Slaframine synthesis

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... 

A trail pheromone of the Pharaoh ant was identified as 3-butyl-5-methylindolizidine of the stereochemistry given in (219) (75JHC289). Slaframine (220) is a metabolite isolated from Rhizoctonia leguminicola responsible for producing excessive salivation in cattle. A stereoselective synthesis was reported (73JOC3848). Swainsonine (221), a potent inhibitor of a-mannosidase, has been isolated from Swainsona caneszens. The stereochemistry was derived from the NMR spectrum (79AJC2257). 

The indolizines constitute the core structure of many naturally occurring alkaloids, such as (-)-slaframine, (-)- dendroprimine, indalozin 167B and coniceine. There are a number of different routes to the synthesis of indolizines and they are most commonly synthesised by sequential N-quaternisation, intramolecular cyclocondensation reactions or the cycloaddition reaction of /V-acyl/alkyl pyridinium salts. 

The Weinreb group has used an intramolecular imino Diels-Alder cycloaddition as the key step in a total synthesis of the fungal neurotoxin slaframine (74) (equation 25). Thus, thermolysis of acetate (71) produced an intermediate A -acyl imine (72) which underwent [4 + 2] cycloaddition to afford bicyclic lactam (73) as a 1.8 1 mixture of epimers. Both compounds were converted to the natural product in a few steps. 

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-... 

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). 

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... 

An intramolecular imino Diels-Alder reaction has also been used as the key step in a total synthesis of the neurotoxic fungal metabolite slaframine (49) 91 [4 2] cycloaddition of an ( , )-diene was used to establish... 

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... 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Hua has recently extended this methodology as a route toward the asymmetric total synthesis of alkaloids including (+)-epilupinine (43) and (—)-lupimne (44) [34], and (-)-slaframine (45) and (-)-6-epislaframine (46), in enantiomerically pure form [35]. 

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). ... 

Weinreb and co-workers have applied the im/Wu-Diels-Alder reaction to a synthesis of streptonigrin (81), and also the intramolecular variant of the same reaction in a neat synthesis of the fungal toxin slaframine (82). In addition, full details of Martin s formal synthesis of lycorine (85), based on the intramolecular Diels-Alder reaction (83) -> (84), have now been published. ... 

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