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Mit der Verbesserung unserer Kenntnisse zur Bedeutung bestimmter Molekuleigenschaften bei Anwendungen im Rahmen der Wirkstoffsuche wird das Ausmas immer klarer, in dem veroffentlichte Synthesemethoden erwunschten Kriterien genugen (oder nicht genugen). Wir beschreiben hier, wie die Anwendung einfacher (und in vielen Fallen frei verfugbarer) Rechenprogramme genutzt werden kann, um ein semiquantitatives Verstandnis des Potenzials von neuen Methoden in der Wirkstoff-Forschung zu entwickeln. Diese Analyse kann sich unter anderem auf die Planung verbesserter Studien zum Substratspektrum auswirken, die Priorisierung von bestimmten Beispielstrukturen fur die Synthese leiten und Anspruche fur potenzielle kunftige Anwendungen von neuen Methoden begrunden.

Aryl ethers are prepared by cross-coupling of phenols with aryl iodides in isopropyl acetate as solvent.

As our understanding of the impact of specific molecular properties on applications in discovery-based disciplines improves, the extent to which published synthetic methods meet (or do not meet) desirable criteria is ever clearer. Herein, we show how the application of simple (and in many cases freely available) computational tools can be used to develop a semiquantitative understanding of the potential of new methods to support molecular discovery. This analysis can, among other things, inform the design of improved substrate scoping studies; direct the prioritization of specific exemplar structures for synthesis; and substantiate claims of potential future applications for new methods.

Bicyclic hydantoins are efficiently obtained utilizing a three-component Ugi—Joullie reaction/cyclization sequence as key complexicity-generation process using trifluoroacetic acid as synthetic equivalent for chloroformic acid.

Four amino acid-derived building blocks are converted into 22 scaffolds, e.g. azides (III) and (XIV), hydantoins (IV), lactams (VI), tetrahydropyridines (IX), and azepanes (XII).

The condensation of substituted allylsiloxanes with aldehydes leads to the highly stereoselective construction of 2,3,4,5-tetrasubstituted tetrahydrofurans. With electron-rich aryl and alpha,beta-unsaturated aldehydes as substrates, the stereochemical outcome at C5 can be dictated by appropriate choice of Lewis acid. The reaction has been applied to a concise (nine step) synthesis of (+)-virgatusin (ent-1). [reaction: see text]

Double deprotonation of α-ketoamides generates dienediolates, which undergo regioselective α-alkylation to yield α-substituted-α-hydroxy-β,γ-unsaturated amides. 1,2-Disubstituted alkenes are generated exclusively as the E-isomer. 1,1-Disubstituted and 1,1,2-trisubstituted olefins can also be prepared. The amides can be readily converted to the corresponding acids.

A concise (six-step) synthesis of the indolizidine alkaloid tashiromine (1) has been achieved. Olefin cross-metathesis was used to prepare a key functionalised allylsilane, which subsequently underwent electrophile-induced ring-closure to establish the bicyclic framework with complete control of stereochemistry.

Allylic carbonates are aminated by a wide range of amines in the presence of a catalyst formed from an iridium complex, a chiral phosphoramidite and a base.

Amines have been formylated using aqueous formaldehyde or paraformaldehyde and the iridium catalyst [Cp∗IrI2]2. Paraformaldehyde acts as both a formylating agent and an oxidant.

This article reviews the oxidations of a wide range of molecules with tetrapropylammonium perruthenate including examples of both double oxidations and selective oxidations. Mechanistic studies are discussed and general experimental procedures are reported. In addition several interesting developments in the chemistry of this reagent are outlined, that is, heteroatom oxidation, cleavage reactions and also its use in sequential reaction processes. In order to present a complete picture examples of failed reactions have been included

Vinyl dioxazaborocines 1a-c have been subjected to 1,3-dipolar cycloadditions with benzonitrile oxide. The products are enantiomerically enriched 5-substituted Δ 2 -isoxazolines 2a-c .

Silylketenes bearing a range of substituents (alkyl, alkenyl, aryl, heteroaryl) are prepared by an unusual rhodium mediated Wolff rearrangement of the corresponding silyl diazo ketones.

An efficient and convergent one-step synthesis of substituted dihydroquinolin-2-ones from α,β-unsaturated esters and aminoaryl pinacolboronates under rhodium catalysis is reported. The reaction is easily applicable in parallel synthesis format and provides convenient access to this pharmaceutically-relevant motif.

Stable silylketenes, prepared by rhodium-catalysed decomposition of silyldiazoketones, undergo addition/cyclocondensation sequences with aminophenols and aminomalonate to give α-silylalkylbenzoxazoles and oxazoles, respectively. The silicon can be retained throughout functional group interconversions or can be removed by protodesilylation under acidic conditions as desired.

Amine-functionalised allylsilanes, readily prepared by olefin cross metathesis of protected homoallylamines with allyltrimethylsilane, undergo stereoselective condensation with aldehydes to yield trisubstituted pyrrolidines.

A direct convergent two-component synthesis of quinolines from α,β-unsaturated ketones and o-aminophenylboronic acid derivatives is reported. The reaction is regiocomplementary to the traditional Skraup−Doebner−Von Miller synthesis and proceeds under basic rather than strongly acidic conditions. Quinolines substituted in the benzenoid ring can be accessed by using substituted o-aminophenylboronates prepared by direct palladium-catalyzed borylation of the corresponding o-bromoanilines.

Medicinally important 3-alkoxy-3-aryloxindoles are conveniently prepared by the rapid microwave-promoted palladium-catalyzed intramolecular enolate arylation of mandelate-derived anilides.

The first examples of heterocycle synthesis by iminophosphorane formation/intramolecular aza-Wittig cyclizations that are catalytic in the organophosphorus component are reported. The reaction has been demonstrated in the synthesis of both azine (phenanthridine) and azole (benzoxazole) heterocycles. Catalyst loadings down to 1 mol % have been used with little or no loss in reaction efficiency. The intimate involvement of the phosphine oxide in the catalytic cycle has been verified by in situ infrared spectroscopy.

Prochiral substituted enediolates undergo diastereoselective alkylation with β-chiral primary iodohydrin derivatives, with selectivities up to 97:3. The most selective reactions occur with dienedio...

A wide variety of P-stereogenic aryldialkylphosphines were prepared in enantioenriched form by a systematic diversification of the (−)-sparteine-mediated dynamic kinetic resolution of racemic lithiophosphine−boranes reported by Livinghouse. Excellent asymmetric induction was observed provided that the intermediate lithiophosphine/sparteine complex precipitated from solution; more soluble derivatives returned poor ee's or racemic material. The resulting phosphine−boranes were deprotected and used as reagents in the desymmetrizing asymmetric aza-Wittig reaction of 2-alkyl-2-(3-azidopropyl)cyclohexane-1,3-diones, delivering the highest ee's yet observed in this process (up to 84% ee). Phosphines bearing bulky substituents required heating for the aza-Wittig reaction to proceed to completion, which 31P NMR studies showed to be due to interception of the reaction by the formation of unreactive (E)-phosphazides. This was circumvented by use of methyltrioxorhenium to catalyze the formation of iminophosphoranes f...

A two-step protocol for the asymmetric synthesis of protected quaternary (E)-vinylglycines from simple aldehydes is reported. The key step is a regiocontrolled deconjugative asymmetric alkylation of dehydroamino acids, giving the targets as single geometric isomers with high diastereoselectivity (92-96% de). The products can be converted to valuable quaternary beta-amino alcohols by chemoselective reduction. [reaction: see text].

[reaction: see text] Putative enantioenriched carbenoid species, (R)-1-chloro-2-phenylethylmagnesium chloride (9) and (S)-1-chloro-2-phenylethyllithium (26), generated in situ by sulfoxide ligand exchange from (-)-(R(S),R)-1-chloro-2-phenylethyl p-tolyl sulfoxide (8), effected the stereocontrolled homologation of boronic esters. sec-Alcohols derived from the product boronates by oxidation with basic hydrogen peroxide exhibited % ee closely approaching that of sulfoxide 8 in examples employing Li-carbenoid 26.

[reaction: see text] A practical and general two-step synthesis of carbamate-protected (E)-vinylglycines from aliphatic aldehydes is reported. The key step involves the kinetic alpha-protonation of dianionic dienolates derived from dehydroamino acids.

The reaction of ring-closing metathesis-derived cyclic allylsiloxanes 3 with aldehydes in the presence of a Lewis acid gives 2,3,4-trisubstituted tetrahydrofurans related to the furanolignan family of natural products. The reactions proceed with complete 3,4-trans stereoselectivity, whereas the C-2 stereochemistry depends on both the aldehyde and Lewis acid used. When boron trifluoride etherate is used with aliphatic or electronically neutral aryl aldehydes, the reactions favor the production of the 2,3-cis isomer 8, whereas electron-rich aryl aldehydes lead to the 2,3-trans isomer 9 by Lewis acid-mediated isomerization of the kinetically favored cis isomer. The isomerization can be avoided by use of TMSOTf as a promoter, and hence, the stereochemistry can be tuned by appropriate choice of reagent. Cleavage of the pendant 3-ethenyl group installs the 3-hydroxymethyl group common to the furanolignans.

The first examples of the addition of organometallic reagents to electron deficient boron-substituted olefins are reported. Thus, copper catalysed addition of Grignard reagents to chiral acryloyl and vinylsulfonyl dioxazaborocines, followed by oxidative removal of the boron, gives β-hydroxy esters and sulfones with asymmetric inductions up to 81 and 95% ee, respectively.

Vinyl dioxazaborocines 5 with asymmetric centres on the nitrogen bridgehead substituent have been prepared and assayed in nitrile oxide and nitrone cycloadditions, giving asymmetric inductions of up to 70 and 74% ee, respectively.

A novel one-pot, two-component condensation reaction between readily available allylsiloxanes 5 and electron-rich aldehydes 6 generates aryltetralins 7 with complete control of stereochemistry.