Trachelanthamidine

In addition, deoxoprosphylline [36], pipecolic acids, izidines [37], and the bicyclic alkaloids ( )-isoretronecanol, ( )-trachelanthamidine [38] and 6-epi-poranthellidine [39] were synthesized via tandem hydroformyla-... 

Both pyrrolizidine and indolizidine alkaloids can be synthesized by taking advantage of the anodic a-alkoxylation of Ai-alkoxycarbonylpyrroKdines (e.g. (131) to (132), Scheme 31). The method has been utilized to synthesize isoretronecanol (137), trachelanthamidine (138), elaeoka-nine A (135), and elaeokanine C (136) [57]. 

Silylformylation and hydroformylation reactions figured prominently in Ojima s approach to isoretronecanol and trachelanthamidine [40]. Thus, silylformylation of alkyne 70 proceeded smoothly to produce aldehyde 71 (Scheme 5.26). Reduction and protodesilylation provided allylic alcohol 72, which was protected to give 73. Hydroformylation in the presence of HC(OEt)3 led to a 2 1 mixture of 74 and 75. Deprotection and amide and amidal reduction then provided the target compounds. 

Pyrrolizidine alkaloids are usually composed of two moieties-the pyrrolizidine alcohol and a carboxylic (usually hydroxy) acid, which are combined by an ester linkage. The pyrrolizidine moieties may appear as monohydric (trachelanthamidine, 2), dihydric (platynecine, 3), or trihydric alcohols (rosmarinecine, 4). 

The stereochemistry of the other pyrrolizidine alcohols and related compounds was determined on the basis of comparison of their configurations with those of the above basic compounds.2,45,81 For example, platynecine can be converted into (— )-isoretronecanol (134) under conditions which cannot affect the configuration at C-l, and 134 can then be transformed into (— )-heliotridane (135). On the basis of these data, the compounds can be named, respectively, as 1 -endo-hydroxymethylpyrrolizidine and 1 -ewdo-methylpyrrolizidine, and their diastereoisomers (- )-trachelanthamidine (136) and (— )-pseudoheliotridane (137) as I -exo-hydroxymethylpyrrolizidine and 1 -eso-methylpyrrolizidine. 

The properties and reactions of amino-alcohols, obtained largely by hydrolysis of naturally occurring alkaloids, were investigated primarily for the purposes of structural analysis and the preparation of physiologically active derivatives. Many authors have described acylation of pyrrolizidine alcohols with benzoyl chloride and acetic anhydride (see, e.g., refs. 83 and 101). Trachelanthamidine benzoate and p-aminobenzoate were prepared especially for testing of their physiological activity.102 The p-aminobenzoate was obtained by treatment of trachelanthamidine with p-nitrobenzoyl chloride and subsequent reduction of the nitro group with iron in 20% acetic acid. The compound exhibited an anesthetic activity close to that of cocaine. 

Silylformylation is successfully applied to the syntheses of pyrrolizidine alkaloids, ( )-isoretronecanol and ( )-trachelanthamidine, from 5-ethynyl-2-pyrrolidinone (334) via /J-silylenal 335 in combination with amidocarbonylation (Scheme 33)324,335. 

A new route to ( )-trachelanthamidine (6) and ( )-isoretronecanol (5) has been reported by Nossin and Speckamp.12 Cyclization of the ethoxy-lactam (28), which is formed on reduction of the imide (27), led to ring-closure with the acetylene to give, after hydrolysis, a 4 1 mixture of the epimers (29) and (30) (Scheme 7). The preferential formation of the five-membered ring is considered to be due to stabilization of an exocyclic vinyl cationic intermediate by the phenylthio group. Reduction of the separated diastereoisomers (29) and (30) yielded ( )-trachelanthamidine (6) and ( )-isoretronecanol (5), respectively. 

Triazines are trimers of unstable imines and may serve as imine precursors. Treatment of trimer of A1-pyrrol ine with a trimethylsilylmethyl triflate gives trimethylsilylmethyl-imonium triflate which may be desilylated by cesium fluoride, providing an ylid suitable for 1,3-dipolar cycloaddition reactions and constmction of the hexahydro-pyrrolizine framework.386 This strategy has been applied to prepare trachelanthamidine, supinidine and isoretronecanol alkaloids.387... 

The use of another type of bis(trimethylsilylmethyl)amine leads to the synthesis of l-azabicyclo[m.3.0]alkanes also present in the skeleton of a number of alkaloids as trachelanthamidine, isoretronecanol, and tashiramine.447 451... 

Several syntheses of 1-hydroxymethylpyrrolizidines have been reported. Borch and Ho1 have utilized a reductive cyclization method for their synthesis of ( )-isoretronecanol (6) and ( )-trachelanthamidine (7). The cycloheptenone ester (1), prepared by a novel route (Scheme 1), was reductively aminated to give a mixture of the diastereoisomeric amino-esters (2) and (3) in 48% yield. These esters could not be separated. Oxidative cleavage of the double bond of the esters, followed by reductive cyclization, gave a 35% yield of the pyrrolizidine esters (4) and (5). Separation of these compounds was achieved by preparative t.l.c., and a final reduction step afforded the racemic alkaloids (6) and (7). The second reductive amination process was stereoselective, because reduction of the unseparated ester mixture (4) and (5) gave a 1 2 ratio (g.l.c.) of the 1-hydroxymethylpyrrolizidines. 

Another route to ( )-isoretronecanol (3) and ( )-trachelanthamidine (6) is outlined in Scheme 2.5 This Reporter can hardly agree with the authors extravagant claim that this is the most direct and operationally convenient synthesis [of these bases] yet reported . Unfortunately, the intramolecular alkylation step is not stereospecific, and a mixture of diastereoisomers (4) and (5), in a ratio of 1 4, was formed. This mixture was separated chromatographically, in order to effect the synthesis of the bases (3) and (6). 

Robins and Sakdarat have published full details of their route to optically active (+)- and (—)-forms of isoretronecanol (3), trachelanthamidine (6), and supinidine (8).6 In addition, the synthesis of two new optically active bases (7) and (9) (isolated as its diacetate) is described. 

However, there has been no report on the highly stereoselective chiral synthesis of (- )-trachelanthamidine (100a) and ( + )-epilupinine (enr-lOOd) type alkaloids without the use of a chiral building block, except for Takano s chiral synthesis (33% optical purity) (81H(16)915),... 

Achiwa reported a short synthesis of pyrrolizidine derivatives by the cycloadditions using a nonstabilized azomethine ylide 23 (m = 1) (82CPB3167). When the trimer of 1-pyrroline is treated with a silylmethyl triflate, N-alkylation of the 1-pyrroline takes place. Then the resulting iminium salt is desilylated with fluoride ion in the presence of ethyl acrylate to give ethyl pyrrolizidine-l-carboxylate 295 as a mixture of stereoisomers (28%). After the epimerization of 295 with LDA, the ester moiety is reduced with lithium aluminum hydride in ether to provide (+ )-trachelanthamidine (296). A double bond can be introduced into 295 by a sequence of phenyl-selenylation at the 1-position, oxidation with hydrogen peroxide, and elimination of the selenyl moiety. The 1,2-dehydropyrrolizidine-l-carboxylate 297 is an excellent precursor of (+ )-supinidine (298) and (+)-isoretronecanol (299). Though in poor yield, 297 is directly available by the reaction of 23 with ethyl 3-chloropropenoate. 

Both pyrrolizidine and indolizidine alkaloids can be synthesized by taking advantage of the anodic a-alkoxylation of A -alkoxycarbonylpyrrolidines (e.g., 83 to 84). The method, first developed by Ross, Finkelstein, and Petersen, and later explored by Ban and coworkers [24, 25], has been utilized by Shono s group to synthesize isoretronecanol (87), trachelanthamidine (88), elaeokanine A (89), and elaeokanine C (90) [26] (Scheme 7). Once the or-methoxy group has been installed via electrooxidation and nucleophilic capture of the intermediate by methanol, the product 84 is treated with enol ether 85 and titanium tetrachloride to affect C-C bond formation adjacent to nitrogen and afford 86. The latter served nicely in syntheses of both indolizidine alkaloids elaeokanine A (89) and C (90). 

Pyrrolizidine alkaloids ( )-trachelanthamidine (240) and ( )-supinidine (244) were synthesized, based on the Michael addition of an aziridine to an a,/J-unsaturated ester and subsequent ring opening of an aziridinium intermediate. Interest in these alkaloids stems from their biological activities. Treatment of ethyl 6-chloro-2-hexenoate (236) with excess aziridine at 0°C gave the pyrrolidine derivative 238 in one step, probably via the aziridinium salt 237 in 73% yield. The intramolecular cyclization of 238 with lithium diisopropylamide in tetrahydrofuran provided the thermodynamically more stable ester 239 as the sole product, (86%), which was then converted to ( )-trachelanthamidine (240) by reduction with lithium aluminum hydride. Since necine bases must contain a 1,2-didehydro system in their molecule to exhibit physiological activity, the following reactions were carried out to introduce a 1,2-didehydro system. Treatment of 238 with 2.4 equiv of lith-... 

Russian workers have prepared for pharmacological studies simple carbamates of trachelanthamidine (68) by treatment with the appropriate isocyanate. Some cholinesterase inhibitors based on the standard decamethonium model have been prepared. Decamethylene bistrachelanthamine dibromide (69) showed marked curare-like activity in cats and rabbits. New procedures for the iodometric determination of platyphylline bitartrate and for the colorimetric determination of trichodesmine and incanine in the organs of poisoned animals have been described. 

This intramolecular reaction proved to be very useful for the synthesis of a number of pyr-rolizidine-based natural products including trachelanthamidine, isoretronecanol, di-hydroxyheliotridane, and mitosane derivatives. ... 

Reductive cyclization has been used in a novel, recent synthesis of the alkaloids ( )-isoretronecanol (22) and ( )-trachelanthamidine (23) by Borch and Ho. Condensation of the dianion derived from methyl acetoacetate with Z-l,4-dichlorobut-2-ene, followed by cyclization with sodium meth-oxide yielded the cycloheptenone ester intermediate (32) (Scheme 2). Reductive amination of this ketoester with sodium cyanoborohydride and ammonium nitrate gave a mixture of the diastereoisomeric aminoesters 33 and 34. Oxidation with osmium tetroxide and periodate, followed by reductive cyclization, again using sodium cyanoborohydride, gave the two pyrrolizidine esters 35 and 36 in a ratio of 1 2 [gas-liquid chromatography (GLC) analysis]. The esters were separated by preparative layer chromatography, and lithium aluminum hydride reduction of the individual esters gave the two pyrrolizidine alkaloids 22 and 23. 

A group of Russian workers has achieved the first total syntheses in the pyrrolizidine ester-alkaloid series. ( + )-Trachelanthamidine, synthesised... 

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