Enantio-and diastereoselective cyclocondensation reactions. Stereocontrolled access to azabicycles and application to natural product synthesis

Resumo

Enantio- and Distereoselective Cyclocondensation Reactions. Stereocontrolled Access to Azabicycles and Application to Naturfal Product Synthesis- Elena Ghirardi The first objective of this Thesis was the study of the preparation of octhydro-1H-cyclopenta[b]pyridines and octahydro-1H-indoles, through the synthesis of (R)-phenylglycinol derived tricyclic lactams. Following the previous reported methodology a carbon substituent would be present at the carbocyclic ring and we planned to find the conditions for controlling its absolute configuration. Unfortunately, the reaction of ketoester 4 and ketoacid 7, provided undesired enamines 8 and 9. On the other hand, the reaction of ketoacid derivatives 16 and 17 with (R)-phenylglycinol led to a mixture of epimeric amides 18. With the aim to extend the methodology, we planned to study the cyclocondensation reaction of (R)-phenylglycinol and (1S, 2R)-aminoindanol with C-3 and C-5 substituted cyclohexanepropionate derivatives. These reactions provided enantiopure tricyclic or pentacyclic lactams: in every run, a major lactam was isolated or identified, and a minor one was detected. The use of (1S, 2R)-aminoindanol resulted in better results. These tricyclic and pentacyclic lactams are precursors of C-8 (and C-6,8) substituted cis-decahydroquinolines. The conversion required the stereoselective reductive cleavage of C-O oxazolidine bond with simultaneous reduction of lactam carbonyl group, and debenzylation. A library of enantiopure cis-decahydroquinolines was obtained. To illustrate the usefulness of our method, we decided to undertake the synthesis of some alkaloids of Myrioneuron nutans family, which contain an 8-substituted cis-decahydroquinoline core. In particular, we prepared the enantiopure alcohol 82, which was described to be a common intermediate in the synthesis of various Mirioneuron nutans alkaloids. Our synthetic procedure greatly improved the previous results reported for the synthesis of this alcohol. The cyclocondensation reaction of (R)-phenylglycinol and (1S,2R)-aminoindanol with 3-alkyl-2-oxo-cyclohexane-1-acetate derivatives was finally considered. Reaction of (R)-phenylglycinol and 3-alkyl-2-oxocyclohexaneacetate derivatives 97-100 and 107 provided with high yield and stereoselectivity tricyclic lactams 110, 112a, 114, 116 and 118, which incorporate an alkyl or aryl substituent at C-10, while (1S,2R)-aminoindanol did not furnish so good outcomes. These reactions stereoselectively provided an additional minor hexahydroindole by-product. The absolute configuration of these compounds 111a, 113a, 115a and 117a was confirmed by X-ray crystallography. In the case of any or aryl substituent at C-10 of the tricyclic lactam, no by products were detected. We demonstrated that these unsaturated products derived from the opening of the oxazolidine ring of the minor lactams, which are epimers at C-10 of the major lactams, in the presence of acids. The stereoselective opening of the oxazolidine ring of the major lactams, in the presence of strong acids provided unsaturated compounds 111b, 113b, 115b and 117b, in which H-7 and H-7a resulted in cis relative disposition. In the case of lactam 118, with an aryl substituent at C-10, provided the unsaturated compound 125, in which H-7 and H-7a are in relative trans disposition. This different relative configuration can be accounted for by considering the structure rigidity of this system. Major tricyclic lactams were converted into C-7 exo substituted cis-octahydroindoles and cis-octahydroindolones, by selection of the appropriate reductive conditions. Hexahydroindolones 111b, 113b, 115b and 117b were converted stereoselectively into the corresponding enantiopure C-7 endo substituted cis-octahydroindolones, by catalytic hydrogenation of the carbon-carbon double bond, followed by elimination of the chiral inductor through reaction with sodium radical. Moreover, these hexahydroindolones and 125 were transformed into the corresponding trans-octahydroindolones 146c-149c and 126b by simultaneous reduction and debenzylation in sodium ammonia. The presence of the amide function allowed the stereoselective insertion of a new substituent by -alkylation and -amidoalkylation. Finally, in order to demonstrate the utility of this methodology, (+)--Lycorane was synthesized in only four steps, starting from easily available ketone 171, in 35% of overall yield, which resulted an improvement with respect to previously reported synthesis