Diastereoselective synthesis of a highly functionalized cyclohexene embedded with a quaternary stereogenic centre by self Diels-Alder dimerization of a [3]dendralene attached to a (-)-menthol auxiliary

Article abstract of DOI:10.1016/j.tetasy.2013.11.005

A novel route to a chiral functionalized [3]dendralene attached to a (-)-menthol auxiliary has been developed, which involves a dimethylsulfonium methylide mediated olefination of a substituted ethenylidene phosphonoacetate (-)-menthyl ester, followed by

Full text of DOI:10.1016/j.tetasy.2013.11.005

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective synthesis of a highly functionalized cyclohexene
embedded with a quaternary stereogenic centre by self Diels–Alder
dimerization of a [3]dendralene attached to a (ꢀ)-menthol auxiliary
⇑
Rekha Singh, Sunil K. Ghosh
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel route to a chiral functionalized [3]dendralene attached to a (ꢀ)-menthol auxiliary has been
developed, which involves a dimethylsulfonium methylide mediated olefination of a substituted etheny-
lidene phosphonoacetate (ꢀ)-menthyl ester, followed by a Horner–Wordsworth–Emmons reaction with
4-bromobenzaldehyde. The chiral [3]dendralene was reactive enough to undergo intermolecular Diels–
Alder cyclodimerization to give the highly substituted cyclohexene with very high regio- and
diastereoselectivity.
Received 22 August 2013
Accepted 7 November 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
OHC
Although chiral cyclohexenes have been used as intermediates in
organic synthesis,1–4 they are not very common structural units in
medicinal chemistry. This is probably due to the poor availability
of suitable synthetic methods that provide chiral substituted cyclo-
hexenes with high enantiomeric excess and in large quantities. In
contrast, the cyclohexene ring is common in natural products such
as steroids, terpenes, alkaloids, vitamin A and taxol. The synthesis
of highly functionalized cyclohexene with multiple stereocentres
and having quaternary chiral centre5 is a challenging task. Recently,
a highly functionalized cyclohexene with a quaternary centre has
been found in the dimeric triterpenoid dibelamcandel A (Fig. 1)
wherein the six-membered ring links two iridal type triterpenoid
nuclei.6 It has been proposed6 that the natural product is probably
formed by a highly regio- and stereoselective Diels–Alder cyclodi-
merization of an iridal triterpenoid (Fig. 1) with a linear conjugated
triene feature.
OH
HO
CHO
O
R
O
OH
OH
R
O
O
R = (CH2)12CH3
dibelamcandal A
H
R
HO
R =
CHO
O
OH
R
Compared to linear conjugated systems, cross-conjugated
molecules contain three unsaturated groups in which two of them
are conjugated to a third unsaturated centre, but not conjugated to
each other. One such class of molecules is that of the [3]dendra-
lenes7 (Fig. 2, n = 1), which have remained relatively unexplored,
probably due to limited preparation methods8–17 especially for
substituted systems18–21 and together with an unusual reactivity
pattern.22–24
iridal triterpenoid
O
Figure 1. Dimeric triterpenoid dibelamcandel A and its biosynthetic precursor
iridal triterpenoid.
Recently we developed25
a method for the synthesis of
n
[3]dendralenes substituted at multiple positions based on
a
n
linear polyenes
dendralenes
⇑
Corresponding author. Tel.: +91 22 25595012; fax: +91 22 25505151.
E-mail address: ghsunil@barc.gov.in (S.K. Ghosh).
Figure 2. Structural features of linear polyenes and dendralenes.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.11.005
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2
R. Singh, S. K. Ghosh / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
CO2Et
Ph
P(O)(OCH2CF3)2
1
Me
Me
H2C
S
-10 o
C
to 28 oC 1 h
Li
CO2Et
H3O+
CO2Et
Ph
Ph
P(O)(OCH2CF3)2
P(O)(OCH2CF3)2
2
ArCHO
28 oC, 5 h
NaH, Ar-CHO
28 oC, 4 - 6 h
63-78%
33%
EtO2C
Ar
Ph
Ar
Ph
CO2Et
Ph
CO2Et
3
Ar
4
Scheme 1. Synthesis of functionalized [3]dendralenes and their Diels–Alder cyclodimerization.25
dimethylsulfonium methylide26 mediated sequential tandem dou-
ble olefination27–30 of suitably substituted 1,3-dienyl phosphonate
1 and aldehydes (Scheme 1). The reaction took place via 1,3-buta-
dien-2-ylphosphonoacetate 2. The desired [3]dendralenes 3 were
formed as reactive intermediates, which could only be monitored
during the reaction but not isolated. Under the reaction conditions,
they underwent an in situ Diels–Alder cyclodimerization to give
highly functionalized cyclohexene products 4 embedded with a
quaternary centre. The overall process proceeded with moderate
to good yield but with excellent regio- and stereoselectivity. This
prompted us to investigate the possibility of an asymmetric
induction strategy for making such cyclohexenes. Herein we report
a novel route to a chiral functionalized [3]dendralene attached to a
(ꢀ)-menthol auxiliary and its self Diels–Alder cyclodimerization to
give a highly substituted cyclohexene embedded with a quaternary
stereogenic centre with high regio- and diastereoselectivity.
The diastereoisomeric Diels–Alder homodimerisation products
should have formed via the intermediate [3]dendralene 10. The
diastereoisomers (ꢀ)-11 and (+)-12 were separated and the struc-
ture of the major diastereoisomer (ꢀ)-11 was confirmed by spec-
troscopic data and by X-ray crystallography32,33 (Fig. 3).
The regio- and stereoselectivity of this Diels–Alder reaction was
very distinctive in the sense that the 3-methylene group of the
[3]dendralenes 10 participated exclusively as the dienophile com-
ponent. Furthermore, this 3-methylene group and the double bond
at the 4-position of the [3]dendralene 10 acted together as the
diene component in the Diels–Alder reaction. The orientation of
the diene component and the dienophile component are such that
bonding took place between the unsubstituted carbons of the
3-methylene groups (from both the diene and dienophile, both)
and two substituted carbons, at the 3-position (dienophile) and
the 5-position (diene) leading to only one regio-isomer with the
generation of a quaternary stereogenic centre in 11/12. The
diastereoselectivity was controlled by the chirality present in
the (ꢀ)-menthol auxiliary.
2. Results and discussion
For the synthesis of chiral [3]dendralenes,31 (ꢀ)-menthol was
chosen as the chiral auxiliary. At first, (ꢀ)-menthyl bromoacetate
5 upon Arbuzov reaction with triethylphosphite gave the ester of
diethylphosphonoacetate 6, which was then treated with phospho-
rus pentachloride followed by 2,2,2-trifluoroethanol to give the
3. Conclusion
In conclusion, a route to a densely functionalized chiral [3]den-
dralene has been reported on using a (ꢀ)-menthol auxiliary and
dimethylsulfonium methylide as the olefination agent. The chiral
[3]dendralene could not be isolated but was reactive enough to un-
dergo intermolecular Diels–Alder cyclodimerization to give a
highly substituted cyclohexene with very high regio- and diastere-
oselectivity. The present methodology, thus holds promise to syn-
thesize densely functionalized complex chiral cyclohexenes with a
quaternary centre similar to dibelamcandel A.
menthyl ester of bis-(2,2,2-trifluroethyl)phosphonoacetate
7
(Scheme 2). Knoevenagel condensation of phosphonoacetate 7
with cinnamaldehyde in the presence of piperidinium benzoate
provided the desired 2-phenylethenylidene phosphonoacetate 8
in 78% yield (Scheme 2) as a mixture of the (2E,4E)- and (2Z,4E)-
isomers in a ratio of 7:3. This mixture of phosphonoacetates was
added to dimethylsulfonium methylide (generated from trim-
ethylsulfonium iodide and n-butyl lithium in THF) and then
quenched with water to give the 1,3-butadien-2-ylphosphonoace-
tate 9 in 64% yield as an inseparable 1:1 mixture of diastereoiso-
mers. This mixture of phosphonates 9 was then mixed with
1 equiv of 4-bromobenzaldehyde and treated with NaH in THF
which resulted in the formation of two diastereoisomeric Diels–
Alder homodimerisation products 11 and 12 in a ratio of 8:2
(Scheme 2) in 52% overall yield from dienic phosphonoacetates 9.
4. Experimental
4.1. General
All reactions were performed in oven-dried (120 °C) or
flame-dried glass apparatus under dry N2 or argon atmosphere.
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R. Singh, S. K. Ghosh / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
(EtO)3P, 100oC
100%
O
O
P
OCOCH2Br
O
OEt
OEt
5
6
1. PCl5
2.CF3CH2OH
3.iPr2EtN
cinnamaldehyde,
piperidinium
benzoate, Bz,
reflux
O
O
O
P
OCH2CF3
54%
OCH2CF3
78%
7
O
O
P
O
O
P
OCH2CF3
OCH2CF3
OCH2CF3
O
O
Me2S=CH2
64%
OCH2CF3
Ph
Ph
9
8
Br
NaH,
4-Br-C6H4CHO
O
52%
O
Ph
10
Br
Br
O
O
O
O
O
Ph
Ph
+
Ph
Ph
O
Br
O
O
Br
(-)-11
Scheme 2. Synthesis of a functionalized chiral [3]dendralene and its Diels–Alder cyclodimerization.
(+)-12
Tetrahydrofuran (THF) was dried by distillation from sodium/
benzophenone. n-BuLi (1.6 M in hexane) was purchased from
Aldrich. (ꢀ)-Menthol, 2,2,2-trifluoroethanol and 4-bromobenzal-
dehyde were purchased from Aldrich. Solvent removal was carried
out using a rotary evaporator connected to a dry ice condenser. TLC
(0.5 mm) was carried out using homemade silica plates with a
fluorescence indicator. Column chromatography was performed
on silica gel (230–400 mesh). The 1H NMR and 13C NMR spectra
were recorded with Bruker 200/700 MHz spectrometers. The spec-
tra were referenced to residual chloroform (d 7.25 ppm, 1H; d
77.00 ppm, 13C). The IR spectra were recorded with a JASCO FT IR
spectrophotometer in NaCl cells or in KBr discs. Peaks are reported
in cmꢀ1. Melting points (mp) were determined on a Fischer John’s
melting point apparatus and are uncorrected. Optical rotations
were measured with a JASCO DIP-360 polarimeter. Elemental
analyses (C, H, N) were carried out at Bio-Organic Division BARC,
Mumbai, India.
Suitable X-ray quality crystals of (ꢀ)-11 were grown in hex-
anes–EtOAc and X-ray diffraction studies were undertaken. X-ray
crystallographic data were collected from single crystal samples
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4
R. Singh, S. K. Ghosh / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
Figure 3. ORTEP diagram of (ꢀ)-11.
of volume 0.23 ꢁ 0.18 ꢁ 0.13 mm3 at 150(2) K mounted on a
step. Rf = 0.54 (hexane–EtOAc, 50:50); ½a D24
¼ ꢀ52:25 (c 1.24,
ꢂ
OXFORD DIFFRACTION XCALIBUR-S CCD system equipped with
MeOH); IR (film): 2955, 2931, 2870, 1731, 1453, 1390, 1369,
graphite monochromated Mo K
a
radiation (0.71073 Å). The data
1273, 1115, 1053, 1026, 972, 840, 786 cmꢀ1
;
1H NMR (200 MHz,
were collected by -2h scan mode, and absorption correction
x
CDCl3): 4.76 (1H, dt, J = 10.3, 4.4 Hz, OCH), 4.22 (2H, q,
d
was applied by using multi-Scan. The structure was solved by di-
rect methods SHELX-97 and refined by full-matrix least squares
against F2 using SHELX-9734 software. Non-hydrogen atoms were
refined with anisotropic thermal parameters. All hydrogen atoms
were geometrically fixed and allowed to refine using a riding
model.
J = 7.3 Hz, OCH2), 4.19 (2H, q, J = 7.3 Hz, OCH2), 2.99 (2H, d,
J = 21.6 Hz, PCH2), 2.10–1.90 (2H, m, CH and CHAHB), 1.80–1.65
(4H, m, CH, CH2 and CHAHB), 1.38 (6H, t, J = 7.1 Hz, 2 ꢁ OCH2CH3),
1.17–0.86 (3H, m, CH and CH2), 0.94 (6H, d, J = 7.2 Hz, CH3CHCH3),
0.79 (3H, d, J = 7 Hz, CHCH3); 13C NMR (50 MHz, CDCl3): d 164.6 (d,
J = 6 Hz), 74.9, 61.9, (d, J = 6 Hz), 46.4, 40.2, 34.1 (d, J = 132.8 Hz),
33.7, 30.9 (2C), 25.3, 22.7, 21.4, 20.2, 15.8, 15.7, 15.5.
4.2. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-bromoacetate 5
4.4. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-[bis(2,2,2-tri-
A solution of (ꢀ)-menthol (3 g, 19 mmol) and pyridine (1.54 mL,
19 mmol) in dichloromethane (30 mL) was cannulated slowly to a
solution of bromoacetyl bromide (1.67 mL, 19 mmol) in dichloro-
methane (20 mL) at ꢀ78 °C. After stirring for 10 min, the reaction
mixture was allowed to return to room temperature. The reaction
mixture was then poured into water and extracted with dichloro-
methane. The organic extract was concentrated and the residue
was purified by column chromatography to provide bromoacetate
5 (5.25 g, 100%) as a colourless liquid. Rf = 0.71 (hexane–EtOAc,
fluoroethoxy)phosphoryl]acetate 7
Phosphorus pentachloride (11.9 g, 57 mmol) was added por-
tionwise to the phosphonate 6 (6.34 g, 19 mmol) at 0 °C over
5 min after which the mixture was then heated at 75 °C for 14 h.
The reaction mixture was then brought to room temperature and
placed under high vacuum to remove volatiles. The residue was
dissolved in benzene (40 mL), cooled to 0 °C and 2,2,2-trifluoroeth-
anol (4.15 mL, 57 mmol) was added via a dropping funnel followed
by the addition of diisopropylethylamine (9.93 mL, 57 mmol). The
reaction mixture was stirred at room temperature for 4 h, poured
into ice-water and extracted with benzene. The combined organic
extract was dried over anhydrous MgSO4 and evaporated under re-
duced pressure. The residue was purified by column chromatogra-
phy to provide acetate 7 (4.51 g, 54%) as a thick liquid. Rf = 0.3
95:5); ½a 2D4
¼ ꢀ64:8 (c 4.08, MeOH); IR (film): 2956, 2928, 2870,
ꢂ
1731, 1456, 1422, 1387, 1370, 1278, 1168, 1178, 1009, 983, 921,
843 cmꢀ1 1H NMR (200 MHz, CDCl3): d 4.77 (1H, dt, J = 10.9,
;
4.4 Hz, OCH), 3.85 (2H, s, BrCH2), 2.15–1.87 (2H, m, CH and CHAHB),
1.8–1.65 (2H, m, CH2), 1.58–1.39 (2H, m, CH and CHAHB), 1.20–0.87
(3H, m, CH2 and CH), 0.95 (3H, d, J = 6.4 Hz, CH3CH), 0.94 (3H, d,
J = 7 Hz, CH3CH), 0.81 (3H, d, J = 6.9 Hz, CH3); 13C NMR (50 MHz,
CDCl3): d 166.6, 76.3, 46.9, 40.4, 34.1, 31.3, 26.1, 26.0, 23.4, 21.8,
20.6, 16.2.
(hexane–EtOAc, 85:15); ½a D24
¼ ꢀ38:0 (c 2.32, MeOH); IR (film):
ꢂ
3019, 2998, 2937, 2877, 1719, 1451, 1418, 1393, 1373, 1298,
1171, 1075, 961, 852, 837, 786 cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d 4.74 (1H, dt, J = 10.9, 4.4 Hz, OCH), 4.47 (2H, q, J = 8.1 Hz,
OCH2), 4.42 (2H, q, J = 8.1 Hz, OCH2), 3.14 (2H, d, J = 21.1 Hz,
PCH2), 2.10–1.95 (1H, m, CH), 1.91–1.79 (1H, m, CH), 1.75–1.60
(2H, m, CH2), 1.50–1.31 (2H, m, CH2), 1.15–0.81 (3H, m, CH and
CH2), 0.90 (3H, d, J = 6.5 Hz, CH3CH), 0.89 (3H, d, J = 6.8 Hz, CH3CH),
0.75 (3H, d, J = 7 Hz, CHCH3); 13C NMR (50 MHz, CDCl3): d 164.9 (d,
J = 4.6 Hz), 122.4 (2C, dq, J = 275, 5 Hz), 76.4, 62.3 (2C, dq, J = 37.50,
5.5 Hz), 46.8, 40.4, 34.0 (1 C, d, J = 142 Hz, PCH2), 33.92, 31.2, 25.9,
23.1, 21.5, 20.3, 15.7.
4.3. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-(diethoxyphos-
phoryl)acetate 6
A
mixture of bromoacetate 5 (5.3 g, 19.1 mmol) and tri-
ethylphosphite (3.28 mL, 19.1 mmol) was heated at 100 °C under
an inert atmosphere for 3 h. The mixture was cooled to room tem-
perature and the volatiles were removed under high vacuum to
give 6 (6.38 g, 100%) as a thick syrup sufficiently pure for the next
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R. Singh, S. K. Ghosh / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
5
4.5. (2E,4E)-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-[bis(2,
2,2-trifluoroethoxy)phophoryl]-5-phenylpenta-2,4-dienoate 8
(200 MHz, CDCl3): d 7.22–7.45 (5H, Ph), 6.82 (1H, d, 16.2 Hz,
PhCH@CH), 6.69 (1H, d, J = 16.2 Hz, PhCH@CH), 5.60 (s, 1H, C@CHA,
diast-1), 5.59 (s, 1H, C@CHB, diast-2), 5.57 (s, 1H, C@CHA, diast-1),
5.56 (s, 1H, C@CHB, diast-2), 4.73 (1H, dt, J = 11, 4.3 Hz, OCH), 4.60–
4.25 (5H, m, 2 ꢁ POCH2 and PCH), 2.10–1.90 (1H, m, CH), 1.90–1.69
(1H, m, CH), 1.69–1.55 (2H, m, CH2), 1.55–1.20 (2H, m, CH2), 1.10–
0.70 (3H, m, CH and CH2), 0.91 (3H, d, J = 6.5 Hz, CH3CH), 0.79 (3H,
d, J = 7 Hz, CH3CH), 0.65 (3H, d, J = 6.9 Hz, CH3CH); 13C NMR
(50 MHz, CDCl3): d 166.3, 136.3, 135.3 (d, J = 9 Hz), 130.3, 128.5
(2C), 128.1 (d, J = 9.5 Hz), 128.0, 126.6 (2C), 122.4 (2C, dq, J = 276,
8.6 Hz), 120.9 (d, J = 9.5 Hz, diast-1), 120.8 (d, J = 9.2 Hz, diast-2),
76.8 (dist-1), 76.7 (diast-2), 62.9 (2C, dq, J = 5.3 and 37.9 Hz,
diast-1), 62.8 (2C, dq, J = 4.9 and 37.5 Hz, diast-2), 48.4 (d,
J = 144.6 Hz, diast-1), 48.3 (d, J = 144 Hz, diast-2), 46.9 (diast-1),
46.7 (diast-2), 40.4 (diast-1), 40.0 (diast-2), 34.0, 31.3 (diast-1),
31.2 (diast-2), 26.0 (diast-1), 25.8 (diast-2), 23.2 (diast-1), 23.1
(diast-2), 21.6, 20.4 (diast-1), 20.3 (diast-2), 15.9 (diast-1), 15.7
(diast-2).
A solution of phosphonate 5 (4.5 g, 10.2 mmol), cinnamalde-
hyde (1.3 mL, 10.2 mmol) and piperidinium benzoate (415 mg,
2 mmol) in benzene (50 mL) was refluxed for 5 h under the
Dean–Stark apparatus. The reaction mixture was then brought to
room temperature, diluted with water and extracted with ethyl
acetate. The organic extract was concentrated under reduced pres-
sure and the residue was purified by column chromatography to
give dienoate 8 (4.45 g, 78%) contaminated with 30% of its (2Z)-iso-
mer. A small portion was carefully fractionated to give the individ-
ual diastereoisomers in pure form.
Data for (2E,4E)-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl
2-[bis(2,2,2-trifluoroethoxy)phophoryl]-5-phenylpenta-2,4-dieno-
ate: Rf = 0.4 (hexane–EtOAc, 85:15); ½a D23
¼ ꢀ37:1 (c 1.26, MeOH);
ꢂ
IR (CHCl3 film): 3018, 2961, 2923, 2868, 1708, 1608, 1579, 1565,
1451, 1415, 1371, 1290, 1254, 1215, 1174, 1104, 1073, 963,
873 cmꢀ1 1H NMR (200 MHz, CDCl3): d 8.06 (1H, ddd, J = 2.2,
;
11.6 and 15 Hz, PhCH@CH–), 7.74 (1H, dd, J = 23.2, 11.4 Hz, P–
C@CH), 7.60–7.53 (2H, m, Ph), 7.42–7.38 (3H, m, Ph), 7.17 (1H, d,
J = 15.3 Hz, PhCH), 4.89 (1H, dt, J = 10.8, 4.4 Hz, OCH), 4.55–4.28
(4H, m, 2 ꢁ OCH2), 2.13–1.93 (2H, m, CH, CH), 1.80–1.60 (2H, m,
CH2), 1.53–1.39 (2H, m, CH2), 1.29–0.98 (3H, m, CH and CH2),
0.93 (3H, d, J = 6.4 Hz, CH3CH), 0.91 (3H, d, J = 6.9 Hz, CH3CH),
0.78 (3H, d, J = 6.9 Hz, CH3CH); 13C NMR (50 MHz, CDCl3): d 163.0
(d, J = 15.1 Hz), 157.3 (d, J = 31.6 Hz), 148.7, 135.1, 130.3, 128.7
(2C), 128.1 (2C), 123.8 (d, J = 20.7), 122.5 (2C, dq, J = 275.8,
9.2 Hz), 118.5, 114.6, 62.3 (2C, q, J = 38.8 Hz), 46.9, 40.5, 33.9,
31.2, 25.6, 22.8, 21.5, 20.4, 15.4. Anal. Calcd for C25H31F6O5P: C,
53.96; H, 5.62. Found: C, 54.16; H, 5.66.
4.7. (2Z,20Z)-Bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] 2,20-
[(1R,2R)-2-{(E)-styryl}-1,2,3,4-tetrahydro-(1,10-biphenyl)-2,5-
diyl]bis[3-(4-bromophenyl)acrylate] 11
A solution of phosphonate 9 (0.54 g, 0.94 mmol), and 4-bromo-
benzaldehyde (0.175 g, 0.94 mmol) in THF (8 mL) was cannulated
to a suspension of NaH (0.41 g, 55% in oil, 0.94 mmol) in THF
(2 mL) at 0 °C and the mixture was stirred for 17 h at room
temperature. The reaction mixture was diluted with water and
extracted with ethyl acetate. The organic extract was concen-
trated under reduced pressure and the residue was purified by
column chromatography to give a mixture of two diastereoiso-
mers 11 and 12 (11/12 = 80:20, 0.24 g, 52%). The individual
diastereoisomers were separated by preparative thin layer
chromatography.
Data for (2Z,4E)-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl
2-[bis(2,2,2-trifluoroethoxy)phophoryl]-5-phenylpenta-2,4-dieno-
ate: Rf = 0.6 (hexane–EtOAc, 85:15); ½a D23
¼ ꢀ43:5 (c 0.38, MeOH);
ꢂ
IR (CHCl3 film): 2959, 2930, 2864, 1709, 1608, 1578, 1563, 1451,
Data for (2Z,20Z)-bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]
2,20-[(1R,2R)-2-{(E)-styryl}-1,2,3,4-tetrahydro-(1,10-biphenyl)-2,5-
diyl]bis[3-(4-bromophenyl)acrylate] 11: Rf = 0.6 (hexane–EtOAc,
1286, 1244, 1171, 1102, 1071, 962, 869, 750 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 8.12 (1H, dd, J = 39.8, 12 Hz, P–C@CH), 8.07
(1H, ddd, J = 15.8, 12 and 3.8 Hz, PhCH@CH), 7.63–7.55 (2H, m,
Ar), 7.42–7.30 (3H, m, Ar), 7.2 (1H, d, J = 15.0 Hz, PhCH), 4.86
(1H, dt, J = 10.8, 4.3 Hz, OCH), 4.70–4.30 (4H, m, 2 ꢁ OCH2), 2.10–
1.98 (1H, m, CH), 1.98–1.85 (1H, m, CH), 1.80–1.62 (2H, m, CH2),
1.57–1.36 (2H, m, CH2), 1.20–0.90 (3H, m, CH and CH2), 0.91 (3H,
d, J = 6.4 Hz, CH3CH), 0.90 (3H, d, J = 7 Hz, CH3CH), 0.77 (3H, d,
J = 7 Hz, CH3CH); 13C NMR (50 MHz, CDCl3): d 164.4 (d, J = 15 Hz),
158.8 (d, J = 10 Hz), 149.6 (d, J = 2 Hz), 135.2, 130.6, 128.9 (2C),
128.4 (2C), 123.7 (d, J = 6 Hz), 122.6 (2C, dq, J = 275, 9 Hz), 115.8
(d, 194 Hz), 76.0, 62.4 (dq, J = 38, 5 Hz), 62.3 (dq, J = 38, 5 Hz),
47.0, 40.5, 34.1, 31.4, 25.8, 23.0, 21.9, 20.7, 15.8.
98:2); mp. 200 °C; ½a D25
¼ þ156:8 (c 0.31, CHCl3); IR (film): 3023,
ꢂ
2957, 2927, 2869, 1708, 1587, 1486, 1454, 1369, 1215, 1175,
1073, 1011, 981, 913, 811, 757 cmꢀ1 1H NMR (700 MHz, CDCl3):
;
d 7.41 (2H, d, J = 9.1 Hz, Ar), 7.38 (2H, d, J = 8.4 Hz, Ar), 7.27–7.21
(8H, m, Ar), 7.19–7.15 (4H, m, Ar), 7.07 (2H, d, J = 8.4 Hz, Ar),
6.59 (1H, s, ArCH@C), 6.30 (1H, d, J = 16.1 Hz, PhCH@CH), 6.29
(1H, s, ArCH@C), 6.19 (1H, d, J = 16.1 Hz, PhCH@CH), 6.04 (1H, d,
J = 3.5 Hz, PhCHCH@C), 4.70 (1H, dt, J = 10.5, 4.2 Hz, OCH), 4.61
(1H, dt, J = 11.2, 4.9 Hz, OCH), 4.17 (1H, s, broad, PhCHCH@C),
2.65–2.58 (1H, m, CH), 2.49–2.43 (1H, m, CH), 2.27 (2H, t,
J = 5.6 Hz, CH2), 1.86 (1H, d, broad, J = 11.9 Hz, CH), 1.72 (1H, d,
broad, J = 12.6 Hz, CH), 1.63–1.47 (6H, m, 3 ꢁ CH2), 1.44–1.32
(2H, m, 2 ꢁ CH), 1.22 (2H, q, broad, J = 11.2 Hz, CH2), 0.93 (2H,
dq, J = 12.6, 2.8 Hz, CH2), 0.82 (3H, d, J = 6.3 Hz, CH3CH), 0.81 (3H,
d, J = 6.3 Hz, CH3CH), 0.70–0.78 (2H, m, CH2), 0.65 (3H, d, J = 7 Hz,
CH3CH), 0.64 (3H, d, J = 6.3 Hz, CH3CH), 0.66–0.60 (1H, m, CHAHB),
0.52–0.47 (1H, m, CHAHB), 0.49 (3H, d, J = 7 Hz, CH3CH), 0.42 (3H,
d, J = 7 Hz, CH3CH); 13C NMR (175 MHz, CDCl3): d 168.9 (2C),
141.7, 140.1, 138.3, 137.3, 135.4, 134.9, 133.7, 132.1, 131.4 (2C),
131.2 (2C), 130.7, 130.6 (3C), 130.3, 130.0 (2C), 129.9 (2C), 128.4
(2C), 127.6 (2C), 127.3, 126.8, 126.2 (2C), 124.9, 121.8, 121.5,
75.5, 75.4, 49.4, 46.8, 46.6, 46.5, 40.0 (2C), 33.9, 31.2 (3C), 25.4,
25.3 (2C), 23.0, 22.7, 22.6, 21.9, 21.8, 20.6 (2C), 15.4, 15.3.
4.6. (4E)-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-[bis(2,2,2-
trifluoroethoxy)phosphoryl]-3-methylene-5-phenyl-4-pentenoate 9
Freshly titrated n-butyl lithium (2.5 mL, 1.5 M in hexanes,
3.77 mmol) was added dropwise to a stirred suspension of trim-
ethylsulfonium iodide (0.77 g, 3.77 mmol) in THF (15 mL) at
ꢀ10 °C. After 20 min at ꢀ10 °C, a solution of the phosphonoacetate
8 (mixture of isomers) (0.7 g, 1.26 mmol) in THF (13 mL) was cann-
ulated into the reaction mixture and stirred for 1 h. The reaction
mixture was then allowed to gradually return to room tempera-
ture, diluted with water and extracted with ethyl acetate. The or-
ganic extract was concentrated on a rotary evaporator and the
residue was purified by column chromatography to give product
9 (0.463 g, 64%) as a white solid and an inseparable mixture of dia-
stereoisomers in a ratio of 1:1. Rf = 0.3 (hexane–EtOAc, 90:10); IR
(film): 3019, 2959, 2929, 2872, 1723, 1600, 1451, 1417, 1296,
Data for (2Z,20Z)-bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]
2,20-[(1S,2S)-2-{(E)-styryl}-1,2,3,4-tetrahydro-(1,10-biphenyl)-2,5-
diyl]bis[3-(4-bromophenyl)acrylate] 12: Rf = 0.6 (hexane–EtOAc,
98:2); mp 215 °C; ½a D25
¼ ꢀ140:6 (c 0.33, CHCl3); IR (film): 3082,
ꢂ
3025, 2952, 2867, 1708, 1487, 1453, 1366, 1214, 1169, 1074,
1264, 1215, 1173, 1105, 1073, 962, 881, 845, 757 cmꢀ1
;
1H NMR
1011, 981, 910, 875, 811, 761 cmꢀ1 1H NMR (700 MHz, CDCl3):
;
Please cite this article in press as: Singh, R.; Ghosh, S. K. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.005

6
R. Singh, S. K. Ghosh / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
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47, 910–912.
d 7.40 (2H, d, J = 8.4 Hz, Ar), 7.39 (2H, d, J = 7.7 Hz, Ar), 7.28 (2H, d,
J = 7.7 Hz, Ar), 7.24–7.20 (6H, Ar), 7.18–7.13 (4H, m, Ar), 7.11 (2H,
d, J = 7.7 Hz, Ar), 6.55 (1H, s, ArCH@C), 6.38 (1H, s, broad, ArCH@C),
6.26 (1H, d, J = 16.8 Hz, PhCH@CH), 6.16 (1H, d, J = 16.8 Hz,
PhCH@CH), 6.01 (1H, d, J = 3.5 Hz, PhCHCH@C), 4.70 (1H, dt,
J = 10.5, 4.2 Hz, OCH), 4.52 (1H, dt, J = 10.5, 4.2 Hz, OCH), 4.19
(1H, s, broad, PhCHCH@C), 2.63–2.56 (1H, m, CH), 2.52–2.45 (1H,
m, CH), 2.35–2.31 (1H, m, CH), 2.25–2.21 (1H, m, CH), 1.88 (1H,
d, J = 11.9 Hz, CHAHB), 1.79 (1H, d, J = 11.9 Hz, CHAHB), 1.60 (2H, t,
broad, J = 14.7 Hz, CH2), 1.54–1.49 (2H, m, CH2), 1.42–1.34 (2H,
m, CH2), 1.32–1.26 (1H, m, CH), 1.25 (1H, t, broad, J = 11.9 Hz,
CH), 1.11 (1H, t, broad, J = 11.2 Hz, CHAHB), 0.94 (1H, dq, J = 13.3,
2.8 Hz, CHAHB), 0.88 (1H, dq, J = 12.6, 2.8 Hz, CHAHB), 0.79–0.85
(1H, m, CHAHB), 0.76 (3H, d, J = 6.3 Hz, CHCH3), 0.72–0.79 (2H, m,
CH2), 0.69 (3H, d, J = 7 Hz, CHCH3), 0.62–0.68 (1H, m, CHAHB),
0.61 (3H, d, J = 7 Hz, CHCH3), 0.59 (3H, d, J = 6.3 Hz, CHCH3),
0.57 (3H, d, J = 7 Hz, CHCH3), 0.55–0.49 (1H, m, CHAHB), 0.48
(3H, d, J = 7 Hz, CHCH3); 13C NMR (175 MHz, CDCl3): d 169.32,
169.09, 142.0, 140.2, 138.3, 137.2, 135.7, 135.0, 133.7, 132.0,
131.5 (2C), 131.4 (3C), 130.8 (2C), 130.3, 129.9 (2C), 129.6 (2C),
129.3, 128.4 (2C), 127.6 (2C), 127.3, 126.9, 126.2 (2C), 124.6,
121.8, 121.6, 75.5, 75.4, 49.2, 46.9, 46.7, 46.5, 40.5 (3C), 34.0,
33.9, 31.3, 31.2, 25.2, 24.7, 23.0, 22.7, 22.6, 21.9, 21.7, 20.9, 20.8,
15.8, 15.7; Anal. Calcd for C58H66Br2O4: C, 70.58; H, 6.74. Found:
C, 70.46; H, 6.98.
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Acknowledgements
The authors are grateful to Professor Shaikh M. Mobin, Single
Crystal X-ray Diffraction Facility, Sophisticated Instrumentation
Centre, Indian Institute of Technology, Indore, India for single crys-
tal X-ray diffraction and structural analyses.
32. Crystallographic data (excluding structure factors) for the structure (ꢀ)-11
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC 949055.
33. Selected X-ray crystallographic data: C58H66Br2O4; M = 986.93; crystal system:
0
monoclinic; space group:
P 21; unit cell dimensions: a = 11.0951(9) ÅA,
References
0
0
0
b = 13.5369(10) ÅA, c = 35.534(3) ÅA; V = 5316.8(8) ÅA3; Z = 2, Dcalcd = 1.233 g cmꢀ3
(mmꢀ1)/F(000) = 1.568/2064; theta for data collection (°) = 2.82–25.00;
reflections collected/unique: 35771/18325; data/restraints/parameters: 18325/
1/1165; final R1, R2 indices = 0.0477, 0.0946; R1, R2 (all data) = 0.1458, 0.1116;
goodness of fit on F2 = 0.729.
;
l
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2980.
x
x
34. Sheldrick, G. M. SHELX-97-A Program for Crystal Structure Solution and
Refinement; University of Gottingen: Germany, 1997. Release 97-2.
Please cite this article in press as: Singh, R.; Ghosh, S. K. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.005