Indolizidine derivative

The NMR spectra of indolizidine derivatives have already been described accurately <1984CHEC(4)443 1996CHEC-II(8)237> more recently, the extensive use of mono- and bidimensional H and 13C NMR spectra allowed the structural assignment of natural compounds such as grandisine A possessing an indolizidine nucleus (Figure 3) <2005JOC1889>. 

A 1,3-dipolar cycloaddition of the nonstabilized azomethine ylide 6 is the key step in a three-component reaction. The azomethine ylides were generated from (2-azaallyl)stannanes or (2-azaallyl)silanes 5 through an intramolecular iV-alkylation/demetallation cascade. The ylides underwent cycloaddition reactions with dipolarophiles yielding indolizidine derivatives 7-9 <2004JOC1919> (Scheme 1). 

An azomethyne ylide is also invoked as an intermediate in the three-component reaction between the dihydro-isoquinoline 10, an alkylating reagent 11, and the dipolarophile 12, which, in a one-pot process, afforded the indolizidine derivatives 13 <2005S2039> (Scheme 2). 

Finally, intramolecular Diels-Alder reactions, catalyzed by Lewis acids <1999TL7215> or thermally induced <1997JOC2093>, were used to obtain cyano-substituted indolizidine derivatives (Scheme 6). 

Phosphorylated derivatives of /3-nitroalcohols, upon exposure to Bu3SnH and AIBN, afford /3-(phosphatoxy)alkyl radicals. These radicals undergo heterolytic cleavage of the phosphate group to afford an alkene radical cation which is trapped intramolecularly in a tandem polar/radical crossover sequence. Derivative 37 (Scheme 13), through a 6-exol 5-exo overall cyclization, afforded the indolizidine derivative 38 as an equimolecular mixture of two diastereoisomers <2003JA7942, 2002OL2573>. 

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>. 

Pyridinium salts tethered to ketones also undergo cathodic cyclization [1]. The reaction provides a convenient diastereoselective route to quinolizidine and indolizidine derivatives such as 203, 204 and 206, 208, and 209, and appears to hold significant promise as a route to alkaloids. Examples are portrayed and the optimal conditions are listed below the equations. A mercury cathode is preferred, as passivation occurs when lead is used, and the reaction does not occur... 

A simple synthesis of [2.2.3]cyclazine (229) has been reported which starts from the indolizidine derivative (253]. Heating with sodium carbonate yields 48% of the dehydroin-dolizidine (254), which was subsequently dehydrogenated by palladium on charcoal to give (229) (76CPB2265). 

Very close to this type of precursor is l-silylmethyl-6-cyano-4-methyl-l,2,5, 6-tetrahydropyridine, which upon treatment with silver fluoride and V-methyl maleimide gives equal amounts of two isomeric indolizidine derivatives.445... 

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>. 

Steric control of the Diels-Alder reaction of the enone 56 has been reported (82H2053). The ene adduct 57 (4.5%) was obtained in a reaction with 1,3-bis(trimethylsilyloxy)butadiene at 180°C, together with the main product 58 (39.5%) resulting from an ene addition. Under the same conditions, the analogous indolizidine derivative 59 gave only ene adducts. 

A case of a high stereoselective reduction is reported in which indolizidine derivatives were reduced predominantly to the corresponding cis isomers by catalytic hydrogenation and to the trans isomers by sodium cyanoborohydride132 (Scheme 97). 

Mariano and coworkers have exploited this PET bond cleavage chemistry in intramolecular as well as intermolecular cyclization reactions [38]. The combined iminium-benzylsilane functionalities undergo intramolecular PET to provide an intramolecular amine radical/benzyl silane cation-radical pair by exciting either the iminium salt or the arene chromophore [38]. Cleavage of the benzyl C—Si bond presumably takes place with assistance of moderately weak n ldeophiles such as methanol. The diradical couples intramolecularly to provide an indolizidine derivative [38] in 90% yield. 

Benzindolizidine systems 963 are generated in moderate yields by a hexabutylditin-mediated consecutive radical addition, cyclization, and oxidation process from easily accessible l-(2-iodoethyl)indoles 962 and methyl acrylate, in one step (Scheme 186) <2000TL10181>. l-(2-Iodoethyl)-l//-pyrrole-2-carbaldehyde was also subjected to the tandem radical addition-cyclization process, and the indolizidine derivative 964 was isolated in modest yield as the major product together with a small amount of starting material (Equation 229). 

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. 

Only a few compounds of these classes of alkaloids have been reported from marine organisms. Clavepictine B (107), which was isolated from the ascidian Clavelinapicta, is marginally cytotoxic. Stellettamine A (108), which is an indolizidine derivative from a sponge Stelletta sp., is antifungal and cytotoxic. It... 

For an intramolecular asymmetric Heck-type reaction of alkenyl iodide 73 to form an optically active indolizidine derivative, a palladium catalyst coordinated... 

Indolizidine derivatives Asymm. intramol. HR of an alkenyl iodide [121]... 

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... 

Reduction of Pyridinium Salts—Quinolizidine and Indolizidine Derivatives Mediated Processes... 

VI. REDUCTION OF PYRIDINIUM SALTS—QUINOLIZIDINE AND INDOLIZIDINE DERIVATIVES... 

Oxoalkyl-pyridinium salts can be converted in a one-pot reaction to quinolizidine and indolizidine derivatives (Eq. 30) [170]. From the comparison of the reduction... 

Two comparatively simple indolizidine derivatives accompany crepidine (1) in Dendrobium crepidatum Lindl. Crepidamine (2), C18H25NO2, an optically inactive base, exhibits an n.m.r. spectrum similar to that of the tertiary base (3) obtained by the reaction of crepidine methiodide with base, apart from the... 

An example of nucleophilic fluorination to prepare an indolizidine derivative is found in the synthesis of a fluorinated analogue of (+ )-castanospermine, a naturally occurring glucosidase inhibitor. The epoxylactam 84 was treated with HF-Et3N. Stereospecific attack at position 6 gave, after acylation, the acetyl-protected... 

New polyhydroxylated quinolizidine and indolizidine derivatives (azasugars) were synthesised by intramolecular cycloaddition of a-D-glucose derived AI-(3-alkenyl)nitrones. The cycloadduct 87 was obtained as a unique diastereoisomer and transformed into 88 and 89 in two- and three-step sequence, respectively <01CC915>. 

Recent developments on the synthesis of indolizidine derivatives (—)-swainsonine and analogs 05COS39. 

The coupling reaction between an electron-deficient alkene and an aldehyde (Baylis-Hillman reaction) usually requires a cata-lyst/catalytic system (typically, a tertiary amine and a Lewis acid) to be successful. The base catalyst is not necessary when pyridine-2-carboxaldehyde is employed as electrophile it is enough with the activation effected by stoichiometric amounts of TMSOTf for the reaction to proceed to give indolizidine derivatives (eq 71). ... 

In another example, a vinyl iodide bearing a cyclic alkene on the heteroatom-containing side chain was employed (Scheme 6.28) [79]. It describes the asymmetric synthesis of indolizidine derivatives with optimized conditions to get asymmetric 108 with good ee of 81%. As compound 107 can be readily isomerized to 108 using Pd/C in methanol, this method gives ready access to a whole range of indoUzidines. 

Nukui, S., Sodeoka, M. and Shibasaki, M. (1993) Catalytic asymmetric synthesis of a functionalized indolizidine derivative. A useful intermediate suitable for the s3mthesis of various glycosidase inhibitors. Tetrahedron Lett., 34, 4965-8. 

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