New access to chiral pyrrolidine and piperidine β -enamino ketones. Application to the enantioselective synthesis of (–)-hygroline

We report here a new access to chiral pyrrolidine and piperidine β -enamino ketones by condensation of ( S )-phenylglycinol with ω -oxo alkynones. As an illustration of the synthetic potential of the target compounds, the total enantioselective synthesis of alkaloid (–)-hygroline was achieved.


Introduction
Synthesis of β-enaminones has attracted much interest because of their intrinsic biological properties. 1 Moreover, β-enaminones constitute useful precursors for the preparation of a number of heterocycles and natural products.Indeed, due to their versatile reactivity, they can be condensed to fused heterocycles 2 or be reduced into either β-amino carbonyl derivatives 3 or 1,3amino alcohols. 4In our continuing efforts towards the synthesis of natural products, we have been interested in the enantioselective preparation of heterocyclic β-enaminones bearing an exocyclic double bond.The classical general method for the preparation of such compounds relies on the Eschenmoser sulphide contraction.3a,3b, 5 Alternative procedures have been developed to synthesize morpholinone, 6 pyrrolidine 7 and piperidine 4a,7 derivatives.More recently, we described the preparation of chiral bicyclic pyrrolidine and piperidine β-enamino esters (7aR)-1 and (8aR)-2, by condensation of (S)-phenylglycinol with ω-oxo alkynoates 3 and 4 (R = OMe) 8 (Scheme 1).During the course of this work, we realized that our strategy could be extended towards the obtention of oxazolidine β-enamino ketone analogues 5 and 6 (Scheme 1).Herein, we wish to report our study concerning the synthesis of these compounds by the condensation of the same chiral amine with various ω-oxo alkynones 3 and 4 (R = alkyl, aryl) (Scheme 1).The interest of such compounds as precursors of chiral amino alcohols will be demonstrated by the total enantioselective synthesis of the pyrrolidine alkaloid (-)-hygroline.

Results and Discussion
To evaluate the feasibility of our approach, we carried out the present study using various alkyl and phenyl alkynones 3 (R = Me, Ph) and 4 (R = Me, Ph, n-Pr, i-Pr) as the starting products (Scheme 2).The resulting pyrrolidine and piperidine enamino ketones were viewed as useful building blocks for the total synthesis of various alkaloids. 9The required dioxo alkynes 3a-b and 4a-d were easily obtained in four steps starting from the tetrahydropyrannyl ether 10 of pent-4-yn-1-ol 7 and hex-5-yn-1-ol 8 (Scheme 2).Condensation of the acetylide anions on the various aldehydes afforded the corresponding propargyl alcohols 9a-b and 10a-d in high yields.Subsequent deprotection of the ω-hydroxy functions was performed using Dowex W50 in methanol to give the corresponding diols 11a-b 11 and 12a-d.During these studies, we noted that the benzylic alcohol (9b and 10b) were prone to solvolysis by methanol. 12Indeed, we observed the formation of the corresponding methyl ethers after prolonged reaction times. 12Consequently, the reaction was monitored by gas chromatography and stopped before the appearance of these by-products, even if some unreacted starting material remained.The latter was however easily recovered after column chromatography.Finally, double oxidation of the previously obtained diols was efficiently achieved using Swern conditions 13 to yield the expected ketoaldehydes 3a-b and 4a-d (Scheme 2).

Scheme 2
With the required linear precursors in hands, we turned our attention to their condensation with (S)-phenylglycinol.The results obtained starting from the various substituted ketoaldehydes are summarized in Table 1.
Table 1.Synthesis of oxazolidine β-enamino ketones 5-6 by condensation of keto aldehydes 3-4 with (S)-phenylglycinol When reacted in CH 2 Cl 2 in the presence of the chiral amine and 4Å molecular sieves at room temperature, ketoaldehyde 3a afforded the expected chiral β-enamino ketone 5a as a mixture of epimers at C-7a in a 75:25 ratio (estimated by GC and NMR) and 66% overall yield (Table 1, entry 1).Column chromatography readily afforded the isolation of the two diastereomers in respectively 48% and 18% yields.The configuration at C-7a of the major isomer of 5a was assigned to (R), by analogy with analogous pyrrolidine β-enaminoester 1 8 (Scheme 1), based on the comparison of their chemical shifts in 13 C NMR.In particular, similar chemical shifts for C-2 and C-3 were observed for the major isomer of 5a and for (7aR)-1.In contrast, the (7aS) minor isomer of 5a displayed very different chemical shifts (Table 2).
Likewise, when reacted with (S)-phenylglycinol the phenylketone 3b gave rise to a 85:15 mixture of β-enaminoketones (7aR)-5b and (7aS)-5b that were subsequently isolated in 66% and 11% respective yields (Table 1, entry 2).The absolute configurations of both isomers were assigned as above by comparison of the chemical shifts of C-2 and C-3 (Table 2).It was of note that the minor diastereomer (7aS)-5b slowly isomerized in CDCl 3 solution into (7aR)-5b, which in turn evolved to the corresponding pyrrole derivative as substantiated by the characteristic 1 H As for the homologous ketoaldehydes 4a-d, their condensation with (S)-phenylglycinol afforded the corresponding piperidine β-enaminoketones 6a-d respectively as single isomers, in high isolated yields (Table 1, entries 3-6).X-ray analysis 14 performed on crystalline 6b allowed us to assign the (8aR) absolute configuration.The same stereochemistry was attributed to piperidine compounds 6a, 6c and 6d, based on the comparison of 13 C NMR spectroscopic data.Indeed, compounds 6a-d and the piperidine β-enaminoester (8aR)-2 displayed similar chemical shifts for C-2 and C-3 (Table 3).In the above study, we demonstrated that the present methodology consisting in the condensation of a chiral amine with alkynoates could be successfully extended to alkynones, allowing the efficient synthesis of the target pyrrolidine and piperidine β-enamino ketones.Noteworthy, as conjugated alkynones reacted much faster than the corresponding alkynoates, the follow-up of the reaction by NMR experiment that would give clues on the involved intermediates proved impossible.As for the ester analogue, piperidine derivatives 6a-d were obtained with excellent diastereoselectivities.In contrast, poorer diastereomeric excesses were obtained for pyrrolidine compounds 5a and 5b (d.e.50 to 70%) for unclear reasons.
Reduction of β-enamino ketones may lead to γ-amino alcohols some of which are interesting for their biological and pharmaceutical properties as well as their wide application in synthesis. 15n this context, the previously synthesized chiral β-enamino ketones appear as convenient precursors of chiral pyrrolidine and piperidine γ-amino alcohols.In this work, we turned our attention towards the total synthesis of 2-(2-hydroxypropyl)-1-methylpyrrolidine (13) (Scheme 3) whose four enantiomers have been described, 16 three of them being natural products.Starting from enantiopure pyrrolidine β-enaminoketone (7aR)-5a, the key step of our synthesis relied on a diastereoselective reduction.The absolute configurations of the two newly created stereogenic centers were to be assigned based on the identification of the final generated product(s).Various methods including catalytic hydrogenations, 4b dissolving metal reduction, 17 and treatment with LiBH 4 /CeCl 3 18 or with NaBH 4 in glacial acetic acid 19 have been described to afford predominantly syn amino alcohols.We decided to perform the reduction with in situ generated sodium triacetoxy borohohydride in acetic acid, as this method had been successfully used in our laboratory to reduce pyrrolidine β-enamino ester 1 into the corresponding β-amino ester with a high diastereoselectivity. 3c To our delight, these reaction conditions applied to compound (7aR)-5a cleanly led to the reduction of the C-C double bond and of the ketone moiety along with the cleavage of the oxazolidine ring to give pyrrolidine diol 14, as a single isomer according to NMR.Noteworthy, the reduction performed on isomer (7aS)-5a yielded to the same diastereomer 14, showing that the lack of diastereoselectivity during the formation of the oxazolidine 5a is of little importance in this case.Compound 14 was submitted to debenzylation (H 2 , Pd(OH) 2 /C) followed by the in situ carbamatation in the presence of Boc 2 O, to give amino alcohol 15.Unfortunately, column chromatography did not allow the separation of the latter from 2-phenylethanol.To allow easier isolation, compound 14 was thus subjected to a bisacetylation to give pyrrolidine acetate 16 in 46% overall yield from 5a.Debenzylation of compound 16 (H 2 , Pd(OH) 2 /C) followed by the in situ carbamatation in the presence of Boc 2 O, gave rise to acetate 17 in 85% yield.Treatment with lithium aluminium hydride led to the simultaneous reduction of the carbamate and to the deprotection of the alcohol function to yield the expected compound 13 in 88% yield.The spectroscopic data 16,20 and the optical rotation of this compound {[α] D 24 -50 (c 1.28, MeOH)} were identical with those reported in the literature for the (2R,2'R)-13 diastereomer { [α] D 22 -49 (c 0.4, EtOH) 20 ; [α] D 20 -50.2 (c 0.466, EtOH) 21 ; [α] D 25 -53 (c 1.025, EtOH) 16 }, (-)-hygroline, an alkaloid isolated from Eryhroxylum coca. 22This result allowed us to assign the (2R, 2'R) absolute stereochemistry to compounds 14-17 (Scheme 3).As for mechanistic considerations, the observation that both (7aR) and (7aS) isomers of compound 5a were reduced into the same diastereomer showed that the geometry of the ring fusion did not control the stereochemistry at the C-2 center of pyrrolidine 14.So, we reasoned that the control of the stereochemistry of the latter was induced by the chiral center bearing the phenyl substituent, the oxazolidine moiety being initially cleaved or not.The key step of the reaction would then consist in the reduction of the iminium moiety of intermediate boro enolates I or II 23 via an hydride transfer from the less hindered face (Re face at C-5 or C-2 respectively) anti to the phenyl substituent (Scheme 4).In our scenario, subsequent reduction of the resulting ketone moiety of intermediates III or IV would lead to a syn 1,3-amino alcohol, as previously reported for the reduction of linear β-enaminoketones. 20RKAT USA, Inc.

Conclusions
In conclusion, we developed a valuable methodology for the synthesis of chiral oxazolo pyrrolidine and piperidine β-enamino ketones by condensation of (S)-phenylglycinol with ω-oxo alkynones.The synthetic potential of these compounds was illustrated by the total enantioselective synthesis of alkaloid (-)-hygroline.

Experimental Section
General Procedures.Unless otherwise specified, materials were purchased from commercial suppliers and used without further purification.THF was distilled from sodium/ benzophenone ketyl immediately prior to use.CH 2 Cl 2 was distilled from calcium hydride.All reactions were carried out under argon.Thin layer chromatography analyses were performed on Merck precoated silica gel (60 F 254 ) plates and column chromatography on silica gel Gerudan SI 60 (40-60 µm) (Merck).Melting points are uncorrected.IR: Philips PU 9700.Gas chromatographies were performed on a capillary Chrompack CP-SIL5.Optical rotation: Perkin-Elmer 241 polarimeter.Elemental analysis: Service de Microanalyse de l'ICSN (Gif sur Yvette).HMRS were recorded on a JEOL MS 700 mass spectrometer and a Thermo Electron Orbitrap mass spectrometer.NMR: Bruker ARX 250 spectrometer (250 MHz and 62.9 MHz for 1 H and 13 C, respectively).Spectra were recorded in CDCl 3 as solvent.Chemical shifts (δ) were expressed in ppm relative to TMS at δ = 0 for 1 H and to CDCl 3 at δ = 77.16for 13 C and coupling constants (J) in Hertz.

General procedure for the preparation of 5a-b and 6a-d
A mixture of the required ketoaldehyde (5 mmol) 3a-b or 4a-d in CH 2 Cl 2 (50 mL), (S)phenylglycinol (1.1 equiv) and 4 Å molecular sieves (10 g) was stirred at room temperature for 4 h.The reaction mixture was filtered over a Celite ® pad.The cake was washed with CH 2 Cl 2 and the combined filtrates were evaporated in vacuo.Silica gel column chromatography (AcOEt/cyclohexane 1:1) allowed the isolation of the expected compounds.(-)-Hygroline (13).To a suspension of LiAlH 4 (310 mg, 8.10 mmol) in dry THF (10 mL) was added dropwise a solution of compound 16 (0.22g,0.81 mmol) in THF (4 mL).The reaction mixture was refluxed for 12 h.After cooling to 0 °C, water (0.31 ml), 15% NaOH solution (0.31 mL), water (0.93 mL) and anhydrous K 2 CO 3 were successively added.The resulting reaction mixture was stirred at room temperature for 1 h and then filtered on a glass-frit.The residue was washed with THF.The solvent was carefully removed at room temperature under reduced pressure (110 mm Hg) to yield the expected compound (102 mg, 87%).The spectroscopic data are in accordance with that of the literature. 16,20,21 [] D 24 -50 (c 1.28, MeOH).