Indolizidine chiral

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. 

Nucleophilic addition of furan to nitrone occurs upon treatment with trimethyl-silyl triflate (TMSOTf) (586, 587). Catalyzed TMSOTf stereoselective addition of 2-[(trimethylsilyl)oxy]furan to chiral nitrones was carried out in a short synthesis of [IS (la, 2[), 7f>, 8a, 8aa)]-l,2-di(t-butyldiphenylsilyloxy)-indolizidine-7,8-diol (588). Addition to N -gulosyl-C-alkoxymethyl nitrones led to the synthesis of the core intermediate of polyoxin C (218). 

Bicyclic alkaloids. Nagao et al. have developed a general synthesis of chiral bicyclic alkaloids with a nitrogen atom at the ring juncture, such as pyrrolizidines [5.5], quinolizidines [6.6], and indolizidines [6.5], based on a highly diastereose-lective alkylation of 3-a>-chloroacyl-(4S)-isopropyl-l,3-thiazolidine-2-thiones (1, m = 1,2) with 5-acetoxy-2-pyrrolidinone (2, n = 1) or 6-acetoxy-2-piperidinone (2, n = 2). Thus the tin enolate of 1 (m = 1), prepared with Sn(OTf) and N-... 

Swainsonine is a trihydroxylated bicyclic indolizidine alkaloid with four chiral centres, whose relative stereochemistry was determined by X-ray crystallographic analysis and the absolute configuration was deduced on the basis of biosynthetic and asymmetric induction studies, and then confirmed by an enantiospecific synthesis from D-mannose [2a]. 

The dipolar cycloaddition of nitronates has been applied to the synthesis of several natural products in the context of the tandem [4+2] / [3 + 2] nitroalkene cycloaddition process. All of these syntheses have focused on the construction of pyrrolidine, pyrrolizidine, and indolizidine alkaloids. For example, the synthesis of ( )-hastanecine (316), a necine alkaloid, involves the elaboration of a p-benzoy-loxynitroalkene 311 via [4 + 2] cycloaddition with a chiral vinyl ether (312) in the presence of a titanium based Lewis acid, to provide the nitronate 313 with high diastereo- and facial selectivity (Scheme 2.30) (69). The dipolar cycloaddition of... 

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. 

Alkenyl nitrones, having the alkene connected to the nitrone nitrogen atom, have been used in another approach to intramolecular reactions (231-235). Holmes and co-workers have this method for the synthesis of the alkaloid (—)-indolizidine 209B 137 (210,231). The alkenyl nitrone 134, was obtained from the chiral hydroxylamine 133 and an aldehyde. In the intramolecular 1,3-dipolar cycloaddition, 135 was formed as the only isomer (Scheme 12.45). The diastereofacial selectivity was controlled by the favored conformation of the cyclohexane-like transition state in which the pentyl group was in a pseudoequatorial position, as indicated by 134. Further transformation of 135 led to the desired product 137. 

Heterocyclic products such as indolizidines and quinolizidine (Scheme 9.7) could also be obtained, as was shown by Takacs et al. for the synthesis of 5 in a stereoselective fashion applying a chiral bisoxazoline ligand [18]. The product was obtained in 65% yield with excellent diastereoselectivity and the enol ether was formed exclusively as the E-isomer. 

Smith has employed a related process using the ligand 3 developed by Jiang to obtain a chiral propargyl alcohol. This served as a key building block in an elegant synthesis of (-)-indolizidine 223AB (Eq. 21) [26],... 

By using a sequence involving regio and diastereoselective reduction of the adducts (it only affects the carbonyl far away from the sulfinyl group, yielding y-oxygenated lactones), stereoselective AT-acyliminium addition, and retro Diels-Alder reactions as the main key steps, Koizumi et al. have synthesized chirally functionalized pyrrolidines [96, 97], pyrrolizidines [98], and indolizidines [98-100], depicted in Scheme 56. The milder conditions required for the evolution of the adducts derived from furan preserve the chirality of the substrates. 

The 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines are the more common structural patterns found in amphibian skin[21]. None of these alkaloids has so far been reported from any other source. In addition, the biological activity of only a few 5,8-disubstituted indolizidines has been investigated due to the isolation in minute quantities from the skin. Among them, the relative stereochemistry of quinolizidine 2071 was anticipated to be 75 by our chiral synthesis of 76[35] followed by stereocontrolled synthesis of 75[36]. A sample of synthetic racemate of 75 had produced the best separations on GC analysis with (3-dextrin chiral column[36]. 

Interestingly, all other diols, tried as a protecting group on the acetal, led to lower diastereoselectivity of the addition. This synthetic strategy was used in the synthesis of indolizidine alkaloids,279 bis(l-arylethyl)amines,280 a protease inhibitor.281 The addition reaction of 1,2-bisimines, easily available from glyoxal and chiral cr-phenylethy-lamine, gives under optimized conditions a diastereomerically pure product, that was converted to a chiral 1,2-diamine. Interestingly, decrease of the temperature below the optimum (50 °C) leads to a sharp drop of the stereoselectivity (Scheme 96).282... 

A new convenient procedure for the chiral alkylation of 5-acetoxy-2-pyrrolidinone (91) and 6-acetoxy-2-piperidinone (92) has been developed. This procedure should be useful for an extremely short chiral synthesis of the bicyclic alkaloids involving pyrrolizidine, indolizidine, and quinolizidine skeletons (88JA289). 

The pyrrolidine synthon (48) is useful for the chiral synthesis of pyrrolizidine, pyrrolidine, indolizidine and azabicyclic alkaloids (see Scheme 23). 

Scheme 12.7) [26]. Access to an indolizidine was realized by starting from a pen-tadienylstannane and chiral aldehyde (Scheme 12.8) [27]. 

Also the hydroamination/cyclization of chiral aminoallenes has been utilized in the synthesis of various alkaloid skeletons [120]. The pyrrolidine alkaloid ( + ) 197B (Scheme 11.25), as well as the indolizidine alkaloid (+) xenovenine (Scheme 11.26),... 

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