Synthesis of [7]Helicene Enantiomers and Exploratory Study of Their Conversion into Helically Chiral Iodoarenes and Iodanes

Article abstract of DOI:10.1002/chem.201805761

The facile and convenient preparation of both enantiomers of a [7]helicene scaffold from inexpensive (l)-(+)-tartaric acid and 4-methylstyrene is described. These helical structures were transformed into bis-iodinated ether derivatives in order to explore their potential as precursors of novel chiral organoiodane reagents or as iodoarene pre-catalysts. Promising results were obtained in hydroxylative phenol dearomatization/[4+2] cycloaddition cascade and dearomative spirolactonization reactions with encouraging enantiomeric excesses.

Full text of DOI:10.1002/chem.201805761

A Journal of
Accepted Article
Title: Synthesis of [7]Helicene Enantiomers and Exploratory Study of
their Conversion into Helically Chiral Iodoarenes and Iodanes
Authors: Kevin Antien, Laurent Pouységu, Denis Deffieux, Stéphane
Massip, Philippe A. Peixoto, and Stephane Quideau
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To be cited as: Chem. Eur. J. 10.1002/chem.201805761
Link to VoR: http://dx.doi.org/10.1002/chem.201805761
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Synthesis of [7]Helicene Enantiomers and Exploratory Study of
their Conversion into Helically Chiral Iodoarenes and Iodanes
Kevin Antien,[a] Laurent Pouységu,[a] Denis Deffieux,[a] Stéphane Massip,[b] Philippe A. Peixoto,*[a] and
Stéphane Quideau*[a]
Abstract: The facile and convenient preparation of both
enantiomers of a [7]helicene scaffold from inexpensive (L)-(+)-
tartaric acid and 4-methylstyrene is described. These helical
structures were transformed into bis-iodinated ether derivatives in
order to explore their potential as precursors of novel chiral
organoiodane reagents or as iodoarene pre-catalysts. Promising
results were obtained in hydroxylative phenol dearomatization/[4+2]
cycloaddition cascade and dearomative spirolactonization reactions
with encouraging enantiomeric excesses.
asymmetry in hypervalent iodine-mediated transformations.[64]
Our long-standing interest in this field thus prompted us to
examine the stereodiscriminating potential of enantiopure
iodinated helicenes.[65–69] In this context, the work of Marinetti
and her colleagues particularly attracted our attention, as they
reported a fully diastereoselective synthesis of the pentane-2,4-
diol-tethered [5]helicene (S,S,P)-4a (Scheme 1a).[47] Such a
bridged [5]helicene is configurationally locked and showed no
racemization even after prolonged heating at 80 °C.[47] We
assume that the usual thermal instability of regular [5]helicenes,
which can slowly racemize even at room temperature,[70–72] was
the reason why the authors did not attempt to cleave off the
chiral tether. However, since the racemization barriers of higher
helicenes require temperatures well above 100°C,[73–75] we
thought of employing a strategy adapted from that of Marinetti
and her co-workers[47] to build helicenes that could fulfill our
needs and wishes.
Introduction
Helicenes are polycyclic molecules composed of ortho-fused
aromatic rings that confer an inherently chiral helical shape to
their structures.[1–4] Owing to their unique structural, electronic
and chiroptical properties, these compounds are the focus of
considerable attention in various fields of research,[3–5] notably
for their potential utility in asymmetric catalysis,[6–10] molecular
recognition,[11–15] supramolecular chemistry,[16–18] molecular
machines design,[19–23] liquid crystal technology,[24–27] organic
(opto)electronics,[28–32] as well as new materials.[33–36] Several of
these applications necessitate access to optically pure
helicenes.[2–4] Although a few asymmetric synthesis approaches
have relied on the use of chiral reagents or catalysts,[10,37–45]
most of the others were based on substrate control through the
installation of chiral moieties onto molecular scaffolds prior to
their annulation into helicenic systems.[46–59] However, fully
optically pure materials, which are of paramount importance for
any application, are rarely obtained,[45–50] and diastereoenriched
mixtures generated with the help of chiral auxiliaries still need to
be separated by conventional chromatography.[51–53] Thus, the
separation of helicene racemates by chiral chromatography
remains today the most commonly used access to separated
pairs of helicene enantiomers.[15,34,60–63]
Herein, we wish to report a facile, inexpensive and scalable
synthesis of a [7]helicene scaffold. Both enantiomers of such
helices were quickly accessed through a strategy relying on the
double photocyclization of a macrocyclic tartaric acid-tethered
bis-stilbene (S,S)-3b, which was easily prepared via a double
Wittig reaction between the bis-aldehyde (S,S)-1b and the
phenanthrene-based bis-phosphonium salt 2b (Scheme 1b).
a) Marinetti and co-workers
O
4
6
O
O
O
O
2
EtOLi
EtOH, 50 °C
S
S
O
S
S
O
O
1
7
I2, hν
PhMe
BrPh3P
14
13
9
11
(S,S)-1a
(S,S)-3a
35%
(S,S,P)-4a
63%
100% dr
2a
O
BrPh3P
b) This work
O
Despite the wide range of applications of helicenes, their
helical chirality has yet never been evaluated as inductor of
O
3
O
O
4
O
S
O
6
O
O
S
2
S
O
O16
O
O
7
aq. K2CO3
CH2Cl2, rt
15
18
11
I2, hν
PhMe
O
S
[a]
[b]
K. Antien, Prof. L. Pouységu, Dr. D. Deffieux, Dr. P. A. Peixoto, Prof.
S. Quideau
Univ. Bordeaux, ISM (CNRS-UMR 5255)
351 cours de la Libération, 33405 Talence Cedex (France)
E-mail: philippe.peixoto@u-bordeaux.fr
stephane.quideau@u-bordeaux.fr
PPh3Br
O
13
9
O
(S,S)-3b
92%
(S,S)-4b
74%
dr ?
(S,S)-1b
2b
Dr. S. Massip
PPh3Br
Univ. Bordeaux, Institut Européen de Chimie et Biologie (CNRS-
UMS 3033)
2 rue Robert Escarpit, 33607 Pessac Cedex (France)
Scheme 1. a) Marinetti’s synthesis of the [5]helicenophane (S,S,P)-4a. b) Our
synthesis of the [7]helicenophane (S,S)-4b.
Supporting information for this article can be found under:
https://doi.XXX
This choice of substrates dictated that the chiral bridge had
to be installed on positions 3 and 16 of the helical scaffold rather
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10.1002/chem.201805761
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than on positions 2 and 17 (Scheme 1), which were viewed by
molecular modeling (AM1-RHF) to be hard to connect. On the
basis of Marinetti’s precedent, our initial assumption was that the
double photocyclization of (S,S)-3b into 4b, performed under
classical conditions using molecular iodine and propylene oxide,
could proceed with absolute diastereocontrol (Scheme 1).[47]
Should this not be the case, we would then expect an easy
chromatographic separation of the resulting helicene
diastereomers (S,S,P)- and (S,S,M)-4b, ready for further
transformations toward iodinated derivatives and first examples
of right-handed and/or left-handed helically chiral iodanes.
With both the bis-aldehyde (S,S)-1b and the phenanthrene-
based bis-phosphonium salt 2b in hands, we turned our
attention to their coupling into the macrocyclic bis-stilbene (S,S)-
3b via a double Wittig reaction (Table 1) with the hope of
reaching higher yields than that obtained by Marinetti and her
colleagues in their analogous double Wittig macroannulation
(Scheme 1a). In a preliminary study, we determined that the use
of organic and inorganic bases such as KOt-Bu, n-BuLi, LiHMDS
(Lithium hexamethyldisilazane), DBU (diazabicyclo[5.4.0]undec-
7-ene), TBD (triazabicyclo[4.4.0]dec-5-ene), t-BuTMG (tert-
butyltetramethylguanidine) and NaH were inadequate, as only
degradation of the starting materials was observed. When
sodium methoxide in methanol was employed,
a
very
Results and Discussion
satisfactory yield of 47% was obtained (entry 1). The resulting
macrocycle (S,S)-3b was thus isolated as a 1:1:1:1 mixture of all
four torsional diastereomers (Z/Z, Z/E, E/Z, E/E) with the Z/E
and E/Z diastereomers being indissociable. Scaling-up the
reaction at room temperature unfortunately led to a drastic yield
decrease (entry 2).
Our synthesis of the [7]helicene precursor (S,S)-3b thus
started from readily available (L)-(+)-tartaric acid (5), which was
transformed through a multigram-scale 4-step sequence into
the dimethylketal bis-tosylate (S,S)-6 in an overall yield of 52%
(Scheme 2a, and see the Supporting Information). Displacement
of the tosylate groups by two molecules of 3-
hydroxybenzaldehyde (7) furnished the bis-aldehyde (S,S)-1b in
a quasi quantitative yield. The preparation of the phenanthrene-
based bis-phosphonium salt 2b began with an olefin metathesis
reaction using 4-methylstyrene (8) to forge the stilbene 9
(Scheme 2b). Its exploratory conversion (i.e., 230 mg of 9 in
1.10 L of toluene) into the phenanthrene 10 was quantitative
under classical photocyclization conditions (i.e., using I2 and
propylene oxide),[76] but this process became troublesome at
higher scales. We then had to rely on the use of the λ3-iodane
(diacetoxyiodo)benzene (DIB) reagent, which was recently
reported to promote oxidative photocyclization of stilbenes in
satisfactory yields.[77] In our case, the phenanthrene 10 could
thus be obtained in 84% yield using a concentration 10-fold
higher than that used under classical conditions. Higher
concentrations still gave excellent conversions, but removal of
the iodobenzene by-product became problematic. The benzylic
positions of 10 were then easily brominated and both bromine
atoms were finally substituted by PPh3 to furnish the desired
bis(benzyltriphenyl-phosphonium) salt 2b in 97% yield (Scheme
2b).
Table 1. Double-Wittig macroannulation of 1b and 2b
O
O
PPh3Br
O
O
O
O
O
O
conditions
rt
+
O
O
(S,S)-1b
2b
PPh3Br
(S,S)-3b
Yield[a]
Scale (1b)
25 mg
Solvent
MeOH
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
Base (equiv.)
t (h)
0.75
0.75
48
1
2
3
4
5
MeONa (10)[b]
47%
15%
32%
31%
92%
150 mg
25 mg
MeONa (10)[b]
aq. K2CO3[c] (10)
aq. K2CO3[c] (30)[e]
aq. K2CO3[c] (30)
250 mg
2.65 g
96
120
[1b] = 0.01 M. [a] Isolated yield. [b] The bis-phosphonium salt 2b was added to
a solution of bis-aldehyde 1b and MeONa in MeOH. [c] Aqueous solution of
K2CO3 (8.1 M). [e] Portionwise addition of 10 equiv. at t = 0, t = 24 h, and
t = 48 h.
a)
OH
1) TsOH, MeOH
O
2) BF3.OEt2, acetone
3) NaBH4, MeOH
4) TsCl, pyridine
7
O
O
OTs
OTs
CO2H
CO2H
O
HO
HO
O
O
O
O
We then decided to explore the use of K2CO3 as base and
implemented a technical change by adding a concentrated
aqueous solution of K2CO3 (10 equiv.) to a premixed solution of
bis-aldehyde 1b and bis-phosphonium salt 2b in CH2Cl2.
Although the reaction progressed at a relatively slow pace, the
first results were encouraging on a small scale, since (S,S)-3b
was obtained in 32% yield after 48 h (entry 3). When scaling up
the reaction 10-fold, we observed that additional equivalents of
K2CO3 (i.e., 3 x 10 equiv.) were required over the longer course
of the reaction to drive the transformation and reach a similar
chemical yield (entry 4). Further upscaling of the reaction by
another factor of 10 (i.e., > 2.5 g of 1b), using 30 equiv. of
K2CO3 added in one portion, pleasingly afforded 3b in an
K2CO3
DMF, 95 °C
5
(S,S)-6
(S,S)-1b
99%
O
52%
b)
Br
PPh3Br
Grubbs II
CH2Cl2
PPh3
MeCN
NBS
CCl4
DIB
PhMe, hν
8
Br
PPh3Br
2b 97%
10 84%
11 71%
9 94%
Scheme 2. a) Preparation of the bis-aldehyde (S,S)-1b. b) Preparation of the
bis-phosphonium salt 2b.
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10.1002/chem.201805761
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excellent yield of 92% after 120
temperature (entry 5).
h
of reaction at room
below 300 nm, which could be assigned to π-π* transitions.
Absorption bands between 300-400 nm can potentially be
assigned to either π-π* or n-π* transitions. The large difference
in the absorption spectra of (S,S,M)-4b and (S,S,P)-4b at 320
nm is probably due to some conformational differences affecting
orbital overlaps, and hence electronic transitions. On can also
observe that the presence of chiral centers on the molecular
bridge seems to have little to no effect on the chiroptical
properties of these helicenoid molecules.
The photocyclization reaction that followed involved the use
of a double-walled photochemical reactor equipped with a built-
in pyrex® immersion well, and combined with a Sylvania HSW
400W high-pressure mercury lamp (see the Supporting
Information). The bis-stilbene mixture (S,S)-3b (622 mg in 1.15 L
of toluene, i.e., 1 mM) was successfully photocyclized to give
rise to both (S,S,P)- and (S,S,M)-4b as a 1:1 diastereomeric
mixture in a moderate combined yield of 33% after 6 h of
irradiation using 4 equivalents of I2. When only 2 equivalents of
I2 were used, the reaction was complete after only 2 h, and the
yield surprisingly increased to 48%. It was found that the mode
of addition of I2 needed to be adjusted to reach optimal reaction
conditions. Starting the reaction with only half an equivalent of I2
and adding the remaining 1.5 equivalents dropwise over the
course of the irradiation led to an even substantially better yield
of 74% (Scheme 3). The reproducibility of this process was
verified by repeating the reaction 4 times on the same scale to
furnish the helicenes (S,S,P)- and (S,S,M)-4b in a global yield of
78% (1,93 g). Of course, we were startled by the total lack of
asymmetry induction during this electrocyclization step. The fact
that the reaction had to be conducted in toluene under reflux
was incriminated, although a sample of pure (S,S,P)-4b did not
either epimerize or even degrade upon refluxing in toluene for
24 h. Notwithstanding this lack of diastereoselectivity and the
reasons thereof, we were nevertheless quite satisfied with the
possibility of easily separating the two helicene diastereomers
by standard column chromatography in similar quantities for the
pursuit of this work.
a)
0
b)
Séries1
(S,S,P)-4b
0
0
0
0
0
0
'phenolM-+CPL'!
(S,S,M)-4b
λ (nm)
250 300 350 400 450 500
Séries1
λ (nm)
(S,S,P)-4b
'phenolM-+CPL'!
(S,S,M)-4b
250
300
350
400
450
500
Figure 1. a) CD spectra and b) UV absorption spectra of the helicene
diastereomers (S,S,P)-4b and (S,S,M)-4b in CHCl3; [4b] ~ 10-5 M.
At this stage, we were thus ready to release the two phenol
functionalities of these helicenoid systems by removing the
chiral bridge. It was initially conceived that this acetonide-
bearing bis(alkyl aryl ether) tether should collapse upon a simple
treatment with a strong Lewis acid in the presence of a (latent)
nucleophile. The acetonide moiety was indeed quantitatively
cleaved off in a few minutes at –78 °C in the presence of BBr3,
but the alkyl aryl ether linkages resisted these conditions. We
surmised that this surprisingly high stability of these linkages
could be due to the in situ formation of cycloboronate bridges on
the released 1,2-diol unit, which could sterically block the
nucleophilic attack of BBr3-derived bromide anions at the two
methylene centers. Experimentally, it was found crucial to work
up the reaction mixture with some methanolic aqueous HCl in
order to facilitate product isolation, perhaps owing to the
hydrolytic cleavage of those boronates (Scheme 4). In any event,
under these conditions, the diol (S,S,P)-12 was cleanly obtained
from (S,S,P)-4b in a quasi quantitative yield.
O
O
O
(100 equiv.)
O
I2 (0.5 + 1.5 equiv.)
O
hν, PhMe (1 mM), reflux, 1.5 h
74-78%
O
O
O
O
O
O
2
O
O
17
(S,S)-3b
(S,S,P)-4b 1 : 1 (S,S,M)-4b
Scheme 3. Bis-stilbene photocyclization.
The macrocyclic helicenes 4b display 1H NMR resonance
signals that are characteristic of the shielded protons on
positions 2 and 17 of the helical backbone (Scheme 3, and see
The solution for the rupture of the alkyl aryl ether linkages
came from the use of aqueous KOH in DMSO according to a
protocol adapted from the work of Chae and his co-workers.[79]
the
Supporting
Information).
Moreover,
they
exhibit
diagnostically high specific rotation values ([ꢀ]ꢀꢀꢁ = +3270 and –
2970 for the right-handed and left-handed diastereomers), as
well as strong circular dichroisms (Figure 1). The CD spectra are
comparable in terms of absolute values and global curve
topology, with expected notable differences in the low
wavelengths region. The diastereomer (S,S,P)-4b displays a
positive Cotton effect that is characteristic of (P)-(+)-
carbohelicenic frameworks.[78] The diastereomer (S,S,M)-4b
displays a negative Cotton effect, which is coherent with a left-
handed helix. The UV spectra show strong absorption bands
Thus, treating
a solution of (S,S,P)-12 in DMSO with a
concentrated aqueous solution of KOH in large excess at 100 °C
gave rise to the formation of the open helicene (P)-13 in 94%
yield (Scheme 4). It must be highlighted that the use of
anhydrous oxygen-free DMSO was crucial for ensuring the
desired outcome of the reaction. Interestingly, running the
reaction in
a 20:1 DMSO/H2O solvent mixture completely
inhibited the formation of (P)-13 and instead led to the
generation of the 1,3-dioxolane derivative (S,S,P)-14 in 78%
yield. Although DMSO has already been described to act as a
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10.1002/chem.201805761
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methylene bridge donor upon either thermal or chemical
activation,[80–83] the role of the presence of H2O in DMSO in the
change of reaction pathway we observed herein remains
obscure. In any event, (M)-13 could also be obtained from
(S,S,M)-4b in an overall yield of 98% by following the same
optimized procedure as for (P)-13 (Scheme 4).
N-iodosuccinimide in the presence of a catalytic amount of
silver(I) triflimide to furnish (M)-15 in 34% yield (Scheme 5).
I
4
OH
OH
OH
15
OH
NIS, AgNTf2
CH2Cl2, rt
I
O
O
O
HO
HO
O
1) BBr3, CH2Cl2, _78 °C to rt
2) aq. HCl, MeOH, CH2Cl2, rt
O
O
(M)-13
(M)-15
34%
Scheme 5. Bis-iodination of the helicene (M)-13.
ou (S,S,P)-12
or (S,S,M)-12
ou (S,S,P)-4b
or (S,S,M)-4b
99%
A one-pot bridge cleavage-etherification sequence was then
implemented by simply quenching in situ the bisphenolates
generated during the alkaline treatment of (S,S,P)- and (S,S,M)-
12 with iodomethane or 2-iodopropane (Scheme 6). The
dimethoxylated and diisopropoxylated [7]helicenes (M)-16a and
(P)-16b were conveniently prepared, albeit in modest yields of
51% and 47%. These [7]helicene alkyl aryl ethers were
subsequently subjected to the same iodination conditions and
their corresponding halogenated derivatives (M)-17a and (P)-
17b were obtained in very good yields of 95% and 85%
(Scheme 6).
O
O
HO
HO
O
O
(a) aq. KOH
(a) DMSO, 100 °C
(b) aq. KOH
(b) DMSO/H2O, 100 °C
(S,S,P)-14: (b) 78%
(P)-13: (a) 94%; (b) 0%
or (M)-13: (a) 99%
Scheme 4. Cleavage of the acetonide-bearing bis(alkyl aryl ether) bridge.
Both of these [7]helicenes display perfectly opposite CD
spectra and fully identical UV spectra (Figure 2). The signs of
their respective cotton effects are the same as those of their
precursors, confirming that no racemization occurred in the
course of the bridge cleavage sequence. Thus, both helicene
enantiomers (P)-13 and (M)-13 were obtained from bis-aldehyde
1b [52% yield over 4 steps from (L)-(+)-tartaric acid (5)] and
phenanthrene-based bis-phosphonium salt 2b [54% yield over 4
steps from 4-methylstyrene (8)] in 4 steps with 33% and 35%
overall yields, respectively.
O
OMe
i-PrO
i-PrO
OH
OH
O
OMe
a
b
(S,S,M)-12
(M)-16a 51%
(P)-16b 47%
or (S,S,P)-12
I
I
i-PrO
OMe
a)
0
b)
1
i-PrO
OMe
1
1
0
0
0
0
0
0
0
0
0
0
0
0
c
c
I
I
Séries1
(P)-13
'phenolM
-+CPL'!
(M)-13
(M)-17a 95%
(P)-17b 85%
λ (nm)
Scheme 6. One-pot bridge cleavage-etherification sequence and bis-
iodination of the resulting [7]helicenes. a) aq. KOH, DMSO, 100 °C, 1 h, then
MeI, 20 °C, 25 min. b) aq. KOH, DMSO, 100 °C, 1 h, then i-PrI, 20 °C, 45 min.
c) N-iodosuccinimide (NIS), AgNTf2, rt, 1 h.
250
350
450
(P)-13
(M)-13
λ (nm)
Tiny crystals of (M)-(–)-16a and (M)-(–)-17a were obtained
and subjected to X-ray crystallography analysis (Figure 3a,c).
Carbon-carbon bonds along the inner helical rim display in each
case a notable increase in length [1.42 - 1.45 Å (16a); 1.41 -
1.46 Å (17a)] with respect to those in benzene (1.39 Å) (see the
Supporting Information for details). Bonds along the outer rim
are legitimately shortened [1.34 - 1.36 Å (16a); 1.34 - 1.39 Å
(17a)]. Torsion angles along the inner rim relate in both cases to
those of other heptahelicenes [–14° - –29° (16a); –20° - –25°
(17a)],[84] although helicene 16a exhibits a much larger outer
250
350
450
Figure 2. a) CD spectra and b) UV absorption spectra of the helicene
enantiomers (P)-13 and (M)-13 in CHCl3; [13] ~ 10-5 M.
Next, we focused our attention to the installation of iodine
atoms onto these phenolic [7]helicenes, or their simple ether
derivatives, in the aim of accessing for the first time helically
chiral iodanes. The bisphenol (M)-13 was regioselectively
iodinated on positions 4 and 15 of the helicene by treatment with
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10.1002/chem.201805761
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helical pitch (5.23 Å) than that of 17a (3.85 Å). Of particular note
is the remarkable columnar supramolecular arrangement
adopted by both (M)-(–)-16a and (M)-(–)-17a in their crystalline
state (Figure 3b,d). Moreover, these X-ray data allow us to
confirm that all of our levorotatory helicenes display left-handed
(M)-helicity, and hence that all of our dextrorotatory helicenes
display right-handed (P)-helicity.
conversion of carvacrol (18) into biscarvacrol (19) clearly
indicated that the bis-iodinated helicene (M)-17a could be in part
transformed into an iodosyl (ArIO) or an iodyl (ArIO2) species,
which was capable of transferring an oxygen atom onto a 2-
methylphenol substrate with a moderate but real level of
enantiocontrol (see Scheme 7). However, the low yield of the
reaction, the use of the iodane reagent in stoichiometric
amounts and the difficulties of producing it in pure form were
arguments against the continuation of this work.
I
OMe
OH
i-Pr
O
OMe
I
1) DMDO (8 equiv.), acetone, rt, 24 h
2) OH
, TFA (5 equiv.), CH2Cl2,
_50 to _40 °C,1 h
O
HO
i-Pr
9
(_)-19 18%
10
er 18:82
18
(M)-17a
Scheme 7. DMDO oxidation of (M)-17a and (HPD)/[4+2] cyclodimerization
cascade reaction of carvacrol (18).
We decided to redirect our efforts towards one of the iodane-
mediated benchmark reactions that would only require catalytic
amounts
of
our
helicenes,
i.e.,
the
dearomative
spirolactonization of naphthols.[87–92] The propanoic acid-tethered
1-naphthol 20 was treated with 15 mol% of (M)-17a as pre-
catalyst in the presence of m-CPBA as terminal oxidant in
CH2Cl2 at 20 °C. The expected spirolactone 21 was thus
obtained in 32% yield, but with a negligible enantiocontrol (Table
2, entry 1). The use of (P)-17b, appended with bulkier
isopropoxy groups, improved neither the yield of the
spirolactonization reaction, nor its enantioselectivity (entry 2).
Figure 3. a) ORTEP drawing of the crystal structure of (M)-(–)-16a. b)
Columnar supramolecular arrangement of (M)-16a in the solid state. c)
ORTEP drawing of the crystal structure of (M)-(–)-17a. b) Columnar
supramolecular arrangement of (M)-17a in the solid state.
With three bis-iodinated [7]helicenes in hands [i.e., (M)-15,
(M)-17a and (P)-17b], we started to explore their utilisation as
precursors of λ3- or λ5-iodanes. The bis-iodinated helicene (M)-
17a was subjected to classical oxygenation conditions in
attempts to generate iodosyl- or iodyl-type iodanes as oxygen-
atom transfer reagents (see the Supporting Information).
Regrettably, the degradation of (M)-17a was observed under
most of these conditions. However, the use of an excess of
freshly prepared dimethyldioxirane (DMDO) in acetone[66] gave
rise to an insoluble beige powder, which was directly used to
mediate the hydroxylative phenol dearomatization (HPD)/[4+2]
cyclodimerization cascade reaction of the natural 2-
methylphenol carvacrol (18). Pleasingly, the expected ortho-
quinol-derived cyclodimer bis-carvacrol (19)[66,85,86] was
generated with an enantiomeric excess (ee) of 64%, but in only
18% yield (Scheme 7). The helicene (M)-17a was recovered in
20% yield, alongside with a mixture of compounds that were
tentatively identified by mass spectrometry to be helicenic
quinones. It thus appeared that (M)-17a is prone to oxygenation
on sites other that its iodine atoms, notably on positions 9 and
10 of the helicene framework (see Scheme 7 and the Supporting
Information). This unfortunate sensitivity of (M)-17a toward
oxygenation is corroborated by the electrochemical studies of
Storch and his colleagues, who recently reported that
[7]carbohelicenes are more sensitive to oxidation than their
smaller [5] and [6]helicene counterparts.[34] Nevertheless, the
Table 2. [7]Helicenic iodoarene/iodane-catalyzed naphthol spirolactonization.
I
RO
RO
I
O
CO2H
17 (15 mol%)
OH
O
O
m-CPBA (1.2 equiv.)
*
CH2Cl2 (0.02M)
17a: R = Me
17b: R = i-Pr
17c: R =
20
21
R
R
CO2Me
CONHMes
17d: R =
17
T (°C)
t (h)
2.5
3
Yield[a]
er (R:S)[b]
51:49
51:49
43:57
54:46
51:49
76:24
78:22
1
2
3
4
5
6
7
(M)-17a
(P)-17b
(M)-17c
(P)-17c
(M)-17d
(P)-17d
(P)-17d
20
20
20
20
20
20
–40
32%
28%
55%
58%
58%
58%
90%
3
3.5
5
5
48
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Acknowledgements
[a] Isolated yield. [b] Determined by chiral HPLC analysis.
At this stage, the total lack of enantiocontrol led us to
contemplate further elaboration of our bis-iodinated helicenes by
installing additional motifs in order to extent the helical scaffold.
We thus opted for chiral lactate/lactamide units, which have
amply demonstrated their high efficiency in spirolactonization
reactions[87–90] and can be mounted onto our bisphenol 13 (see
the Supporting Information for details on the synthesis of these
Financial support from the CNRS and the Ministère de la
Recherche, including doctoral assistantship for K.A., is
a
gratefully acknowledged.
Conflict of interest
The authors declare no conflict of interest.
lactate/lactamide derivatives). We indeed saw
a
net
improvement when the reaction was run using the bis-methyl
lactate (M)-17c, as the spirolactone 21 was isolated in 55% yield
with 14% ee (entry 3). Of particular note is that the pre-catalyst
(M)-17c was entirely recovered afterwards (2.0 mg), which is
indicative of its clean conversion into an iodanyl species during
the catalytic process, and hence of its stability and resistance
toward overoxygenation. Inverting the helicity of the pre-catalyst
by using (P)-17c only and slightly impacted the enantiomeric
excess, which was down to 8% (entry 4). Since lactamide
derivatives were reported to be systematically far superior to
their simple ester counterparts in similar catalytic processes,[87–
90] we were eager to test pre-catalysts (M)- and (P)-17d. Since
the (M)-helix of the bis-lactate 17c appeared to be a slightly
better asymmetry inductor, the mesitylamide (M)-17d was the
first to be used, but disappointingly, no enantiocontrol was
observed (entry 5). Surprisingly, it is its diastereomer (P)-17d
that pleasingly gave us the best result with the formation of 21 in
58% yield with 52% ee (entry 6). Decreasing the temperature to
–40 °C drastically affected downwards the reaction kinetics, but
the spirolactone 21 was obtained in a much higher yield of 90%
with a comparable 56% ee (entry 7). Even though the level of
enantiocontrol was not as high as we could have expected by
using these lactamide units, this significant gain in
enantioselectivity (i.e., from ca 0% to 56% ee, entries 5-7) using
the same type of pre-catalyst but of opposite helicity seems to
strongly indicate that a real synergistic effect between both the
helical and central chiralities of our pre-iodane catalysts is at
play here.
Keywords: helicenes • asymmetric synthesis • photocyclization • iodanes •
dearomatization
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Both enantiomers of [7]carbohelicenes
were conveniently prepared from
inexpensive starting materials. Bis-
iodinated ether derivatives of such
helical systems were examined, for
the first time, as precursors of novel
chiral iodane reagents and catalysts.
Promising results were obtained in
asymmetric oxygenative
Kevin Antien, Laurent Pouységu, Denis
Deffieux, Stéphane Massip, Philippe A.
Peixoto,* and Stéphane Quideau*
Page No. – Page No.
Synthesis of [7]Helicene Enantiomers
and Exploratory Study of their
Conversion into Helically Chiral
Iodoarenes and Iodanes
dearomatization reactions.
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