Diastereoselective preparation of cyclic β -aminoketals. Application to the total synthesis of piperidine alkaloids

We describe here the diastereoselective synthesis of cyclic β -aminoketone derivatives which are very powerful synthons for alkaloid synthesis. They were stereoselectively prepared by condensation of a chiral lithium amide on an α , β -unsaturated ester which possesses a leaving group in ω− position. The usefulness of these compounds was demonstrated through the synthesis of indolizidine 209D, an alkaloid isolated from skin extracts of South American frogs and also in the preparation of allosedridine which has been isolated from Sedum acre .


Introduction
The piperidine moiety constitutes a structural unit of many alkaloids presenting various biological activities. 1 For this main reason, stereoselective synthesis of this framework is the object of continuous and intensive efforts. 2 Among them, our laboratory has developed an original approach which relies on the use of an aldehyde and an α-chiral β-aminoketal, together involved in a Mannich type cyclization, to give rapidly and highly stereoselective access to the corresponding cis-2,6-disubstituted piperidines (Scheme 1).This methodology has been successfully applied to the total synthesis of various alkaloids 3 .

Scheme 1
In order to explore the scope and limitation of this strategy, we decided to try, as new precursor, a "preformed" cyclic β-aminoketal, compounds 1 or 2, in the cyclization step.Accordingly, we reasoned that this strategy, applied to aldehyde derivatives, should furnish a rapid stereoselective entry to a bicyclic ring system 4 via intramolecular cyclization of the intermediate 3 (Scheme 2).Moreover, if we were able to prepare efficiently the cyclic βaminoketal 1 or 2 in a non racemic form, we could hope that a chiral bicyclic compound could be obtained.Cyclic β-aminoketal derivatives 1 and 2 were prepared according to our general method previously described 4 .The key step of this synthesis involves a highly diastereoselective addition of a chiral lithium amide on an α, β-unsaturated ester 5 which could be further transformed into a ketone.When the ester has a potential leaving group (LG) in ω-position, intramolecular substitution can be obtained, furnishing the desired cyclic derivatives 6 (scheme 3).

Results and Discussion
The preparation of the cyclic β-aminoketals was realized as described in Scheme 4. The ω functionalized α,β-unsaturated esters 5 6,7 and 6 6,7 were prepared in two steps starting from the corresponding commercial α,ω-chloroalcohols, by oxidation of the alcohol function in an aldehyde followed by a Wittig-Horner reaction with carbomethoxymethyltriphenylphosphorane.
The condensation of the chiral amide 7 on esters 5 and 6 provided the Michael adducts 8 and 9 in good yields and excellent diastereoselectivity (de > 95%).The selective cleavage of the para-methoxybenzyl group was realized using ceric ammonium chloride which led to compounds 10 and 11 in a very fast and clean reaction.Cyclization of compound 10 was first realized in the presence of potassium iodide and potassium carbonate in refluxing ethanol. 8An equimolecular mixture of two diastereoisomers 12 and 13 (epimers at C-2 position), was obtained with an average yield of 58% (Scheme 5).The relative configuration of these two diastereosiomers has been established by comparison of their NMR data with those described in the literature. 9This epimerization process, already observed in alkaloid synthesis 10 , could be explained by a retro-Michael type reaction occurring on cyclized compound 12, consecutively to the extended reflux in basic conditions.When the reaction was carried out under milder conditions (methanol, room temperature), the cyclic β-aminoesters 12 and 14 were now obtained stereoselectively and with better yields.Treatment of the ester with N,O-dimethylhydroxylamine hydrochloride in dichloromethane at 0 °C in the presence of trimethylaluminium led to the corresponding Weinreb amide 15 and 16, 11 precursors of the corresponding ketones.These two synthons were then separately involved in total alkaloid synthesis.
ARKAT USA, Inc. Amide 15 was used for the preparation of indolizidine 209D. 12This alkaloid was isolated from cutaneous glandular secretions of the South American batrachians of the Dendrobates species.As others compounds of the same family, this indolizidine acted as noncompetitive inhibitor of the nicotinic receptor and thus has an activity on the central nervous system. 13Thus, amide 15 was first transformed into ketone 17 using methylmagnesium bromide.Protection of the carbonyl group under mild conditions 14 (trimethylorthoformate, p-TsOH, ethylene glycol, room temperature) led to the β-aminoketal 18 in 74% yield (Scheme 6).

Scheme 6
Treatment of amine 18 with ammonium formate in the presence of palladium on charcoal in refluxing methanol led to the desired cyclic aminoketal 1 in 73% yield.Condensation of amine 1 with hepten-2-al followed by acidic treatment led in a stereoselective manner to the indolizidine 20 in 40% yield.Transacetalation of compound 20 was carried out using ethanedithiol in dichloromethane in the presence of borontrifluoride etherate complex and gave 21 in 79% yield. 15Further hydrogenolysis of thioketal 21 in refluxing methanol (W2 Raney nickel 16 ) furnished (±)-indolizidine 209D 22 with an excellent yield.The spectroscopic data obtained for this compound are in full agreement with those described in the literature. 12.
On the other hand, piperidine derivative 16 is an excellent precursor for the stereoselective synthesis of (±)-allosedridine, 17 a piperidine alkaloid isolated from Sedum Acre. 18Treatment of amide 16 with methylmagnesium bromide (Scheme 7) led to ketone 23, albeit in moderate yield, mainly due to problems of stability and purification.To circumvent this problem, we decided to change the nitrogen protective group.Hydrogenolysis of the α-methylbenzyl group of 16 with palladium on charcoal in the presence of ammonium formate furnished piperidine 24, which, without further purification, was immediately reprotected with benzyl chloroformate. 19By this route, piperidine 25 was obtained in two steps with a 70% overall yield after purification.
ARKAT USA, Inc. Amide 25 was now treated with methylmagnesium bromide and provided ketone 26.Reduction of the latter using Superhydride ® reagent furnished, with a good yield, two diastereoisomeric alcohols 27 and 28 (7/3 ratio) which were easily separated by silica gel chromatography.The relative configuration of the stereogenic center of each compound was established by comparison of their spectroscopic data with those published in the literature 17c .Finally, hydrogenolysis of the carbamate group in the presence of Pearlman's catalyst led to (±)allosedridine 29 with a very good yield.

Experimental Section
General Procedures.Unless otherwise specified, reagents were obtained from commercial suppliers.Solvents were dried and freshly distilled following the usual procedures.Product organic solutions were dried over sodium sulfate prior to evaporation of the solvents under reduced pressure on a rotatory evaporator.Thin layer chromatography was performed on TLC precoated aluminium backed silica plates and spots were visualized using UV light (254 nm) before using ethanolic phosphomolybdic acid solution (heating).Column chromatography was carried out on silica gel (70-230 mesh). 1 H and 13 C NMR spectra were measured at 400.13 and 100.61MHz respectively.Chemicals shifts are reported in ppm relative to SiMe 4 .Signals are quoted s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad) and coupling constant (J) values are given in Hz.Infrared spectra were recorded on a FTIR spectrophotometer.Compositions of stereoisomeric mixtures were determined by NMR analysis on crude products before any purification.High Resolution Electro Spray Impact Mass Spectra (HR-ESI-MS) were obtained from the Centre Régional de Mesures Physiques de l'Université Blaise Pascal (Clermont II), France.

General procedure for preparation of β-aminoesters 8 and 9
To a cold (0°C) solution of N-para-methoxybenzyl-N-α-methyl benzylamine 7 (1.1 equiv) in dry THF (5 mL/mmol of 7) was added slowly under argon n-butyllithium solution 1.6M in hexanes (1.2 equiv.).The resultant pink solution of lithium amide was stirred for 15 minutes then cooled at -78°C before dropwise addition of a solution of α,β-unsaturated ester (5 or 6) (1 equiv.) in dry THF (2 mL/mmol of 5 or 6).The mixture was stirred at -78°C until TLC showed no starting conjugated ester.Then a saturated NH 4 Cl aqueous solution was added dropwise and the resulting solution was allowed to warm to room temperature.β-aminoester (8 or 9) was then extracted with diethylether.Combined organic extracts were dried, filtered and evaporated.The crude product was purified by column chromatography.

General procedure for preparation of mono protected amines 10 and 11
To a cold (0°C) solution of β-aminoester (8 or 9) (1 equiv) in a 1:1 mixture of water and acetonitrile (3 mL/mmol of β-aminoester) CAN (3.0 equiv.) was added.The resultant solution was stirred for 30 minutes then hydrolized with a saturated aqueous NaCl solution.The resulting mono protected amine (10 or 11) was then extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate, filtered and evaporated.The crude product was purified by column chromatography.

General procedure for the cyclization of mono protected amines
To a solution of mono protected amine (10 or 11) (1 equiv) in methanol (7 mL/mmol of mono protected amine) was added potassium carbonate (1.1 equiv.)then sodium iodide (1.1 equiv.).The resulting solution was stirred 2 hours at room temperature before the solvent was removed in vacuo.The crude mixture was dissolved in diethyl ether and hydrolysed with a saturated aqueous NaCl solution.The combined organic layers were dried over sodium sulfate, filtered and evaporated.The crude product was purified by column chromatography.

General procedure for preparation of Weinreb amides
To a cold (0°C) stirred solution of N,O-dimethylhydroxylamine hydrochloride (2 equiv.) in dry dichloromethane (5 mL/mmol of amine) a commercial 2.0 M solution of trimethylaluminium in hexane (2 equiv.) was slowly added.The mixture was stirred at room temperature for 2 hours and amine (12 or 14) (1 equiv.)diluted in dichloromethane (2 mL/mmol of pyrrolodine) was added.The resulting solution was stirred at room temperature until TLC indicated that the reaction had gone to completion.Then the mixture was carefully quenched with a saturated aqueous solution of NH 4 Cl and extracted with dichloromethane.The organic extract was dried, filtered and concentrated in vacuo.The crude Weinreb amide thus obtained was purified by column chromatography.