Isoretronecanol synthesis

Scheme 13. Retrosynthetic Analysis and Synthesis of Isoretronecanol 37a b NH4C1, xylene c CH3OH, HC1 d LAH then Raney Ni (No yields)...

The preparation of an enamine ester from thiopyrrolidone is a key step in a total synthesis [447] of (t)-isoretronecanol (2). 

Tufariello has reviewed his strategy for the synthesis of alkaloids (including necine bases) using the 1,3-dipolar cycloaddition of nitrones to alkenes.5 This work began with the synthesis of ( )-supinidine (7) from 1-pyrroline 1-oxide (see these Reports, Vol. 2, Ch. 4). A related approach has been used by Iwashita et al. in their synthesis of ( )-isoretronecanol (5).6 The stereochemistry of the exo-product (8), formed by regiospecific 1,3-dipolar cycloaddition of 1-pyrroline 1-oxide to dihydrofuran (Scheme 2), was confirmed by its conversion into... 

The stereochemical aspect of these cyclizations has been investigated. They have been found to be non-stereoselectives.342 On the contrary, diastereoselective 1-azabicyclo-alkanes have been prepared in the same way, the stereochemistry being dependent upon the size of the ring formed, namely, 1,5-cis and 1,6-trans.343 This methodology has been applied to the synthesis of ( )-isoretronecanol, ( )-epilupinine344 and retronecanol.345... 

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... 

Pandey, G., Devi Reddy, G., and Chakrabarti, D. (1996) Stereoselectivity in the photoinduced electron transfer (PET) promoted intramolecular cyclisations of l-alkenyl-2-silyl-piperidines and -pyrrolidines rapid construction of 1-azabicyclo [m.n.o] alkanes and stereoselective synthesis of ( )-isoretronecanol and ( )-epilupinine. Journal of the Chemical Society, Perkin Transactions 1, 219-224. 

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. 

Cyclization of a h-amino alcohol to a pyrrolidine. This reaction was used in the final steps of a synthesis of isoretronecanol (4) from the 5-amino alcohol (2), prepared as shown in equation (I). 

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. 

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 transannular reaction has been successfully applied to the stereo-specific synthesis of (+ )-isoretronecanol (22) by Leonard and Sato. The... 

Addition of the titanium enolate of Af-acetyl-4-isopropyl-l,3-thiazohdme-2-thione 150 to the A-acyl iminium ions from 151 furnishes the corresponding Mannich-type adducts 152 and 153 with good diastereoselectivity <05JOC4214>. A similar diastereoselective addition of the titanium enolate derived from Af-4-chlorobutyryl-l,3-thiazolidine-2-thione 154 to A -Boc-2-methoxypyrrohdine 155 has been used to provide 2-substituted pyrrolidine 156, a key intermediate in the synthesis of (+)-isoretronecanol <05TL2691>. 

A new, stereospecific synthesis of (+)-isoretronecanol, by a transannular route, has been developed by Leonard et al. Dieckmann cyclisation of NN-bis-(y-ethoxycarbonylpropyl)benzylamine gave ethyl l-benzyl-5-oxo-l-azacyclo-octane-4-carboxylate (20), whose perchlorate was shown to possess a bicyclic structure. Hydrogenation of this perchlorate in ethanol, using palladised charcoal catalyst, afforded ethyl ( )-isoretronecanolate perchlorate (22) as sole product, presumably by stereospecific addition of hydrogen at the less hindered face of the intermediate debenzylated immonium ion (21). Reduction of the free base corresponding to (22), by means of lithium aluminium hydride, gave (+ )-isoretronecanol (23), the stereochemical purity of which was shown by g.l.c. analysis to be >98%. 

Two further quaternary pyrrolizidine alkaloids have been isolated by Sasaki and Hirata from Anodendron affine Druce. These are anodendrine (26) and its C-1 epimer alloanodendrine. In confirmation of these structures, anodendrine gave (+ )-laburninic acid (27) on palladium-catalysed hydrogenolysis, whereas alloanodendrine gave (-t-)-isoretronecanolic acid, the C-1 epimer of (27). The structures of both zwitterionic alkaloids were then finally established by synthesis. 

Anodendrine (17) and alloanodendrine (18) are a pair of zwitterionic alkaloids whose structure was determined by a combination of physical and chemical methods. The synthesis of the former was achieved by treating the methyl ester of labrnninic acid with isopentenyl bromide and hydrolysing the product. The alio base was similarly prepared from (+ )-isoretronecanolic acid (12). 

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