Synthesis of Aglycon

Ketal 73 can be formed in a yield of about 60 % by refluxing a solution of tetronic acid (36), ethylene glycol, and a catalytic amount of para-toluenesulfonic acid in benzene for approximately 12 hours. With only one electrophilic site, 73 reacts smoothly with Dibal-H to give lactol 35 in 84% yield. Compound 35, a participant in a ring-chain tautomeric equilibrium process,18 should be regarded as a latent aldehyde. This substance can, in fact, serve as 

It will be noted that intermediate 33 contains all of the carbon atoms and the two stereocenters of the targeted aldoxime 32. At the outset, it was anticipated that the terminal oxime function in 32 could be formed by the condensation of hydroxylamine with the 

30 and 78, in 65% overall yield (30 78 ca. 3.5 1) together with 20 % of acyclic unsaturated ester 80. It is presumed that the action of sodium hypochlorite on 32 generates, through the intermediacy of an a-chloroaldoxime, unsaturated nitrile oxide 31. This substance is not isolated once formed, it readily participates in the desired 1,3-dipolar cycloaddition reaction to give a ca. 3.5 1 diastereomeric mixture of isoxazolines 30 and 78. Unsaturated ester 80 presumably arises from the decomposition of nitrile oxide 31, a process that is likely induced by one of the adjacent ketal oxygen atoms (see 

With the exocyclic alkylidene at C-13 properly in place, the elaboration of the l,5-diyn-3-ene moiety can now be addressed. Cleavage of both acetate and trimethylsilyl functions in 86 with basic methanol, followed by triethylsilylation of the newly formed tertiary hydroxyl group, efficiently affords alkyne 25 (86 % overall yield). This substance was regarded as a viable candidate for a Pd-catalyzed coupling reaction.12 Indeed, treatment of 25 with (Z)-chloroenyne 26 in the presence of a catalytic amount of Pd(PPh3)4 and Cu1 results in the formation of enediyne 24 in 91 % yield. 

3 Coupling of Intermediates 8 and 9 and Completion of the Total Synthesis of Calicheamicin y  

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Total synthesis of aglycone of venturicidines A and B 90YZ789 91 YGK657. 

The synthesis of aglycon 154c is summarized in Scheme 64. The synthesis of 442, corresponding to the southern segment, started with aldehyde 439 derived... 

These derivatives were obtained by total synthesis of aglycone. The 14-fluoro-IDA/DAUNO 54 was obtained in several steps by 7-deoxy-idarubicinone/ daunorubicinone (Scheme 13) [42-47]. 

The fact that many published homochiral intermediates lack any functionality at the future 7-position makes these less than ideal for the efficient synthesis of aglycones. Kishi has developed a synthesis of 11-deoxyanthracyclinones in which both 7- and 9-hydroxyl functions are introduced stereoselectively during the construction of ring-A. Thus asymmetric crossed aldol reaction of the acetal 193 with 194 gave a 17 1 mixture of 195 and its C-7 epimer. Base catalysed cyclisation followed by removal of the C-10 ester function yielded the trans-dioxygenated product 197. This was epimerised to give an 8 1 mixture of 198... 

Scheme 14.30 Combined DoM-Suzuki-Miyaura cross-coupling-DreM. Synthesis of aglycones of gilvocarcins V 148, M 149, and E 150 and arnottin I 151 [144aj.

The cyclized products 393 can be prepared by the intramolecular coupling of diphenyl ether or diphenylamine(333,334]. The reaction has been applied to the synthesis of an alkaloid 394[335]. The intramolecular coupling of benzoyl-A-methylindole affords 5-methyl-5,10-dihydroindenol[l,2-b]indol-10-one (395) in 60% yield in AcOH[336]. Staurosporine aglycone (396) was prepared by the intramolecular coupling of an indole ring[337]. 

Erythromycins. Erythromycin A (14, R = OH, R = CH3, R" = H), the most widely used macroHde antibiotic, was the principal product found in culture broths of Streptomjces eTythreus (39), now reclassified as Saccharopoljspora eythraea (40). It contains a highly substituted aglycone, erythronoHde A, (16, R = R = OH) to which desosamine (1, R = OH, R = H) and cladinose (8, R = CH ) are attached (41). The complete stereochemistry of erythromycin A was estabUshed by x-ray analysis of its hydroiodide dihydrate (42) total synthesis of erythromycin A was a landmark achievement (43), a task previously considered hopeless (44). 

Chemical degradation of erythromycin A yielded its aglycone, erythronoHde A (16, R = R = OH), whereas erythronoHde B (16, R = H, R = OH) was obtained from fermentation (63,64). Biosynthesis of erythromycin proceeds via 6-deoxyerythronoHde B (16, R = R = H) and then erythronoHde B (64,65). The first total synthesis of erythromycin-related compounds was erythronoHde B (66) syntheses of erythronoHde A and 6-deoxyerythronoHde B soon foUowed (67,68). 

The Michael addition of the carbanions derived from esters to nitroalkenes followed by reductive cycLizadon has been used extensively for the preparation of pyrrondin-3-ones fEq 1076 This strategy is used for synthesis of the carbaaole alkaloid staurosporine aglycon CK-352c ... 

The described chemistry leading to the synthesis of key building blocks 16-19 sets the stage for the completion of the total synthesis of both amphotericin B (1) and its aglycon, amphoteronolide B (2). 

Finally, although ultimately successful, the glycosidation studies on amphotericin B (1) reemphasize the difficulties encountered in this important area of synthesis. Of course, the /J-glycosidic bond linking the aglycon with the mycosamine, in combination with the... 

Scheme 34. The Stille reaction in Evans s synthesis of (+)-A83543A (lepicidin) aglycon (131).

A similar synthetic strategy was applied in the synthesis of menogaril 83, another important anthracycline antitumour antibiotic, and to the synthesis of the tricyclic core of olivin 87, the aglycon of the antitumour antibiotic olivomycin [61,62]. In both cases a tandem benzannulation/Friedel-Crafts cyclisation sequence yielded the tetracyclic and tricyclic carbon core, respectively (Scheme 42). 

The utility of RCM methodology for the synthesis of open-chain building blocks from a,fi-unsaturated d-lactones is exemplified by the partial syntheses of Cossy aimed for (+)-methynolide (the aglycon of the methymicin family of macrolide antibiotics) [45], and the anticancer agent discodermolide [46], as well as during a recent total synthesis of the highly cytotoxic marine natural depsipeptide apratoxin A by Forsyth and Chen [47]. 

Chlorothricolide, the aglycon of the chlorothricin antibiotic, is a complex molecule containing an octahydronaphthalene unit. Roush and Sciotti [121] recently reported the total enantioselective synthesis of chlorothricolide. The multiple Diels-Alder reaction between poliene 130 and chiral dienophile (R)-131 was the key step in the synthetic process (Scheme 2.50). The interaction... 

Recently, Mander and coworkers [122] reported the total synthesis of sordaricin (4-347), the aglycone of the potent antifungal diterpene sordarin which was first isolated in 1971 from the ascomycete Sordaria araneosa. Two approaches were explored the first method utilized a possible biogenetic Diels-Alder reaction the second was based on a domino retro-Diels-Alder/intramolecular Diels-Alder process. Thus, heating of 4-348 led, with extrusion of cyclopentadiene, to a 1,3-butadiene as intermediate which underwent an intramolecular Diels-Alder reaction to give the desired 4-349 as the main product, together with a small amount of 4-350 (Scheme 4.77). 

The oxidative formation of p-benzoquinones from anilides such as 7-108 was used for the synthesis of the core scaffold of the natural products elisabethin A (7-106) and pseudopterosin A aglycone (7-107) (Scheme 7.30). Exposure of anilide 7-108 to DMP [53] led to the formation of the o-imidoquinone 7-109, which underwent an intramolecular Diels-Alder reaction to give 7-110 in 28% yield after hydration. In a competitive pathway, the p-quinone 7-111 is also formed from 7-108, which on heating in toluene again underwent an intramolecular Diels-Alder reaction to give cycloadduct 7-112 in 25% overall yield. Hydrolysis of 7-112 furnished the carbocyclic skeleton 7-113 of elisabethin A (7-106). 

Clive and coworkers have reported a total synthesis of calicheamicinone, the aglycon of the antitumor agent calicheamicin starting from the Diels-Alder reaction of methyl 3-nitro-propenoate with ketene acetal (Eq. 8.32).54 An asymmetric Diels-Alder reaction between ketene acetal presented in Eq. 8.32 and 3-nitropropenoate derived from (-)-8-phenyl-menthol affords the optically pure adduct, which can be converted into either enantiomer of calicheamicinone (Eq. 8.33).55... 

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