Of -slaframine

The construction of an indolizidine skeleton has been successfully obtained by radical cyclizations mediated by (TMS)3SiH. Reaction (7.44) represented a key step in the total synthesis of (—)-slaframine. The two pairs of diastereomers were first separated and then hydrolysed to the corresponding alcohols in a 76% overall yield [55]. On the other hand the cyclization of the A-iodopropyl pyridinones in Reaction (7.45) occurs smoothly at room temperature using Et3B/02 as initiator, to give the desired products with a trifluoromethyl group at the bridgehead position in a syn/anti ratio of 7 3 [56]. 

Cha and co-workers (54) described an enantioselective total synthesis of (—)-slaframine (269) based on an intramolecular cycloaddition of an azide (Scheme 9.54). On reaction with NaN3 in DMF at 60 °C followed by intramolecular... 

The mass spectra of indolizine alkaloids have been reviewed in detail (B-75MI30800). Some principles may be taken from the fragmentation pattern of slaframine, given in Scheme 3. 

Pyrrolizidines compounds have been produced in connection with syntheses of other types of natural products. For example, Gensler and Hu prepared the dioxopyrrolizidine ester (46) as an intermediate in the synthesis of ( + )-slaframine, an indolizidine alkaloid obtained from cultures of Rhizoctonia leguminicola. The pyrrolidone ester (47), prepared from l-glutamic acid [Eq. (14)], was optically active, but the cyclized product, formed in quantitative yield from 47, was completely racemized. The synthesis of 2-acetyl-1,3-dioxopyrrolizidine (48) was carried out by Kruger and Arndt to assist with their investigations on model compounds aimed toward the total synthesis of a-cyclopiazonic acid, the main toxic principle of Penicillium cyclopium The spectra of the product (48) obtained in 30% overall yield was typical of an intramolecularly H-bonded enolized )S-... 

An intriguing stereodivergent approach to both enantiomers of slaframine, devised by Carretero and Gdmez Arrayds, commenced with the reductive amination of (/J)-glyceraldehyde acetonide 50 with the diethyl acetal of 4-aminobutanal (Scheme 7) (48). The secondary amine product 51 was transformed in three steps into a 1 1 diastereomeric mixture of a, 3-un5atuiated y-hydroxysulfones 52,... 

Sibi and co-workers devised an enantiospecific synthesis of (+ )-109 from the same 3-oxoproline ethyl ester 16 previously used in their synthesis of ( + )-slaframine (3) (cf. Section II.A, Scheme 2) (39). In this case, Wittig reaction between the aldehyde 129 and the ylide prepared from 3-hydroxypropyl-phosphonium chloride gave a 2 1 mixture of cis- and /rons-alkenes 130 in 50% yield. Catalytic hydrogenation followed by mesylation of the primary alcohol group set the scene for the ensuing cyclization, which took place spontaneously upon hydrolysis of the N-Boc protecting group of 131. The overall yield of (-I- )-109 was 16.3% based on 16 (Scheme 18). 

Syntheses of slaframine (1) and its analogues from noncarbohydrates have been reported."" ... 

Synthesis from n-threose A synthesis of (-)-slaframine (1) has been reported from the 3-deoxy-D-threose derivative 2 by reaction with the chiral ylide 4, obtained from 3, in the presence of KN(TMS)2 to produce 5 in 89% yield (Scheme 1). Subsequent tosylation followed by opening of the oxazoline ring by reduction afforded the alcohol... 

Slaframine.—Further details are now available on the biosynthesis of slaframine (39), a toxin produced by the mould Rhizoctonia leguminicola. Both dl-[1- C]-and DL-[6- " C]-lysine afforded labelled slaframine, indicating intact incorporation of all the carbons of the amino-acid. Addition of inactive pipecolic acid (34) to the cultures diluted the lysine label in the derived slaframine, and pipecolic acid was labelled by radioactive lysine. Further carboxyl- and ring-labelled pipecolic acids [as (34)] were both well incorporated into slaframine. A clear indication is thus obtained of the biosynthetic sequence lysine —> pipecolic acid (34) — slaframine (39) 2-hydroxymethylpiperidine is not a precursor. Attention is drawn to the discovery of a similar pathway to a metabolite of similar structure also produced by R. leguminicola. ... 

The incorporation of (36), (35), and (37) with increasing efficiency allowed further definition of the pathway to slaframine.The results indicate that a tritium label at C-1 of (36) is retained on formation of (39), and so (36) must follow (35) on the pathway. Further support for this relationship comes from the discovery that a cell-free extract of R. leguminicola would catalyse the NADPH-dependent reduction of (35) to (36). This extract also catalysed the acetyl-CoA-dependent formation of slaframine (39) from (38). The pathway to slaframine so far deduced is illustrated in Scheme 2. 

A second synthesis has been described of slaframine (11), the amine which causes excessive salivation in livestock foraging on red clover infected with Rhizoctomia leguminicola. Condensation of L(-l-)-glutamic acid with acrylonitrile, followed by esterification, gave ethyl iV-()5-ethoxycarbonylethyl)-5-oxopyrrolidine-2-car-boxylate (12), which on Dieckmann cyclization, hydrolysis, and decarboxylation afforded the racemic 3-oxopyrrolidine acid (13). Platinum-catalysed hydrogenation of the hydrochloride of (13) in methanol solution gave the alcohol-ester... 

An intramolecular Diels-Alder reaction of (72) was used to produce the indolizine skeleton and to establish the stereochemistry of slaframine (73) <82JA7065>. 

The keto-imine (5) has been shown to be active in stimulating exocrine glands. Because purified porcine hepatic microsomal flavoprotein oxidase has been shown to oxidize slaframine to (5), this enzyme is postulated to be primarily responsible for activation of slaframine in vivo. ... 

The biosynthesis of slaframine (38) and swainsonine (35) in Rhizoctonia leguminicola involves lysine and proceeds via the intermediacy of pipecolic acid. Carbon atoms 2 and 3 have been demonstrated to come from acetate via malonate (Fig. 30.14). The biosynthesis of swainsonine and related compounds in plants does not appear to have been investigated (Elbein and Molyneux, 1987 Harris et al, 1987 Howard and Michael, 1986). 

Fig. 30.14. Biosynthesis of slaframine and swainsonine in Rhizoctonia leguminocola (modified from Howard and Michael, 1986 used with permission of the copyright owner, Academic Press, Orlando, FL),...

The fact that (TMS)3SiH reacts with alkyl radicals ca. 10 times slower than Bu3SnH supported the expectation that it would be more efficient in cyclization reactions. Scheme 1 shows three examples which represent the key steps in the total synthesis of (-)-slaframine[15], (-)-zearalenone[16] and ( )-tacamonine[17], respectively. 

In alkaloid synthesis, cyclization strategies have been mediated by (TMS)3SiH. An example is given by the total synthesis of (—)-slaframine starting from a phenylseleno derivative (eq 31). ... 

Harris et al. postulated that (15,8a5)-( + )-l-hydroxyindolizidine (109) and (17f,8a5)-l-hydroxyindolizidine (110) were pivotal intermediates in the biosynthesis of slaframine (3) and swainsonine (cf. Section III.C) in the fungus Rhizoctonia leguminicola (74). Compound 110 was subsequently isolated as the acetate from extracts of the diablo locoweed, Astragalus oxyphysus (75). 

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