Isoquinuclidine derivative

Chiral dihydropyridines such as 103 were also accessible from Zincke-derived N-alkyl pyridinium salt 102 (Scheme 8.4.34). The dihydropyridine underwent cycloaddition with methylacrylate, providing chiral isoquinuclidine derivative 104 as the major diastereomeric product. ... 

Another example in which A-methyl-l,2-dihydropyridine (41a) behaves as an enamine rather than a diene is its reaction with methyl vinyl ketone (44) (64JCS2165). The product is a pyran 45, which is obtained in 100% yield, rather than an isoquinuclidine derivative (80JOC1657). 

In the preceding example we did not consider cycloaddition reactions since these would not offer any suitable alternative synthetic pathway. The bicyclic isoquinuclidine derivative given below (G. Biichi, 1963, 1966A) contains only unstrained six-membered rings, and the refro-Diels-Alder transform is obviously the furthest-reaching simplification and the fastest antithetical route to commercial starting materials. Both bridgehead atoms can be introduced in one step. 

Furthermore, the ring opening of the aziridinium salt 181, prepared from the aziridine 172 with methyl iodide at low temperature, by reaction with a number of nucleophiles also yielded the isoquinuclidine derivatives 182 predominantly, together with the isomer 183 (Scheme 35). 

When aniline or meta or / ara-substituted haloaniline derivatives were utilized, the isoquinuclidine derivatives (e.g., 97) were obtained nearly exclusively in high yield. Use of aniline derivatives containing an ort/zo-halogen, on the other hand, resulted in the formation of the unsaturated secondary amines (e.g., 98) in 70-80% yield, with the exception of o-fluoroaniline, which resulted in the formation of the isoquinuclidine. 

Horii and co-workers discovered that the aminolactone 97 (Scheme 15) upon standing at room temperature or upon distillation produced the isoquinuclidine derivative 105 in good yield (Scheme 16) (40). This interesting isomerization has its counterpart in the degradative chemistry of securinine (Section II, A, 3) but requires milder conditions. The structure of 105 rests mainly on this securinine analogy and on spectral evidence. The presence of an a,j8-unsaturated y-lactone was indicated by IR and NMR spectroscopy. The absence of IR absorption due to NH and the inability to obtain an X-acetyl derivative showed the tertiary nature of the nitrogen. Furthermore, the presence in the... 

Positively activated olefins have also been condensed with dienamines derived from aldehydes 321,330,347,348) and ketones. Of special interest is the formation of bridged systems from homoannular dienes (229-231) which has been applied to the isoquinuclidine system of the iboga alkaloids (137-140,349). 

When methyl 2-(indol-2-yl)acrylate derivative (22a) reacted with A-methoxy-carbonyl-l,2-dihydropyridine (8a) in refluxing toluene, in addition to the dimer of 22a (25%), a mixture of the expected isoquinculidine 23a and the product 24a (two isomers) was obtained in 7% and 45% yields, respectively (81CC37). The formation of 24a indicates the involvement of the 3,4-double bond of dihydropyridine. Similarly, Diels-Alder reaction of methyl l-methyl-2-(indol-2-yl)acrylate (22b) with 8a gave, in addition to dimer of 22b, a mixture of adducts 23b and 24b. However, in this case, product 23b was obtained as a major product in a 3 2 mixture of two isomers (with a- and (3-COOMe). The major isomer shows an a-conhguration. The yields of the dimer, 23b, and 24b were 25%, 30%, and 6%, respectively. Thus, a substituent on the nitrogen atom or at the 3-position of indole favors the formation of the isoquinuclidine adduct 23. 

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. 

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). 

Hence, the initial reactions were conducted using BINOL-phosphate 5 in combination with various achiral Brpnsted acids, including pro-tonated pyridine derivatives, alcohols and acids. Best enantioselectiv-ities were observed with the addition of carbonic acids, phenol and hexafluoro isopropanol which provided the isoquinuclidines 28 with up to 88% ee. Further explorations concentrated on varying the reaction parameters including different protected imines, catalyst load-... 

Stereoselective Diels-Alder reactions have been reported in several cases. Enantioselective Diels-Alder reactions of l-phenoxycarbonyl-l,2-dihydropyridine with 1-alkylated acryloyl-pyrazolidin-3-ones using a chiral cationic palla-dium-phophinooxazolidine catalyst afforded chiral isoquinuclidines with excellent enantioselectivity <2005TL5677>. Bismuth(lll) chloride-mediated diasteroselective intramolecular [4-f2] cycloaddition reactions of A-allyl derivatives of pyrazole aldehydes led to fused sulfur-containing pyrazole heterocycles <2003SC3063>. A highly diastereoselective intramolecular hetero-Diels-Alder approach toward tetracyclic pyrazoles from 5-(3-methyl-2-butenylthio)-3-methyl-l-phenyl-4-pyrazolecarboxaldehyde has been reported <1997SL1155>. 

A series of 5- and 6-substituted isoquinuclidine 4-amino-5-chloromethoxy benzoates and benzamides (11-16) was found to have binding affinity for 5-HT3, 5-HT4 and dopamine (DA) D2 receptors. In general, although 5-substituted ISQs demonstrated more potential as 5-HT3 ligands while also possessing 5-HT4 and D2 properties, the 6-substituted derivatives afforded the most promising compounds in terms of both receptor affinity and selectivity [20],... 

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]. 

Another approach [104] utilizing asymmetric cycloaddition involved the reaction of A-glycopyranosyl 1,2-DHPs derived from glucopyranosyl (115), xylopyranosyl (116) and arabinosyl (117) bromides. Reduction of 115 with NaBH4 yielded 1,2-DHP (118) and 1,4-DHP (119). Reduction of 116 and 117 gave a mixture of 1,2-DHPs and 1,4-DHPs that were not separated prior to subsequent reaction. Treating the A-glycopyranosyl-1,2-DHPs (115-117) with methylacrylate and subsequent treatment with methylchloroformate yielded the isoquinuclidine carbamates (-)-119 (in 84% e.e.) and (+)-120 (in 72% e.e.) (Scheme 17). 

Additional 1,2,4-oxadiazole derivatives containing 1-azanorbornane (124a and 124b) and isoquinuclidine (125) rings were studied (158). These compounds can exist as geometric isomers, and the exo-l-azanorbornane isomer (124b) was described as one of the most potent and efficaceous muscarinic agonists known. 

Piperidine Alkaloids.—The hypothesis that dioscorine (112) was derived from six acetate units has been tested by administration of sodium [l- " C]acetate to Dioscorea hispida. Degradation of the dioscorine isolated showed, significantly, that of the carbons of the isoquinuclidine ring only C-5 was heavily labelled (30% of total). The remaining activity was located equally at C-10 and C-12. Thus dioscorine is built of only four acetate units, the remaining carbons of the skeleton being derived probably from lysine via a piperidine moiety such as A -piperideine (Scheme 10). 

Trost et al. [39] later reported the formal total synthesis of ( )-catharanthine, applying a similar reaction to indole 88 (Scheme 9.13). Although 89 was obtained in modest yield, it could be readily converted in three steps to alcohol 90, which Biichi and coworkers [40] have shown can be further transformed to catharanthine. Trost and Fortunak [41] also investigated this reaction by studying structural derivatives without the isoquinuclidine moiety. Indole 92a cyclized efficiently under carefully optimized conditions (l.lequiv... 

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