Cyclization A-acyliminium ion

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. 

Another efficient synthesis of 3-demethoxyerythratidinone has been reported by the Zard group (Eq. 23) [51]. Trichloracetamide 77 was prepared in 3 steps from the monoketal of cyclohexan-l,4-dione. Treatment of 77 with excess nickel in acetic acid gave 78 in 49% yield. An A-acyliminium ion cyclization converted 78 to 79, and the synthesis was then completed via a 2-step sequence. This nickel-mediated cyclization-oxidation chemistry has also been used in model studies directed toward ( )-mesembrine [52]. 

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. 

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. 

This catalytic system has been applied to the synthesis of the core of complex antibiotic tetrapetalones. Hong and coworkers have successfully established the W-acyliminium ion cyclization in the preparation of 1-benzazepine derivatives. A combination of FeCls (0.5 equiv) and TMSCl (2 equiv) was selected as an optimized condition for such stereoselective cyclization (Scheme 35) [45]. 

Padwa s group has not only developed highly efficient domino reactions using transition metal catalysis, but they are also well known for their unique combinations of a cycloaddition and a N-acyliminium ion cyclization. An example of this strategy, which is very suitable for the synthesis of heterocycles and alkaloids, is the reaction of 4-98 to give 4-101 via the intermediates 4-99 and 4-100 (Scheme 4.22). Furthermore, 4-101 was transformed into the alkaloid (+)-y-lycorane 4-102 [32]. 

Hiemstra and co-workers reported the first example of an iodine-promoted allenyl N-acyliminium ion cyclization for the total synthesis of (+)-gelsedine, the enantiomer of the naturally occurring (-)-gelsedine [72], Compound 341 was prepared from (S)-malic acid. When 341 was dissolved in formic acid with a large excess of Nal and heated at 85 °C for 18 h, 343 was found to be the major product isolated in 42% yield. The latter was then successfully converted to (+)-gelsedine in a multi-step manner. Other routes without the allene moiety failed to provide the desired stereoisomer. The successful one-step transformation of 341 to 343 was key to the success of this synthesis. 

The domino cycloaddition-iV-acyliminium ion cyclization cascade has been extensively reviewed. Tandem reactions combining Diels-Alder reactions and sigma-tropic rearrangement reactions in organic synthesis have been extensively reviewed. The tandem Diels-Alder reaction between acetylenedicarboxaldehyde and N,N -dipyrrolylmethane has been extensively studied at the RHT/3-21G and RHF/6-31G levels.The molecular mechanism of the domino Diels-Alder reaction between hexafluorobut-2-yne and A,A -dipyrrolylmethane has been studied using density functional theory. 

Cheng JF, Chen M, Arrhenius T, Nadzan A (2002) A convenient solution and solid-phase synthesis of delta(5)-2-oxopiperazines via N-acyliminium ions cyclization. Tetrahedron Lett 43(36) 6293-6295... 

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 key step of this synthesis is a sequential asymmetric Heck-N-acyliminium ion cyclization of dienyl carbamate triflate 13 to provide enantiopure 3,4-dihydro-9a,4a-(iminoethano)-9/f-carbazole 16. This intermediate and related structures containing a 2,3-double bond should represent versatile precursors for constructing a variety of pentacyclic indole alkaloids containing the (hydroiminoethano)-carba-zole fragment. 

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... 

A particularly effective strategy for the design of new heterocyclic libraries employs a tandem N-acyliminium ion cyclization/nucleophilic addition for ring-forming processes [108] (Scheme 19). The described methodology provides access to bi-, tri-, and tetracyclic derivatives of l-acyl-3-oxopiperazines. The bicyclic variants in particular represent an interesting probe for a constrained type I p-turn motif with potential for combinatorial diversification. 

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