Synthesis intramolecular dehydrative acylations

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

In a recent report, Padwa [64] disclosed a general method of wide applicability for constructing a variety of heterocyclic systems. It involved an amino furan ester as a more reactive four carbon component vis avis a pyrone in intramolecular Diels-Alder addition to an unactivated olefin. This method as applied to the synthesis of anhydrolycorinone consisted of the preparation of the tertiary amide 240 (Scheme 40) and its subsequent thermolysis to the N-o-bromoaroylindoline 241. It is believed that the initially formed cycloadduct 242 opened to the acyl iminium oxyanion 243, which by prototropy and dehydration generated 241. The latter, on photolysis in the presence of bis (tri-n-butyltin), furnished the tetracyclic ester 244, which was hydrolysed and decafboxylated to anhydrolycorinone as in the previous synthesis. 

The dimethylamide function in 27 was reduced by the action of Ti(0/-Pr)4 and phenylsilane [35] to give aldehyde 29, which was then treated with p-TsOH in toluene at room temperature (Scheme 6). Under these reaction conditions, the intramolecular Friedel—Crafts-type cyclization occurred, and the subsequent dehydration of a benzylic alcohol also took place to afford phenanthrofuran skeleton (A-B-C-E ring) 30. The formation of the B-ring by way of intramolecular Friedel—Crafts acylation was first reported by Ginsburg in his synthesis of dihy-drothebainone in 1954 [36]. This transformation was also employed by White in the synthesis of (+)-morphine [37], and by Multzer in the synthesis of dihydrocodei-none [38 -0]. The Friedel—Crafts-type cyclization with an aldehyde function was used by Evans [41] in the formal synthesis of morphine and by Hudlicky in the... 

Inspired by these results, Nicolaou et al. used a temporary boronate tether to overcome the undesired regiochemical bias in the intermolecular Diels-Alder reaction of diene 56 and dienophile 57, required for their approach to the C-ring of taxol 58 [21a, b, 24], Thermolysis of a benzene solution of 56 and 57 in the presence of PhB(OH)2 under dehydrating conditions provided the cycloadduct 59 in 79% yield (77% conversion) after transacetalization of the boron tether with 2,2-dimethylpropane-l,3-diol and intramolecular acyl transfer to the less strained [4.3.0]bicyclic system. This was further elaborated to an advanced intermediate in the ultimately successful synthesis of taxol (Scheme 10-21) [21c]. 

The enantioselective total synthesis of streptazolin (609), a neutral lipophilic antibiotic isolated from cultures of Streptomyces viridochromogenes, utilizes a tandem iminium ion— vinylsilane cyclization of the tartrate-derived 607 together with intramolecular acylation as a way of achieving high stereoselectivity. Heating a mixture of 570 and ( )-4-bromo-4-(tri-methylsilyl)-3-buten-l-amine (605) followed by dehydration with acetyl chloride provides the imide (606) in reproducible yields of 90%. Reduction of 606 with sodium borohydride affords 607, which is refluxed in trifluoroacetic acid to provide, after careful purification, the single bicyclic adduct 608 in 74% yield. This is then transformed in four steps to the desired streptazolin (609) [196] (Scheme 134). 

Davis and coworkers have used an intramolecular asymmetric Michael addition to an optically pure a,(3-unsaturated sulfoxide as part of the synthesis of the dihydropyridine sulfone (132), a potent antihypertensive agent [108], The Hantzsch reaction (treatment with 3-aminocrotonate (130) in MeOH under reflux) of the a-acyl-a,P-unsaturated sulfoxide (129) gave the product (131) as a single diastereoisomer in 48% yield, resulting from an asymmetric Michael addition followed by dehydrative cyclization. The sulfoxide was then oxidized to the corresponding sulfone (132) (Scheme 5.44). 

This and other information show that nine Cg units from malonyl-coenzyme A and one C3 unit from propionyl-coenzyme A condense to form the linear polyketide intermediate shown below. These units are joined by acylation reactions that are the biosynthetic equivalent of the malonic ester synthesis we studied in Section 18.7. These reactions are also similar to the acylation steps we saw in fatty acid biosynthesis (Special Topic E in WileyPLUS). Once formed, the linear polyketide cyclizes by enzymatic reactions akin to intramolecular aldol additions and dehydrations (Section 19.6). These steps form the tetracyclic core of akiavinone. Phenolic hydroxyl groups in akiavinone arise by enolization of ketone carbonyl groups present after the aldol condensation steps. Several other transformations ultimately lead to daunomycin ... 

The Vilsmeier reaction is used to this day in largely the same way as it was originally conceived, though its substrate scope continues to expand. One important variation, known as the Bischler-Napieralski isoquinoline synthesis, involves an intramolecular Fiedel-Crafts acylation reaction where the acylating agent resembles a Vilsmeier electrophile. If the acylated phenethylamine substrate contains an a-hydroxyl group, a subsequent dehydration yields an isoquinoline. ... 

Keeping in mind that 1 was projected as a key intermediate for the synthesis of a variety of steroids, the Woodward group next turned to contraction of the D-ring to the required acyl cyclopentene. The diol was liberated and cleaved to a dialdehyde using periodic acid. The dialdehyde was then subjected to piperidinium ion mediated intramolecular aldol-dehydration to provide 18. The aldol-dehydration also provided the regioisomeric enal as a minor product. The regioselectivity of this reaction was attributed to the apparent steric accessibility of the C17 methylene in the intermediate dialdehyde relative to the C15 methylene. The synthesis of 1 was completed in a straightforward manner. 

Reduction of the ketone 2 and dehydration of the resulting alcohol led, after deprotection and oxidation, to the ketone 12. Protection followed by P-ehmination gave the enone 13. Direct reductive amination of 13 failed, hut reduction of the methoxime was successful, giving, after acylation, the formamide 14. Reductive N-O bond cleavage followed by deprotection and isonitrile formation then set the stage for the planned intramolecular acylation to complete the synthesis of Welwitindolinone A Isonitrile 3. 

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