Indolizidines, substituted synthesis

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

Often, in the synthesis of natural products containing the indolizidine substructure, it is necessary to modify a preformed indolizidine ring. This is the case in the synthesis of (+)-myrmicarin 217 191 where the key step is the closure of the third ring through an electrophilic substitution on the pyrrole nucleus (Scheme 45) <2000JOC2824>. 

Stereoselective intramolecular conjugate addition reactions (Scheme 4) of dithiane anions tethered to an a,/ -unsaturated nitrile have been developed to advantage for the synthesis of axially substituted indolizidines and quinolizidines.81 The control of axial nitrile orientation by a peg-in-a-pocket template effect has been discussed. 

Enantiopure a, ft -unsaturated 5-lactams react stereoselectively with carbon-, nitrogen-, sulfur-, and oxygen-centred nucleophiles [N3-, Me(CH2)nS, MeO-, and n-Bu-]. The synthetic potential of these conjugate additions has been demonstrated through the synthesis of two new substituted indolizidines, (7/f)-7-amino-8-deoxy-swainsonine and (7/ )-7-acetylaminoswainsonin.133... 

The copper complexed aminyl radical cyclization has been used as a key step in a short total synthesis of ( )-gephyrotoxin 223AB (60). The alkenyl substituted ALchloropiperidine 59 was stereoselectively cyclized to construct the indolizidine ring system (Scheme 17) (86JOC5043). Tribu-... 

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... 

The concise enantioselective total synthesis of (+)-monomorine I, a 3,5-dialkyl-substituted indolizidine alkaloid, was completed by S. Blechert et al. using a sequential cross-metathesis double reductive cyclization strategy. The enedione substrate was prepared in two steps. The Stetter reaction between the masked equivalent of acrolein and butyl vinyl ketone was followed by a retro Diels-Alder reaction under flash vacuum pyrolysis (FVP) conditions. 

Randl, S., Blechert, S. Concise Enantioselective Synthesis of 3,5-Dialkyl-Substituted Indolizidine Alkaloids via Sequential Cross-Metathesis-Double-Reductive Cyclization. J. Org. Chem. 2003, 68, 8879-8882. 

Heterocycles. While several reports deal with formation of furan derivatives by reaction of 2-diazo-l,3-cyclohexanediones and alkynes which are substituted with electron-withdrawing or electron-donating groups, an a-pyridone synthesis based on an analogous reaction of Af-(a-diazoacyl)amides is applicable to the elaboration of the indolizidine skeleton, and accordingly, a synthesis of ipalbidine. ... 

A novel synthesis of antofine 22, an indolizidine alkaloid, and cryptopleurine 23, a quinolizidine alkaloid, involves lithiation of trimethoxy-fihenanthrene-carbox mide. The key step in both these cases is the generation of substituted phthalides 92)... 

The second set of examples involves the use of thionium ions as electrophiles in inter- and intramolecular processes to obtain a-substituted sulfides (see 24 25, Scheme 20.7T which is the most common type of Pummerer reaction. Applications of this classical Pummerer rearrangement are exemplified in the synthesis of trans-solamin, the synthesis of indolizidine alkaloids, and the synthesis of the CDE ring of erinacine E. The first exanple fScheme 20.10 uses Pummerer chemistry in the generation of a thionium ion, which reacts in an intermolecular tin-mediated ene reaction the second one fScheme 20.11 uses Pummerer chemistry to introduce a nitrogen-containing heterocycle by intramolecular addition to form the coniceine core and the third example fScheme 20.12 is an intramolecular silicon-induced Pummerer reaction with oxygenated nucleophiles applied to the synthesis of a precursor of erinacine. Details of these Pummerer-based strategies are discussed below. 

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