Balanol

Regioselective Beckmann rearrangements were used as key steps in the synthesis of phosphonoalkyl azepinones (Scheme 36) [43b] and in a formal total synthesis of the protein kinase C inhibitor balanol (Scheme 37) the optically active azide 197 derived from cyclohexadiene mono-oxide was converted into ketone 198 in several steps. After preparation of the oxime tosylates 199 (2.3 1 mixture), a Lewis acid mediated regioselective Beckmann rearrangement gave the lactams 200 and 201 in 66% and 9% yield, respectively. Lactam 201 underwent a 3-e im-ination to give additional 200, which served as a key intermediate in a balanol precursor synthesis (Scheme 37) [43 cj. 

A radical cyclization of this type was used to synthesize the 4-amino-5-hydroxyhexahydroazepine group found in the PKC inhibitor balanol. The cyclization involves an a-stannyloxy radical formed by addition of the stannyl radical to the aldehyde oxygen. 

Various efforts have been made to produce the Balanol nucleus, a chiral azepine ring, and many of the synthetic routes include a Beckmann rearrangement to produce the... 

Pollini and colleagues converted D(—)-quinic acid in five steps into a chiral oxime 395, R = H in an enantiomeric pure form and subjected this oxime to a Beckmann rearrangement (equation 161). Even though the reaction lacked selectivity, 395 was useful in the synthesis of the chiral epoxide 396, a key intermediate in the synthesis of (—)-Balanol 397. The same authors also prepared the isomeric epoxide 398. 

Another chiral synthesis of the azepine nucleus of Balanol (397) was developed by Wu and Jacobsen, once again converting a cyclohexanone oxime tosylates 399 to a seven-membered lactam (equation 162). The use of a mixture of oxime isomers did not cause... 

The same catalyst IX was used in the RCM of a functional diene to give, in 87% yield, a tetrahydroazepine derivative which is a precursor in the synthesis of the metabolite (-)-Balanol (Equation 8.9) [44]. 

This reaction was utilized to establish the vincinal amino alcohol stereochemistry required for the construction of key intermediates 251 and 252 for the synthesis of the natural product balanol 253 (Scheme... 

Several truncated analogs of the natural product balanol 71 were prepared on a solid phase by Nielsen and Lynso.33 Thus, symmetrical di-acids were linked to Wang resin, followed by coupling a number of FMOCprotected... 

Nielsen, J. Lynso, L. O. Combinatorial Solid-Phase Synthesis of Balanol Analogues, Tetrahedron Lett. 1996, 37, 8439. 

A stereoselective synthesis of the azepane core of the protein kinase C inhibitor and fungal metabolite, (—)-balanol, and involving C-N bond formation in the ring forming step, has been described (Scheme 13) <2006TL1585>. The... 

The azepane-ring containing metabolite (—)-balanol, 349, from the fungus Verticillium balanoides <1993JA6452, 1994JAN639>, was found to be a potent ATP-competitive inhibitor of the protein kinase A (PKA) (Ki = 3.9nM)... 

Sullivan B, Hudlicky T (2008) Chemoenzymatic formal synthesis of (—)-balanol. Provision of optical data for an often-reported intermediate. Tetrahedron Lett 49 5211-5213... 

An impressive application of an aldehyde-oxime coupling was reported by Nicolaou in their studies on the total synthesis of the complex natural product diazonamide A (see Chapter 7, Section 7.4).29,30 Naito31 and Skrydstrup32 have reported impressive applications of the heteropinacol cyclisation for the stereoselective synthesis of the azepine ring of the PKC-inhibitor balanol (see Chapter 7, Section 7.4). 

During a synthesis of the protein kinase C inhibitor Balanol. Lampe and co-workers77 found that deprotection of the tert-butyl ester 30.1 [Scheme 6.30] with trifluoroacetic or formic acid was accompanied by substantial quantities of a debenzylated by-product. The same side reaction accompanied thermolytic cleavage of the terf butyl ester in neutral solvents presumably due to add catalysis by the carboxylic acid product 30.2. Thermolysis in quinoline at 205 °C led cleanly to the desired benzophenone carboxylic acid 30.2 in 68% yield. 

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