Competitive intramolecular Diels-Alder reactions of bis-α,β-unsaturated ester derivatives of enzymatically derived and enantiopure cis-1,2-dihydrocatechols. Enantiodivergent synthesis of monochiral bicyclo[2.2.2]oct-2-enes

Article abstract of DOI:10.1071/CH03112

bis-Crotonate and related α,β-unsaturated ester derivatives of readily available and enantiomerically pure cis-1,2-dihydrocatechols engage, upon heating in refluxing toluene, in two competitive intramolecular Diels-Alder reactions to give varying mixtures

Full text of DOI:10.1071/CH03112

Full Papers
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 861–869
Competitive Intramolecular Diels–Alder Reactions of bis-α,β-
Unsaturated Ester Derivatives of Enzymatically Derived and
Enantiopure cis-1,2-Dihydrocatechols. Enantiodivergent
Synthesis of Monochiral Bicyclo[2.2.2]oct-2-enes
Martin G. Banwell,A,B Cai Chun,A Alison J. EdwardsA and Markus M. VögtleA
A Research School of Chemistry, Institute of Advanced Studies, The Australian National University,
Canberra 0200, Australia.
B Author to whom correspondence should be addressed (e-mail: mgb@rsc.anu.edu.au).
bis-Crotonate and related α,β-unsaturated ester derivatives of readily available and enantiomerically pure cis-
1,2-dihydrocatechols engage, upon heating in refluxing toluene, in two competitive intramolecular Diels–Alder
reactions to give varying mixtures of chromatographically separable and pseudo-enantiomeric bicyclo[2.2.2]oct-2-
enes. Such adducts, many of which have been characterized by single-crystal X-ray analysis, are likely to serve as
useful building blocks in natural products synthesis.
Manuscript received: 30 April 2003.
Final version: 22 May 2003.
Introduction
the basis of the foregoing, we now report on the preparation
of a series of bis-α,β-unsaturated derivatives of the cis-
1,2-dihydrocatechols (1a)–(1e), and an examination of their
capacities to engage in intramolecular Diels–Alder reactions
so as to produce monochiral bicyclo[2.2.2]oct-2-enes.
Bicyclo[2.2.2]-octanes and -octenes serve as useful build-
ing blocks in the chemical synthesis of both natural and
non-natural products.[1] However, developing flexible and
enantioselective routes to highly functionalized derivatives
of these ring systems remains a challenge.[2] In connec-
tion with several on-going projects in this laboratory, we,[3]
like others,[4] have been generating such derivatives through
the intermolecular Diels–Alder reaction of acetal deriva-
tives of the enzymatically derived and enantiomerically
pure cis-1,2-dihydrocatechols[5] with various dienophiles.
Related intramolecular processes have also been investigated,
although to a lesser extent, with the most notable studies
having been carried out by Hudlicky’s group.[6] In partic-
ular, these workers have connected, through either ether or
ester linkages, a single dienophilic residue to the cis-1,2-
dihydrocatechol core and shown that the resulting conjugate
engages, under thermal conditions, in the expected cycload-
dition process to generate ring-fused bicyclo[2.2.2]octenes.
An interesting extension of such work would be to explore
the behaviour of systems in which two potentially dienophilic
moieties are attached, one through each oxygen of the cis-
1,2-dihydrocatechol framework, since two competing Diels–
Alder processes could now occur and, thereby, lead to pseudo-
enantiomeric bicyclo[2.2.2]octenes. Despite the potential of
such processes to provide enantiodivergent routes to the
title frameworks, relevant studies have not been reported
to date, perhaps because of concerns that the requisite bis-
ester derivatives of the cis-1,2-dihydrocatechols would be
prone to elimination and subsequent re-aromatization. On
Results and Discussion
Preliminary studies were carried out using, as starting mate-
rial, the meso-cis-1,2-dihydrocatechol (1a) (Diagram 1),
which is obtained on a large scale by enzymatic dihydroxyl-
ation of benzene.[5] The readily derived (see Experimental
section) and surprisingly stable bis-crotonate derivative (2a)
(91%) did indeed engage in the anticipated intramolecu-
lar Diels–Alder reaction upon heating in refluxing benzene,
and the structure of the crystalline adduct ( )-(3a) (96%)
was confirmed by single-crystal X-ray analysis (Fig. 1 and
Table 1).
Encouraged by the results just described, an examination
of the Diels–Alder reactions of the bis-crotonate derivative
(−)-(2b) of the enantiomerically pure and chloro-substituted
dihydrocatechol (+)-(1b)[5] was undertaken. Substrate (−)-
(2b), which is clearly electronically less activated toward
Diels–Alder cycloaddition than the parent system (2a), failed
to react in refluxing benzene but in boiling toluene smooth
conversion into a chromatographically separable 1.3 : 1 mix-
ture of adducts (+)-(3b) and (−)-(4b) (87% combined yield)
was observed (Table 2). The structure of the chromatographi-
cally less mobile and dextrorotatory adduct (+)-(3b) was
established by single-crystal X-ray analysis (see Table 1 and
Experimental section).
© CSIRO 2003
10.1071/CH03112
0004-9425/03/090861

862
M. G. Banwell et al.
The thermochemical aspects of this conversion could
crotonic acid from the starting material (−)-(2b). Interest-
ingly, AM1 calculations carried out using the MacSpartan
Pro software package predict that the observed Diels–Alder
be evaluated using differential scanning calorimetry (DSC)
techniques.[7] Thus, heating a small sample of the neat
bis-crotonate (−)-(2b) in the relevant apparatus at a rate of
5◦C min−1 from 20◦C results in the detection of a melt-
ing point endotherm of 4.21 kcal mol−1 at 48◦C (Fig. 2)
and a 23.72 kcal mol−1 exotherm from ca. 121◦C. 1H NMR
analysis of the reaction mixture so formed reveals that it
is composed entirely of the expected Diels–Alder adducts,
that is, there was no contamination of these products by aro-
matic compounds arising from elimination of the elements of
reactionsshouldbeexothermictotheextentof29 kcal mol−1
which is in line with the experimentally determined value.
,
Under the same conditions as used for congener (−)-
(2b), the bis-crotonate derivative (−)-(2c), derived from the
enantiopure ‘bromodiol’ (+)-(1c), afforded a 1.4 : 1 mix-
ture of adducts (+)-(3c) and (−)-(4c), with the structure
of both products being confirmed by X-ray analysis (see
Table 1 and Experimental section). In a similar manner, the
bis-ester (+)-(2d) of iodobenzene-derived ‘diol’ (+)-(1d)
afforded a 1 : 1.5 mixture of the expected adducts (+)-(3d)
and (−)-(4b), with the structure of the former product once
again being confirmed by single-crystal X-ray analysis (see
O
O
OH
OH
O
X
O
X
(2a)XϭH
(Ϫ)-(2b)Xϭ Cl
(Ϫ)-(2c)Xϭ Br
(ϩ)-(2d)Xϭ I
(1a)XϭH
(ϩ)-(1b)XϭCl
(ϩ)-(1c)XϭBr
(ϩ)-(1d)XϭI
(ϩ)-(2e)Xϭ CH3
(ϩ)-(1e)XϭCH3
5
6
4
5
3
4
8
3a
3
6
8
3a
7a
7
7a
7
X
2
X
2
O 1
O
O
O
O
O
1
O
O
(Ϯ)-(3a)XϭH
(ϩ)-(3b)XϭCl
(ϩ)-(3c)XϭBr
(ϩ)-(3d)XϭI
(Ϫ)-(4b)X=Cl
(Ϫ)-(4c)X=Br
(Ϫ)-(4d)X=I
(Ϫ)-(4e)Xϭ CH3
(ϩ)-(3e)Xϭ CH3
Fig. 1. ADEP derived from single-crystal X-ray analysis of compound
(
)-(3a).
Diagram 1.
Table 1. X-Ray crystal data for selected compounds
(
)-(3a)
(+)-(3b)
(+)-(3c)
(+)-(3d)
(−)-(4c)
(−)-(4f)
(−)-(4g)
Formula
FW
Crystal system
Space group
a [Å]
C14H16O4
C14H15ClO4
282.723
monoclinic
P21
8.7451(2)
7.72190(10)
10.5382(2)
107.0087(9)
680.51(2)
2/1
C14H15BrO4
327.179
monoclinic
P21
11.5138(3)
7.8470(2)
16.5849(5)
110.4440(13)
1404.05(7)
4/2
C14H15IO4
374.174
monoclinic
P21
8.04640(10)
8.33230(10)
10.6972(2)
99.4297(8)
707.50(2)
2/1
C14H15BrO4
327.179
monoclinic
P21
8.31880(10)
15.5371(2)
21.7500(4)
90.1467(6)
2811.18(7)
8/4
C14H15ClO4
282.723
orthorhombic
P22121
6.69030(10)
16.5627(2)
24.7344(3)
–
C15H18O4
262.305
monoclinic
P21
6.79020(10)
11.9873(2)
8.2956(2)
90.2959(7)
675.22(2)
2/1
248.278
monoclinic
P21/a
11.5121(2)
9.6644(2)
11.8275(3)
106.9630(11)
1258.65(5)
4/1
b [Å]
c [Å]
β [◦]
V [Å3]
2740.80(6)
8/2
Z/Zꢀ
T [K]
µ [mm−1
200
0.096
200
0.29
200
2.93
200
2.27
200
2.93
200
0.286
200
0.09
]
No. of reflections
2863
3098
5994
4135
12705
6300
3069
Unique reflections
1318
2477
3391
3016
7535
3557
2065
R
Rw
0.048
0.056
0.028
0.031
0.034
0.035
0.022
0.024
0.041
0.047
0.029
0.033
0.028
0.032

Enantiodivergent Synthesis of Monochiral Bicyclo[2.2.2]oct-2-enes
863
Table 2. Products, product ratios, and yields observed in the intramolecular Diels–Alder reactions of bis-esters (2)
Substrate (2)
Diene
substituent X
Dienophilic residues
(+)-Product (3)
(−)-Product (4)
Ratio (3) : (4)
Combined
yield [%]A
(−)-(2b)
(−)-(2c)
(+)-(2d)
(+)-(2e)
(+)-(2f)
(+)-(2g)
(−)-(2h)
(2i)
Cl
Br
I
Me
Cl
Me
Cl
Cl
Cl
Cl
bis-crotonate
bis-crotonate
bis-crotonate
bis-crotonate
bis-α-methylacrylate
bis-α-methylacrylate
bis-senecioate
C1–crotonate C2–α-methylacrylate
C1–acrylate C2–senecioate
C1–senecioate C2–acrylate
(3b)
(3c)
(3d)
(3e)
NOB
(3g)
(3h)
NO
(4b)
(4c)
(4d)
(4e)
(4f)
(4g)
NO
(4i)
NO
(4k)
1.3 : 1
1.4 : 1
1.5 : 1
1 : 1.5
87
93
83
86
62
83
11
88
84
84
–
1 : 2.1
–
–
–
–
(2j)
(2k)
(3j)
NO
A Total yield of isolated material(s).
B NO = not observed.
Table 3. Specific rotations of Diels–Alder adducts (3) and (4)
1.0
156.58°C
Compound
Specific rotationA
Compound
Specific rotationA
(+)-(3b)B
(+)-(3c)B
(+)-(3d)B
(+)-(3e)
(+)-(3f)
(+)-(3g)
(+)-(3h)
(3j)
+209◦ (c 0.7)
+180◦ (c 0.4)
+100◦ (c 0.85)
+219◦ (c 0.6)
+162◦ (c 0.45)
+210◦ (c 0.6)
+31◦ (c 0.2)
NDC
(−)-(4b)
(−)-(4c)B
(−)-(4d)
(−)-(4e)
(−)-(4f)B
(−)-(4g)B
(−)-(4i)
(−)-(4k)
(−)-(5)
−97◦ (c 0.2)
−65◦ (c 0.4)
−35◦ (c 0.9)
−88◦ (c 1.5)
−86◦ (c 1.6)
−133◦ (c 0.6)
−90◦ (c 1.8)
−135◦ (c 3.3)
−111◦ (c 0.6)
0.5
47.79°C
62.66 J/g
0.0
121.45°C
353.0 J/g
Ϫ0.5
Ϫ1.0
Ϫ1.5
(+)-(5)
+112◦ (c 0.3)
A All optical rotations were carried out in CHCl3.
B Structure proven by X-ray analysis.
C ND = not determined.
50.15°C
0
50
100
150
200
250
Temperature (°C)
Fig. 2. DSC curve associated with the intramolecular Diels–Alder
reactions of compound (−)-(2b).
O
O
X
Table 1 and Experimental section). Reaction of the bis-
crotonate derivative (+)-(2e) in refluxing toluene gave a
1 : 1.5 mixture of Diels–Alder adducts (+)-(3e) and (−)-
(4e), which could be separated chromatographically and
fully characterized. Unfortunately, the derived data did not
allow for unequivocal differentiation between these pseudo-
enantiomeric compounds. Furthermore, and despite various
attempts, it was not possible to grow crystals of either prod-
uct (+)-(3e) or (−)-(4e) that were amenable to single-crystal
X-ray analysis. At this stage, therefore, the structure assigned
to these compounds is based upon using the sign of the optical
rotation to indicate which pseudo-enantiomeric series, that is
(3) or (4), each belongs to (see Table 3).
X
O
O
O
O
O
O
O
O
X
O
O
(ϩ)-(2f) Xϭ Cl
(ϩ)-(2g) Xϭ Me
(3f) Xϭ Cl (not observed) (Ϫ)-(4f) XϭCl
(Ϫ)-(4g)
(ϩ)-(3g) Xϭ Me
Xϭ Me
O
O
Cl
Cl
O
O
O
O
O
O
O
O
O
The selectivity of the competing Diels–Alder reactions
just described, which must necessarily proceed through exo-
type transition states, appears be sensitive to steric effects in
that the crotonate residue furthest from the C3 substitutent
(X) on the diene preferentially engages in the cycloaddition
process (see Table 2) and, at least for the halogenated sys-
tems, all the more so as the size of X increases. In order
to assess the steric effect of substituents on the dienophilic
residue in these kinds of processes, the bis-α-methylacrylate
(+)-(2f) (see Diagram 2) was prepared by standard methods
from (+)-(1b). Heating a toluene solution of this bis-ester
afforded, as the only characterizable reaction product, the
Cl
O
(Ϫ)-(2h)
(ϩ)-(3h)
(4h)
(not observed)
Diagram 2.
crystalline ‘ortho’-adduct (−)-(4f) (62%), the structure of
which was confirmed by single-crystal X-ray analysis (see
Table 1 and Experimental section). The anticipated iso-
mer (3f) was not observed, although small amounts of an

864
M. G. Banwell et al.
O
O
O
O
O
O
O
O
Cl
O
O
O
Cl
O
O
O
O
O
O
O
O
Cl
O
(ϩ)-(5)
(Ϫ)-(5)
(2i)
(3i)
(not observed)
(Ϫ)-(4i)
Diagram 4.
‘meta’-adduct (3i) being detected. However, the presumably
electronically-derived preference for formation of ‘ortho’-
Diels–Alder adducts can be overridden by steric effects as
evidenced by the behaviour of bis-ester (2j) (produced by
the usual methods as a mixture with regioisomer (2k); 67%
combined yield) under the same conditions. Thus, heating a
toluene solution of bis-esters (2j) and (2k) at reflux for 16 h
afforded a chromatographically separable mixture of adducts
(+)-(3j) (84% from (2j)) and (−)-(4j) (84% from (2k)), which
were each characterized in the usual fashion.
O
O
O
O
O
O
Cl
Cl
O
O
(2j)
(2k)
The pseudo-enantiomeric relationship between the Diels–
Alder adducts of type (3) and (4) was confirmed by inde-
pendent subjection of the iodinated compounds (+)-(3d) and
(−)-(4d) to reaction with hydrogen in the presence of 10%
Pd on C and N,N-diisopropylethylamine. In each instance,
the two double bonds within these substrates were hydro-
genated and the iodine reductively cleaved such that (+)-(5)
and (−)-(5) (see Diagram 4), respectively, were formed, each
in essentially quantitative yield. These products were identi-
cal, as judged by NMR, IR, and mass spectral analysis, whilst
optical rotations were of essentially the same magnitude but
opposite sign (see Table 3). Hydrogenation of lactone ( )-
(3a) under essentially the same conditions (no added base)
afforded the racemic modification of compound (5), also in
near quantitative yield.
Cl
Cl
O
O
O
O
O
O
O
O
(3j)
(Ϫ)-(4k)
Diagram 3.
unidentified waxy by-product were obtained. The same pref-
erence was observed with the methyl-substituted system
(+)-(2g) (X = Me), which yielded 27% of adduct (+)-(3g)
and 56% of isomer (−)-(4g), the structures of which were
confirmed by X-ray analysis (see Table 1 and Experimen-
tal section). Heating a toluene solution of the bis-senecioic
ester (−)-(2h) at reflux for 48 h failed to induce any reac-
tion, and is presumably an indication of the steric demands
of the anticipated Diels–Alder cycloaddition process. How-
ever, using xylene as the reaction solvent and heating the
resulting solution at reflux afforded the gem-dimethylated
bicyclo[2.2.2]octene (+)-(3h) (11%) as the only isolable
product of reaction. None of the anticipated regio-isomeric
product (4h) was observed, but given the poor mass bal-
ance associated with the process no real significance can be
attributed to this result.
In an effort to gain further insight into these compet-
ing intramolecular Diels–Alder reactions, mixed diesters
such (−)-(2i) (see Diagram 3) were sought. Indeed, through
sequential reaction of the diol (+)-(1b), in the presence of
butyllithium, with one equivalent of crotonyl chloride then
a second equivalent of butyllithium and one equivalent of
α-methylacryloyl chloride, compound (2i) could be formed
preferentially. Heating a benzene solution of this mixed bis-
ester at reflux for 12 h afforded, in 88% yield, the crystalline
‘ortho’-adduct (−)-(4i) with none of the corresponding
Conclusion
The work detailed here indicates that α,β-unsaturated bis-
esters of the enantiomerically pure cis-1,2-dihydrocatechols
(+)-(1b), (+)-(1c), (+)-(1d), and (+)-(1e) engage in com-
peting intramolecular Diels–Alder reactions to give pseudo-
enantiomeric Diels–Alder adducts of the general type (+)-(3)
and (−)-(4). These products are, generally speaking, readily
separated from one another by flash chromatographic and/or
fractional crystallization techniques. The ratio of products
(3) and (4) is influenced by the nature of the substituent
(X) in substrate (2) but even more so by the nature of
the groups associated with the ester residues. The capacity
to generate either enantiomeric form of lactone-annulated
bicyclo[2.2.2]octanes, e.g. (+)-and (−)-(5), from a com-
mon precursor, such as (+)-(2d), by the methods described
here provides a further illustration of the synthetic potential
arising from the ‘hidden symmetry elements’[5] associated
with cis-1,2-dihydrocatechols. Diels–Alder adducts of the
type reported should be of value in developing enantio-
selective syntheses of important natural product targets such

Enantiodivergent Synthesis of Monochiral Bicyclo[2.2.2]oct-2-enes
865
as the phomoidrides,[3f] morellin, scortechinones A and B,
forbesione, gaudichaudione H, and lateriflorone.[8]
(1S,2S)-3-Chlorocyclohexa-3,5-diene-1,2-diol bis-Crotonate (−)-(2b)
Reaction of diol (+)-(1b) with crotonyl chloride under the conditions
specified in the general procedure afforded a light-yellow oil upon
workup. Subjection of this material to flash chromatography (5 : 95 v/v
ethyl acetate/hexane elution) afforded, after concentration of the relevant
fractions (Rf 0.25 in 1 : 4 v/v ethyl acetate/hexane), the title bis-ester
(−)-(2b) (93%) as a clear, colourless oil, which solidified on standing
in the fridge to give a solid, mp 49◦C, [α]D −20◦ (c 0.6 in CHCl3)
(Found: M+•, 282.0653. C14H1535ClO4 requires M+•, 282.0659). νmax
(KBr)/cm−1 1728, 1658, 1443, 1293, 1251, 1170, 1102, 968. δH 7.08–
6.90 (2 H, complex m), 6.30 (1 H, d, J 6.0), 6.04 (1 H, m), 5.92–5.72
(5 H, complex m), 1.85 (6 H, m). δC 165.4, 146.4, 146.2, 130.9, 125.4,
125.3, 124.4, 122.0(4), 121.9(6), 69.1, 68.9, 18.5 (two signals obscured
or overlapping). m/z (EI, 70 eV) 284 and 282 (3 and 9%, M+•), 247 (5),
178 (100), 149 (58), 128 (46), 121 (84), 93 (95), 91 (91).
Experimental
Melting points were recorded with a Kofler hot-stage apparatus and are
uncorrected. Proton and carbon NMR spectra (δH and δC) were recorded
with a Varian Unity 300 or Varian Gemini 300 spectrometer operating
at 300 MHz for proton and 75 MHz for carbon. All such spectra were
recorded in CDCl3 solution at 22◦C. The ‘protonicities’ of the car-
bon atoms observed in 13C NMR spectra were determined by attached
proton test (APT) experiments. Infrared spectra (νmax) were recorded
with either a Perkin–Elmer 983G IR spectrophotometer or a Perkin–
Elmer 1800 FTIR instrument. Samples were analyzed either as thin films
on sodium chloride plates (for liquids) or as potassium bromide disks
(for solids). Low-resolution electron-impact mass spectra (m/z) were
recorded at 70 eV on either a VG Micromass 7070F mass spectrometer
or a JEOL AX-505H mass spectrometer. High-resolution mass spectra
were recorded with a VG Micromass 7070F instrument. Optical rota-
tions were measured at 20◦C with a Perkin-Elmer 241 polarimeter at the
sodium D-line (589 nm) using spectroscopic grade chloroform (Merck)
and at the concentration (c) (g per100 mL) indicated. The measurements
were carried out in a cell with a path length of 1 dm. Specific rotations
([α]D20) were calculated using [α]D = (100 α)/(c), and are given in units
of 10−1 deg cm2 g−1. Tetrahydrofuran (THF) was distilled under nitro-
gen from sodium benzophenone ketyl, dichloromethane from calcium
hydride, and methanol from magnesium methoxide. DSC studies were
carried out using a TA Instruments DSC 2920 apparatus.
(1S,2S)-3-Bromocyclohexa-3,5-diene-1,2-diol bis-Crotonate (−)-(2c)
Reaction of diol (+)-(1c) with crotonyl chloride under the conditions
specified in the general procedure afforded a light-yellow oil upon
workup. Subjection of this material to flash chromatography (1 : 9 v/v
ethyl acetate/hexane elution) afforded, after concentration of the rele-
vant fractions (Rf 0.5 in 1 : 4 v/v ethyl acetate/hexane), the title bis-ester
(−)-(2c) (89%) as a clear, colourless oil, [α]D −10◦ (c 0.8 in CHCl3)
(Found: M+•, 326.0157. C14H1579BrO4 requires M+•, 326.0154). νmax
(KBr)/cm−1 1729, 1658, 1293, 1250, 1177, 1102, 968. δH 7.10–6.90
(2 H, complex m), 6.76 (1 H, d, J 6.0), 6.04–5.74 (6 H, complex m),
1.87 (6 H, m). δC 165.3, 146.4, 146.2, 129.4, 125.9, 125.0, 122.1, 122.0,
120.8, 69.9, 69.0, 18.5 (two signals obscured or overlapping). m/z (EI,
70 eV) 328 and 326 (4 and 4%, M+•), 247 (36), 178 (100), 121 (41), 93
(64), 91 (83), 77 (79).
Synthetic Studies
General Procedure for Formation of bis-Esters (2a), (−)-(2b),
(−)-(2c), (+)-(2d), (+)-(2e), (+)-(2f), (+)-(2g), and (−)-(2h)
(1S,2S)-3-Iodocyclohexa-3,5-diene-1,2-diol bis-Crotonate (+)-(2d)
Reaction of diol (+)-(1d) with crotonyl chloride under the conditions
specified in the general procedure afforded a light-yellow oil upon
workup. Subjection of this material to flash chromatography (5 : 95 v/v
ethyl acetate/hexane elution) afforded, after concentration of the relevant
fractions (Rf 0.35 in 1 : 4 v/v ethyl acetate/hexane), the title bis-ester
(+)-(2d) (89%) as a clear, colourless oil, [α]D +3◦ (c 3.1 in CHCl3).
νmax (KBr)/cm−1 1728, 1658, 1560, 1443, 1293, 1250, 1177, 1101,
968, 835. δH 7.12–6.89 (2 H, m), 6.83 (1 H, d, J 6.0), 6.00–5.69 (6 H,
complex m), 1.90 (6 H, m). δC 146.5, 146.1, 137.1, 126.4(4), 126.3(6),
126.1, 125.8, 122.2, 122.1, 95.0, 71.7, 68.0, 18.6, 18.5. m/z (EI, 70 eV)
374 (9%, M+•), 247 (3), 105 (2), 93 (3), 91 (5), 69 (100).
A magnetically stirred solution of the relevant cis-1,2-dihydrocatechol
(1) (1–15 mmol) in dry THF (ca. 15 mL mmol−1) was cooled to −78◦C
(dry-ice/acetone bath) and was then treated, dropwise, with BunLi (1.05
mole equiv. of a 2.5 M solution in hexane) over 5 min. The resulting solu-
tion was stirred at −78◦C for 10 min, at which time the appropriate acid
chloride (1 mole equiv.) was added over 5 min. The resulting solution
was stirred for 1 h at −78◦C then the dry-ice/acetone bath was removed
and replaced with an ice/water bath. The reaction mixture was stirred
for a further 1 h at ca. 0◦C then cooled again to −78◦C and treated,
dropwise, with BunLi (1.05 mole equiv. of a 2.5 M solution in hexanes).
After 10 min the relevant acid chloride (1 mole equiv.) was added over
5 min and stirring was continued at −78◦C for 1 h. The dry-ice/acetone
bath was then replaced by an ice/water bath and stirring was contin-
ued for a further 1 h. The reaction mixture was then quenched with
(1S,2R)-3-Methylcyclohexa-3,5-diene-1,2-diol bis-Crotonate (+)-(2e)
Reaction of diol (+)-(1e) with crotonyl chloride under the conditions
specified in the general procedure afforded a light-yellow oil upon
workup. Subjection of this material to flash chromatography (1 : 9 v/v
ethyl acetate/hexane elution) afforded, after concentration of the rele-
vant fractions (Rf 0.5 in 1 : 4 v/v ethyl acetate/hexane), the title bis-ester
(+)-(2e) (96%) as a clear, colourless oil, [α]D +96◦ (c 1.5 in CHCl3).
νmax (KBr)/cm−1 1722, 1657, 1444, 1308, 1293, 1256, 1175, 1102, 968.
δH 7.04–6.86 (2 H, complex m), 6.05 (1 H, dd, J 9.5 and 5.6), 5.91–5.72
(4 H, complex m), 5.60 (2 H, br s), 1.85 (9 H, m). δC 166.1, 165.9, 145.7,
145.5, 134.8, 126.8, 123.0, 122.6, 122.4, 122.0, 69.8, 68.2, 20.0, 18.5,
18.4. m/z (EI, 70 eV) 262 (<1%, M+•), 177 (4), 176 (5), 109 (9), 108
(21), 92 (4), 91 (9), 69 (100).
NaHCO3 (5 mL of a sat. aqueous solution per mmol of (1)) and diluted
−1
with diethyl ether (ca. 20 mL mmol
of (1)). The separated organic
phase was washed with NH4Cl (ca. 1 × 5 mL of a sat. aqueous solution
per mmol of (1)), then dried (MgSO4), filtered, and concentrated under
reducedpressure. Theresultingoilwaspurifiedbyflashchromatography
on silica gel to afford the relevant bis-ester (2). The instability of some
of these compounds has precluded the acquisition of the usual range of
spectroscopic and analytical data.
cis-Cyclohexa-3,5-diene-1,2-diol bis-Crotonate (2a)
Reaction of diol (1a) with crotonyl chloride under the conditions spec-
ified in the general procedure afforded a light-yellow oil upon workup.
Subjection of this material to flash chromatography (5 : 95 v/v ethyl
acetate/hexane elution) afforded, after concentration of the relevant frac-
tions (Rf 0.3 in 1 : 9 v/v ethyl acetate/hexane), the title bis-ester (2a)
(91%) as a clear, colourless oil (Found: M+•, 248.1046. C14H16O4
requires M+•, 248.1049). νmax (KBr)/cm−1 1721, 1659, 1444, 1311,
1293, 1258, 1174, 1102, 968. δH 6.95 (2 H, m), 6.14 (2 H, m), 5.97 (2 H,
m), 5.82 (2 H, d, J 15.0), 5.60 (2 H, br s), 1.90 (6 H, d, J 10.0). δC 165.8,
145.7, 126.4, 125.8, 122.5, 67.2, 18.5. m/z (EI, 70 eV) 248 (5%, M+•),
180 (16), 163 (41), 162 (48), 95 (45), 94 (60), 78 (100), 77 (45).
(1S,2S)-3-Chlorocyclohexa-3,5-diene-1,2-diol
bis-α-Methylacrylate (+)-(2f)
Reaction of diol (+)-(1b) with α-methylacryloyl chloride under the con-
ditions specified in the general procedure afforded a light-yellow oil
upon workup. Subjection of this material to flash chromatography (5 : 95
v/v ethyl acetate/hexane elution) afforded, after concentration of the rel-
evant fractions (Rf 0.2), the title bis-ester (+)-(2f) (69%) as a clear,
colourless oil, [α]D +11◦ (c 0.8 in CHCl3) (Found: M+•, 282.0659.
C14H1535ClO4 requires M+•, 282.0659). νmax (KBr)/cm−1 1728, 1638,

866
M. G. Banwell et al.
1451, 1328, 1291, 1161, 944, 810, 683. δH 6.31 (1 H, d, J 6.0), 6.13 (1 H,
m), 6.09–6.01 (2 H, complex m), 5.89–5.72 (3 H, complex m), 5.58 (2 H,
m), 1.93 (3 H, m), 1.91 (3 H, m). δC 166.3(2), 166.2(8), 135.9, 135.8,
130.8, 126.7, 126.6, 125.3, 125.1, 124.6, 69.5, 69.4, 18.6(4), 18.5(7).
m/z (EI, 70 eV) 284 and 282 (1 and 3%, M+•), 247 (1), 196 (15), 128
(17), 112 (14), 69 (100).
(1S,2S)-3-Chlorocyclohexa-3,5-diene-1,2-diol 1-Acrylate
2-Senecioate (2j)
and (1S, 2S)-3-Chlorocyclohexa-3,5-diene-1,2-diol 2-Acrylate
1-Senecioate (2k)
Reaction of diol (+)-(1b) (1.465 g, 10 mmol) with senecioyl chloride
and then acryloyl chloride under the conditions specified immediately
above afforded a ca. 1 : 1 mixture of the compounds (2j) and (2k) in 67%
yield. Since these bis-esters could not be separated from one another the
mixture was subjected to the competitive intramolecular Diels–Alder
reaction (see below).
(1S,2R)-3-Methylcyclohexa-3,5-diene-1,2-diol
bis-α-Methylacrylate (+)-(2g)
Reaction of diol (+)-(1e) with α-methylacryloyl chloride under the
conditions specified in the general procedure afforded a light-yellow
oil upon workup. Subjection of this material to flash chromatography
(5 : 95 v/v ethyl acetate/hexane elution) afforded, after concentration of
the relevant fractions (Rf 0.6 in 1 : 5 v/v ethyl acetate/hexane), the title
bis-ester (+)-(2g) (70%) as a clear, colourless oil, [α]D +113◦ (c 0.7 in
CHCl3) (Found: M+•, 262.1207. C15H18O4 requires M+•, 262.1205).
νmax (KBr)/cm−1 1723, 1638, 1451, 1317, 1169, 943. δH 6.08 (3 H, m),
5.85 (1 H, m), 5.78 (1 H, m), 5.65–5.48 (4 H, complex m), 1.92 (3 H, br
s), 1.90 (3 H, br s), 1.82 (3 H, s). δC 166.8, 166.7, 136.3, 136.1, 134.6,
126.9, 126.0, 125.8, 122.6, 121.8, 70.3, 68.3, 19.6, 18.3(3), 18.2(8). m/z
(EI, 70 eV) 280 (5%, M+•), 262 (15), 235 (10), 176 (14), 148 (100), 128
(40), 119 (38), 107 (67), 91 (57).
(3SR,3aRS,6SR,7RS,7aSR,8RS)-2,3,3a,6,7,7a-Hexahydro-8-methyl-
2-oxo-3,6-methanobenzofuran-7-yl Crotonate ( )-(3a)
A solution of bis-crotonate (2a) (497 mg, 2 mmol) in benzene (10 mL)
maintained under a nitrogen atmosphere was heated at reflux for 4 h then
cooled to 18◦C and concentrated under reduced pressure. The result-
ing light-yellow oil was purified by flash chromatography (silica, 1 : 4
v/v ethyl acetate/hexane elution) and concentration of the appropriate
fractions (Rf 0.5) then afforded the title compound ( )-(3a) (479 mg,
96%) as white crystalline masses, mp 90◦C (Found: M+•, 248.1049.
C14H16O4 requires M+•, 248.1049). νmax (KBr)/cm−1 1791, 1713,
1652, 1316, 1290, 1190, 1167, 1040, 1013, 709. δH 6.98 (1 H, m), 6.39
(1 H, tm, J 7.0), 6.11 (1 H, tm, J 7.0), 5.86 (1 H, dq, J 15.5 and 1.8), 4.53
(1 H, t, J 6.0), 4.36 (1 H, dd, J 6.0 and 2.5), 3.50 (1 H, m), 2.82 (1 H, m),
2.51 (1 H, m), 2.10 (1 H, dm, J 3.2), 1.88 (3 H, dd, J 6.9 and 1.8), 0.94
(3 H, d, J 7.0). δC 179.2, 165.8, 146.1, 134.5, 126.1, 122.1, 71.8, 69.8,
45.1, 41.8, 41.2, 31.9, 20.1, 18.5. m/z (EI, 70 eV) 248 (47%, M+•), 179
(11), 134 (14), 128 (9), 107 (30), 105 (52), 93 (100), 91 (96), 77 (74).
(1S,2S)-3-Chlorocyclohexa-3,5-diene-1,2-diol bis-Senecioate (−)-(2h)
Reaction of diol (+)-(1b) with senecioyl chloride under the condi-
tions specified in the general procedure afforded a light-yellow oil upon
workup. Subjection of this material to flash chromatography (1 : 9 v/v
ethyl acetate/hexane elution) afforded, after concentration of the rele-
vant fractions (Rf 0.3), the title bis-ester (−)-(2h) (94%) as a clear,
colourless oil, [α]D −43◦ (c 1.4 in CHCl3) (Found: M+•, 310.0970.
C16H1935ClO4 requires M+•, 310.0972). νmax (KBr)/cm−1 1728, 1651,
1575, 1446, 1379, 1352, 1262, 1226, 1146, 1112, 1088, 1042, 990, 847,
675. δH 6.28 (1 H, d, J 6.0), 6.03 (1 H, m), 5.83 (1 H, m), 5.77–5.68
(3 H, complex m), 5.63 (1 H, m), 2.15 (6 H, dm, J 4.0), 1.89 (6 H, dm,
J 3.5). δC 165.4, 165.3, 158.4, 158.2, 131.3, 125.8, 125.1, 124.3, 115.6,
115.5, 68.5, 68.2, 27.8, 20.7 (two signals obscured or overlapping). m/z
(EI, 70 eV) 312 and 310 (7 and 17%, M+•), 275 (2), 211 (15), 128 (17),
114 (21), 112 (44), 100 (26), 84 (100), 83 (68), 82 (34).
(3R,3aR,6R,7S,7aS,8S)-6-Chloro-2,3,3a,6,7,7a-hexahydro-8-methyl-
2-oxo-3,6-methanobenzofuran-7-yl Crotonate (+)-(3b)
and (3S,3aR,6S,7S,7aS,8S)-3a-Chloro-2,3,3a,6,7,7a-hexahydro-
8-methyl-2-oxo-3,6-methanobenzofuran-7-yl Crotonate (−)-(4b)
A solution of bis-crotonate (−)-(2b) (420 mg, 1.5 mmol) in toluene
(15 mL) maintained under a nitrogen atmosphere was heated at reflux for
5 h then cooled to 18◦C and concentrated under reduced pressure. The
resulting light-yellow oil was purified by flash chromatography (silica,
1 : 4 v/v ethyl acetate/hexane elution) to afford two fractions, A and B.
Concentration of fraction A (Rf 0.1) gave the title compound (+)-
(3b) (208 mg, 49%) as white crystalline masses, mp 104◦C (Found: C
59.1, H 5.5, Cl 12.3%; M+•, 282.0653. C14H1535ClO4 requires C 59.5,
H 5.4, Cl 12.5%; M+•, 282.0659). νmax (KBr)/cm−1 1786, 1730, 1659,
1443, 1341, 1296, 1166, 1103, 1018, 972, 883, 715. δH 7.04 (1 H, m),
6.36 (1 H, dd, J 8.6 and 1.2), 6.14 (1 H, m), 5.93 (1 H, dm, J 15.5), 4.64
(1 H, m), 4.57 (1 H, d, J 6.9), 3.48 (1 H, m), 2.66 (1 H, q, J 7.0), 2.23
(1 H, m), 1.91 (3 H, dm, J 6.9), 1.10 (3 H, d, J 7.0). δC 177.4, 165.4,
146.8, 138.2, 125.5, 121.6(8), 72.9, 72.5, 70.0(7), 70.0(5), 46.4, 40.4,
39.9, 18.6, 17.4. m/z (EI, 70 eV) 284 and 282 (3 and 8%, M+•), 247
(10), 127 (27), 105 (39), 91 (100), 77 (70).
(1S,2S)-3-Chlorocyclohexa-3,5-diene-1,2-diol 1-Crotonate
2-α-Methylacrylate (2i)
A magnetically stirred solution of cis-1,2-dihydrocatechol (+)-(1b)
(730 mg, 5 mmol) in dry THF (75 mL) was cooled to −78◦C (dry-
ice/acetone bath) then treated, dropwise, with BunLi (2.1 mL of a 2.5 M
solution in hexane, 5.25 mmol) over 5 min. The resulting solution was
stirredat−78◦Cfor10 minthencrotonylchloride(479µL, 5 mmol)was
added over 5 min. The ensuing mixture was stirred for 1 h at −78◦C then
the dry-ice/acetone bath was removed and replaced with an ice/water
bath. The reaction was stirred for a further 1 h at ca. 0◦C then cooled
again to −78◦C and treated, dropwise, with BunLi (2.1 mL of a 2.5 M
solution in hexane, 5.25 mmol). After 10 min α-methylacryloyl chlo-
ride (483µL, 5 mmol) was added over 5 min and stirring was continued
at −78◦C for 1 h. The dry-ice/acetone bath was then replaced by an
ice/water bath and stirring was continued for a further 1 h. The reac-
tion mixture was then quenched with NaHCO3 (25 mL of a sat. aqueous
solution) and diluted with diethyl ether (100 mL). The separated organic
phase was washed with NH4Cl (1 × 25 mL of a sat. aqueous solution),
then dried (MgSO4), filtered, and concentrated under reduced pres-
sure. The resulting oil was purified by flash chromatography (silica
gel, 2.5 : 97.5 v/v ethyl acetate/hexane) and concentration of the rele-
vant fractions (Rf 0.3) afforded the title bis-ester (2i) (440 mg, 31%) as
a clear, colourless oil. δH (C6D6) 6.82 (1 H, m), 6.16 (1 H, br s), 5.93
(1 H, d, J 6.5), 5.74 (2 H, m), 5.64 (1 H, dm, J 15.5), 5.50 (1 H, dd, J 9.5
and 3.3), 5.37 (1 H, m), 5.14 (1 H, br s), 1.77 (3 H, d, J 1.1), 1.20 (3 H,
dm, J 7.0). δC 166.2, 165.3, 146.1, 135.7, 130.9, 126.7, 125.1, 125.0,
124.8, 122.0, 69.4, 68.6, 18.6, 18.5.
Concentration of fraction B (Rf 0.2) gave the title compound (−)-
•
(4b) (161 mg, 38%) as white crystalline masses, mp 88◦C (Found: M+
,
282.0654. C14H15ClO4 requires M+•, 282.0659). νmax (KBr)/cm−1
1795, 1718, 1657, 1444, 1263, 1181, 1155, 1026, 972, 860, 727, 705.
δH 7.01 (1 H, m), 6.40 (1 H, t, J 8.4), 6.24 (1 H, dd, J 8.6 and 1.3), 5.86
(1 H, dq, J 15.5 and 1.6), 4.60 (1 H, dd, J 6.7 and 1.5), 4.45 (1 H, dd,
J 6.7 and 2.3), 2.82 (1 H, m), 2.64 (1 H, m), 2.25 (1 H, t, J 1.5), 1.90
(3 H, dd, J 6.9 and 1.5), 1.01 (3 H, d, J 7.2). δC 176.4, 165.5, 146.8,
133.4, 131.1, 121.7, 78.2, 70.9, 69.9, 55.1, 41.5, 35.0, 20.0, 18.6. m/z
(EI, 70 eV) 284 and 282 (0.5 and 1.5%, M+•), 178 (11), 149 (6), 121
(11), 93 (16), 91 (13), 77 (10), 69 (100).
(3R,3aR,6R,7S,7aS,8S)-6-Bromo-2,3,3a,6,7,7a-hexahydro-8-methyl-
2-oxo-3,6-methanobenzofuran-7-yl Crotonate (+)-(3c)
and (3S,3aR,6R,7R,7aS, 8S)-3a-Bromo-2,3,3a,6,7,7a-hexahydro-
8-methyl-2-oxo-3,6-methanobenzofuran-7-yl Crotonate (−)-(4c)
A solution of bis-crotonate (−)-(2c) (1.00 g, 3.07 mmol) in toluene
(15 mL) maintained under a nitrogen atmosphere was heated at reflux

Enantiodivergent Synthesis of Monochiral Bicyclo[2.2.2]oct-2-enes
867
for 12 h then cooled to 18◦C and concentrated under reduced pressure.
The resulting light-yellow oil was purified by flash chromatography
(silica, 5 : 95 v/v ethyl acetate/hexane elution) to afford two fractions,
A and B.
(silica, 1 : 9 v/v ethyl acetate/hexane elution) to afford two fractions,
A and B.
Concentration of fraction A (Rf 0.25) gave the title compound (+)-
(3e) (135 mg, 35%) as a clear, colourless oil (Found: M+•, 262.1206.
C15H18O4 requires M+•, 262.1205). νmax (KBr)/cm−1 2970, 1790,
1723, 1657, 1446, 1260, 1171, 1024, 972, 895, 711. δH 6.97 (1 H, m),
6.07 (2 H, m), 5.86 (1 H, dm, J 15.5), 4.58 (1 H, m), 4.15 (1 H, d, J 6.7),
3.43 (1 H, m), 2.23 (1 H, m), 2.03 (1 H, dm, J 4.7), 1.87 (3 H, dm, J
6.9), 1.21 (3 H, s), 0.89 (3 H, d, J 7.0). δC 179.3, 166.0, 145.9, 139.6,
125.6, 122.1, 73.6, 73.1, 47.1, 42.4, 41.0, 37.2, 19.3, 18.5, 17.4. m/z
(EI, 70 eV) 262 (44%, M+•), 176 (26), 119 (33), 107 (78), 91 (100).
Concentration of fraction B (Rf 0.3) gave the title compound (−)-
(4e) (200 mg, 51%) as a clear, colourless oil (Found: M+•, 262.1207.
C15H18O4 requires M+•, 262.1205). νmax (KBr)/cm−1 2966, 1789,
1723, 1657, 1445, 1262, 1180, 1041, 1019, 969, 945, 849, 713. δH
6.94 (1 H, m), 6.33 (1 H, t, J 7.8), 5.90–5.76 (2 H, complex m), 4.33
(1 H, dd, J 6.6 and 2.2), 4.17 (1 H, dm, J 6.6), 2.73 (1 H, m), 2.48
(1 H, m), 1.84 (3 H, dd, J 6.9 and 1.5), 1.66 (1 H, s), 1.36 (3 H, s),
0.90 (3 H, d, J 7.0). δC 179.2, 165.8, 145.9, 133.7, 131.9, 122.1,
77.1, 70.7, 52.3, 45.5, 42.0, 33.7, 21.1, 20.1, 18.5. m/z (EI, 70 eV)
262 (9%, M+•), 148 (37), 128 (100), 119 (53), 107 (58), 105 (27),
91 (56).
Concentration of fraction A (Rf 0.3 in 3 : 7 v/v ethyl acetate/hexane)
gave the title compound (+)-(3c) (541 mg, 54%) as white crystalline
masses, mp75◦C(Found:C51.4, H4.7, Br24.3%;[M + H]+, 327.0239.
C14H1579BrO4 requires C 51.4, H 4.6, Br 24.4%; [M + H]+, 327.0232).
νmax (KBr)/cm−1 2983, 1788, 1731, 1658, 1443, 1341, 1297, 1261,
1165, 1085, 1064, 1016, 973, 953, 880, 715. δH 6.99 (1 H, m), 6.45
(1 H, d, J 8.6), 6.04 (1 H, dd, J 8.6 and 6.4), 5.86 (1 H, dm, J 15.5), 4.56
(2 H, br s), 3.46 (1 H, m), 2.67 (1 H, q, J 7.0), 2.22 (1 H, d, J 4.3), 1.86
(3 H, dd, J 6.9 and 1.8), 1.09 (3 H, d, J 7.0). δC 177.4, 165.3, 146.8,
138.8, 126.0, 121.7, 73.5, 72.6, 64.5, 46.2, 40.5, 40.2, 18.8, 18.6. m/z
(EI, 70 eV) 328 and 326 (5 and 5%, M+•), 247 (10), 133 (20), 105 (52),
93 (55), 91 (100).
ConcentrationoffractionB(Rf 0.35 in3 : 7v/vethylacetate/hexane)
gave the title compound (−)-(4c) (388 mg, 39%) as white crystalline
masses, mp88◦C(Found:C51.6, H4.7, Br24.5%;[M + H]+, 327.0242.
C14H1579BrO4 requires C 51.4, H 4.6, Br 24.4%; [M + H]+, 327.0232).
νmax (KBr)/cm−1 2971, 1794, 1717, 1657, 1262, 1181, 1155, 1026, 972,
714, 704. δH 6.97 (1 H, m), 6.34 (2 H, m), 5.84 (1 H, dm, J 15.5), 4.65
(1 H, dm, J 6.7), 4.41 (1 H, dd, J 6.7 and 2.2), 2.81 (1 H, m), 2.64 (1 H,
m), 2.34 (1 H, br s), 1.88 (3 H, dd, J 6.9 and 1.8), 0.99 (3 H, d, J 7.2).
δC 176.5, 165.5, 146.8, 133.7, 132.0, 121.7, 78.6, 70.0, 62.3, 56.1, 41.0,
35.4, 20.1, 18.6. m/z (EI, 70 eV) 328 and 326 (each <1%, M+•), 247
(6), 178 (24), 149 (6), 121 (9), 93 (10), 91 (10), 69 (100).
(3S,3aR,6S,7S,7aS)-3a-Chloro-2,3,3a,6,7,7a-hexahydro-8-methyl-
2-oxo-3,6-methanobenzofuran-7-ylα-Methylacrylate (−)-(4f)
A solution of bis-ester (−)-(2f) (320 mg, 1.13 mmol) in toluene (10 mL)
maintained under a nitrogen atmosphere was heated at reflux for 16 h
then cooled to 18◦C and concentrated under reduced pressure. The
resulting light-yellow oil was purified by flash chromatography (silica,
1 : 9 v/v ethyl acetate/hexane elution) to afford two fractions, A and B.
Concentration of fraction A (Rf 0.04) gave a wax (30 mg) of
undetermined composition and structure.
(3R,3aR,6R,7S,7aS,8S)-6-Iodo-2,3,3a,6,7,7a-hexahydro-
8-methyl-2-oxo-3,6-methanobenzofuran-7-yl Crotonate (+)-(3d)
and (3S,3aR,6S,7S,7aS,8S)-3a-Iodo-2,3,3a,6,7,7a-hexahydro-8-
methyl-2-oxo-3,6-methanobenzofuran-7-yl Crotonate (−)-(4d)
A solution of bis-crotonate (+)-(2d) (255 mg, 0.68 mmol) in toluene
(5 mL) maintained under a nitrogen atmosphere was heated at reflux
for 24 h then cooled to 18◦C and concentrated under reduced pressure.
The resulting light-yellow oil was purified by flash chromatography
(silica, 1 : 9 v/v ethyl acetate/hexane elution) to afford two fractions, A
and B.
Concentration of fraction A (Rf 0.1) gave the title compound (+)-
(3d) (128 mg, 50%) as white crystalline masses, mp 96◦C (Found: C
45.2, H 4.3, I 33.7%. C14H15IO4 requires C 44.9, H 4.0, I 33.9%).
νmax (KBr)/cm−1 2971, 1784, 1723, 1654, 1442, 1304, 1170, 1105,
1063, 1012, 968, 836, 715. δH 7.05 (1 H, m), 6.68 (1 H, dm, J 8.6),
5.98–5.86 (2 H, complex m), 4.58 (1 H, d, J 6.7), 4.51 (1 H, m), 3.50
(1 H, m), 2.71 (1 H, q, J 7.0), 2.29 (1 H, dt, J 4.7 and 1.5), 1.90 (3 H, dd,
J 7.0 and 1.8), 1.16 (3 H, d, J 7.0). δC 177.5, 165.2, 147.0, 141.4, 126.4,
121.7, 74.9, 72.3, 46.4, 45.2, 41.8, 39.9, 21.5, 18.7. m/z (EI, 70 eV) 374
(10%, M+•), 91 (6), 69 (100).
Concentration of fraction B (Rf 0.08) gave the title compound (−)-
(4f) (200 mg, 62%) as white crystalline masses, mp 75◦C (Found: C
59.3, H 5.5, Cl 12.7%; M+•, 282.0662. C14H1535ClO4 requires C 59.5,
H 5.4, Cl 12.5%; M+•, 282.0659). νmax (KBr)/cm−1 1797, 1715, 1453,
1163, 1076, 1019, 951, 816, 716. δH 6.52 (1 H, dd, J 8.5 and 7.2), 6.16
(1 H, dm, J 8.5), 6.13 (1 H, br s), 5.63 (1 H, m), 4.66 (1 H, d, J 6.7),
4.48 (1 H, m), 2.86 (1 H, m), 2.45 (1 H, dd, J 13.8 and 3.2), 1.93 (3 H,
s), 1.30 (1 H, dt, J 13.8 and 1.9), 1.20 (3 H, s). δC 178.7, 166.5, 135.5,
134.7, 131.0, 127.1, 77.6, 75.4, 69.6, 48.1, 35.8, 35.0, 18.6, 18.1. m/z
(EI, 70 eV) 284 and 282 (<1 and <1%, M+•), 247 (<1), 170 (8) and
168 (25), 128 (19), 121 (9), 93 (15), 91 (12), 77 (8), 69 (100).
(3S,3aS,6S,7R,7aS)-2,3,3a,6,7,7a-Hexahydro-6-methyl-2-oxo-
3,6-methanobenzofuran-7-yl α-Methylacrylate (+)-(3g)
and (3R,3aS,6R,7S,7aR)-3a,8-Dimethyl-2,3,3a,6,7,7a-hexahydro-
2-oxo-3,6-methanobenzofuran-7-yl α-Methylacrylate (−)-(4g)
A solution of compound (+)-(2g) (1.31 g, 5 mmol) in toluene (50 mL)
was heated at reflux for 24 h then cooled to 18◦C and concentrated under
reduced pressure. The residue thus obtained was subject to flash chro-
matography (silica, hexane to 6 : 94 v/v ethyl acetate/hexane gradient
elution) thereby affording two fractions, A and B.
Concentration of fraction A (Rf 0.45 in 1 : 3 : 7 v/v/v ethyl
acetate/dichloromethane/hexane) gave the title compound (+)-(3g)
(353 mg, 27%) as a clear, colourless oil (Found: M+•, 262.1207.
C15H18O4 requires M+•, 262.1205). νmax (KBr)/cm−1 1786, 1722,
1453, 1291, 1161, 998, 717. δH 6.20 (1 H, d, J 8.2), 6.08 (1 H, s), 6.03
(1 H, dd, J 8.2 and 6.4), 5.56 (1 H, s), 4.57 (1 H, m), 4.10 (1 H, m), 3.09
(1 H, m), 1.99 (1 H, d, J 13.8), 1.91 (3 H, s), 1.15 (3 H, s), 1.06 (3 H, s),
0.94 (1 H, m). δC 181.3, 166.8, 141.5, 135.7, 126.4, 125.2, 71.9, 71.0,
46.3, 42.8, 40.2, 38.3, 20.6, 20.4, 18.3. m/z (EI, 70 eV) 262 (23%, M+•),
234 (4), 176 (18), 148 (21), 128 (25), 119 (17), 107 (28), 91 (22), 69
(100).
Concentration of fraction B (Rf 0.2) gave the title compound
(−)-(4d) (85 mg, 33%) as a clear, colourless oil. νmax (KBr)/cm−1
1791, 1723, 1656, 1443, 1259, 1176, 1101, 1025, 967, 790, 702.
δH 6.99 (1 H, m), 6.57 (1 H, d, J 8.0), 6.22 (1 H, t, J 8.0), 5.85
(1 H, dm, J 15.5), 4.70 (1 H, d, J 6.7), 4.40 (1 H, dd, J 6.7
and 2.2), 2.83 (1 H, m), 2.70 (1 H, m), 2.42 (1 H, s), 1.89 (3 H,
dm, J 7.2), 1.00 (3 H, d, J 7.0). δC 177.0, 165.5, 146.8, 134.7,
134.1, 121.7, 80.1, 69.7, 58.5, 40.4, 38.6, 35.4, 20.2, 18.6. m/z (EI,
70 eV) 374 (ꢁ1%, M+•), 247 (8), 93 (10), 91 (10), 77 (10), 69
(100).
(3S,3aR,6S,7R,7aS,8R)-6,8-Dimethyl-2,3,3a,6,7,7a-hexahydro-
2-oxo-3,6-methanobenzofuran-7-yl Crotonate (+)-(3e)
and (3R,3aS,6R,7S,7aR,8S)-3a,8-Dimethyl-2,3,3a,6,7,
7a-hexahydro-8-methyl-2-oxo-3,6-methanobenzofuran-
7-yl Crotonate (−)-(4e)
A solution of bis-crotonate (+)-(2e) (400 mg, 1.5 mmol) in toluene
(10 mL) maintained under a nitrogen atmosphere was heated at reflux
for 30 h then cooled to 18◦C and concentrated under reduced pressure.
The resulting light-yellow oil was purified by flash chromatography
Concentration of fraction B (Rf 0.5 in 1 : 3 : 7 v/v/v ethyl
acetate/dichloromethane/hexane) gave the title compound (−)-(4g)
(733 mg, 56%) as white crystalline masses, mp 63.5–64◦C (Found: C
69.0, H 7.2%; M+•, 262.1207. C15H18O4 requires C 68.7, H 6.9%; M+
,
•
262.1205). νmax (KBr)/cm−1 1783, 1716, 1448, 1346, 1320, 1287, 1163,

868
M. G. Banwell et al.
1078, 1028, 949, 821, 720. δH 6.48 (1 H, t, J 8.2), 6.08 (1 H, s), 5.76
(1 H, br d, J 8.2), 5.55 (1 H, s), 4.34 (1 H, m), 4.20 (1 H, m), 2.74 (1 H,
m), 2.27 (1 H, dm, J 13.9), 1.89 (3 H, br s), 1.25 (3 H, s), 1.07 (1 H,
d, J 13.9), 0.93 (3 H, s). δC 181.4, 166.7, 135.7, 135.3, 131.4, 126.4,
76.2, 69.9, 47.4, 44.7, 34.9(3), 34.9(0), 18.2(3), 18.2(1), 16.9. m/z (EI,
70 eV) 262 (13%, M+•), 234 (5), 177 (4), 148 (55), 128 (25), 119 (26),
107 (32), 91 (22), 69 (100).
requires C 59.5, H 5.35, Cl 12.5%; M+•, 282.0659). νmax (KBr)/cm−1
1797, 1712, 1647, 1443, 1232, 1192, 1133, 1088, 1044, 1011, 951, 850,
717, 706. δH 6.52 (1 H, t, J 7.3), 6.19 (1 H, m), 5.70 (1 H, s), 4.63 (1 H,
m), 4.38 (1 H, m), 2.87 (1 H, br s), 2.59 (1 H, dm, J 11.1), 2.29 (1 H,
broadened d, J 13.3), 2.14 (3 H, s), 1.90 (3 H, s), 1.72 (1 H, t, J 13.3).
δC 177.2, 165.5, 159.3, 135.4, 131.2, 115.0, 78.8, 70.9, 69.0, 47.0, 34.5,
28.1, 28.0, 20.8. m/z (EI, 70 eV) 284 and 282 (1 and 5%, M+•), 164
(100), 154 (27), 107 (61), 103 (23), 91 (41).
(3R,3aR,6R,7S,7aS)-6-Chloro-8,8-dimethyl-2,3,3a,6,7,7a-hexahydro-
2-oxo-3,6-methanobenzofuran-7-yl Senecioate (+)-(3h)
(3SR,3aRS,6SR,7RS,7aSR,8RS)-8-Methyl-2,3,3a,4,5,6,7,7a-
octahydro-2-oxo-3,6-methanobenzofuran-7-yl Butyrate ( )-(5),
(3S,3aR,6S,7R,7aS,8R)-8-Methyl-2,3,3a,4,5,6,7,7a-octahydro-
2-oxo-3,6-methanobenzofuran-7-yl Butyrate (+)-(5),
A solution of diester (−)-(2h) (650 mg, 2.1 mmol) in xylene (10 mL)
maintained under a nitrogen atmosphere was heated at reflux for 48 h
then cooled to 18◦C and concentrated under reduced pressure. The
resulting light-yellow oil was purified by flash chromatography (sil-
ica, 1 : 9 v/v ethyl acetate/hexane elution) and preparative TLC (silica,
5 : 95 v/v ethyl acetate/hexane elution) to afford, after concentration
of the relevant fractions (Rf 0.2 in 1 : 4 ethyl acetate/hexane), the title
compound (+)-(3h) (71 mg, 11%) as white crystalline masses, mp 80–
85◦C (Found: M+•, 310.0971. C16H1935ClO4 requires M+•, 310.0972).
νmax (KBr)/cm−1 1787, 1722, 1650, 1446, 1226, 1141, 849, 711. δH 6.46
(1 H, dd, J 8.5 and 1.1), 6.04 (1 H, dd, J 8.5 and 6.5), 5.76 (1 H, br s),
4.69 (1 H, m), 4.62 (1 H, d, J 6.5), 3.50 (1 H, m), 2.30 (1 H, d, J 5.0),
2.18 (3 H, s), 1.93 (3 H, s), 1.41 (3 H, s), 1.05 (3 H, s). δC 176.6, 165.4,
159.4, 142.4, 123.7, 115.2, 73.8, 73.4, 72.2, 49.7, 43.3, 41.0, 28.0, 27.9,
22.7, 20.9. m/z (EI, 70 eV) 312 and 310 (3 and 9%, M+•), 275 (8), 141
(24), 131 (49), 125 (35), 105 (44), 91 (100).
and (3R,3aS,6R,7S,7aR,8S)-8-Methyl-2,3,3a,4,5,6,7,7a-octahydro-
2-oxo-3,6-methanobenzofuran-7-yl Butyrate (−)-(5)
A magnetically stirred solution of compound ( )-(3a) (74 mg,
0.3 mmol) in ethanol (15 mL) was treated with 10% Pd on C (30 mg)
and a hydrogen atmosphere was then established above the reaction
mixture. Stirring was continued at ca. 18◦C for 16 h then the reaction
mixture was filtered through a short pad of Celite which was washed
with ethanol (15 mL). The combined filtrates were concentrated under
reduced pressure and the resulting pale-yellow oil was purified by flash
chromatography (silica, 3 : 7 v/v ethyl acetate/hexane elution). Concen-
tration of the appropriate fractions (Rf 0.35) then afforded the title
•
compound ( )-(5) (74 mg, 97%) as a clear, colourless oil (Found: M+
,
252.1360. C14H20O4 requires M+•, 252.1362). νmax (KBr)/cm−1 2963,
1789, 1736, 1255, 1174, 1068, 1015, 972, 884. δH 4.83 (1 H, br t,
J 6.6), 4.71 (1 H, dd, J 6.6 and 1.9), 2.59 (1 H, m), 2.43–2.23 (2 H,
complex m), 2.08 (1 H, br d, J 4.5), 1.95 (1 H, m), 1.87–1.58 (6 H, com-
plex m), 1.44 (1 H, m), 1.17 (3 H, d, J 7.2), 0.96 (3 H, t, J 7.3). δC
179.5, 173.3, 76.5, 72.2, 44.5, 37.0, 36.2, 34.9, 26.6, 20.2, 18.8, 18.2,
15.0, 14.1. m/z (EI, 70 eV) 252 (<1%, M+•), 224 (26), 181 (34), 164
(24), 136 (25), 109 (22), 107 (14), 71 (100).
(3S,3aR,6S,7S,7aS)-3a-Chloro-2,3,3a,6,7,7a-hexahydro-
3-methyl-2-oxo-3,6-methanobenzofuran-7-yl Crotonate (−)-(4i)
Asolutionofbis-ester(2i)(50 mg, 0.18 mmol)inbenzene(15 mL)main-
tained under a nitrogen atmosphere was heated at reflux for 12 h then
cooled to 18◦C and concentrated under reduced pressure. The resulting
light-yellow oil was purified by flash chromatography (silica, 1 : 4 v/v
ethylacetate/hexaneelution). Concentrationoftherelevantfractions(Rf
0.1) then afforded the title compound (−)-(4i) (44 mg, 88%) as white
crystalline masses, mp 55◦C (Found: M+•, 282.0662. C14H1535ClO4
requires M+•, 282.0659). νmax (KBr)/cm−1 1792, 1719, 1651, 1297,
1180, 1108, 1079, 1026, 792, 715. δH 7.01 (1 H, m), 6.51 (1 H, t,
J 8.5), 6.15 (1 H, d, J 8.5), 5.75 (1 H, dm, J 14.7), 4.66 (1 H, d, J
6.7), 4.45 (1 H, dt, J 6.7 and 1.9), 2.83 (1 H, m), 2.46 (1 H, dd, J 13.8
and 3.4), 1.90 (3 H, dm, J 6.9), 1.28 (1 H, dm, J 13.8), 1.19 (3 H, s). δC
178.8, 165.5, 146.7, 134.8, 130.9, 121.7, 77.5, 75.4, 69.3, 48.1, 35.6,
35.0, 18.6, 18.1. m/z (EI, 70 eV) 284 and 282 (<1 and 1%, M+•), 178
(6), 170 (6), 168 (18), 150 (6), 149 (4), 139 (6), 128 (15), 121 (14), 93
(18), 91 (14), 77 (8), 69 (100).
Subjection of compound (+)-(3d) to the same reaction condi-
tions as defined immediately above [except for the addition of N,N-
diisopropylethylamine (180 mole equiv. with respect to the substrate) to
the reaction mixture] afforded lactone (+)-(5) (98%) as a clear, colour-
less oil, which was identical, in all respects, with the racemic material
(
)-(5) save for being optically active (see Table 3).
Subjection of compound (−)-(4d) to the same reaction condi-
tions as defined immediately above [except for the addition of N,N-
diisopropylethylamine (180 mole equiv. with respect to the substrate) to
the reaction mixture] afforded lactone (−)-(5) (99%) as a clear, colour-
less oil, which was identical, in all respects, with the racemic material
(
)-(5) save for being optically active (see Table 3).
Crystallography
(3R,3aR,6R,7S,7aS)-6-Chloro-2,3,3a,6,7,7a-hexahydro-
2-oxo-3,6-methanobenzofuran-7-yl Senecioate (3j)
Crystal Data
and (3S,3aR,6S,7S,7aS)-3a-Chloro-2,3,3a,6,7,7a-hexahydro-
2-oxo-3,6-methanobenzofuran-7-yl Senecioate (−)-(4k)
The mixture of bis-esters (2j) and (2k) (1.05 g, 3.7 mmol), prepared as
described above, was dissolved in toluene (10 mL) and the resulting
solution was heated at reflux under a nitrogen atmosphere for 16 h then
cooled to 18◦C and concentrated under reduced pressure. The resulting
light-yellow oil was purified by flash chromatography (silica, 1 : 4 v/v
ethyl acetate/hexane) to afford two fractions, A and B.
The crystal data for compounds ( )-(3a), (+)-(3b), (+)-(3c), (+)-(3d),
(−)-(4c), (−)-(4f), and (−)-(4g) are presented in Table 1.
Structure Determinations
IntensitydatawerecollectedbyaNoniusKappaCCDdiffractometerand
extracted from diffraction images by the DENZO[9] package. Analyti-
cal absorption corrections were applied.[10] All structures were solved
by direct methods[11] and expanded using Fourier techniques.[12] Full-
matrix least-squares refinement was on F, non-hydrogen atoms were
refined anisotropically, while hydrogen atoms were included at geomet-
rically determined positions and ride on the carbon of attachment. The
ADEP of ( )-(3a) was generated using CAMERON software.[13] The
structure of (−)-(4c) comprises of four crystallographically independent
molecules per asymmetric unit with one molecule being conformation-
ally disordered. Compound (−)-(4f) crystallizes with two molecules
per asymmetric unit with one of the two molecules being disordered
at the side chain terminus. The disordered portions were restrained to
reasonable bonding geometry and occupancy refined.
Concentration of fraction A (Rf 0.1) gave the title compound (+)-
•
(3j) [436 mg, 84% from (2j)] as a clear, colourless oil (Found: M+
,
282.0647. C14H1535ClO4 requires M+•, 282.0659). νmax (KBr)/cm−1
1794, 1718, 1648, 1450, 1226, 1139, 849, 705. δH 6.53 (1 H, m), 6.10
(1 H, m), 5.78 (1 H, m), 4.65 (1 H, m), 4.48 (1 H, m), 3.50 (1 H, m), 2.56
(1 H, m), 2.46 (1 H, d, J 13.3), 2.16 (3 H, s), 1.99 (1 H, tm, J 11.1), 1.93
(3 H, s). δC 177.9, 165.5, 159.4, 140.9, 125.3, 115.1, 72.6, 71.8, 64.2,
40.2, 38.7, 35.5, 28.0, 20.9. m/z (EI, 70 eV) 284 and 282 (7 and 20%,
M+•), 247 (16), 183 (4), 91 (6), 83 (100), 82 (25).
Concentration of fraction B (Rf 0.2) gave the title compound (−)-
(4k) [435 mg, 84% from (2e)] as white crystalline masses, mp 88◦C
(Found: C 59.3, H 5.6, Cl 12.5%; M+•, 282.0658. C14H1535ClO4
Atomic coordinates, bond lengths and angles, and displacement
parameters have been deposited with the Cambridge Crystallographic

Enantiodivergent Synthesis of Monochiral Bicyclo[2.2.2]oct-2-enes
869
Data Centre (CCDC nos: ( )-(3a) 208 292, (+)-(3b) 208 293, (+)-(3c)
208 294, (+)-(3d) 208 296, (−)-(4c) 208 295, (−)-(4f) 208 297, and
(−)-(4g) 208 291).
H. F. Olivo, C. Andersen, T. Nugent, J. D. Price, J. Chem.
Soc., Perkin Trans. 1 1991, 2907. (d) T. Hudlicky, E. E. Boros,
H. F. Olivo, J. S. Merola, J. Org. Chem. 1992, 57, 1026. (e)
T. Hudlicky, H. F. Olivo, J. Am. Chem. Soc. 1992, 114, 9695.
(f) T. Hudlicky, C. H. Boros, Tetrahedron Lett. 1993, 34, 2557.
(g) T. Hudlicky, B. P. McKibben, J. Chem. Soc., Perkin Trans 1
1994, 485. (h) T. Hudlicky, H. F. Olivo, B. McKibben, J. Am.
Chem. Soc. 1994, 116, 5108. (i) M. Balci, Pure Appl. Chem.
1997, 69, 97.
Acknowledgments
We are grateful to the Institute of Advanced Studies (IAS)
and the Australian Research Council for financial support.
The Deutsche Forschungsgemeinschaft (DFG) is thanked for
provision of a post-doctoral stipend to M.M.V. C.C. acknowl-
edges Nanjing University of Science and Technology for
financial support and for providing a period of study leave
that enabled him to spend time in the Research School of
Chemistry.
[5] For an extensive commentary on the production and
synthetic utility of cis-1,2-dihydrocatechols, see: T. Hudlicky,
D. Gonzalez, D. T. Gibson, Aldrichimica Acta 1999, 32, 35.
[6] (a) T. Hudlicky, G. Seoane, T. Pettus, J. Org. Chem. 1989, 54,
4239. (b) T. Hudlicky, C. H. Boros, E. E. Boros, Synthesis 1992,
174. (c) G. Butora, A. G. Gum, T. Hudlicky, K. A. Abboud,
Synthesis 1998, 275. (d) J. Zezula, T. Hudlicky, I. Ghiviriga,
Collect. Czech. Chem. Commun. 2001, 66, 1269.
References
[7] M. J. Richardson, Thermochim. Acta 1997, 300, 15.
[8] E. J. Tisdale, C. Chowdhury, B. G. Vong, H. Li,
E. A. Theodorakis, Org. Lett. 2002, 4, 909.
[1] B. C. Ranu, S. K. Guchhait, K. Ghosh, A. Patra, Green Chem.
2000, 5, and references therein.
[9] Z. Otwinowski, W. Minor, in Methods in Enzymology (Eds
C. W. Carter Jr, R. M. Sweet) 1997, Vol. 276, pp. 307–326
(Academic: New York, NY).
[10] P. Coppens, in Crystallographic Computing (Eds F. R. Ahmed,
S. R. Hall, C. P. Huber.) 1970, pp. 255–270 (Munksgaard:
Copenhagen).
[11] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi,
M. C. Burla, G. Polidori, M. Camalli, J. Appl. Crystallogr.
1994, 27, 435.
[12] (a) J. R. Carruthers, D. J. Watkin, Acta Crystallogr., Sect. A
1979, 35, 698. (b) D. J. Watkin, C. K. Prout, J. R. Carruthers,
P. W. Betteridge, CRYSTALS Issue 10 1996 (Chemical
Crystallography Laboratory: Oxford).
[2] F. Almquist, T. Frejd, J. Org. Chem. 1996, 61, 6947, and
references therein.
[3] (a) M. G. Banwell, J. R. Dupuche, Chem. Commun. 1996, 869.
(b) M. G. Banwell, J. R. Dupuche, R. W. Gable, Aust. J. Chem.
1996, 49, 639. (c) M. G. Banwell, P. Darmos, M. D. McLeod,
D. C. R. Hockless, Synlett 1998, 897. (d) M. G. Banwell,
M. D. McLeod, Chem. Commun. 1998, 1851. (e) M. G. Banwell,
D. C. R. Hockless, J. W. Holman, R. W. Longmore, K. J. McRae,
H. T. T. Pham, Synlett 1999, 1491. (f ) M. G. Banwell,
K. J. McRae, A. C. Willis, J. Chem. Soc., Perkin Trans. 1
2001, 2194.
[4] (a) C. A. Pittol, R. J. Pryce, S. M. Roberts, G. Ryback,
V. Sik, J. O. Williams, J. Chem. Soc., Perkin Trans. 1 1989,
1160. (b) S. V. Ley, A. J. Redgrave, S. C. Taylor, S. Ahmed,
D. W. Ribbons, Synlett 1991, 741. (c) T. Hudlicky, H. Luna,
[13] D. J. Watkin, C. K. Prout, L. J. Pearce, CAMERON 1996
(Chemical Crystallography Laboratory: Oxford).