Enantioselective synthesis of [7]helicene: Dramatic effects of olefin additives and aromatic solvents in asymmetric olefin metathesis

Article abstract of DOI:10.1002/chem.200801033

The asymmetric synthesis of [7]helicene was accomplished in good ee (80%) by kinetic resolution by means of asymmetric olefin metathesis. Three key factors contributed to the success of the kinetic resolution: the use of new Rubased olefin metathesis catalysts bearing C₁-symmetric N-heterocyclic carbene ligands, simple olefins as additives to control the nature of the propagating alkylidene and hexafluorobenzene as a solvent.

Full text of DOI:10.1002/chem.200801033

FULL PAPER
DOI: 10.1002/chem.200801033
Enantioselective Synthesis of [7]Helicene: Dramatic Effects of Olefin
Additives and Aromatic Solvents in Asymmetric Olefin Metathesis
Alain Grandbois and Shawn K. Collins*[a]
Abstract: The asymmetric synthesis of [7]helicene was accomplished in good ee
(80%) by kinetic resolution by means of asymmetric olefin metathesis. Three key
Keywords: asymmetric synthesis ·
catalysis · helicenes · kinetic resolu-
tion · olefin metathesis
factors contributed to the success of the kinetic resolution: the use of new Ru-
based olefin metathesis catalysts bearing C1-symmetric N-heterocyclic carbene li-
gands, simple olefins as additives to control the nature of the propagating alkyli-
dene and hexafluorobenzene as a solvent.
Introduction
to prepare enantioenriched all-carbon helicenes was report-
ed by Martin, Kagan and co-workers more than 30 years
ago.[5a] Unfortunately, enantioinduction by photocyclisation
using circularly polarised light failed to afford significant
levels of enantioexcess. In the past decade, an efficient
method to access enantiopure helicenes was developed that
employs an asymmetric Diels–Alder reaction of quinones
bearing enantioenriched sulfoxides as chiral auxiliaries.[6] In
Helicenes continue to be topics of intense interest as their
helically chiral structures have interesting potential optical,
electronic and medicinal properties.[1] Despite the relatively
high level of interest in these structures, the synthetic meth-
ods available for their preparation remain relatively under-
developed.[2] All new synthetic methods that are developed
must construct the strained carbon skeletons that result
from the ortho-fused aromatic rings.[3] Consequently, the
asymmetric synthesis of helicenes is also challenging. New
methods for the asymmetric preparation of heterohelicenes
have appeared and usually involve the enantioselective for-
mation of a carbon-heteroatom bond.[4] The synthetic chal-
lenge associated with an asymmetric synthesis of carboheli-
cenes is associated with enantioselectively inducing helicity
while forming a carbon–carbon bond. Herein, we report a
novel catalytic and enantioselective synthetic protocol for
the formation of [7]helicene by kinetic resolution by means
of asymmetric ring-closing metathesis (ARCM) that exploits
the use of olefin additives.
´
the late 90s, Stary and co-workers reported the first catalytic
and asymmetric approach to helicenes consisting of an imag-
inative [2+2+2] cyclotrimerisation of alkynes that yielded
tetrahydro[6]helicenes with moderate levels of ee (42–
48% ee).[7] Although the racemic tetrahydrohelicenes pre-
pared in this manner could be subsequently oxidised to the
corresponding [6]helicene, elevated temperatures were re-
quired and no mention of whether the enantioenriched tet-
rahydrohelicenes retained their enantiomeric excess was re-
ported. In 2007, Tanaka and co-workers revisited this cyclo-
trimerisation approach and prepared oxygen-containing di-
hydroheterohelicenes and some related helically chiral mol-
ecules by using a cationic RhI/modified BINAP complex.[8b]
Our laboratories have been developing new protocols to
access strained molecules by olefin metathesis. In 2006, our
group published a new synthetic route to various substituted
[5]helicenes as well as [6]- and [7]helicene by using ring-
closing olefin metathesis (Scheme 1).[8] Two separate olefin
metathesis protocols were developed that utilised either
Grubbs 2nd-generation catalyst 5 in CH2Cl2 at 1008C under
microwave irradiation or Blechertꢀs catalyst 6 at 408C in a
sealed tube vessel. Under the optimised conditions employ-
ing microwave irradiation, [6]helicene could be prepared
with excellent conversion (100%) and isolated yield (80%).
[7]Helicene could also be prepared and similar yields were
Enantioenriched carbohelicenes can be obtained by reso-
lution on chiral stationary phases; however, the develop-
ment of a practical asymmetric synthesis of enantioenriched
all-carbon helicenes remains of interest.[5] The first attempt
[a] A. Grandbois, Dr. S. K. Collins
Department of Chemistry, UniversitØ de MontrØal
C.P. 6128 Station Downtown, MontrØal
QuØbec, H3C 3J7 (Canada)
Fax : (+1)514-343-7586
E-mail: shawn.collins@hotmail.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801033.
Chem. Eur. J. 2008, 14, 9323 – 9329
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9323

alkene structure or the use of
halide additives helped to in-
crease enantioselection.[10a,b,11]
Recently, Hoveyda and Giudici
reported a novel method of in-
creasing enantioselection in
the AROM/CM of cyclopro-
penes with catalyst 2 that uses
enoate or ynoate motifs as di-
recting groups.[12]
Results and Discussion
We were concerned that the
elevated temperatures associat-
ed with the previously devel-
oped olefin metathesis proto-
cols could be detrimental to in-
ducing significant levels of
enantioexcess. As such, we in-
Scheme 1. Olefin metathesis as a route to [5]-, [6]- and [7]helicene.
vestigated the rate of ring-clos-
ing metathesis of 7 and 9 at
room temperature by using catalyst 5. We found that 9
would undergo complete ring closure to afford [7]helicene
in approximately 4 h. This is in starkcontrast to the forma-
tion of [5]helicene from 7, in which only traces of helicene
can be observed under identical conditions after two weeks.
While the origin of the increased rate of ring closure of 9
versus 7 are still under study, the fact that the ring-closing
metathesis reaction of 9 could be conducted at room tem-
perature with catalyst 5 implied that catalysts 1a–d would
likely be potential catalysts for the study of a kinetic resolu-
tion to form [7]helicene. Consequently, our initial investiga-
tions into a novel catalytic and enantioselective synthesis of
[7]helicene began with treating the divinyl precursor 9 with
catalyst 1a.
Upon treatment of the divinyl precursor 9 with catalyst
1a, good conversions to [7]helicene were obtained; however,
only a 6% ee was observed [Eq. (1)].
obtained by using either of the optimised synthetic protocols
(81 and 80% isolated yield).
An obvious advantage to using olefin metathesis to form
these structures was the possibility of using a mild transi-
tion-metal complex controlled process to effect an asymmet-
ric synthesis of helicenes. Asymmetric olefin metathesis rep-
resents a novel and potentially powerful method for the for-
mation of enantiomerically enriched helicenes as it con-
structs carbon–carbon bonds under relatively mild reaction
conditions.[9] To date, chiral Ru-based olefin metathesis cata-
lysts 1 have been developed that can afford both enantioen-
riched cyclic or acyclic products through asymmetric ring-
closing desymmetrisation and asymmetric cross metathe-
sis.[10] Both catalysts 1 and 2 have been shown to be effective
for tandem asymmetric ring opening/cross metathesis pro-
cesses (AROM/CM).[11] In cases for which catalysts 1 and 2
were not highly selective for ARCM, modification of the
In an effort to boost the enantioselectivity of the process,
we turned to substrate modification. In ARCM reactions,
the substitution pattern of the olefins in the substrates often
plays a large role in determining the overall enantioselectivi-
ty of the process.[10a,13a] Consequently, we prepared the divin-
yl precursor 10. A significant increase in enantioselectivity
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Chem. Eur. J. 2008, 14, 9323 – 9329

Enantioselective Synthesis of [7]Helicene
FULL PAPER
Table 2. Kinetic resolution to afford [7]helicene by using halide additives.[a]
was observed (6!56–60% ee); however, low conversions
were obtained (11–13%). Analysis of the reaction mixture
revealed that the olefins of starting material 10 had com-
pletely isomerised to the trans configuration. All attempts to
coerce this trans isomer to undergo ring closure, which in-
cluded excessive heating in a microwave reactor, failed.[13]
In an effort to boost enantioselection and avoid problem-
atic isomerisation, we continued to study the effects of mod-
ifying the substrate structure and we prepared a series of
substituted divinyl precursors (Table 1). The propenyl deriv-
Di-vinyl
Additive[b]
ee [%] (conf.)[b]
conv. [%][c]
9
none
NaBr
NaI
none
NaBr
NaI
6 (P)
8 (P)
46
30
48
11–13
<5
<5
10[d]
14 (P)
56–60 (P)
61 (P)
61 (P)
22 (M)
10
Table 1. Kinetic resolution to afford [7]helicene.[a]
16
NaI
[a] Reaction concentration [M]=0.012. [b] Enantiomeric excesses were
determined by chiral HPLC: see the Supporting Information for chroma-
tograms. [c] Determined by the 1H NMR spectrum of the crude reaction
mixture: see the Supporting Information. [d] Reaction conducted in THF.
NR=no reaction.
Di-vinyl[a]
R1
R2[b]
ee [%] (conf.)[b]
conv. [%][c]
9
H
H
H
H
Ph
iPr
H
Me
Et
Ph
Ph
iPr
6 (P)
22 (P)
30 (P)
17 (M)
–
46
15
4
21
NR
NR
NaI resulted in even lower levels of conversion to the de-
sired helicene and only isomerisation was observed. The re-
action of the relay side chain containing substrate 16 with
NaI as an additive also failed to produce significant increas-
es in selectivity and a noticeable drop in conversion was
once again observed.
11
12
13
14
15
–
16
17 (M)
53
We began to suspect that the enantiodetermining step in
the catalytic cycle may be the first metathesis sequence that
leads to the binding of the substrate to the catalyst. Hence,
we believed that the nature of the propagating carbene
would play an influential role, as is the case in asymmetric
cross metathesis (ACM) processes, in which control over un-
wanted dimerisation pathways is essential.[10c] In the kinetic
resolution of 9, a Ru–methylidene is the expected propagat-
ing species. With substrate 10, a Ru–ethylidene would be
the propagating species and would likely be responsible for
the observed isomerisation. We envisioned controlling the
nature of the propagating carbene in our kinetic resolution
to form helicenes through the addition of achiral olefins to
the reaction mixture. Following ring closure, the resulting
carbene would react primarily with the terminal olefin of
the additive instead of the sterically encumbered divinyl
substrate 9. This is in contrast to ACM, in which the carbene
is eventually incorporated into the product.
Potential olefin additives must not engage in a productive
cross-metathesis reaction with the substrate. As none of the
metathesis reactions described in Tables 1 and 2 ever pro-
duced a cross-metathesis product between the substrates,
such as 9, and the residual styrene produced from the preca-
talyst during the first catalytic cycle, styrenes emerged as po-
tential additive candidates. Vinyl cyclohexane was also se-
lected due to its steric similarity to styrene. We also investi-
gated 1-hexene and 4-methylpentene as additives, as they
would afford propagating alkylidenes structurally similar to
the ethylidene that afforded a good ee with catalyst 1a and
substrate 10 [Eq. (1)]. In addition to testing the catalyst 1a,
we also screened several new chiral Ru-based catalysts (3,
[a] Reaction concentration [M]=0.012. [b] Enantiomeric excesses were
determined by chiral HPLC: see the Supporting Information for chroma-
tograms. [c] Determined by the 1H NMR spectrum of the crude reaction
mixture, see the Supporting Information. NR=no reaction.
ative 11, butenyl derivative 12 or styrenyl derivative 13 af-
forded higher ee values (17–30% ee) than had been previ-
ously obtained with 9 (6% ee). Unfortunately, once again,
the level of conversion remained problematic and increasing
the reaction time had no beneficial effect. Then, we evaluat-
ed symmetric divinyl precursors, such as 14 and 15; however,
these substrates were not reactive. We also evaluated the
precursor 16 containing relay ring-closing metathesis side
chains.[14] While the conversions could then be improved,
the stereoselectivity of the process had once again dropped
(17–25% ee) below that obtained with substrate 10 (56–
60% ee).
Thwarted by our efforts to use substrate modification to
improve the selectivities and conversions, we next turned
our attention to the use of halide additives. When 1a is
treated with NaI in THF, an exchange of the chloride li-
gands in 1a for iodides is observed. The use of NaI, in par-
ticular, as an additive has been well documented; in desym-
metrisation reactions significant increases (>50% ee) in
enantioselectivity have been observed.[10a,b] When 9 was
treated with catalyst 1a in CH2Cl2 with either NaBr or NaI
as the additive, only minimal increases in enantioselectivity
were observed (Table 2). In addition, performing the kinetic
resolution of 10 by using 1a in CH2Cl2 in the presence of
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9325

S. K. Collins and A. Grandbois
4a and 4b) developed in our group that have displayed im-
proved reactivity profiles and enantioselectivities in desym-
metrisation reactions.[15]
When 10 equivalents of 1-hexene were added to substrate
9 in the presence of catalyst 1a, a small increase in enantio-
selectivity from 6 to 12% ee was observed (Table 3). Larger
2 h. More exotic olefin additives, such as a vinyl boronate,
were ineffective.
We also tested various styrene derivatives as additives to
probe subtle steric and electronic effects (Scheme 2). As
Table 3. Additive effects on kinetic resolution.[a]
Cat.[a]
Additive
ee [%] (conf.)[b]
conv. [%][c]
1a
none
1-hexene
none
1-hexene
none
1-hexene
none
1-hexene
6 (P)
12 (P)
7 (P)
35 (M)
rac
30 (M)
10 (M)
48 (M)
53 (M)
55 (M)
26 (M)
55 (M)
–
46
30
55
55
48
54
50
40
43[d]
25
45
12
–
Scheme 2. Choice of additive provides access to either stereoisomer of
[7]helicene.
3
4a
4b
such, 4-methoxystyrene caused a significant inhibition of the
reaction as the conversion dropped to 9% and ee decreased
to 20%. However, replacement of the MeO group with an
electron-withdrawing CF3 group restored the high conver-
sions and pushed the ee to 56%. Interestingly, the switch in
the electronic properties caused a switch in the enantiomeric
preference: 4-methoxystyrene afforded the P enantiomer,
whereas 4-trifluoromethylstyrene preferred the M enantio-
mer. The influence of the steric properties of the additives
on the kinetic resolution was also investigated. The use of o-
methylstyrene caused the ee to decrease relative to styrene
(55!26% ee), whereas m-methylstyrene provided similar ee
values and conversions relative to styrene. We were also in-
trigued as to whether a “bidentate” additive could be ap-
plied. Unfortunately, when 9 was treated with catalyst 4b
and allyl methacrylate as an additive, the kinetic resolution
afforded low conversions (<5%).[16] We also investigated
1,2-divinylbenzene as an additive. Grubbs and co-workers
recently reported that X-ray crystal structures obtained for
the reaction of 1,2-divinylbenzene with Grubbs 2nd-genera-
tion catalyst revealed that one of the vinyl groups was
bound in a “side-on” fashion.[17] Given that a similar mode
of binding was proposed by Hoveyda for catalyst 2 with
allyl methacrylate, we investigated 1,2-divinylbenzene as an
additive. Unfortunately, the use of 1,2-divinylbenzene results
in a complete inhibition of the reaction and no RCM is ob-
served, even under forcing conditions.
The olefin additives could play two roles. The first possi-
bility is that the olefin additive acts to enable reversible
binding of the substrate to catalyst (Scheme 3A). In the ab-
sence of simple olefins in solution, once the catalyst has
bound to substrate, the reverse reaction is likely slow. The
reverse reaction would require a cross metathesis with an-
other olefin in solution, either from another molecule of the
starting material 9 or residual styrene formed from the first
catalytic cycle of the precatalyst itself.[18] Therefore, the
olefin additive may act to facilitate this reverse reaction
and, therefore, aid in the enantioselection of the catalyst.[19]
vinylcyclohexane
styrene
2-methylstyrene
3-methylstyrene
1,2-divinylbenzene
p-CF3-styrene
p-methoxysytrene
vinyl boranic acid
pinacolic ester
4-methylpentene
56 (M)
20 (P)
–
56
9
–
–
54
–
44 (M)
[a] Reactions at [M]=0.012. [b] Enantiomeric excesses were determined
by chiral HPLC: see the Supporting Information for chromatograms.
[c] Determined by the 1H NMR spectrum of the crude reaction mixture:
see the Supporting Information. [d] The starting material 5 was obtained
in 51 ee. rac=racemic.
quantities of additive (>25 equiv) resulted in significantly
lower conversions and longer reaction times and lower
quantities (<5 equiv) provided little effect on the ee of the
process. By using catalyst 3 with substrate 9, the ee increased
from 7 to 35% ee when using 1-hexene as an additive. Inter-
estingly, the addition of the olefin additive resulted in the M
isomer being favored over the P isomer. When 1-hexene
was used as an additive in the kinetic resolution with cata-
lyst 4a, a 30% ee was obtained in which the product had
been obtained as a racemic mixture in the absence of addi-
tive. The greatest increase in enantioselectivity came from
using catalyst 4b, in which the ee increased from 10 to 48%
when 1-hexene was added to the reaction mixture. Upon
identifying catalyst 4b as the optimal catalyst, we screened
other additive types. The use of 4-methylpentene gave simi-
lar results as were obtained with 1-hexene. In terms of both
ee and conversion, vinylcyclohexane was observed to pro-
vide modest ee (53%) and good conversion (43%). Excess
styrene as an additive resulted in a 55% ee, but the reaction
was sluggish and only a 25% conversion was obtained after
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Enantioselective Synthesis of [7]Helicene
FULL PAPER
Table 4. Solvent effects on kinetic resolution.[a]
Substrate[a] Additive
Solvent
ee [%]
conv.
[%][c]
(conf.)[b]
9
vinylcyclohexane CH2Cl2
vinylcyclohexane PhH
vinylcyclohexane trifluorotoluene 70 (M)
vinylcyclohexane C6F6
vinylcyclohexane C6F6/CH2Cl2
53 (M)
65 (M)
43
32
15
38
26
<5
80 (M)
60 (M)
33 (M)
none
C6F6
[a] Reactions at [M]=0.012. [b] Enantiomeric excesses were determined
by chiral HPLC: see the Supporting Information for chromatograms.
[c] Determined by the 1H NMR spectrum of the crude reaction mixture,
see the Supporting Information.
lysts,[20] and the large p-surface of 9 could potentially inter-
act with aromatic solvents. By using catalyst 4b and switch-
ing from CH2Cl2 to benzene as the solvent produced a
modest increase in ee (53!65% ee), and a further increase
was observed when using trifluorotoluene (65% ee in
PhH!70% ee in PhCF3). The conversions also begin to de-
crease due to the lesser solubility of 9. The use of hexafluor-
obenzene allowed for the highest ee of [7]helicene achieved
to date (80% ee, 38% conv.), which was surprising since 9
appears to be sparingly soluble in C6F6. Trying to obtain a
homogeneous solution by conducting the reaction in a 1:1
mixture of CH2Cl2 and C6F6 resulted in a decrease in ee and
conversion. Despite the poor solubility, the solvent effect is
apparent even in the absence of olefin additive, as the ee ob-
tained was 33% (compared to 10% in CH2Cl2). These re-
sults suggest that the additive and solvent effects workin
tandem to afford the observed enantioselectivity. While it is
clear that the solvent plays an important role in the prepara-
tion of [7]helicene, it is unclear if this is due to interactions
with the N-aryl group of the catalyst. The N-aryl group of
catalyst 4b is highly substituted and in a sterically crowded
environment, which likely makes p–p interactions with the
solvent difficult. Considering the large p-surface of substrate
9, it is more likely that the solvent is interacting with the
substrate.
Scheme 3. Possible dual role of olefin additives in the kinetic resolution
to form [7]helicene.
The second possible role is to alter the propagating car-
bene species in the catalytic cycle (Scheme 3B). Not only
would this likely increase the stability of the propagating
species and hence conversions, but it is also likely to exert
an influence on the ee of the overall process. This is similar
to what was observed by Hoveyda and Giudici.[4] We believe
this mechanism is likely due to the results obtained with the
electronically different styrene additives. It is obvious that
these olefins play a large role in enantioselection as modifi-
cation of the electronic characteristics of the styrene change
the preference for either the P or M isomer. In the enantio-
selective AROM/CM processes reported by Hoveyda and
Giudici enantioselection is believed to be augmented
through coordination of the ynoate or enoate moiety with
the Ru catalyst resulting in diastereomeric carbenes. In the
AROM/CM process, the ynoate or enoate groups are even-
tually incorporated in the final product. The achiral olefins
presented herein are used solely as inexpensive additives
that are not incorporated into the metathesis products.
Conclusion
We have reported that the combination of simple achiral
olefins can be used as additives and hexafluorobenzene can
be used as a solvent to improve asymmetric olefin metathe-
sis reactions. As a result, hexafluorobenzene has been ap-
plied in a novel protocol for the synthesis of enantioen-
riched [7]helicene. The kinetic resolution reported herein is
noteworthy in that 1) it illustrates that control of the propa-
gating alkylidene can be an effective method for improving
Following the optimisation of the olefin additive, we tried
to fine-tune the enantioselectivity of the kinetic resolution
protocol by examining different solvents (Table 4). We
chose to examine the effects of aromatic solvents based
upon two key factors: It has been reported that aromatic
solvents can interact with the N-aryl groups of the N-hetero-
cyclic carbene ligands in Ru-based olefin metathesis cata-
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S. K. Collins and A. Grandbois
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enantioselection in ARCM processes and can at times be
more effective than the use of halide additives that can
result in lower catalyst reactivity, 2) it represents a rare ex-
ample of an asymmetric and catalytic preparation of [7]hel-
icene, 3) it is the first reported application of asymmetric
olefin metathesis towards helically chiral molecules, and
4) demonstrates the importance of solvent in olefin metathe-
sis reactions. This workalso highlights the effectiveness of
chiral Ru-based olefin metathesis catalysts bearing C1-sym-
metric NHC ligands. The mild reaction conditions suggest
that this method could be used for the preparation of heter-
ohelicenes for both materials and medicinal applications.
Further catalyst development, investigation of the use of
chiral olefins and solvent effects in ARCM,[19] and asymmet-
ric preparation of heterohelicenes are currently underway in
our laboratories.
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ꢀ
Experimental Section
ˇ
´
´
er strategy involving C C-bond formation, see: d) J. Misek, F. Teply,
All experimental procedures and characterisation data for all new com-
pounds can be found in the Supporting Information. A general procedure
for the kinetic resolution to form [7]helicene by using olefin additives is
as follows: 3,3’-Divinyl-4,4’-biphenanthryl (5; 10 mg, 0.025 mmol), and vi-
nylcyclohexane (27 mg, 10 equiv, 0.25 mmol) were added in a glove box
to a flame-dried sealed tube and the mixture was suspended in hexafluor-
obenzene (1 mL). A stocksolution of ruthenium catalyst 4b (1 mL of a
1.0 mgmLꢀ1 solution in hexafluorobenzene, 0.05 equiv, 0.0013 mmol) was
then added, the tube is sealed, and the reaction mixture was stirred at
RT for 2 h. The reaction mixture was then filtered through a silica pad
(CH2Cl2) and the solvent was evaporated under vacuum. Conversions
were measured directly by 1H NMR spectroscopy and enantiomeric ex-
cesses were measured by chiral HPLC (ChiralCel OD (0.46 cm”25 cm):
90% hexanes, 10% iPrOH, 1 mLminꢀ1, 238C, 10 min runtime, tR =5.34
(M) and 6.57 min (P). The [7]helicene and residual 5 can also be purified
ˇ
´
ˇ
ˇ
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We thankthe NSERC (Canada), FQRNT (QuØbec), CFI (Canada),
Boehringer Ingelheim (Canada) Ltd., MerckFrosst Centre for Therapeu-
tic Research and the UniversitØ de MontrØal for generous financial sup-
port.
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9328
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Chem. Eur. J. 2008, 14, 9323 – 9329

Enantioselective Synthesis of [7]Helicene
FULL PAPER
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allyl methacrylate is still faster than metathesis with 5. The slow
metathesis with 5 may be due to the “bidentate nature” of allyl
methacrylate with Ru-catalysts. However, this is purely speculative
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[18] The use of ethylene as an additive completely shut down the reac-
tion.
Received: May 28, 2008
Published online: August 26, 2008
Chem. Eur. J. 2008, 14, 9323 – 9329
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