Synthesis of chiral bridled porphyrins in their two enantiomeric forms

Article abstract of DOI:10.1002/ejoc.200900347

We describe the synthesis of a new family of chiral bridled porphyrins. They were obtained by reaction between pyrrole and a chiral 2-formylcyclohexanol derivative. Thanks to an enzymatic kinetic resolution method, these compounds were obtained in both en

Full text of DOI:10.1002/ejoc.200900347

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900347
Synthesis of Chiral Bridled Porphyrins in their Two Enantiomeric Forms
Alexandra Fateeva,[a] Jacques Pécaut,[a] Pierre-Alain Bayle,[a] Pascale Maldivi,[a] and
Lionel Dubois*[a]
Keywords: Porphyrinoids / Enzymes / Kinetic resolution / Circular dichroism / NMR spectroscopy / Nitrogen heterocycles
We describe the synthesis of a new family of chiral bridled
porphyrins. They were obtained by reaction between pyrrole
and a chiral 2-formylcyclohexanol derivative. Thanks to an
enzymatic kinetic resolution method, these compounds were
obtained in both enantiomeric forms. This resolution method
allows easy synthesis of chiral precursors in high yield and
on large scale. These new porphyrins exhibited an (αα)(αα)
conformation and the less usual (αα)(ββ) one, depending of
the bridle length.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
meso cyclohexyl substituents, obtained by kinetic resolution
of a racemic cyclohexanol derivative with Amano PS lipase.
This procedure is exemplified by the synthesis of the two
enantiomers of the bridled chiroporphyrin (R,S) or (S,R)-
H2BChPn illustrated in Scheme 1. We also describe the un-
usual conformations exhibited by these new bridled porphy-
rins, which could lead to practical applications in the field
of molecular bistability.[6]
Introduction
Chiral metalloporphyrins have been widely used for sev-
eral years as catalysts for enantioselective epoxidation and
aziridination reactions, mainly as single enantiomers.[1,2] It
would be of high practical interest to have access to both
catalyst enantiomorphs in order to select the favoured en-
antiomer product, but surprisingly asymmetric syntheses of
metalloporpyrins in their two enantiomeric forms are
scarce.[3,4] Previous work in our laboratory on chiral por-
phyrins H2BCPn synthesised from biocartol (Scheme 1) suf-
fer from the same difficulties to synthesise both enantio-
mers of the catalyst.[5] We decided to synthesise a new chiro-
porphyrin family close to the biocartol one. In this new
family, the rigidity of the chiral cyclopropyl substituent is
partly held by the use of chiral cyclohexyl substituents. So,
we present here a general procedure that enables the synthe-
sis of the two enantiomers of porphyrins bearing chiral
Results and Discussion
As reported earlier[2] for the bridled chiroporphyrins de-
rived from biocartol, the synthesis of H2BChPn relies on
the design of a new chiral bifunctional aldehyde in which a
methylene chain is introduced to provide the link between
two adjacent meso cyclohexyl substituents of the strapped
porphyrin. Consequently, the key point of the synthesis was
to obtain chiral aldehyde–alcohol 3 in its two enantiomeric
forms (Scheme 2).
Protected 1-cyclohexene-1-carboxaldehyde was synthe-
sised according to a published procedure,[7] and the C–C
double bond was hydroxylated by a hydroboration–oxi-
dation sequence. The cis orientation of the hydroboration
reaction led to a racemic mixture of (R,R)-3 and (S,S)-3,
and the next step was the resolution of this racemate by
enzymatic transesterification. Following a classical kinetic
enzymatic resolution method,[8] Amano PS lipase in neat
vinyl acetate conveniently afforded enantioenriched alcohol
(S,S)-3 and acetate (R,R)-4. These two compounds were
easily separated by column chromatography on basic alu-
mina. The absolute configuration of the enantioenriched
alcohol was established by a published NMR procedure[9]
and is in agreement with the enantioselectivity of Amano
PS lipase established by Kazlauskas.[8] The NMR method
enabled quantification of the ee value, which was found to
be 80% for (S,S)-3. Next, (R,R)-3 was obtained with a
Scheme 1. H2BCPn (8ՅnՅ16) and (S,R) H2BChPn (S,R refer to
1S,2R; n = 5–8, 10).
[a] Laboratory of Inorganic and Biological Chemistry, UMR_E 3,
CEA/UJF, CEA, INAC, SCIB, RICC,
17 rue des Martyrs, 38054 Grenoble, France
Fax: +1-4-38785090
E-mail: lionel.dubois@cea.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900347.
Eur. J. Org. Chem. 2009, 3845–3848
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3845

A. Fateeva, J. Pécaut, P.-A. Bayle, P. Maldivi, L. Dubois
SHORT COMMUNICATION
Scheme 2. Synthesis of (S,R)- and (R,S)-H2BChPn (n = 5–8, 10).
Reagents and conditions: (a) ethylene glycol/MgSO4/tartaric acid/
C6H6, reflux, 6 h, 88%; (b) BH3·DMS/THF room temp., 16 h,
NaBO3, 32%; (c) amino lipase PS/neat vinyl acetate, room temp.,
10 d, 84% of (S,S)-3; (d) amino lipase PS/THF/water (pH 7.5
buffer) mixture, room temp., 10 d, 87% of (R,R)-3; (e) pyridine/
corresponding diacid chloride (n = 5–8, 10), room temp., 16 h, 50–
80% yield; (f) I2/acetone, room temp., 16 h then saturated solution
of Na2S2O3; (g) pyrrole/BF3·Et2O/CHCl3 (1%EtOH), room temp.,
reaction time 48–140 h, then DDQ, 3–15% yield.
Figure 1. Drawing of chiral bridled porphyrins and symmetry ele-
ment associated to different conformations.
the more thermodynamically stable atropisomer of the
92%ee by hydrolysis of (R,R)-enantioenriched 4, which was H2BCChP6 porphyrin. This also suggests that the porphy-
also catalysed by Amano PS lipase in a THF/pH 7 buffer rinogen intermediate is probably stabilised in the (αα)(ββ)
mixture. To create the bridle, two molecules of enantioen- conformation. After DDQ oxidation the corresponding
riched 3 were treated with one molecule of an α,ω-diacid porphyrin slowly rearranges to the more stable (αα)(αα)
chloride (chain length n = 5–8 and 10 methylene groups) in conformation.
pyridine to afford diester 5n. Iodine-catalysed removal of
For porphyrins with longer bridles (n = 8, 10), the NMR
the 1,3-dioxolanne protection afforded dialdehyde 6n. The spectra become more intricate as these compounds exist as
crude dialdehyde was then allowed to react under Lindsey mixtures of atropisomers, which cannot be isolated by chro-
conditions with pyrrole (2 equiv.) and BF3·Et2O (0.3 equiv.) matographic methods. Nevertheless, the prevalent and
as catalyst. After DDQ oxidation, the new bridled chiropor- therefore more stable atropisomer becomes (αα)(ββ) as the
phyrins (R,S)- or (S,R)-H2BChPn were obtained in a yield chain length increases beyond n = 6. Thus for H2BCChP10
varying from 3% for the shortest bridles (n = 5) to 15% for the (αα)(ββ) atropisomer is the predominant species in the
the longer ones (n = 8 or 10).
mixture (Supporting Information, Figure 1). This is corrob-
NMR spectroscopy suggested that the conformation of orated by the crystal structure of (S,R)-H2BCChP10 (Fig-
these free base porphyrins is dependent on the bridle length ure 2), which exhibits the (αα)(ββ) conformation.
(Supporting Information, Figure 1). Indeed, the porphyrin
The structure shows a rather distorted porphyrin core in
with the shortest straps, H2BChP5, exhibits a 1H NMR the ruffle mode, probably resulting from steric hindrance
spectrum with four doublets for the β-pyrrolic proton reso- of the meso substituents. As an attempt from the synthesis
nances corresponding to a C2 symmetry with the C2 axis conditions, the ester strap and the porphyrin are linked in
perpendicular to the porphyrin core, that is, a (αα)(αα) con- an anti fashion on the cyclohexyl ring. One bridle is above
formation (Figure 1).[10]
and the other one is below the porphyrin mean plane, corre-
When one more methylene group is added to the strap, sponding to a (αα)(ββ) conformation. Short distances be-
a different behaviour is observed. In the immediate tween some bridle hydrogen atoms and the porphyrin mean
H2BCChP6 product, two different conformers can be iso- plane (around 2.5 Å) suggest some kind of C–H–π interac-
lated by chromatography in roughly the same amounts. tion. A similar disposition is expected to be adopted in
Their 1H NMR spectra (Supporting Information, Figure 2) solution, as the chemical shifts of some methylene protons
are very different: the less polar one exhibits two singlets of the strap are largely upfield shifted (ca. –4 ppm) in the
and two doublets for its β-pyrrolic proton signals, indicat- 1H NMR spectrum. This shift is due to the anisotropic cone
ing a C2 symmetry with the C2 axis parallel to the porphy- of the porphyrin.[12] This bridle layout may explain the con-
rin core and a (αα)(ββ) conformation. In contrast, the more formational changes observed on going from the shortest
polar fraction exhibits a (αα)(αα) conformation as deduced bridle (n = 5), where the bridles do not interact sterically in
from the four doublets observed in the β-pyrrolic region. a (αα)(αα) conformation, to the longest (n = 10), where a
Surprisingly, if the (αα)(ββ) atropisomer is left in solution strong steric constraint is created if the bridles are on the
for several hours, it slowly converts quantitatively into the same side of the porphyrin, which forces a (αα)(ββ) confor-
(αα)(αα) form. Thus, the (αα)(αα) form is considered to be mation to be adopted.
3846
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3845–3848

Synthesis of Chiral Bridled Porphyrins in Two Enantiomeric Forms
(S,R)-H2BCChP6 fraction] exhibit a negative Cotton effect,
whereas a positive effect is observed for the (αα)(ββ) con-
former [less polar (S,R)-H2BCChP6 fraction]. In this last
case, when the atropisomer composition changes from
(αα)(ββ) to (αα)(αα), we also notice a signal inversion on
the CD spectrum (see the Supporting Information).
The CD spectra of porphyrins that are isolated as a mix-
ture of atropoisomers present a more complex feature.
However, even in that case (i.e., for the H2BCChPn where n
= 8, 10), an opposite signal is still observed for the two
enantiomers, confirming the achievement and the repeat-
ability of the chiral synthesis.
Conclusions
In summary, we have achieved the synthesis of a new
family of chiral porphyrins. Thanks to an enzymatic kinetic
resolution method, these compounds were obtained in both
their enantiomeric forms. This resolution method allows the
easy synthesis of chiral precursors in high yield and on a
large scale. These new porphyrins exhibit an unusual
(αα)(ββ) conformation, in sharp contrast to biocartol-de-
rived bridled porphyrins, which are isolated in the (αβ)(αβ)
or (αα)(αα) conformation. An influence of the bridle length
on the atropisomer distribution was observed. The influ-
ence of metal complexation on the conformations of these
free-base porphyrins is under investigation and will be re-
ported in due course.
Figure 2. Top: X-ray structure (ORTEP view 30% probability) of
(S,R)-H2BChP10 (top and side view of one of the two independent
molecules of the asymmetric unit). Bottom: NSD analysis[11] of the
porphyrin core distortion (for the two independent molecules of
the asymmetric unit).
The achievement of a chiral synthesis of two porphyrin
enantiomers was confirmed by circular dichroism (CD)
measurements. Indeed, the two enantiomeric porphyrins
present opposite CD spectra as expected (Figure 3). For a
given enantiomer of a bridled porphyrin [(S,R) for exam-
ple], a link between the porphyrin conformation and the
sign of the Cotton effect on the Soret region of the CD
spectra can be outlined. For instance, porphyrins of
(αα)(αα) conformation [(S,R)-H2BCChP5 or the more polar
CCDC-703905 [for (S,R)-H2BChP10] for contains the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterisation data (1H and
13C NMR spectra, UV/Vis spectra) for 2–6n and the corresponding
porphyrins; evolution of the 1H NMR and CD spectra of (αα)(ββ)
H2BChP6 with time.
Acknowledgments
We would like to thank Jean-Claude Marchon for helpful dis-
cussions and for critical reading of this manuscript.
[1] a) Y. Naruta in Metalloporphyrins in Catalytic Oxidations (Ed.:
R. A. Sheldon), Marcel Dekker, New York, 1994, pp. 241–259;
b) J. P. Collman, X. Zhang, V. J. Lee, E. S. Uffelman, J. I. Brau-
man, Science 1993, 261, 1401–1411; c) L. A. Campbell, T. J.
Kodadek, J. Mol. Catal. A 1996, 113, 293–310; d) K. S. Suslick,
S. V. Deusen-Jeffries, Comprehensive Supramolecular Chemistry
(Eds.: J. L. Atwood, J. E. D. Davies, D. D. MacNicol, F. Vögtle,
J. M. Lehn), Elsevier, Oxford, 1996, vol. 5, pp. 141–170; e) E.
Rose, M. Quelquejeu, A. Kossanyi, B. Boitrel, Coord. Chem.
Rev. 1998, 178, 1407–1431; f) J. P. Collman, Z. Wang, Chem-
tracts 1999, 12, 229–263 ; g) E. Rose, B. Andrioletti, S. Zrig,
M. Quelquejeu-Ethève, Chem. Soc. Rev. 2005, 34, 573–583.
[2] J. C. Marchon, R. Ramasseul, The Porphyrin Handbook (Eds.:
K. M. Kadish, K. M. Smith, R. Guilard), Academic Press, San
Diego, CA, 2003, vol. 11, p. 75–132.
Figure 3. Circular dichroism spectrum in the Soret band of (A)
(R,S)-H2BChP5 (dashed line) and (S,R)-H2BChP5 (solid line) and
(B) (S,R)-H2BChP10 (solid line) and (R,S)-H2BChP10 (dashed line).
Eur. J. Org. Chem. 2009, 3845–3848
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3847

A. Fateeva, J. Pécaut, P.-A. Bayle, P. Maldivi, L. Dubois
SHORT COMMUNICATION
[3] a) R. L. Halterman, S. T. Jan, H. L. Nimmons, D. J. Standlee,
M. A. Khan, Tetrahedron 1997, 53, 11257–11276; b) R. L. Hal-
terman, S. T. Jan, J. Org. Chem. 1991, 56, 5253–5254.
[4] a) P. R. Allen, J. H. Reek, A. C. Try, M. J. Crossley, Tetrahe-
dron: Asymmetry 1997, 8, 1161–1164; b) Y. Chen, K. B. Fields,
X. P. Zhang, J. Am. Chem. Soc. 2004, 126, 14718–14719.
[5] S. Gazeau, J. Pécaut, R. Haddad, J. A. Shelnutt, J. C. Marchon,
Eur. J. Inorg. Chem. 2002, 2956–2960.
[8] R. J. Kazlauskas, A. N. E. Weissfloch, A. T. Rappaport, L. A.
Cuccia, J. Org. Chem. 1991, 56, 2656–2665.
[9] R. T. Williamson, A. C. B. Sosa, A. Mitra, P. J. Seaton, D. B.
Weibel, F. C. Schroeder, J. Meinwald, F. E. Koehn, Org. Lett.
2003, 5, 1745–1748.
[10] S. Gazeau, J. Pecaut, J. C. Marchon, Chem. Commun. 2001,
1644–1645.
[11] W. Jentzen, X. Z. Song, J. A. Shelnutt, J. Phys. Chem. B 1997,
[6] G. Maheut, A. Castaings, J. Pecaut, L. M. Daku, G. Pescitelli,
L. D. Bari, J. C. Marchon, J. Am. Chem. Soc. 2006, 128, 6347–
6356.
101, 1684–1699.
[12] B. Boitrel, A. Lecas, Z. Renko, E. Rose, New J. Chem. 1989,
13, 73–99.
[7] T. J. Lu, J. F. F. Yang, L. J. Sheu, J. Org. Chem. 1995, 60, 2931–
Received: March 31, 2009
Published Online: July 1, 2009
2934.
3848
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3845–3848