Witkop reaction

The Witkop reaction was also applied to the synthesis of (+)-decursivine (Scheme 29.9) [49]. Photochemical cyclization of the 5-hydroxytiyptophane derivative 59 followed by elimination of HCl leads to the intermediate 60. It was shown by a detailed mechanistic study that this intermediate undergoes photochemical cyclization in order to generate the benzotetrahydrofuran moiety. Two diastereoisomers 61 and 62 are obtained in a ratio of 1/6. The major isomer 62 doesn t possess correct configuration in the a-position of the lactam function. A base-catalyzed epimerization to 63 is therefore necessary to advance in the synthesis. (+)-Decursivine was isolated from leaves of... 

SCHEME 29.8 Various mechanistic steps in a Witkop reaction. 

SCHEME 29.9 Witkop reaction applied to the synthesis of a polycyclic natural product. The irradiations were carried out with a high-pressure mercury lamp. 

In addition to the natural isomerides of yohimbine listed in the foregoing table, several resulting from chemical reactions with yohimbine are known. Witkop has described e-yohimbine, C21H26O3N21 m.p. 203° dec.), [a] " 29-8° (pyridine) produced along with yohimbine, by the... 

Witkop and Goodwyn reported (288) that ozonolysis of yohimbine (74) and its derivatives led to the corresponding quinolone derivatives. This reaction has been thoroughly investigated by Winterfeldt (289). For example, autooxidation of lactam 347 resulted in quinolone 599, which upon treatment with phosphoryl chloride, followed by catalytic reduction, gave pyrrolo[3,4-h]quioline derivative 600 (290). This transformation was also used as a key step in the biomimetic synthesis of camptothecin (601), performed by Winterfeldt et al. (291, 292). 

The first method for the preparation of tetrahydroazocino[4,5,6-cd]indoles was reported in 1966. In succeeding years, this reaction came to be known as the Witkop photocyclization. 

Recently, Senoh, Tokuyama, and Witkop (37) have studied a metal-activated enzymatic reaction in the presence and the absence of enzyme, and have discovered that the order of effectiveness of the metals is exactly the reverse in the enzymatic and nonenzymatic processes. The reaction was O-methylation of 3,4-dihydroxybenzaldehyde. In the absence of divalent metal ions, the nonenzymatic reaction yields very predominantly the paramethylated product in neutral solution, since the p-hydroxyl group is the more electronegative. Metal complex formation... 

In an attempt to learn whether collagen hydroxyproline synthesized in granuloma minces incubated with tritiated proline contained tritium at the 4 position, we converted such tritiated hydroxyproline to the corresponding N-carbobenzoxy derivative and then oxidized this derivative with chromic acid to N-carbobenzoxy-4-ketoproline according to the procedure of Patchett and Witkop(29). In most of these experiments very little tritiated water was formed although some tritiated water was detected in several experiments, the small amount formed could logically be attributed to adventitious oxidative reactions or perhaps to enolization of ketoproline. The evidence was therefore consistent with the absence of tritium at carbon atom 4 of the isolated hydroxyproline. 

It is further apparent that increasing alkalinity affects release of glycine and formation of dienone to different extents and possibly in different ways. Although the spirodienone lactone is unstable in alkaline media, destruction of preformed dienone lactone by this pathway can be no more than 5 % under the reaction conditions employed. Compoxmds (CXVII and CXVIII) which show dienone absorption but fail to release glycine may also be formed at higher pH values (Goodwin and Witkop, 1957 cf. Scott et al., 1957 Heine, et al., 1955 Stirling, 1960). 

E. Gross and B. Witkop used this reaction for the selective cleavage of methionine peptides, as illustrated in the formulation ... 

Gross and Witkop found gel filtration over Sephadex G-25 invaluable for the separation of fragments resulting from the cleavage of methionine-peptide bonds in ribonuclease by reaction with cyanogen bromide. In this case 0.2 N acetic acid was used as solvent. 

Witkop (946) has discussed chemical analogies to these changes. Reactions of the following type can be realized ... 

The tryptophyl residues were modified by oxidation with N-bromo-succinimide (NBS) according to Spande and Witkop (48) and by reaction with 2-hydroxy-5-nitrobenzyl bromide according to Horton and Kosh-land (21). Oxidation of tryptophyl residues with NBS has been shown... 

The biosynthesis of bufotenine has not been entirely elucidated experimentally. Some biochemical observations, however, prompted Witkop (141) even at early stages of investigation to make the accepted (157) suggestion of the possibility of direct hydroxylation of the benzene ring in tryptophan prior to any reaction on the pyrrole part of the molecule. Since the hydroxyamino acid was found not only in toad secretions but later also in the mushrooms, it may be the precursor of serotonin and hence A/ -dimethyl derivative, bufotenine. 5-Hydroxytryptophan was first found... 

A soln. of DL-methionine, 3 moles diethyl azodicarboxylate, ethanol, and water stirred 3 hrs. at room temp. DL-methionine sulfoxide. Y 97,5%. - The reaction is dependent on the presence of a proton-donating group. F. e. and limitations s. R. Axen, M. Chaykovsky, and B. Witkop, J. Org. Chem. 52, 4117 (1967). 

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