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Oxidation with Palladium Salts Stereo- and Regiospecific Acetoxylation of 4-Vinylcyclohexene Derivatives.

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The enzyme analogue was catalytically inactive with artificial electron acceptors.
Investigation of the stereospecificity of natural succinate
dehydrogenase from yeast mitochondria indicated considerable agreement with that of the enzyme from porcine
heart mitochondria. Hence, the same initial ratio (2 : I)f2"1
of mono- and dideuterated succinate was found upon
anaerobic incubation in D20. Partial oxidation of (R)-,
(RS)-, and (S)-12-3H]succinate led to similar tritium enrichments in the unreacted substrates[2h1,corresponding to a
large isotope effect (k(H,+)/k(T)= 10) for the abstraction
of HRc,and to a smaller effect (k(H,,)/k(T) = 1.5) for the
abstraction of Hsi.
After these preliminaries, 5-deazaflavin-containingsuccinate dehydrogenase was incubated with (R)- and with
(S)-[2-3H, U- ''C]-succinate. Subsequently, the main portion of the excess radioactive substrate and the stoichiometrically formed product were removed by dialysis. The residual low-molecular weight material was separated by gel
chromatography of the radioactive protein on Bio-Gel P2.
From the radioactivity (3H and I4C) and the protein content of the individual fractions (Fig. I ) it could be deduced
that tritium was only transferred from (S)-[2-3H]succinate
to the protein. The 3H/'4C ratio of the later fractions corresponds to that of the substrate.
The main portion of the radioactive acids was then isolated from the dialysis water using anion exchanger. Following chromatographic separation the radioactivity of the
samples of succinic and malic acids (the initially formed
fumaric acid was largely converted by the contaminating
fumarase into L-malic acid, which, however, should not alter the radioactivity, in particular the 'H/I4C ratio) was
measured. As expectedr2'I, the 'H/I4C ratio following dehydrogenation with succinate dehydrogenase decreased to
approximately half the original value irrespective of the
sense of chirality of the [3H]succinic acid used.
141 F. Lingens, 0. Oltmanns, A. Bacher, Z . Notuforsch. 22 (1967) 755.
[5] T. P. Singer, V. Massey, E. B. Kearney, Arch. Biochem. Biophys. 6 9 (1957)
Oxidation with Palladium Salts:
Stereo- and Regiospecific Acetoxylation
of 4-Vinylcyclohexene Derivatives**
By Andreas Heumann. Marius Reglier, and
Bernard WaegeIP
The Pd-catalyzed reaction of alkenes can proceed via direct addition of PdX2 to the double bond (route a) or by
abstraction of an H-atom a to the double bond (route b)"].
It has so far remained unclear which factors determine the
reaction path''].
A + PdX,
In the case of the catalytic oxidation of non-conjugated
mono- and bicyclic alkadienes, exclusively route a has
been rep~rtedl'~.We now report on the oxidation of related
alkadienes such as 1 and 8, which under similar conditions (PdC12 as catalyst in buffered glacial acetic acid,
varying amounts of CuCI, or CuC12-LiCI-02)react-regioselectively and, in part, stereoselectively-according to
route b.
Reaction of 4-vinylcyclohexene 1 under these conditions in the presence of excess triphenylphosphane (or "diphos") leads to formation of the allylic acetate 2, whose
structure is confirmed by 'H- and I3C-NMR spectroscopy,
and by conversion into the unsaturated and the saturated
alcohols [2, 'H-NMR: 6 = 1.4-2.6 (m, 5H), 2.05 (s, 3 H,
OAc), 4.95,5.04,5.12 (m, m, m, 2H), 5.25 (m, 1 H, CHOAc),
5.6-6.1 (m, 3 H)].
PdC12, CuC12, 6OnC/24 h
2, 30%
HOAc, NaOAc, PPh,
The formation of the trans-isomer 2 and the high regioselectivity can be explained in terms of a homogeneous catalytic mechanism. The palladium(0) formed in the reaction is reoxidized by CuC12.
+ 2 CUCl*
Fig. 2. Relative position of substrate and coenzyme in the active center of
succinate dehydrogenase.
2 CUCl
1 + PdC1,
The steric behavior at the active center can therefore be
represented as shown in Fig. 2.
Received: December I I , 1981 [Z 70 IE]
German version: Angew. Chem. 94 (1982) 396
CAS Registry numbers:
2, 19342-73-5; succinate dehydrogenase, 9002-02-2: (R)-[2-'H, U-"C]-succinic acid, 81456-76-0: (S)-[2-'H, U-'4C]-succinic acid, 81456-77-1.
[I] T. T. Tchen, H. van Milligan, J. Am. Chem. Soc. 82 (1960) 4115.
[21 a) J. Retey, J. Seibl, D. Arigoni, J. W. Cornforth, G. Ryback, W. P. Zeylemaker, C. Veeger, Eur. J. Biochem. 14 (1970) 232; b) W. P.Zeylemaker, C.
Veeger, F. Kunz, J. Retey, D. Arigoni, Chimia 24 (1970) 33.
[3] a) R. Spencer, J. Fisher, R. Laura, C. Walsh in T. P. Singer: Rauins and
Rauoproteins. Elsevier, Amsterdam 1976, p. 349; b) S. Grossman, J. Goldenberg, F. B. Kearney, G. Oestreicher, T. P. Singer, ibid., p. 302.
0 Verlag Chemie GmbH, 6940 Weinheim. 1982
[*I Dr. A. Heumann, Dr.
M. Reglier, Prof. Dr. B. Waegell
Laboratoire de Stereochimie, associe au CNRS (LA109)
Universite d'Aix-Marseille
Centre de S t - J e r h e , F-13013 Marseille (France)
We thank Hiils (Marl) for a supply of 4-vinylcyclohexene, and ShellChimie (Fos) for I ,4-dimethyl-4-vinylcyclohexene.
0570-0833/82/0505-0366 $02.50/0
Angew. Chem. Int. Ed. Engl. 21 (1982) No. 5
The question as to why the oxidation of 1 leads to allylic
end products (route b) is difficult to answer. According to
models it would seem that the course of reaction is determined not only by steric effects (proximity of the abstracted H-atom to the metal in the intermediary PdCI2-1
complex) but also by stereoelectronic effects. That the
trans-isomer 2 is formed is understandable: The better ligand triphenylphosphane, present in excess, blocks the
metal center in 7,so that the poorer acetate-ligand can attack only from ''outside"161.
As can be seen from the mechanistic scheme, the vinyl
group in 1 is decisive for the steric course of the reaction,
though additional phosphane ligands appear to be necessary for the stabilization of the intermediates 6 or 7. On
increasing the nucleophilicity of the vinyl group, for example by introduction of a methyl group, the catalytic acetoxylation should take place, even in the absence of phosphanes. Indeed, reaction of limonene 8 without additional
phosphane ligands (25 "C, 72 h) leads stereospecifically to
a-carvyl acetate 9 (63% yield).
of intact cells with cyclonucleotides produced no or only
slight activity; because of their negative charge they
can only penetrate the cell membrane with difficulty. In
consequence, cyclonucleotides with lipophilic groups, e. g.
butyryl residues, were synthesized. We report here the synthesis and properties of the first 7-deaza-cGMP analogue.
Pyrrolo[2,3-d]pyrimidinenucleosides are more lipophilic
than the corresponding purine compounds, since they do
not contain an N atom in the 7-position. Furthermore, the
7-deaza derivative of guanosine is the only ring-modified
guanosine analogue of which naturally occurring derivatives have been found. We recently synthesized 7-deazaguanosine l a by phase transfer catalysis[61.In contrast to
guanosine, the more lipophilic compound l a shows no
tendency to aggregate, thus increasing its availability in
aqueous solution.
9, 63%
12 h
After modification of the limonene structure, as in 1,4dimethyl-4-vinylcyclohexene,the acetoxylation is less selective: both isomeric acetates are formed in about equal
Received: October 21, 1981 [Z 69 IE]
revised: March 5, 1982
German version: Angew. Chem. 94 (1982) 397
The complete manuscript of this communication appears in:
Angew. Chem. Suppl. 1982. 922-928
[I] Reviews: P. M. Henry: Palladium Catalysed Oxidation of Hydrocarbons,
Academic Press, New York 1980; J. Tsuji: Organic Synrhesis wirh Palladium Compounds, Springer, Berlin 1980.
[2] B. M.Trost, Acc. Chem. Res. I 1 (1980) 453; for a theoretical treatment cf.
S. Sakaki, M. Nishikawa, A. Ohyoshi, J. Am. Chem. SOC. 102 (1980)
131 A. Heumann, B. Waegell, Noun J. Chim. I (1977) 277: A. Heumann, M.
Reglier, B. Waegell, Angew. Chem. 91 (1979) 924,925; Angew. Chem. Int.
Ed. Engl. 18 (1979) 866, 867.
161 a) B. M. Trost, Tetrahedron 33 (1977) 2615; B. M. Trost, T. R. Verhoeven,
J. M. Fortunak, Tetrahedron Left. 1979, 2301 ; b) cf. J. E. Backvall, R. E.
Nordberg, E. E. Bjorkman, C. Moberg, J . Chem. SOC.Chem. Commun.
1980. 943.
7-Deazaguanosine-3',5'-phosphate-An Isosteric
cCMP Analogue with High Affinity for
Cyclonucleotide Phosphodiesterase**
By Quynh-Hoa Tran-mi, Doris Franzen, and
Frank Seela*
Guanosine-3',5'-phosphate (cGMP), like adenosine3',5'-phosphate (CAMP), occupies a key position in the regulation of hormone activity, but exhibits partial antagonistic functions; furthermore it activates a series of enzymes,
e. g. protein kinases. This provided entry to the synthesis
of a series of cyclonucleotide analogues[*].Recently it has
been established that cGMP is also of great importance in
vision : photoactivation of one rhodopsin molecule leads to
enzymic hydrolysis of 10' cGMP r n o l e ~ u l e s ~Incubation
[*] Prof. Dr. F. Seela, Dr. Q.-H. Tran-Thi, D. Franzen
Fachbereich 13-Organische Chemie der Universitat
Warburger Strasse 100, D-4790 Paderborn (Germany)
This work was supported by the Deutsche Forschungsgemeinschaft.
Angew. Chem. Int. Ed. Engl. 21 (1982) No. 5
Phosphorylation of l a with PC130 in trimethyl phosphate leads regioselectively to the 5'-monophosphate l b
[3'P-NMR (D20): 6=3.17], which can be cyclized with
N,N-dicyclohexylcarbodiimidein pyridine yielding the cyclophosphate 2. Subsequent anion-exchange chromatography and lyophilization produces pure 2 [3'P-NMR (D20):
6=9.40] as the amorphous triethylammonium salt. The
structure of 2 is confirmed by its 'H-NMR spectrum. The
fused cyclophosphate ring results in angular distorsion of
the 0-D-ribofuranosyl residue and hence the ]'-proton does
not participate in vicinal coupling, a result which is also
found with cGMP.
Cyclophosphate-specific phosphodiesterase cleaves the
cyclonucleotide 2 to afford the 5'-monophosphate l b . Table 1 shows that 2 is hydrolyzed more rapidly than cGMP.
The 7-purine nitrogen is thus not a requirement for the
binding of cGMPf8]and its analogues to the phosphodiesterase and their hydrolysis by this enzyme, a phenomenon
which is also found with t~bercidin-3',5'-phosphate""'~.
Table 1. Relative initial rates of the enzymic hydrolysis of purine and 7-deazapurine nucleoside-3,5'-phosphateswith cyclonucleotide phosphodiesterase
from bovine heart.
Relative initial rates of hydrolysis
I .o
In contrast to cGMP, 2 does not aggregate in aqueous
solution; we presume that this is due to the absence of the
7-purine nitrogen, avoiding Hoogsteen base-pairing, which
causes the aggregation in guanidine nucleotides.
The higher rate of hydrolysis of 2, which is not achieved
by other cGMP derivatives, may be due to the following:
1) increased availability of 2 due to diminished aggregation, 2) increased affinity of the more hydrophobic substrate to the active center of the phosphodiesterase, and 3)
increased ring strain in the cyclophosphate residue in-
0 Verlag Chemie GmbH. 6940 Weinheim, 1982
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salt, oxidation, stereo, palladium, vinylcyclohexene, regiospecific, acetoxylation, derivatives
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