Cyclization Pictet-Spengler acyliminium

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-... 

Scheme 6.53 Proposed mechanism for the 53-catalyzed asymmetric Pictet-Spengler-type cyclization of P-indolyl ethyl hydroxylactams Hydroxylactam (1) forms chlorolactam (2) followed by chiral N-acyliminium chloride-thiourea complex (3) and the observed product generated by intramolecular cyclization catalysis and enantioinduction result from chloride abstraction and anion binding.

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. 

Mechanistically, the sequence commences by coupling of the (hetero)aroyl chloride 7 and the aUcyne 4 to give the alkynone 8 (Scheme 43). Upon addition of the tryptamine derivative 73 the enaminone 75 is obtained. Finally, the addition of the a, p-unsaturated acid chloride 71 triggers the aza-annulation reaction to furnish the acyliminium ion 76 which terminates the sequence by a Pictet-Spengler 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-... 

Strictly catalytic enantioselective Pictet-Spengler cyclizations of tryptamine imi-nes have been rather elusive to date. The most successful results were achieved with A-acyliminium intermediates and thiourea catalysts. The reactions proceed through... 

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

Previously, Ascic et al. [43] reported the same reaction with the Hoveyda-Grubbs II catalyst and trifluoroacetic acid as a bicatalytic system, but as a racemic version [43]. The intermediate acyliminium ion readily attacks also other tethered nucleophiles, such as trimethoxybenzene, benzothiophene, thiophene, 0,0-dimethyl catechol, and furan, intramolecularly. When tryptophane or the corresponding alanine derivatives are employed, reasonable levels of diastere-oselectivity can be observed for the terminal Pictet-Spengler acyhminium cyclization. Even a tethered alcohol functionahty diastereoselectively traps the chiral acyhminium intermediate, furnishing bicychc OAf-acetals. 

However, the final Pictet-Spengler intramolecular cychzation required the further optimization because there are two modes of nucleophilic attack by indole or DOPA moiety. When indoles underwent Pictet-Spengler-type cyclization with cyclic A-acyliminium moieties that were generated in situ from masked aldehyde and amide nitrogen under acidic conditions, two modes of nucleophilic attack became possible—at carbon positions C2 and C3 in indole (Scheme 5.2a). C2 attack can afford the formation of a 3,9-diazabicyclo... 

On the basis of the successful application of intramolecular tandem Pictet-Spengler cyclization of active V-acyliminium intermediates to construct small molecules library embedded with diaza-bridged heterocycles in Section 5.2.1.1, we also developed a solid-... 

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