Abstract
The novel aryl platynecines 3a/3b were synthesized from endocyclic 4-aryl enecarbamates 8a/8b by a concise and practical route. The synthesis was based on an efficient preparation of 4-aryl enecarbamates 8a/8b from 3-pyrrolines by means of a Heck arylation using aryldiazonium tetrafluoroborates, followed by a highly stereoselective cycloaddition of the 4-aryl enecarbamates 8a/8b to 2-chloroethyl ketene to afford exclusively the 7-endo-(2-chloroethyl) cyclobutanones 12a/12b in good yields (67% and 65%). Baeyer-Villiger oxidation of the cyclobutanones 12a/12b occurred with high regioselectivity to furnish the aza-lactones 13a/13b in 96% and 90% yields. Reduction of lactones 13a and 13b with LiAlH4 gave the desired aryl platynecines 3a/3b. The total synthetic sequence involved 6 steps and provided the aryl platynecines 3a/3b in an overall yield of 41% and 38%, respectively. These compounds are the first examples of necine bases bearing an aromatic substituent on the azabicyclo[3.3.0]octane framework and incorporate some of the key structural element of the pharmacologically active 1,3,4-trisubstituted pyrrolines which act as antagonists of the chemokine receptor CC5.
Highlights
Pyrrolizidine alkaloids (PAs) are a large family of natural products bearing an azabicyclo[3.3.0]octane as the main structural core
We have previously reported on the synthesis of pyrrolizidines, necine bases and indolizidines, following an efficient synthetic methodology that involved the [2+2] cycloaddition of endocyclic enecarbamates to ketenes.4a-c Recently we decided to apply this methodology to the synthesis of hybrid necine bases and other pyrrolizidines in order to evaluate the influence of such modifications on the biological activities of these compounds
All three enecarbamates were obtained in good overall yields by the Heck arylation of 3-pyrroline 6 using the corresponding aryldiazonium tetrafluoroborate salts
Summary
Pyrrolizidine alkaloids (PAs) are a large family of natural products bearing an azabicyclo[3.3.0]octane as the main structural core. We have previously reported on the synthesis of pyrrolizidines, necine bases and indolizidines, following an efficient synthetic methodology that involved the [2+2] cycloaddition of endocyclic enecarbamates to ketenes.4a-c Recently we decided to apply this methodology to the synthesis of hybrid necine bases and other pyrrolizidines in order to evaluate the influence of such modifications on the biological activities of these compounds. We were interested in the introduction of aromatic groups to the azabicyclo[3.3.0]octane core, in view of recent reports on the outstanding pharmacological properties displayed by 1,3,4-trisubstituted pyrrolidines such as compounds 4 and 5, which exhibit subnanomolar activity against HIV infection.[5] These compounds act as potent antagonists by selectively binding to the chemokine receptor CC5, a co-receptor for HIV infection. To the best of our knowledge arylated pyrrolizidines are unreported compounds and their pharmacological properties could be interesting in establishing some structure-activity relationship between them and the recently reported 1,3,4-trisubstituted pyrrolidines. The availability of several 4-aryl endocyclic enecarbamates by this methodology was a motivation for the construction of the new aryl pyrrolizidines in our laboratory
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