Acyliminium cyclization

M-Acyliminium cyclizations of optically active mono- and di-oxygenated hydroxylactam derivatives have been used in the synthesis of a number of natural products. In case of a five-membered lactam the oxygen function adjacent to the iminium carbon directs attack of the internal nucleophile from the least hindered side, opposite to the substituent. In the examples given the size of the newly formed ring is determined by the electronic bias of the alkene substituent. 

Vertaline (61) was synthesized through two routes that involve an W-acylimin-ium ion cyclization (20) and an intermolecular [3 + 2] cycloaddition (21,22) as the key steps, respectively. Model studies (20, 24) for assembling the quinolizi-dine moiety by the W-acyliminium ion cyclization are shown in Scheme 7. The benzyl alcohol 65 was converted to glutarimide 66 by the Mitsunobu procedure in 55% yield. Reduction of imide 66 with diisobutylaluminum hydride afforded 67, which was subjected to V-acyliminium cyclization to give the lactam 68 in 40% overall yield from 66. Lactam 68 possesses the correct stereochemistry at all chiral centers required for vertaline (61). 

The asymmetric syntheses of tetrahydroisoquinoline derivatives were also reported. Optically pure 3,4-disubstituted tetrahydroisoquinolines such as 78 were prepared by Friedel-Crafts cyclization of amino alcohols 77 <02TL1885>. Enantioselective syntheses of dihydropyrrolo[2,l-a]isoquinolines via a highly diastereoselective, chiral auxiliary assisted N-acyliminium cyclization was disclosed <02SL593>. The enantioselective synthesis (-)-tejedine, a seco-bisbenzyltetrahydroisoquinoline was also reported. One key step in this synthesis involved a chiral auxiliary-assisted diastereoselective Bischler-Napieralski cyclization <02OL2675>. Additionally, an asymmetric Bischler-Napieralski was reported for the preparation of 1,3,4-trisubstituted 1,2,3,4-tetrahydroisoquinolines <02JCS(P1)116>. 

The second proposal by Speckamp and co-woikers used an allylsilane as an excellent nucleophile for an A -acyliminium cyclization reaction (Esch et al. 1987) (Scheme 7.13). The 3-effect of the silicon atom is a powerM determinant of the regiochemistry of allylsilane reactions with electrophiles, so the new carbon-carbon bond is formed at the vinyl caibon distal to silicon, that is, at the y-position (Hiemstra et al. 1984,1985). 

Ent, H., De Koning, H., Speckamp, W. N. N-Acyliminium cyclizations via reversible 2-aza-Cope rearrangements. Tetrahedron Lett. 1985,... 

The N-acyliminium ion cyclization method for the synthesis of nitrogen heterocycles, developed by Speckamp and his collaborators, has also been applied to the synthesis of the vindorosine intermediate 529 (315). In this synthesis, the imine 531, derived from 3-(o-aminophenyl)-N-benzylsuccini-mide, was cyclized by base and acetylated to give 532, which was partially reduced to give the substrate 533 for N-acyliminium cyclization. Treatment of 533 with acid then gave the tetracyclic enol ester 534, which was converted into the target tetracyclic amino ketone 529a by obvious methods (Scheme 61) 315). 

Two more complex examples of this reaction type are used in work on the total synthesis of quinocar-cin and gelsemine. A vinyl sulfide is employed as nucleophile in an Af-acyliminium cyclization to produce the bridged substructure of quinocarcin (equation 96).A genuine equivalent of the Mannich reaction is put to practice in a synthetic approach to gelsemine (equation 97). The iminium intermediate, simply generated by protonation of the enecarbamate, apparently reacts only with the enol shown in (128). 

A practical synthesis of the unsaturated pyrrolizidine (+ )-heliotridane (101) was achieved via stereoselective acyliminium cyclization of (100). The ketene dithioketal substituent served both as an efficient cationic cyclization terminator and as a means of controlling double-bond migration regioselectively into the correct position <93JA3653>. 

The ability of succinimides 793 to be manipulated at C-2 in conjunction with the location of the acetoxy group makes such compounds ideal candidates for the synthesis of the pyrroli-zidine alkaloid framework (845). Strategically, this is accomplished by N-alkylation of 793a with a suitable group followed by regioselective reduction of the C-2 carbonyl and intramolecular acyliminium cyclization. 

New modifications of the traditional approach to isoquinoline synthesis via carbocation intermediates continue to be reported. Abnormal products of the Bischler-Napieralski reaction were observed <97JCS(P1)2217>. A stereoselective introduction of a quaternary carbon center in the A-acyliminium cyclization (Scheme 14) of the chiral enamide 46 affords an asymmetric synthesis of tetrahydroisoquinolines <97T2449,3045>. An asymmetric Pictet-Spengler reaction has been developed mediated by the chiral urethane 47 <97T16327>. A Pummerer reaction of A-acyl-A-(aryl)methyl-2-(phenylsulfinyl)ethylamine allows cyclization to the 4-phenylthio-... 

Scheme 14.21 Iwabuchi s synthesis of the BCD ring system of ent-(—)-daphnicyclidin A (139) via domino acyliminium cyclization/Mannich-type reaction.

D Asymmetric Pictet-Spengler and Related N-Acyliminium Cyclizations... 

SCHEME 40.77. Enantioselective JV-acyliminium cyclization cascades under chiral phosphoric acid catalysis. 

Dixon et al. reported on a direct enantioselective and diastereoselective intramolecular A-acyliminium cyclization through condensation of triptamines 350 with y- and 8-keto acid derivatives 351 using chiral phosphoric acid as the catalyst (Scheme 40.77). Tetracyclic ring 352 was obtained with good-to-excellent yield and excellent stereoselectivity. 

Acyliminium Cyclizations. Formation of acyliminium ions by treatment of a-hydroxy amides with methanesulfonyl chloride is a mild way of effecting acyliminium ion cyclizations. Under... 

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