Isoquinuclidine

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

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). 

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. ... 

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). 

For example, the Diels-Alder reaction of A-benzyl-3-carboxamido-1,6-dihydro-pyridine (14a) andlV-benzyl-3-cyano-l,6-dihydropyridine (14b) with methyl vinyl ketone yielded isoquinuclidines 15a and 15b, respectively, which can be converted into ibogamine alkaloid (16). 

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. 

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 Dioscorea hispida, Trigollenine is incorporated into the isoquinuclidine moiety of the alkaloid Dioscorine (208), as proved by a feeding experiment with [TOer/ y/- " C,2- H, H]trigollenine (88P3793). These results are consistent with the hypothesis for the biosynthesis of Dioscorine (208), Dumetorine and Dihydrodioscorine, which is presented in Scheme 68. 

Some workers allow the amine and carbonyl compound to stand together some time before hydrogenation (i,59), but this procedure is not always necessary nor even desirable (ii). The delay technique is illustrated by reductive alkylation of ethyl-4-aminocyclohexane carboxylate (4) with benzaldehyde to S, a route that permitted an important improvement in the production of isoquinuclidine (8) (59). 

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. 

On the other hand, novel diastereomeric p-amino thiol ligands possessing an isoquinuclidine skeleton have been readily prepared by Hongo et al. via imino-Diels-Alder reactions.As shown in Scheme 3.15, when applied to the enantioselective addition of ZnEt2 to various aldehydes, one of these ligands afforded the products with high enantioselectivities of up to 94% ee. 

Scheme 3.15 P-Amino thiol ligand based on isoquinuclidine skeleton for additions of ZnEt2 to aldehydes.

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. 

Initial unsuccessful attempts at biomimetic coupling of catharanthine and vindoline by the Kutney group had been directed at cleavage of the C-16-C-21 isoquinuclidine bond by ionization of a C-20 oxygenated pre-... 

In another search for an alternative to Potier s modified Polonovski reaction of catharanthine A-oxide (45), it has now been found that anhy-drovinblastine (42) can be generated directly, in 77% yield, from a reaction of catharanthine and vindoline in 0.01 N acid, promoted by ionized ferric salts, followed by reduction with sodium borohydride (Scheme 30) (Wl). Remarkably, the cation radical 106 generated by Fe(III), in accord with other simple amine oxidations by Lindsay Smith and Mead (102), resulted in isoquinuclidine fragmentation and coupling to vindoline at 0°C, without the conformational inversion observed in the modified Polonovski reaction at that temperature (see Scheme 15). Other metal oxidants or ligand-bound Fe(lll) did not promote the coupling reaction. It will be of interest to see if the overwhelming competition of C-5-C-6 bond... 

In 2006, two groups independently developed an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder-type reaction of iV-aryl aldimines 86 with cyclohexenone 101 to provide isoquinuclidines 102 in good yields (51-84%), endo-diastereoselec-tivities (3 1-9 1), and enantioselectivities (76-88% ee) (Scheme 39). 

Mechanistically, the present transformation probably comprises two steps. Mannich reaction of in situ-generated cyclohexadienol 103 with iminium ion 104 is followed by an intramolecular aza-Michael reaction to furnish isoquinuclidine 102 (Scheme 41). Three stereogenic centers are created in this process. 

The groups of Rueping [25] and Gong [26] have developed the aza-hetero-Diels-Alder reaction of aryl imines and cyclohexenone to give isoquinuclidines in good endojexo selectivities and high yields and ee s by 1 and la, respectively (Scheme 5.13). In the presence of acid, cyclohexenone enolizes to afford the dienol which subsequently undergoes a Mannich reaction with the protonated aldimine followed by intramolecular aza-Michael addition to produce the formal Diels-Alder adducts. 

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). 

A potentially useful route to reserpine alkaloids has been suggested by the application of the amino-Claisen reaction (Scheme 52) to the indolyl-substituted isoquinuclidine (268). Treatment of (268) with methyl propiolate gave the intermediate zwitterion (269) which rapidly rearranged to (270). This latter compound has all the necessary functionality for further elaboration into the reserpine ring system (B-82MI20700). 

A search of the literature revealed a 1982 Trost and Fortunak paper [58] wherein PdCL and AgBF4 were utilized to effect the Heck-type cyclialkylations of various isoquinuclidine model compounds. Compound 100 was exposed to these conditions, affording the heptacycle 101 in 63-82% yields. 

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. 

The development of chiral Diels-Alder reactions to form enantiomerically enriched isoquinuclidines has been of considerable interest. Older examples focused on the use of chiral auxiliaries, generally attached to the nitrogen of the 1,2-dihydropyridine, the best of which were carbohydrate based <1990TL1995>. Recently, amidines have been shown to be very efficient chiral auxiliaries with l-A-amidine-l,2-dihydropyridine 96 undergoing [4+2] cycloaddition with maleic anhydride to give only the endo-product 97 with >95% diastereomeric excess (Equation 4) <2005OL5773>. 

The Diels-Alder reaction of chiral 1,2-dihydropyridine 98, which can be prepared as a single enantiomer from L-lysine, with iV-acryloyloxazolidinone 99 gave 2-azabicyclo[2.2.2]octene product 100, which was converted into isoquinuclidine 101 with 97% ee (Scheme 26) <2000TL7685>. 

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.

XLI R = CH3). Hydrogenation (12) of catharanthine led to only one isomer, dihydrocatharanthine (XLII, 18-carbomethoxy-4-epi-iboga-mine), mp 63°-65°, [ ]D + 35° (CHCI3), the hydrogen coming in on the less hindered side of the isoquinuclidine residue (40). 

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

Isoquinuclidines 28 (aza-bicyclo [2.2.2]octanes) consist of IV-bicyclic structures which are the structural element of numerous natural occurring alkaloids with interesting biological properties (Sundberg and Smith 2002). Furthermore, these products can be readily converted to the biologically active pipecolic acids (Krow et al. 1982, 1999 Holmes et al. 1985). A retrosynthetic analysis shows that these isoquinuclidines 28 can be prepared from imines 29 and cyclohexenone 30 (Babu and Perumal 1998 Shi and Xu 2001 Sunden et al. 2005). 

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-... 

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