Stereoselective synthesis of functionalized trans-2,5-disubstituted tetrahydrofurans

[reaction: see text] The addition of the titanium enolates of N-acetyl, N-propionyl, and N-bromoacetyl (R)-oxazolidin-2-ones to gamma-lactol 2, derived from (S)-glutamic acid, afforded trans- and cis-2,5-disubstituted tetrahydrofurans (trans/cis ratio: R = H, 2:1; R = Me, 8:1; R = Br, 10:1) after desilylation with aqueous HF/CH3CN. Chromatographic separation and LiBH4 reduction allowed the efficient preparation of the corresponding trans-2,5-disubstituted tetrahydrofuran diols and the recovery of the chiral auxiliary.     

Highly diastereoselective synthesis of trans-2,5-disubstituted tetrahydrofurans

trans-2,5-Disubstituted tetrahydrofurans were obtained as major diastereomers (trans/cis ratio 90:10-100:0) when acetylated gamma-lactols derived from (S)-glutamic acid were treated with titanium enolates of N-acetyl (R)-oxazolidin-2-thiones. A simple transesterification allowed us to obtain the corresponding methyl esters and recover the chiral auxiliary.     

Facile route to 3,5-disubstituted morpholines: enantioselective synthesis of O-protected trans-3,5-bis(hydroxymethyl)morpholines

[reaction: see text] (3R,5R)-1 R1 & R2 = TBDPS, (3S,5R)-2 R1 = Bn,R2 = TBDPS, (3S,5S)-3 R2 & R2 = Bn. trans-3,5-Bis(benzyl/tert-butyldiphenylsilyloxymethyl)morpholines, promising candidates for the C(2)-symmetric class of chiral reagents, were prepared with excellent optical purity. A key step in the synthesis is the coupling of a serinol derivative with 2,3-O-isopropylideneglycerol triflate or its equivalent. This methodology was extended to the synthesis of chiral trans-3-(benzyloxymethyl)-5-(tert-butyldiphenylsilyloxymethyl)morpholine, a potentially useful chiral building block.     

Highly stereoselective synthesis of 2,5-disubstituted 3-vinylidene tetetrahydrofurans via Prins-type cyclization

[reaction: see text]. A novel synthetic methodology for 2,5-disubstituted tetrahydrofurans having an allenyl group at the 3-position via Prins-type cyclization was developed. The reaction led to excellent selectivity and moderate to high yields.     

A new convergent and stereoselective synthesis of 2,5-disubstituted N-acylpyrrolidines

A new synthesis of 2,5-disubstituted N-acylpyrrolidines through an S_N2′ reaction promoted by the nitrogen anion of a secondary amide onto an allylic bromide is reported. A moderate stereoselectivity, in favour of the trans heterocycle, was observed during the cyclization of a chiral precursor, while a good stereoselectivity, this time in favour of the cis one, was obtained when the second stereocentre was introduced after the cyclization step to give the same product.     

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.     

An unexpected carbon dioxide insertion in the reaction of trans-2, 4-disubstituted azetidine, trans-2,5-disubstituted pyrrolidine, or trans-2,6-disubstituted piperidine with diphenylthiophosphinic chloride and diphenylselenophosphinic chloride

In the reaction of trans-2,4-disubstituted azetidine, trans-2, 5-disubstituted pyrrolidine, or trans-2,6-disubstituted piperidine with diphenylthiophosphinic chloride or diphenylselenophosphinic chloride in acetonitrile in the presence of potassium carbonate at room temperature, an unexpected carbon dioxide insertion produced carbamic diphenylthiophosphinic or diphenylselenophosphinic anhydride in good yield. The same product could be also obtained when the reaction was carried out under carbon dioxide atmosphere using potassium hydroxide or triethylamine as a base. This is a very simple reaction process related to the fixation of carbon dioxide without a metal catalyst.     

Diastereoselective synthesis of 2,5-disubstituted tetrahydrofurans

This review focuses on synthetic methods allowing the preparation of 2,5-disubstituted tetrahydrofurans reported in the literature between 1993 and 2008.     

InBr3-catalyzed stereoselective synthesis of trans-2,6-disubstituted 3,6-dihydro-2H-pyrans

A new method for the stereoselective synthesis of trans-2,6-disubstituted 3,6-dihydro-2H-pyrans with a variety of substitution patterns is described, involving Lewis acid induced tandem allylation or cyanation of δ-hydroxy-α,β-unsaturated aldehydes to produce dihydropyrans in good yields and with trans-selectivity. This method is very useful for the synthesis of trans-2,6-disubstituted dihydropyran ring-containing natural products such as laulimalide, scytophycin C and many others.     

Asymmetric synthesis of trans-2,3-disubstituted indoline derivatives

A novel method for asymmetric synthesis of trans-2,3-disubstituted indolines has been developed. The strategy involves the (-)-sparteine-mediated electrophilic substitution of 2-benzyl N-pivaloylaniline with aromatic or α,β-unsaturated aldehydes and subsequent intramolecular nucleophilic substitution. The simple protocol for two-step process can produce highly enantioenriched indolines 3a-o up to 98:2 er.     

Sulfinimine-mediated asymmetric synthesis of 1,3-disubstituted tetrahydroisoquinolines: a stereoselective synthesis of cis- and trans-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline

[reaction: see text] The highly diastereoselective addition of lateral lithiated o-tolunitriles to sulfinimines followed by treatment of the resulting sulfinamide with MeLi, hydrolysis, and reduction represents a concise new methodology for the asymmetric synthesis of 1,3-disubstituted tetrahydroisoquinolines.     

New method for synthesis of 2,5-disubstituted thiophenes

The use of hydrogen sulfide at the moment of formation is proposed for the recyclization of furans into thiophenes in acidic media. The advantages of this method are shown.N. G. Chernyshevskii Saratov State University, Saratov 410026, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 736–738, June, 1999.     

cis-Selective synthesis of 2,5-disubstituted pyrrolidines

A concise approach to cis-2,5-disubstituted pyrrolidines is reported, which relies upon N-tert-butoxycarbonylmethyl substitution in a substrate derived from pyroglutamic acid. The method is especially noteworthy since a significant improvement in the conditions for a key Lawesson’s reaction have been established. Regioselective enolate generation and alkylation permits extension of the C-5 side chain.     

Concise and stereoselective synthesis of 2,5- and 2,4-disubstituted thiazole amino acid subunits for synthesizing thiazole-containing peptides

A concise, highly stereoselective synthesis of 2,4- and 2,5-disubstituted thiazole amino acids was developed. These are important building blocks for various biologically active thiazole-containing natural peptides and their regioisomeric analogues. The fundamental reactions are diastereoselective addition of (4- or 5-bromothiazol-2-yl)lithium to N-tert-butanesulfinyl imine with subsequent Pd-catalyzed phenoxycarbonylation.     

Gold-catalysed synthesis of amino acid-derived 2,5-disubstituted oxazoles

Amino acid-derived propargylic amides are cyclised in a one-pot, Au(III)-catalysed operation to yield 5-bromomethyl oxazoles. These compounds are further elaborated to bis-heterocycles, dipeptide mimics and more.     

Stereoselective synthesis of orthogonally protected 2,3-disubstituted morpholines using a base-catalysed cascade reaction

The stereoselective synthesis of differentially protected [3-(hydroxymethyl)morpholin-2-yl]methanols is described, starting from chiral epoxides. The key step involves a one-pot oxazolidinone formation via intramolecular epoxide opening and concomitant cyclisation to form the morpholine ring. Selective deprotection reveals the free hydroxymethyl group at either the 2- or 3-position of the morpholine.     

A regio- and stereoselective synthesis of 1,2-disubstituted vinylsilanes

The alkylcopper reagents prepared from RMgBr and CuBr react with trimethylsilylacetylene to give regio- and stereo-selectivity 1-trimethylsilyl-1(Z)-alkenylcopper adducts. Hydrolysis affords 1-trimethylsilyl-1(E)-alkenes exclusively. Alkylation, acylation, halogenation, and stannylation proceed stereoselectively to afford synthetically useful intermediates. Homopropargylation of alkyl 1-trimethylsilyl-1(Z)-alkenylcuprates provided better yield than that of the original vinylcopper reagents.     

A stereoselective synthesis of β,γ-disubstituted allylic alcohols of z-configuration

Reaction of alkyllithiums $\text{1}$ with isoprene epoxide $\text{2}$ gives β,γ-disubstituted allylic alcohols $\text{3}$ of Z-configuration. The reaction of π-lithiotricyclene as alkyllithium gives α-santalol $\text{5}$, which is one of the main constituents in East Indian sandalwood oil.     

Asymmetric synthesis of cis- and trans-2,5-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates: synthesis of (+)-preussin and analogs

Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine allylic alcohols. The alcohols on hydrogenation (Pd/H2) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH3CN undergo a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.     

A new synthesis of symmetrical 2,5-disubstituted 1,3,4-oxadiazoles

Several new 2,5-disubstituted 1,3,4-oxadiazoles have been synthesized in good yields by reaction of aromatic acids with hydrazine dihydrochloride in a mixture of orthophosphoric acid, phosphorus pentoxide and, in general, with addition of phosphorus oxychloride to the reaction mixture. The structures of new oxadiazoles derivatives were confirmed by analytical and spectral data.