Facile approach to versatile chiral intermediates for fused cyclopentanoid natural products

Article abstract of DOI:10.1515/znb-2001-1119

A facile approach to cis- and trans-2-(1-hydroxymethyl)vinyl-1-vinylcyclohexan-1-ols and to the corresponding cyclopentane, cycloheptane, and cyclooctane derivatives has been developed, starting from cycloalkanones involving the key steps of Rupe and Claisen orthoester rearrangements. The formation of intervening products could be explained by allylic strain and π-stacking, respectively.

Full text of DOI:10.1515/znb-2001-1119

Facile Approach to Versatile Chiral Intermediates for Fused Cyclopentanoid
Natural Products
Fazila Zulfiqar and Abdul Malik*
HEJ Research Institute of Chemistry, University of Karachi, Karachi 75270 Pakistan
Reprints request to Dr. Abdul Malik. E-mail: hej@digicom.net.pak
Z. Naturforsch, 56b, 1227-1234 (2001); received December 4, 2000
Chiral Intermediates, Fused cyclopentanoids
A facile approach to cis- and rrans-2-(l-hydroxymethyl)vinyl-l-vinylcyclohexan-l-ols and
to the corresponding cyclopentane, cycloheptane, and cyclooctane derivatives has been devel-
oped, starting from cycloalkanones involving the key steps of Rupe and Claisen orthoester
rearrangements. The formation of intervening products could be explained by allylic strain
and jr-stacking, respectively.
Introduction
the epimeric alcohols 4a-d [5], Claisen rearrange-
ment with triethyl orthoacetate provided com-
pounds 5a-d. In the reaction sequence phenol was
used as the acid catalyst and its superiority over
the traditional pivalic acid has already been re-
ported by us in a previous short communication
[6],
The diols of type A and B (n - 1) are chiral
versatile intermediates which have been used by
Sworin and Lin [1] for the syntheses of fused
cyclopentanoid natural products [2] such as guaia-
nolides, pseudoguaianolides, isocomene, carioline,
estafiatin etc. Our interest was not only to develop
a high yielding facile route to these intermediates
but also to extend the strategy to their ring ana-
logues (n = 0,2,3). In our methodology we have
used a combination of Rupe and Claisen orthoes-
ter rearrangements [4, 6] to arrive at the target
molecules.
The ester moiety at C -l' in compounds 5a-d was
expected to occupy the less hindered equatorial
position which was confirmed by decoupling ex-
periments on 5b as a representative example. Irra-
diation at the resonance of protons at C-2 (<3 =
2.26) simplified the multiplet of methine protons
at C -l' into a doublet of doublets showing axial-
axial and axial-equatorial coupling of the magni-
tude of 10 and 3 Hz, respectively. The compounds
5a, 5c, and 5d showed similar chemical shifts and
coupling constants, revealing equatorial disposi-
tion of the ester moiety. An equatorial disposition
of the ester moiety was expected to lead to £-al-
kylidene isomers [7] which was authenticated by
NOE difference measurements. In each case,
strong NOE interactions were observed between
olefinic protons and the methylene protons of the
ethoxy groups, thereby revealing their spatial
proximity.
OH
Result and Discussion
The starting materials were readily available
cycloalkanones la-d which were reacted with the
mono anion of acetylene following a modification
of the Heilbron method [3] in which four equiva-
The reaction of 4a-d with trimethyl ß-(methoxy)
lents of sodium metal were used and the reaction orthopropionate in the presence of phenol yielded
mixture was stirred at -78 °C for 12 h. The result- the corresponding orthoester Claisen rearrange-
ing alcohols 2a-d were subjected to Rupe re- ment products 6 a-d in yields ranging from 65 to
arrangement [4] to obtain the corresponding 1- 79%. In each case, a mixture of diastereoisomers
acetyl-cycloalkenes 3a-d in yields ranging between was obtained and their ratios were determined in
85-95% . These were reduced with NaBH4 in the each case through XH NMR spectra. From the
presence of cerium chloride in methanol to afford foregoing it is apparent that allylic strain is not
0932-0776/2001/1100-1227 $06.00 © 2001 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
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1228
F. Zulfiqar and A. Malik • Facile Approach to Versatile Chiral Intermediates
of a- and /3-epoxides 1 1 which was, without sepa-
ration, subjected to base induced /3-elimination of
methanol to obtain a 4:1 mixture of a-epoxide 12
and /3-epoxide 8b. The conversion of these types
of epoxides into the corresponding target com-
4 *
^
2a’d
3a-d
pounds 13 (type A) and 14 (type B) has been
achieved through their reaction with DIBAL to
the corresponding epoxy primary alcohols which,
without isolation, were reacted with 1.5 equivalent
of diphenyl diselenide and 3 equivalent of sodium
borohydride in ethanol. A similar strategy may be
applied to 6a, 6c, and 6d to obtain the correspond-
ing diols.
OH
Experimental
IR spectra were recorded in CF[C13 on a Shi-
madzu IR-460 spectrometer. The XH NMR (500,
400 and 300 MHz) and 13C NMR (125, 100 and 75
MHz) spectra were recorded on Bruker AM-500,
AM-400 and AM-300 spectrometer with CDC13 as
a solvent. The chemical shifts are in ppm from in-
ternal TMS. Mass spectra were obtained either on
a MAT-312 or on a JEOL JMS-HX 110 instru-
ment. Analytical TLC was carried out on pre-
coated Merck silica gel 60 F254 (0.25 mm thick-
ness) plates. Flash chromatography was performed
on silica gel 60 (70-230 mesh).
Scheme 1. Reagents and conditions: i, liq. NH3, Na
metal, CH = CH, - 78 °C, 42-95%; ii, AcOH/H20, Do-
wex-50 resin, reflux, 85-95%; iii, NaBH4, CeCl3x7H20,
MeOH, 2h, 65-90%; iv, CH^C(OEt)3, phenol, 145 °C, 1
h, 62-76%; v, CH,OCH2CH2C(OCH,K phenol, 145 °C,
1 h, 81-98%.
only effective in six-membered rings [8] but also
operates in both smaller and larger rings. The
strategy, therefore, provides a general stereocon-
trolled approach to £-alkylidene cycloalkanes.
Base induced /^-elimination of methanol from 6a-
d led to the diene esters 7a-d in excellent yields.
Epoxidation with ra-CPBA in CH2C12 at 0 °C in
the presence of 0.5 M N aH C 03 gave stereoselec-
tively the /3-epoxides 8a-d. An equatorial ester
moiety was expected to sterically hinder the ap-
proach of the electrophilic reagent from the syn-
axial face, therefore, in each case the a-epoxide
was the expected product. The exclusive formation
of the /3-epoxides 8a-d may be attributed to the n-
stacking [9], which overrides the steric factor. The
effect of jr-stacking was further demonstrated
through regioselective bromination of the more
activated double bond of 7b to afford 10 via the
intervening intermediate 9 which arises through
formation of cyclic bromonium ion by the ap-
proach of bromine atom from the axial and /3-face.
Further studies were initiated on 6b as represen-
tative example. It was first subjected to epoxida-
General procedure for the preparation o f
1-ethynyl-cycloalkanols (2a-d)
A rapid stream of acetylene was passed into li-
quid ammonia (500 ml) and sodium metal (4 eq)
was added in small pieces at -78 °C at such a rate
that no permanent blue color developed. A solu-
tion of cycloalkanone (1 mol) in ether was then
added dropwise followed by stirring and cooling
for a further 12 h to allow completion of reaction.
The reaction mixture was allowed to stand at room
temperature to permit the evaporation of most of
ammonia. The solid residue was diluted with cold
water, the resulting mixture carefully acidified
with 50% sulfuric acid, and extracted with CHC13.
The organic layer was dried over anhydrous mag-
nesium sulfate, filtered, concentrated and purified
by vacuum distillation to afford 2a-e as a colorless
liquid. Their spectral data was in good agreement
with the literature [3,4,10].
1-Ethynylcyclopentanol (2a): 42%; b.p. 52-
54 °C/12 mbar. - C7H 10O (110.1): calcd. C 76.36,
H 9.09; found C 76.39, H 9.05.
1
-Ethynylcyclohexanol (2b): 97%; b.p. 41 °C/12
mbar. - C8H 120 (124.1): calcd. C 77.41, H 9.67;
tion with m-CPBA which resulted in a 3:2 mixture found C 77.47, H 9.69.
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F. Zulfiqar and A. Malik • Facile Approach to Versatile Chiral Intermediates
1229
/ I /, iii
(7li)
CO;Me
COiVfe
CCWe
OH
jy (12) H coivle
(8b) H
OH
3 :2 a , ß
OMe
OH
4:1 a,ß
Scheme 2. Reagents and conditions: i, t-
BuOK, THF, 0 °C, ii, m-CPBA, CH2C12, 0.5 M
NaHCCh, 0 °C; iii, Br2, CC14, -5 °C; iv, DI-
BAL, C6H 14-CHX12, -78 °C then (PhSe)2,
EtOH, NaBH4.
6a^,il
8 a,e,d c O ^ e
CÜ2Me
1-Ethynylcycloheptanol (2c): 90%; b.p. 65-
66 °C/12 mbar. - C9H 140 (138.1): calcd. C 78.26,
H 10.14; found C 78.24, H 10.19.
1-Ethynylcyclooctanol (2d): 81%; b.p. 82-84 °C/
12 mbar. - C10H 16O (152.1): calcd. C 78.94, H
10.52; found C 78.89, H 10.58.
Their spectral data was in good agreement with
the literature [10 ].
1-Acetylcyclopentene (3a): 92%; b.p. 41-42°C /
0.3 mbar. - HRMS: m/z = 110.0734 (calcd. for
C7H 10O: 110.0730).
1-Acetylcyclohexene (3b): 95%; b.p. 58 °C/0.3
mbar.
C8H 120: 124.0888).
1-Acetylcycloheptene (3c): 90%; b.p. 64 °C/0.3
mbar. HRMS: m/z = 138.1040 (calcd. for
C9H 140 : 138.1044).
1-Acetylcyclooctene (3d): 86%; b.p. 76 °C/0.3
-
HRMS: m/z = 124.0885 (calcd. for
General procedure for the preparation o f
1-acetyl-cycloalkenes (3a-d)
-
A mixture of 1-ethynylcycloalkanol 2a-d (0.31
mol), acetic acid (100 ml), water (10 ml) and resin
Dowex-50 (20 g) was stirred under reflux. As soon
as the reflux temperature was reached, the resin
started to darken and within few minutes changed
from the original brown to almost black. After
cooling the resin was filtered and washed with
ether. The filtrate and the washings were diluted
with water and made slightly alkaline by cautious
mbar.
-
HRMS: m/z
-
152.1202 (calcd. for
C7H 120 : 152.1201).
General procedure for the preparation o f allylie
alcohols (4a-d)
1-Acetylcycloalkenes
3a-d
(517 mmol),
addition of 40% sodium hydroxide solution. The CeCl3x7H20 (133 mmol) and MeOH (1200 ml)
organic product was extracted with ether and the were placed in a round-bottom flask. Sodium bor-
ether solution was washed with saturated sodium
chloride solution, dried over anhydrous magne-
sium sulfate, evaporated, and the residue on vac-
uum distillation yielded 1-acetylcycloalkenes 3a-d.
ohydride (518 mmol) was added at 0 °C and the
reaction mixture was stirred for 2 h, diluted with
H20 (800 ml), acidified with 5% HCI (pH ~ 2) and
extracted with CH2C12 (2x 1000 ml). The com-
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1230
F. Zulfiqar and A. Malik • Facile Approach to Versatile Chiral Intermediates
bined organic extracts were dried over anhydrous was purified by high vacuum distillation to afford a
Na2S 0 4, concentrated, and purified by vacuum mixture of diastereoisomers as colorless liquid.
distillation to afford 4a-d as a colorless liquid.
Methyl 2-(2-ethylidenecyclopentyl)-3-methoxy-
propionate (6a): 81%; b.p. 108-110 °C/12 mbar;
l-(Cyclopenten-l-yl)-l-ethanol (4a): 65%; b.p.
53-55 °C/0.3 mbar. - IR (CHC13): v = 3440, 2910, 3:2 mixture of diastereoisomers according to :H
2875, 1620 cm“1. - lH NMR (400 MHz, CDC13): NMR analysis of the crude product. IR
-
d = 1.28 (d, J = 6.5 Hz, 3H, CH3), 1.84-1.92 (m,
2H, CH2), 2.30-2.32 (m, 4H, 2x CH2), 4.38 (q, J =
6.5 Hz, 1H, CHOH), 5.56 (br. s, 1H, = CH). -
13C{XH} NMR (100 MHz, CDC13): (3 = 22.1 (C-l),
23.4, 31.4, 32.2 (all CH2), 67.2 (CHOH), 124.1 (C-
4), 148.4 (C-3). - HRMS: m/z = 112.0884 (calcd.
for C7H 120 : 112.0881).
l-(Cyclohexen-l-yl)-l-ethanol (4b): 90%; b.p.
64 °C /0.3 mbar. - IR (CHC13): v = 3450, 3050,
2935, 1640 cm -1. - XH NMR (300 MHz, CDC13):
(CHC13): v = 3050, 2990, 2880, 1735, 1615 cm“1. -
HRMS: m/z = 212.1415 (calcd. for C12H20O3:
212.1412).
Major diastereoisomer: XH NMR (300 MHz.
CDC13): Ö = 1.48-1.79 (m, 4H, 2x CH2), 1.54 (m,
3H, CH3), 2.09-2.29 (m, 2H, CH2), 2.51-2.65 (m,
1H, CH), 2.68-2.77 (m, HCCO), 3.30 (s, 3H,
OCH3), 3.39-3.66 (m, 2H, OCH2), 3.67 (s, 3H,
C 0 2CH3), 5.18 (m, 1H, = CH). - ^CpH} NMR
(125 MHz, CDC13): (5 = 14.7, 23.7, 28.6, 29.9, 43.9,
(5 = 1.20 (d, J = 8.6 Hz, 3H, CH3), 1.42-1.70 (m, 49.4, 51.3, 58.8, 71.9, 115.7, 143.9, 175.8.
4H, 2x CH2), 1.85-2.18 (m, 4H, 2x CH2), 4.12 (q,
Minor diastereoisomer: XH NMR (300 MHz,
J = 8.6 Hz, 1H, C//O H ), 5.82 (br. s, 1H, = CH). -
CDC13): d = 1.48-1.79 (m, 4H, 2x CH2), 1.56 (m,
13C{1H | NMR (75 MHz, CDC13): d = 21.4 (C-l), 3H, CH3), 2.09-2.29 (m, 2H, CH2), 2.51-2.65 (m,
22.5, 22.6, 23.6, 24.8 (all CH2), 72.1 (C-2), 121.4
(C-4), 141.2 (C-3). HRMS: m/z = 126.1045 OCH3), 3.39-3.66 (m, 2H, OCH2), 3.67 (s, 3H.
(calcd. for C8H 140 : 126.1044).
l-(Cyclohepten-l-yl)-l-ethanol (4c): 75%; b.p. (125 MHz, CDC13): (3 = 14.6, 23.3, 27.9, 30.1, 44.1,
1H, CH), 2.68-2.77 (m, 1H, HCCO), 3.31 (s, 3H,
-
C 0 2CH3), 5.24 (m, 1H, = CH). - 13C{1H} NMR
78 °C/0.3 mbar. - IR (CHC13): v = 3600, 3055,
2910, 1646 cm -1. - XH NMR (300 MHz, CDC13):
48.2, 51.4, 58.9, 72.9, 116.8, 143.8, 175.7.
Methyl 2-(2-ethylidenecyclohexyl)-3-methoxy-
ö = 1.20 (d, J = 6.8 Hz, 3H, CH3), 1.40-1.55 (m, propionate (6b): 92%; b.p. 110-115 °C/12 mbar;
4H, 2x CH2), 1.62 (m, 2H, CH2), 2.0-2.15 (m, 4H,
2x CH2), 4.13 (q, J = 6.8 Hz, 1H, C//O H ), 5.57 (t, NMR analysis of the crude product.
J = 6.4 Hz, 1H, = CH). - 13C{1H} NMR (100 MHz, (CHC13): v = 3060, 2985, 2875, 1735, 1608 cm "1. -
3:2 mixture of diastereoisomers according to XH
IR
-
CDC13): <5 = 21.6 (C-l), 27.0, 27.3, 28.0, 28.1, 32.6
(all CH2), 73.4 (C-2), 126.2 (C-4), 147.8 (C-3). -
HRMS: m/z 140.1206 (calcd. for C9H 10O:
140.1201).
HRMS: m/z = 226.1566 (calcd. for C13H220 3:
226.1568).
Major diastereoisomer: XH NMR (500 MHz,
CDC13): <5 = 1.18-1.31 (m, 2H, CH2), 1.49 (d, J =
6.5 Hz, 3H, CH3), 1.52-1.79 (m, 4H, 2x CH2),
l-(Cycloocten-l-yl)-!-ethanol (4d): 70%; b.p.
84 °C/0.3 mbar. - IR (CHC13): v = 3525, 3060, 1.99-2.28 (m, 2H, CH2), 2.29-2.39 (m, 1H, CH),
2930, 1650 cm"1. - XH NMR (400 MHz, CDC13): 3.02-3.08 (m, HCCO), 3.30 (s, 3H, OCH3), 3.48-
6 = 1.25 (d, / = 6.4 Hz, 3H, CH3), 1.41-1.64 (m,
3.54 (m, 2H, OCH2), 3.57 (s, 3H, C 0 2CH3), 5.11
4H, 2x CH2), 2.06-2.14 (m, 4H, 2x CH2), 2.15-
(q, J = 6.5 Hz, 1H, = CH). - 13C{1H} NMR (125
2.24 (m, 4H, 2x CH2), 4.20 (q, J = 6.4 Hz, 1H, MHz, CDC13): (3 = 12.6, 22.2, 24.8, 27.2, 29.5, 44.8,
C//O H), 5.57 (t, J = 8.2 Hz, 1H, = CH). - 13C{1H}
NMR (100 MHz, CDC13): (5 = 22.2 (C-l), 25.4,
25.7, 26.3, 26.4, 29.2, 28.2 (all CH2), 72.8 (C-2),
47.1, 51.2, 59.0, 72.6, 117.4, 139.5, 174.7.
Minor diastereoisomer: 1H NMR (500 MHz,
CDC13): <5 = 1.18-1.31 (m, 2H, CH2), 1.55 (d, J =
124.5 (C-4), 144.2 (C-3). - HRMS: m/z = 154.1352 6.5 Hz, 3H, CH3), 1.52-1.79 (m, 4H, 2x CH2),
(calcd. for C10H 18O: 154.1357).
1.99-2.28 (m, 2H, CH2), 2.29-2.39 (m, 1H, CH),
3.02-3.08 (m, 1H, HCCO), 3.26 (s, 3H, OCH3).
3.31-3.47 (m, 2H, OCH2), 3.69 (s, 3H, C 0 2CH3),
5.18 (q, J = 6.5 Hz, 1H, -CH ). - ^C^H} NMR
(125 MHz, CDC13): (5= 12.5, 21.91, 24.5, 27.4, 31.1,
44.7, 45.9, 51.5, 58.9, 73.6, 118.0, 138.9, 175.4.
Methyl 2-(ethylidenecycloheptyl)-3-methoxypro-
pionate (6c): 98%; b.p. 120-124 °C/12 mbar; 2.4:2
mixture of diastereoisomers. - IR (CHC13): v -
3080, 2970, 1730, 1615 cm“1. - HRMS: m/z =
240.1728 (calcd. for C14H240 3: 240.1725).
General procedure for the preparation o f methyl
2-(2-ethylidenecycloalkyl)-3-methoxy propionates
(6 a-d)
Allylic alcohols 4a-d (1 mol) were treated with
1.5 eq of trimethyl /3-(methoxy)othopropionoate
and phenol (0.06 eq) and heated at ~ 145 °C for 1
h. The excess orthoester was recovered by vacuum
distillation (b.p. 50-52 °C/12 mbar) and the residue
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F. Zulfiqar and A. Malik • Facile Approach to Versatile Chiral Intermediates
1231
*H NMR (500 MHz, CDC13): <3 = 1.21 (t, J = 7.0
Major diastereoisomer:
NMR (500 MHz,
CDCI3): <5 = 1.09-1.30 (m, 4H, 2x CH2), 1.53 (d, Hz, 3H, OCH2 CH3), 1.19-1.33 (m, 2H, CH2),
J = 6.5 Hz, 3H, CH3), 1.55-1.79 (m, 4H, 2x CH2), 1.54 (d, J = 7.0 Hz, 3H, CH3), 1.58-1.94 (m, 2H,
1.86-2.33 (m, 2H, CH2), 2.35-2.39 (m, 1H, CH), CH2), 2.14 (dd, J = 15.0, 9.0 Hz, 1H, CHH C 0 2),
2.62-2.67 (m, 1H, HCCO), 3.30 (s, 3H, OCH3), 2.17-2.31 (m, 2H, CH2), 2.45 (dd, J = 15.0, 5.5 Hz,
3.45-3.56 (m, 2H, OCH2), 3.57 (s, 3H, C 0 2CH3), 1H, C H //C 0 2), 2.70 (m, 1H, CH), 4.08 (q, J = 7.0
Hz, 2H, OCH2), 5.14 (m, 1H, = CH). - 13C pH}
NMR (75 MHz, CDC13): <5 = 14.2 (CH3), 14.5
(CH3), 23.8, 28.7, 33.1, 39.5 (all CH2), 40.7 (C -l'),
60.0 (OCH2CH3), 114.5 (=CH), 145.7 (C-2'), 173.1
(C 0 2Et). - HRMS: m/z = 182.1302 (calcd. for
5.17 (q, J = 6.5 Hz, 1H, = CH). - ^CpH} NMR
(75 MHz, CDCI3): d = 12.8, 25.6, 26.3, 28.9, 31.3,
31.8, 47.6, 51.1, 52.6, 58.9, 72.3, 122.1, 141.6, 174.2.
Minor diastereoisomer: :H NMR (500 MHz,
CDCI3): <5 = 1.09-1.30 (m, 4H, 2x CH2), 1.58 (d,
J = 6.5 Hz, 3H, CH3), 1.55-1.79 (m, 4H, 2x CH2), C nH 180 2: 182.1306).
1.86-2.33 (m, 2H, CH2), 2.35-2.39 (m, 1H, CH),
2.53-2.58 (m, HCCO), 3.25 (s, 3H, OCH3), 3.33-
Ethyl 2-(2-ethylidenecyclohexyl)ethanoate (5b):
72%. - IR (CHC13): = 3070, 1735, 1620 cm“1. -
v
3.42 (m, 2H, OCH2), 3.68 (s, 3H, C 0 2CH3), 5.15 XH NMR (500 MHz, CDC13): d = 1.20 (t, J = 7.0
(q, J = 6.5 Hz, 1H, = CH). - ^CpH} NMR (75 Hz, 3H, OCH2C //3), 1.21-1.71 (m, 8H, 4x CH2),
MHz, CDC13): (5 = 12.8, 25.1, 26.0, 28.6, 31.1, 31.6, 1.54 (d, J = 7.0 Hz, 3H, CH3), 2.26-2.30 (m, 2H,
CH2C 0 2), 2.56 (m, 1H, CH), 4.07 (q, J = 7.0 Hz,
47.5, 50.6, 51.4, 58.8, 73.7, 122.8, 140.9, 175.2.
Methyl 2-(2-ethylidenecyclooctyl)-3-methoxypro- 2H, OCH2), 5.67 (dq, J = 7.0,1.0 Hz, 1H, = CH). -
pionate (6 d): 89%; b.p. 130-134 °C/12 mbar; 2.3:2 13C pH} NMR (75 MHz, CDC13): <3= 12.5 (CH3),
mixture of diastereoisomers; IR (CHC13): v = 14.2 (CH3), 24.4, 26.8, 27.6, 33.8, 38.1 (all CH2),
41.1 (C -l'), 60.0 (OCH2CH3), 114.3 (=CH), 141.4
(C-2'), 173.2 (C 0 2Et). - HRMS: m/z = 196.1463
3080, 2875, 1735, 1620 cm"1. - HRMS: m/z =
254.1886 (calcd. for C15H 260 3: 254.1881).
Major diastereoisomer. ]H NMR (300 MHz, (calcd. for Ci2H20O2: 196.1463).
Ethyl 2-(2-ethylidenecycloheptyl)ethanoate (5c):
CDC13): (5 = 1.16-1.94 (m, 12H, 6x CH2), 1.54 (d,
J = 6.5 Hz, 3H, CH3), 2.18-2.29 (m, 1H, CH), 64%. - IR (CHC13) v = 3060, 1740, 1660 cm"1. -
2.54-2.69 (m, 1H, HCCO), 3.29 (s, 3H, OCH3), *H NMR (500 MHz, CDC13): 6 = 1.19 (t, J = 7.0
3.47-3.55 (m, 2H, OCH2), 3.56 (s, 3H, C 0 2CH3), Hz, 3H, OCH2C //3), 1.12-1.25 (m, 4H, 2x CH2),
5.17 (q, J = 6.5 Hz, 1H, = CH). - ^CpH} NMR 1.54 (d, J = 6.5 Hz, 3H, CH3), 1.56-1.91 (m, 6H,
(125 MHz, CDC13): <3 = 13.5, 25.6, 26.3, 27.3, 27.8, 3x CH2), 2.24-2.33 (m, 2H, CH2 C 0 2), 2.61 (m,
1H, CH), 4.05 (q, J = 7.0 Hz, 2H, OCH2), 5.19 (dq,
28.1, 48.0, 50.4, 51.4, 58.8, 73.5, 122.6, 140.0, 175.4.
Minor diastereoisomer: XH NMR (300 MHz, J = 6.5, 1.0 Hz, 1H, = CH. - 13C pH} NMR (75
CDC13): (5 = 1.16 -1.94 (m, 12H, 6x CH2), 1. 54 MHz, CDC13): <5 = 12.8 (CH3), 14.2 (CH3), 26.0,
(d, J = 6.5 Hz, 3H, CH3), 2.18-2.29 (m, 1H, CH), 26.3, 28.5, 30.7, 34.0, 41.7 (all CH2), 44.1 (CH),
2.54-2.69 (m, 1H, HCCO), 3.29 (s, 3H, OCH3), 59.9 (OCH2CH3), 120.4 (=CH), 143.1 (C-2'), 172.8
3.47-3.55 (m, 2H, OCH2), 3.56 (s, 3H, C 0 2CH3), (C 0 2Et). - HRMS: m/z = 210.1621 (calcd. for
5.17 (q, J = 6.5 Hz, 1H, = CH). - ^CpH} NMR
(125 MHz, CDC13): <5 = 13.5, 25.9, 26.0, 26.2, 26.7,
C13H220 2: 210.1619).
Ethyl 2-(2-ethylidenecyclooctyl)ethanoate (5d):
27.5, 28.5, 47.9, 51.1, 52.0, 58.7, 72.5, 122.3, 73%. - IR (CHC13):
v
= 3065, 1735, 1655 cm "1. -
141.10, 174.3.
XH NMR (500 MHz, CDC13): d = 1.17 (t, J = 7.0
Hz, 3H, OCH2C //3), 1.22-1.67 (m, 12H, 6x CH2),
1.55 (d, J = 6.5 Hz, 3H, CH3), 2.19 (dd, J = 14.0,
8.5 Hz, 1H, C /m C 0 2), 2.23 (dd, / = 14.0, 7.0 Hz,
1H, C H tfC 02), 4.03 (q, J = 7.0 Hz, 2H, OCH2),
General procedure for the preparation o f E-alkyli-
dene cycloalkanes (5a-d)
Allylic alcohols 4a-d (1 mol) were treated with 5.23 (dd, J = 6.5, 1.0 Hz, 1H, = CH). - 13C pH}
NMR (75 MHz, CDC13): (5 = 13.4 (CH3), 14.2
1.5 equivalents of triethyl orthoacetate at 145 °C
for 1 h in the presence of a catalytic amount of (CH3), 25.9, 26.0, 26.1, 26.7, 27.6, 30.6, 42.0 (all
phenol (0.06 eq). The excess of orthoester was re- CH2), 44.7 (CH), 59.9 (OCH2), 120.6 (=CH), 142.5
moved by distillation under reduced pressure and (C-2'), 172.7 (C 0 2Et). - HRMS: m/z = 224.1778
the resulting residue was purified by flash chroma- (calcd. for C14H240 2: 224.1776).
tography over silica gel using hexane and hexane-
ethyl acetate (199:1) as eluent to obtain 5a-d as
colorless oils.
Epoxidation o f compound 6b (11)
Ethyl 2-(2-ethylidenecyclopentyl)ethanoate (5a):
62%. - IR (CHC13): v = 3050, 1735, 1615 cm“1. -
A mixture of 6b (1.0 g, 4.4 mmol), ra-CPBA
(1.1 g tech. 75%, 4.8 mmol), CH2C12 (25 ml), 0.5
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F. Zulfiqar and A. Malik • Facile Approach to Versatile Chiral Intermediates
M N aH C 03 (75 ml) was stirred at 0 °C for 2 h. CHCI3. The combined extracts were washed with
The organic portion was successively washed with
brine, dried (anhydrous M gS04) and concen-
5% Na2S20 3, 5% N aH C 03, H20 and brine, dried trated. Purification of the residue by flash chroma-
(anhydrous Na2S 0 4) and concentrated to give tography (silica gel, 95:5 hexane-ethyl acetate) af-
0.8 g (80%) of expoxide 11 as a colorless oil which
was a 3:2 mixture of diastereoisomers.
forded 7a-d as colorless oils.
Methyl
2-(2-ethylidenecyclopentyl)propenoate
Major diastereoisomer: XH NMR (500 MHz,
(7a): 65%. - IR (CHC13): v = 3070, 2990, 1720,
CDC13): d = 1.25 (d ,/ = 5.5 Hz, 3H, CH3), 1.40-1.97 11620, 1275, 1160 cm“1. - XH NMR (300 MHz,
(m, 9H, cyclic H), 2.89 (q, / = 5.5 Hz, OCH), 2.97
(m, 1H, CH), 3.30 (s, 3H, OCH3), 3.42-3.52 (m, 2H, 2x CH2), 2.19-2.35 (m, 2H, CH2), 3.41 (m, 1H,
OCH2), 3.67 (s, 3H, C 0 2CH3). - 13C{XH} NMR
CH), 3.72 (s, 3H, C 0 2CH3), 5.08 (m, 1H, = CH),
(100 MHz, CDC13): <5= 13.0, 21.3, 21.3, 24.2, 26.0, 5.50 (dd, J = 1.5,1.2 Hz, 1H, = C //H ), 6.15 (d, J =
CDC13): (3 = 1.56 (m, 3H, CH3), 1.61-1.96 (m, 4H,
28.5, 43.8, 45.4, 51.6, 59.0, 59.4, 62.8, 72.7,174.0.
Minor diastereoisomer: XH NMR (500 MHz,
CDC13): d = 1.24 (d, J = 5.5 Hz, 3H, CH3), 1.40-
1.5 Hz, = CH//).
CDC13): Ö= 24.2, 29.1, 33.5, 47.1, 51.5,116.4,124.5,
144.0, 114.9, 167.8. - HRMS: m/z = 180.1154
-
13C{1H} NMR (75 MHz,
1.97 (m, 9H, ring H), 2.76 (q, J = 5.5 Hz, OCH), (calcd. for Cn H 160 2: 180.1150).
2.99 (m, 1H, CH), 3.31 (s, 3H, OCH3), 3.42-3.52
Methyl
2-(2-ethylidenecyclohexyl)propenoate
(m, 2H, OCH2), 3.71 (s, 3H, C 0 2CH3).
(7b): 90%. - IR (CHC13): v = 3060, 2875, 1725,
1625, 1280, 1190 cm -1. - XH NMR (500 MHz,
CDC13): <3 = 1.22-1.35 (m, 2H, CH2), 1.52 (d, J =
6.6 Hz, 3H, CH3), 1.69-1.87 (m, 4H, 2x CH2),
2.57-2.61 (m, 2H, CH2), 3.20 (br. d, J = 10.5 Hz,
IH, CH), 3.71 (s, 3H, C 0 2CH3), 4.88 (q, J = 6.6
Hz, 1H, = CH), 5.48 (dd, J = 1.5, 1.0 Hz, 1H, =
CH//), 6.25 (dd, J = 1.0, 0.5 Hz, 1H, C//H ). - 13C
pH} NMR (125 MHz, CDC13): (5 = 12.7, 26.2, 27.8,
28.6, 32.8, 45.4, 51.8, 114.9, 124.4, 141.7, 143.2,
168.2. - HRMS: m/z = 194.1303 (calcd. for
C12H 180 2: 194.1306).
Methyl 2-[3ß(s*)-2a-methyl-l-oxaspiro [2.5] oct-
4ß-yl]-propenoate (12)
To a mixture of potasium f-butoxide (1.21 g,
10.8 mmol) in THF (50 ml) at 0 °C was rapidly
added a solution of ester 11 (1.68 g, 6.9 mmol) in
THF (25 ml). The reaction mixture was main-
tained at 0 °C for 1 h, diluted with cold brine
(8 ml), neutralized with 5% HCl, and the aqueous
portion extracted with CH2C12. The combined or-
ganic extract was dried (anhydrous Na2S 0 4) and
concentrated to afford 1.1 g (75%) of a 4:1 mixture
of 12 and 8b. It was subjected to flash chromatog-
raphy (silica gel, hexane-ethyl acetate 95:5) to af-
ford 12 (0.75 g, 52%) as a colorless oil. - XH NMR
(300 MHz, CDC13): (5 = 1.20-1.95 (m, 8H, 4x
CH2), 1.22 (d, J = 5.5 Hz, 3H, CH3), 2.71 (q, J =
5.5 Hz, 1H, OCH), 3.07 (br.d, J = 10.5 Hz, 1H,
CH), 3.72 (s, 3H, C 0 2CH3), 5.36 (t, J = 1.2 Hz, =
CH//), 6.10 (t, J = 1.2 Hz, =CHH). - 13C NMR
(75 MHz, CDCI3): d = 13.2 (CH3), 25.2, 25.5, 29.8,
30.3 (all CH2), 43.4 (C-H), 51.9 (HC-O), 53.9
(C 02CH3), 64.3 (C-O), 123.7 (=CH2), 141.1 (=C-
C 0 2CH3), 169.1 (C 0 2CH3). - HRMS m /z: molec-
ular ion peak not observed; characteristic ions at
m/z = 195.1015 (M-CH3)+ (calcd. for Cn H 150 3 :
Methyl
2-(2-ethylidenecycloheptyl)propenoate
(7c): 69%. - IR (CHC13): v = 3060, 2970, 2865,
1725, 1630, 1280, 1190 cm -1. - XH NMR (300
MHz, CDC13): (3 = 1.18-1.48 (m, 4H, 2x CH2),
1.55 (d, J = 6.7 Hz, 3H, CH3), 1.61-2.09 (m, 4H,
2x CH2), 2.29-2.36 (m, 2H, CH2), 3.32 (dd, J =
10.7, 5.0 Hz, 1H, CH), 3.68 (s, 3H, C 0 2CH3), 5.17
(q, J = 6.7 Hz, 1H, = CH), 5.44 (t, J = 1.2 Hz, 1H,
CH//), 6.06 (dd, J = 1.2, 1.0 Hz, 1H, C//H ). - 13C
pH} NMR (75 MHz, CDC13): <5 = 12.9, 26.9, 27.6,
28.1, 29.8, 32.6, 47.4, 51.5,121.1,121.9, 142.1, 145.5
168.0.
-
HRMS: m/z = 208.1468 (calcd. for
Ci3H20O2: 208.1463).
Methyl
2-(2-ethylidenecyclooctyl)propenoate
(7d): 67%. - IR (CHC13): v = 3050, 2970, 2880,
1730, 1635, 1280, 1190 cm“1. - XH NMR (500
MHz, CDC13): (5 = 1.55 (dd, J = 6.7, 1.0 Hz, 3H,
CH3), 1.34-1.72 (m, 8H, 4x CH2), 2.05-2.19 (m,
2H, CH2), 2.23-2.27 (m, 2H, CH2), 3.30 (br. d, J =
II.5 Hz, 1H, CH), 3.69 (s, 3H, C 0 2CH3), 5.25 (dq,
J = 6.7, 1.5 Hz, 1H, = CH), 5.42 (dd, J = 1.5, 1.0
195.1012) and m/z
= 178.0992 (M-CH3OH)+
(calcd. for C nH 140 2: 178.0993).
General procedure for the preparation o f methyl 2-
(2-ethylidenecycloalkyl)propenoates 7a-d
To a mixture of potassium J-butoxide (2 eq) in Hz, 1H, = CH//), 6.02 (t, J = 1.0 Hz, 1H, =
CHH). - 13C {XH} NMR (75 MHz, CDC13): d =
6a-d (1 mol) in THF. The reaction mixture was 13.5, 25.6, 26.5, 26.6, 26.9, 27.4, 33.1, 46.2, 51.5,
maintained at 0 °C for 1 h, diluted with H 20 and 120.9, 121.5, 141.2, 145.7, 168.1.- HRMS: m/z =
THF at 0 °C was rapidly added a solution of ester
ice, neutralized with 5% HCl, and extracted with 222.1611 (calcd. for C14H220 2: 222.1619).
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F. Zulfiqar and A. Malik • Facile Approach to Versatile Chiral Intermediates
tion of bromine (68 mg, 0.43 mmol) in CC14
(0.5 ml) with constant stirring. The solvent was
evaporated under reduced pressure. Purification
of the residue by flash chromatography (silica
gel, hexane-ethyl acetate 95:5) afforded 280 mg
(77%) of 10 as a pale yellow oil. - *H NMR
(500 MHz, CDC13): 6 = 1.33-2.08 (m, 8H, 4x
CH2), 1.89 (d, J = 7.0 Hz, 3H, CH3), 3.14 (dd,
J = 11.5, 3.0 Hz, 1H, CH), 3.74 (s, 3H, C 0 2CH3),
4.43 (q, / = 7.0 Hz, 1H, CHBr), 6.12 (s, 1H,
General procedure for epoxidation o f compounds
7a-d
A mixture of diene 7a-d (1 mol), m-CPBA
(75%, 1.2 mol), CH2C12 (4 ml), and 0.5
M
N aH C 03 (5 ml) was stirred at 0 °C under argon.
When the reaction was completed, the organic
portion was successively washed with 5%
Na2S20 3, 5% N aH C 03, H20, brine, dried (anhy-
drous Na2S 0 4), and concentrated to give the crude
product 8a-d as a colorless oil. Purification of 8a-d CH//), 6.15 (s, 1H, = C//H).
-
C12H 18Br20 2
over silica gel (3% ethyl acetate-hexane) afforded
pure products.
(354.1): calcd. C 40.90, H 5.11, Br 44.88; found
C 40.90, H 5.17, Br 44.82.
Methyl
2-[3a(R*)-2ß-methyl-l-oxaspiro[2.4]-
NMR (300
hept-4ß-yl]propenoate (8a): 45%. -
General procedure for chiral diols 13 and 14
To a solution of 8b or 12 (2.28 g, 10.8 mmol) in
MHz, CDCI3): (5 = 1.24 (d, J = 5.4 Hz, 3H, CH3),
1.53-2.03 (m, 6H, 3x CH2), 2.79 (q, / = 5.4 Hz,
1H, OCH), 3.12 (dd, J = 10.8, 4.7 Hz, 1H, CH),
3.73 (s, 3H, C 0 2CH3), 5.64 (dd, J = 1.2, 1.0 Hz, hexane (65 ml) and CH2C12 (40 ml) at -78 °C was
1H, = CH //), 6.25 (d, J = 1.2 Hz, 1H, = C/TH). -
HRMS: m/z = 196.1096 (calcd. for Cn H 160 3:
196.1099).
added DIBAL (25.1 ml, 1.0 m solution in CH2C12,
25.7 mmol) over 1.5 h via a syringe. The reaction
mixture was diluted with ether (65 ml), quenced
with MeOH (4.0 ml), followed by brine (4.0 ml)
Methyl 2-[3a(R*)-2ß-methyl-l-oxaspiro[2.5]oct-
4ß-ylJpropenoate (8b): 75%.
-
lH NMR (300 and M gS04 (9.0 g). After warming to room tem-
perature, the mixture was filtered and concen-
trated to afford crude epoxy alcohol (1.29 g, 66%)
which was used directly in the next reaction.
To a solution of (PhSe)2 (3.72 g, 11.9 mmol) in
absolute EtOH (65 ml) at 0 °C was slowly added
NaBH4 (1.0 g, 26. mmol) until the yellow colour
had disappeared. The resulting solution was re-
fluxed and a solution of the crude epoxy alcohol
(1.92 g, 7.1 mmol) in absolute EtOH (15.5 mmol)
MHz, CDC13): d = 1.17 (d, J = 5.6 Hz, 3H, CH3),
1.38-1.89 (m, 8H, 4x CH2), 2.52 (q, J = 5.6 Hz,
1H, OCH), 2.99 (dd, J = 10.7, 4.9 Hz, 1H, CH),
3.72 (s, 3H, C 0 2CH3), 5.56 (dd, J = 1.2, 1.0 Hz,
1H, = CH//), 6.23 (d, J = 1.2 Hz, 1H, = C /m ). -
^C^H} NMR (125 MHz, CDC13): d = 13.0, 23.9,
26.0, 29.2, 30.4, 40.9, 51.9, 56.5, 62.2, 127.0 138.4,
168.5.
-
HRMS: m/z = 210.1254 (calcd. for
Ci2H 180 3: 210.1255).
Methyl
2-[3a(R*)-2ß-methyl-l-oxaspiro[2.6]- was added via a syringe over 3 h. The reaction
mixture was allowed to stir for an additional 1 h,
non-4ß-yl]propenoate (8c): 59%. - *H NMR (300
MHz, CDC13): d = 1.20 (d, J = 5.5 Hz, 3H, CH3), cooled to 0 °C and 30% H20 2 (25 ml) was cau-
tiously added over a period of 1 h. The reaction
Hz, 1H, OCH), 2.92 (ddd, J = 10.7, 4.4, 1.1 Hz, mixture was allowed to warm to room temper-
1.28-1.87 (m, 10H, 5x CH2), 2.66 (q, / = 5.5
ature, diluted with H20 (65 ml), and extracted
CH), 3.37 (s, 3H, C 0 2CH3), 5.50 (t, J = 1.1 Hz,
with CH2C12. The combined extract was succes-
1H, = CH//), 6.14 (d, / = 1.1 Hz, 1H, = C//H ). -
HRMS: m/z = 224.1413 (calcd. for C13H20O3: sively washed with 5% NaH2C 0 3, H20 , brine,
dried (anhyd. M gS04) and concentrated. Purifica-
224.1412).
Methyl 2-[3a(R*)-2ß-methyl-l-oxoaspiro[2.7]- tion by flash chromatography (silica gel, 9:1 hex-
dec-4ß-yl]propenoate (8d): 50%. - *H NMR (300 ane-EtOAc) afforded the target molecules.
lß-Ethenyl-2ß-[l-(hydroxymethyl)ethenyl]cyclo-
MHz, CDC13): (5 = 1.20 (d, J = 5.6 Hz, 3H, CH3),
1.13-1.95 (m, 12H, 6x CH2), 2.75 (q, / = 5.6 Hz, hexanol (13): 63%. - M.p. 70-72 °C. - XH NMR
1H, OCH), 2.93 (ddd, J = 11.4, 4.5, 1.2 Hz, 1H, (300 MHz, CDC13): (5 = 1.12-1.91 (m, 8H, 4x
CH), 3.74 (s, 3H, C 0 2CH3), 5.48 (dd, J = 1.21, 1.0 CH2), 2.28 (dd, / = 13.0, 3.5 Hz, 1H, CH), 4.05
Hz, 1H, = CH//), 6.13 (d, / = 1.0 Hz, 1H, = (AB q, / = 13.0 Hz, 2H, C //2OH), 4.83 (s, 1H, =
CH//), 5.12 (dd, J = 9.5, 1.8 Hz, 1H, HC = C//H ),
5.15 (s, 1H, = C /m ), 5.25 (dd, J = 17.5, 1.8 Hz,
1H, HC = CH//), 6.21 (dd, J = 17.5, 9.5 Hz, 1H,
C//H ).
Ci4H220 3: 238.1568).
Methyl 2-[2-bromo-2-(l-bromoethyl)cyclohexyl-
-
HRMS: m/z = 238.1567 (calcd. for
jpropenoate (10): To
a solution of diene 7b HC = CH2). - 13C {XH} NMR (75 MHz, CDC13):
(200 mg, 1.0 mmol) in CC14 (0.5 ml) and absolute (5 = 23.6, 26.2, 29.5, 41.2 (all CH2), 51.9 (CH), 67.9
EtOH (0.2 ml) at -5 °C was slowly added a solu- (CH2), 74.5 (C-OH); 114.1 (= CH2) 115.0 (= CH2),
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F. Zulfiqar and A. Malik • Facile Approach to Versatile Chiral Intermediates
C/ZH), 5.12 (dd, / = 17.5, 1.4 Hz, 1H, HC =
CH//), 5.83 (dd, / = 17.5, 10.6 Hz, 1H, HC =
CH2). - 13C ^H} NMR (75 MHz, CDC13): <5 =
21.1, 26.1, 26.8 38.1 (all CH2), 52.1 (CH), 64.6
139.4 (= CH), 149.0 (s, = C). - Cn H180 2 (182.1):
calcd. C 72.49, H 9.95; found C 72.56, H 9.90.
la-Ethenyl-2ß-[l-(hydroxymethyl)ethenyl]cylo-
hexanol 14): 52%. - M.p. 80-82 °C. - XH NMR
(
(300 MHz, CDC13): (5 = 1.23-1.95 (m, 8H, 4x (CH2OH), 72.8 (C-OH), 111.2 (= CH2), 116.3 (=
CH2), 145.9 (=CH), 148.8 (=C).
-
Cn H 180 2
CH2), 2.23 ( dd, / = 12.5, 3.3 Hz, 1H, CH), 3.95
(182.1): calcd. C 72.49, H 9.95; found C 72.46,
(AB q, J = 12.5 Hz, 2H, CH2OH), 4.82 (d, J =
1.2 Hz, 1H, CH //), 4.95 (dd, / = 10.6, 1.4 Hz, H 9.99.
1H, HC = C/ZH), 5.02 (dd, J = 1.2 Hz, 1H, =
[8] F. Johnson, Chem. Rev. 68, 375 (1968).
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