Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

An approach to 2,4,5-trisubstituted piperidines is reported, in which the key step is the Prins or carbonyl ene cyclisation of aldehydes of the type 1. Prins cyclisation catalysed by concentrated hydrochloric acid in CH(2)Cl(2) at -78 degrees C afforded good yields of two of the four possible diastereomeric piperidines, with the 4,5-cis product 7 predominating in a diastereomeric ratio of up to 94:6. The diastereoselectivity of the cyclisation decreased as the 2-substituent increased in size, becoming unselective for very bulky 2-substituents. In contrast, cyclisation catalysed by MeAlCl(2) in CH(2)Cl(2) or CHCl(3) at temperatures of between 20-60 degrees C, favoured the 4,5-trans diastereomer 8, in a diastereomeric ratio of up to 99:1. The low-temperature cyclisations catalysed by HCl proceed under kinetic control via a mechanism involving the development of significant carbocationic character, in which the 4,5-cis cation is more stable than the 4,5-trans cation as a result of overlap with the neighbouring oxygen. The cyclisations catalysed by MeAlCl(2) proceed under thermodynamic control, affording the product in which both the 4- and 5-substituents are equatorial.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines via radical cyclization

A novel approach to 2,4,5-trisubstituted piperidines is reported, involving the 6-exo cyclization of stabilized radicals onto α,β-unsaturated esters. Only two of the four possible diastereoisomers are observed, with diastereomeric ratios ranging from 3:2 to 40:1 when the radical stabilizing group is vinyl or phenyl. Cyclization of a (triethylsilyl)vinyl-stabilized radical gives the corresponding piperidine radical as a single diastereoisomer that may either be trapped by tributyltin hydride to afford the 2,4,5-trisubstituted piperidine or undergo a second 5-endo cyclization onto the (triethylsilyl)vinyl substituent to produce the 3,5,7-trisubstituted octahydro[2]pyrindene as a single diastereoisomer.     

Stereoselective synthesis of 2,5,6-trisubstituted piperidines

[reaction: see text] A short and efficient synthesis of 2,5,6-trisubstituted piperidines was achieved by a combination of an aza-Achmatowicz oxidation of a furyl benzenesulfonamide, conjugate addition to the resulting 2H-pyridinone, and subsequent addition of various nucleophiles to a transient N-sulfonyliminium ion. The steric bulk of the tosyl group directs attack of the nucleophile from its opposite side, thereby leading to the formation of cis-substituted products.     

Stereoselective synthesis of 3,4-disubstituted and 3,4,5-trisubstituted piperidines by Lewis acid-catalysed ene cyclisation of 4-aza-1,7-dienes

The thermal or Lewis acid-catalysed ene cyclisation of a variety of 4-aza-1,7-dienes afforded 3,4-disubstituted or 3,4,5-trisubstituted piperidines. Activation of the enophile with a single ester facilitated a thermal ene cyclisation, although the reaction was not amenable to Lewis acid catalysis. With other activating groups on the enophile it was found that Lewis acid catalysis was facile, although there was a fine balance between the desired ene cyclisation and the competing hetero-Diels-Alder reaction, with the product distribution being influenced by the activating group on the enophile, the nature of the ene component, and the Lewis acid used. Activation of the enophile with an oxazolidinone function facilitated Lewis acid-catalysed cyclisation to afford mixtures of ene and hetero-Diels-Alder products. Activating the enophile with two ester groups gave a substrate that underwent a very facile ene cyclisation catalysed by MeAlCl(2) to give the corresponding trans 3,4-disubstituted piperidines with diastereomeric ratios of >200 : 1.     

Silatropic carbonyl ene cyclizations in the synthesis of pseudosugars and hydroxylated piperidines

[reaction: see text] We describe two applications of silicon-tethered thermal allyl transfer reactions of alpha-silyloxyaldehydes; formally, these processes can be regarded as silatropic carbonyl ene reactions in which the silicon tether is transferred to the aldehyde oxygen concurrent with carbonyl allylation. In the first application, isoserinal substrates, which bear side-chain nitrogen functionality, are elaborated to dihydroxypiperidines. In the second application, a product of cyclohexadienyl transfer is taken on to carbocylic analogues of, for example, mannose. In both series, the silatropic ene reactions are effected thermally, with no added Lewis acid, and are both stereospecific and highly stereoselective.     

Stereoselective synthesis of 2,4,5-trisubstituted tetrahydropyrans using an intramolecular allylation strategy

A highly stereoselective route to 2,4,5-trisubstituted tetrahydropyrans is reported. The key step employs an intramolecular allylation of a (Z)-allylsilane onto an aldehyde under Br?nsted acid activation. Complete 1,4-stereoinduction accounts for the formation of only two out of the possible four THP products. The level of 1,3-stereoinduction is optimal when the reaction is carried out in an apolar solvent, which is in accord with electrostatics being key to controlling this aspect of the stereoselectivity.     

Asymmetric synthesis of 2,4,5-trisubstituted piperidines from sulfinimine-derived delta-amino beta-ketoesters. Formal synthesis of pseudodistomin B triacetate

[reaction: see text] N-Sulfinyl delta-amino beta-ketoester enaminones, a new sulfinimine-derived chiral building block, undergoes, on hydrolysis in one pot, an intramolecular Michael addition followed by a retro-Michael-type elimination to give enantiopure 2,4,5-trisubstituted piperidines, a structural motif found in numerous biologically active alkaloids. This new chiral building block is readily prepared by treating N-sulfinyl delta-amino beta-ketoesters with dimethylformamide dimethyl acetal. This new protocol was illustrated with a concise formal asymmetric synthesis of marine alkaloid pseudodistomin B triacetate.     

Stereoselective syntheses of (−)-tetrahydrolipstatin via Prins cyclisations

Stereoselective syntheses of (−)-tetrahydrolipstatin have been achieved via two divergent approaches through Prins cyclisations as the key steps. PCC mediated oxidative cleavage, Frater alkylation, Keck allylation, Sharpless asymmetric epoxidation and allylic cleavage were the other key steps employed.     

Intramolecular Prins cyclisations for the stereoselective synthesis of bicyclic tetrahydropyrans

Methyl (4E,7R)-7-hydroxyoctanoate was prepared in 71% yield from ethyl (R)-3-hydroxybutanoate and on reaction with a series of aldehydes in the presence of TMSOTf gave bicyclic oxygen heterocycles in good yields and with the creation of three new stereogenic centres in a single pot.     

Stereoselective synthesis of tetralins using cationic cyclisations

Tetralins, including the terpene calamenene, were prepared by 6-endo cationic cyclisations, effected by addition of an I(I) reagent to alkenylarenes, followed by reductive deiodination. An activating group on the arene was required for efficient cationic cyclisation. Good diastereoselectivity, relative to a chiral centre in the chain linking the alkene to the arene, was observed, with Z-alkenes giving predominantly 1,4-cis disubstituted tetralins, and E-alkenes giving predominantly 1,4-trans derivatives. Analogous 6-exo cationic cyclisations proved very limited in scope.     

Stereoselective synthesis of 2,3,4-trisubstituted tetrahydrothiophenes

We describe an efficient new approach for the synthesis of highly substituted chiral tetrahydrothiophenes, based on the oxidation of a chiral furan substrate with singlet oxygen, followed by intramolecular hetero Michael addition.     

General route to 2,4,5-trisubstituted piperidines from enantiopure beta-amino esters. Total synthesis of pseudodistomin B triacetate and pseudodistomin F

The Michael addition reaction of enantiopure beta-amino esters with methyl acrylate followed by Dieckmann condensation and enol silylation affords the enol ethers 6, which are hydrogenated with catalysis by Raney-Ni at 80 atm and 80 degrees C to provide 2,4, 5-trisubstituted piperidines with high diastereoselectivity. In this case Ni-H attacks the C-C double bond from the direction of the 2-alkyl group to provide the products in which 2,4,5-trisubstrited groups are all cis to each other. While hydrogenation of enol ether 13 without a N-Boc protecting group gives the product 15 in which the 4-hydroxy group and 5-ester moiety are trans to the 2-alkyl group. By using the diastereoselective hydrogenation products 9d and 9e as key intermediates, pseudodistomin B triacetate and pseudodistomin F are synthesized. The key steps for these transformations include Curtius rearrangement and Julia olefination.     

Stereoselective approaches to 2,3,6-trisubstituted piperidines. An enantiospecific synthesis of quinolizidine (-)-217A

The enantiospecific and diastereocontrolled total synthesis of alkaloid (-)-217A is described that employs a stepwise [3+3] annelation strategy and a piperidine 2,3-cyclopropanation-ring opening reaction as the key steps.     

Stereoselective synthesis of tarchonanthuslactone via the Prins cyclisation

The stereoselective total synthesis of tarchonanthuslactone, a polyketide natural product, has been achieved. The synthesis exploits the high stereochemical control in the Prins cyclisation along with ring closing metathesis (RCM) as a key step.     

Stereoselective synthesis of simplactone B via Prins cyclisation

The synthesis of simplactone B has been achieved through a series of nine steps in 85% overall yield using Prins cyclisation as the key step with high stereochemical control.     

Efficient stereoselective synthesis of enantiopure cis- and trans-1,2,4-trisubstituted piperidines

Enantiomerically pure (2R,4S)- and (2R,4R)-2-[(S)-1,2-dibenzyloxyethyl]-4-[2-(diphenylmethoxy)ethyl]-1-[(S)-1-phenylethyl]piperidines cis-1 and trans-1 have been synthesised from N-[(S)-1-phenylethyl]-(S)-2,3-di-O-benzylglyceraldimine in six steps in 31% and 18% overall yields, respectively. The efficiency of the synthetic strategy developed for the synthesis of these compounds relies on: (a) the totally diastereoselective tandem Mannich–Michael reaction between Danishefsky’s diene and the starting glyceraldimine, (b) the high yielding Wadsworth–Emmons reaction of the 4-piperidone intermediate and (c) the diastereodivergent reduction of the exocyclic C–C double bond at C₄ of the piperidine ring. These transformations led to 1,2,4-trisubstituted piperidines with two new stereogenic centres with excellent stereoselectivity.     

Stereoselective synthesis of 4-hydroxy-2,3,6-trisubstituted tetrahydropyrans

[reaction: see text] Reaction of homoallylic alcohols with aldehydes in the presence of TFA gives, after hydrolysis of the ester, 4-hydroxy-2,3,6-trisubstituted tetrahydropyrans with the creation of three new stereocenters in a single-pot process. By varying the aldehyde component, a variety of functionalized side chains are installed at C-2. The utility of this approach is extended to the enantioselective synthesis of tetrahydropyrans with >99% ee.     

Probing the mechanism of Prins cyclisations and application to the synthesis of 4-hydroxytetrahydropyrans

Trapping intermediates on the Prins cyclisation pathway with carbon-based nucleophiles has given further insight into factors affecting the acid-mediated reactions of homoallylic alcohols with aldehydes, enabling the design of efficient syntheses of 4-hydroxy-2,6-disubstituted tetrahydropyrans.