Quinolizidine ring formation

Radical cyclization reactions have proven to be a very efficient approach for polycyclic natural product synthesis. In many cases, the last step involves a reduction of a cyclic radical with formation of a new stereogenic center. Very good stereochemical control has been achieved with such polycyclic radicals. For example, Beckwith has reported a highly stereoselective formation of a quinolizidine ring (Scheme 19, Eq. 19.1) [41b]. This process is the key reaction in a four-step synthesis of epilupinine and the stereochemical outcome results from a stereoselective axial reduction by tin hydride of a bicyclic radical. In a related process, Tsai has prepared silylated hydroxyquinolizidine by radical cyclization to an acylsilane followed by a radical-Brook rearrangement (Scheme 19, Eq. 19.2) [42]. 

The scope of this process has been extended in a more detailed investigation to the synthesis of quinolizidines [21] and the influence of alkyl substituents in various positions of the dialkenylamine substrate on product diastereoselectivity was probed. Neodymium-based catalysts are particularly efficient for six-membered ring formation (12). The methodology has found further application in the synthesis of tri- and tetracyclic alkaloidal skeletons (13) [22]. 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

The application of the RCM reaction to the construction of nitrogen-containing ring systems, including quinolizidine derivatives, has been reviewed <1999EJ0959>. From that date, this strategy has become more and more common in quinolizidine synthesis, especially in cases where the cyclization takes place by formation of a bond 7 to the heteroatom. Some examples are given below. 

Lasubines I and II are alkaloids containing a 4-arylquinolizidine substructure that have been isolated from plants of the Lythraceae family and have attracted the attention of synthetic chemists for some time. While numerous racemic syntheses of these and related compounds have been reported, only a few enantioselective syntheses are known. Some examples of these syntheses are given below, and the strategies involved in these examples are summarized in Scheme 92. Three of these syntheses involve the creation of the quinolizidine system by formation of one bond at the a- or 7-positions, while the fourth approach is based on a ring transformation associated with a photochemical Beckmann rearrangement. 

Three syntheses of homopumiliotoxin alkaloids are compared below, and one more reaction leading to homo-pumiliotoxin-related compounds was mentioned in Section 12.01.9.3.7. The strategies involved for the ring-closure procedures leading to the quinolizidine system involved the formation of a- or 7-bonds from piperidine precursors and are summarized in Scheme 97. 

The rare reports of quinolizidine formation by a nitrone cycloaddition strategy include the racemic total synthesis of lasubine II (58), one of a series of related alkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme 1.14) (104). While these alkaloids were previously accessed by infennolecular nitrone cycloaddition reactions, this more recent report uses an intramolecular approach to form the desired piperidine ring. Thus, cycloaddition of nitrone 59 affords predominantly the desired bridged adduct 60 along with two related... 

The preparation of fused nitrogen heterocycles such as pyrrolizidines, indolizidines, quinolizidines, pyrrolidinoazocines and piperidinoazocines by the RCM of appropriate dienes (equation 38), is another case where presence of a ring assists the RCM reaction. However, when n = 7 (with x = 1), the C=C bonds, separated by 11 single bonds, are too far apart for RCM to occur. Applications of this general strategy are in prospect for the formation of fused nitrogen heterocyclic systems in problems of alkaloid synthesis240. 

The quinolizidine system in monomeric C15 alkaloids in some cases is susceptible to inversion of the ring junction, which is accompanied by inversion of the relative configuration of C-7. Protonation of the nitrogen atom, quaternization, or V-oxide formation are the conditions which cause such transformations. 

The cascade sequence was also used to synthesize indolizidine, pyrrolizidine, and quinolizidine structures. Thus, heating oximes 52 at 180 °C in a sealed tube provided cycloadducts 53 or 54 in 60-76% yields (equation (1)) (89TL2289). Each of the products were isolated as single diastereomers. When five-membered rings were obtained from the cycloaddition, cis-anti isomers (i.e. 53a,b) were formed, whereas formation of a six-membered ring led only to the cis-syn isomer (i.e. 54a,b). 

Intramolecular enamine formation between an aldehyde or ketone and the nitrogen atom of a piperidine ring can serve as the key step in the preparation of quinolizidine derivatives. For example, the ketal (184), prepared by double addition of the lithio derivative (183) to 6-methoxy-2,3,4,5-tetrahydropyridine, can be easily cyclized to the quinolizidine derivative (185) by double acid-catalyzed deprotection, cyclization, and dehydration (Scheme 31). These reactions constitute the first steps of a stereocontrolled total synthesis of the alkaloid ( )-porantherine <87JA4940>. 

Intramolecular tandem Michael addition-amide formation in the intermediate (291) afforded an epilupinine precursor (Scheme 60) <89H(29)1209>. Another quinolizidine synthesis forming two a bonds in its key step is the reductive double alkylation of azido epoxides with an (o leaving group (292). This strategy has been applied to the synthesis of ring-expanded analogues of indolizidine alkaloids (e.g. (293)) from D-arabinose (Scheme 61) <93TL822l>. 

In some convenient and efficient syntheses reported, annelation of the terminal six-membered ring with the formation of C—N bond was involved <60AC(R)75, 68JHC799, 730PP55, 84AJC367>. One example demonstrated in Scheme 33, is the synthesis of indolo[2,3-u]quinolizidine (131) which has been obtained in 74% overall yield from amide (186) <75CPB304>. 

Bicyehe nitrogen-containing heterocyclic compounds were also fluorinated by ECF. ECF of AT-methyl-decahydroquinoline forms a mixture of cis- and tra/j5-isomerie perfluorinated derivatives. Ring contraction and formation of per-fluorocyclohexanes are side processes. Trows-quinolizidine gives perfluoro-tra/w-quinolizidine (yield 16-23%) and a large amount of other compounds with unknown... 

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