Isoretronecanol, preparation

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

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... 

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... 

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. 

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). 

This procedure is representative of a general and versatile method for the preparation of cyclic 8-enamino esters which are known to be precursors of many alkaloids such as caraptothecin, (+)-1ampro1obine, ( )-lupinine or isoretronecanol... 

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 similar strategy generated two of the simplest members in the pyrrolizidine family of alkaloids, isoretronecanol (120) and trachelanthamidine (121). The enamino ester (117) was prepared via the Es-chenmoser reaction by the condensation of thiolactam (116) and ethyl bromoacetate (Scheme 23). A second alkylation with bromoacetate on the resulting vinylogous carbamate (117) yielded the amino diester... 

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). 

In spite of the low regioselectivity observed in Eq. (3), we were able to develop a number of pyrrolizidine alkaloid syntheses through rational modifications of the cyclization substrate. Our first examples of pyrrolizidine alkaloid syntheses are outlined in Scheme 1 [7]. Imide 7 was prepared from succinimide and 3-butyn-l-ol in 6 steps. Reduction of 7 followed by hydroxy-thiophenoxy exchange gave cyclization substrate 8. Treatment of 8 with TBTH gave a 71% isolated yield of pyrrolizi-dinone 9, which was converted to isoretronecanol in 4 steps. The radical cyclization step also gave small amounts of the C] isomer of 9, reduction product 10 (5%), and... 

An interesting two-step procedure has been reported which allows the stereospecific synthesis of the racemate (3) in 80% overall yield. AT-Formyl-L-proline, prepared from L-proline and acetic-formic anhydride, is treated with ethyl propiolate in acetic anhydride to give the ester (4), the cycloaddition presumably proceeding via the dipolar intermediate (5). Hydrogenation of (4) in the presence of palladized charcoal affords the stereochemically pure ethyl ( )-isoretrone-canolate (3), which on reduction provides (+ )-isoretronecanol (6). Since the ester (3) can be efficiently epimerized at C-1 this synthesis also affords a convenient route to the pseudoheliotridine series. 

Allylsilanes have been used in heterocycle preparation, and in the synthesis of the Prelog-Ljerassi lactone, (+)-mosembrine, such hydroxylactams as (+)-isoretronecanol and ( )-epilupinine, while oxidation to give -silyl enones is used in the preparation of... 

They are used to prepare heterocycles such as 1,2-dihydropyridines, the pyrrolizidine alkaloid (+)-isoretronecanol and J-butyrolactone, and couple with allyIX to give 1,5-dienes. ot-EthoxybutenylSnBu is intermediate in the preparation of dihomoallyl ethers, and Me vSnCH2 allyl ethers provide for chiral transfer in the stereospecific synthesis of hydroxylated steroid side chains. The... 

A number of necine bases have been synthesised by intramolecular opening of activated cyclopropanes by Danishefsky etal. (95). Initially, ( )-isoretronecanol (26) was prepared as outlined in Scheme 8. Intramolecular homoconjugate addition of the amine (31) took place with complete inversion of stereochemistry to give the pyrrolizidinone (32). Removal of the hydrazide group from (32) and reduction of the product (33) yielded ( )-isoretronecanol (26). Analogous treatment of a stereoisomer of (31) afforded ( )-trachelanthamidine (9) (95). 

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