Hyperconjomer stereocontrol of cationic polyene cyclisations

Article abstract of DOI:10.1039/c9ob01364d

Polyene cyclisations are a powerful method for the direct generation of molecular complexity. This paper describes the use of computational methods to investigate the stereoselectivity of cationic polyene cyclisations of geranylbenzene derivatives. The ou

Full text of DOI:10.1039/c9ob01364d

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DOI: 10.1039/C9OB01364D
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Hyperconjomer stereocontrol of cationic polyene cyclisations
Received 00th January 20xx,
Accepted 00th January 20xx
Robert T. Rodger,a Marlowe S. Grahama and Christopher S. P. McErlean,*a
DOI: 10.1039/x0xx00000x
Polyene cyclisations are a powerful method for the direct generation of molecular complexity. This paper describes the use
of computational methods to investigate the stereoselectivity of cationic polyene cyclisations of geranylbenzene derivatives.
The outcomes highlight the different reactivity of hyperconjomers during the key Friedel-Crafts alkylation step, and informed
a successful strategy for the synthesis of (±)-taiwaniaquinone G with improved levels of stereoselectivity.
depicted in Figure 1. Many synthetic approaches to this
4
structural motif been reported,3,
and include ring
palladium-catalysed
Introduction
contraction,5-7
electrocyclisation,8
Interrogation of the Super Natural II online database1,2 of over
325,000 natural products reveals more than 60 compounds
cyclisation,9-11 and Nazarov cyclisation/hydrogenation.12-15
Arguably the most straight-forward approach employs a
cascade cationic polyene cyclisation16-20 that terminates with a
containing
a hexahydro-1H-fluorene fragment, with the
majority possessing a 4a-methyl substituent. Of these, only 14
possess a cis-configured 6,5-ring fusion, while the majority
possess a trans-configured ring fusion. Illustrative examples are
Friedel-Crafts alkylation.21-24
.
We have previously reported a concise total synthesis of the
cis-fused compound (±)-5-epi-taiwaniaquinone G (13) using a
cationic polyene cyclisation (Scheme 1).25 In opposition to our
expectations, cyclisation of the geranylbenzene derivative 7
favoured production of the cis-fused hexahydro-1H-fluorene
Figure 1. Prominent hexahydro-1H-fluorene containing natural products
Scheme 1. Previous synthesis of epi-taiwaniaquinone G (13).25
a. School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia. Email:
christopher.mcerlean@sydney.edu.au
Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra, and
cartesian coordinates of all stationary points. See DOI: 10.1039/x0xx00000x
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product 10 in a ratio of ~7:1. Isolation of alkene by-product 11
and rearranged product 14 unambiguously demonstrated that
the cascade cyclisation, Friedel-Crafts sequence proceeded in a
step-wise fashion rather than being a concerted process. The
stereochemistry of the ring fusion was set during the Friedel-
Crafts-type arylation of the carbocation intermediate 8.
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DOI: 10.1039/C9OB01364D
Targeting a total synthesis of the trans-fused natural product
26, 27
taiwaniaquinone G (12),12,
we planned to alter the
stereoselectivity of this cyclisation by redesigning the
cyclisation substrate. In order to understand the structural
elements that would result in the desired trans-configured
product 9 being generated, we used computational methods to
examine cationic cyclisations that produced the hexahydro-1H-
fluorene architecture. In contrast to the large number of
computational studies on cationic polyene cyclisations leading
to 6,6,6-fused ring systems,28-40 studies on the corresponding
cyclisations giving 6,5,6-fused ring systems are absent from the
literature. The outcomes of our investigations are reported
below, and they informed our subsequent synthetic studies and
enabled a polyene cyclisation with enhanced stereoselectivity
for the rapid synthesis of (±)-taiwaniaquinone G (12).
Scheme 3. Cyclisation of E-configured alkene 7.
Results and discussion
Cis-selective cyclisation: (±)-epi-Taiwaniaquinone G
All calculated
G values reported in Schemes 3 and 4 are
relative to this cation. In analogy to the work of Antoniotti,
Dunach and co-workers who studied cycloisomerisation
reactions of polyenes,41 our calculations showed that A-ring
cyclisation of 16 occurred from conformer 16a through a chair-
like transition state (TS8a) (Scheme 3 and Figure 2) to give the
cationic intermediate 8a. The benzylic unit in intermediate 8a
occupied the equatorial position and was indeed oriented to
undergo reaction with the proximal cation to give either 17 or
18. The transition state leading to 17 was substantially lower in
energy and would, as desired, deliver the trans-configured
product 9.
The protonated cyclisation precursor 19 from the Z-
configured alkene 15 was 17 kJ/mol higher in energy than the
corresponding E-configured compound 16 (Scheme 4).
Cyclisation of the reactive conformer 19a occurred through a
boat-like transition state 8b. Consequently it possessed a higher
activation barrier than cyclisation of the E-configured substrate.
The lowest energy product cation 8b from this reaction was
appropriately oriented to be trapped by the aromatic ring to
give 20 or 21, with both intermediates leading to the cis-
configured product 10.
At the outset of our previous synthesis of epi-taiwaniaquinone
G (13)25 we had anticipated that the initial cyclisation would
proceed via a chair-like transition state TS8a to give an
intermediate that was appropriately arranged for Friedel-Crafts
reaction to deliver the desired trans-configured ring fusion 9
(Scheme 2). The fact that we obtained predominantly the cis-
configured product 10 led us to consider the alternative
cyclisation of the Z-configured alkene 15. Given the acidic
reaction conditions under which the cyclisations were
performed, it was conceivable that the E-configured alkene 7
isomerised into the Z-alkene 15 prior to cyclohexane formation.
Our work began by performing DFT gas phase calculations (-
B97X-D/6-31G*) to examine the intermediates and transition
states leading to the possible products 9 and 10.
In the first instance, protonation of the distal olefin of the E-
configured compound 7 gave the cationic species 16 (Scheme3).
Scheme 2. Proposed cyclisations of alkene diastereomers 7 and 15.
Figure 2. Comparison of TS8a and TS8b
.
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Figure 3. Hyperconjomers of 1-methylcyclohexyl cation.
derivative 7 did not arise by selective cyclisation of the E- and Z-
configured alkenes 7 and 15 respectively.25 Indeed, in situ NMR
monitoring of a mixture of the E-configured alkene 7 and
various acids did not provide evidence for the generation of the
Z-configured compound 15. It was therefore likely that the
intermediate cations 8a and 8b were able to interconvert faster
than the subsequent Friedel-Crafts alkylation.
In 1996, Sorensen and co-workers predicted that 1-
methylcyclohexyl cations could exist in two isomeric forms, 22a
and 22b (Figure 3), that they termed hyperconjomers.42 These
isomers differ by the mode of hyperconjugative stabilization. In
22a electron density is provided by C-C bonds within the
cyclohexyl framework, whereas in 22b the stabilization results
from orbital overlap of the axial C-H bonds and the cation. The
calculated barrier for the interconversion of 1-methylcyclohexyl
cation hyperconjomers was less than 4 kJ/mol.42 Nonetheless,
in 2001 Sorensen, Schleyer and co-workers obtained definitive
spectroscopic evidence for the existence of hyperconjomers,43
and they suggested that the different hyperconjugation modes
may govern pathways for nucleophilic attack.† In 2011, Lepore
and co-workers reported the first example of hyperconjomers
affecting stereocontrol over an intermolecular reaction.44, 45
The cationic intermediates 8a and 8b (Schemes 3 and 4) are
isomeric cyclohexyl cations, i.e. hyperconjomers, with
intermediate 8b being 9.4 kJ/mol more stable. The
consequence of hyperconjomer interconversion being a low
energy process,‡
Scheme 4. Cyclisation of Z-configured alkene 15.
Clearly the product ratio that was observed experimentally
(~7:1 cis:trans) from cyclisation of the geranylbenzene
Figure 4. Reaction profile for the cyclisation of compound 7.
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is a Curtin-Hammett scenario in which the product ratio for the
cyclisation of compound 7 was determined by the relative
differences in activation energies (G‡) of the Friedel-Crafts
alkylation step. The transition state leading to the cis-configured
intermediate 21 was lower in energy than the corresponding
transition state leading to the trans-configured intermediate 17
(
G‡ = 3.2 kJ/mol). It is pertinent to remember that solvent
effects were not included in our calculations. A reaction profile
that accounts for the observed product distribution is depicted
in Figure 4. Protonation of the E-configured alkene 7 gave 16
which cyclised via a chair-like transition state (TS8a) to give
intermediate 8a. Slow Friedel-Crafts reaction allowed for a
conformational ring-flip to give 8b which positioned the benzyl
unit in an axial orientation. Subsequent cyclisation
preferentially gave the cis-configured intermediate 21, which
underwent elimination to give the cis-configured product 10.
The minor amount of trans-configured product 9 resulted from
cyclisation of initially formed intermediate 8a via the trans-
configured intermediate 17.
The relative stability of the axially oriented isomer 8b can be
rationalised by noting the enhanced hyperconjugative
stabilisation of the carbocation. Figure 5 shows the LUMO plots
for intermediates 8a and 8b and clearly illustrates that the
relatively electron-rich bond connecting the benzylic carbon to
the cyclohexyl ring provides enhanced stabilisation of the
carbocation when it is axially oriented, lengthening the benzylic
bond from 1.547 Å to 1.604 Å. Although Sorensen, Schleyer and
co-workers have shown that the magnitude of this
hyperconjugative stabilisation can be affected by solvent,43
neither explicit nor continuum solvent models were included in
our calculations.
Interconversion of intermediates 8a and 8b also accounted
for the observed by-products of the reaction, compounds 11
and 14 (scheme 5). The initial product of cyclisation 8a
possessed an axially oriented hydrogen atom. The barrier for
[1,2-H] migration to give 23 was too great for the process to be
feasible.‡‡ Elimination to form alkenes 11 was therefore
preferred. In contrast, intermediate 8b possessed a benzyl unit
in the axial position. The corresponding type II dyotropic
rearrangement to give 24 had an activation barrier of only 19
kJ/mol.46, 47 Due to stabilisation of developing positive charge
on the benzylic carbon, this was a concerted asynchronous
process in which the [1,2]-benzyl shift was significantly
Scheme 5. Reaction pathway to rearranged compounds 11 and 14.
advanced before the [1,2]-methyl shift occurred.48, 49 Cation 24
that underwent Friedel-Crafts alkylation, leading to product 14.
The preferential formation of the cis-configured product 10
and the rearranged product 14 is the direct result of the
existence of hyperconjomers 8a and 8b and their different
reactivity in an intramolecular Friedel-Crafts reaction. As such,
this work represents a clear vindication of Sorensen and
Schleyer’s prediction that hyperconjugation modes may dictate
pathways for nucleophilic attack.
In terms of designing a synthetic strategy toward (±)-
taiwaniaquinone G (12) (Scheme 1), the outcomes of these
computational studies suggested that one way to maximise
production of the desired trans-fused product 10, would be to
slow the rate of interconversion of the two intermediate cations
8a and 8b. In related work, Antoniotti, Dunach and co-workers
concluded that interconversion of cationic intermediates was
the stereo-determining step in the cyclisation of polyenes to
give 6,6-fused systems.41 To investigate if this was synthetically
practicable we examined some related trans-selective
cyclisations. For these investigations, barriers to cyclisation
were calculated directly from the reactive conformations of the
intermediate cyclohexyl cations. We recognize that for slow
Friedel-Crafts reactions, elimination to the alkene and
subsequent re-protonation is a viable route to alternative
products.22 However, given the high energy associated with
protonation of an alkene in the gas phase, we have elected to
study only the direct conversion of cation intermediates into
products.
Figure 5. LUMO plots of intermediates 8a and 8b.
Trans-selective polyene cyclisations
During their synthesis of the marine sponge metabolite pelorol
(25), Andersen and co-workers utilised a cationic cyclisation of
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However, translating this to the design of a synthetic strategy
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DOI: 10.1039/C9OB01364D
to
Scheme 7. Yamamoto’s brominative cyclisation of geranylbenzene derivative 36.
(±)-taiwaniaquinone G (12) would necessitate the introduction
of a cleavable fused-ring system mimicking the decalin
framework. Such an approach would add significant complexity
to any proposed synthesis.
Recently, Yamamoto and co-workers reported an
enantioselective brominative polyene cyclisation of
geranylbenzene derivative 36 that gave exclusively the trans-
configured product (Scheme 7).50 We wondered if the large
bromine atom was acting as
a
(readily cleavable)
conformational constraint that slowed hyperconjomer
interconversion. Our calculations show that initial cyclization of
36 gives intermediate 37, which possesses an equatorially
oriented benzyl group.§ This intermediate could undergo
Friedel-Crafts cyclisation to give the observed trans-fused
compound 38. Compound 38 bears striking similarity to
intermediate 8a in our previous (±)-epi-taiwaniaquinone G (13)
synthesis (see Scheme 3). The ring-flipped hyperconjomer 39,
in which the benzyl unit is axially oriented, is significantly lower
in energy than 37. Therefore, the stereoselectivity of this
process was not be the result of the bromine atom acting as a
conformational constraint that biased the system towards
conformer 37, but was due to the difference in activation
energies leading to the cis and trans-configured compounds 38
and 40. Friedel-Crafts cyclisation of intermediate 39, which
would lead to the cis-fused intermediate 40, had a relatively
high activation barrier, and was not experimentally
observed.51§§
From a synthetic design viewpoint, it was instructive that
Yamamoto and co-workers reported that the cyclisation of 36
to give 38 was extremely facile and occurred at low
temperature (-78 ˚C). We wondered if it was possible for trans-
selective cyclisations from non-favoured hyperconjomers to be
affected by the nucleophilicity of the aromatic ring, which could
lead to Friedel-Crafts transition states being engaged (at low
temperature) before hyperconjomer interconversion occurred.
Scheme 6. Andersen’s synthesis of pelorol (25)
the scarleolide derivatives 26 and 27 to give exclusively the
trans-fused hexahydro-1H-fluorene product 34 (Scheme 6).24
Gas phase DFT calculations (-B97X-D/6-31G*) show that the
reaction of both starting alcohols 26 and 27 with acid produces
the cationic species 28, which possesses an equatorially
oriented benzylic group and can engage in a Friedel- Crafts
alkylation to give the trans-configured compounds 30 and 31,
with the transition state leading to 31 being lower in energy and
ultimately leading to the observed product 34. Intermediate 28
is significantly lower in energy than the corresponding
hyperconjomer 29, which possesses an axially oriented benzyl
unit. Intermediate 29 could undergo reaction to give
compounds 32 and 33, which both lead to the non-observed but
thermodynamically more stable product 35 (see ESI). In that
instance, the preference for the trans-configured products
arises by virtue of intermediate 28 being substantially more
populated during the reaction course. While the intermediates
in the previous discussion possessed a very flexible cyclohexyl
ring, in this instance hyperconjugative stabilization of the cation
29 is over-ridden by ring-strain and developing 1,3-diaxial steric
interactions.
Clearly, in the pelorol case, the conformational constraints
imposed by the presence of a trans-decalin ring system controls
the stereochemical course of the Friedel-Crafts alkylation.
Overman has previously shown the requirement for
a
nucleophilic arene to avoid alkene by-products,22 but the effect
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on stereochemistry was not discussed. Relating this to our cyclisation involving the phenolic oxygen is favoured in that
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instance. The trimethoxy compound 45 DisOpI:r1e0d.1i0c3t9e/dC9tOoBd0i1s3p6l4aDy
improved trans:cis selectivity in the Friedel-Crafts alkylation
step. Despite the hyperconjomers 46a and 46b being
energetically similar and the barrier to Friedel-Crafts cyclisation
being higher that for 8a to 17 (Scheme 3), the difference in
activation energies (G‡ = 4 kJ/mol) for the trans- and cis-
fused intermediates 47 and 48 (lowest energy transition states)
favours the desired stereochemistry. And finally, the most
electron-rich cyclisation precursor 49 is predicted to have the
highest selectivity and lowest activation barrier for the desired
trans-selective cyclisation, and one that is broadly comparable
with Yamamoto’s trans-selective cyclisation. Substrates 45 and
49 were therefore considered to be appropriate compounds to
use for the total synthesis of taiwaniaquinone G (12).
Total synthesis of (±)-taiwaniaquinone G
As shown in Scheme 9, compound 45 was generated by
modifiying the procedure described by Bisai and co-workers.15
1,2,4-Trimethoxybenzene (53) was subjected to ortho-lithiation
and reacted with acetone to give 54. Dehydration and in situ
transfer hydrogenation gave 55, which was regioselectively
brominated to give 56. Suzuki cross-coupling with the
previously described geranylboronate 5725 afforded the desired
cyclisation precursor 45 and set the stage for the cationic
polyene cyclisation.
proposed synthetic strategy toward (±)-taiwaniaquinone G (12),
Scheme 8. Possible cyclisation precursors.
the incorporation of a more electron-rich aromatic ring into the
cyclising polyene may bias the reaction towards generation of
the desired trans-fused hexahydro-1H-fluorene. But how
nucleophilic did the aromatic ring have to be? Our next step was
to survey the energetic requirements leading to trans-fused ring
systems.
Surveying the energetic requirements for trans-selective
cyclisation
We computationally examined the cyclisation of three possible
precursors for the stereoselective generation of the trans-fused
hexahydro-1H-fluorene system corresponding to (±)-
taiwaniaquinone G (12). As shown in Scheme 8, phenol 41,
which differs from our previous substrate only by the absence
of a methyl group, is not predicted to be nucleophilic enough to
undergo fast Friedel-Crafts alkylation as the activation barrier
from 42 to 43 is large compared to the corresponding barrier
from 8a to 17 (
G‡ 14.8 kJ/mol, see Scheme 3). Indeed, Friedel-
Crafts cyclisation is not on the lowest energy pathway, and
Scheme 9. Synthesis of substrate 45, and (±)-taiwaniaquinone G (12).
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trans-fused product 61 as the minor product in a slightly
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improved 1:2 mixture of with the cis-fused diastereomer 60.
Frustratingly, conducting the reaction at lower temperatures,
which were expected to return higher levels of trans-
stereoselectivity, resulted in no cyclisation. In the cationic
polyene cyclisation of geranylbenzene derivatives such as those
discussed above, the highest energy barrier corresponds to the
initial cyclisation to form the A-ring (see Figure 3), and this failed
to occur at low temperatures.
1
0.5
0
-0.5
-1
Experimental
General methods and materials
Atom number
DFT calculations were carried out with Spartan’16 or Spartan’18
programs. Geometries and energies of transition states and
intermediates were obtained using the range separated hybrid
Figure 6. Comparison of 1H NMR chemical shifts of natural27 and synthetic
taiwaniaquinone G (12).
generalized gradient approximation functional
the 6-31G* basis set.53 The
B97X-D with
B97X-D functional has been shown
Cyclisation of 45 with either BF3∙OEt2 or ClSO3H at room
to have comparable performance to the M06-2X functional and
superior performance to the more commonly used B3LYP
functional.53-55 The vibrational frequencies of stationary points
were inspected to ensure that they corresponded to minima on
the potential energy surface and the Intrinsic Reaction
Coordinate (IRC) method was used to confirm that they
corresponded to motion along the reaction coordinate. All
temperature produced
configured hexahydro-1H-fluorene 59 in a 1:3 ratio with the
non-desired cis-isomer 58. The product ratio from the
a mixture of the desired trans-
cyclisation reaction was a significant improvement on the 1:7
ratio observed in our previous work, but was not as high as
anticipated. The discrepancy between the levels of selectivity
observed in the cyclisation versus the level expected from the
calculations shown in Scheme 8 (predicted ratio = 5:1) may be
due to the gas phase nature of those calculations. Nonetheless,
subsequent oxidation of the 1:3 mixture and HPLC separation
provided (±)-taiwaniaquinone G (12) (21% after oxidation and
separation), which was spectroscopically identical to the
reported data for the isolated compound (Figure 6 and ESI).27
We sought to further increase the selectivity of the Friedel-
Crafts alkylation by employing the phenol 49 (Scheme 10). As
such, compound 45 was treated with BBr3 in an attempt to
effect the in situ generation of phenol 49. Disappointingly, the
rate of BBr3-mediated polyene cyclisation proved to be greater
than the rate of demethylation, and the same 1:3 product ratio
of desired compound 59 to non-desired 58 was returned.
Selective demethylation of 45 was accomplished by the action
of L-Selectride™ in the manner described by Majetich and co-
workers.52 Cyclisation of phenol 49 at 0 °C delivered the desired
relative energies (
kJ/mol (see ESI).

G) are reported uncorrected at 298 K in
2-(2,3,6-Trimethoxyphenyl)propan-2-ol
(54). 1,2,4-
Trimethoxybenzene (980 mg, 5.80 mmol) and N,N,N,N-
tetramethylethylenediamine (1.0 mL, 6.8 mmol) were dissolved
in tetrahydrofuran (58 mL) and cooled to −78 °C. n-Butyllithium
(2.0 M in hexanes; 3.0 mL, 6.0 mmol) was added dropwise and
the mixture was stirred for 1 h, warming to room temperature.
The reaction mixture was again cooled to −78 °C, then acetone
(1.3 mL, 1.8 mmol) was added dropwise and the mixture was
stirred for 2 h, warming to room temperature. Saturated
aqueous ammonium chloride solution (20 mL) was added, then
the mixture was extracted with ethyl acetate (3 × 30 mL) and
the combined extracts were dried over sodium sulfate and the
solvent was removed in vacuo. The residue was purified by
column chromatography on silica gel, eluting with 10% ethyl
acetate in hexanes to give 55 as a yellow oil (650 mg, 2.9 mmol,
50%). 1H NMR (400 MHz, CDCl3): δ = 6.76 (1 H, d, J = 9.0 Hz), 6.63
(1 H, d, J = 9.0 Hz), 5.89 (1 H, s), 3.85 (3 H, s), 3.81 (6 H, s), 1.66
(6 H, s) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.6, 148.2, 147.5,
130.2, 110.7, 107.5, 74.4, 61.5, 56.4, 31.4 ppm. MS (ESI) m/z
(%): 249 ([M + Na]+, 100).
Scheme 10. Synthesis and cyclisation of phenol substrate 48
.
2-Isopropyl-1,3,4-trimethoxybenzene (55). Compound 54
(2.0 g, 8.9 mmol) and palladium-on-carbon (10 wt%, 380 mg,
mmol) were taken up in ethanol (60 mL) and hydrochloric acid
(10 M; 2.0 mL) was added. The reaction mixture was stirred for
5 h under an atmosphere of hydrogen, then the reaction
mixture was sparged before opening to the air and filtering over
Celite, eluting with ethanol (50 mL). The solvent was removed
in vacuo, then the residue was dissolved in ether (50 mL),
washed with saturated aqueous sodium bicarbonate solution
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(50 mL) and dried over magnesium sulfate. The solvent was dichloromethane in hexanes to give desired trans-fluorene 59
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removed in vacuo to give 55 as a yellow oil (1.1 g, 5.3 mmol, as an inseparable mixture of diastereomers with the cis isomer
59%). 1H NMR (400 MHz, CDCl3): δ = 6.69 (1 H, d, J= 8.9 Hz), 6.56 58 (1:3 trans:cis) (150 mg, 0.43 mmol, 50%). Compound 59
(1 H, d, J = 8.9 Hz), 3.81 (3 H, s), 3.80 (3 H, s), 3.76 (3 H, s), 3.54 (some peaks obscured): 1H NMR (400 MHz, CDCl3): δ = 3.81 (3 H,
(1 H, septet, J = 7.1 Hz), 1.31 (6 H, d, J = 7.1 Hz) ppm. 13C NMR s), 3.75 (3 H, s), 3.39 (1 H, septet, J = 7.2 Hz), 2.74 (1 H, dd, J =
(100 MHz, CDCl3): δ = 153.1, 148.0, 147.5, 131.1, 109.7, 106.5, 14.3, 6.3 Hz), 2.55 (1 H, dd, J = 14.3, 12.9 Hz), 2.39 (1 H, m), 1.73
61.1, 56.3, 56.0, 25.3, 21.3 ppm. MS (ACPI): m/z (%): 210 ([M]+, (1 H, dd, J = 12.9, 6.3 Hz), 1.58–1.53 (2 H, m), 1.24–1.17 (1 H, m),
100).
1.12 (3 H, s), 1.03 (3 H, s), 0.96 (3 H, s) 13C NMR (100 MHz,
1-Bromo-3-isopropyl-2,4,5-trimethoxybenzene (56). To a CDCl3): δ = 151.1, 150.5, 145.5, 144.9, 131.8, 129.4, 59.7, 47.0,
solution of 55 (240 mg, 1.20 mmol) in dichloromethane (10 mL) 41.4, 36.8, 33.3, 33.1, 27.2, 21.1, 20.3, 20.1 ppm. Compound 58:
was added N-bromosuccinimide (210 mg, 1.20 mmol). The 1H NMR (400 MHz, CDCl3): δ = 3.80 (3 H, s), 3.79 (3 H, s), 3.72 (3
reaction mixture was stirred at room temperature for 2 h, then H, s), 3.39 (1 H, septet, J = 7.2 Hz), 2.83 (1 H, dd, J = 15.4, 7.9 Hz),
the solvent was removed in vacuo and the residue was purified 2.62 (1 H, dd, J = 15.4, 11.3 Hz), 1.81 (1 H, dd, J = 11.3, 7.9 Hz),
by column chromatography on silica gel, eluting with 5% ether 1.80–1.74 (1 H, m), 1.61 (3 H, s), 1.46–1.42 (1 H, m), 1.42–1.36
in hexanes to give 56 as a yellow oil (300 mg, 1.0 mmol, 91%). (2 H, m), 1.32(6 H, d, J = 7.2 Hz), 1.29–1.24 (2 H, m), 1.13 (3 H,
1H NMR (400 MHz, CDCl3): δ = 6.93 (1 H, s), 3.83 (3 H, s), 3.81 (3 s), 0.93 (3 H, s) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.0, 150.3,
H, s), 3.77 (3 H, s), 3.46 (1 H, septet, J = 7.2 Hz), 1.33 (6 H, d, J = 146.4, 144.3, 132.3, 128.9, 60.5, 60.4, 56.6, 47.2, 35.2, 35.0,
7.2 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.2, 149.1, 148.2, 32.2, 31.3, 31.1, 25.6, 25.5, 22.24, 22.20, 18.7 ppm. HRMS (ESI):
136.9, 114.3, 110.9, 61.7, 60.9, 56.2, 26.9, 21.9 ppm. MS (ESI): calcd. for C22H34O3Na+ 369.24002; found 369.24035.
m/z (%): 311/313 ([M+Na]+, 30).
Taiwaniaquinone G (12). The diastereomeric mixture of 58
and 59 (120 mg, 0.35 mmol) was dissolved in acetonitrile (3 mL)
(E)-1-(3,7-Dimethylocta-2,6-dien-1-yl)-3-isopropyl-2,4,5-
trimethoxybenzene (45). Compound 56 (610 mg, 2.1 mmol), and cooled to 0 °C. A solution of ceric ammonium nitrate (950
geranyl pinacol boronate25 (560 mg, 2.1 mmol), powdered mg, 1.7 mmol) in water (1 mL) was added dropwise and stirred
sodium hydroxide (1.0 g, 25 mmol) and tetrakis- 1 h, warming to room temperature. Saturated aqueous sodium
(triphenylphosphine) palladium(0) (230 mg, 0.20 mmol) were sulfite solution (10 mL) was added and the mixture was
dissolved in toluene (30 mL) and water (7.5 mL), placed under extracted with ether (2 × 20 mL), dried over anhydrous sodium
an argon atmosphere and sparged with argon for 10 min. The sulfate, and the solvent was removed in vacuo. The residue was
reaction mixture was heated to 90 °C for 20 h, then cooled to purified by column chromatography on silica gel, eluting with
room temperature, diluted with hexane (30 mL) and water (20 25% dichloromethane in hexanes to give taiwaniaquinone G
mL), separated and the aqueous layer was extracted with and 5-epi-taiwaniaquinone G as a mixture (94 mg, 0.30 mmol,
diethyl ether (3 × 30 mL). The combined organic extracts were 86%). A diasteromerically pure sample of taiwaniaquinone G
dried over anhydrous sodium sulfate and the solvent was was obtained by preparative HPLC (water/acetonitrile 25:75
removed in vacuo. The residue was purified by column isocratic, Sunfire C18) (20 mg, 21%) as a yellow oil. 1H NMR (500
chromatography on silica gel, eluting with 30% MHz, CDCl3): δ = 3.93 (3 H, s), 3.22 (1 H, septet, J = 7.1 Hz), 2.59
dichloromethane in hexanes to give 45 as a yellow oil (485 mg, (1 H, dd, J = 6.4, 16.8 Hz), 2.31 (1 H, dd, J = 12.7, 16.8 Hz), 2.30–
1.4 mmol, 67%). 1H NMR (400 MHz, CDCl3): δ = 6.59 (1 H, s), 5.31 2.26 (1 H, m), 1.82–1.71 (1 H, m), 1.64 (1 H, dd, J = 6.4, 12.7 Hz),
(1 H, tq, J = 7.1 Hz, 1.4 Hz), 5.12 (1 H, tt, J = 6.6 Hz, 1.3 Hz), 3.83 1.65–1.59 (1 H, m), 1.51–1.48 (1 H, m), 1.45 (1 H, dd, J = 4.2,
(3 H, s), 3.80 (3 H, s), 3.67 (3 H, s), 3.44 (1 H, septet, J = 7.2 Hz), 12.8 Hz), 1.21 (3 H, d, J = 7.1 Hz), 1.20 (3 H, d, J = 7.1 Hz), 1.14 (1
3.35 (2 H, d, J = 7.1 Hz), 2.19-2.03 (4 H, m), 1.73 (3 H, s), 1.67 (3 H, dd, J = 4.8, 13.9), 1.08 (3 H, s), 0.99 (3 H, s), 0.93 (3 H, s) ppm.
H, s), 1.59 (3 H, s), 1.35 (6 H, d, J = 7.2 Hz) ppm. 13C NMR (100 13C NMR (125 MHz, CDCl3): δ = 187.4, 182.4, 156.3, 153.9, 148.5,
MHz, CDCl3): δ = 149.8, 149.6, 146.9, 136.3, 134.9, 131.6, 129.5, 137.3, 61.2, 58.4, 48.2, 41.2, 35.0, 33.2, 32.9, 27.2, 24.7, 21.2,
124.3, 123.3, 111.2, 61.9, 60.8, 55.9, 39.9, 28.3, 26.9, 26.2, 25.8, 20.8, 20.7, 19.8, 18.2 ppm. HRMS (ESI): calcd. for C20H28O3Na+
22.2, 17.8, 16.3 ppm. HRMS (ESI): calcd. for C22H34O3Na+ 339.19307; found 339.19331.
369.240002; found 369.24044. IR (film): νmax= 2955, 2931, 2872,
(E)-5-(3,7-Dimethylocta-2,6-dien-1-yl)-3-isopropyl-2,4-
2833, 1591, 1482, 1454, 1426, 1343, 1253, 1226, 1111, 1042, dimethoxyphenol (49). Compound 45 (350 mg, 1.0 mmol) was
1015, 981, 846, 789, 720 cm-1.
dissolved in tetrahydrofuran (10 mL) and L-selectride (1.0 M in
THF; 3.0 mL, 3.0 mmol) was added. The reaction mixture was
7-Isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-
2,3,4,4a,9,9a-hexahydro-1H-fluorene (58 and 59). Compound heated to reflux and stirred for 24 h, then cooled to room
45 (300 mg, 0.87 mmol) was dissolved in nitroethane (9 mL) and temperature and saturated aqueous ammonium chloride
cooled to 0 °C. Boron trifluoride etherate (0.020 mL, 0.15 mmol) solution (20 mL) was added. The reaction mixture was extracted
was added and the reaction mixture was stirred for 18 h at room with ether (3 × 30 mL) and the combined organic layers were
temperature. Saturated aqueous sodium bicarbonate solution dried over magnesium sulfate and solvent was removed in
(5 mL) was added, then the reaction mixture was extracted with vacuo. The residue was purified by column chromatography
ethyl acetate (3 × 10 mL). The combined organic layers were over silica gel, eluting with 30% dichloromethane in hexanes to
dried over anhydrous sodium sulfate, the solvent was removed give 49 as a yellow oil (160 mg, 0.48 mmol, 48%). 1H NMR (500
in vacuo and the residue was purified by column MHz, CDCl3): δ = 6.53 (1 H, s), 5.62 (1 H, s), 5.32–5.26 (1 H, m),
chromatography on silica gel, eluting with 35% 5.18–5.08 (1 H, m), 3.83 (3 H, s), 3.67 (3 H, s), 3.42 (1 H, septet),
8 | J. Name., 2012, 00, 1-3
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3.32 (2 H, d, J = 7.2 Hz), 2.20–2.02 (4 H, m), 1.73 (3 H, s), 1.67 (3 not engage in the desired cyclisation and will result in the
View Article Online
22
H, s), 1.60 (3 H, s), 1.38 (6 H, d, J = 7.2 Hz) ppm. 13C NMR (125 preferential generation of alkene products. Compounds with
DOI: 10.1039/C9OB01364D
MHz, CDCl3): δ = 149.9, 143.3, 136.1, 131.6, 127.2, 124.8, 124.4, only moderately nucleophilic arenes will cyclise at a rate that is
123.7, 109.1, 62.0, 56.3, 39.9, 28.1, 26.9, 26.0, 25.8, 20.9, 17.8, slow enough to allow the conformational interconversion of the
16.3 ppm. HRMS (ESI): calcd. for C21H32O3Na+ 355.22437; found intermediate hyperconjomers, and will proceed through the
355.22483. IR (film): νmax = 3539, 2956, 2925, 2853, 1486, 1455, lowest energy transition state. This was the case for our
1421, 1339, 1288, 1242, 1213, 1103, 1039, 987, 847, 780, 457 previous synthesis of (±)-epi-tawaniaquinone G (13) (Scheme
cm-1.
1).25 Compounds possessing a highly nucleophilic arene will
7-Isopropyl-6,8-dimethoxy-1,4,4a-trimethyl-2,3,4,4a,9,9a- undergo fast Friedel-Crafts reaction and result in the trans-
hexahydro-1H-fluoren-5-ol (60) and (61). Compound 49 (50 fused product, as seen in the work of Yamamoto (Scheme 7).50
mg, 0.15 mmol) was dissolved in nitroethane (1.5 mL) and boron
We used this information to design and execute a concise
trifluoride etherate (0.020 mL, 0.15 mmol) was added. The total synthesis of the (±)-taiwaniaquinone G (12) that employed
reaction was stirred at -5 °C for 3 days, then saturated aqueous a cationic polyene cyclisation of a geranyl derivative containing
sodium bicarbonate solution (5 mL) was added and the reaction a trimethoxyphenyl unit. As anticipated, the cyclisation of this
mixture was warmed to room temperature, then extracted with more electron rich substrate exhibited improved trans-
ether (10 mL). The organic layer was dried over anhydrous stereoselectivity at the 5,6-ring fusion. Although we were able
sodium sulfate, filtered and the solvent was removed in vacuo. to access the desired natural product, the level of
The residue was purified by column chromatography over silica stereoselectivity could not be further enhanced for this
gel, eluting with 25% dichloromethane in hexanes to give an particular polyene cyclisation due to the energetic
inseparable 2:1 mixture of diastereomers 60 and 61 as a yellow requirements for forming the A-ring. Nonetheless, we
oil (11 mg, 0.033 mmol, 22%).Compound 60 1H NMR (400 MHz, anticipate that judicious choice of aromatic ring will enable the
CDCl3): δ = 5.51 (1 H, s), 3.75 (3 H, s), 3.71 (3 H, s), 3.40 (1 H, stereoselective synthesis of other cis- and trans-fused natural
septet, J = 7.1 Hz), 2.81 (1 H, dd, J = 15.1, 7.7 Hz), 2.62 (1 H, dd, products possessing a hexahydro-1H-fluorene fragment.
J = 15.1, 10.9 Hz), 1.80 (1 H, dd, J = 10.9, 7.3 Hz), 1.66–1.61 (2 H,
m), 1.60 (3 H, s), 1.47–1.41 (2 H, m), 1.34 (6 H, dd, J = 7.1, 6.0
Hz), 1.30–1.24 (2 H, m), 1.11 (3 H, s), 0.91 (3 H, s). 13C NMR (100
MHz, CDCl3): δ = 150.9, 147.2, 143.1, 140.4, 125.4, 125.1, 62.2,
60.8, 57.5, 47.3, 35.4, 35.3, 32.4, 30.9, 29.9, 25.6, 25.4, 21.3,
21.2, 18.9 ppm. HRMS (ESI): calcd. for C21H32O3Na+ 355.22437;
found 355.22483. IR (film): νmax = 3523, 2930, 2868, 1456, 1422,
1336, 1260, 1100, 1037, 887 cm−1. Compound 61 (partial data;
some peaks obscured): 1H NMR (400 MHz, CDCl3): δ = 5.46 (1 H,
s), 3.77 (3 H, s), 3.73 (3 H, s), 3.40 (1 H, septet, J = 7.1 Hz), 2.72
(1 H, dd, J = 14.1, 6.2 Hz), 2.54 (1 H, dd, J = 14.1, 12.5 Hz), 2.35–
2.30 (1 H, m), 1.70 (1 H, dd, J = 12.5, 6.2 Hz), 1.54–1.48 (2 H, m),
1.32 (6 H, d, J = 7.2 Hz), 1.23–1.14 (2 H, m), 1.12 (3 H, s), 1.03 (3
H, s), 0.96 (3 H, s) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.6,
146.9, 144.6, 139.1, 125.5, 124.9, 62.3, 60.8, 60.1, 47.1, 41.2,
36.9, 33.5, 33.2, 31.0, 27.0, 21.4, 21.3, 20.5, 20.2 ppm.
Acknowledgements
RTR and MG are grateful for Australian Government Research
Training Program Scholarships. RTR also acknowledges receipt
of a Bruce Veness Chandler Research Support Scholarship.
Conflicts of interest
There are no conflicts to declare.
Notes and references
†
Similar isomeric structures are predicted for polyene
cyclisations that yield 6,6-fused ring systems. In those instances
the issue is complicated by efficient π-cation interactions that
push the cyclisations toward concerted bond-forming events. See
references 28–40.
‡
Semi-empirical calculations suggest an energy barrier of ~ 13
Conclusions
kJ/mol for interconversion of these hyperconjomers. Semi-
empirical estimates for the interconversion of all hyperconjomers
in the manuscript appear in the ESI, and are broadly similar.
‡‡ Determined using semi-empirical calculations. as we were
unable to locate a valid transitions state using DFT.
These studies have shown that the cationic polyene cyclisation
of geranylbezene derivatives proceed through an initial chair-
like transition state to give an intermediate possessing an
equatorially disposed aromatic unit. Although this intermediate
is appropriately oriented to undergo a trans-selective Friedel-
Crafts alkylation, the existence of hyperconjomers (cyclohexyl
cation isomers) and their different reactivity in the ensuing
intramolecular Friedel-Crafts reaction, results in the
preferential production of the cis-fused 5,6-ring system. This
outcome is in line with Sorensen and Schleyer’s prediction that
hyperconjugation modes may dictate reaction pathways.42, 43 In
the absence of conformational constraints (such as in the
pelorol case),24 the stereochemical outcome of the Friedel-
Crafts reaction is intimately linked to the nucleophilicity of the
aromatic ring. Compounds with poorly nucleophilic arenes will
§
We were unable to locate a transition state for the
corresponding concerted polyene cyclisation.
§§ We are also cognizant of the fact that Yamamoto's work
involved a spectacularly bulky counter-ion, which may affect the
stereoselectivity of the reaction by forming a tight ion-pair. For an
example of this see reference 51.
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