N-acyliminium ion cyclizations

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. 

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). 

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). 

Manteca, L Sotomayor, N. Villa, M.-J. Lete, E. Tandem carbophilic addition-N-acyliminium ion cyclization for the synthesis of functionalized pyrrolo[2,l-a]isoquinolones Key intermediates for the preparation of Erythrina -type alkaloids. Tetrahedron Lett., 1996, 37, 7841-7844. 

In another beautiful application, Overman et al. developed the total synthesis of the natural product (+)-minfiensine (130), having a l,2,3,4,-tetrahydro-9a,4a-(iminoethano)9H-carbazol core (Scheme 7.29) [80]. The key step in their synthesis is a tandem process consisting of a catalytic asymmetric Mizoroki-Heck ring closure and an N-acyliminium ion cyclization of dienyl carbamate triflate 127 (127—>128). The reaction proceeded smoothly using the Pfaltz ligand (S)- Bu-PHOX (85), providing (dihydroiminoethano)carbazole 129 after the addition of excess trifluoroacetic acid, with 75% overall yield and 99% enantiomeric purity (127 129). 

In 1997, the controversial mechanism of the Biginelli reaction was reinveshgated by Kappe using NMR spectroscopy and trapping experiments [94], and the current generally accepted process was elucidated (see Scheme 9.23). The N-acyliminium ion 9-112 is proposed as key intermediate this is formed by an acid-catalyzed reaction of an aldehyde with urea or thiourea via the semiaminal 9-111. Intercephon of 9-112 by the enol form of the 1,3-dicarbonyl compound 9-113 produces the open-chain ureide 9-114, which cyclizes to the hexahydropyrimidine 9-115. There follows an elimination to give the final product 9-116. 

Other types of N-acyliminium ion-based cyclizations that are assisted by micro-wave irradiation are highlighted in Scheme 6.235 [418],... 

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. 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

In 2004, Taylor and Jacobsen suggested a procedure for the enantioselective acetyl-Pictet-Spengler reaction, that is the cyclization of electron-rich aryl or heteroaryl groups onto N-acyliminium ion enabling access to substituted tetrahydro-P-carbolines and tetrahydroisoquinolines that are core structure elements in natural and synthetic organic compounds [202, 203]. Screening various thiourea catalyst candidates such as 47 in the formation of model product Np-acetyl-... 

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. 

We used this method as the key sequence in the synthesis of ( )-lycopodine (78). The intramolecular isomiinchnone cycloadduct 81 was envisaged as the precursor of the key Stork intermediate 79 (via 80) [42]. The heart of our synthetic plan was the formation of the latter intermediate by a Pictet-Spengler cyclization of the N-acyliminium ion derived from 81. Central to this strategy was the expectation that the bicyclic iminium ion originating from 81 would exist in a chair-like conformation [42,43]. Cyclization of the aromatic ring onto the iminium ion center should take place readily from the axial position. The readily available heptenoic acid 82 would serve as the precursor for the a-dia-zoimide, the direct progenitor of the isomiinchnone dipole. This extension of the tandem cycloaddition-cationic 1-cyclization protocol to the formal synthesis of ( )-lycopodine (78) is outlined below. 

The cycHc urea moiety provides structural rigidity as well as hydrogen-bonding possibihties similar to those of the imidazoles described above. The corresponding 2-imidazolones have been prepared on a soHd phase by tandem aminoacylation of a resin-bound allylic amine with an isocyanate followed by intramolecular Michael addition [73]. However, due to the paucity of data presented on the characterized compounds and the brief experimental procedure, this synthesis is not discussed in detail. Access to cyclic ureas or thioureas has also been obtained by reaction with carbonyl- or thiocarbonyldiimidazole through a cyclo-release mechanism [74—76]. 1,3-Dihydroimidazolones have been obtained by treatment of ureido acetals with TFA and subsequent conversion in an intramolecular cyclization via an N-acyliminium ion [77]. 

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