Indolizidines, formation

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. 

Reactions where the reduction of a functionalized nitrogen, or the deprotection of an amine group, start a domino process with the sequential formation of the two rings of the indolizidine system, find many examples in the literature. A recent one is provided by the synthesis of (—)-indolizidine 223AB <20040L1493> (Scheme 10). 

An efficient sequential reaction process was developed from y-amino chlorides 42 with propargylate 41 (Scheme 16). In the proposed mechanism, after the alkylation of the nitrogen atom, a subsequent cyclization by the same nucleophilic center induced the formation of intermediate 43, which cyclized to afford the indolizidine 44 <20010L3927, 20050L705>. This synthetic approach found application in the synthesis of indolizidine 223A. 

Again, rhodium-complexes, although in a completely different process, catalyzed the formation of indolizidine derivatives through the hydroformylation of pyrroles bearing a terminal double bond. The intermediate aldehyde reacted to afford the final product 74 (Scheme 23) <2004TA1821>. 

Once the methoxy group has been installed and nucleophilic capture of the intermediate has occurred, the product (132) can be treated with an enol ether (e.g. 133) and titanium tetrachloride to affect C-C bond formation adjacent to nitrogen. This sequence served nicely in syntheses of both indolizidine alkaloids elaeokanine A (135) and C (136). 

An efficient kinetic resolution was also observed during the (—)-sparteine-mediated deprotonation of the piperidin-2-yhnethyl carbamate rac-112 (equation 25). By treatment of rac-112 with s-BuLi/(—)-sparteine (11), the pro-S proton in (/ )-112 is removed preferentially to form the lithium compound 113, which undergoes intramolecular cyclo-carbolithiation, and the indolizidinyl-benzyllithium intermediate 114 was trapped with several electrophiles. The mismatched combination in the deprotonation of (5 )-112, leading to cp/-113, does not significantly contribute to product formation. Under optimized conditions [0.75 equivalents of s-BuLi, 0.8 equivalents of (—)-sparteine, 22 h at —78°C in diethyl ether] the indolizidine 115 was isolated with 34% yield (based on rac-112), d.r. = 98 2, e.r. = 97 3 optically active (5 )-112 was recovered (46%, 63% ee). 

The a is L-lysine, as in the case of piperidine, but the f3 is different. The /3 is a-aminoadipic acid 6-semialdehyde. The q> is L-pipecolic acid, which is synthesized in plants from piperideine-6-carboxylic acid. In the case of many other organisms, the obligatory intermedia (q>) is derived from the /3. The

ring structure. The indolizidine nucleus will be formed only in the synthesis of the x- The deep structmal change occms when

Claisen reaction with acetyl or malonyl CoA (Cra/mCoA) and the ring closme process (by amide or imine) to 1-indolizidinone, which is the x- The second obligatory intermedia ( k ) only has the indolizidine nucleus. 

The formation of spirocyclopropanes from the reaction of diazodiphenylmethane and ( )-8-phenylmenthyl esters of acrylic acid and methyl fumarate occurred with a modest level of diastereofacial selectivity (136). In contrast, diastereoselectivities of 90 10 were achieved in the cycloadditions of diazo(trimethylsilyl)methane with acrylamides 65 derived from camphor sultam as the chiral auxiliary (137) (Scheme 8.16). Interestingly, the initial cycloadducts 66 afforded the nonconjugated A -pyrazolines 67 on protodesilylation the latter were converted into optically active azaproline derivatives 68. In a related manner, acrylamide 69 was converted into A -pyrazolines 70a,b (138). The major diastereoisomer 70a was used to synthesize indolizidine 71. The key step in this synthesis involves the hydrogenolytic cleavage of the pyrazoline ring. 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

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. 

Regioselective formation of linear aldehydes is important in industrial process. The ligand BIPHEPHOS (L), developed by Union Carbide, gives the highest ratio of butanal from propylene. This ligand is useful for regioselective formation of linear aldehydes from various functionalized 1-alkenes under mild conditions. The linear aldehyde 40 was obtained from 39 and converted to the indolizidine alkaloid 41 [27]. 

The formation of the y-lactams is almost perfectly diastereoselective if cyclic a-amino aldehydes or the aldehyde prepared from valine are used as starting materials. As it is shown in the following scheme, the electroreduction of the obtained optically pure y-lactams followed by the reduction with LAH yields the corresponding optically pure pyrrolizidine and indolizidine skeletons. 

A selective amide cleavage of proline-tethered azetidin-2-one 329 with sodium methoxide followed by cyclization of the resulting /3-amino ester resulted into formation of the ring-expanded indolizidine derivative 330 (Equation 115) <2005JOC8890>. 

The formation of thiocarbonyl ylids by the reaction of metallocarbenoids with thiocarbonyl compounds has not been extensively studied, as noted by Padwa and Weingarten in a review [167]. However, formation of rings by interaction of these compounds has recently received some attention. A key step in the synthesis of a polyhydroxylated indolizidine alkaloid related to castanospermine is the reaction of diazoketone with a thioamide, in the presence of rhodium acetate [135]. After desulfurisation an enaminone was obtained. 

Thermal intramolecular cycloaddition reactions of unsaturated nitrones 1341 derived from a series of N- 2-alkenyl)-2-pyrrolecarbaldehydes 1340 and benzylhydroxylamine lead to competitive formation of two kinds of intramolecular cycloadducts, namely the fused- and the bridged-ring regioisomers 1342 and 1343, respectively (Scheme 255) <2001T8323>. Further elaboration of compounds 1342 and 1343 has given pyrrolizidine and indolizidine derivatives, respectively. A similar regiochemical trend was observed when aldehydes 1340 were reacted with (/ )-a-methylbenzylhydroxylamine in order to synthesize optically active compounds. 

Trost and Scanlan reported a Pd-catalyzed condensation of a vinyl epoxide 75 and an allyl sulfone 76 in the presence of dppf under neutral conditions [231]. This alkylation allows a room temperature entry to a basic indolizidine ring system as a step towards the synthesis of (+)-aj//o-Pumiliotoxin 339B [232], The modification of allylic alkylations by condensation of a diene 77 with a pronucleophile 78 also leads to C-C bond formation at the allylic position in both 1 1 (79 and 80) and 2 1 (81 and 82) products [233]. Reactions between ketene silyl acetals 83 with allyl... 

Reductive formation of a carbanion, either by reduction of a C-halogen bond or by removal of a proton by an electrogenerated base, followed by an intermolecular nucleophilic substitution, has been used in the synthesis of substituted lactams [11]. A similar reaction is used for the formation of quinolizidine and indolizidine derivatives from... 

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