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Biomimetic Synthesis of an Octavinylogous Porphyrin with an Aromatic [34]Annulene System.

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C
I
+ CH3
CHZR
Me3C
\@/
171 B. Giese, Angew. Chem. 95 (1983) 711; Angew. Chem. I n f . Ed. Engl. 22
(1983) 753.
181 a) M e ( 3 - 4 ) ; ; -20 kJ/mol 1111; AAH?(Meo-Et0)=28 kJ/mol [8b];
b) J. J. Russel, J. H. Seetula, D. Gutman, J . Am. Chem. Soc. I10 (1988)
3092.
191 0.01 mol/L solutions of the alkene 5 in cyclohexane were heated at 350450°C and 200 bar for 20 min as described in [3]. The conversions were
maximally 4 mol-%.
[lo] As models for examining the stability of the alkenes 7 and 8, alkenes
were chosen in which the CH2C6HIIgroup is replaced by the CHI
group. The thermochemical data of these alkenes are tabulated in Ref.
[ 111 (e.g. MG&,=28 kJ/mol for 2,3,3-trimethyl-l-buteneand 2,3-dimethyl-2-pentene).
[I I ] R. A. Alberty, C. A. Gehrig, J. Phys. Chem. Ref. Data 14 (1985) 803.
[12] J. M. Tedder, Angew. Chem. 94 (1982) 433; Angew. Chem. Int. Ed. Engl.
21 (1982) 401.
1131 In the selected systems polar effects play only a minor role. Thus, the
rate of addition of methyl radicals to alkenes is influenced only slightly
by the polar effects of methyl substituents [12].
1141 A. G. Davies, B. Muggleton, B. P. Roberts, M.-W. Tse, J. N. Winter, J.
Organomef. Chem. 178 (1976) 289.
1151 P. J. Baker, J. N. Winter in S. Patai (Ed.): The Chemistry ojrhe MetalCarbon-Bond, Vol. 2.Wiley, Chichester 1985, p. 190.
CH2Me
Biomimetic Synthesis of an Octavinylogous Porphyrin
with an Aromatic I34lAnnulene System**
C
1
CH~R
By Georg Knubel and Burchard Franck*
+
Reaction coordinate
Fig. I . Reaction coordinate of the b-cleavage of radical 6a
to the alkene 8 by the larger number of methyl groups on
the C atom that is attacked. This means that the transition
state of the a-cleavage is correspondingly also raised and
the reaction retarded.[l3I
The steric effects of substituents in fi-cleavages should
also play an important role in a-cleavages. Evidence to this
effect is provided, for example, in SH reactions of alkyltin['"] and alkylboron compounds.11sJ
Our results show that
it is essential that polar and steric effects be taken into account as well the generally dominating influences of product stability"] when considering the selectivity of p-cleavage.
Received: March 2, 1988:
revised: June 10, 1988 [Z 2645/2646 IE]
German version: Angew. Chem. I00 (1988) 1195
CAS Registry numbers:
la, 3070-70-0; Ib, 26452-86-8; lc, 115982-37-1; Id, 115982-38-2; Za, 11598239-3; Zb, 115982-40.6; Zc, 115982-41-7; Zd, 115982-42-8; 3a, 115982-43-9; 3b,
115982-44-0; 3c, 115982-45.1; 3d, 115982-46-2; (E)-4a, 115982-47-3; (Z)-4a,
115982-51-9; (E)-4b, 115982-48-4: (Z)-4b, 115982-52-0; (E)-4c, 115982-49-5;
(Z)4c, 115982-53-1: (E)-4d, 115982-50-8; (Z)-4d, 115982-54-2: 5a, 18231.533; 5b, 20442-64-2; 5c, 7357-93-9; 6a, 115982-55-3; 6b, 115982-56-4; 6c,
115982-57-5: 7a, 115982-58-6; 7b, 115982-59-7; (Z)-7c, 115982-60-0; (E)-7c,
115982-61-1; 8a, 115982-62-2; (Z)-8b, 115982-63-3; (E)-8b, 115982-64-4; 8c,
115982-65-5; cyclohexane, 110-82-7; cyclohexyl, 3170-58-9.
[I] a) E. S. Huyser: Free Radical Chain Rencrions, Wiley, New York 1970, p.
21 1; b) J. A. Kerr, A. C. Lloyd, Q . Reu. London 22 (1968) 549.
[2] M. Ramaiah, Tetrahedron 43 (1987) 3541.
[3] 0.03 mol/L solutions of the alkene Z in cyclohexane were heated at 300450°C and 200 bar for 2 min in a high-pressure/high-temperature flow
reactor 141. The radical chain reaction was initiated by molecule-induced
homolysis [4b]. The product solutions were analyzed by capillary gas
chromatography. The products were identified by independent syntheses and/or GC/MS.
[4] a) P. KOII, J. 0. Metzger, Angew. Chem. 90 (1978) 802; Angew. Chem.
l n t . Ed. Engl. 77(1978) 754; b) I. Hartmanns, K. Klenke, J. 0. Metzger,
Chem. Ber. 119 (1986) 488.
[5] A steric effect o n the 6-cleavage in this system can be largely ruled out,
since the steric interaction of a methyl radical with a n ethyl substituent
should be the same as that of an ethyl radical with a methyl substituent.
161 C. Ruchardt : Die Bindung zwischen Kohlensfoffafomen,das Ruckgrat der
Organischen Chemie. und ihre Grenzen, Springer, Berlin 1984, p. 67.
1170
0 VCH Verlagsgesellschafr mbH. 0-6940 Weinheirn, 1988
Application of the principles of natural products chemistry allows extension of the theoretically and methodologically inspiring field of annulenes"] to higher ring systems.
The series of well-defined, normal annulenes ended previously with the diatropic (aromatic) [22]annulene 2 and
the paratropic (antiaromatic) [24]annulene['] (Scheme 1).
Using porphyrin biosynthesis as our model, we recently
synthesized a tetravinylogous porphyrin, 7, containing a
[26]annulene system.[*"] Compound 7 displays unusual
properties with possible topical application^.[^'
1, n=O [18]annulene
2
, n = 1 [22]annulene
....................................
3, n = 2 [26]annulene
4, n = 4 [34]annulene
5 , n, m = O
[ISlporphyrin
6 , n = 1, m=O [22]porphyrin-[1.3.1.3]
7, n, m = 1
[26]porphyrin-[3.3.3.3]
8,
n,
m
=2
[34]porphyrin-[5.5.5.5]
....................
Scheme 1. Structures of previously reported (above the broken line) and still
unknown diatropic annulenes 1-4 together with the corresponding vinylogous porphyrins 5-8 151.
Herein we report on the synthesis of an eightfold vinylogously enlarged porphyrin, 17, containing a cyclic conjugated 34~-electronsystem. The basic structure of 17, being
a bridged diaza derivative of [34]annulene 4, is named
[34]porphyrin-[5.5.5.5] according to our nomenclature proposal.[']
To develop a synthesis of the [34]porphyrin 17 involving
as few steps as possible, we followed the pathway of porthat porphyrin biosynthesis'61 (Scheme 2). It is
phobilinogen 9, the biogenetic precursor of all porphyrin
[*] Prof. Dr. B. Franck, DipLChem. G. Knubel
Organisch-chemisches Institut der Universitat
Orleansring 23, D-4400 Miinster (FRG)
[**I Novel Porphyrinoids, Part 6. This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen 1ndustrie.Part 5 : [2b].
0570-0833/88/0909-1170 $ 02.50/0
Angew. Chem. Inf. Ed. Engl. 27 (1988) No. 9
12 A 1 4 + 1 6
natural products, as well as similar 2-(aminomethy1)- and
2-(hydroxymethyl)pyrroles, can undergo acid-catalyzed
condensation in vitro to give porphyrins.
This biomimetic cyclotetramerization is even suitable for
the synthesis of sterically highly strained N,N',N",N"'-tetraalkylated and N,N-bridged porphyrinogens and porp h y r i n ~ . Even
~ ~ ~ though
, ~ ~ such condensations lead to porphyrinogens, which are (still?) unknown as natural products, these reactions are by definition[" biomimetic, since
they are closely related to biosynthesis.
14, n = l
15, n = o
HOzC
k..,
kj
Et
Et
+
H
9
Et
[
k
2
n
10
~
0
I
pCle
0
c
1
2
Et
11
Et
Et
~
Et
{arb
16
w
12
Scheme 2. Porphobilinogens 9 and synthesis of the S-pyrrylpentadienol 12.
Reaction conditions: a) N.N-dimethylaminopentadienal/P0Cl3, CH2C12,
-4O"C, inert gas, 4 h, 44% yield. b) NaH, dry dimethylformamide, CH31,
20°C. 30 min, 87% yield; 13: m.p. 55°C.
The key building block for the biomimetic construction
of a [34Jporphyrin system 8 is the pyrrylpentadienol 12
(Scheme 2). Owing to its high reactivity, 12 is generated
from the stable aldehyde precursor 13 by NaBH., reduction immediately prior to the acid-catalyzed condensation.
Compound 13 was synthesized from 3,4-diethylpyrrole
loc9]by doubly vinylogous Vilsmeier formylation using the
complex 11, followed by N-methylation.
Of decisive importance for the further synthesis of the
[34Jporphyrin derivative 17 was the question whether, in
analogy to the porphobilinogen 9 , a derivative 12 having a
doubly vinylogous side chain would also undergo acid-catalyzed condensation. The high selectivity in the biomimetic condensation of suitable monopyrroles to cyclic tetrapyrroles may be ascribed to steric interactions of substituents in the @ positions of neighboring pyrrole ring^.['^,^^
This effect should be strongly diminished when the bridges
linking the pyrrole rings are lengthened, as in 14 and 15.
Nonetheless, the acid-catalyzed condensation of 12 gave
the colorless, cyclically nonconjugated, octavinylogous
[34]porphyrinogen 14"'] (Scheme 3). However, the yield of
this reaction (4.1% based on 13) was, as expected, smaller
than that of the tetravinylogous [26]porphyrinogen 15
(27%).'2"1Still, this yield reveals a remarkable selectivity in
this complex cyclization when one considers that the yield
of 14 refers to a five-step synthesis-comprising reduction
and four cyclization steps-and therefore represents an average yield of 53% for each reaction step.
The lesser tendency of 12 to form cyclic tetramers is also
revealed in the fact that, in addition to 14, a more slowly
eluting product was isolated by flash chromatography (silica gel, cyclohexane/ethyl acetate 20 :l) in nearly the same
amount. On the basis of its mass spectrum ( M O 1005,25%),
it can be assigned the structure of a pentamer, 16.
Angew Chem. l n t . Ed. Engl. 27 (1988) No. 9
Et
Et
13
Scheme 3. Acid-catalyzed biomimelic condensation of the S-pyrrylpentadieno1 12. Reaction conditions: a) p-toluenesulfonic acid, acetic acid, MeOH,
S O T , inert gas, 30 min; 4.1% yield; 14, m.p. 168°C.
The cyclic conjugated target molecule 17 is so stable
that the educt 14-like the [26]porphyrinogen 15[2"J-can
be dehydrogenated by treatment with bromine. The
[34]porphyrin-[5.5.5.5] was thereby obtained as the bisquaternary dibromide 17.
14
ia
H%L
, - ,
,
,
,
6
Etd
Et
I
Et
\
Et
Ha,He
16.18 d
Hb, Hd -14.27 t
17.19 t
H'
H'
- 11.44 s
H8, H h
6.04 br
H', Hk
2.83 t
3 [Hzl
13.1
13.1
13.1
7.2
17
Scheme 4. Synthesis of the [34]porphyrin-[5.5.5.5] 17 and ' H NMR data (in
[DJDMSO, see Fig. 1). Reaction conditions: a) Br2/CCI4, polymer base (diethylaminomethylpolystyrene), 20"C, 5 h; 12.5%yield after chromatographic
purification (silica gel, CH2CI2/MeOH lo/]).
The [34]porphyrin 17, which forms deep blue
(A,, = 664 nm) solutions, exhibits an extraordinarily large
ring-current effect in the 'H NMR spectrum (Scheme 4).
The maximum shift difference A 6 of the resonance signals
between the inner (6= - 14.27) and outer protons
(6= 17.19) is 31.5 ppm. This value indicates that the dia-
0 VCH Verlagsgesellschaji mbH, 0-6940 Weinheim. 1988
0570-0833/88/0909-1171 $ 02.50/0
1171
magnetic ring-current effect of 17 significantly surpasses
the A 6 value (25.3 ppm)[*"] found for the analogous
[26]porphyrin and that found for [18]annulene 1 (12.1
ppm)."] The 'H NMR spectrum of 17 (Fig. 1) is probably
the first obtained for a non-organometallic compound in
which the measured proton resonances extend over a
range of more than 30 ppm. Splitting of the signals for the
protons Ha, Hb, and H' of 17 (Fig. la), observed only at
extreme dilution, indicates a tendency toward association.
[4] B. Franck, Angew. Chem. 94 (1982) 327; Angew. Chem. Int. Ed. Engl. 21
(1982) 343.
IS] For the nomenclature of vinylogous porphyrins, see M. Gosmann, B.
Franck [2a]. The compounds are thus named in analogy to annulenes.
To describe the structure unambiguously, the number of C atoms between the pyrrole rings is also given. Examples are: [26]porphyrinL3.3.3.31 or [18]porphyrin-[l.l.l.1] 5 (the "simple" porphyrin).
161 L. Bogorad in D. Dolphin (Ed.): The Porphyrins, Vol. 6, Academic Press,
New York 1979, p. 125.
[7] G. H. Cookson, C. Rimington, Biochem. J . 57 (1954) 476.
[8] R. Breslow, Q.Rev. Chem. Soc. f (1972) 553.
[9] H. W. Withlock, R. Hanauer, J. Org. Chem. 33 (1968) 2169.
[lo] P. J. Garratt in D. H. R. Barton, W. D. Ollis (Eds.): Comprehensive Organic Chemistry, Vol. I , Pergamon, Oxford 1979, p. 224.
[I 11 M. I. S. Dewar, G. J. Gleicher, 1. Am. Chem. SOC.87 (1965) 685.
[I21 The new compounds 13, 14, and 17 have been fully characterized by
elemental analysis and spectroscopic data: 14: MS (EI): m/z 804 (64%,
M"),775 (26, M-C,H,), 402 (26, M/2); ' H NMR (C6D6): 6=2.78 (s,
12H, N-CH,), 3.15 (d, 8 H , =CH-CH,-pyrrole),
5.60 (dt, J=4.8, 15.1
Hz, 4 H , =CH-CH>); 1R (KBr): 1=2950, 2920, 2860 (CH), 1605, 960
cm-' (trans C=C); R f =0.41 (silica gel, cyclohexane/ethyl acetate
lO/l).-l7: MS(FD):m/z800(100%,M-2Bre);
' H NMRseeScheme
4 and Fig. I ; F T I R (KBr): V=2963, 2926, 2870, 2853 cm-' (CH);
UV/VIS/NIR (chloroform): &,.,(&)=663 (370000), 997 nm (24000);
Rf=0.40 (RP 18, MeOH/THF 5:1,0.005 M sodium dodecylsulfate).
An Antibody-Mediated Redox Reaction**
By Kevan M . Shokat, Christian J. Leumann,
Renee Sugasawara, and Peter G . Schultz*
Fig. I . 300-MHz ' H NMR spectra of [34]porphyrin 17 in [D6]DMS0. Concentrations: a) 0.1 g L - ' ; b) 3.0g L-'.
The synthesis of the [34]porphyrin 17 with its high ringcurrent effect, characterizing its aromaticity,'"] s u p p o r t as already shown for the [26]porphyrin system-the validity of the (4n+2) rule for higher annulene systems. That
the annulenes so far available exhibit diatropic behavior
only in the range of 14-22 K electrons-as experimentally
found and as calculated[lll-can no longer be regarded,
therefore, as a limitation of the (4n 2) rule.
The diatropic behavior of the vinylogous porphyrins is
appreciably more pronounced than for the annulenes. We
ascribed this finding to the flattening effect of the pyrrole
rings, which hinders inversions of the ring system.[2a1The
present results show that this principle is so efficient that
even vinylogous porphyrins having the large 34n ring system-that is, C5 chains between the pyrrole rings-are
conformationally more stable that the [18]annulene 1.
+
Received: April 25. 1988;
supplemented: June 3, 1988 [Z 2721 IE]
German version: Angew. Chem. 100 (1988) 1203
[I] a) F. Sondheimer, Acc. Chem. Res. 5 (1972) 81; b) P. J. Garratt: Arornaticity, Wiley, New York 1986, p. 100ff.
[2] a) M. Gosmann, B . Franck,Angew. Chem. 98 (1986) 1107; Angew. Chem.
Int. Ed. Engl. 25 (1986) 1100; German Pat. Appl. P3635820 (1986),
BASF; b) R. Timmermann, R. Mattes, B. Franck, Angew. Chem. 99
(1987) 74; Angew. Chem. Inr. Ed. Engl. 26 (1987) 64; c) G. Bringmann,
B. Franck, Liebigs Ann. Chem. 1982, 1261; d) ibid. 1982, 1272.
[3] One possible application is in the phototherapy of tumors. Cf. H. van
den Bergh, P. Cornaz, Nachr. Chem. Tech. Lab. 33 (1985) 582; A. Andreoni, R. Cubeddu: Porphyrins in Tumor Photorherapy, Plenum Press,
New York 1984.-Since the [26]porphyrin [2a] exhibits more advantageous properties, in terms of the wavelength of its fluorescence emission, its chemical stability, and its solubility, than the derivatives of hematoporphyrin so far employed, it is now being tested in medical applications.
1172
0 VCH Verlagsgesellschaft mbH. D-6940 Weinheim. 1988
The advent of monoclonal antibodies makes possible the
generation of highly selective receptors to a vast number of
structurally diverse ligands."' Recently, the high binding
affinity and specificity of antibody combining sites has
been exploited in the development of selective catalysts for
acyl transfer,'*' carbon-carbon b~nd-forming,'~]
and carbon-carbon bond-cleaving reactions.'" We now report that
antibody combining sites can modulate the thermodynamics of redox processes. The use of antibody specificity to
alter flavin redox potentials is the first step toward developing antibodies capable of using cofactors to catalyze stereoselective reductions.
Oxidized flavin 1 and the two-electron-reduced 1,5-dihydroflavin l a have substantially different electronic and
conformational properties.[51 The dipole moment of oxidized flavin is reduced by 40% upon two-electron reduction and the N' position becomes an H-bond donor.[61In
fact, the pK, of the N'-H bond in l a is 6.5, indicating it
may exist largely as the anion in solution. In terms of
structural differences, a bent (N5-N" axis) conformation
is preferred by reduced flavin, whereas a planar form is
favored by the oxidized flavin (however, the calculated energy difference between the two conformations is small, 1Consequently, antibodies generated speci2 kcal mol fically to the oxidized flavin should preferentially bind 1
relative to 1,5-dihydroflavin l a . This differential stabilization of the oxidized and two-electron-reduced flavin by the
[*] Prof. P. G. Schultz, K. M. Shokat
[**I
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
Dr. C. J. Leumann
lnstitut fur Organische Chemie der
Eidgenossischen Technischen Hochschule, ETH-Zentrum
Universitatsstrasse 16, CH-8092 Zurich (Switzerland)
Dr. R. Sugasawara
IGEN Incorporated
Rockville, M D 20852 (USA)
The authors gratefully acknowledge support by the Department of Energy, contract C87-I01226 (P. G . S.), and the Swiss National Science
Foundation (C. J. L.). We thank Dr. W . Mclntire and Dr. T. Singer for
helpful contributions to this work.
0570-0833/88/0909-I172 $ 02.50/0
Angew. Chem. Inl. Ed. Engl. 27 (1988) No. 9
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