Asymmetric organocatalytic desymmetrization of 4,4-disubstituted cyclohexadienones at high pressure: A new powerful strategy for the synthesis of highly congested chiral cyclohexenones

Article abstract of DOI:10.1039/c4ob00733f

A highly diastereoselective and enantioselective method for the asymmetric desymmetrization of 4,4-disubstituted cyclohexadienones using the Michael addition reaction of malonates under catalysis with the primary amine-thiourea conjugate catalyst and PPY at high pressure was developed. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00733f

Volume 12 Number 31 21 August 2014 Pages 5791–6016
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
ISSN 1477-0520
PAPER
Hiyoshizo Kotsuki et al.
Asymmetric organocatalytic desymmetrization of 4,4-disubstituted
cyclohexadienones at high pressure: a new powerful strategy for the
synthesis of highly congested chiral cyclohexenones

Organic &
Biomolecular Chemistry
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PAPER
Asymmetric organocatalytic desymmetrization
of 4,4-disubstituted cyclohexadienones at high
pressure: a new powerful strategy for the synthesis
of highly congested chiral cyclohexenones†
Cite this: Org. Biomol. Chem., 2014,
12, 5847
Naomu Miyamae, Naruhisa Watanabe, Maya Moritaka, Keiji Nakano,
Yoshiyasu Ichikawa and Hiyoshizo Kotsuki*
Received 7th April 2014,
Accepted 14th May 2014
A highly diastereoselective and enantioselective method for the asymmetric desymmetrization of 4,4-
disubstituted cyclohexadienones using the Michael addition reaction of malonates under catalysis with
the primary amine–thiourea conjugate catalyst and PPY at high pressure was developed.
DOI: 10.1039/c4ob00733f
www.rsc.org/obc
Introduction
Asymmetric desymmetrization can provide a powerful and
highly expedient strategy for the construction of two or more
new chiral stereogenic centers from prochiral compounds in a
single-step operation. Accordingly, a variety of methods that
use both enzymatic and non-enzymatic processes have been
developed that show high to excellent enantioselectivity, and
most involve the intrinsic nature of meso-anhydrides, epoxides
and diols.2 In addition to these precedents, recent efforts have
been directed to explore the versatile utility of organocatalytic
transformations.3 These include, for example, functionali-
zation of meso-diols and anhydrides,4 aldol and related reac-
tions,5 discrimination of cyclohexadienes,2f,6 Baeyer–Villiger
oxidation of cyclobutanones,7 and others.8 Among these, we
were particularly interested in devising an efficient method for
differentiating between the two double bonds in 4,4-disubsti-
tuted cyclohexadienones based on organocatalytic asymmetric
Michael addition reactions, since functionalized cyclo-
hexenones or cyclohexanones are important key components
in synthetic and natural products chemistry.9
Fig. 1 Catalysts A and B.
challenge for the synthesis of cyclohexenone derivatives con-
taining up to two stereocenters, in which an all-carbon qua-
ternary stereogenic center was part of the stereoarray. In view
of the great advances in the organocatalytic construction of
quaternary stereogenic carbon centers,11 this should contri-
bute to progress in this field. Herein, we report a highly success-
ful method for realizing this expectation by taking advantage
of our recent findings on asymmetric Michael addition reac-
tions using a dual catalyst system composed of the primary
amine–thiourea conjugate catalyst A or B and 4-pyrrolidino-
pyridine (PPY) (Fig. 1).12
Although there have been reports on intramolecular
approaches to the desymmetrization of cyclohexadienones,6g,h, j–n
to the best of our knowledge, very little information is avail-
able on intermolecular variants.6p,10 Presumably, this might be
the result of severe steric congestion at β-carbon atoms.
Despite this fairly limited accessibility, we thought that the
asymmetric discrimination of cyclohexadienones based on an
intermolecular Michael addition strategy would be a great
Results and discussion
The starting 4,4-disubstituted cyclohexadienones 1a–f used in
this work were prepared by α-selenylation followed by oxidative
elimination of the corresponding cyclohexenone precursors,13
which were readily accessible from α,α′-disubstituted acet-
aldehydes and methyl vinyl ketone via Robinson-type annula-
tion.14 On the other hand, 4-methyl-4-trichloromethyl-2,2-
cyclohexadienone (1g) was prepared from p-cresol by the
Zincke–Suhl reaction, as described in the literature.15
Laboratory of Natural Products Chemistry, Faculty of Science, Kochi University,
Akebono-cho, Kochi 780-8520, Japan. E-mail: kotsuki@kochi-u.ac.jp
†See ref. 1. Electronic supplementary information (ESI) available: See DOI:
10.1039/c4ob00733f
First, we examined the asymmetric desymmetrization of
4-methyl-4-phenyl-2,5-cylohexadienone (1a) through the Michael
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Table 1 Catalytic asymmetric desymmetrization: optimizationa
Entry
1a : 2
Cat. A (mol%)
PPY (mol%)
Conditions
Yieldb (%)
dr (3a/4a)c
ee (%) (3a/4a)d
1
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 3
3 : 1
3 : 1
10
10
10
30
30
30
30
30
30
10
10
10
30
30
30
30
30
30
4.5 days
11
22
90/10
88/12
92/82
94/86
2
0.8 GPa, 24 h
0.8 GPa, 24 h
0.8 GPa, 2 days
0.8 GPa, 3 days
0.8 GPa, 2 days
0.6 GPa, 2 days
0.4 GPa, 2 days
0.8 GPa, 2 days
3e
4f
5
Trace
54
87/13
85/15
84/16
89/11
89/11
84/16
88/82
94/88
92/86
94/86
92/76
−92/−85
46g
82
6
7
73
54
82
8
3 : 1
3 : 1
9h
a Reactions performed at a concentration of 0.2 M in the solvent listed. b Combined yields of isolated products 3a and 4a. Yields based on the
reacted 1a (entries 1–5) or 2 (entries 6 and 7). c Determined by 1H NMR (500 MHz). d Determined by chiral HPLC analysis using Chiralcel AD
(hexane–i-PrOH = 90 : 10, flow rate 1.0 mL min−1, λ = 254 nm). e THF was used as a solvent. f 0.5 M in the solvent. g By-product 5 was isolated in
43% yield. h Catalyst B was used in place of catalyst A.
addition reaction of diethyl malonate (2). The results are sum-
marized in Table 1.
Under our previously established standard conditions with
10 mol% of catalyst A and 10 mol% of PPY at atmospheric
pressure,12a the desired reaction proceeded sluggishly to afford
the desymmetrization products, the anti-adduct 3a and the
syn-adduct 4a, with high diastereo- and enantioselectivity, but
Fig. 2 By-product 5.
in only 11% yield (entry 1). We applied a high-pressure tech-
nique to accelerate this reaction,12b,16 and observed that the
toluene at 0.8 GPa and rt for 2 days in the presence of 30 mol%
of the respective catalyst A and PPY. Various 4-alkyl-4-aryl-di-
pressure played an essential role in the present system
(entry 2). Consistent with our previous observations,17 when
THF was used as a solvent, the reaction was completely sup- substituted cyclohexadienones 1b–f reacted smoothly with 2 to
give the products in good yields (up to 99%) and with high dia-
pressed, which indicated that a hydrogen-bonding interaction
between the substrate and the catalyst may be inhibited in this
stereo- (up to 93 : 7) and enantioselectivity (up to 93% ee for 3
HBD solvent (entry 3).18 While an increase in the catalyst and 99% ee for 4). When the size of the 4-alkyl group was
loading to 30 mol% improved the product yield (entry 4),19
increased from Me to Et (compare 3a with 3b), the diastereo-
selectivity significantly decreased, while the enantioselectivity
large amount of the double-Michael adduct 5 due to the ease remained roughly the same. Unexpectedly, cyclohexadienone
the use of 3 equiv. of 2 resulted in the formation of a
1g could react only very slowly even with 1 equiv. of 2 at
0.8 GPa for 4 days and the product 3g was obtained as an
of the second-step reaction (entry 5) (Fig. 2).
After several experiments, we concluded that this problem
could be easily solved using an excess of 1a, and the products almost single diastereomer in 10% yield with 33% ee.
The absolute configurations of the products 3a and 4a were
determined unambiguously by conversion to the corres-
3a and 4a were obtained in 82% combined yield with high
diastereo- (3a/4a = 84 : 16) and enantioselectivity (3a, 92% ee;
4a, 86% ee) (entry 6). In this case we also recognized the criti- ponding cyclohexanone derivatives 7 and 10, and by compari-
son of their optical rotations with those of the authentic
samples prepared independently from optically pure (R)-cyclo-
hexenone 814 (Scheme 1). Thus, catalytic hydrogenation of 3a
in EtOH as a solvent at rt in the presence of a catalytic amount
of Pd/C afforded 7, [α]2D7 +5.4 (c = 0.49, EtOH, 92% ee), in 36%
cal factor of pressure and yields decreased at lower pressures
(entries 6–8).12b As expected, the use of catalyst B completely
reversed this desymmetrization dictation (entry 9).
With our optimized reaction conditions in hand, we then
explored the general scope of the reaction, and the results are
summarized in Table 2.20 All reactions were performed in yield21 without the loss of diastereomeric and enantiomeric
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Table 2 Catalytic asymmetric desymmetrization: generalitya
a Reactions performed at a concentration of 0.2 M in toluene. b The combined yield of isolated products 3 and 4, and based on the reacted 2. The
absolute configuration of the products was surmised in analogy with 3a. c By-product 6 was formed in 8% yield. d Determined by 1H NMR
(500 MHz). e Determined by chiral HPLC analysis using Chiralcel AD (hexane–i-PrOH = 90 : 10, flow rate 1.0 mL min−1, λ = 254 nm) except for 3b,
3e (hexane–i-PrOH = 95 : 5, flow rate 0.5 mL min−1), and 3f (hexane–i-PrOH = 99 : 1, flow rate 0.5 mL min−1).
excess. On the other hand, the authentic sample of (3S,4R)-9, favorable axial position.22 On the other hand, the interaction
[α]2D6 −5.8 (c = 1.0, EtOH, 97% ee), was prepared from 8 and 2 between the C4 methyl and the C3 methine in (3R,4R)-11
in 77% yield with high anti-selectivity (syn/anti = 7 : 93) via the reflected the existence of a severe steric repulsion between the
diastereoselective Michael addition reaction using catalyst B at equatorial phenyl ring and the axial malonate substituent.
atmospheric pressure and rt for 2.5 days. The results of optical
Based on the experimental results described above and our
rotation revealed that 7 and 9 are enantiomers of each other, recent studies, we propose a mechanism to account for the
and hence 7 has a (3R,4S)-configuration for the all-carbon sub- present high level of asymmetric desymmetrization of cyclo-
stituted quaternary stereogenic center and the adjacent tertiary hexadienones (Fig. 4).12,16 First, the dual catalyst system com-
stereogenic center, and therefore also for the corresponding posed of catalyst A and PPY can activate both 2 as a Michael
moieties in 3a. In a similar manner, the absolute configuration donor via double hydrogen bonding with a thiourea part of
of 4a was determined to be (3R,4R) after it was reduced to 10; catalyst A and 1a as a Michael acceptor by anchoring to form
this compound was in good agreement with (3R,4R)-11 derived the ketiminium ion intermediate with a free amine part of
from (R)-8 with the assistance of catalyst A. The latter reaction catalyst A (I). After proton abstraction by PPY, the resulting
proceeded fairly slowly due to steric congestion at the C3 posi- malonate anion then attacks one of the two enantiotopic
tion, but with good syn-selectivity (syn/anti = 86 : 14) as a result double bonds from the less-hindered side opposite a rather
of the so-called catalyst control. Meanwhile, the relative stereo- bulky phenyl ring in an intramolecular fashion (II). As a result
chemistry of syn- and anti-adducts, i.e., (3S,4R)-9 and (3R,4R)- of the main control from the cyclohexanediamine chiral motif
11, was confirmed by NOESY experiments (Fig. 3). Thus, of catalyst A, high discrimination would be enforced to
(3S,4R)-9 revealed an NOE interaction between the C4 methyl give the desired chiral adduct (III), 3a after hydrolysis, which is
and the malonate proton, indicating that a phenyl ring has a consistent with the experimental results.
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Scheme 1 Determination of the absolute configurations of the products 3a and 4a.
Fig. 3 NOESY experiments on (3S,4R)-9 and (3R,4R)-11 (500 MHz,
CDCl3). Characteristic correlations are shown. Important vicinal coupling
constants are indicated by dashed arrows.
Conclusions
Fig. 4 Plausible mechanism.
In conclusion, we have developed a highly diastereoselective
and enantioselective method for the asymmetric desymmetri-
zation of 4,4-disubstituted cyclohexadienones using the
Michael addition reaction of malonates under catalysis with
the primary amine–thiourea conjugate catalyst A or B and PPY
at high pressure. This method is particularly useful for con-
structing highly functionalized cyclohexenones containing a
quaternary carbon stereogenic center and two contiguous
stereocenters in only one step. Further studies on the appli-
cation of this method to natural product synthesis are now in
progress in our laboratory.
Experimental section
Typical procedure for the asymmetric desymmetrization of 1a
(Table 1, entry 6)
A mixture of 1a (166 mg, 0.9 mmol) and diethyl malonate
(2, 48 mg, 0.3 mmol) in the presence of catalyst A (34.7 mg,
30 mol%) and PPY (13.3 mg, 30 mol%) in toluene (1.4 mL) was
placed in a Teflon reaction vessel and the mixture was allowed
to react at 0.8 GPa and rt for 2 days. After the pressure was
released, the mixture was concentrated and purified by
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column chromatography on alumina (eluted with hexane– Diethyl 2-((1S,2R)-1-ethyl-4-oxo-1,2,3,4-tetrahydro-
AcOEt) to give 3a (71.4 mg, 69%) and 4a (13.4 mg, 13%) along [1,1′-biphenyl]-2-yl)malonate (3b)
with the recovered 1a (103 mg).
Colorless oil; Rf 0.33 (hexane–AcOEt = 5 : 1); [α]2D6 +67.9 (c = 1.0,
1
EtOH, 91% ee); FTIR (KBr) ν 1754, 1730, 1684 cm−1; H NMR
(500 MHz, CDCl3) δ 0.84 (3H, t, J = 7.5 Hz), 1.14 (3H, t, J =
Diethyl 2-((1S,2R)-1-methyl-4-oxo-1,2,3,4-tetrahydro-
7.5 Hz), 1.28 (3H, t, J = 7.5 Hz), 1.87 (1H, dq, J = 13.5, 7.5 Hz),
[1,1′-biphenyl]-2-yl)malonate (3a)
2.18 (1H, dq, J = 13.5, 7.5 Hz), 2.49 (1H, dd, J = 17.5, 5.0 Hz),
Colorless oil; Rf 0.26 (hexane–AcOEt = 5 : 1); [α]2D5 +91.6 (c =
2.74 (1H, dd, J = 17.5, 10.5 Hz), 3.18 (1H, dt, J = 10.5, 5.0 Hz),
0.93, EtOH, 92% ee); FTIR (KBr) ν 1754, 1730, 1683 cm−1
;
3.47 (1H, d, J = 5.0 Hz), 3.98 (2H, q, J = 7.5 Hz), 4.13–4.23 (2H,
m), 6.22 (1H, d, J = 10.0 Hz), 6.97 (1H, d, J = 10.0 Hz),
7.25–7.38 (5H, m); 13C NMR (125.8 MHz, CDCl3) δ 8.90, 13.83,
13.93, 25.11, 37.35, 46.12, 48.00, 51.45, 61.52, 61.67, 127.09,
127.58 (×2), 128.67 (×2), 128.98, 142.38, 155.67, 168.14, 168.66,
197.83; HRMS calcd for C21H26O5 358.1780, found 358.1777.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
95 : 5, 0.5 cm3 min−1): Rt (major) = 33.8 min; Rt (minor) =
36.7 min.
1H NMR (500 MHz, CDCl3) δ 1.10 (3H, t, J = 7.5 Hz), 1.28 (3H,
t, J = 7.5 Hz), 1.52 (3H, s), 2.59 (1H, dd, J = 17.0, 4.0 Hz), 2.71
(1H, dd, J = 17.0, 12.0 Hz), 3.27 (1H, ddd, J = 12.0, 5.5, 4.0 Hz),
3.35 (1H, d, J = 5.5 Hz), 3.80–3.92 (2H, m), 4.19 (2H, q, J =
7.5 Hz), 6.07 (1H, d, J = 10.0 Hz), 6.72 (1H, d, J = 10.0 Hz),
7.25–7.38 (5H, m); 13C NMR (125.8 MHz, CDCl3) δ 13.77, 13.96,
18.04, 37.64, 44.23, 44.52, 52.11, 61.54, 61.60, 126.96 (×2),
127.04, 127.31, 128.62 (×2), 144.31, 158.00, 167.80, 168.37,
198.11; HRMS calcd for C20H24O5 344.1624, found 344.1623.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
90 : 10, 1.0 cm3 min−1): Rt (major) = 12.6 min; Rt (minor) =
14.1 min.
Diethyl 2-((1R,2R)-1-ethyl-4-oxo-1,2,3,4-tetrahydro-
[1,1′-biphenyl]-2-yl)malonate (4b)
Colorless oil; Rf 0.26 (hexane–AcOEt = 5 : 1); [α]2D5 −29.9 (c =
0.48, EtOH, 86% ee); FTIR (KBr) ν 1759, 1730, 1683 cm−1
;
Diethyl 2-((1R,2R)-1-methyl-4-oxo-1,2,3,4-tetrahydro-
[1,1′-biphenyl]-2-yl)malonate (4a)
1H NMR (500 MHz, CDCl3) δ 0.90 (3H, t, J = 7.5 Hz), 1.10 (3H,
t, J = 7.5 Hz), 1.19 (3H, t, J = 7.5 Hz), 2.11 (1H, dq, J = 14.5,
7.5 Hz), 2.20 (1H, dq, J = 14.5, 7.5 Hz), 2.62 (1H, dd, J = 18.0,
5.0 Hz), 2.84 (1H, dd, J = 18.0, 9.5 Hz), 3.22 (1H, dt, J = 9.5,
5.0 Hz), 3.38 (1H, d, J = 5.0 Hz), 3.79 (2H, q, J = 7.5 Hz),
4.01–4.14 (2H, m), 6.25 (1H, d, J = 10.5 Hz), 6.93 (1H, d, J =
10.5 Hz), 7.27–7.37 (5H, m); 13C NMR (125.8 MHz, CDCl3)
δ 8.98, 13.69, 13.90, 31.66, 36.76, 41.83, 47.66, 51.97, 61.11,
61.78, 127.44, 128.21 (×2), 128.52 (×2), 129.49, 138.21, 154.21,
167.63, 168.68, 198.25; HRMS calcd for C21H26O5 358.1780,
found 358.1778.
Colorless oil; Rf 0.19 (hexane–AcOEt = 5 : 1); [α]2D5 −71.7 (c =
0.09, EtOH, 86% ee); FTIR (KBr) ν 1756, 1730, 1683 cm−1
;
1H NMR (500 MHz, CDCl3) δ 1.09 (3H, t, J = 8.5 Hz), 1.20 (3H,
t, J = 8.5 Hz), 1.67 (3H, s), 2.55 (1H, dd, J = 22.0, 6.0 Hz), 2.88
(1H, dd, J = 22.0, 14.0 Hz), 3.11 (1H, dt, J = 14.0, 6.0 Hz), 3.46
(1H, d, J = 6.0 Hz), 3.67–3.81 (2H, m), 4.03–4.16 (2H, m), 6.18
(1H, d, J = 12.0 Hz), 6.78 (1H, d, J = 12.0 Hz), 7.28–7.38 (5H,
m); 13C NMR (125.8 MHz, CDCl3) δ 13.72, 13.94, 26.51, 36.92,
43.91, 44.16, 51.91, 61.13, 61.89, 127.58, 127.89, 128.03 (×2),
128.45 (×2), 138.50, 155.80 (×2), 167.43, 168.64, 198.71; HRMS
calcd for C20H24O5 344.1624, found 344.1622.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
95 : 5, 0.5 cm3 min−1): Rt (major) = 28.2 min; Rt (minor) =
49.4 min.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
90 : 10, 1.0 cm3 min−1): Rt (major) = 10.7 min; Rt (minor) =
17.6 min.
Diethyl 2-((1S,2R)-4′-methoxy-1-methyl-4-oxo-1,2,3,4-
tetrahydro-[1,1′-biphenyl]-2-yl)malonate (3c)
Colorless oil; Rf 0.15 (hexane–AcOEt = 5 : 1); [α]2D6 +105.8 (c =
0.97, EtOH, 92% ee); FTIR (KBr) ν 1754, 1729, 1683, 1609,
Tetraethyl 2,2′-(2-methyl-5-oxo-2-phenylcyclohexane-1,3-diyl)-
dimalonate (by-product 5; Table 1, entry 5)
1514 cm−1 1H NMR (500 MHz, CDCl3) δ 1.12 (3H, t, J =
;
Colorless oil; Rf 0.15 (hexane–AcOEt = 5 : 1); FTIR (KBr) ν 1028, 7.0 Hz), 1.28 (3H, t, J = 7.0 Hz), 1.49 (3H, s), 2.60 (1H, dd, J =
1
1148, 1304, 1729 cm−1; H NMR (500 MHz, CDCl3)δ 1.07–1.26 17.5, 5.0 Hz), 2.71 (1H, dd, J = 17.5, 12.5 Hz), 3.22 (1H, dt, J =
(12H, m), 1.62 (3H, s), 2.64 (2H, dd, J = 5.3 Hz), 2.72–2.85 (3H, 12.5, 5.0 Hz), 3.35 (1H, d, J = 5.0 Hz), 3.81 (3H, s), 3.84–3.95
m), 3.17 (1H, d, J = 4.0 Hz), 3.40 (1H, d, J = 3.5 Hz), 3.64 (1H, (2H, m), 4.20 (2H, q, J = 7.0 Hz), 6.05 (1H, d, J = 10.0 Hz), 6.70
dt, J = 3.9, 13.0 Hz), 3.85–4.06 (6H, m), 4.09–4.19 (2H, m), (1H, d, J = 10.0 Hz), 6.89 (2H, m), 7.24 (2H, m); 13C NMR
7.24–7.27 (1H, m), 7.33–7.39 (4H, m); 13C NMR (125.8 MHz, (125.8 MHz, CDCl3) δ 13.80, 13.98, 18.07, 37.67, 43.63, 44.68,
CDCl3) δ 13.71, 13.78, 13.85, 13.92, 38.69, 39.10, 39.57, 43.58, 52.10, 55.27, 61.53, 61.65, 113.93 (×2), 126.87, 128.09 (×2),
46.31, 52.10, 52.36, 61.39, 61.48, 61.68, 61.75, 127.23, 127.47 136.29, 158.45, 158.63, 167.90, 168.47, 198.31; HRMS calcd for
(×2), 128.59 (×2), 142.69, 168.39, 168.45, 168.49, 168.55, C21H26O6 374.1729, found 374.1727.
208.41; HRMS calcd for C27H36O9 + H 505.2438, found
505.2437.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
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90 : 10, 1.0 cm3 min−1): Rt (major) = 15.9 min; Rt (minor) =
18.8 min.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
90 : 10, 1.0 cm3 min−1): Rt (major) = 19.3 min; Rt (minor) =
27.0 min.
Diethyl 2-((1R,2R)-4′-methoxy-1-methyl-4-oxo-1,2,3,4-
tetrahydro-[1,1′-biphenyl]-2-yl)malonate (4c)
Diethyl 2-((1S,2R)-1-methyl-4-oxo-1,2,3,4-tetrahydro-[1,1′:4′,1″-
terphenyl]-2-yl)malonate (3e)
Colorless oil; Rf 0.13 (hexane–AcOEt = 5 : 1); [α]2D5 −68.7 (c =
0.31, EtOH, 89% ee); FTIR (KBr) ν 1756, 1729, 1683, 1609,
Colorless oil; Rf 0.23 (hexane–AcOEt = 5 : 1); [α]2D6 +152.8 (c =
1513 cm−1 1H NMR (500 MHz, CDCl3) δ 1.11 (3H, t, J =
;
1.0, EtOH, 92% ee); FTIR (KBr) ν 1754, 1729, 1683 cm−1 1H
;
7.5 Hz), 1.22 (3H, t, J = 7.5 Hz), 1.64 (3H, s), 2.53 (1H, dd, J =
17.5, 4.5 Hz), 2.85 (1H, dd, J = 17.5, 11.5 Hz), 3.08 (1H, dt, J =
11.5, 4.5 Hz), 3.45 (1H, d, J = 4.5 Hz), 3.72–3.85 (2H, m), 3.80
(3H, s), 4.06–4.17 (2H, m), 6.15 (1H, d, J = 10.0 Hz), 6.74 (1H,
d, J = 10.0 Hz), 6.87 (2H, d, J = 9.0 Hz), 7.23 (2H, d, J = 9.0 Hz);
13C NMR (125.8 MHz, CDCl3) δ 8.99, 13.70, 13.91, 31.66, 36.76,
41.83, 47.66, 51.96, 61.12, 61.78, 127.44, 128.20 (×2), 128.53
(×2), 129.49, 138.21, 154.23, 167.64, 168.69, 198.27; HRMS
calcd for C21H26O6 374.1729, found 374.1737.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
90 : 10, 1.0 cm3 min−1): Rt (major) = 14.0 min; Rt (minor) =
23.6 min.
NMR (500 MHz, CDCl3) δ 1.10 (3H, t, J = 7.5 Hz), 1.30 (3H, t,
J = 7.5 Hz), 1.56 (3H, s), 2.64 (1H, dd, J = 17.5, 5.0 Hz), 2.74
(1H, dd, J = 17.5, 12.0 Hz), 3.32 (1H, dt, J = 12.0, 5.0 Hz), 3.41
(1H, d, J = 5.0 Hz), 3.80–3.94 (2H, m), 4.22 (2H, q, J = 7.5 Hz),
6.10 (1H, d, J = 10.0 Hz), 6.76 (1H, d, J = 10.0 Hz), 7.34–7.46
(5H, m), 7.58–7.61 (4H, m); 13C NMR (125.8 MHz, CDCl3)
δ 13.79, 13.98, 18.08, 37.70, 44.07, 44.50, 52.26, 61.58, 61.68,
126.92 (×2), 127.11, 127.25 (×2), 127.47 (×3), 128.81 (×2),
140.14, 140.22, 143.32, 157.92, 167.83, 168.39, 198.09; HRMS
calcd for C26H28O5 420.1937, found 420.1936.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD-H column, 0.46 × 25 cm, hexane–i-PrOH =
95 : 5, 0.5 cm3 min−1): Rt (major) = 71.7 min; Rt (minor) =
86.6 min.
Diethyl 2-((1S,2R)-4′-bromo-1-methyl-4-oxo-1,2,3,4-tetrahydro-
[1,1′-biphenyl]-2-yl)malonate (3d)
Diethyl 2-((1R,2R)-1-methyl-4-oxo-1,2,3,4-tetrahydro-[1,1′:4′,1″-
Colorless oil; Rf 0.20 (hexane–AcOEt = 5 : 1); [α]2D5 +94.0 (c = terphenyl]-2-yl)malonate (4e)
0.87, EtOH, 93% ee); FTIR (KBr) ν 1755, 1729, 1684 cm−1
;
White solid, mp 74–79 °C; Rf 0.14 (hexane–AcOEt = 5 : 1); [α]D25
−88.5 (c = 0.06, EtOH, 87% ee); FTIR (KBr) ν 1759, 1725,
1H NMR (500 MHz, CDCl3) δ 1.12 (3H, t, J = 7.5 Hz), 1.28 (3H,
t, J = 7.5 Hz), 1.50 (3H, s), 2.59 (1H, dd, J = 17.0, 5.0 Hz), 2.69
(1H, dd, J = 17.0, 12.5 Hz), 3.21 (1H, dt, J = 12.5, 5.0 Hz), 3.31
(1H, d, J = 5.0 Hz), 3.83–3.95 (2H, m), 4.20 (2H, q, J = 7.5 Hz),
6.08 (1H, d, J = 10.0 Hz), 6.66 (1H, d, J = 10.0 Hz), 7.21 (2H, d,
J = 9.0 Hz), 7.49 (2H, d, J = 9.0 Hz); 13C NMR (125.8 MHz,
CDCl3) δ 13.78, 13.97, 18.06, 37.58, 44.03, 44.41, 52.09, 61.64,
61.77, 121.48, 127.36, 128.80 (×2), 131.72 (×2), 143.44, 157.08,
167.69, 168.20, 197.72; HRMS calcd for C20H23BrO5 422.0729,
found 422.0735.
1683 cm−1 1H NMR (500 MHz, CDCl3) δ 1.07 (3H, t, J =
;
7.5 Hz), 1.20 (3H, t, J = 7.5 Hz), 1.71 (3H, s), 2.59 (1H, dd, J =
17.5, 5.0 Hz), 2.91 (1H, dd, J = 17.5, 11.5 Hz), 3.15 (1H, dt, J =
11.5, 5.0 Hz), 3.51 (1H, d, J = 5.0 Hz), 3.67–3.81 (2H, m),
4.03–4.16 (2H, m), 6.20 (1H, d, J = 10.0 Hz), 6.81 (1H, d, J =
10.0 Hz), 7.31–7.46 (5H, m), 7.56–7.58 (4H, m); 13C NMR
(125.8 MHz, CDCl3) δ 13.72, 13.94, 26.58, 36.98, 43.73, 44.26,
52.02, 61.18, 61.92, 126.90 (×2), 127.00 (×2), 127.54, 127.94
128.55 (×2), 128.85 (×2), 137.57, 140.14, 140.35, 155.69, 167.50,
168.62, 198.61; HRMS calcd for C26H28O5 420.1937, found
420.1938.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
90 : 10, 1.0 cm3 min−1): Rt (major) = 21.6 min; Rt (minor) =
25.6 min.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD-H column, 0.46 × 25 cm, hexane–i-PrOH =
95 : 5, 0.5 cm3 min−1): Rt (major) = 67.5 min; Rt (minor) =
124.0 min.
Diethyl 2-((1R,2R)-4′-bromo-1-methyl-4-oxo-1,2,3,4-tetrahydro-
[1,1′-biphenyl]-2-yl)malonate (4d)
Tetraethyl 2,2′-(2-([1,1′-biphenyl]-4-yl)-2-methyl-5-
oxocyclohexane-1,3-diyl)dimalonate (6) (Table 2, footnote c)
White solid, mp 102–106 °C; Rf 0.18 (hexane–AcOEt = 5 : 1);
[α]2D5 −87.2 (c = 0.24, EtOH, 90% ee); FTIR (KBr) ν 1743, 1719,
1682 cm−1 1H NMR (500 MHz, CDCl3) δ 1.12 (3H, t, J = Colorless oil; Rf 0.08 (hexane–AcOEt = 5 : 1); FTIR (KBr) ν 1728,
;
1
7.0 Hz), 1.21 (3H, t, J = 7.0 Hz), 1.65 (3H, s), 2.58 (1H, dd, J = 1313, 1148, 1028 cm−1; H NMR (500 MHz, CDCl3) δ 1.09 (3H,
17.5, 4.5 Hz), 2.83 (1H, dd, J = 17.5, 10.5 Hz), 3.10 (1H, dt, J = t, J = 7.3 Hz), 1.15 (5H, dt, J = 4.3, 7.1 Hz), 1.24 (4H, t, J =
10.5, 4.5 Hz), 3.41 (1H, d, J = 4.5 Hz), 3.72–3.86 (2H, m), 7.0 Hz), 1.66 (3H, s), 2.67 (2H, dd, J = 5.5, 17.0 Hz), 2.76–2.91
4.04–4.16 (2H, m), 6.17 (1H, d, J = 10.0 Hz), 6.74 (1H, d, J = (3H, m), 3.24 (1H, d, J = 4.0 Hz), 3.44 (1H, d, J = 3.5 Hz), 3.66
10.0 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.47 (2H, d, J = 8.5 Hz); 13C (1H, dt, J = 4.0, 12.5 Hz), 3.84–4.07 (6H, m), 4.11–4.21 (2H, m),
NMR (125.8 MHz, CDCl3) δ 13.73, 13.93, 26.54, 36.83, 43.61, 7.36 (1H, t, J = 7.5 Hz), 7.44–7.47 (4H, m), 7.59 (4H, d, J =
44.10, 51.87, 61.32, 62.00, 121.91, 128.19, 129.81 (×2), 131.52 8.5 Hz); 13C NMR (125.8 MHz, CDCl3) δ 13.74, 13.81, 13.88,
(×2), 137.90, 154.87, 167.37, 168.44, 198.13; HRMS calcd for 13.96, 21.85, 38.86, 39.12, 39.58, 43.44, 46.30, 52.18, 52.30,
C20H23BrO5 422.0729, found 422.0747.
61.46, 61.52, 61.76, 61.82, 126.76 (×2), 127.02 (×2), 127.52,
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128.06 (×2), 128.88 (×2), 139.79, 140.00, 141.68, 168.40, 168.49 62.15, 107.73, 130.47, 148.76, 168.12, 168.23, 196.45; HRMS
(×2), 168.56, 208.48; HRMS calcd for C33H40O9 + H 581.2751, calcd for C15H19Cl3O5 + H 385.0376, found 385.0381.
found 581.2743.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
99 : 1, 1.0 cm3 min−1): Rt (minor) = 24.0 min; Rt (major) =
30.9 min.
Diethyl 2-((1S,6R)-4-oxo-3′,4′-dihydro-2′H-spiro[cyclohex[2]ene-
1,1′-naphthalen]-6-yl)malonate (3f)
Colorless oil; Rf 0.20 (hexane–AcOEt = 5 : 1); [α]2D6 +107.3 (c =
Diastereoselective Michael addition reaction of (R)-8 using
catalyst B
1.0, EtOH, 78% ee); FTIR (KBr) ν 1754, 1729, 1682 cm−1
;
1H NMR (500 MHz, CDCl3) δ 1.06 (3H, t, J = 7.5 Hz), 1.25 (3H,
t, J = 7.5 Hz), 1.67–1.76 (1H, m), 1.93–2.03 (2H, m), 2.26 (1H,
dt, J = 12.5, 2.5 Hz), 2.65 (1H, dd, J = 17.0, 5.0 Hz), 2.69 (1H,
dd, J = 17.0, 12.5 Hz), 2.76–2.81 (1H, m), 2.86 (1H, ddd, J =
16.0, 11.5, 5.0 Hz), 3.35 (1H, d, J = 5.5 Hz), 3.58–3.64 (2H, m),
3.73 (1H, ddd, J = 14.5, 11.0, 7.0 Hz), 4.15–4.21 (2H, m), 5.92
(1H, d, J = 10.0 Hz), 6.93 (1H, d, J = 10.0 Hz), 7.10–7.22 (4H,
m); 13C NMR (125.8 MHz, CDCl3) δ 13.74, 14.00, 19.94, 30.15,
30.33, 37.73, 43.36, 43.46, 53.07, 61.48, 61.55, 125.25, 126.56,
126.99, 128.11, 129.63, 138.36 (×2), 159.64, 167.68, 168.26,
197.94; HRMS calcd for C22H26O5 + H 371.1859, found
371.1834.
A mixture of (R)-8 (140 mg, 0.75 mmol; 97% ee)14 and diethyl
malonate (2, 180 mg, 1.125 mmol) in the presence of catalyst B
(29 mg, 10 mol%) and PPY (11 mg, 10 mol%) in toluene
(0.75 mL) was reacted at rt for 2.5 days (a small amount of
unreacted (R)-8 remained in the mixture). Then, the mixture
was concentrated and purified by column chromatography on
silica gel (eluted with hexane–AcOEt) to give (3S,4R)-9 (187 mg,
72%) as a colorless oil and its diastereomer (13 mg, 5%).
Diethyl 2-((1S,2R)-2-methyl-5-oxo-2-phenylcyclohexyl)-
malonate ((3S,4R)-9)
Colorless oil; Rf 0.20 (hexane–AcOEt = 5 : 1); [α]2D6 −5.8 (c = 1.0,
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD-H column, 0.46 × 25 cm, hexane–i-PrOH =
99 : 1, 0.5 cm3 min−1): Rt (minor) = 103.7 min; Rt (major) =
111.6 min.
EtOH, >97% ee); FTIR (KBr) ν 1751, 1720 cm−1 1H NMR
;
(500 MHz, CDCl3) δ 1.12 (3H, t, J = 7.5 Hz), 1.26 (3H, t, J =
7.5 Hz), 1.54 (3H, s), 1.82 (1H, ddd, J = 14.0, 6.0, 3.0 Hz), 2.23
(1H, dt, J = 14.0, 5.0 Hz), 2.42 (1H, m), 2.53–2.59 (2H, m), 2.79
(1H, dd, J = 15.5, 13.0 Hz), 3.17 (1H, d, J = 4.0 Hz), 3.30 (1H, dt,
J = 13.0, 4.0 Hz), 3.85–3.94 (2H, m), 4.12–4.23 (2H, m), 7.24
(1H, t, J = 7.5 Hz), 7.35 (2H, t, J = 7.5 Hz), 7.42 (2H, d, J = 7.5
Hz); 13C NMR (125.8 MHz, CDCl3) δ 13.82, 13.96, 17.54, 38.18,
40.49, 40.81, 40.90, 44.52, 52.46, 61.33, 61.56, 125.94 (×2),
126.76, 128.62 (×2), 145.84, 168.19, 168.53, 209.52; HRMS
calcd for C20H26O5 346.1780, found 346.1789.
Diethyl 2-((1R,6R)-4-oxo-3′,4′-dihydro-2′H-spiro[cyclohex[2]ene-
1,1′-naphthalen]-6-yl)malonate (4f)
White solid, mp 163–165 °C; Rf 0.21 (hexane–AcOEt = 5 : 1);
[α]2D5 +7.70 (c = 0.13, EtOH, >99% ee); FTIR (KBr) ν 1743, 1718,
1682 cm−1 1H NMR (500 MHz, CDCl3) δ 1.06 (3H, t, J =
;
7.5 Hz), 1.19 (3H, t, J = 7.5 Hz), 1.76–1.82 (1H, m), 1.89–1.96
(1H, m), 2.09–2.20 (2H, m), 2.64 (1H, dd, J = 17.5, 5.0 Hz), 2.82
(1H, dd, J = 17.5, 8.0 Hz), 2.84 (1H, dd, J = 17.5, 6.0 Hz), 2.96
(1H, ddd, J = 17.0, 7.0, 5.0 Hz), 3.38 (1H, q, J = 6.0 Hz), 3.57
(1H, d, J = 7.5 Hz), 3.62–3.68 (1H, m), 3.78–3.85 (1H, m),
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
90 : 10, 1.0 cm3 min−1): Rt (major) = 15.2 min.
3.92–4.04 (2H, m), 6.10 (1H, d, J = 10.5 Hz), 6.82 (1H, dd, J = Catalytic hydrogenation of 3a
10.5, 1.0 Hz), 7.09–7.18 (4H, m); 13C NMR (125.8 MHz, CDCl3)
To a solution of 3a (50 mg, 0.145 mmol) in EtOH (0.7 mL) was
δ 13.77 (×2), 18.71, 28.36, 33.37, 37.18, 40.61, 43.10, 52.60,
61.41, 61.57, 125.44, 127.39, 127.51, 129.55, 129.59, 137.38,
138.31, 156.27, 167.89, 168.54, 196.97; HRMS calcd for
C22H26O5 + H 371.1859, found 371.1856.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD-H column, 0.46 × 25 cm, hexane–i-PrOH =
95 : 5, 0.5 cm3 min−1): Rt (major) = 85.4 min.
added 10% Pd/C (5 mg), and the mixture was stirred under
hydrogen at rt. After consumption of the starting material
(1 h), the mixture was filtered and concentrated. The crude
sample was purified by column chromatography on silica gel
(eluted with hexane–AcOEt) to give (3R,4S)-7 (18 mg, 36%) as a
colorless oil.21
Diethyl 2-((1R,2S)-2-methyl-5-oxo-2-phenylcyclohexyl)-
malonate ((3R,4S)-7)
Diethyl 2-((1S,2R)-1-methyl-1-trichloromethyl-4-oxo-1,2,3,4-
tetrahydrophenyl)malonate (3g)
Colorless oil; Rf 0.20 (hexane–AcOEt = 5 : 1); [α]2D7 +5.4 (c = 0.49,
Colorless oil; Rf 0.30 (hexane–AcOEt = 5 : 1); [α]2D5 −10.5 (c = EtOH, 92% ee); FTIR (KBr) ν 1754, 1718 cm−1 1H NMR
;
0.50, EtOH, 33% ee); FTIR (KBr) ν 1747, 1731, 1691 cm−1
;
(500 MHz, CDCl3) δ 1.12 (3H, t, J = 7.0 Hz), 1.26 (3H, t, J =
1H NMR (500 MHz, CDCl3) δ 1.26 (3H, t, J = 7.5 Hz), 1.27 (3H, 7.0 Hz), 1.54 (3H, s), 1.83 (1H, ddd, J = 14.0, 6.0, 3.0 Hz), 2.24
t, J = 7.5 Hz), 1.65 (3H, s), 2.83 (1H, dd, J = 17.5, 6.0 Hz), 2.88 (1H, dt, J = 14.0, 5.0 Hz), 2.43 (1H, m), 2.53–2.60 (2H, m), 2.80
(1H, dd, J = 17.5, 9.0 Hz), 3.78 (1H, ddd, J = 9.0, 6.0, 2.5 Hz), (1H, dd, J = 15.0, 13.0 Hz), 3.18 (1H, d, J = 4.5 Hz), 3.30 (1H, dt,
4.11–4.27 (4H, m), 4.26 (1H, d, J = 2.5 Hz), 6.16 (1H, d, J = J = 13.0, 4.5 Hz), 3.86–3.95 (2H, m), 4.12–4.22 (2H, m), 7.24
11.0 Hz), 6.94 (1H, d, J = 11.0 Hz); 13C NMR (125.8 MHz, (1H, t, J = 7.5 Hz), 7.36 (2H, t, J = 7.5 Hz), 7.43 (2H, d, J =
CDCl3) δ 13.92, 14.02, 19.62, 37.87, 38.31, 53.04, 56.10, 61.70, 7.5 Hz); 13C NMR (125.8 MHz, CDCl3) δ 14.01, 14.15, 17.70,
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38.38, 40.68, 40.98, 41.08, 44.72, 52.64, 61.53, 61.76, 126.13
(×2), 126.95, 128.81 (×2), 146.01, 168.38, 168.74, 209.75; HRMS
calcd for C20H26O5 346.1780, found 346.1786.
Acknowledgements
We are grateful to Prof. Y. Fukuyama of Tokushima Bunri Uni-
The ee of the product was determined by chiral HPLC ana- versity for MS/HRMS measurements. Helpful discussions with
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH = Drs M. De Paolis and J. Maddaluno (Université de Rouen,
95 : 5, 1.0 cm3 min−1): Rt (major) = 15.4 min; Rt (minor) = France) are also acknowledged. This work was supported in
14.5 min.
part by a Grant-in-Aid for Scientific Research on Innovative
Areas “Advanced Molecular Transformations by Organocata-
lysts” from the MEXT (Japan) (no. 24105523 & 26105743).
Diastereoselective Michael addition reaction of (R)-8 using
catalyst A
A mixture of (R)-8 (140 mg, 0.75 mmol; 97% ee)14 and diethyl
malonate (2, 180 mg, 1.125 mmol) in the presence of catalyst A
(29 mg, 10 mol%) and PPY (11 mg, 10 mol%) in toluene
(0.75 mL) was reacted at rt for 6.5 days (a considerable amount
of unreacted (R)-8 remained in the mixture). Then, the mixture
was concentrated and purified by column chromatography on
silica gel (eluted with hexane–AcOEt) to give (3R,4R)-11 (96 mg,
37%) as a colorless oil and its diastereomer (16 mg, 6%). The
latter compound was indistinguishable from (3S,4R)-9 pre-
pared as above.
Notes and references
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Diethyl 2-((1R,2R)-2-methyl-5-oxo-2-phenylcyclohexyl)-
malonate ((3R,4R)-11)
Colorless oil; Rf 0.15 (hexane–AcOEt = 5 : 1); [α]2D8 +68.1 (c =
0.92, EtOH, >97% ee); FTIR (KBr) ν 1751, 1731, 1713,
1279 cm−1
;
1H NMR (500 MHz, CDCl3) δ 1.10 (3H, t, J = 7.5
Hz), 1.21 (3H, t, J = 7.5 Hz), 1.56 (3H, s), 2.03–2.07 (1H, m),
2.44–2.55 (3H, m), 2.63 (1H, dd, J = 17.5, 2.5 Hz), 2.78 (1H, dd,
J = 17.5, 7.0 Hz), 3.09 (1H, d, J = 3.5 Hz), 3.23 (1H, m),
3.90–4.01 (2H, m), 4.03–4.14 (2H, m), 7.21–7.25 (1H, m),
7.33–7.35 (4H, m); 13C NMR (125.8 MHz, CDCl3) δ 13.77, 13.83,
27.30, 30.17, 36.70, 39.40, 39.72, 44.18, 52.84, 61.38, 61.53,
125.86 (×2), 126.61, 128.59 (×2), 146.30, 168.94, 168.98, 208.51;
HRMS calcd for C20H26O5 346.1780, found 346.1779.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
90 : 10, 1.0 cm3 min−1): Rt (major) = 8.4 min.
Catalytic hydrogenation of 4a
Following the previous procedure for the preparation of
(3R,4S)-7, (3R,4R)-10 was obtained in 31% yield and found to
be indistinguishable from (3R,4R)-11 prepared as above except
for the chiral behavior.
(3R,4R)-10
Colorless oil; Rf 0.15 (hexane–AcOEt = 5 : 1); [α]2D7 +60.9 (c =
0.23, EtOH, 85% ee); HRMS calcd for C20H26O5 346.1780,
found 346.1785.
The ee of the product was determined by chiral HPLC ana-
lysis (Chiralpak AD column, 0.46 × 25 cm, hexane–i-PrOH =
90 : 10, 1.0 cm3 min−1): Rt (major) = 8.3 min; Rt (minor) =
9.8 min.
5854 | Org. Biomol. Chem., 2014, 12, 5847–5855
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