High-yield synthesis of a chiroporphyrin by hydrogen bond-directed cyclisation

Article abstract of DOI:10.1039/a904134f

A new chiroporphyrin is prepared in 60% yield using complementary intramolecular hydrogen-bonding interactions between N-acylurea substituents to direct the cyclisation of the tetrapyrrolic intermediate; similar hydrogenbond assistance by carboxylic acid

Full text of DOI:10.1039/a904134f

High-yield synthesis of a chiroporphyrin by hydrogen bond-directed cyclisation
a
a
a
b
a
Céline Pérollier, Jacques Pécaut, René Ramasseul, Robert Bau and Jean-Claude Marchon*
a
Laboratoire de Chimie de Coordination, Service de Chimie Inorganique et Biologique, Département de Recherche
Fondamentale sur la Matière Condensée, CEA-Grenoble, 38054 Grenoble, France. E-mail: jcmarchon@cea.fr
Department of Chemistry, University of Southern California, Los Angeles, California 90089-0744, USA
b
Received (in Basel, Switzerland) 24th May 1999, Accepted 29th June 1999
A new chiroporphyrin is prepared in 60% yield using
complementary intramolecular hydrogen-bonding interac-
tions between N-acylurea substituents to direct the cyclisa-
tion of the tetrapyrrolic intermediate; similar hydrogen-
bond assistance by carboxylic acid functions is suggested for
cyclisation of hydroxymethylbilane to uroporphyrinogen I.
tion reaction carried out on the related N-ethyl-N-phenyl amide
of 1 led only to a 12% yield of chiroporphyrin. Isolation of the
9
abundant porphyrinogen intermediate of 3 was attempted, but
this compound was still contaminated with linear oligopyrrole
side-products after silica gel chromatography and single
crystals could not be obtained. Crystals of the nickel(ii)-
substituted derivative of 3 were successfully grown from a
DMSO solution.
Esters and disubstituted amides of (1R, 3S)-(2)-2,2-dimethyl-
3
-formylcyclopropane-1-carboxylic acid 1 [also called (1R,
1,2
cis)-caronaldehyde or biocartol] are valuable building blocks
for the synthesis of porphyrins bearing chiral meso-cyclopropyl
2
groups. These chiroporphyrins are obtained as the D -symmet-
ric a,b,a,b atropisomer exclusively by classical condensation
reaction between the formyl group and pyrrole in modest yield
(
2–20%). We have shown recently that their manganese(iii)
complexes are competent catalysts in the asymmetric epoxida-
3
4
tion and aziridination of aromatic alkenes. We have also
found that the ruthenium(ii) and cobalt(iii) complexes of
tetramethylchiroporphyrin (derived from the methyl ester of 1)
5
display multipoint binding of axial ligands such as alcohols,
6
7
amines and amino alcohols: in addition to the metal–ligand
interaction, the host–guest bonding array involves two con-
vergent ester carbonyl groups which act as hydrogen bond
acceptors on each face and are instrumental in ligand enantiose-
lection. In order to obtain a new type of chiroporphyrin bearing
both hydrogen bond donors and acceptors, we have now
synthesized the N-acylurea 2 by reaction of 1 with DCC, and the
corresponding chiroporphyrin. To our surprise, the amphoteric
nature of 2 led to an unprecedented high yield of chiroporphyrin
3
(60%), presumably by directing cyclisation of the porphyr-
inogen intermediate via intramolecular hydrogen bonding.
Compound 2 was previously obtained as a side-product
Scheme 1
(
18%) in esterification reactions of 1 catalyzed by DCC–
DMAP, and it has been characterised as an N-acylurea on the
1
13
1
basis of its H and C NMR spectra. Without competing
alcohol or amine reactant, reaction between 1, 1.2 equiv. of
DCC and 1.2 equiv. of Et
purification by silica gel chromatography (CH
3
N in DMF, followed by workup and
2
Cl –EtOAc 9+1)
2
affords 2 in 50% yield (Scheme 1). The structure assignment
was confirmed by X-ray crystallography† (Fig. 1). Notable
features of the stereochemistry of 2 are the planarity of the
disubstituted amide and urea moieties, and the near orthogon-
ality of the two corresponding planes. The urea is flanked by
two sterically bulky cyclohexyl substituents, yet its C11–O12
group is able to interact with the N13–H group of a
neighbouring molecule in the crystal, resulting in a chain of
strong head-to-tail N–H···ONC–N–H···ONC hydrogen bonds
(
1
N13A···O12, 2.889 Å; H13···O12, 1.937 Å; N13A–H···O12,
70.6°) along the c axis. There is no hydrogen bond to the amide
carbonyl group C8–O9.
After the classical condensation reaction between 2 and
pyrrole, subsequent aromatisation of the porphyrinogen inter-
8
mediate with DDQ and neutralisation with Et
3
N, the purple
color and nearly clean porphyrin UV–visible spectrum of the
reaction mixture came as a surprise. In fact, the D -symmetric
free base porphyrin 3 was obtained in an unprecedented yield of
0% after purification by silica gel chromatography with
CH Cl –MeOH mixtures. For comparison, a similar condensa-
2
Fig. 1 Molecular structure of 2 showing the planar amide (C1–C8–O9–
N10–C11–C20) and urea (N10–C11–O12–N13–C14) moieties, and the
near orthogonality of the two corresponding planes (dihedral angle around
N10–C11: 76.4°).
6
2
2
Chem. Commun., 1999, 1597–1598
1597

directing the spontaneous macrocyclisation of the hydroxy-
1
2
methylbilane tetrapyrrole to uroporphyrinogen I [Fig. 3(b)].
Finally, the high yield synthesis of 3 from a readily accessible
N-acylurea derivative of 1 makes this macrocycle a convenient
precursor of other chiroporphyrins, as exemplified by the
3
preparation of the tetra-N-cyclohexylamide 4 by POCl -induced
cleavage of the ureido groups,13 which will be described
elsewhere.
Notes and references
†
1
Crystal data for 2: C20
0.861(2), b = 20.595(3), c = 8.948(2) Å, U = 2001.5(6) Å , T = 163 K,
32 2 3 r
H N O , M = 348.5, orthorhombic, a =
3
2
1
1 1 1
space group P2 2 2 , Z = 4, m(Cu-Ka) = 0.615 mm , 1574 reflections
measured, 1425 unique, of which 1273 with F > 4.0 s(F) were used in all
calculations, R = 0.0608 [I > 2s(I)], wR = 0.1553, GOF = 1.19. For
Ni-3: C96 Ni•5C SO•3H O, M = 2085.53, tetragonal, a = b =
5.091(3), c = 63.54(2) Å, U = 14472(6) Å , T = 193 K, space group
1
2
H
132
N
12
O
8
H
2 6
2
Fig. 2 ORTEP view (30% probability) of the molecular structure of Ni-3
showing the conformations of the N-acylurea substituents with inward
oriented amide carbonyl (O1, O11) and urea N–H (N12, N32) groups, and
the absence of intramolecular hydrogen bonds.
3
1
21
3 1
P4 2 2, Z = 4, m(Mo-Ka) = 0.257 mm , 46236 reflections measured,
1
0825 unique (Rint = 0.3052), of which 2864 with F > 4.0 s(F) were used
in all calculations, R = 0.1192 [I > 2s(I)], wR = 0.2614, GOF = 1.004,
1
2
Flack index 0.04(5). The relatively poor quality of the data set collected for
Ni-3, as judged from the large Rint value, probably contributes to the large
final R factors. CCDC 182/1314. See http://www.rsc.org/suppdata/cc/
The X-ray structure of Ni-3† (Fig. 2) shows a highly ruffled
a,b,a,b porphyrin with inward oriented amide carbonyl and
urea N–H groups, and indicates that the distance between two
opposite a or b substituents is too large to allow any
intramolecular hydrogen bonding interaction. However, exam-
ination of a molecular model of the porphyrinogen intermediate
suggests that conformations in which the opposite meso groups
on each face are close enough to allow double hydrogen
1
999/1597/ for crystallographic data in .cif format.
1
M. Veyrat, L. Fantin, S. Desmoulins, A. Petitjean, M. Mazzanti, R.
Ramasseul, J.-C. Marchon and R. Bau, Bull. Soc. Chim. Fr., 1997, 134,
7
03.
2 C. Pérollier, J. Pécaut, R. Ramasseul and J.-C. Marchon, Bull. Soc.
Chim. Fr., 1997, 134, 517.
bonding between the urea N–H donor and amide CNO acceptor
3 M. Veyrat, O. Maury, F. Faverjon, D. E. Over, R. Ramasseul, J.-C.
Marchon, I. Turowska-Tyrk and W. R. Scheidt, Angew. Chem., Int. Ed.
Engl., 1994, 33, 220; C. Pérollier, J. Pécaut, R. Ramasseul and J.-C.
Marchon, Inorg. Chem., 1999, in the press.
groups10 are accessible. We conclude that the self-com-
plementary nature of the N-acylurea substituent of 2 leads to a
preorganised, quadruply hydrogen-bonded tetrapyrrole inter-
mediate in which the close proximity of the two reactive end
groups directs intramolecular cyclisation11 and leads to a high
yield of porphyrinogen [Fig. 3(a)].
4
J.-P. Simonato, J. Pécaut, W. R. Scheidt and J.-C. Marchon, Chem.
Commun., 1999, 989.
5
M. Mazzanti, M. Veyrat, R. Ramasseul, J.-C. Marchon, I. Turowska-
Tyrk, M. Shang and W. R. Scheidt, Inorg. Chem., 1996, 35, 3733.
The carboxylic acid function is another classical example of
self-complementary hydrogen-bonding groups, and it is tempt-
ing to speculate that the carboxylic acid substituents on the b-
pyrrolic positions of porphobilinogen may serve the function of
6 D. Toronto, F. Sarrazin, J. Pécaut, J.-C. Marchon, M. Shang and W. R.
Scheidt, Inorg. Chem., 1998, 37, 526.
7 J.-P. Simonato, J. Pécaut and J.-C. Marchon, J. Am. Chem. Soc., 1998,
1
20, 7363.
8
9
J. S. Lindsey and R. W. Wagner, J. Org. Chem., 1989, 54, 828.
C. Pérollier, Doctoral Thesis, Université Joseph Fourier, Grenoble,
1
998.
1
0 For structurally characterised examples of strong dimerisation via
complementary hydrogen bonding between urea N–H donors and amide
CNO acceptors, see: F. H. Beijer, R. P. Sijbesma, H. Kooijman, A. L.
Spek and E. W. Meijer, J. Am. Chem. Soc., 1998, 120, 6761.
1 For reviews of hydrogen-bonded self-assembling complexes, see: D. S.
Lawrence, T. Jiang and M. Levitt, Chem. Rev., 1995, 95, 2229; M. M.
Conn and J. Rebek, Jr., Chem. Rev., 1997, 97, 1467. For a previous
example of macrocyclisation directed by hydrogen bonding, see: F. J.
Carver, C. A. Hunter and R. J. Shannon, J. Chem. Soc., Chem.
Commun., 1994, 1277.
1
Fig. 3 (a) The conformation of the tetrapyrrole intermediate, preorganised
by hydrogen bonding between self-complementary N-acylurea substituents,
which leads to a high yield of porphyrinogen and to a 60% yield of 3. For
the sake of clarity, only the H-bonding pattern on the top face is shown, and
each of the two H-bonded meso substituents on the bottom face is
abbreviated as R. (b) Proposed hydrogen-bond assistance by carboxylic acid
functions in the cyclisation of hydroxymethylbilane to uroporphyrinogen I.
For the sake of clarity, the double hydrogen bond between each of the
opposite acetic (A) and propionic (P) substituent pairs on the lower face has
been omitted.
12 For a recent review of heme biosynthesis, see: A. R. Battersby and F. J.
Leeper, Top. Curr. Chem., 1998, 195, 143. For structurally characterised
uroporphyrinogen derivatives, see: G. Sawitzki and H. G. von
Schnering, Angew. Chem., Int. Ed. Engl., 1976, 15, 552; C. Lehmann, B.
Schweizer, C. Leumann and A. Eschenmoser, Helv. Chim. Acta, 1997,
80, 1421.
13 S. Avramovici-Grisaru and S. Sarel, Nouv. J. Chim., 1982, 6, 455.
Communication 9/04134F
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Chem. Commun., 1999, 1597–1598