Isoquinuclidine synthesis

The ability of 1,2 (or l,6)-dihydropyridines to undergo a Diels-Alder reaction with dienophiles such as methyl vinyl ketone, methyl acrylate, and acrylonitrile has been utilized in the synthesis of polyfunctional isoquinuclidine as a key intermediate in the synthesis of aspidosperma- and iboga-type alkaloids (66JA3099). 

Hodgson, D.M. Galano, J.M. (2005) Enantioselective Access to Isoquinuclidines by Tropen-one Desymmetrization and HomoaHylic Radical Rearrangement Synthesis of (-F)-Ibogamine. Organic Letters, 1, 2221-2224. 

Two RCM reactions were employed in a new and efficient route to a key chiral intermediate, isoquinuclidine 150, in the synthesis of alkaloid (-F)-catharanthine <06AG(I)5334>. The first RCM makes use of chiral enone 151, derived from L-serine, to generate a chiral dihydropyridinone 152. Intramolecular alkene metathesis of dialkenyl piperidine 153 generates 150, which represents the first example of the use of RCM in the generation of an azabicyclo[2.2.2]alkene system. 

It has been known since 1939 that the 1,2-dihydropyridine ring system is capable of behaving as a four-electron component in the Diels-Alder reaction (39LA(538)195). This reaction produces the isoquinuclidine ring system and has proven to be the method of choice for the synthesis of this heterocyclic ring system. For example, a classic synthesis of ibogamine (248) used the Diels-Alder reaction of 1,2-dihydropyridine (246) to construct the isoquinuclidine portion of this alkaloid (Scheme 45) (66JA3099). 

Dihydropyridines have also been starting points for stereospecific syntheses of hydro-phenanthridines and isoquinolines. Interest exists in these compounds because of the occurrence of this structural feature in alkaloids. For example, isoquinuclidine (263), derived from JV-alkoxycarbonyl-l,2-dihydropyridine, undergoes a Cope rearrangement to give the isoquinoline derivative (264) (80JA6157). Further chemical transformations of (264) provided a formal total synthesis of reserpine (Scheme 50). 

Trost s synthesis138 of desethylibogamine (233) illustrates the application of a new approach to alkaloid synthesis, in which the two vital cyclization processes involve catalysis by palladium complexes protection of the nitrogen by formation of an amide, so often necessary in conventional syntheses, is here unnecessary. The first of the cyclization processes, (234)—>(235), results in a very neat formation of the isoquinuclidine ring system via a palladium-catalysed SN2 cyclization of the tryptamine derivative (234) (Scheme 24). 

Scheme 11.13 An improved synthesis of isoquinuclidine from ethyl p-aminobenzoate.

Cooperative Co-Catalysis The Effective Interplay of Two Brpnsted Acids in the Enantioselective Synthesis of Isoquinuclidines... 

The products are reasonably stable, and are useful for Diels-Alder reactions. An example is the synthesis of an isoquinuclidine (4). ... 

Isoquinuclidine (2-azabicyclo[2,2,2]octane), catalytic synthesis of 88MI25. 

Further applications can be mentioned briefly. SAMP was used in the resolution of 4-demethoxy-7-deoxydaunomycinone/ in ee determinations (Scheme 1), as a chelate for tetracarbonylmolybdenum complexes/ in intramolecular Heck reactions, as polysilylated hydrazine, in the enantioselective synthesis of isoquinuclidines, and in the conversion of hydrazones to aldehydes and nitriles. The structure of a chiral lithium SAMP hydrazone azaenolate has been determined. In cases where SAMP did not lead to satisfactory inductions, a modified auxiliary, (S)-l-amino-2-dimethylmethoxymethylpyrrolidine (SADP), enhanced the stereochemical control. 

The propensity of 1,2-dihydropyridines to undergo the Diels-Alder reaction has been used to separate mixtures of 1,2 and 1,4 isomers. - Fowler separated out 1,4-dihydropyridines by reaction of the 1,2 isomer 82 with maleic anhydride (85). Other workers have utilized the Diels-Alder adducts 84 in the synthesis of isoquinuclidines. ... 

The isoquinuclidine ring system is readily accessible through various synthetic routes. The most widely used approach to the construction of the ISQ ring system is through Diels-Alder or 4+2 cycloaddition reactions. Dihydropyridines (DHPs) or 1,3-cyclohexadienes are most commonly employed as diene components and various dienophiles have been employed based on the substitution pattern of the final desired product. Intramolecular cyclizations, tandem-Michael addition/aldolizations or cyclization via tricyclic aziridines or perhydro / -aminobenzoic acid derivatives have also been reported. Several synthetic routes employing asymmetric or chiral synthetic approaches have also been reported. Most recently, solution-phase parallel synthesis of ISQ derivatives using several of these approaches has been reported [49,50,51]. 

A convenient synthesis of functionalized isoquinuclidines, with very good endo (64, 90%)/exo (65, 10%) selectivity, from N-benzyl-3-ethyl-l,6-dihydropyridine that offers the advantage of avoiding the need to isolate and purify the unstable DHP entity (generated in situ and trapped by the dienophile present in the reaction mixture) was recently reported [69]. This approach is outlined below ... 

In a manner similar to N-substituted 2-pyridones, 2-methylene analogs such as 74, were found to react stereoselectively with various dienophiles to give endo adducts 75 [79,80]. This approach allowed for the synthesis of isoquinuclidines having a carbon side chain at the 3-position ... 

A study describing the stereochemical synthesis of an isoquinuclidine building block for the synthesis of iboga-type alkaloids has been recently described [105]... 

---