Stereoselective cyclization of silylated epoxy aldehydes into piperidines. Effect of the silicon group

A series of 2-or 3-silyl-epoxy aldehydes derivatives bearing a glycinyl sidechain have been prepared and tested in intramolecular aldolization. Highly stereoselective cyclization occurs and provides the N-heterocycle framework which is useful for the synthesis of polyhydroxylated piperidines. The presence of the silicon group on the epoxy moiety strongly influenced the stereochemical outcome of the reaction.


Introduction
Palladium plays an important role in organic chemistry due to the broad scope and versatility of its utilization in homogeneous 1 or heterogeneous reactions. 2Among others, palladium-catalyzed allylation of various nucleophiles (the Tsuji-Trost reaction) is one of the major achievements in this field.However, the possibility of controlling the chemo-, regio-and enantio-selectivity of the attack of the nucleophiles onto the η 3 -allyl ligand is still a challenging research area. 3Much work has dealt with the variation of the ligands around the metal, 4 the role of the solvent, 5 or the steric and electronic influence of the substituents of the allyl moiety. 6Silicon groups have been recognized as strong directing substituents. 7Organosilicon compounds are also versatile and powerful reagents leading to many applications in organic synthesis. 8They have attracted considerable attention not only as biologically acceptable analogues of natural products 9 but also because silicon acts as a directing atom that increases 10 or reverses selectivities usually observed for its carbon analogues. 11Since the first reports of Hiyama, organosilanes have also been extensively studied in cross-coupling reactions catalyzed by palladium. 12Some years ago, we demonstrated for the first time the highly chemo-and stereoselective alkylation of 2-silylbut-2ene-1,4-diol derivatives. 13Depending on its position, the silicon group strongly influences the formation and the reactivity of the cationic π-allyl palladium complex. 14The ionization takes place with complete chemoselectivity so as to expel the acetoxy group vicinal to silicon.These studies allowed the development of a new palladium-catalyzed cyclization reaction, wherein 2trialkylsilyl-1,4-diacetoxy-but-2-ene are converted, via two palladium-catalyzed reactions, into silyl-substituted cyclopentenes (Scheme 1).In this overall annulation process the role of silicon is crucial and twofold.In fact, in the first C-C bond formation the bulky trialkylsilyl group regiodirects the ionization of the starting bisallylic system.In addition, the same group is expected to prefer a syn disposition in the transiently generated η 3 -allylpalladium complex, 15 so as to allow the 5-endo process to take place in the second reaction. 16e also took advantage of these efficient alkylations giving stereoselectively (E) compounds, to prepare in few steps some silylated epoxy cyclopentanols. 17The high level of stereoselectivity observed during the aldolization was attributed, in part, to the presence of the three membered ring in the tether (Scheme 2).We recently extended this process towards the construction of a 6-membered nitrogen heterocycle. 18Substituted piperidines, in general, 19 and polyhydroxylated derivatives 20 more precisely, have been the targets of a large number of synthetic approaches 21 due to their potential as therapeutic agents, and the need to find efficient access to biologically active analogues.Our synthetic approach to the piperidine skeleton is based on the stereoselective palladium-catalyzed amination as well as an intramolecular aldol condensation (Scheme 3). 22e decided to study the effect of the silicon substitution on the above cyclization.In particular, we were intrigued to verify the effect of the presence of the silyl group vicinal to the carbonyl function.We report herein the preparation and the result of the cyclization of two epoxy aldehydes 1 and 2 substituted by a triethylsilyl group at the 2 or 3 position, respectively (Scheme 4).

Results and Discussion
Our synthesis started from either the silyl derivative 3 bearing two allylic acetates or the corresponding dicarbonate 3'.As previously reported, 18 the direct palladium-catalyzed chemoand stereo-selective amination gave the expected compound 4 in 50% yield with no detectable trace of the product derived from the substitution of the other acetate (Scheme 5).The same reaction using the more reactive dicarbonate 3' delivered the expected product 4' in 75% yield in a 90/10 E/Z ratio.Again, no product coming from the ionization of the second leaving group was detected.To prepare the other regioisomer, some more steps were required.Indeed, 3 has two primary allylic acetates and the less hindered one needed to be deprotected.This was efficiently realized using the transesterification protocol developed by Seebach. 23One should notice that it is crucial to use a relatively hindered alcoholic solvent to perform the mild deprotection with a good chemoselectivity.Moreover, it is important to control the evolution of the reaction and to stop it when traces of the corresponding diol appear, which usually requires three hours at room temperature.Purification by flash chromatography allowed the isolation of the desired allylic alcohol 5 in 75% yield (Scheme 6).After transformation of the alcohol into bromide, the reaction with the potassium salt of the N-tosyl glycine methyl ester delivered the desired allylic amino derivative 6 in 71% overall yield.Having in hand the two regioisomers of the amino-allylic acetates 4 and 6, we pursued the synthesis of the targeted precursors.Methanolysis of the acetate function of 4 and 6 delivered, in good yields, the corresponding allylic alcohols 7 and 8, which were then transformed into the silylated epoxides 9 and 10 in 79 and 92% yields, respectively (Scheme 7).The mild oxidations of the primary alcohols into the desired aldehydes bearing all the functions needed for the construction of the piperidine ring were performed with IBX in DMSO.The stable precursors 1 and 2 were both isolated in 68 % yield.We first studied the acyclic precursor 1 bearing the triethylsilyl group at the position remote from the aldehyde function.After some misleading preliminary experiments, using KHMDS, LDA or NEt 3 , we found that DBU in THF at room temperature was a correct base to convert 1 into the corresponding piperidine ring 11.Careful examination of the 1 H NMR of the crude material indicated two diastereomers (11a and 11b) in a 80/20 mixture (Scheme 8).These two compounds were difficult to separate by flash chromatography.However, as expected, the transrelationship between the oxirane and the created hydroxyl was totally controlled.The two diastereomers 11a and 11b correspond to the two epimers at the ester position.In the major product 11a, the ester function is trans-relative to the hydroxyl group.Attempts to improve the diastereoselectivity, by lowering the temperature considerably decrease the kinetics of the cyclization and degradation started to be competitive.To facilitate the purification and the isolation of the major diastereomer, we reasoned that in our basic conditions, only the minor diastereomer 11b could dehydrate into the corresponding enamino ester 12.To our pleasure, after a reaction time of 3 days, 1 gives a 75/25 mixture of 11a and the expected dehydroamino ester 12.This allowed for an easier isolation of pure 11a in 65% yield.

N RO
The second acyclic precursor 2 bearing the vicinal aldehyde and silyl functions was mixed with an equivalent amount of DBU in THF.We observed a fast consumption of the starting material and isolated after 4 hours a 1/1/0.2mixture of three diastereomers 13 in 89% yield (Scheme 9).Attempts to separate these piperidine derivatives by flash chromatography were unsuccessful.We thus decided to apply a longer reaction time in order to favor the diastereoselective dehydration.Unfortunately, after 4 days we still isolated, in a moderate 57% yield, a mixture of the same three diastereomers.Thus we can conclude that the presence or the absence of the triethylsilyl group adjacent to the aldehyde strongly influence the overall selectivity of the cyclization.Indeed, cyclization of 1 furnished only two diastereomers whereas from 2 we isolated 13 as a mixture of three diastereomers.We propose a model to explain the control of the relative configuration between the oxiranyl and the hydroxyl functions (Scheme 10).Starting from 1, where R is a hydrogen atom, we consider a Felkin-Ahn type model where the attack of the nucleophile occurs anti-to the electronegative group (the oxiranyl function). 24This approach should be much more favored than the approach B which develops electronic repulsions between the two oxygen atoms.On the other hand, starting from the molecule 2 (R = SiEt 3 ), the presence of the triethylsilyl group adjacent to the carbonyl group should develop strong steric interactions in the conformation A. Since the carbonyl group will no longer be securely syn-to a hydrogen, it could rotate to the conformation B. That might explain the loss of stereocontrol in this series and contribute to the production of the minor diastereomer of 13.To explain the major trans-relative configuration between the ester group and the hydroxyl function in the piperidine 11, we consider a chair-like transition state.Due to the pseudoequatorial position of the ester function, the approach C seems to be more favorable than D. This model could explain why 11a, the anti-anti isomer, is the major isomer (11a/11b: 80/20).
Finally, we further demonstrate that the obtained piperidines could be selectively functionalized.For example, after protection of the secondary alcohol of 11a as a silyl ether, the ester group of 14 could be smoothly reduced using LiAlH 4 .After 1h at 0°C in Et 2 O, the primary alcohol 15 could be isolated in 84% yield (Scheme 11).
ARKAT USA, Inc.On the other hand, longer reaction times allowed the clean reduction of both the ester and epoxide groups of 14.After 22h at room temperature, we isolated the mono-protected triol 16 in 54% yield as well as traces of the corresponding detosylated analogue of 16.As expected, the reduction of the epoxysilane function is totally chemoselective and controlled by the silicon group. 25n conclusion, we report an original access to hydroxylated piperidines.The preparation of the first acyclic precursor has been performed by a chemo-and stereo-selective palladiumcatalyzed amination of a silylated diacetate.The piperidine cycle could be obtained in a highly stereoselective aldolization.The presence or the absence of a triethylsilyl group in a neighboring position relative to the aldehyde strongly influences the overall selectivity of the cyclization.Work is underway to extend this approach to more functionalized piperidines in an enantiomeric version.

Experimental Section
General Proedures.Reagents and chemicals were purchased from commercial sources and used as received.All reactions requiring anhydrous conditions were performed under a positive pressure of argon in oven-dried glassware.All solvents were purified and distilled by standard methods.Thin layer chromatography (TLC) was performed on 0.25 mm E. Merck silica gel (60F-254) plates using UV light, p-anisaldehyde or ninhydrin.Column chromatography was carried out on Merck silica gel 60 (40-63 µm).NMR spectra were recorded on a Bruker ARX 400. 1 H NMR were recorded at 400 MHz, and 13 C NMR at 100 MHz with the sample solvent being CDCl 3 unless otherwise noted.Chemical shifts are given in ppm, referenced to the residual proton resonances of the solvents.Coupling constants (J) are given in Hertz (Hz).The letters m, s, d, t, q mean respectively multiplet, singlet, doublet, triplet, quartet: br means that the signal is broad.IR spectra were recorded on a Bruker Tensor 27 using ATR method.Elemental analyses were carried out by the "Service de microanalyse", ICSN -CNRS, 91198 Gif sur Yvette, France or by the "Service de microanalyse", SIARE, 4 place Jussieu 75252 Paris cedex 05, France.Compounds 3, 4 and 4' have already been described in refs 13b,14 and 18, respectively.

Scheme 1 .
Scheme 1. Palladium-catalyzed reactions controlled by a silicon group.