 (d, J = 7.53 Hz, 0.62 H), 3.46 (d, J = 7.53 Hz, 0.27),
3.72–3.78 (m, 6 H), 4.91–5.09 (m, 2 H), 5.59–5.82 (m, 1 H);
13C NMR (101 MHz, CDCl3) δ ppm (only for major diastereo-
mer): 23.6, 25.4, 31.9, 33.2, 35.1, 37.2, 45.9, 50.0, 52.5, 52.5,
57.1, 116.7, 135.5, 168.7, 168.8, 216.8; m/z (%): 319.66 (M +
23, 100), 297.72 (M + 1, 100), 265.92 (55), 264.58 (100), 246
(12), 232.91 (100). Elemental analysis calcd (%) for C16H24O5:
C 64.84, H 8.16; found: C 64.68, H 8.35; HRMS-ESI (m/z):
[M + Na]+ calcd for C16H24O5Na, 319.1516; found, 319.1524.
HPLC: major diastereomer: τR = 22.517 min (major enantiomer),
277.1046; found, 277.1054. HPLC: major diastereomer: τR
=
τR = 28.058 min (minor enantiomer); minor diastereomer: τR
=
57.392 min (major enantiomer), τR = 69.808 min (minor enantio-
mer); minor diastereomer: τR = 87.192 min (major enantiomer);
τR = 65.525 min (minor enantiomer); (Chiralpak AS-H, pet-
roleum ether–i-propanol 98.0 : 2.0, 0.5 mL min−1, 230 nm).
46.867 min (major enantiomer); τR = 83.650. min (minor enan-
tiomer); (Kromasil 5-Amycoat, EtOH–n-Hexane 2.0 : 98.0,
0.5 mL min−1, 230 nm).
Dimethyl 2-(9-((tert-butyldimethylsilyloxy)methyl)-8-oxo-1,4-
dioxaspiro[4.5]decan-6-yl)malonate (11A). Colourless liquid,
Dimethyl 2-(4-allyl-3-oxocyclohexyl)malonate (8A). Colour-
less liquid, [α]2D5: +6.12 (c = 1.03, CHCl3, 98% de, 74% ee); IR
[α]2D5: +6.0 (c = 0.57, CHCl3, 20% de, 80% ee); IR ν
max
1
(CHCl3): 2955, 2630, 1736, 1435, 1257, 1153, 837, 757; 1H
NMR (400 MHz, CDCl3) δ ppm: 0.04 (s, 6 H), 0.87 (s, 9 H),
1.64–1.70 (m, 0.7 H), 1.79 (s, 0.3 H), 2.30 (dd, J = 13.69,
5.87 Hz, 1 H), 2.51 (dd, J = 14.43, 4.65 Hz, 1 H), 2.66–2.81 (m,
2 H), 2.97–3.09 (m, 1 H), 3.64–3.72 (m, 2 H), 3.73 (s, 2 H),
3.72 (s, 4 H), 3.78 (d, J = 5.68 Hz, 0.3 H), 3.87 (dd, J = 10.51,
4.16 Hz, 1 H), 3.97–4.08 (m, 4 H); 13C NMR (101 MHz,
CDCl3) δ ppm: −5.5, 18.2, 25.8, 35.7, 41.6, 43.9, 48.7, 50.8,
52.5, 52.6, 61.13, 64.6, 64.7, 64.9, 108.1, 168.4, 168.5, 207.9;
m/z (%): 469.15 (M + K, 70), 453.21 (M + Na, 100), 150.25
(10); Elemental analysis calcd (%) for C20H34O8Si: C 55.79, H
7.96; found: C 55.60, H 8.01; HRMS-ESI (m/z): [M + Na]+
calcd for C20H34O8NaSi, 453.1915; found, 453.1930. HPLC:
νmax (CHCl3): 2953, 1752, 1735, 1710, 1435, 1252, 1157; H
NMR (400 MHz, CDCl3) δ ppm: 1.27–1.40 (m, 1 H), 1.49–1.62
(m, 1 H), 1.93–2.02 (m, 2 H), 2.12–2.20 (m, 1 H), 2.24–2.34
(m, 2 H), 2.40–2.60 (m, 3 H), 3.34 (d, J = 7.53 Hz, 1 H), 3.75
(s, 3 H), 3.75 (s, 3 H), 4.97–5.06 (m, 2 H), 5.70–5.83 (m, 1 H);
13C NMR (101 MHz, CDCl3) δ ppm: 29.29, 31.1, 33.2, 39.1,
45.4, 49.46, 52. 6, 56.8, 116.5, 136.1, 168.1, 168.2, 209.5; m/z
(%): 307.31 (M + K, 20), 291.14 (M + Na, 100); Elemental
analysis calcd (%) for C14H20O5: C 62.67, H 7.51; found: C
62.89, H 7.88; HRMS-ESI (m/z): [M + Na]+ calcd for
C14H20O5Na, 291.1203; found, 291.1210. HPLC: major diaster-
eomer: τR = 19.308 min (major enantiomer), τR = 70.667 min
(minor enantiomer); minor diastereomer: τR = 62.317 min (major
enantiomer); τR = 58.517 min (minor enantiomer); (Chiralcel
major diastereomer: τR = 20.14 min (major enantiomer), τR
21.78 min (minor enantiomer); minor diastereomer: τR
=
=
OJ-H, petroleum ether–i-propanol 95 : 05, 0.5 mL min−1
,
230 nm).
18.91 min (major enantiomer); τR = 18.11 min (minor enantio-
mer); (Kromasil 5-Amycoat, i-propanol–petroleum ether
1.5 : 98.5, 0.5 mL min−1, 220 nm).
Diethyl 2-(4-allyl-3-oxocyclohexyl)malonate (8B). Colourless
liquid, [α]2D5: +7.38 (c = 1.45, CHCl3, 82% de, 82% ee); IR νmax
(CHCl3): 2981, 2937, 1750, 1732, 1713, 1155; 1H NMR
(400 MHz, CDCl3) δ ppm: 1.27 (td, J = 7.15, 1.00 Hz, 6 H),
1.30–1.40 (m, 1 H), 1.57 (qd, J = 12.72, 3.26 Hz, 1 H),
1.91–2.03 (m, 2 H), 2.09–2.21 (m, 1 H), 2.24–2.35 (m, 2 H),
2.42–2.59 (m, 3 H), 3.29 (d, J = 7.53 Hz, 1 H), 4.16–4.25 (m,
4 H), 4.96–5.08 (m, 2 H), 5.70–5.83 (m, 1 H); 13C NMR
(101 MHz, CDCl3) δ ppm: 14.0, 29.3, 31.2, 33.2, 39.02, 45.4,
Dimethyl-2-(4-(3-ethoxy-3-oxopropyl)-3-oxocyclohexyl)malonate
(12A). Colourless liquid, [α]2D5: +6.42 (c = 2.93, CHCl3, 70%
de, 68% ee); IR νmax (CHCl3): 2955, 1755, 1738, 1732, 1714,
1
1435, 1250, 1179, 1155; H NMR (400 MHz, CDCl3) δ ppm
1.24 (t, J = 7.09 Hz, 3 H), 1.31–1.44 (m, 1 H), 1.48–1.69 (m, 2
H), 1.91–2.17 (m, 3 H), 2.24–2.54 (m, 6 H), 3.29–3.36 (m,
1 H), 3.74 (s, 3 H), 3.75 (s, 3 H), 4.11 (q, J = 7.09 Hz, 2 H); 13
C
This journal is © The Royal Society of Chemistry 2012
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NMR (101 MHz, CDCl3) δ ppm 14.2, 24.3, 29.3, 31.7, 31.8,
39.2, 45.4, 48.9, 52.6, 56.7, 60.3, 168.09, 168.2, 173.5, 209.7;
m/z (%) = 351.54 (M + Na, 100), 319.78 (10), 297 (25), 151.15
(5); Elemental analysis calcd (%) for C16H24O7: C 58.52, H
7.37; found: C 58.3, H 7.25; HRMS-ESI (m/z): [M + Na]+ calcd
for C16H24O7Na, 351.1414; found, 351.1422. HPLC: major dia-
stereomer: τR = 90.38 min (major enantiomer), τR = 98.43 min
(minor enantiomer); minor diastereomer: τR = 70.03 min (major
enantiomer): τR = 66.67 min (minor enantiomer); (Chiralcel
OD-H, n-hexane–EtOH 1.5 : 98.5, 0.5 mL min−1, 230 nm).
167.9, 210.5, 212.5; m/z (%): 309.18 (M + K, 100), 293.43
(M + Na, 45), 154.46 (5); Elemental analysis calcd (%) for
C14H22O5: C 62.20, H 8.20; found: C 62.32, H 8.33;
HRMS-ESI (m/z): [M + Na]+ calcd for C14H22O5Na, 293.1359;
found, 293.1369. HPLC: major diastereomer: τR = 30.267 min
(major enantiomer), τR = 26.45 min (minor enantiomer); minor
diastereomer: τR = 25.008 min (major enantiomer), τR
=
28.5 min (minor enantiomer); (Chiralcel OJ-H, n-hexane–EtOH
99.4 : 0.6, 0.7 mL min−1, 230 nm).
2-Methyl-5-(2-nitropropan-2-yl)cyclohexanone (13C). Colour-
less solid; M.P.: Compound decomposes above 189 °C; [α]2D5:
+9.67 (c = 0.34, CHCl3, 88% de, 76% ee); IR νmax (CHCl3):
Diethyl-2-(4-(3-ethoxy-3-oxopropyl)-3-oxocyclohexyl) malonate
(12B). Colourless liquid, [α]2D5: +7.91 (c = 1.92, CHCl3, 92%
de, 80% ee); IR νmax (CHCl3): 2982, 2937, 1751, 1735, 1725,
1719, 1710, 1369, 1247, 1222, 1178, 1154; 1H NMR (400 MHz,
CDCl3) δ ppm: 1.21–1.30 (m, 9 H), 1.31–1.44 (m, 1 H),
1.48–1.63 (m, 2 H), 1.94–2.17 (m, 3 H), 2.25–2.55 (m, 6 H),
3.27–3.31 (d, J = 7.53 Hz, 1 H), 4.11 (q, J = 7.28 Hz, 2 H), 4.20
(qd, J = 7.19, 3.26 Hz, 4 H); 13C NMR (101 MHz, CDCl3) δ
ppm: 14.0, 14.2, 24.3, 29.3, 31.7, 31.9, 39.1, 45.5, 48.9, 57.0,
60.3, 61.5, 167.7, 167.8, 173.5, 209.8; m/z (%): 379.14 (M +
Na, 100), 368.5 (2), 151.44 (1); Elemental analysis calcd (%) for
C18H28O7: C 60.66, H 7.92; found: C 60.44, H 7.67;
HRMS-ESI (m/z): [M + Na]+ calcd for C18H28O7Na, 379.1727;
found, 379.1738. HPLC: major diastereomer: τR = 48.5 min
(major enantiomer), τR = 57.14 min (minor enantiomer); minor
diastereomer: τR = 40.5 min (major enantiomer), τR = 37.5 min
(minor enantiomer); (Chiralcel OD-H, n-hexane–EtOH
98.5 : 1.5, 0.5 mL min−1, 230 nm).
1
3019, 2400, 1540, 1475, 1215, 758, 66; H NMR (500 MHz,
CDCl3) δ ppm: 0.97 (td, J = 7.32, 2.44 Hz, 0.6 H), 1.04 (d, J =
6.41 Hz, 3 H), 1.12–1.17 (m, 0.4 H), 1.30–1.39 (m, 1 H),
1.49–1.55 (m, 1 H), 1.58 (s, 3 H), 1.57 (s, 2 H), 1.76–1.82 (m,
1 H), 2.11–2.19 (m, 2 H), 2.30–2.44 (m, 3 H); 13C NMR
(126 MHz, CDCl3) δ ppm 14.1, 22.5, 23.8, 26. 6, 33.7, 42.8,
44.7, 47.6, 90.6, 210.1; m/z (%): 254.06 (20), 222.05 (M + Na,
100), 102.31 (5); Elemental analysis calcd (%) for C10H17NO3:
C 60.28, H 8.60, N 7.03; found: C 60.32, H 8.77; N 7.15;
HPLC: major diastereomer: τR = 19.008 min (major enantiomer),
τR = 22.358 min (minor enantiomer); minor diastereomer: τR
=
20.417 min (major enantiomer); τR = 21.283 min (minor enantio-
mer); (Chiralcel OD-H, petroleum ether–i-propanol 95 : 05,
0.5 mL min−1, 230 nm).
Diethyl 2-(4-ethyl-3-oxocyclohexyl)malonate (14B). Colour-
less liquid, [α]2D5: +5.04 (c = 1.2, CHCl3, 50% de, 76%); IR νmax
1
Dimethyl 2-(4-methyl-3-oxocyclohexyl)malonate (13A). Col-
ourless liquid, [α]2D5: +3.98 (c = 1.08, CHCl3, 98% de, 58% ee);
IR νmax (CHCl3): 2935, 2956, 1735, 1713, 1436, 1251, 1157; 1H
NMR (400 MHz, CDCl3) δ ppm: 1.02 (d, J = 6.53 Hz, 3 H),
1.38 (qd, J = 13.09, 3.39 Hz, 1 H), 1.58 (qd, J = 12.72, 3.51 Hz,
1 H), 1.88–1.98 (m, 1 H), 2.09 (ddd, J = 13.24, 6.09, 3.26 Hz, 1
H), 2.25–2.54 (m, 4 H), 3.34 (d, J = 7.78 Hz, 1 H), 3.74 (s, 3
H), 3.75 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ ppm: 14.2,
29.4, 33.9, 39.1, 44.7, 45.1, 52.5, 56.8, 168.1, 168.2, 210.6; m/z
(%): 281.15 (M + K, 100), 265.49 (M + Na, 42), 257.14 (10);
Elemental analysis calcd (%) for C12H18O5: C 59.94, H 7.35;
found: C 60.06, H 7.13; HRMS-ESI (m/z): [M + Na]+ calcd for
C12H18O5Na, 265.1046; found, 265.1054. HPLC: major diaster-
eomer: τR = 74.26 min (major enantiomer), τR = 67.33 min
(minor enantiomer); minor diastereomer: τR = 58.33 min (major
enantiomer), τR = 54.95 min (minor enantiomer); (Chiralcel
OD-H, n-hexane–EtOH 99.6 : 0.4, 0.5 mL min−1, 230 nm).
(CHCl3): 2937, 2872, 1750, 1732, 1716, 1224, 1174; H NMR
(400 MHz, CDCl3) δ ppm (diastereomeric mixture 3 : 1): 0.89
(td, J = 7.34, 1.63 Hz, 3 H), 1.27 (t, J = 7.03 Hz, 6 H),
1.34–1.48 (m, 1 H), 1.56–1.6 (m, 0.4 H), 1.65–1.94 (m, 4 H),
2.08–2.20 (m, 1 H), 2.22–2.33 (m, 1 H), 2.36–2.56 (m, 2 H),
2.61–2.72 (m, 0.51 H), 3.26–3.32 (m, 0.88 H), 3.45–3.49 (m,
0.11 H), 4.17–4.26 (m, 4 H); 13C NMR (101 MHz, CDCl3) δ
ppm (major diastereomer only): 14.0, 14.2, 29.4, 33.9, 39.0,
44.7, 45.2, 57.1, 61.5, 167.8, 167.9, 210.8; m/z (%): 323.3 (M +
K, 15), 307.15 (M + Na, 100), 284.27 (M + 1, 10); Elemental
analysis calcd (%) for C15H24O5: C 63.36, H 8.51; found: C
62.98, H 8.65; HPLC: major diastereomer: τR = 35.717 min
(major enantiomer), τR = 41.6 min (minor enantiomer); minor
diastereomer: τR = 26.892 min (major enantiomer), τR
=
33.792 min (minor enantiomer); (Kromasil 5-Amycoat, n-
hexane–EtOH 98.0 : 02, 0.7 mL min−1, 230 nm).
Dimethyl 2-(4-methyl-3-oxo-1-phenylhexyl) malonate (16A).
Diethyl 2-(4-methyl-3-oxocyclohexyl)malonate (13B). Colour-
less liquid, [α]2D5: +5.26 (c = 5.25, CHCl3, 16% de, 76% ee); IR
νmax (CHCl3): 2964, 2937, 1715, 1733, 1713, 1243, 1156, 1032.
1H NMR (diastereomeric mixture 3 : 2) M + K M + K
(400 MHz, CDCl3) δ ppm: 1.03 (d, J = 6.53 Hz, 2.26 H), 1.10
(d, J = 7.03 Hz, 0.75 H), 1.27 (td, J = 7.09, 1.63 Hz, 6 H), 1.38
(qd, J = 13.13, 3.26 Hz, 0.8 H), 1.53–1.71 (m, 1.3 H), 1.89–2.00
(m, 1.27 H), 2.05–2.14 (m, 0.75 H), 2.27–2.54 (m, 4 H),
3.24–3.32 (m, 1 H), 4.20 (qd, J = 7.11, 3.51 Hz, 4 H); 13C NMR
(diastereomeric mixture 3 : 2) (101 MHz, CDCl3) δ ppm: 11.6,
11.7, 14.1, 21.8, 23.5, 25.0, 28.6, 29.4, 31.3, 37.8, 39.1, 42.8,
45.5, 51.2, 51.5, 56.0, 57.1, 61.5, 61.6, 61.7, 77.3, 167.8, 167.9,
Colourless liquid, IR νmax (CHCl3): 2963, 1752, 1735, 1710,
1434, 1253, 1157; H NMR (400 MHz, CDCl3) δ ppm (diaster-
1
eomeric mixture 1 : 1): 0.61–0.70 (m, 1 H), 0.74 (t, J = 7.40 Hz,
2 H), 0.87 (d, J = 7.03 Hz, 1 H), 0.94 (d, J = 6.78 Hz, 2 H),
1.17–1.33 (m, 1 H), 1.53 (ddt, J = 18.51, 14.05, 6.93, 6.93 Hz,
1 H), 2.31 (dq, J = 15.65, 6.83 Hz, 1 H), 2.86–3.07 (m, 2 H),
3.51 (s, 2 H), 3.56 (brs., 1 H), 3.71–3.84 (m, 4 H), 4.01 (ddt, J =
11.67, 9.10, 2.42, 2.42 Hz, 1 H), 7.14–7.35 (m, 5 H); 13C NMR
(101 MHz, CDCl3) δ ppm (diastereomeric mixture 1 : 1): 11.2,
11.5, 15.2, 15.4, 25.5, 25.5, 40.3, 44.6, 44.7, 47.9, 48.1, 52.3,
52.6, 57.0, 127.1, 128.1, 128.4, 140.6, 168.1, 168.6, 211.7; m/z
(%): 359 (M + K, 10), 343 (M + Na, 100), 321 (M + H, 30),
8266 | Org. Biomol. Chem., 2012, 10, 8260–8267
This journal is © The Royal Society of Chemistry 2012

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Tetrahedron, 2004, 60, 9569; (b) Y. Haruta, K. Onizuka, K. Watanabe,
K. Kono, A. Nohara, K. Kubota, S. Imoto and S. Sasaki, Tetrahedron,
2008, 64, 7211; (c) J. Jiricek and S. Blechert, J. Am. Chem. Soc., 2004,
126, 3534.
4 (a) K. Majima, R. Takita, A. Okada, T. Ohshima and M. Shibasaki,
J. Am. Chem. Soc., 2003, 125, 15837; (b) K. Majima, S. Y. Tosaki,
T. Ohshima and M. Shibasaki, Tetrahedron Lett., 2005, 46, 5377;
(c) Y. Xu, K. Ohori, T. Ohshima and M. Shibasaki, Tetrahedron, 2002,
58, 2585.
5 (a) R. Dalpozzo, G. Bartoli and G. Bencivenni, Symmetry, 2011, 3, 84;
(b) D. Almaşi, D. A. Alonso and C. Nájera, Tetrahedron: Asymmetry,
2007, 18, 299; (c) S. B. Tsogoeva, Eur. J. Org. Chem., 2007, 1701;
(d) R. Dalpozzo, G. Bartoli and G. Bencivenni, Eur. J. Org. Chem.,
2002, 1877; (e) O. M. Berner, L. Tedeschi and D. Ender, Eur. J. Org.
Chem., 2002, 1877.
274 (37), 239 (34); Elemental analysis calcd (%) for C18H24O5:
C 67.48, H 7.55; found: C 67.78, H 7.37; HRMS-ESI (m/z):
[M + Na]+ calcd for C18H24O5Na, 343.1516; found, 343.1522.
HPLC: major diastereomer: τR = 20.500 min (major enantiomer),
τR = 24.033 min (minor enantiomer); minor diastereomer: τR
=
32.325 min (major enantiomer); τR = 42.231 min (minor enantio-
mer); (Kromasil 5-Amycoat, EtOH–n-Hexane 7.0 : 93.0, 0.5 mL
min−1, 230 nm).
Diethyl 2-(4-methyl-3-oxo-1-phenylhexyl)malonate (16B).
Colourless liquid, IR νmax (CHCl3): 2966, 1788, 1734, 1722,
1
1369, 1299, 1250; H NMR (500 MHz, CDCl3) δ ppm (diaster-
eomeric mixture 4 : 1): 0.64 (t, J = 7.48 Hz, 1.5 H), 0.73 (t, J =
7.48 Hz, 1.5 H), 0.86 (d, J = 7.02 Hz, 1.5 H), 0.93 (d, J = 7.02
Hz, 1.5 H), 1.01 (t, J = 7.17 Hz, 3 H), 1.16–1.31 (m, 4 H),
1.45–1.58 (m, 1 H), 2.30 (dq, J = 18.92, 6.82 Hz, 1 H),
2.85–3.04 (m, 2 H), 3.73 (dd, J = 9.92, 1.68 Hz, 1 H), 3.95 (q,
J = 7, 2 H), 3.98–4.03 (m, 1 H), 4.20 (qdd, J = 7.12, 7.12, 7.12,
2.29, 1.07 Hz, 2 H), 7.15–7.20 (m, 1 H), 7.23–7.26 (m, 4 H);
13C NMR (126 MHz, CDCl3) δ ppm (diastereomeric mixture
4 : 1): 11.2, 11.5, 13.7, 14.0, 15.2, 15.4, 40.3, 44.9, 44.9, 47.9,
48.1, 57.3, 61.3, 61.5, 127.0, 128.3, 167.7, 168.3 211.7, 211.8;
m/z (%): 256.92 (100), 387.01 (M + K, 8), 371.94 (M + Na, 31),
370.94 (98), 349.07 (M + 1, 95), 302.92 (81); Elemental analysis
calcd (%) for C20H28O5: C 68.94, H 8.10; found: C 68.78, H
8.34; HRMS-ESI (m/z): [M + Na]+ calcd for C20H28O5Na,
6 Selected references for the total synthesis using dihydrocarvone,
menthone, isopulegone(a) H. M. Cheng, W. Tian, P. A. Peixoto,
B. Dhudshia and D. Y.-K. Chen, Angew. Chem., Int. Ed., 2011, 50, 4165;
(b) D. M. Hodgson, S. Salik and D. J. Fox, J. Org. Chem., 2010, 75,
2157; (c) M. E. Flanagan, T. A. Blumenkopf, W. H. Brissette,
M. F. Brown, J. M. Casavant, C. Shang-Poa, J. L. Doty, E. A. Elliott,
M. B. Fisher, M. Hines, C. Kent, E. M. Kudlacz, B. M. Lillie,
K. S. Magnuson, S. P. McCurdy, M. J. Munchhof, B. D. Perry,
P. S. Sawyer, T. J. Strelevitz, C. Subramanyam, J. Sun, D. A. Whipple
and P. S. Changelian, J. Med. Chem., 2010, 53, 8468; (d) M. Friedel,
G. Golz, P. Mayer and T. Lindel, Tetrahedron Lett., 2005, 46, 1623;
(e) A. Hartikka and P. I. Arvidsson, Tetrahedron: Asymmetry, 2004, 15,
1831; (f) B. A. Sÿolaja, N. Terzic, G. Pocsfalvi, L. Gerena, B. Tinant,
D. Opsenica and W. K. Milhous, J. Med. Chem., 2002, 45, 3331.
7 (a) J. Yang, T. Wang, Z. Ding, Z. Shen and Y. Zhang, Org. Biomol.
Chem., 2009, 7, 2208; (b) Y. Wang, Z. Shen, B. Li, Y. Zhang and
Y. Zhang, Chem. Commun., 2007, 1284.
8 H. Pellissier, Adv. Synth. Catal., 2011, 353, 659.
9 K. R. Knudsen, C. E. T. Mitchell and S. V. Ley, Chem. Commun., 2006,
66.
10 Enone 6 was selected for optimization of the reaction conditions as
masked ketone functionality at the 4th position was visualized as an
additional handle for the synthesis of highly substituted cyclohexanone
moiety.
11 CCDC-861580 contains the supplementary crystallographic data for this
paper.†
371.1829; found, 371.1841. HPLC: major diastereomer: τR
=
35.342 min (major enantiomer), τR = 39.825 min (minor enantio-
mer); minor diastereomer: τR = 68.767 min (major enantiomer);
τR = 78.158 min (minor enantiomer); (Kromasil 5-Amycoat,
i-PrOH–n-Hexane 2.5 : 97.5, 0.5 mL min−1, 230 nm).
12 Computational studies for better understanding of the transition state to
justify the observed relative trans stereochemical outcome is planned in
future.
13 A. J. A. Cobb, D. M. Shaw and S. V. Ley, Synlett, 2004, 558.
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16 L. Zhang, L. Cui, X. Li, J. Li, S. Luo and J.-P. Cheng, Eur. J. Org.
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Acknowledgements
We gratefully acknowledge Mrs Sunita Kunte, Dr Rahul
Banerjee and Mr Tamas Panda, Dr Rajmohanan and his group
for helping with HPLC analysis, X-ray crystallography and
NMR studies, respectively. The authors would like to thank
DST-India for funding. P. A. thanks CSIR, New-Delhi, for the
Research Fellowship.
17 P. Li, S. Wen, F. Yu, Q. Liu, W. Li, Y. Wang, X. Liang and J. Ye, Org.
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Notes and references
19 At this moment, we are not very sure on the exact role of the base in
DKR, however, from the studies mentioned above it is clear that changing
base affects diastereoselectivity as well as enantioselectivity. It may be
possible that malonate and base forms contact ion pair which participates
in the addition reaction affecting diastereoselectivity and enantioselectiv-
ity (see: A. J. A. Cobb, D. A. Longbottom, D. M. Shaw and S. V. Ley,
Chem. Commun., 2004, 1808).
20 It might be due to the conformation of 7-substituted cycloheptenone but
at present we are unable to reason this observation.
21 We limited our studies to the use of dimethyl and diethyl malonate only,
owing to the utility of the Michael addition product.(a) A. P. Krapcho,
Synthesis, 1982, 805; (b) A. P. Krapcho, Synthesis, 1982, 893.
1 (a) B. E. Rossiter and N. M. Swingle, Chem. Rev., 1992, 92, 771–808;
(b) P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
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2 (a) B. E. Rossiter and N. Swingle, Chem. Rev., 1992, 92, 771;
(b) M. P. Sibi and S. Manyem, Tetrahedron, 2000, 56, 8033;
(c) N. Krause and A. Hoffmann-Röder, Synthesis, 2001, 171;
(d) S. C. Jha and N. N. Joshi, Arkivoc, 2002, vii, 167; (e) T. Hayashi and
K. Yamasaki, Chem. Rev., 2003, 103, 2829; (f) J. Comelles, M. Moreno-
Mañas and A. Vallribera, Arkivoc, 2005, ix, 207.
3 Selected references for the synthetic utility of dimethyl 2-(3-oxocyclo-
hexyl)malonate: (a) T. Ohshima, Y. Xu, R. Takita and M. Shibasaki,
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