Acid cyclative cleavage

Solid-Phase Synthesis Terminated by Tetramic Acid Cyclative Cleavage (Scheme 2). The Fmoc-L-Val resin (loading 0.7 mmol/g) is first deprotected with 20% piperidine in DMF for 20 min, and the resin washed and dried. The resin ( 0.3 g, 0.67 mmol/g) is shaken with p-anisaldehyde (0.25 ml, 10 molar equiv.) and sodium triacetoxyborohydride (0.65 g, 15 molar equiv.) in 10 ml CH2C12 for 8 h, followed by washing and drying to give resin 4. 

Piperazinediones by Acid Cyclative Cleavage Method A, including Reductive Alkylation... 

Fig. 19 Synthesis and cyclative cleavage of 2,4,6-trisubstituted pyrimidines using microwave-assisted solid-phase protocol. Reagents and conditions a DMF, camphorsul-phonic acid, MW 80 °C, 30 min, open vessel b EtONa, EtOH/THF (4/1), MW 130 °C, to min, closed vessel. Y = O, NEt2 R = Me, i-Pr R = Et R" = H, alkyl, cycloalkyl, aryl, benzyl R" = H, Me, Et...

Libraries of the pyrazino[2,l-A [l,3]oxazines 373 with variable R1 and R2 substituents were synthesized on solid phase, the last step being the cyclative cleavage of 372 with formic acid (Equation 42) <2002W02002/092010>. 

The cyclative-cleavage strategy is different to the cases in which the cycUzation occurs in solution after the cleavage (Scheme 3.6). This is true for most acidic cleavage conditions in these cases the uncyclized reactant is also found in the hquid-phase. Examples of this strategy are the synthesis of benzofurans [184], imidazo-quinoxalinones [185, 186] and diketopiperazines [187]. 

Solid-phase syntheses have become increasingly popular during the period of this review, with examples including the synthesis of 5,6,7,8-tetrahydro[l,6]naphthyridines from Meldrum s acids derived from /3-amino alcohols via Hantzsch condensation and cyclization with cyclative cleavage from the resin (using 70% trifluoroacetic acid (TFA)/dichloromethane (DCM) followed by 5% triethylamine/DCM) <1999S1951> and also of isoquinolinones and 5-oxo-5,6-dihydro-[l,6]naphthyridines <1995JOC5748>. 

Propionyl-CoA is first carboxylated to form the d stereoisomer of methylmalonyl-CoA (Pig. 17—11) by propionyl-CoA carboxylase, which contains the cofactor biotin. In this enzymatic reaction, as in the pyruvate carboxylase reaction (see Pig. 16-16), C02 (or its hydrated ion, HCO ) is activated by attachment to biotin before its transfer to the substrate, in this case the propionate moiety. Formation of the carboxybiotin intermediate requires energy, which is provided by the cleavage of ATP to ADP and Pi- The D-methylmalonyl-CoA thus formed is enzymatically epimerized to its l stereoisomer by methylmalonyl-CoA epimerase (Pig. 17-11). The L-methylmal onyl -CoA then undergoes an intramolecular rearrangement to form succinyl-CoA, which can enter the citric acid cycle. This rearrangement is catalyzed by methylmalonyl-CoA mutase, which requires as its coenzyme 5 -deoxyadenosyl-cobalamin, or coenzyme Bi2, which is derived from vitamin B12 (cobalamin). Box 17—2 describes the role of coenzyme B12 in this remarkable exchange reaction. 

The oxidative cleavage of an a-oxoacid is a major step in the metabolism of carbohydrates and of amino acids and is also a step in the citric acid cycle. In many bacteria and in eukaryotes the process depends upon both thiamin diphosphate and lipoic acid. The oxoacid anion is cleaved to form C02 and the remaining acyl group is combined with coenzyme A (Eq. 15-33). 

At the end of this sequence, the P-oxoacyl-CoA derivative is cleaved (Fig. 17-1, step e) by a thiolase (see also Eq. 13-35). One of the products is acetyl-CoA, which can be catabolized to C02 through the citric acid cycle. The other product of the thiolytic cleavage is an acyl-CoA derivative that is two carbon atoms shorter than the original acyl-CoA. This molecule is recycled through the P oxidation process, a two-carbon acetyl unit being removed as acetyl-CoA during each turn of the cycle (Fig. 17-1). The process continues until the fatty acid chain is completely degraded. 

Both catalyze chain cleavage and transfer reactions (Eqs. 17-14 and 17-15) that involve the same group of substrates. These enzymes use the two basic types of C-C bond cleavage, adjacent to a carbonyl group (a) and one carbon removed from a carbonyl group ((3). Both types are needed in the pentose phosphate pathways just as they are in the citric acid cycle. The enzymes of the pentose phosphate pathway are found in the cytoplasm of both animal and plant cells.n7c Mammalian cells appear to have an additional set that is active in the endoplasmic reticulum and plants have another set in the chloroplasts.117c... 

Three modifications of the conventional oxidative citric acid cycle are needed, which substitute irreversible enzyme steps. Succinate dehydrogenase is replaced by fumarate reductase, 2-oxoglutarate dehydrogenase by ferredoxin-dependent 2-oxoglutarate oxidoreductase (2-oxoglutarate synthase), and citrate synthase by ATP-citrate lyase [3, 16] it should be noted that the carboxylases of the cycle catalyze the reductive carboxylation reactions. There are variants of the ATP-driven cleavage of citrate as well as of isocitrate formation [7]. The reductive citric acid... 

This category represents the most popular subclass of cyclative cleavage reactions. There are many solid-phase sequences with resin attachment via carboxylic acids, followed by elaboration to a free amine five centers away... 

Among the six-membered ring heterocycles, diketopiperazines are most commonly prepared by cyclative cleavage. Indeed, diketopiperazine formation is often observed as an undesirable by-product during peptide synthesis20 and the facile nature of this cyclization makes it an obvious choice for library generation. In an early example from Pfizer,21 a set of 10 immobilized a-amino acids was reductively alkylated with 10 aldehydes, followed by acylation with 10 a-amino acids and cyclization (Fig. 6). By... 

The first cyclative cleavage of a small molecule was Crowley and Rapo-port s study41 of intramolecular Dieckmann condensations on solid phase (Fig. 13), which was complicated by the reversible nature of the cyclization. Despite the unique opportunities afforded by C-C rather than C-X bond formation during cleavage, there are few examples from the combinatorial age. A modern version of the Claisen-type condensation by Kulkarni and Ganesan42 uses a strongly acidic active methylene group to ensure unidirectional cyclization, and furnishes tetramic acids with three points of diversity. 

The commercially available, supported amino acid 1.49 was elaborated to complex linear intermediates that can easily be cyclatively cleaved to produce tetramic acids the cleavage conditions included aqueous NaOEt (107), tetrabutyl ammonium hydroxide (108), and methanolic KOH (109). The procedures afforded the desired heterocycles in good yields and purities. 

Many biologically active peptides are cyclic in nature, and the SPS of this class of peptides, exemplified by 2.7, has also received attention with several different strategies for the final cyclization. The phenomenon of pseudodilution on bead in which each resin site is essentially isolated from its neighbors favors the intramolecular cyclization reaction compared to the intermolecular dimerization, which occurs in solution even at high dilutions. The SPS of cyclic peptides has recently been covered in two excellent reviews (31, 32). The technique of cyclative cleavage via the N- or the C-terminus (see Section 1.2.7) has been used, as has anchoring through amino acid side chains with sequential cyclization and peptide release. 

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