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A diastereoselective trans-alkylation of aza-enolates of orthogonally protected chiral bis-lactim ethers with electrophiles, such as alkyl halides, and subsequent deprotection via hydrolysis/hydrogenation leads to dipeptide ester derivatives.

Aza-conjugate addition of the lithium anion of N-trimethylsilyl-p-methoxybenzylamine to tert-butyl enoate acceptors, in the presence of a stoichiometric amount of enantiopure 1,2-dimethoxy-1,2-diphenylethane and excess trimethylsilyl chloride, affords tert-butyl-N-p-methoxybenzyl-β-amino esters with excellent levels of enantiocontrol. These N-p-methoxybenzyl-β-amino-esters may be deprotected under oxidative conditions via treatment with ceric ammonium nitrate, followed by acid hydrolysis of the resultant imine intermediates, to afford enantiopure β-amino-esters containing hydrogenolytically sensitive functionality.

A clean, mild and sustainable method for the functionalization of pyridines and their analogues is reported. A zinc-based Lewis acid is used to activate pyridine and its analogues towards nucleophilic aromatic substitution, conjugate addition, and cyclization reactions by binding to the nitrogen on the pyridine ring and activating the pyridine ring core towards further functionalization.

The title compounds are obtained by reaction of aryl-aldehydes containing ortho-substituted α,β-unsaturated carboxylic acid derivatives with hydroxylamine leading to reactive N-hydroxy-carbinolamine intermediates which undergo intramolecular aza-conjugate addition reactions.

Acid chlorides can be activated by using simple iodide sources, e.g., KI or LiI, to undergo nucleophilic attack by a variety of relatively weak nucleophiles.

Treatment of a range of trisubstituted β,γ-unsaturated esters with 2 equiv of (−)-monoisopinocampheylborane results in hydroboration of their alkene functionalities and reduction of their ester groups to afford chiral 1,3-diols containing two new vicinal β,γ-( anti )-stereocentres in 67–85% enantiomeric excess.

The title compounds (II) react with primary and secondary alcohols to yield the corresponding esters.

The title salts (IVa)—(IVe) are efficient N-acylating agents, which allow the convenient formation of a number of secondary and tertiary amides as well as acylated sulfonamides.

Over the last ten years there has been a huge increase in development and applications of organocatalysis in which the catalyst acts as a nucleophile. Amidines and guanidines are often only thought of as strong organic bases however, a number of small molecules containing basic functional groups have been shown to act as efficient nucleophilic catalysts. This tutorial review highlights the use of amidine, guanidine, and related isothiourea catalysts in organic synthesis, as well as the evidence for the nucleophilic nature of these catalysts. The most common application of these catalysts to date has been in acyl transfer reactions, although the application of these catalysts towards other reactions is an increasing area of interest. In this respect, amidine and guanidine derived catalysts have been shown to be effective in catalysing aldol reactions, Morita–Baylis–Hillman reactions, conjugate additions, carbonylations, methylations, silylations, and brominations.

Treatment of unsaturated amides of type (I), (IV), and (IX) with NMO/OsO4 leads to triols which spontaneously undergo cyclization to afford biologically important optically active hydroxy-γ-butyrolactones.

Enolates of N-substituted amino esters (I) and (III) undergo intramolecular cyclization reactions to afford (syn)-aza-anions that undergo 4-exo-trig cyclization onto their ester carbonyl group to afford cyclic β-lactams (II) and (IV) in high diastereoselectivity.

A practically simple three-component Strecker reaction for the asymmetric synthesis of enantiopure α-arylglycines has been developed. Addition of a range of aryl-aldehydes to a solution of sodium cyanide and (S)-1-(4-methoxyphenyl)ethylamine affords highly crystalline (S,S)-α-aminonitriles that are easily obtained in diastereomerically pure form. Heating the resultant (S,S)-α-aminonitriles in 6 M aqueous HCl at reflux resulted in cleavage of their chiral auxiliary fragments and concomitant hydrolysis of their nitrile groups to afford enantiopure (S)-α-arylglycines. The enantiopurities of these (S)-α-arylglycines were determined via derivatization of their corresponding methyl esters with 2-formylphenylboronic acid and (S)-BINOL, followed by 1H NMR spectroscopic analysis of the resultant mixtures of diastereomeric iminoboronate esters.

The cyclopropane ring opening reaction is mediated by Hg(O-CO-CF3)2, leads after demetalation to chiral δ-lactones with multiple stereocenters.

The method allows the synthesis of various derivatives including ester (XIV) as the immediate precursor of the antiinflammatory drug tolmetin (XV).

Chiral auxiliary (3S)-N,N′-bis(p-methoxybenzyl)-3-isopropylpiperazine-2,5-dione employs a chiral relay network based on non-stereogenic N-benzyl protecting groups to enhance diastereocontrol during enolate alkylation.

Investigations reveal that the structures assigned to D-α-amino acid containing diketopiperazines (DKPs) 21–25 isolated from the sponge Calyx CF. podatypa have been reported incorrectly. Synthetic studies and comparison with literature data have enabled the structures of these DKPs to be correctly reassigned. Evidence is presented to suggest that naturally occurring D-Pro-L-Xxx-DKPs are artifacts resulting from non-enzymatic epimerisation of the corresponding L-Pro-L-Xxx-DKP natural products.

A new chiral auxiliary (3S)-N,N′-bis(p-methoxybenzyl)-3-isopropylpiperazine-2,5-dione 7 has been developed for the asymmetric synthesis of α-amino acids. The auxiliary 7 employs a novel chiral relay network based on non-stereogenic N-benzyl protecting groups which enhance the diastereoselectivity observed during alkylation of its C6 enolate 25.

The nucleophilic substitution of (+)-(R)-benzaldehyde methyl isopropyl acetal (αR)-1 (93% ee) and (+)-(R)-o-anisaldehyde methyl isopropyl acetal (αR)-2 (homochiral) with Me2CuLi–BF3·OEt2 occurs completely chemoselectively to afford (+)-(αR)-α-methyl(benzyl) isopropyl ether (+)-(αR)-3 (40% ee) and (+)-(αR)-α-methyl(o-methoxybenzyl) isopropyl ether (+)-(αR)-4 (34% ee) respectively, demonstrating that the mechanism of the former reaction involves a free oxonium ion to the extent of 56% and the latter to the extent of 66%.

Schollkopf's auxiliary 16 was added to bis-lactim iodide 21 to give 1,2-bis[(3S,6R)-3,6-dihydro-2,5-dimethoxy-3-isopropylpyrazin-6-yl]ethane22 in 50% d.e. Dimer 22 was separated from its diastereoisomer 23 and deprotected using 6M HCl to afford homochiral (2R,5R)-2,5-diaminohexan-1,6-dioic acid 24.

An asymmetric synthesis of homochiral α-amino acids has been developed which is based on the conjugate addition of organocuprates to the dehydroalanine equivalent (3S)-N,N′-bis(p-methoxybenzyl)-3-isopropyl-6-methylenepiperazine-2,5-dione 6.

Studies on the alkylation of enolates derived from a range of N-acyl-5,5-dimethyloxazolidin-2-ones and N-acyl-5,5-diphenyloxazolidin-2-ones reveal that high yields and high diastereoselectivities are best obtained when homochiral 4-isopropyl-5,5-dimethyloxazolidin-2-one is employed as a chiral auxiliary.

N -acyl-5,5-dimethyl-oxazolidin-2-ones can function as versatile latent aldehyde equivalents - reductive cleavage with DIBAL-H affords aldehydes in good yield, while tandem DIBAL-H/Wittig methodology affords α,β-unsaturated esters.

Lithium (E)-N-benzyl-O-(4-methoxy-4-phenylbut-2-enyl)- hydroxylamide undergoes a highly diastereoselective rearrangement via a chelated transition state, to afford after reduction, syn-3-benzylamino-4-methoxy-4-phenylbut-1-ene as a single diastereoisomer.

An air and moisture stable C(3)-symmetric titanium(IV) triflate, supported by a tripodal amine-(tris-phenolate) ligand, has been synthesized and characterized by X-ray crystallography and shown to be a good Lewis acid catalyst for a range of aza-Diels-Alder, Diels-Alder, syn aldol, allylation, and alkylation reactions.

Treatment of tertiary amines containing one or more N-benzyl protecting groups with aqueous ceric ammonium nitrate results in clean N-debenzylation to afford the corresponding secondary amine.

Enantioselective reduction of a series of substituted aryl trichloromethyl ketones with the CBS-catecholborane reagent afforded homochiral aryl trichloromethyl carbinols which have been elaborated to give homochiral α-arylglycines in high e.e.

β-Amino esters derived from the stereoselective conjugate addition of homochiral lithium N-benzyl-N-α-methyl-4-methoxybenzylamide to α,β-unsaturated esters may be orthogonally mono-N-deprotected under either oxidative or acid-promoted reaction conditions. Further oxidative deprotection affords β-amino acids or β-lactams.

Addition of a range of organocuprates to (S)-N,N′-bis(p-methoxybenzyl)-3-methylene-6-isopropylpiperazine-2,5-dione 8 affords cis-3-isopropyl-6-alkyldiketopiperazines in excellent yield and >95% de. Subsequent deprotection and hydrolysis of these cis-3-isopropyl-6-alkyldiketopiperazines affords homochiral (S)-α-amino acids in excellent yield.

Addition of two or three equivalents of lithium (S)-N-benzyl-N-α-methylbenzylamide to conjugate acceptors containing two or three α,β-unsaturated ester fragments respectively and subsequent hydrogenolytic deprotection afford homochiral bis- or tris-β-amino esters containing two or three new stereogenic centres in high de and ee.

Treatment of allylic alcohols containing a 1,1-disubstituted alkene with a palladium catalyst and hydrogen gas (1 bar) results in facile isomerization to their corresponding trisubstituted (E)-allylic alcohols, along with small amounts of the corresponding hydrogenated products.

Treatment of β-vinyl-β-hydroxy-N-acyloxazolidin-2-ones with VO(acac)2 and tert-butyl hydroperoxide results in formation of unstable epoxides that are ring-opened by intramolecular nucleophilic attack of their exocyclic carbonyl fragments to afford highly functionalized trisubstituted hydroxy-γ-butyrolactones in >95% de, with a polymer-supported oxazolidin-2-one having been used to transfer this methodology to the solid phase.

Alkylation of the aza-enolate of valerolactim methyl ether with electrophiles affords a-alkyl lactims that may be hydrolysed under mild acidic conditions to afford their corresponding alpha-alkyl-8-amino esters as their hydrochloride salts. Neutralisation of these salts with base results in smooth intramolecular cyclisation to afford their corresponding alpha-alkyl lactams in excellent yield.

Semiplenamides are anandamide-like fatty acid amide metabolites previously isolated from a marine cyanobacterium that display a range of biological activity. Novel syn-aldol/dehydration methodology has been developed for the stereoselective synthesis of the core (E)-α,β-unsaturated amide functionality of this class of natural product, and employed for the efficient synthesis of semiplenamide C.

An air- and moisture-stable titanium(IV) triflate, 3, supported by a C3-symmetric amine tris(phenolate) ligand has been synthesised, characterised by X-ray crystallography and demonstrated to be an excellent catalyst for formal aza-Diels–Alder reactions.

Recent advances in the use of non-enzymatic chiral catalysts for the kinetic resolution or dynamic kinetic resolution of racemic substrates are described. Successful protocols that afford recovered starting material or products in high enantiomeric excess are included, and mechanistic detail is discussed where appropriate. Relevant examples illustrate the wide range of different reaction scenarios where kinetic resolution has recently been employed as a strategy for the efficient synthesis of enantiopure compounds.

Studies towards a N,N′-bis(p-methoxybenzyl)diketopiperazine asymmetric glycine cation equivalent for the synthesis of homochiral α-amino acids are described. The oxidation of enolate 3 with molecular oxygen provides either a mixture of hydroxylated diketopiperazines 7 and 8 or trione 10 depending upon the reaction conditions. The nucleophilic reduction of trione 10 and the reaction of acetoxy N-acyliminium ion precursors 5 and 6, derived from 7 and 8, with allyltrimethylsilane and boron trifluoride etherate is examined and a model for the stereoselectivity observed in these additions is presented.

Treatment of a range of N-benzyl tertiary amines with aqueous ceric ammonium nitrate results in N-debenzylation to afford the corresponding secondary amine. Chemoselective mono-N-debenzylation of N-benzyl tertiary amines is shown to occur in the presence of N-benzyl amides, O-benzyl ethers, O-benzyl esters, O-benzyl phenolates and S-benzyl ethers.

Reduction of α-substituted-(S)-N-acyl-4-benzyl-5,5-dimethyl-oxazolidin-2-ones with DIBAL-H in CH2Cl2 affords α-substituted aldehydes with no loss of stereochemical integrity at their α-centre.