Diastereoselective Alkylation Research Articles

A chemoenzymatic asymmetric synthesis of (9 S,12 S,13 S)- and (9 S,12 RS,13 S)-pinellic acids

A brief and facile synthesis of the title compounds has been developed by using an efficient lipase-catalyzed acylation and a chiral template-directed diastereoselective alkylation for incorporating the stereogenic centres. A cross-metathesis was employed to get the required E-olefin geometry.

Total synthesis and determination of the absolute stereochemistry of the squalene synthase inhibitors CJ-13,981 and CJ-13,982

The absolute and relative stereochemistries of the potent squalene synthase inhibitors CJ-13,981 and CJ-13,982 were determined to be 3 S,4 S by total synthesis of their antipodes using, as a key step, the diastereoselective alkylation of a chiral dioxolanone.

Enantioselective formal total synthesis of (−)-trachyspic acid

An enantioselective formal total synthesis of (−)-trachyspic acid was carried out using, as key steps, an asymmetric aldol reaction of a chiral oxazolidinone and a diastereoselective alkylation of a chiral 1,3-dioxolan-2-one. The key lactone 3 was synthesized in five steps starting from dioxolanone 9.

Aminolithiation of carbon-carbon double bonds as a powerful tool in organic synthesis

Abstract A conjugate amination of α,β-unsaturated carbonyl compounds with lithium amides has become a powerful method of N-C bond-forming reactions. Chiral ligand-controlled asymmetric version of the conjugate amination of enoates was developed for practical bench chemistry, giving the enantioenriched amination product with over 99 % ee. In situ diastereoselective alkylation of resulting lithium enolates allowed us to form vicinal N-C and C-C bonds in a one-pot operation. This protocol enabled us to realize a short-step asymmetric synthesis of otamixaban key intermediate. Treatment of product 3-benzylamino- and 3-allylaminoesters with tert-butyllithium gave five- or seven-membered lactams through [1,2]- or [2,3]-rearrangement of intermediate β-lactams. Isolated C-C double bonds were also found to accept intramolecular aminolithiation affording the corresponding hydroamination products. Chiral lithiophilic ligand-catalyzed reaction gave enantioenriched hydroamination products with high ee. Stereoselective intramolecular aminolithiation of allylaminoalkenes was coupled with subsequent carbolithiation to give doubly cyclized product amines.

Asymmetric Solid-Phase Alkylation of Ketones Immobilized via SAMP Hydrazone Analogue Linkers

The preparation and application of new solid supports with chiral linkers, analogues of SAMP hydrazine on solid-phase, are described. The supports were used for immobilization of ketones (diethylketone, cyclohexanone, 4- tert-butylcyclohexanone), and diastereoselective alkylation of formed chiral ketone hydrazones. The enantiomeric purities of cleaved alpha-alkylated chiral ketones ranged from 10 to 73%. The use of chiral lithium amides for metalation of hydrazones of t-butylcyclohexanone increased the enantiomeric excess of the alkylated product by 25-47%.

Stereoselective alkylations of chiral nitro imine and nitro hydrazone dianions. Synthesis of enantiomerically enriched 3-substituted 1-nitrocyclohexenes.

Dianions of chiral nitro imines (generated by a combination of LDA and s-BuLi) underwent diastereoselective alkylation with methyl, butyl, isopropyl, allyl, and methallyl iodides. In contrast to the behavior of simple metalloenamines, the most selective auxiliary contained no coordinating groups but did possess a large steric difference between the two substituents. The yield and selectivity of the alkylations were improved by the addition of HMPA or DMPU. The use of (S)-1-naphthylethylamine as the auxiliary afforded the R absolute configuration of the alkylation products. This stereochemical outcome could be rationalized by simple steric approach controlled alkylation in a conformationally fixed, internally coordinated dianion. A SAMP nitro hydrazone gave poorer yields and selectivities.

Total Synthesis of Citrafungin A

The antifungal natural product citrafungin A was synthesized using, as key steps, an asymmetric aldol reaction of a chiral oxazolidinone, diastereoselective alkylation of a chiral 1,3-dioxolan-2-one, semihydrogenation of an enyne, and selective methyl ester deprotection.

Total synthesis of potent antitumor agent (-)-lasonolide A: a cycloaddition-based strategy.

A detailed account of the enantioselective total synthesis of (-)-lasonolide A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an alpha-alkoxyacetimide derivative containing an alpha' stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero-Diels-Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively.

Stereocontrolled Alkylative Construction of Quaternary Carbon Centers

Protocols for the stereodefined formation of alpha,alpha-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereoselective alkylation reactions. Direct alkylation of alpha,alpha-disubstituted pseudoephedrine amide substrates is demonstrated to be both efficient and diastereoselective across a range of substrates, as exemplified by alkylation of the diastereomeric pseudoephedrine alpha-methylbutyramides, where both substrates are found to undergo stereospecific replacement of the alpha-C-H bond with alpha-C-alkyl, with retention of stereochemistry. This is shown to arise by sequential stereospecific enolization and alkylation reactions, with the alkyl halide attacking a common pi-face of the E- and Z-enolates, proposed to be opposite the pseudoephedrine alkoxide side chain. Pseudoephedrine alpha-phenylbutyramides are found to undergo highly stereoselective but not stereospecific alpha-alkylation reactions, which evidence suggests is due to facile enolate isomerization. Also, we show that alpha,alpha-disubstituted pseudoephedrine amide enolates can be generated in a highly stereocontrolled fashion by conjugate addition of an alkyllithium reagent to the s-cis-conformer of an alpha-alkyl-alpha,beta-unsaturated pseudoephedrine amide, providing alpha,alpha-disubstituted enolate substrates that undergo alkylation in the same sense as those formed by direct deprotonation. Methods are presented to transform the alpha-quaternary pseudoephedrine amide products into optically active carboxylic acids, ketones, primary alcohols, and aldehydes.

Diastereoselective Synthesis of α,β′-Disubstituted Aminomethyl(2-carboxyethyl)phosphinates as Phosphinyl Dipeptide Isosteres

A new and efficient method has been developed for the diastereoselective synthesis of unnatural dipeptide analogues containing the metabolically stable phosphinic moiety, NH 2XaaPsi[P(O)OHCH 2]XaaOH, which mimics the transition state of tetrahedral geometry of a scissile peptide bond in hydrolysis by protease. The method is based upon stereospecific Michael addition of stereodefined alpha-aminoalkyl- H-phosphinates to acrylates and subsequent diastereoselective alkylation at the beta'-position of the resulting Michael adducts.

ChemInform Abstract: Gold(III) Chloride‐Catalyzed Diastereoselective Alkylation Reactions with Chiral Benzylic Acetates.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Preparation of C-Glycoside Pendant β2- and β2,2-Amino Acids

Abstract Facile preparations of C-glycosyl β2- and β2,2-amino acids are described. Selective formation of a β-C-glycoside linkage was achieved by the reaction of a 2,3,4,6-tetra-O-acetyl-α-d-gluco/galactopyranosyl bromide (α-acetobromoglucose/galactose) with the carbanion of a cyanoacetate ester. Crystallization selectively afforded one of two diastereomers with respect to the chiral center at the α-carbon of the side chain (C-2), however, this compound was found to epimerize during the following nitrile reduction. Separation of the diastereomers was achieved via the Fmoc derivatives. Diastereomerically pure C-glycosyl β2,2-amino acids were prepared by diastereoselective alkylation of C-glycosylated enolate, followed by nitrile hydrogenation. The present procedure serves as an efficient route to C-glycosylated β-amino acids containing a non-biodegradable linkage.

An enantioselective synthesis of ( S)-4-fluorohistidine

We report a new synthesis of enantiomerically pure ( S)-4-fluorohisitidine based on diastereoselective alkylation of MOM-protected 4-fluoro-5-bromomethyl imidazole using the Schöllkopf bis-lactim amino acid synthesis. Improvements in procedures for preparation of key intermediates are also described. ( S)-4-Fluorohisitidine prepared by this new method was identical in all respects to material prepared by previous procedures.

Acylation, Diastereoselective Alkylation, and Cleavage of an Oxazolidinone Chiral Auxiliary

An introduction to the concepts and experimental techniques of diastereoselective synthesis using a chiral auxiliary is described. The 4-benzyl-2-oxazolidinone chiral auxiliary developed by Evans is acylated with propionic anhydride under mild conditions using DMAP as an acyl transfer catalyst. Deprotonation with NaN(TMS)2 at -78 °C leads to a rigidly chelated enolate that is alkylated by allyl iodide preferentially from the least hindered diastereoface with 98:2 selectivity. Chromatographic purification followed by hydrolytic cleavage of the auxiliary using LiOH/H2O2 gives 2-methyl-4-pentenoic acid in high enantiomeric purity. This exercise gives students the opportunity to gain proficiency with the techniques of modern organic synthesis, including the manipulation of moisture-sensitive reagents, low temperature reactions, column chromatography, TLC, and NMR analysis. The experiment also provides a context for the discussion of important reaction mechanisms, such as acylation and enolate alkylation, and serves to reinforce the critical conceptual distinction between absolute and relative stereochemical control.

Asymmetric Synthesis of L-[3-13C]Tryptophan

Synthesis of L-[3-13C]tryptophan (2) from N,N-dimethyl[13C]formamide (4) and Dellarias oxazinone 1 as a chiral glycine equivalent was achieved. Vilsmeier reaction of indole (5) and N,N-dimethyl[13C]formamide (4) afforded a good yield of indole-3-[13C]carbaldehyde (3), which was converted to the bromide 8. Diastereoselective alkylation of the enolate of 1 with the bromide 8 proceeded with high diastereoselectivity to give 9. Ethanolysis, hydrogenolysis and hydrolysis of 9 gave L-[3-13C]tryptophan (2).

Gold(III) Chloride‐Catalyzed Diastereoselective Alkylation Reactions with Chiral Benzylic Acetates

AbstractGold(III) chloride was shown to be an efficient catalyst for the diastereoselective CC bond formation of various chiral para‐methoxybenzylic acetates and different nucleophiles. All electrophilic acetates carried next to the reacting center a stereogenic carbon center bound to a functional group (FG), a methyl substituent and a proton. Selectivities were good (dr>80/20) in favor of the anti‐product for FG=COOMe, NO2, CN and in favor of the syn‐product for FG=SO2Et, PO(OEt)2. The reactions proceed most likely via a free carbocation, in which a face differentation is facilitated by a preferred conformation. Several arene nucleophiles were shown to be compatible with the catalysis conditions providing the corresponding substitution products in high yields (13 examples, 62–98%). Moreover, other nucleophiles (allyltrimethylsilane, trimethylsilyl cyanide, 2,2‐dimethyl‐3‐(trimethylsilyloxy)butane, p‐toluenesulfonamide, and acetylacetone) reacted with a representative chiral electrophile in a high yielding and diastereoselective fashion.

Highly efficient synthesis of α-amino amidines from ynamides by the Cu-catalyzed three-component coupling reactions

Using ynamides as one of the reacting components, the Cu-catalyzed three-component reaction of sulfonyl or phosphoryl azides and amines affords α-amino amidines in high yields under mild conditions. Synthetic utility of the produced compounds was demonstrated in the diastereoselective alkylation of α-amino amidines bearing a chiral oxazolidinone moiety. It was also shown that α-amino imidates could be readily prepared by employing alcohols instead of amines.

Development of new thiazole-based iridium catalysts and their applications in the asymmetric hydrogenation of trisubstituted olefins

New thiazole-based chiral N,P-ligands that are open-chain analogues of known cyclic thiazole ligands have been synthesized and evaluated in the iridium-catalyzed asymmetric hydrogenation of trisubstituted olefins. Chirality was introduced into the ligands through a highly diastereoselective alkylation using Oppolzer's camphorsultam as chiral auxiliary. In general, the new catalysts are as reactive and selective as their cyclic counterparts for the asymmetric hydrogenation of various trisubstituted olefins.

Enantioselective Synthesis of 2-Substituted Alcohols Using (+)-(1S,2S)-Pseudoephedrine as Chiral Auxiliary

An improved method for the selective synthesis of enantiopure 2-substituted alcohols is described. Highly diastereoselective alkylation of pseudoephedrine-derived amides and subsequent oxidation of the hydroxyl group in the amide side chain, leads to oxoamides. These oxoamides can be purified by crystallization or preparative HPLC to obtain diastereomeric ratios of >99:1. The following reductive cleavage of the modified auxiliary allows the epimerization-free formation of enantiopure 2-substituted alcohols with up to 99.9% ee.

Diastereoselective Alkylations of Enolates Directed by Chiral Electrophiles

Diastereoselective Alkylations of Enolates Directed by Chiral Electrophiles