Spirolactams

Cu2+ and Hg2+ are perhaps the most obvious targets for reaction-based signaling systems. However, this approach has also been realized for monovalent Ag+. Here, again a rhodamine derivative (rhodamine B spirolactam 48, Fig. 18) allows the highly selective detection of Ag+ with a detection limit of 14 ppb in water containing 20% ethanol. Silver nanoparticles, a topical analyte today, can also be detected, after oxidation of the particles with H2O2/H3PO4 [141]. The selectivity was tested with Ca2+, Ba2+, Mg2+, Cr2+, Mn2+, Fe3+, Co2+, Ni2+, Cu+, Cu2+, Zn2+, Pd2+, Cd2+, Hg+, and Hg2+ and no interference was found. 

On the other hand, we also planned alternative completely new approach (Route B) to Nakadomarin A, which involves the spirolactam followed by coupling reaction with furan derivative and subsequent intramolecular electrophilic substitution reaction of an iminium cation generated from an aminal to give highly functionalized tetracyclic core system (Scheme 10.3). 

For this purpose, the chiral acid (R)-(-)-22 was chosen as the starting material and converted to the spirolactam 25. Condensation with benzylamine followed by catalytic dihydroxylation and oxidation gave aldehyde 23. 

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 °. 

The (7 )-4,4- and the 5,4-spirolactam systems were also used to induce a (1-turn in the H-Pro-Leu-Gly-NH2 sequence (i.e., 79 and 80, Scheme 30).111031 Analysis by X-ray crystallography indicated that the structures form a type-II 3-tumJ104l Previous studies 110 with a series of neurokinin antagonists had shown that the extended conformation is favored for the (/ )-4,4-spirolactam system however, the (5)-4,4-spirolactam demonstrated a type-II l-tum conformation. 

A new approach to spirolactams involving the thermal reaction of A-unsaturated alkyl /1-carboxamidoenamines in which the enamine is the hetero-ene component has been reported.326 A-Alkylnitrilium salts have been shown to undergo ene reactions with electron-rich alkenes to afford either 2-azoniaallene salts (where the nitrilium salt acts... 

The formation of spirolactams 47-49 could be rationalized in terms of a sequence domino cyclization of a-allenols-cross coupling reactions. A palladium (Il)-catalyzed mechanism for the domino sequence leading to spiranic adducts 47-49 is proposed in Scheme 17. It could be presumed that the initially formed allenepalladium complex 50 undergoes an intramolecular attack by the hydroxyl group (oxypalladation), giving rise to the spirocyclic vinylic palladium species 51. 

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). 

The more challenging task of direct C-N bond formation has recently been accomplished by utilization of the oxazoline ring as the nitrogen donor [76 - 78]. This approach was demonstrated by the preparation of spirolactams such as 17 from oxazoline derivatives of tyrosine and related phenolic acids by oxidation with BAIB in trifluoroethanol (Scheme 25), and similar conversions of indole-tethered oxazalones to tetracyclic products through spirolactam intermediates. It is noteworthy that phenolic amides, amines, and iminoethers were not useful for this purpose [78]. 

Lactams.2 N,N-Dialkenyl-P-oxoamides are oxidized by Mn(OAc)3 to lactams and spirolactams via a radical cyclization. Ethanol is a better solvent than acetic acid or acetonitrile. 

The syntheses of the spirolactam part (C26-C41) of sanglifehrin A (1), outlined in Schemes 2 and 3, is discussed first. Both groups start with a stereoselective syn aldol addition to form the bond between C36 and C37. Nicolaou et al. continue with the connection of C33 and C34 by stereoselective anti aldol addition and stereoselective formation of the C39-C40 bond by an Ireland-Claisen rearrangement. Unlike Nicolaou et al., Duan and Paquette chose the formation of the bond between C32 and C33 as their second key step. 

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

The indolic oxazolines 145 appear to behave similarly with DAIB in TFE, but in this case, the putative spirolactam intermediates 146 are converted spontaneously to diastereomeric mixtures of the tetracyclic structures 147 (99TL4985, OOJOC4397). 

The conversions shown in Scheme 18 interrelate a number of alkaloids and in conjunction with optical circular dichroism evidence establish the structure of spiropachysine (359), a major alkaloid in the leaves of Pachysandra terminalis Sieb. et Zucc. (Buxaceae), unique in possessing a five-membered spirolactam system.189 Spiropachysine (359) was reduced by lithium aluminium hydride to the deoxo-compound (360), whose dimethiodide on Hofmann degradation yielded two materials, the more strongly basic being a mixture of two olefins (361) which both afforded on hydrogenation the compound (362). The last compound was also prepared from... 

This reaction type was also reported by Cossy who applied an intramolecular reaction for preparing azaspiranic systems (Scheme 6). A-Diallylaminocarbonyl enamine 10 was oxidized by Mn(III) acetate to generate cation radical CRIO, which cyclized to give spirolactam 11. 

A route to spirolactams involves oxidation of oxazolines derived from t)rosine. Simple amides give the corresponding spirolactones. ... 

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