Proline ring formation

In the first step bromocriptine 2 is isomerized to 2a, followed by an attack on proline ring in aminocyclol moiety of the molecule (formation of a new double bound on lO -ll, and bromination). This dibromo-compound 5 is brominated additionally on C-2 -propyl group. Tribromo-compound fi is very lipophilic and practically devoid of pharmacological activity. Hydroxy group and amide groups remain intact after all these reactions. 

Figure 3 Biosynthesis of ergopeptines from lysergic acid. Ergovaline is presented as an example. Various other ergopeptines differ at amino acid positions I and II as indicated in the table, or, in one case, in position III as indicated in the text. The asterisk in the diagram of lysergyl-alanyl-valyl-proline lactam indicates the position of the carbon that is hydroxylated prior to cyclol ring formation.

A review of approaches to the design and synthesis of azabicycloalkane amino acids as constrained dipeptide mimetics has been reported. These approaches include 7-membered lactam ring formation by free radical cyclization from a substituted proline precursor <04SL1449>. 

Developed in the early 1970s, this reaction, also called the Hajos-Parrish reaction or Hajos-Parrish-Ender-Sauer-Wiechert reaction, is one of the earliest processes for the stereoselective synthesis of Wieland-Miescher ketone, an important building block for steroids and terpenoid synthesis. This reaction is a proline mediated asymmetric variation to the Robinson annulation. Hajos and Parrish of Hoffmann-La Roche Inc. in 1971 and 1974 published an asymmetric aldol cyclization of triketones such as that of structure 39, which affords optically active annulation products in the presence of catalytic amounts of (S)-proline (Z-proline). One of the early examples is the synthesis of 41 from the triketone 39 (a product of the Michael addition of MVK to the corresponding 2-methylcyclopentane-l,3-dione), the reaction is performed in two steps first by ring formation in the presence of 3 mol % of (iS)-proline in DMF to afford the ketol 40 in 100% yield after crystallization with 93% ee and then by reaction with toluenesulfonic acid to give the dehydrated adduct 41. The formation of the Wieland-Miescher Ketone 44 follows the same synthetic route, starting from the tri-ketone 42 to give the end product in 75% optical purity and 99.8% of optical yield. 

Yamada and Otani on a proline derived ring formation. Cyclohexenone 6 was obtained in 48% yield from aldehyde 5 and 3-buten-2-one. 

Another of the amino acids with an essentially unreactive side chain is proline. Strictly speaking proline is not an amino acid but a cyclic secondary amino acid and it is commonly, but incorrectly, called an imino acid. It contains a pyrrolidine ring and may be visualized as being derived from norvaline, a straight chain amino acid containing five carbon atoms in which the amino group has become involved in ring formation with the <3-C atom. 

One of the closest approaches so far developed is by Bizzozero and Zweifel (118) who tried to explain in 1975 why a proline residue involved in a peptide bond is resistant to a-chymotrypsin cleavage. The objective was to find if the unreactivity of the peptide bond results from an unfavorable interaction of the methylene groups of the proline ring with the enzyme active site or whether the steric hindrance occurs upon formation of the enzyme-substrate complex or during the subsequent bond-change steps, and whether this steric hindrance is related to the ring structure of proline or simply to substitution of the amido nitrogen. In order to answer these questions, the dipeptides N-acetyl-L-phenylalanyl-L-proline amide and iV-acetyl-L-phenyl-alanyl-sarcosine amide were synthesized and their behavior as model substrates of a-chymotrypsin studied. 

C-biosynthetic incorporation work established that acetate, glycine, proline, and methionine were prime precursors of prodigiosin. However, the structural complexity, sensitivity, and lability of this molecule made the isolation of fragments difficult. Studies on the mechanism of this biosynthesis were thus ideally suited to and amenable to the method. The mechanism of the pyrrole ring formation in prodigiosin biosynthesis is also unrelated to porphyrin biosynthesis and is thus of special interest. 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

The numerous synthetic approaches relied principally on the formation of a 5-substituted proline ester by reductive amination followed by cyclization of the lactam ring. 

Pyrrolo[l,2-rf [l,2,4]triazinones 21 were synthesized from methyl ester of /ra j-4-hydroxy-L-proline 72. The synthetic route involved formation of hydrazones followed by cyclisation with orthoesters <1998BMC349>. Similar reactions have been developed with 3-benzylindole-2-carbohydrazides 73 in reaction with triethyl orthoformate, giving the corresponding ring systems indolo[l,2-r][ 1,2,4]triazin-4-oncs 74 <2004JHC7>. 

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