Stereocontrol of intramolecular Diels-Alder reactions by an allylic diphenylcyclopropyl group

Article abstract of DOI:10.1039/b708324f

Intramolecular Diels-Alder reactions of ester-linked 1,3,8-nonatrienes carrying a diphenylcyclopropyl substituent attached to C1 proceed with high levels of stereoselectivity. The stereochemical outcomes of these reactions are explained by reference to B3

Full text of DOI:10.1039/b708324f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereocontrol of intramolecular Diels–Alder reactions by an allylic
diphenylcyclopropyl group†
Regis Tripoli,a Tory N. Cayzer,a Anthony C. Willis,‡a Michael S. Sherburn*a,b and Michael N. Paddon-Row*c
Received 1st June 2007, Accepted 19th June 2007
First published as an Advance Article on the web 13th July 2007
DOI: 10.1039/b708324f
Intramolecular Diels–Alder reactions of ester-linked 1,3,8-nonatrienes carrying a diphenylcyclopropyl
substituent attached to C1 proceed with high levels of stereoselectivity. The stereochemical outcomes of
these reactions are explained by reference to B3LYP/6-31G(d) transition structures. Experimentally,
the diphenylcyclopropane rings remain intact through these IMDA reactions, notwithstanding their
predicted extremely high degree of asynchronicity (the B3LYP-computed lengths in the IMDA
˚
transition structures differ by as much as 1.1 A), providing support to the notion that these reactions
are concerted processes.
Introduction
The intramolecular Diels–Alder (IMDA) reaction is a powerful
synthetic transformation. Over the years, many methods have been
devised to steer the stereochemical outcome of the reaction.1 Re-
cently, we demonstrated that allylic stereocontrolling substituents
attached to the terminus of the diene can give high levels of p-
diastereofacial selectivity in IMDA reactions. The key experimen-
tal findings of this work, along with a theoretical model based
upon computational investigations, are summarised in Fig. 1.2
The unlike p-diastereofacial selectivity observed in these reactions
comes about through the preference for a reactive conformation
about the bond connecting the diene and the stereocentre in which
the silyloxy group adopts an inside orientation. The dienophile
reacts at the more accessible p-face of the diene; in the absence of
overriding electronic effects, this will be on the side of the diene in
Fig. 1 Theoretical model for p-diastereofacial selectivity in addition
which the smaller substituent resides. The present work describes
an investigation into IMDA precursors 1, 2 and 3, containing the
diphenylcyclopropyl group at the diene terminus (Fig. 2).
reactions to chiral allylic silyloxy systems.
We studied these IMDA reactions for two reasons. Firstly,
and more importantly, we were interested in learning whether
the cyclopropyl group could exert strong remote stereochemical
control in the IMDA reaction. This enquiry is a logical extension
of our earlier investigations into allylic stereocontrol by a chiral
C1-substituent of the type –CHRꢀ(OSiR3) (Fig. 1). Thus, can
a compact chiral, purely hydrocarbon, cyclopropyl group exert
strong stereochemical control in the IMDA reaction and, if so,
what is the most favourable diastereoisomeric transition structure
(TS) for the reaction? In addition to providing additional mecha-
aResearch School of Chemistry, Australian National University, Canberra,
ACT 0200, Australia. E-mail: sherburn@rsc.anu.edu.au (synthetic)
bARC Centre of Excellence for Free Radical Chemistry and Biotechnology
cSchool of Chemistry, The University of New South Wales, Sydney, NSW
2052, Australia. E-mail: m.paddonrow@unsw.edu.au (computational)
Fig. 2 Can a diphenylcyclopropyl group induce stereoselectivity or trap
biradical intermediates in Diels–Alder reactions?
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of all compounds prepared, 2D NMR spectra of 19a and 17b,
thermal ellipsoid plots for 17a, 18b, and 17c, geometries, scf energies,
enthalpies and free energies of the TSs. See DOI: 10.1039/b708324f
nistic insights into remote allylic stereocontrol in IMDA reactions,
diphenylcyclopropyl substituents could be of synthetic utility,
given their susceptibility to ring-opening reactions with acids,3
‡ Author to whom correspondence should be addressed regarding X-ray
crystal structures. E-mail: willis@rsc.anu.edu.au
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lithium metal,4 and weak nucleophiles under photochemical
conditions.5
some of the IMDA reactions of 4a–4f might proceed by a
non-concerted pathway. However, additional DFT calculations
on the IMDA trans TSs for 4a–4f suggest that these reactions
are concerted. Detailed intrinsic reaction coordinate analyses
show that all of these TSs smoothly lead to adducts without
passing through any intermediate. Also, wavefunction stability
calculations7 show that the B3LYP/6-31+G(d) wavefunctions for
the trans TSs of 4a–4e are stable with respect to allowing the
restricted wavefunction to become unrestricted. Thus, at the level
of theory used, for these TSs, the closed-shell singlet configuration
is stable and the TS has no biradical character. In contrast, the
restricted DFT wavefunction for trans-4f-TS displayed a restricted
→ unrestricted instability. Optimisation of the stable unrestricted
singlet wavefunction gave a new, open-shell, singlet state with a
non-zero expectation value <S2> = 0.36. This suggests biradical
character in trans-4f-TS.
The second reason for our studying C1-substituted-cyclopropyl
IMDA reactions is the finding that quantum chemical computed
TSs of IMDA reactions of 9-substituted, ester linked 1,3,8-
nonatrienes—in which the 9-substituent is p-conjugating—show
remarkable asynchronicity in their forming bonds. Consider, for
example, the restricted B3LYP/6-31+G(d) cis and trans IMDA
TSs for the series 4a–4f. The bond asynchronicity, Dras, is defined
as the numerical difference between the lengths of the forming
peripheral bond, rp, and the forming internal bond, ri and their
values are given in Table 1. We focus attention on Dras values
for the trans IMDA TSs since they are somewhat larger than the
corresponding Dras values for the cis TSs. For the 9-unsubstituted
˚
system, 4a, the bond asynchronicity of 0.2 A is small and falls
within the range for DA reactions involving acrylate dienophiles.
However, upon introduction of a conjugating substituent at C9,
These results, while not confirming that some of the IMDA
reactions of 4a–f might proceed via non-concerted pathways, do
predict very large calculated bond asynchronicities—particularly
for the 9,9-disubstituted TSs—which indicate that these reactions
may be on the borderline between concertedness and non-
concertedness. Perhaps the introduction of a judiciously chosen
substituent might tip the balance in favour of non-concertedness
and the presence of the resulting biradical intermediate8 could
be signalled by its intramolecular trapping by that substituent.
It seemed reasonable, therefore, to probe the possibility of
non-concertedness in these IMDA reactions by attaching a
diphenylcyclopropyl group at C1 of such 1,3,8-nonatrienes, as
depicted by structures 1, 2 and 3 (Fig. 2). This group is
known to intercept and trap radical intermediates on a very
short time-scale (estimated rate of ring opening at 25 ◦C =
4 × 1011 s−1).9 Values of salient geometrical parameters for
˚
the bond asynchronicity increases significantly to 0.53 and 0.72 A
for the 9-E-CO2Me TS, trans-4b-TS, and 9-Z-CO2Me TS, trans-
4c-TS, respectively. This increase in bond asynchronicity appears
˚
to be accumulative because it increases to 1.0 A in the 9,9-diester
˚
TS, trans-4d-TS and to 1.1 A in the 9,9-dicyano TS, trans-4e-
˚
TS. It is even larger—1.3 A—for the 9,9-diethynyl TS, trans-4e-
TS. These rather astonishing bond asynchronicity values are the
result of strong increases in the forming peripheral bond length,
˚
ranging from 2.56 A, for trans-4d-TS, to extraordinarily large
˚
values of 2.94–3.20 A for the 9,9-disubstituted trans TSs. Such
large Dras values raise the mechanistic question of concertedness
of these IMDA reactions, particularly that of 9,9-disubstituted
6
˚
systems. Forming bonds of lengths >2.9 A can hardly contribute
significant energetic advantage towards lowering the activation
barrier of a concerted process and it is possible, therefore, that
Table 1 Peripheral (rp) and internal (ri) distances (in A) and twist-mode asynchronicities, has (in degrees), for IMDA TSs of compounds 4, 5 and 6a
˚
trans TS
cis TS
rp
ri
Dras
has
rp
ri
Dras
has
5.9
4.0
15.6
14.7
8.7
10.2
6.2
6.0
15.7
17.0
6.2
5.6
15.5
16.0
4a-TSb,c
4b-TSb,c
4c-TSb,c
4d-TSb
2.355
2.559
2.703
2.942
3.044
3.198
2.400
2.708
2.948
3.158
2.403
2.786
2.937
3.169
2.159
2.026
1.983
1.923
1.914
1.880
2.089
1.968
1.904
1.962
2.087
1.919
1.908
1.966
0.196
0.533
0.72
1.019
1.13
1.318
0.311
0.74
1.044
1.196
0.316
0.867
1.029
1.203
−8.8
2.310
2.479
2.566
2.960
2.804
2.858
2.345
2.651
2.716
3.144
2.345
2.706
2.728
3.174
2.226
2.094
2.048
1.961
1.952
1.920
2.160
1.997
1.983
1.995
2.159
1.966
1.977
2.007
0.084
0.385
0.518
0.999
0.852
0.938
0.185
0.654
0.733
1.149
0.186
0.74
−9.6
−21.2
−18.3
−21.0
−23.0
−9.6
4e-TSb
4f-TSb
5a-TSd
5b-TSd
−11.8
−25.4
−19.0
−9.8
5c-TSd
5d-TSd
ul-6a-TSd
ul-6b-TSd
ul-6c-TSd
ul-6d-TSd
−11.3
−26.7
−21.0
0.751
1.167
a Values for compounds 5 and 6 are for the most stable TS conformation about the C1–cyclopropyl bond. b B3LYP/6-31+G(d). c ref. 2. d B3LYP/6-31G(d).
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IMDA TSs for 1-cyclopropyl-1,3,8-nonatrienes, 5a–5d, and 1-
(2ꢀ-phenylcyclopropyl)-1,3,8-nonatrienes, 6a–6d—the latter series
serving as models for the diphenylcyclopropyl systems 1, 2 and
3—are given in Table 1. The Dras values for 5-TSs and 6-TSs are
actually slightly larger than the corresponding values for the C1-
unsubstituted trans-4-TSs.
cis : trans ratios for the IMDA reactions of several 9-substituted
pentadienyl acrylates, often with an accuracy of 1 kJ mol−1.16
This level of theory is, therefore, adequate for this study. We have
used gas phase DFT calculations. The excellent agreement found
in previous studies between gas phase B3LYP predicted IMDA
cis : trans and lk : ul ratios and the experimental ratios, obtained
using weakly polar solvents, such as toluene, chlorobenzene or
1,2-dichlorobenzene suggests that weakly polar solvents—which
are often used in IMDA reactions—have no significant influence
on cis : trans and lk : ul15 selectivities. Ideally, calculations should
be carried out on the IMDA reactions of the experimental 1-
(2ꢀ-diphenylcyclopropyl) systems 1, 2 and 3 (Fig. 2). However,
exploratory calculations on maleate 1 failed to achieve conver-
gence ingeometry optimisations within a reasonable time, owing to
failure in obtaining simultaneously stable conformations of both
phenyl groups. Replacement of the trans-phenyl substituent with
a hydrogen atom, to give the series 6a–6d, removed this difficulty
and so this series was used as models for 1, 2 and 3. These models
should be quite reliable because the cis-phenyl substituent is
retained in 6a–6d and it is this substituent, being directed towards
the reaction centre, which should have the major influence on
IMDA stereoselectivity, with the trans-phenyl substituent, being
directed away from the reaction centre, playing only a minor,
indirect role by modifying the conformation of the cis-phenyl
group.
Computational methods
Gas phase transition structures (TSs) for intramolecular Diels–
Alder reactions of 5a–5d and 6a–6d were optimised using the
B3LYP functional10 and, unless stated otherwise, the 6-31G(d) ba-
sis set.11 Restricted B3LYP calculations were employed throughout
because, for all TSs located in this study, the restricted Kohn–
Sham wavefunction was calculated to be stable, thereby indicating
zero biradical character in the TSs. Conformational TSs about the
C1–cyclopropyl bond were obtained following relaxed potential
energy scans (using redundant coordinates). In some instances,
the PE scans revealed only a two-fold rotational barrier, thereby
indicating that there are only two conformationally stable TSs,
the third one presumably being destabilised by steric congestion.
Harmonic vibrational frequencies were carried out to characterise
the TSs and to calculate TS free energies at 298.15 K and 1 atm
pressure. cis : trans Ratios and lk : ul product ratios were calculated
from the free energies at the aforementioned temperature and
pressure using standard methods.12 Because the purpose of the
calculations was to gain qualitative insights into mechanistic
aspects of the systems under study, experimental temperatures
were not used to calculate the TS free energies. The TS free energies,
cis : trans ratios and lk : ul ratios for the IMDA reactions of 5a–5d
and 6a–6d are given in Tables 2 and 3, respectively. Geometries,
scf energies, enthalpies and free energies of the TSs are given in
the ESI†. The Gaussian 03 program was used throughout.13
Results and discussion
Various earlier computational studies2,17,18 involving the location
of TSs for addition reactions to alkenes carrying an allylic
stereocentre (C*) reveal an approximate staggered arrangement of
the C* substituents with respect to the developing C1–C9 bond,
with the allylic substituents distributed among the inside (in), anti
(an), and outside (ou) positions in TSs, as depicted schematically
in Fig. 3
Justification of the theoretical model
The B3LYP functional, in conjunction with the 6-31G(d) basis
set, is known to give acceptable relative energies and geometries
for a broad variety of Diels–Alder reactions.2,14,15 Importantly, we
have shown that the B3LYP/6-31G(d) method correctly predicts
The p-diastereofacial selectivity is determined by the positional
preferences of the C* substituents for the in, an and ou sites in
the TS. Steric effects play an important role because of the quite
different volumes of the an, in and an spaces, with an being the
Table 2 B3LYP/6-31G(d) relative free energies, G‡rel (kJ mol−1) and total cis : trans predicted ratio for the IMDA TSs of compounds 5a–5d at 298.15 Ka
5a (R1 = R2 = H)
5b (R1 = H, R2 = CO2Me)
5c (R1 = CO2Me, R2 = H)
5d (R1 = R2 = CO2Me)
cis TSs
in
0
12.0
4.26
5.96
—
7.09
12.9
23.4
21.0
12.3
21.7
—
b
an
ou
b
trans TSs
in
1.18
12.7
6.44
63 : 37
0
0
—
0
15.4
9.68
0.7 : 99.3
b
an
16.8
6.94
12 : 88
ou
7.43
0.5 : 99.5
cis : trans
a Structures of 5a–5d are defined in Table 1. b No TS could be found for this conformation; see Computational Methods.
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Table 3 B3LYP/6-31G(d) relative free energies,a G‡rel (kJ mol−1) for the IMDA TSs of compounds 6a–6d and total cis : trans and lk : ul predicted product
ratios at 298.15 K and 1 atmb
6a (R1 = R2 = H)
6b (R1 = H, R2 = CO2Me)
6c (R1 = CO2Me, R2 = H)
6d (R1 = R2 = CO2Me)
lk
ul
lk
ul
lk
ul
lk
ul
cis TSs
c
in
3.05
22.5
8.99
0
—
15.3
—
7.56
—
15.2
10.7
—
20.9
7.71
34.3
—
19.6
10.7
—
30.2
c
c
c
c
c
c
an
ou
25.4
11.3
—
c
—
trans TSs
in
c
5.48
23.0
10.8
0.74
—
15.8
5.89
—
10.8
0
—
21.0
—
0
—
10.8
16.9
—
9.39
0
—
17.5
c
c
c
c
c
c
an
18.5
7.58
ou
cis : trans
cis lk : ul
trans lk : ul
60.4 : 39.6
24.2 : 75.8
14.1 : 85.9
5.1 : 94.9
17.2 : 82.8
9.6 : 90.4
5.2 : 94.8
23.0 : 77.0
4.5 : 95.5
1.3 : 98.7
2.7 : 97.3
2.3 : 97.7
a Relative free energies for each system include both lk and ul IMDA TSs. b Structures of 6a–6d are defined in Table 1. c No TS could be found for this
conformation; see Computational Methods.
stabilising electrostatic interaction between the silyloxy oxygen
atom and H-2 of the diene (Fig. 3) and to a destabilising four-
electron interaction between a lone pair on oxygen and the diene
p HOMO electrons.2,15b
It is expected that stereocontrol by a C1-cyclopropyl substituent
should be determined mainly by steric factors. Consider, first of
all, the IMDA TSs for systems 5a–5d, which are achiral. For each
system there are two diastereoisomeric TSs, namely cis and trans,
each of which may exist as three different conformations of the
cyclopropyl substituent about the C1–C(cyclopropyl) bond. These
three conformational TSs—5-in, 5-an and 5-ou—are schematically
depicted at the top of Table 2, the label in, an, and ou referring to
the position of the cyclopropyl methine hydrogen, Hc.
The calculations predict cis stereoselectivity for the IMDA
reaction of the 9-unsubstituted system, 5a (cis : trans = 63 : 37
at 298 K) and this is in accord with experimentally observed
moderate cis stereoselectivity for a variety of IMDA reactions
lacking 9-ester substituents.16a Introduction of ester groups into
the 9-position causes a reversal of stereoselectivity, favouring
formation of the trans adduct. The trans selectivity is weaker
for the 9-E-ester, 5b, than for the 9-Z-ester, 5c, and the 9,9-
diester, 5d, presumably for reasons given in detail elsewhere for
related systems.16b,19 Our DFT calculations predict the most stable
TS conformation to be 5-in—in which the cyclopropyl methine
hydrogen, Hc, adopts the in position—for both cis and trans
Fig. 3 Schematic representations of an IMDA trans TS. The Newman
projection formula on the right depicts a view along the C*–C1 bond of
the structure on the left.
largest and ou being the smallest. Thus, for example, it has been
found that the positional preference of the methyl substituent in
the IMDA TS of the 1-ethyl pentadienyl acrylate system (7, Fig. 4)
is an > in > ou.2
Fig. 4
Electrostatic effects can also influence positional preferences.15b
Thus, the silyloxy group (OSiR3) has the greatest preference for
the in position, which is probably due to a combination of a
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modes of addition and for all systems. This conformation strongly
resembles the most stable conformation observed experimentally
for vinylcyclopropane, in which the vinyl double bond is transoid
to the cyclopropane ring.20 In general, the 5-an conformation
is the least favourable because the two cyclopropyl methylene
groups occupy the less favourable in and ou positions. As expected
from steric arguments, the introduction of 9-ester groups further
destabilises the 5-an TS relative to the 5-in TS, and the magnitude
of this destabilisation is approximately the same for both E and
Z ester groups because the cyclopropyl vertex which is pointing
towards the C9 substituents in the 5-an conformation is roughly
equidistant from the E and Z ester groups. The C9-substituent
effect on the relative energies of the 5-ou and 3-in TSs is also
explicable in terms of steric effects. In the case of the cis TSs,
introduction of an E ester group causes almost complete loss of
the stabilisation energy of 5-in relative to 5-ou (cf. 4.3 kJ mol−1 in
5a and 1.1 kJ mol−1 for 5b) because, in the cis TS, replacing R1 = H
with R1 = CO2Me introduces a steric clash which adversely affects
the energy of cis-5b-in relative to that of cis-5b-ou. The reverse
holds for 9-Z-ester substitution in the cis TS (R1 = CO2Me, R2 =
H) and, indeed, such substitution leads to enhanced stabilisation
of the in TS (cf. 4.3 kJ mol−1 in 5a and 8 kJ mol−1 for 5c). The
stabilisation of the in TS conformation over the ou conformation
in the 9,9-diester is roughly additive (10 kJ mol−1).21 In the case
of the trans TSs, 9-ester substitution brings about a moderately
enhanced stabilisation of the in TS, compared to the ou TS, which
appears odd in the case of 9-Z substitution (R1 = H, R2 = CO2Me),
for which the in TS should be destabilised. Taking twist-mode
asynchronicity16b,19 into account resolves this problem. Twist-mode
asynchronicity is defined by the dihedral angle, has = C1–C4–
C8–C9 and values of has for the IMDA TSs of 4–6 are given in
Table 1. Two significant features of has are (1) they have a positive
sign for cis TSs and a negative sign for trans TSs, and (2) the
magnitude of has is substantially larger for 9-Z-substituted TSs
than for 9-E-substituted TSs, a feature which has been explained
elsewhere.16b These features are illustrated in Fig. 5 for the cis and
trans TSs for 5c. Thus, twist-mode asynchronicity causes C9 and
its attendant 9-Z ester substituent to be driven deeper into the
endo region, thereby further raising the energy of cis-5-ou, relative
to the in TS. In contrast, the 9-Z-CO2Me substituent is markedly
displaced in the exo direction in the trans TS. This should lead to
a reduction in adverse steric interactions between the ester and the
cyclopropane vertex occupying the ou position and, therefore, to
an undiminished stabilisation of the in TS compared to the ou TS,
as is found.
Insights gained from our calculations for the IMDA TSs for
5a–5d may be used to predict the most favourable IMDA TS
for chiral trienes 6a–6d bearing the 1-(cis-2ꢀ-phenylcyclopropyl)
substituent. In these systems, the presence of the two stereocentres
on the cyclopropane ring discriminates the two p-faces of the
diene, thereby leading to like (lk) and unlike (ul) stereoselectivity
for each mode of addition, cis and trans. The possible TSs for
these reactions are depicted in Table 3. The favoured TS should
be ul-6-in, in which Hc adopts the in position and the bulky CHPh
group occupies the an position—this position being less sterically
congested than the ou region. The B3LYP-computed relative free
energies of the IMDA TSs (298 K) for 6a–6d are presented in
Table 3.
Four predictions may be drawn from the data of Table 3. These
are: (1) cis stereoselectivity is predicted for the parent system 6a
and trans selectivity for the 9-ester systems, being the greatest for
the 9,9-diester 6d. This trend has been explained elsewhere for
other 1,3,8-nonatriene IMDA reactions.16 (2) As anticipated from
the above discussion on the IMDA reactions of 5a–5d, ul facial
selectivity is predicted for both cis and trans modes of addition
and the ul TS with the lowest free energy is 6-in. (3) The ul
selectivity is stronger for trans addition than for cis addition. (4)
For both cis and trans modes of addition, ul selectivity increases
with progressive 9-ester substitution becoming greater than 97%
for the 9,9-diester. These predictions were tested experimentally.
Trienes 1, 2 and 3 were prepared from dienol 15, which in turn
was accessed from benzophenone hydrazone 8 in 6 steps and 44%
overall yield (Scheme 1).
Oxidation of benzophenone hydrazone 822 with nickel peroxide
gave diphenyl diazomethane 9,23 which underwent cycloaddition
with methyl acrylate at room temperature24 to afford cyclopropane
ester 10.25 Reduction to primary alcohol 11 with lithium alu-
minium hydride followed by Swern oxidation afforded aldehyde 12
in 75% yield over 4 steps. Horner–Wadsworth–Emmons reaction
of aldehyde 12 with the lithium salt of phosphonate 13 afforded the
E,E-dienoic ester 14 in 62% yield. DIBALH reduction of ester 14
at −78 ◦C26 furnished the desired dienol 15 in 95% yield. The three
IMDA precursors 1, 2 and 3 were easily accessed from dienol 15
by esterification reactions. Thus, reaction with maleic anhydride
gave the half ester of maleic acid, which was converted into methyl
ester 1 by reaction with diazomethane at −78 ◦C. Union of 15 with
methyl fumaroyl chloride gave triene ester 2. Finally, 9,9-diester
triene 3 was accessed by reaction of dienol 15 with the acyl chloride
of known carboxylic acid 16.27 The results from the experimental
IMDA reactions of the three trienes are listed in Table 4.
The relative stereochemistries of three of the five isolated
cycloadducts, namely 17a, 18b and 17c, were secured through
single crystal X-ray analyses (Table 5, Fig. 6).§ The stereo-
chemistries of the remaining two structures—19a and 17b—were
tentatively assigned through 2D NMR techniques (see ESI for
details†). In each case, the relative stereochemistry about the newly
Fig. 5 Optimised TS geometries of (a) cis-5c-in and (b) trans-5b-in.
The direction of dienophile twisting is depicted with green arrows. Some
hydrogens are omitted from the right hand structures for clarity.
§ CCDC reference numbers 644828–644830. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b708324f
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Table 4 Experimental IMDA reactions of trienes 1, 2 and 3
Experimental adduct
ratioc,d 17 : 18 : 19 : 20
Calculated adduct
Triene substrate
E/Z
Solvent
Reaction timea/h
Isolated yieldb (%)
ratioe 17 : 18 : 19 : 20
1
2
3
H/CO2Me
CO2Me/H
CO2Me/CO2Me
PhMe
PhCl
PhH
5
12
3
75
63
72
82 : 0 : 18 : 0
86 : 14 : 0 : 0
>99 : 0 : 0 : 0
86 : 9 : 4 : 1
91 : 4 : 4 : 1
97 : 2 : 1 : 0
a Time required for >95% conversion, as judged by 1H NMR. b Combined isolated yield after chromatography. c Determined from 1H NMR spectra of
crude reaction mixtures. d Kinetic product ratios are reported: control experiments confirmed that all cycloadducts were stable to the reaction conditions.
e Calculated values based upon the cis-2ꢀ-phenylcyclopropyl model systems 6b–d (Table 3).
Scheme 1
formed bicyclic system is secure but the sense of p-diastereofacial
selectivity is not. We assign stereostructures to these com-
pounds on the basis of the computational findings described
herein.
Two conclusions can immediately be drawn upon inspection
of the data in Table 4: (1) all three IMDA reactions are highly
stereoselective; and (2) no ring opened products are observed. The
latter observation leads us to conclude that if these cycloadditions
have biradicaloid character, then their closure to form IMDA
adducts is significantly faster than 4 × 1011 s−1, the rate of ring
opening of the diphenylcyclopropylmethyl radical.9
model system. It is particularly noteworthy that the predicted
increase in stereoselection through the model series maleate 6c
→ fumarate 6b → 9,9-diester 6d is mirrored in the experimental
results with trienes 1, 2 and 3 respectively. These results demon-
strate, once again, the value of DFT as a predictive tool for
stereoselective synthesis. Thus, hydrocarbon substituents around
a stereocentre can induce high levels of p-diastereofacial selectivity
in intramolecular cycloadditions. This is all the more remarkable
when the length of the developing peripheral (C1–C9) bond in the
TS is taken into account. These findings raise interesting questions.
Will high stereoselectivities also be witnessed in intermolecular ad-
dition processes to diphenylcyclopropyl-substituted dienes? Will
other substituted ring systems give similar outcomes? Answers to
these questions are currently being sought.
Experimental stereoselectivities for the three reactions involv-
ing the C1-diphenylcyclopropyl substituent are in very good
agreement with computed values for the mono-phenylcyclopropyl
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Table 5 X-ray crystallographic data for compounds 17a, 18b and 17c
17a
18b
17c
CCDC No.
Formula
M
644828
C25H24O4
388.46
644830
C25H24O4
388.46
644829
C27H26O6
446.5
Crystal system
Space group
Monoclinic
P21/a
Monoclinic
P21
Orthorhombic
Pbca
15.0402(3)
15.3235(3)
19.7863(5)
—
4560.12(17)
8
200
˚
a/A
13.9345(2)
8.7920(2)
16.3108(3)
96.0142(11)
1987.27(6)
4
11.0190(4)
7.6264(3)
12.1306(5)
91.3965(17)
1019.10(7)
2
˚
b/A
˚
c/A
b/◦
V/A
Z
T/K
3
˚
200
41962
200
12952
Measured reflections
40672
Independent reflections
Reflections in refinement
R
Rw
S
4543
3260 [I > 2r(I)]
0.0325
0.0351
1.1283
1943
1460 [I > 1.5r(I)]
0.0353
0.0391
1.0875
4046
2621 [I > 2r(I)]
0.0325
0.0361
1.0664
films on NaCl plates for oils or as KBr pellets for solid products.
Low resolution mass spectra were recorded on a Finnigan
PolarisQ ion trap mass spectrometer using electron impact (EI)
ionisation mode at 40 or 70 eV. High resolution mass spectra
were recorded on a VG Autospec mass spectrometer operating at
70 eV. Microanalyses were performed at the Research School of
Chemistry, Australian National University. Melting points were
measured on a Reichert melting point stage and are uncorrected.
Analytical TLC was performed with Merck silica gel plates,
precoated with silica gel 60 F254 (0.2 mm). Flash chromatography
employed Merck Kiesegel 60 (230–400 mesh) silica gel. Reactions
were conducted under a positive pressure of dry argon or nitrogen.
Diethyl ether, toluene and THF were dried over sodium wire and
distilled from sodium benzophenone ketyl. Dichloromethane was
distilled from calcium hydride. Commercially available chemicals
were purified by standard procedures or used as purchased.
Methyl 2,2-diphenylcyclopropanecarboxylate (10)
Compound 10 was prepared following literature procedures.22–24
A mixture of benzophenone (13.31 g, 73 mmol, 1 equiv.) and
anhydrous hydrazine (8.6 mL, 274 mmol, 3.75 equiv.) in ethanol
(50 mL) was heated to reflux overnight, affording benzophenone
hydrazone (8) as white needles after recrystallisation from ethanol
(12.03 g, 84% yield).22 Careful oxidation of 8 (0.200 g, 1.02 mmol,
1 equiv.) was quantitatively achieved using nickel peroxide in excess
(12 g) in Et2O (50 mL) at rt.23 After evaporation of the reaction
solvent in vacuo at rt, diazo compound 9 was obtained as a deep
purple liquid. Reaction of 9 (1.02 mmol, 1 equiv.) with methyl
acrylate (0.24 mL, 2.69 mmol, 2.64 equiv.) in petroleum spirit
(20 mL) at rt afforded the cyclopropane ester 10.24 No purification
was necessary in this three step preparation. Compound 1025 was
obtained in quantitative yield from 8 as an off-white solid: mp
Fig. 6 Molecular structures from single crystal X-ray analyses of
cycloadducts. Thermal ellipsoids are shown at 30% probability levels.
Experimental
General
NMR spectra were recorded at 298 K using a Varian Unity INOVA
300 MHz spectrometer. Residual protio-chloroform (d 7.26 ppm)
1
was used as an internal reference for H NMR spectra. The 13C
◦
◦
1
NMR resonance of chloroform (d 77.1 ppm) was used as an
41–42 C (lit.,25 40 C). H NMR (300 MHz, CDCl3): d 7.07–
internal reference for 13C NMR spectra. Assignment of proton
7.28 (m, 10H), 3.42 (s, 3H), 2.48 (dd, J = 8.1, 6.0 Hz, 1H), 2.10
signals was assisted by H–1H COSY and NOESY experiments
(dd, J = 6.0, 4.8 Hz, 1H), 1.54 (dd, J = 8.1, 4.8 Hz, 1H) ppm. 13
C
1
when necessary; assignment of carbon signals was assisted by
DEPT experiments. IR spectra were recorded on a Perkin-Elmer
1600 F.T.I.R. or Perkin-Elmer Spectrum One spectrometer as neat
NMR (75 MHz, CDCl3): d 171.4, 145.0, 140.5, 129.8, 128.7, 128.6,
127.8, 127.3, 126.8, 52.0, 40.2, 29.1, 20.4 ppm. IR (KBr disc): mmax
3084, 3059, 3026, 2950, 1732, 1495, 1383, 1270 cm−1. EIMS: m/z
2612 | Org. Biomol. Chem., 2007, 5, 2606–2616
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(%): 252 (M+, 14), 237 (7), 221 (19), 192 (100). HRMS: calcd
for C17H16O2: 252.1150; found 252.1149. All characterisation data
matched those reported.25
then added. Extraction was carried out with Et2O. The combined
organic layers were dried (MgSO4) and concentrated in vacuo.
Column chromatography (petroleum ether 40–60–ethyl acetate,
95 : 5) afforded 14 as a 9 : 1 mixture of E : Z isomers at the newly
formed bond (0.144 g, 62%). The pure (◦E,E)-diene was isolated
after three recrystallisations: mp 100–102 C. 1H NMR (300 MHz,
CDCl3): d 7.15–7.33 (m, 10H), 7.10 (dd, J = 15.3, 11.1 Hz, 1H),
6.35 (dd, J = 15.0, 11.1 Hz, 1H), 5.76 (d, J = 15.3 Hz, 1H), 5.37
(dd, J = 15.0, 10.2 Hz, 1H), 3.71 (s, 3H), 2.31–2.40 (m, 1H), 1.76
(dd, J = 8.7, 5.1 Hz, 1H), 1.63 (dd, J = 5.4, 5.1 Hz, 1H) ppm.
13C NMR (75 MHz, CDCl3): d 168.0, 146.0, 145.7, 145.1, 140.9,
130.9, 128.8, 128.6, 127.7, 127.5, 127.2, 126.4, 118.2, 51.7, 39.3,
31.2, 23.6 ppm. IR (KBr disc): mmax 3025, 3061, 2909, 1714, 1634,
1495, 1309, 1260, 1144 cm−1. EIMS: m/z (%): 304 (M+, 69), 244
(39), 205 (88), 191 (37), 167 (62), 165 (96), 111 (48), 91 (100).
HRMS: calcd for C21H20O2: 304.1463; found 304.1462.
(2,2-Diphenylcyclopropyl)methanol (11)28,29
A solution of compound 10 (0.26 g, 1.02 mmol, 1 equiv.) in THF
was treated with LiAlH4 at 0 ◦C under N2 atm. The reaction
mixture was kept at this temperature for 10 min, then warmed
to rt and stirred for 1 h. On completion of the reaction, the
remaining hydride species was quenched with a mixture of THF
and iced water (1 : 1) at 0 ◦C and stirred until a white precipitate
formed. The solvent was removed under reduced pressure and the
residue dissolved in methanol. The resulting mixture was filtered
through Celite and the solvent evaporated in vacuo. Column
chromatography (petroleum ether 40–60–ethyl acetate, 3 : 1) of
the crude material afforded pure 11 as a yellow oil (0.227 g, 99%).
1H NMR (300 MHz, CDCl3): d 7.17–7.43 (m, 10H), 3.48 (dd,
J = 11.7, 6.6 Hz, 1H), 3.38 (dd, J = 11.7, 7.8 Hz, 1H), 1.97–2.04
(m, 1H), 1.71 (bs, 1H), 1.40 (dd, J = 5.4, 4.8 Hz, 1H), 1.30 (dd,
J = 8.7, 4.8 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): d 146.6,
141.4, 130.4, 128.8, 128.6, 128.1, 127.0, 126.3, 64.0, 35.9, 28.0,
18.2 ppm. IR (thin film): mmax 3401, 3059, 3024, 2930, 2879, 1642,
1495, 1035 cm−1. EIMS: m/z (%): 224 (M+, 47), 207 (69), 206 (99),
194 (73), 193 (100). HRMS: calcd for C16H16O: 224.1201; found
224.1201.
(2E,4E)-5-(2,2-Diphenylcyclopropyl)penta-2,4-dien-1-ol (15)
Compound 14 (0.193 g, 0.634 mmol, 1 equiv.) was stirred in
CH2Cl2 (40 mL) at −78 ◦C under N2 atm. DIBALH (2.12 mL,
3.17 mmol, 5 equiv., 1.5 M in toluene) was then added and the
◦
temperature kept at −78 C until complete disappearance of the
starting material. Ethyl acetate (15 mL), then methanol (15 mL)
were added dropwise at −78 ◦C. A solution of sodium potassium
tartrate (5.219 g, 15.9 mmol, 25 equiv.) in water (30 mL) was then
added at −78 ◦C and the mixture allowed to warm to rt overnight.
Aqueous HCl (2 M, 5 mL) was added to reduce the precipitates
in the mixture. Extraction was carried out using CH2Cl2 (40 mL).
The organic phase was washed with aqueous NaHCO3 (40 mL)
and the combined organic layers were dried (Na2SO4), filtered,
and concentrated in vacuo. The crude material was subjected to
chromatography on silica (ethyl acetate–hexanes 20 : 80) to give 15
(141.9 mg, 0.514 mmol, 81%) as a colourless viscous oil: Rf = 0.24
2,2-Diphenylcyclopropanecarbaldehyde (12)28,29
DMSO (0.145 mL, 2.04 mmol, 2 equiv.) was added dropwise to
a solution of ox◦alyl chloride (0.11 mL, 1.22 mmol, 1.2 equiv.) in
CH2Cl2 at −78 C under N2 atm and stirred at this temperature
for 10 min. A solution of 11 (0.228 g, 1.02 mmol, 1 equiv.) in
CH2Cl2 (10 mL) was added and stirring continued at −70 ◦C
for 30 min. Triethylamine (0.567 mL, 4.08 mmol, 4 equiv.) was
then added dropwise, the mixture stirred at −65 ◦C for a further
30 min and then allowed to warm to rt overnight. Water was
then added and the mixture extracted with Et2O. The combined
organic layers were dried (MgSO4) and concentrated in vacuo.
Column chromatography (petroleum ether 40–60–ethyl acetate,
9 : 1) afforded 12 (0.1699 g, 75% over 4 steps from 8) as a yellow
solid: mp 75–76 ◦C. 1H NMR (300 MHz, CDCl3): d 8.58 (d, J =
6.6, 1H), 7.07–7.34 (m, 10H), 2.17–2.49 (m, 1H), 2.17 (dd, J =
5.4, 5.1 Hz, 1H), 1.78 (dd, J = 8.4, 5.1 Hz, 1H) ppm. 13C NMR
(75 MHz, CDCl3): d 200.8, 144.1, 139.6, 130.3, 129.2, 128.9, 127.7,
127.6, 127.2, 41.2, 37.0, 20.5 ppm. IR (KBr disc): mmax 3058, 3026,
2835, 2764, 1705, 1495, 1447, 1170 cm−1. EIMS: m/z (%): 222
(M+, 72), 221 (28), 193 (96), 192 (61), 178 (55), 165 (55), 115 (100).
Anal. Calcd for C16H14O: C, 86.45; H, 6.35. Found: C, 86.15; H,
6.37. HRMS: calcd for C16H14O: 222.1045; found 222.1045.
1
(ethyl acetate–hexanes 20 : 80). H NMR (300 MHz, CDCl3): d
7.02–7.35 (m, 10H), 6.15 (dd, J = 15.0, 10.5 Hz, 1H), 5.97 (dd, J =
15.0, 10.5 Hz, 1H), 5.61 (ddd, J = 15.0, 6.0, 6.0 Hz, 1H), 4.86 (dd,
J = 15.0, 9.6 Hz, 1H), 4.01 (d, J = 5.4 Hz, 2H), 2.15–2.27 (m, 1H),
1.57 (dd, J = 8.7, 5.1 Hz, 1H), 1.42 (dd, J = 5.7, 5.1 Hz, 1H) ppm.
13C NMR (75 MHz, CDCl3): 146.4 (C), 141.2 (C), 135.8 (CH),
131.7 (CH), 130.9 (CH), 129.1 (CH), 129.0 (CH), 128.4 (CH),
128.3 (CH), 127.2 (CH), 126.6 (CH), 125.9 (CH), 63.4 (CH2), 37.8
(C), 30.6 (CH), 22.9 (CH2). IR (thin film): mmax 3368 (br, OH), 3057,
−1
=
3024 (m, CH), 2924, 2860 (m, Ar–H), 1688, 1654 (m, C C) cm .
EIMS (70 eV): m/z (%): 276 (M+, 40), 258 ([M − H2O]+, 50), 245
(50), 217 (40), 205 (50), 191 (50), 167 (90), 165 (80), 115 (50), 91
(100). HRMS (EI+): calcd for C20H20O: 276.1514; found 276.1514.
Methyl (2E,4E)-5-(2,2-diphenylcyclopropyl)penta-2,4-dienyl
maleate (1)
(2E,4E)-Methyl 5-(2,2-diphenylcyclopropyl)penta-2,4-dienoate
(14)
To a solution of 15 (0.224 g, 0.811 mmol, 1 equiv.) in CH2Cl2
(10 mL) at 0 ◦C under N2 atm were added Et3N (0.181 mL,
1.30 mmol, 1.6 equiv.), maleic anhydride (0.179 g, 1.82 mmol,
2.25 equiv.) and DMAP (10 mg, 0.081 mmol, 0.1 equiv.). The
solution was stirred for 10 min, then Et2O (40 mL) was added
and the mixture washed with aqueous HCl (2 M, 2 × 50 mL)
and brine (1 × 50 mL). The organic fraction was then dried
(Na2SO4) and evaporated to dryness. The crude mixture (288 mg)
To a stirred solution of LHMDS (0.818 mmol, 1.07 equiv.) in THF
(10 mL) was added phosphonate 13 (0.18 g, 0.764 mmol, 1 equiv.)
in THF (4 mL) at −78 ◦C under N2 atm. After 5 min the mixture
was warmed to −40 ◦C and a solution of 12 (0.169 g, 0.764 mmol,
1 equiv.) in THF (5 mL) was added dropwise. The reaction was
allowed to warm to rt overnight. Water, HCl (1 M) and Et2O were
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was diluted in THF (3 mL) and cooled to −78 ◦C under N2 atm. A
solution of diazomethane in Et2O was added dropwise until TLC
showed no starting material. N2 was bubbled into the mixture for
30 min to remove the unreacted diazomethane and the solvent was
then evaporated under reduced pressure. Column chromatography
(CH2Cl2–pentane, 60 : 40) afforded 1 as a yellow oil (0.181 g, 57%
over two steps from the dienol 15). 1H NMR (300 MHz, CDCl3):
d 7.14–7.3 (m, 10H), 6.24 (s, 2H), 6.10–6.30 (m, 2H), 5.65 (ddd,
J = 14.4, 6.9, 6.9 Hz, 1H), 5.01 (dd, J = 14.4, 9.9 Hz, 1H), 4.65
(d, J = 6.9 Hz, 2H), 3.76 (s, 3H), 2.25–2.33 (m, 1H), 1.68 (dd, J =
8.4, 4.8 Hz, 1H), 1.53 (dd, J = 5.4, 4.8 Hz, 1H) ppm. 13C NMR
(75 MHz, CDCl3): d 166.0, 165.2, 146.5, 141.4, 137.6, 135.5, 131.1,
130.1, 130.0, 128.8, 128.7, 128.6, 127.5, 127.0, 126.3, 123.2, 66.0,
52.4, 38.2, 30.9, 23.7 ppm. IR (thin film): mmax 3057, 3025, 2951,
1730, 1650, 1495, 1437, 1391, 1212, 1162 cm−1. EIMS: m/z (%):
388 (M+, 35), 357 (38), 342 (46), 329 (28), 328 (100). HRMS: calcd
for C25H24O4: 388.1675; found 388.1678.
Methyl (2E,4E)-5-(2,2-diphenylcyclopropyl)penta-2,4-dienyl
fumarate (2)
To a solution of 15 (1.674 g, 6.06 mmol, 1 equiv.) in CH2Cl2
(50 mL) at 0 ◦C under N2 atm were added pyridine (1.18 mL,
14.54 mmol, 2.4 equiv.) and 4-dimethylaminopyridine (74 mg,
0.606 mmol, 0.1 equiv.). (E)-Methyl 3-(chlorocarbonyl)acrylate
(1.08 g, 7.27 mmol, 1.2 equiv.) was then added dropwise at
0
◦C. The reaction was stirred at this temperature for 10 min
then allowed to warm to rt. After 1.5 h, water was added. The
organic phase was then collected and washed with 1 M aqueous
HCl, saturated NaHCO3 and brine. The organic layer was dried
(MgSO4) and concentrated in vacuo. Column chromatography
(petroleum ether 40–60–ethyl acetate, 95 : 5) afforded 2 as a yellow
1
oil (1.22 g, 52%). H NMR (300 MHz, CDCl3): d 7.12–7.36 (m,
10H), 6.86 (s, 2H), 6.10–6.29 (m, 2H), 5.65 (ddd, J = 14.5, 6.9,
6.9 Hz, 1H), 5.02 (dd, J = 14.5, 9.7 Hz, 1H), 4.66 (d, J = 6.9 Hz,
2H), 3.80 (s, 3H), 2.25–2.33 (m, 1H), 1.67 (dd, J = 8.7, 4.8 Hz,
1H), 1.53 (dd, J = 5.7, 4.8 Hz, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d 165.6, 164.9, 146.5, 141.3, 137.8, 135.5, 133.9, 133.6,
131.0, 128.7, 128.6, 128.5, 127.5, 126.9, 126.2, 122.9, 66.1, 52.6,
38.2, 30.8, 23.1 ppm. IR (thin film): mmax 3058, 3025, 2951, 1723,
1652, 1495, 1445, 1301, 1259, 1153, 986 cm−1. EIMS: m/z (%): 388
(M+, 7), 259 (42), 258 (96), 217 (50), 206 (54), 205 (56), 191 (75),
167 (100). HRMS: calcd for C25H24O4: 388.1675; found 388.1673.
rel-(3aR,4S,5S,7aS,1ꢀR)-Methyl 1,3,3a,4,5,7a-hexahydro-3-oxo-
5-(2,2-diphenylcyclopropyl)isobenzofuran-4-carboxylate (17a) and
rel-(3aR,4R,5S,7aS,1ꢀR)-methyl 1,3,3a,4,5,7a-hexahydro-3-oxo-
5-(2,2-diphenylcyclopropyl)isobenzofuran-4-carboxylate (19a)
A solution of 1 (0.457 g, 1.17 mmol, 1 equiv.) and 2,6-di-tert-butyl-
4-methylphenol (3 mg, 14 lmol, 0.01 equiv.) in toluene (250 mL)
was heated at reflux under N2 atm for 5 h. The solvent was then
evaporated under reduced pressure and 1H NMR analysis revealed
the presence of two cycloadducts. The two adducts 17a and 19a
were isolated by column chromatography (petroleum ether 40–60–
ethyl acetate–triethylamine, 96 : 2 : 2) in a ratio of 82 : 18 (340.9 mg,
75% combined yield).
rel-(3aR,4R,5S,7aS,1ꢀR)-Methyl 1,3,3a,4,5,7a-hexahydro-3-oxo-
5-(2,2-diphenylcyclopropyl)isobenzofuran-4-carboxylate (17b) and
rel-(3aS,4S,5R,7aR,1ꢀR)-methyl 1,3,3a,4,5,7a-hexahydro-3-oxo-
5-(2,2-diphenylcyclopropyl)isobenzofuran-4-carboxylate (18b)
A solution of 2 (0.244 g, 0.63 mmol, 1 equiv.) and 2,6-di-tert-
butyl-4-methylphenol (2 mg, 9 lmol, 0.01 equiv.) in chlorobenzene
(125 mL) was heated to reflux under N2 atm for 12 h. The solvent
was then removed under reduced pressure and 1H NMR analysis
of the crude mixture revealed the presence of two cycloadducts.
The two adducts 17b and 18b were isolated from a fraction of the
crude mixture by column chromatography (petroleum ether 40–
60–ethyl acetate, 98 : 2, with 2% triethylamine) in a ratio of 86 : 14
(154.2 mg, 63% combined yield).
17a. White solid (279.5 mg, 61%): mp 161 ◦C. 1H NMR
(300 MHz, CDCl3): d 7.08–7.28 (m, 10H), 5.71 (ddd, J = 9.9,
1.5, 1.5 Hz, 1H), 5.67 (ddd, J = 9.9, 3.0, 3.0 Hz, 1H), 4.47 (dd,
J = 14.5, 7.5 Hz, 1H), 3.86 (dd, J = 11.5, 7.5 Hz, 1H), 3.55 (s,
3H), 3.27 (d, J = 3.6 Hz, 1H), 3.09–3.14 (m, 1H), 2.44 (dd, J =
13.6, 3.6 Hz, 1H), 1.88 (d, J = 10.5, 1H), 1.65–1.74 (m, 1H), 1.55
(dd, J = 5.4, 5.1 Hz, 1H), 1.13 (dd, J = 8.7, 5.1 Hz, 1H) ppm. 13
C
NMR (75 MHz, CDCl3): d 175.0, 172.3, 146.4, 140.7, 132.5, 129.9,
129.1, 128.8, 128.6, 126.9, 126.6, 123.9, 70.9, 52.4, 42.6, 42.3, 39.9,
38.7, 36.6, 32.2, 18.5 ppm. IR (KBr disc): mmax 2917, 1785, 1732,
1495, 1445, 1379, 1177, 1090 cm−1. EIMS: m/z (%): 388 (M+, 12),
357 (27), 356 (5), 330 (11), 329 (24), 328 (100). Anal. Calcd for
C25H24O4: C, 77.30; H, 6.23. Found: C, 77.34; H, 6.25. HRMS:
calcd for C25H24O4: 388.1675; found 388.1672.
17b. White solid (132.6 mg, 54%): mp 188–189 ◦C. 1H NMR
(300 MHz, CDCl3): d 7.10–7.20 (m, 10H), 5.71 (ddd, J = 9.9, 1.6,
1.6 Hz, 1H), 5.62 (ddd, J = 9.9, 3.0, 3.0 Hz, 1H), 4.39 (dd, J = 8.1,
6.3 Hz, 1H), 3.92 (dd, J = 11.1, 8.1 Hz, 1H), 3.73 (s, 3H), 2.83 (dd,
J = 11.4, 7.5 Hz, 1H), 2.70 (dd, J = 13.5, 11.4 Hz, 1H), 2.60–2.71
(m, 1H), 1.85–1.95 (m, 1H), 1.61–1.71 (m, 1H), 1.42–1.50 (m, 1H),
1.02 (dd, J = 8.5, 5.2 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): d
174.5, 171.6, 146.4, 140.5, 133.3, 129.7, 129.6, 128.6, 128.4, 126.8,
126.7, 123.2, 70.5, 52.1, 43.6, 42.1, 40.9, 38.3, 35.8, 28.6, 18.5 ppm.
IR (KBr disc): mmax 2950, 2918, 2849, 1787, 1738, 1494, 1445, 1321,
1273, 1178, 1087. EIMS: m/z (%): 388 (M+, 11), 258 (14), 220 (16),
217 (9), 194 (68), 193 (100). HRMS: calcd for C25H24O4: 388.1675;
found 388.1674.
◦
1
19a. White solid (61.4 mg, 14%): mp 159–160 C. H NMR
(300 MHz, CDCl3): d 7.07–7.26 (m, 10H), 5.92 (ddd, J = 9.9, 2.7,
2.7 Hz, 1H), 5.59 (ddd, J = 9.9, 2.7, 2.7 Hz, 1H), 4.40 (dd, J =
8.7, 8.7 Hz, 1H), 4.10 (dd, J = 8.4, 8.4 Hz, 1H), 3.61 (s, 3H), 3.14
(dd, J = 5.8, 5.8 Hz, 1H), 2.97–3.00 (m, 1H), 2.88 (dd, J = 10.6,
5.8 Hz, 1H), 1.61–1.68 (m, 1H), 1.50–1.58 (m, 1H), 1.38 (dd, J =
5.4, 5.4 Hz, 1H), 1.24 (dd, J = 8.6, 5.4 Hz, 1H) ppm. 13C NMR
(75 MHz, CDCl3): d 175.1, 171.6, 146.3, 140.5, 133.3, 130.6, 129.7,
128.7, 128.6, 128.4, 126.7, 123.1, 70.5, 52.1, 43.5, 42.1, 40.9, 38.3,
35.4, 28.6, 18.5 ppm. IR (KBr disc): mmax 3025, 2923, 1765, 1730,
1494, 1445, 1385, 1173, 1019 cm−1. EIMS: m/z (%): 388 (M+, 23),
357 (38), 339 (12), 198 (10), 197 (59), 194 (77), 193 (100). HRMS:
calcd for C25H24O4: 388.1675; found 388.1676.
◦
1
18b. White solid (21.6 mg, 9%): mp 185–187 C. H NMR
(300 MHz, CDCl3): d 7.04–7.27 (m, 10H), 5.82 (ddd, J = 9.6, 2.1,
2.1 Hz, 1H), 5.72 (ddd, J = 9.6, 2.8, 2.8 Hz, 1H), 4.38 (dd, J = 8.2,
6.6 Hz, 1H), 3.90 (dd, J = 11.1, 8.2, 1H), 3.51 (s, 3H), 2.86 (dd, J =
11.1, 7.8 Hz, 1H), 2.72 (dd, J = 13.5, 11.1 Hz, 1H), 2.48–2.66 (m,
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1H), 1.84–1.93 (m, 2H), 1.37 (dd, J = 9.0, 5.1 Hz, 1H), 1.23 (dd, J =
9.0, 5.1 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): d 174.6, 172.8,
146.4, 140.7, 134.6, 130.9, 128.6, 128.4, 127.8, 127.1, 126.1, 124.7,
70.5, 52.3, 44.5, 42.6, 40.7, 37.5, 37.1, 28.6, 19.6 ppm. IR (KBr
disc): mmax 2917, 2849, 1784, 1736, 1495, 1262, 1178, 1087 cm−1.
EIMS: m/z (%): 388 (M+, 8), 258 (9), 220(11), 194 (48), 193 (100).
HRMS: calcd for C25H24O4: 388.1675; found 388.1675.
Notes and references
1 (a) The Diels–Alder Reaction: Selected Practical Methods, ed.
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1,1-Dimethyl 2-(2E,4E)-5-(2,2-diphenylcyclopropyl)penta-
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6 The Dras values for the corresponding cis TSs for these systems (not
given in Table 1) are slightly smaller than those for the respective trans
TSs. The cis TSs are not discussed because, with the exception of 4a,
the trans TS is lower in energy than the cis TS.
2,4-dienyl ethene-1,1,2-tricarboxylate (3)
1,1-Dimethyl 2-hydrogen ethylenetricarboxylic acid (16)27a was
prepared from 2-tert-butyl 1,1-dimethyl ethylenetricarboxylate
using the procedure of Snider.27b Oxalyl chloride (258.7 mg,
2.038 mmol, 2.0 equiv.) and DMF (1.5 mg, 0.0204 mmol,
0.02 equiv.) were added to a solution of 16 (191.7 mg, 1.019 mmol,
1.0 equiv.) in CH2Cl2 (1.0 mL) and stirred at 0 ◦C under N2 atm
for 30 min until the evolution of gas ceased. The mixture was
then concentrated in vacuo, diluted with CH2Cl2 (0.8 mL) and
added to a solution of 15 (172.7 mg, 0.6249 mmol, 1.0 equiv.)
and triethylamine (0.127 mL, 1.250 mmol, 2.0 equiv.) in CH2Cl2
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◦
(0.8 mL) at 0 C under N2 atm. The solution was stirred at this
temperature for 10 min then water (10 mL) was added and the
mixture extracted with CH2Cl2. The combined organic fractions
were dried (Na2SO4), filtered, and evaporated to dryness to give
the crude IMDA precursor 3 (280 mg, quantitative yield) as a
yellow oil. Due to its propensity to cyclise, this material was used
without further purification.
rel-(3aR,5S,7aS,1ꢀR)-Dimethyl 1,3,3a,7a-tetrahydro-3-oxo-5-(2,2-
diphenylcyclopropyl)isobenzofuran-4,4-(5H)-dicarboxylate (17c)
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A solution of IMDA precursor 3 (280 mg) in benzene (62 mL)
◦
was stirred at 25 C under N2 atm for 3 h. The solvent was then
evaporated under reduced pressure and 1H NMR analysis revealed
the presence of a single cycloadduct. Column chromatography
(hexanes–ethyl acetate–triethylamine, 70 : 28 : 2, absorption load
onto silica using ethyl acetate) afforded 17c as a white solid
◦
1
(201.6 mg, 72%): mp 196–198 C. H NMR (300 MHz, CDCl3):
d 7.11–7.24 (m, 10H), 5.63 (ddd, J = 9.9, 1.5, 1.5 Hz, 1H), 5.54
(ddd, J = 9.9, 3.6, 2.4 Hz, 1H), 4.40 (dd, J = 8.1, 6.9 Hz, 1H), 3.86
(dd, J = 11.4, 8.1 Hz, 1H), 3.78 (s, 3H), 3.64 (s, 3H), 2.95 (d, J =
14.1 Hz, 1H), 2.58–2.63 (m, 2H), 1.59–1.66 (m, 1H), 1.53–1.59 (m,
1H), 1.02 (dd, J = 8.4, 4.8 Hz, 1H) ppm. 13C NMR (125 MHz,
CDCl3): d 172.0, 169.4, 168.3, 146.3, 140.1, 132.6, 129.9, 129.4,
128.6, 128.5, 126.9, 126.8, 122.7, 69.7, 57.9, 53.5, 53.1, 44.6, 42.4,
38.0, 35.8, 28.8, 18.4 ppm. IR (KBr disc): mmax 3026, 2954, 1795,
1739, 1737, 1496, 1434, 1265, 1088 cm−1. EIMS: m/z (%): 446 (M+,
30), 414 (19), 258 (24), 220 (22), 197 (28), 193 (100). Anal. Calcd
for C27H26O6: C, 72.63; H, 5.87. Found: C, 72.43; H, 6.10. HRMS:
calcd for C27H26O6: 446.1729; found 446.1727.
Acknowledgements
Funding from the Australian Research Council (ARC) is gratefully
acknowledged, as are computing time allocations from the Aus-
tralian Partnership for Advanced Computing and the Australian
Centre for Advanced Computing and Communications.
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