A -Acyliminium cyclizations

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). 

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-... 

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 A -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). 

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. 

Cyclizations of A-acyliminium ions containing a 3-alkenyl substituent tethered to nitrogen usually proceed with preferential formation of a six-mentbered ring via a chair-like transition state, if the alkene does not have an electronic bias. 

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. 

So far, only reactions in which the internal nucleophile is tethered to the nitrogen atom of the A -acyliminium ion have been discussed, however, cyclizations with nucleophiles attached to other positions are also possible. If the nucleophile is connected to the carbon atom adjacent to the carbonyl group, bridged azabicycloalkane derivatives are obtained in high yield by using the more reactive allyl- or propargylsilanes. 

Enantiospecific syntheses of amino derivatives of benzo[ ]quinolizidine and indolo[2,3- ]quinolizidine compounds have also been achieved via A-acyliminium ion cyclization reactions, as an alternative to the more traditional Bischler-Napieralski chemistry (see Section 12.01.9.2.2). One interesting example involves the use of L-pyroglutamic acid as a chiral starting material to construct intermediates 240 via reaction with arylethylamine derivatives. Diisobutylaluminium hydride (DIBAL-H) reduction of the amide function in 240 and subsequent cyclization and further reduction afforded piperidine derivatives 241, which stereoselectively cyclized to benzo[ ]quinolizidine 242 upon treatment with boron trifluoride (Scheme 47) <1999JOC9729>. 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

Kano and co-workers.Once the 2,4-oxazolidinedione moiety has been incorporated, amide reduction then affords an a-hydroxy lactam, the key N-acyliminium ion precursor. Representative examples of 2,4-oxazolidinediones and the products derived from A -acyliminium ion cyclization are shown in Schemes 6.61-6.63, pp. 110-112. 

Upon addition of boron trifluoride etherate, acetoxylactam 8 eliminates an acetoxy group to produce A-acyliminium ion 9. The indo-lizidinone 10 is formed diastereomerically pure in an iminium-ion-ini bated cyclization reaction of the Overman type ending in a vinyl-silane.14... 

The bromination of the tetracyclic compound (30) affords71 the novel compound (31) formed by capture of the Wheland intermediate by die neighbouring carboxylate ion. The intramolecular reaction of some activated pyridines witii A -acyliminium ions led to some novel heterocycles [e.g. (33) from (32) in the presence of p-toluenesulfonic acid in benzene] by cyclization para to an electron-donating substituent.72... 

Cyclization reactions of a-acyliminium ions with allyl- and propargyl-silanes constitute a useful method for the preparation of various N-bridgehead bicyclic systems. Thus, from a reaction of hydroxylactams 107 and 108, the azaazulenes 109 and 110 were obtained in excellent yields (83TL1407). Similarly, the keto amide 112 was obtained from the imide 111 by reduction to the corresponding hydroxylactam and acid-catalyzed cyclization (84JCS(P1)2477). 

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 first step in the mechanism of the Biginelli reaction is the acid-catalyzed condensation of the urea with the aldehyde affording an aminal, which dehydrates to an A/-acyliminium ion intermediate. Subsequently, the end form of the 3-keto ester attacks the A/-acyliminium ion to generate an open chain ureide, which readily cyclizes to a hexahydropyrimidine derivative. 

A-Acyliminium ions are suitable partners for electrophilic addition reactions of allylstannanes. Although the corresponding silanes have been more widely studied in these cases/ allylic stannanes are fully competent reaction participants, as illustrated by formation of the l-azabicyclo[3.1.0]pentane 159 via intra-molecular cyclization of the fi-allylic stannane 157 (Scheme 5.2.33). The reaction produces the vinyl cyclopropane under protic acid conditions with complete stereocontrol. s... 

In spite of the success of the intra-molecular cyclization, the generation of the reactive A-acyliminium ion under aprotic conditions is desirable, to avoid competing protodestannylation. Yoshida and coworkers have demonstrated a three-component coupling in which the enamide 160 reacts with the A-acyliminium ion 161 yielding a stabilized A-acyliminium species 162, which is captured by allyl-tri-n-butylstannane to give 163 (Scheme 5.2.34).5o... 

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