Pyrrolidine-2-acetoacetic acid

A key stage in the biosynthesis of piperidine alkaloids is reached with the formation of A -piperideine. For the elaboration of diverse alkaloids, this intermediate undergoes condensation with a variety of nucleophiles, commonly a /3-keto-acid. (A similar situation is found for pyrrolidine alkaloid biosynthesis see, e.g., Scheme l).1,2 Existing evidence on Lythraceae alkaloid biosynthesis, taken up again below, indicated that condensation occurred in this case between A piperideine (17) and acetoacetic acid to give pelletierine (26), further elaboration yielding alkaloids like (22). In the event, however, labelled pelletierine was found not to be a precursor for (22) or (23).8 Negative evidence is always difficult to interpret, but is here made persuasive by the fact that other precursors that were fed concurrently were incorporated. Conclusive support for these results depended on others outlined below. 

By substituting (S)-(-)-l-amino-2-(dimethylmethoxymethyl)pyrrolidine (S)-(83) for (S)-(4), Enders has developed an efficient and enantioselective Hantzsch synthesis (Scheme 4). In this synthesis, the more-hindered hydrazone formed from (83) was condensed with an acetoacetic acid ester. Deprotonation of the hydrazone so-formed (the major tautomer present was an enehydrazine) followed by addition of an arylidene malonate derivative yielded (85), which could be closed with mild acid to yield optically active... 

The biosynthesis of cuscohygrine, one of the main alkaloids of belladonna, was examined using C-labeled compounds [11,12]. According to the results, the labeling pattern of C of cuscohygrine obtained 15 days after feeding Cj or C2 labeled sodium acetate to the cultivated belladonna is as shown in the Figure. Namely, the skeleton of this alkaloid is biosynthesized from N-methyl-A -pyrrolidine and acetoacetic acid, as in the case of hyoscyamine biosynthesis. 

The biosynthesis starts from the amino acid ornithine which is converted into the pyrrolidine system by the two paths sketched above. The 3 C or 4 C chain must now be built on. The starting material fdr this is, in both cases, acetate. It is probable that two units of acetate first form acetoacetate which can then be linked with the pyrrolidine ring to give variant 2 of the tropane skeleton. Variant 2 can then be converted to cocaine. However, decarboxylation of variant 2 gives variant 1 of the tropane skeleton which can then be transformed into hyoscyamine or scopolamine. For this tropic acid, which is derived from phenylalanine, is necessary (Fig. 125). 

Ketones can present a problem in specificity. Under basic conditions, they may react with two or more molecules of the electrophile to give a mixture of products. Furthermore, unsymmetric ketones may present a choice of two enolate sites so that control is necessary to direct to the desired one. Many alternatives have been developed for this problem. One solution is to incorporate a temporary group on one enolate site to render that site more acidic so that the electrophile will react there. The familiar p-ketoester reactions (acetoacetic ester synthesis) are widely used. For another alternative, the ketone is first converted to an imine (Section 6.2.3) or a dimethyl hydrazone, and the enolate of that derivative is used with electrophiles [28]. Stereospecificity of the addition is obtained by forming a derivative with (5)-l-amino-2-methoxymethyl-pyrrolidine (SAMP) as shown in Equation 7.15 [29]. Without derivati-zation, alkylation of unsymmetric ketones will occur mostly at the more substituted enolate site under reversible deprotonating conditions. Using a base such as EDA will give alkylation primarily at the least substituted enolate. 

Scheme XXXL Synthesis of the 2,7-epimeric analog of perhydrohistrionicotoxin and a 2,7-epi-dioxa analog (75). A i) Methyl acetoacetate dianion, hexamethylphosphoric triamide, ii) Pyrrolidine. B i) 0s04, ii) NaHSOa, iii) Ag2C03, iv) Triethylphosphonoacetate anion. C i)NH3. D i) Toluenesulphonic acid, ii)NaBH4, iii) Phosgene. E i) Al(i-Bu)2H, ii)Allyl-dimethylphenylphosphonium bromide, potassium methylsulfinylmethylide. F i) Pd/C, H2, ii) Li, CH3NH2. G i) LiBH4, ii) KH, C2H5I, iii) Li, CH3NH2...

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