[3,3]Paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids

Article abstract of DOI:10.1039/c3cc41496e

Cyclic phosphoric acids displaying planar chiral paracyclophane structures, which include a 1,1′-ferrocenediyl unit, have been designed as a new class of chiral organocatalysts. Their synthesis, optical resolution, structural characterization and prelimin

Full text of DOI:10.1039/c3cc41496e

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[3,3]Paracyclophanes as planar chiral scaffolds for the
synthesis of new phosphoric acids†
Cite this: Chem. Commun., 2013,
49, 6084
´ ´
´
Jeremy Stemper, Kevin Isaac, Veronique Duret, Pascal Retailleau, Arnaud Voituriez,
Received 27th February 2013,
Accepted 8th May 2013
Jean-François Betzer* and Angela Marinetti*
DOI: 10.1039/c3cc41496e
www.rsc.org/chemcomm
Cyclic phosphoric acids displaying planar chiral paracyclophane struc-
tures, which include a 1,10-ferrocenediyl unit, have been designed as a
new class of chiral organocatalysts. Their synthesis, optical resolution,
structural characterization and preliminary catalytic tests are reported.
Optically active BINOLs have been demonstrated to be privi-
leged chiral scaffolds for the development of chiral phosphorus
auxiliaries including Brønsted acids1 and chiral anions,2 as well
as of phosphoramidite,3 phosphonite4 and phosphite5 ligands
for organo- and/or organometallic processes. The use of BINOLs
has been complemented recently by the development of alter-
native chiral diols including VAPOL,6 H8-BINOL,7 SPINOL,8 TAD-
DOL9 and others10 for the same applications. All these diols are
C2-symmetrical species displaying either axial or central chirality,
while diols with planar chirality have been barely investigated so
far for analogous purposes.11 We intend to disclose here the
design of an alternative, structurally distinct diol framework
allowing the synthesis of the first phosphoric acids based on
C2-symmetric planar chiral paracyclophane scaffolds.12
The aim of this study is to investigate the availability of
[3,3]paracyclophanes in which one of the chains tethering the
aromatic rings is a three atom O–P–O sequence, as sketched in
Fig. 1 (ꢀI).13 Planar chirality would be generated by adding pseudo-
meta14 substituents, R, on the aryl rings which constitute the
paracyclophane scaffold. The first challenge of this work was to
identify a suitable tethering chain, Z, that would minimize ring
strain while ensuring configurational stability of the planar
chiral paracyclophane structure.15 As the tethering chains, we
have considered at first the three-atom chains CH2–N(Ts)–CH2,
1,8-naphthalenediyl and CH2–S–CH2, which are currently used
in the synthesis of [3.3]- or [2.3]-paracyclophanes.16 None of
these linkers allowed the desired phosphorus macrocycles to be
Fig. 1 (a) Phosphorus catalysts and ligands embedding chiral diol units and (b)
the targeted paracyclophane derivatives ꢀI.
isolated from the corresponding bis-phenols. Later on, based
on theoretical evaluation of ring strain in paracyclophanes of
this class,17 we envisioned bridging of the aromatic rings of ꢀI
by a 1,10-ferrocenediyl unit, a slightly bigger and more flexible
three atom scaffold.18 This design proved appropriate, since the
desired phosphoric acid 5a could be accessed easily by the
reaction sequence in Scheme 1.
Diiodoferrocene 1 was subjected to a Suzuki coupling with
the 1,10-biphenyl-2-ol derived boronate 2a. Optimized conditions
for the coupling reaction involve PdCl2(SPhos)2 as the catalyst
(SPhos = 2-dicyclohexylphosphino-20,60-dimethoxybiphenyl) and
Ba(OH)2ꢁ8H2O as the base. After deprotection of the hydroxyl
functions, the ferrocenic bisphenol 3a was isolated in 52% yield
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche
de Gif, 1 av. de la Terrasse, 91198 Gif-sur-Yvette, France.
E-mail: angela.marinetti@icsn.cnrs-gif.fr, jean-françois.betzer@icsn.cnrs-gif.fr
† Electronic supplementary information (ESI) available: Experimental procedures
and NMR spectra for the new compounds. X-ray data for (5a)2Ca. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc41496e
Scheme 1 Reagents and conditions: (i) PdCl2(SPhos)2 (5 mol%), Ba(OH)2ꢁ8H2O
(4 equiv.), dioxane, 100 1C, 24 h; (ii) MeOH, PTSA (cat), rt, 2 h; (iii) (iPr2N)2PO-
(CH2)2CN, 1H-tetrazole (4 equiv.), CH2Cl2, rt, 4 h; (iv) tBuOOH (3 equiv.), CH2Cl2,
0 1C to rt, 30 min, then HCl 6M; (v) DBU (2 equiv.), CH2Cl2, rt, 30 min.
c
6084 Chem. Commun., 2013, 49, 6084--6086
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over two steps. For the conversion of diol 3a into the corre-
sponding phosphoric acid 5a, the most efficient procedure is a
three step sequence based on the use of (Pri2N)2PO(CH2)2CN as
the phosphinating agent,19 oxidation of the phosphite 4a into
the corresponding phosphate and removal of the cyanoethyl
substituent under basic conditions (DBU).
The macrocyclization reaction converting diol 3a into phos-
phite 4a is a crucial step, as far as stereochemical control in favor
of the dl-isomer is required. This step occurs actually with high
diastereoselectivity, dl-4a being the only well-defined product
observed in the mixture (37% isolated yield). The main side-
products of the macrocyclization are oligomeric species derived
from intermolecular reactions of the bifunctional reactants.
The molecular structure of the final acid 5a has been con-
firmed by X-ray diffraction studies on its calcium salt (5a)2ꢁCa.20
The ORTEP diagram is given as ESI (CCDC 916122).† In the solid
state this salt combines two phosphate units and four methanol
molecules surrounding the Ca2+ atom. The views of the molecular
structure of (5a)2ꢁCa in Fig. 2a show that the cyclopentadienyl
rings and the aryl units have eclipsed conformations, which force
the phosphorus center to lie out of the C2-axis of the paracyclo-
phane scaffold. The molecule therefore lacks C2-symmetry and
displays two non-equivalent oxygen atoms. These solid state struc-
tural features strongly differentiate the paracyclophane based acid
5a from the known chiral phosphoric acids displayed in Fig. 1.
Scheme 2 Reagents and conditions: (i) 2b (3 equiv.), PdCl2(dppf) (5 mol%),
NaOH (4 equiv.), DME/H2O 4 : 1, 85 1C, 18 h, 80% yield; (ii) nBuLi, THF, ꢀ78 1C to
rt, 4 h; 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3 equiv.), rt, 15 h,
89% yield (6); (iii) 1-bromo-3,5-diphenylbenzene (2.5 equiv.), Pd(PPh3)4
(10 mol%), Ba(OH)2ꢁ8H2O (4 equiv.), 1,4-dioxane/H2O 5 : 1, 100 1C, 18 h, 86%;
(iv) PTSA, NaI, THF/H2O 8 : 2, 60 1C, 18 h, quantitative yield (3b); (v) (iPr2N)2PO
(CH2)2CN, 1H-tetrazole (4 equiv.), CH2Cl2, rt,
3 h, 42% yield; (vi) tBuOOH
(3 equiv.), CH2Cl2, 0 1C to rt, 30 min; DBU (2 equiv.), CH2Cl2, rt, 30 min, then
HCl 6N, 84% yield (5b).
aromatic groups are introduced at a later step of the synthetic
sequence. The method is typified in Scheme 2 for the synthesis
of the terphenyl-substituted acid 5b.
The key intermediate is the bis-pinacolborate functionalized
ferrocene 6 which is obtained from diiodoferrocene by Suzuki
arylation and subsequent metalation/boronation. This core
platform will allow introducing various aryl substituents by
Suzuki type reactions, shortly before the macrocyclization step.
The Suzuki reaction has been applied here to the synthesis of
the terphenyl substituted diol 3b (86% yield) which has been
converted then into the corresponding phosphoric acid dl-5b by
following the same procedure as for 5a.
The enantiomeric resolution of the new phosphoric acids
dl-5a,b has been undertaken on a semi-preparative scale by
chiral HPLC. Resolution of 5a has been made very efficiently on
a CHIRALPAKs ID column 60% THF–40% n-heptane–0.3%
Fig. 2 The paracyclophane moiety of the (5a)2ꢁCa salt from X-ray data (a); a and
b angles used to define the deformation of the aryl ring (b).
X-ray data also show an almost parallel arrangement of the TEA–0.5% TFA, 4.7 mL minꢀ1. Retention time is 6.4 min for
cyclopentadiene rings and a moderate curvature degree of the (+)-5a and 14.3 min for (ꢀ)-5a. Acid 5b has been obtained in
aryl units. The a and b angles which define the out-of-plane enantiomerically pure form under analogous conditions (CHIR-
deformation of the aryl rings (Fig. 2b)21 measure 7.5 and 7.8 ALPAKs ID column with a 36% THF–64% n-heptane–0.3%
degrees respectively (average values for a and b angles involving TEA–0.5% TFA mixture (4.7 mL minꢀ1)): retention time is
the C14 and C26 carbons). These values rank between those of 6.4 min for (+)-5b and 12.5 min for (ꢀ)-5b. The acids display
carbon tethered [2.2]- and [3.3]-paracyclophanes,22 suggesting a very high optical rotation values, with [a]D2c = +931 (c = 1, CHCl3)
non-negligible ring strain in the paracyclophane unit.
for (+)-5a and [a]D2c = +775 (c = 1, CH2Cl2) for (+)-5b.
The successful synthesis of 5a (Scheme 1) validates our design
To test the potential application of 5a,b as Brønsted acid
of ferrocene based, chiral phosphoric acids with paracyclophane organocatalysts, we have investigated a model reaction, the
type structures. In designing these acids we have targeted asymmetric transfer hydrogenation of 2-phenylquinoline by the
specifically paracyclophanes with aromatic substituents next to Hantzsch dihydropyridines 7 (Scheme 3).23 In the reduction with
the phosphorus function, since the presence and tuning of these 7a (R = Et), both 5a and 5b displayed good catalytic activity,
aryl groups are expected to play a key role in enantioselective giving total conversion after 2 h at r.t. As anticipated, the nature
catalytic reactions.
of the aromatic substituent in 5 modulates the enantioselectivity
In order to modulate easily these aromatic substituents, we to a large extent, the bulkier and more extended m-terphenyl
have envisioned an alternative synthetic approach by which the group of 5b allowing a more efficient stereocontrol (60% ee),
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Scheme 3 Asymmetric transfer hydrogenation of 2-phenylquinoline.
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with respect to the phenyl substituent in 5a (27% ee). Gratifyingly,
the enantioselectivity level could be improved then to 85% ee
using the 4-methoxybenzyl ester 7b as the reducing agent and 5b
as the catalyst. Thus, these preliminary results clearly demonstrate
the potential of these new paracyclophane-based phosphoric
acids in Brønsted acid organocatalysis.24
11 D. Enders, M. Ludwig and G. Raabe, Chirality, 2012, 24, 215–222.
12 For reviews on chiral paracyclophane derivatives and uses in asym-
metric catalysis, see: (a) S. E. Gibson and J. D. Knight, Org. Biomol.
Chem., 2003, 1, 1256–1269; (b) G. J. Rowlands, Org. Biomol. Chem.,
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13 Achiral paracyclophanes displaying two O–P–O tethering chains
have been described by Nifant’ev: (a) E. E. Nifant’ev, E. N. Rasadkina
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In summary, we have found a suitable access to the first
series of cyclic phosphoric acids displaying C2-symmetric planar
chiral paracyclophane scaffolds including phosphorus. The
presence of ferrocene as a constitutive element of the paracyclo-
phane core is a key structural feature ensuring satisfying
chemical and configurational stability of these compounds. We
have demonstrated the efficiency of the new acids as catalysts in
model organocatalytic H-transfer reductions. The highly versatile
synthetic approach should allow modulation and optimization
of the catalytic behavior of these acids, on a case by case basis.
Besides the potential use of the new phosphoric acids as
organocatalysts, this work also opens new perspectives for the
synthesis of unique ligands based on the same paracyclophane
scaffolds, namely chiral phosphoramidites, phosphites and
others, which will be available by analogous synthetic strategies. 17 Unpublished results.
18 For previous examples of paracyclophanes including ferrocene as a
This work was supported by the Paris-Sud University (Ph.D. grant
to J.S.), the I.C.S.N., the Agence Nationale de la Recherche (ANR
Blanc SIMI7 2011, ‘‘Chiracid’’) and the COST ORCA action CM0905.
tethering unit, see: (a) I. Shimizu, Y. Kamei, T. Tezuka, T. Izumi and
A. Kasahara, Bull. Chem. Soc. Jpn., 1983, 56, 192–198; (b) A. Kasahara,
T. Izumi, I. Shimizu, T. Oikawa, H. Umezawa, M. Murakami and
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19 W. Bannwarth and A. Trzeciak, Helv. Chim. Acta, 1987, 70, 175–186.
20 The calcium salt of 5a has been isolated after column chromato-
graphy of the phosphoric acid on silica gel.
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of Binol-derived phosphoric acids. Given that the structural features
of 5 differ significantly from those of Binol derivatives, the effects of
the substituents on the enantioselectivity levels do not follow the
same trends in the two series. Thus, for instance, in the reduction of
2-phenylquinoline with the Hantzsch ester 7a (Scheme 3), the
phenyl-substituted catalyst 5a performs better than the corresponding
phenyl-substituted Binol-derived phosphoric acid (ee = 27% and 5%
respectively). In the Binol series the highest enantioselectivity has been
obtained with the 9-phenanthryl substituted acid (97% ee, see ref. 23a)
while the ferrocenic acid 5 with 9-phenanthryl substituents gives a
20% ee (unpublished results).
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6086 Chem. Commun., 2013, 49, 6084--6086
This journal is The Royal Society of Chemistry 2013