Isoretronecanol

The heteroatom version of the vinylcyclopropane rearrangement serves to facilitate alkaloid construction. Scheme 13 outlines a strategy for the pyrrolizidine alkaloid isoretronecanol 211 90). Use of a carboxaldehyde (i.e. 213) as a synthon for the primary alcohol provides an ability to adjust stereochemistry. It also sets up formation of the pyrrolidine ring bearing the aldehyde by an aldol-type condensation of an enol of the aldehyde onto an imine derived from 214. Because of the lability of such systems, introduction of X=PhS imparts stability. The resultant azacyclopentene translates to an imine 215 using the iminocyclopropane rearrangement methodology. Simple condensation of the primary amine 216 with aldehyde 37a then initiates this... 

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

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. 

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 absolute configurations of pyrrolizidine bases were established only very recently. Leonard84 attempted to solve the problem by comparing the shifts of molecular rotation of isoretronecanol derivatives with analogous shifts in the lupinine series. However, it was demonstrated later that this approach led to incorrect conclusions. 

The bis-diethylacetal of di-(4-oxo-n-butyl)amine (182) was obtained from y-aminobutyraldehyde diethylacetal (180) and y-chlorobutyral-dehyde acetal (181) and, after removal of acetal protecting groups, converted into 1-formylpyrrolizidine (183) without isolation of the intermediates. The final condensation was achieved by Babor et oZ.,109 who isolated 1-formylpyrrolizidine in ca. 10-15% yield at pH 4—4.5. Hydrogenation of the compound over platinum afforded 1-hydroxymethylpyrrolizidine, which they claimed to be ( + )-isoretronecanol. Leonard and Blum123 carried out the same condensation at pH 7 and reduced the resultant aldehyde, without isolation, with sodium boro-... 

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

Intramolecular cyclization of ally lie stannanes.1 The pyrrolizidine alkaloid isoretronecanol (3) can be synthesized efficiently by cyclization of the mesylate of the hydroxylactam 1 to give 2 stereoselectively. Oxidative cleavage followed by reduction of the keto group gives 3. 

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. 

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... 

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. 

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... 

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