Acyliminium ion cyclization

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]. 

Scheme 35 Stereoselective Prins cyclization by iron(III)-catalyzed W-acyliminium ion cyclization...

Scheme 1.29. Domino acyliminium ion cyclization/Ritter reaction procedure in the synthesis of CPG 49823 (1-116).

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]. 

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>. 

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... 

Tetracyclic benzo[/]-4-oxopyrrolo[l,2-fl]thieno[3,2-c]azepine 103a, as well as its piperidone homolog 103b, can be prepared through intramolecular N-acyliminium ion cyclization of hydroxylactams 102 (Scheme 20 (2001 HI 519)). 

The N-acyliminium ion cyclization of glutarimide 78c with terminal alkene does not show the usual selectivity in favor of ring contraction pyridobenzazepine 78d and the isomeric chloromethylquinolizidine are isolated in nearly equal amounts (10OL1696). 

Tetracyclic lactam 134 was similarly obtained from the hydroxylactam by N-acyliminium ion cyclization (01H(55)1519, 02BKC1623). 

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. 

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 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. 

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. 

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). 

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]. 

Intramolecular acyliminium-ion cyclization of 870 produces 871 with high stereoselectivity. Ozonolysis of the olefin affords 872 (the totally chiral version of 863). Lithium aluminum hydride reduction of 872 gives (— )-dihydroxyheliotridane (851) in 93% yield. 

Treatment with excess trifluoroacetic acid furnished the (dihydroiminoethano) carbazole 107 in 71% overall yield. Epoxidation of the alkene followed by a two-step protecting group modification gave epoxide 108, which underwent an oxidative epoxide opening followed by silyl protection to give silyl ether 109. Alloc deprotection, alkylation with (Z)-2-iodo-2-butenyl tosylate, followed by an intramolecular Heck reaction delivered pentacyclic diamine 110. A three-step formation of the p-ketoester 111 followed by a three-step reduction process afforded ester 112, which underwent a reduction and deprotection sequence to provide minfien-sine (99). A sequential catalytic asymmetric Heck-(V-acyliminium ion cyclization for the delivery of the enantiopure 3,4-dihydro-9a,4a-(iminoethano)-9//-carbazole is the highlight of the synthesis. 

Furthermore, sulfur containing compounds, especially a-S-function-alized acetamide derivatives are suitable precursors to assemble the erythrinane framework via a combined radical/acyliminium ion cyclization. Thus, treatment of the xanthate 178 (Scheme 31) with lauroyl peroxide causes B ring generation via the radicals 179 and 180. After further oxidation of the latter forming the acyliminium ion 181, cat-alytical amounts of p-toluenesulfonic acid induces the ring closure to the aromatic unit furnishing 15,16-dimethoxy-2,8-dioxoeiythrinane (175) in 82% yield (96). 

Finally, there is also only a single report descrihing the sequential formation of the rings A, B, and C of the erythrinane framework in one step. Starting from the complex homoveratrylimide derivative 191 this triple cascade process involves - apart from the initial Pummerer reaction 191 —1192 - the Diels-Alder reaction 192 —> 193 as well as the final acyliminium ion cyclization 194 —1195 providing the erythrinane 195 in 83% yield. This in turn could be converted to ( )-erysotramidine (73) by a sequence already reported (76) (Scheme 34). The requisite educt 191 has been smoothly prepared through six steps in 45% overall yield (80). 

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