Spirolactams, synthesis

The formation of numerous ring-substituted spirolactams (53b) employed this methodology, which to date has also found application in a number of natural product syntheses. For example, the critical spirane junction-forming step in the synthesis of the muscarinic Mj receptor antagonist (—)-TAN1251A (58) from L-tyrosine involves PIFA-induced cyclization of the hydroxamic ester 56 to 57 according to Scheme 12 °. 

Hydroxy-lactam 26 (n=2) gave spiroisomer 27 (n=2), albeit in lower yield, under similar conditions. The same authors 191 have also reported the successful cyclization of hydroxy-lactam 29 into spirolactam 30. Analogous results were obtained by Evans and Thomas (10) who found that the cyclization of a 9 1 mixture of enamides 31 and 32 in anhydrous formic acid gave the spirocompound 30. This compound is a key intermediate in Kishi s total synthesis of perhydrohistrionicotoxin (11, 12). 

Scheme 2. Synthesis of the spirolactam part (2) of sanglifehrin A (1) by Nicolaou et al.

Scheme 17. Synthesis and absolute configuration of the spirolactam inhibitor of UROS...

Further evidence for the specificity of the interaction of UROS with the spirolactam 48 came when its two enantiomers were separately prepared by including a resolution step halfway through the synthesis [70]. One of the two enantiomers inhibited UROS at least 20 times more strongly than the other. The unsubstituted parent spiro ring system of 48 does in fact have a plane of symmetry and the difference between the enantiomers lies only in the arrangement of the acetate and propionate side-chains on the three pyrrolic rings of the macrocycle. This makes the discrimination shown by the enzyme between the two enantiomers all the more impressive. 

In 1990, Bryce and co-workers (79) reported syntheses of several cephalotaxine analogs (Schemes 44 and 45). The synthesis of 257 commenced with the known spirolactam 245, used previously by Hill (75) and these authors... 

In summary, the total synthesis of (-)-FR901483 was accomplished by an oxidative cyclization of a phenolic oxazoline to a spirolactam in the key step. The longest linear sequence leading to FR901483 through a Snider-type inversion encompasses 20 steps from commercial L-tyrosine and it proceeds with an overall yield of 1%. The alternative synthesis involving a Sorensen-type Mitsunobu inversion is shorter (17 steps), and it affords identical overall yield (1.3%). 

Useful synthetic methodologies are based on the cyclization or rearrangement of the nitrogen-centered radicals generated in the reaction of the appropriate amides with (diacetoxyiodo)benzene in the presence of iodine [652-655]. Specific examples are illustrated by the synthesis of bicyclic spirolactams 622 from amides 621 [653] and preparation of the oxa-azabicyclic systems (e.g., 624) by the intramolecular hydrogen atom transfer reaction promoted by carbamoyl and phosphoramidyl radicals generated from the appropriately substituted carbohydrates 623 (Scheme 3.244) [654],... 

Other important applications of Barton reaction are in the synthesis of alkaloids and terpenoids. For example, the photolysis of nitrite 6 was used in a crucial step in the synthesis of alkaloid perhydrohistrionicotoxin 7 [6]. The oxime 8, formed in about 20 % yield, gives the spirolactam ring of the alkaloid 7 on Beckmann rearrangement. 

A formal synthesis of ( )-perhydrohistrionicotoxin has been described.The important aspects of the synthesis are detailed in Scheme 87. Although cycliza-tion to the spirolactam gave two products in almost equal amounts, the desired ring closure to the 6,6-azaspirane system proceeded with high stereoselectivity, thus establishing three of the four requisite stereocentres for perhydro-histrionicotoxin (54) in a single step. 

Romo and coworkers have utilized an enantioselective Cu(II)-catalyzed Diels-Alder cycloaddition to set the key all-carbon quaternary stereocenter in the spiro-cyclic imine core of the marine toxin immunogen (—)-Gymnodimine (251) [76]. Cu(SbF6)2/t-Bu-BOX (13)-catalyzed cycloaddition of diene (248) to a-methylene lactam (247) provides spirolactam (249) in high yield with high stereoselectivity (Scheme 17.55). Subsequent synthetic efforts resulted in an efficient synthesis of the spirocyclic imine portion of (251). 

In 2009, Kemmerer et al. uncovered a phosphine-free carbopalladation/allylic alkylation cascade sequence for the synthesis of 4-(a-styryl) y-lactams 308 [106] (Scheme 6.79). The reaction pathway of this transformation involves the formation of Jt-allylpalladium(n) species 307, which was trapped by the intermolecular active methylene. Both electron-rich and electron-deficient aryl iodides could be introduced efficiently to this cascade process. Li and Dixon developed a stereoselective and efficient protocol for the synthesis of spirolactam 310 employing a similar carbopalladation/jt-allylpalladium trapping strategy [107] (Scheme 6.80). 

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