Two-step cleavage

Hydroxyphenylpyruvic acid plays an important role in the biogenesis of compounds with a phenylpropane skeleton, and it has been used as substrate in several enzyme studies. Published procedures for its preparation are unsatisfactory in many ways. The alkaline hydrolysis of the azlactone of a-bcnzoylamino- -acetoxycinnamic acid 7 makes necessary a tedious separation of the resulting benzoic acid, and the yield is only 34% based on -hydroxybenzaldehyde. The hydrolysis of 5- ( -hydroxybenzal)-3-phenylhydantoin 9 requires a separation of phenylurea. Finally, the two-step cleavage of the azlactone of a-acetamino- -acetoxycinnamic acid 8 does not proceed easily, and impure products are obtained. In applying this procedure to the synthesis of a carboxyl-labeled -hydroxyphenylpyruvic acid, the overall yield was only 9%.u It must be kept in mind that any prolonged isolation procedure will cause some decomposition of this sensitive compound. 

The mechanism involves attack by singlet oxygen on the carbon-carbon double bond, followed by a two-step cleavage of the 1,2-dioxetane intermediate. Formation of polar intermediates such as a 1,4-zwitterion (ZWI) has been proposed in order to account for the fact that radical inhibitors have no effect on the reaction rate, whereas the intermediates can be trapped by alcohols4,7-11. 

The nature of the cyclopropane-forming reaction is still controversial in the sense of a differentiation between a two-step cleavage of the two CN bonds and a concerted formation of a biradical in the azo-extrusion part of the reaction (for a review of the older literature, see Mackenzie, 1975, p. 354, and Engel, 1980, p. 118). This reaction does not strictly belong to the scope of this book. Therefore, we will not discuss it further except to refer to an investigation of Reedich and Sheridan (1988) who reported that, in contrast to earlier results (see, e. g., Cichra et al., 1980, and other references there), both thermal and photochemical processes take place by stepwise cleavage in a pair of isomeric dihydro-pyrazoles. 

Some improvements were noted in a two step-cleavage, in which first HF diluted with dimethyl sulfide is used, followed by the application of neat hydrogen fluoride. 

The SPOR of two fluorous analogues of a tumor PET tracer, aminocyclobutane carboxylic acid (ACBC, 24 and 26) is described in Scheme 13.8." The FACBC ([ F]fluoro-aminocyclobutane carboxylic acid) preciusor was fully protected and attached to the resin by a perfluoroalkyl ether linker. FACBC 24 was obtained in two steps cleavage by a fluorination step, followed by deprotection under acidic conditions. The corresponding methylene-FACBC analogue (25) was obtained by the same strategy. Notably, no linker was... 

Resorcinol or hydroquinone production from m- or -diisopropylben2ene [100-18-5] is realized in two steps, air oxidation and cleavage, as shown above. Air oxidation to obtain the dihydroperoxide (DHP) coproduces the corresponding hydroxyhydroperoxide (HHP) and dicarbinol (DC). This formation of alcohols is inherent to the autooxidation process itself and the amounts increase as DIPB conversion increases. Generally, this oxidation is carried out at 90—100°C in aqueous sodium hydroxide with eventually, in addition, organic bases (pyridine, imidazole, citrate, or oxalate) (8) as well as cobalt or copper salts (9). 

Although the precise mechanism of plasminogen activation is unknown, three principal theories have developed based on studies of the in vitro activation of native human plasminogen. Activation of native Glu-plasminogen in the absence of any plasmin inhibitor yields Lys —plasmin plus the so-called pre-activation peptides (PAP) formed by cleavage at LySg2 S E3 Activation takes place by a two-step mechanism in... 

The most important connective transforms in retrosynthetic analysis are the family of C=C cleavage transforms, including one-step (e.g. ozonolytic) or two-step (e.g. OSO4 followed by Pb(OAc)4) (Chart 25). There are many elegant syntheses of challenging molecules which depend on such processes. Two examples will provide an idea of the underlying retrosynthetic approach. 

A recent communication described the cleavage of 17a-hydroperoxy-20-keto steroids with base to give 17-ketoandrostanes in good yield. Since such hydroperoxides are now accessible from 20-ketopregnanes in one step vide infra), this constitutes a convenient two-step degradation process. In practice, the intermediate hydroperoxide need not be isolated. Other enolizable... 

Ketone body synthesis occurs only in the mitochondrial matrix. The reactions responsible for the formation of ketone bodies are shown in Figure 24.28. The first reaction—the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA—is catalyzed by thiolase, which is also known as acetoacetyl-CoA thiolase or acetyl-CoA acetyltransferase. This is the same enzyme that carries out the thiolase reaction in /3-oxidation, but here it runs in reverse. The second reaction adds another molecule of acetyl-CoA to give (i-hydroxy-(i-methyl-glutaryl-CoA, commonly abbreviated HMG-CoA. These two mitochondrial matrix reactions are analogous to the first two steps in cholesterol biosynthesis, a cytosolic process, as we shall see in Chapter 25. HMG-CoA is converted to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase in a mixed aldol-Claisen ester cleavage reaction. This reaction is mechanistically similar to the reverse of the citrate synthase reaction in the TCA cycle. A membrane-bound enzyme, /3-hydroxybutyrate dehydrogenase, then can reduce acetoacetate to /3-hydroxybutyrate. 

The 4 -pyridylethyl group was found to be more effective for intemucleotide phosphate protection than the 2 -pyridylethyl group, because its cleavage proceeded with greater efficiency. It is cleaved in a two-step process acylation with PhOCOCl increases the acidity of the benzylic protons, facilitating E-2 elimination by ammonia." ... 

In synthesis of the alkaloid tjipanazole E (19b), the required symmetric dichloro-indolo[2,3-fl]carbazole 20a was obtained in a two-step procedure starting fi-om 4-chlorophenylhydrazine hydrochloride and 1,2-cyclohexanedione employing a Fischer indolization. Subsequent attachment of an acetyl-protected glucopyranosyl moiety to one of the nitrogens, followed by cleavage of the protective groups with ammonia in methanol, produced the desired natural product (91X7739). 

The two-step procedure includes formation of a N-substituted phthalimide 3, and its subsequent cleavage to the primary amine 5. Phthalimide (which can be obtained from reaction of phthalic acid with ammonia) shows NH-acidity, since the negative charge of the phthalimide anion (the conjugated base) is stabilized... 

This two-step sequence is a valuable alternative to the direct double bond cleavage by ozonolysis. 

Methyl-5-hexen-2-one has been prepared by alkylation of acetoacetic ester with methallyl chloride, followed by cleavage the overall yield in the two steps was 51%.2... 

Transformation of the amino nitriles to the corresponding amino acids, with removal of the dioxane ring, is carried out in two steps. Treatment with concentrated hydrochloric acid results in the hydrolysis of both the nitrile and the acetal group, and in cyclization to the corresponding 3-substituted 5-hydroxyniethyl-3-methyl-2-oxo-6-phenylmorpholinc hydrochlorides. Oxidative cleavage with 2 N sodium hydroxide solution, air and Raney nickel at 120 CC (ca. 30 h) delivers the hydrochlorides of the free a-methylamino acids in high yield. 

The classic method for establishing the proportion of head addition occurring in VAc polymerization involves a two step process.5 The PVAc is converted to PVA by exhaustive hydrolysis and the number of 1,2-glycol units is determined by periodate cleavage. 

Data are also available with a-acetylenic aliphatic sulphones, which involve only two steps i.e., saturation of the triple bond without subsequent cleavage of the Caliphalic—S bond, since it is not reactive. However, the introduction of an aromatic ring to the S02 group does not lead, contrary to what is observed with enones, to a potential shift toward less reducing potential values. Thus, the aromatic moiety introduced apparently does not bring any additional conjugation effect but even seems to decrease the activation of the unsaturated bond, as shown by data in Tables 6 and 7 where most of the potentials refer to the same saturated calomel electrode under similar experimental conditions. 

The use of aprotic. (and therefore totally unbuffered media in analytical studies of sulphones may lead to wrong conclusions. The voltammetric determination of the benzyl phenyl sulphone26 was aimed to clearly exemplify the deactivation process in dry dimethylformamide. So, in aprotic or low acidity solvents, two main steps (equivalent to the transfer of one electron each) can be seen (Figure 6, curve 1). These two steps were shown at the potential of the cleavage (— 1.7 volt) to correspond, for acidic sulphones, to the following processes ... 

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