No abstract

Mechanosynthesis is av aluable technique, offering attractive alternatives for the preparation of organic,i norganic,a nd organometallic products. Surprisingly,m echanochemical enzymatic transformations have only scarcely been studied until now.H ere, we demonstrate the use of lipase Bf rom Candida antarctica (CALB) in acylative kinetic resolutionso fs econdary alcohols in mixer and planetary mills. Despite the mechanical stress caused by the high-speed ball milling, the biocatalyst provedh ighly effective, stable, and, in part, recyclable under the applied mechanochemicalconditions.The use of mechanical force, especially generated by grinding or milling, to promote chemical transformations [1] in organic synthesis has experienceda ni mpressive growth during the last 20 years.[2] To date, the classical stoichiometric mechanochemicalr eactions, such as condensations, [3] are complemented by more complex bond-forming processes, [4] including catalytic and asymmetricv ersions thereof.[5] As early as 2006, our group demonstrated the use of l-proline to carry out mechanochemical solvent-free asymmetrico rganocatalyses in automated electrical ball mills.[6] Subsequently,a lso other organocatalytic systemsw ere found to be effective under solvent-free milling conditions. [7] In particular, a,a-[8a-c] and a,b-dipeptidesprovedt ob enefit with respect to the induced enantioselectivity.S imultaneously,m echanochemical syntheses of amino acids and peptides have been introduced.[9a] As ac onsequence, compounds such as aspartame (Asp-Phe-OMe), [9b] protected l-carnosine (Boc-b-Ala-His-OMe), [9c] and the naturalp eptide Leu-enkephalin [9d] can now be accessed under millingp ractices.The aforementioned findings indicateadegree of stabilityo f amino acidsa nd peptidic structures in ball mills, which made us wonder about ap otential use of enzymes under mechanochemicalc onditions. To test this idea, we decided to investigate acylativek inetic resolutions of racemic secondary alcohols 1 with isopropenyl acetate (2)a sa cyl donor,c atalyzed by immobilized lipase Bf rom Candida antarctica (CALB), in ab all mill. The first results of this proof-of-concept study are presented here.An initial attempt to evaluate the hypothesized robustness of the biocatalyst led to ar ather disappointing observation. Whereas fresh (un-milled) CALB catalyzed the reaction between racemic 1-phenylethanol (1a)a nd isopropenyl acetate (2)i nh exane to afford a4 8:52 ratio of acetate 3a and alcohol 1a after 8h,n one of acetate 3a was observed if the same transformation was attempted with an immobilized lipase that had been milled before in am ixer mill at 25 Hz for9 0min (Scheme1,t op reactionb ranch). This result was interpreted as indication for denaturation of the enzyme by the high mechanical stress and instant elevated temperature induced in ab all mill. Despite this discouraging result, the study was continued hoping that the envisaged solvent-free system for the catalytic kinetic resolutions, with all reactionc omponents( reagents, catalysts,a ddit...

The ring closing metathesis (RCM) is a powerful method in organic synthesis for the preparation of cyclic compounds by formation of new carbon-carbon bonds. In the past years a particular subclass of the RCM, the ring closing enyne metathesis (RCEYM), has attracted attention due to its synthetic potential in the generation of ring structures with 1,3-diene moieties, which can subsequently be further functionalised. In this tutorial review mechanistic considerations will be described and the synthetic power of this useful and attractive carbon-carbon bond forming reaction will be illustrated by recent examples of RCEYM applications in the preparation of heterocyclic compounds.

An efficient kinetic resolution of sulfoximines with enals was realized using chiral N-heterocyclic carbene (NHC) catalysts. The stereoselective amidation proceeds without additional acyl transfer agent. Both enantiomers of the sulfoximines can be obtained with excellent ee values (up to 99% ee and -97% ee, respectively). Performing the catalysis on a gram scale allowed using the recovered sulfoximine (+)-1j in an asymmetric synthesis of FXa inhibitor F.

Sulfimides are nitrogen analogues of sulfoxides. [1] In organic synthesis, they serve as useful intermediates [1,2] and have been applied as efficient ligands for metal catalysts. [3] Because of their unique biological properties, [1a, 4] sulfimides have also gained considerable attention in agricultural science and medicinal chemistry. As sulfoxides, sulfimides are chiral and have a stereogenic center at the sulfur atom if they originate from unsymmetrically substituted sulfides. Although sulfimides can be easily synthesized by various means, [1,5] their preparation in enantioenriched form is still challenging. The most prominent strategies involve the use of chiral auxiliaries [3a, 6] or reagents. [7] All of those, however, require stoichiometric amounts of chiral compounds that are usually prepared by multi-step syntheses.The field of catalytic asymmetric sulfimidation is scarcely explored, and only very few catalyst systems have been documented. For example, Uemura, Taylor and their coworkers disclosed the use of chiral copper(I)/bis(oxazoline) catalysts. [8] However, only sterically hindered aryl benzyl sulfides gave satisfying results. Subsequently, Katsuki and coworkers introduced chiral manganese(III)/salen [9] and ruthenium(II)/salen [10] (or salalen) [11] complexes as asymmetric sulfimidation catalysts. Excellent results were achieved, but the synthesis of salen ligands proved cumbersome.Inspired by the early work of Bach [5a,b] and encouraged by our findings that simple iron(II) and iron(III) compounds could effectively catalyze non-asymmetric sulfide imidations, [5h-j] we decided to focus our search on chiral iron complexes for asymmetric versions of such reactions. Herein, we report that iron(III)/PyBOX combinations are highly effective catalysts for the aforementioned transformations. Noteworthy, this is the first iron-catalyzed enantioselective sulfimidation reported to date, despite many other breakthroughs in asymmetric iron catalysis. [12,13] The asymmetric imidation of thioanisole (1 a) with N-(ptolylsulfonyl)imino phenyliodinane (PhI=NTs) in acetonitrile was selected as the benchmark reaction for our preliminary screening. Various catalysts formed in situ from chiral ligands and iron(III) acetylacetonate ([Fe(acac) 3 ], 3 a) were tested.

Kinetic resolution of racemic sulfoxides requires either custom substrates or shows moderate enantioselectivity, leading to achiral coproducts (such as sulfones) as an intrinsic part of the process. A new strategy is demonstrated that allows the resolution of racemic sulfoxides through catalytic asymmetric nitrene-transfer reactions. This approach gives rise to both optically active sulfoxides and highly enantioenriched sulfoximines. By using a chiral iron catalyst and a readily available iodinane reagent, high selectivity factors have been achieved under very practical reaction conditions. With respect to the substrate scope, it is noteworthy that this unprecedented imidative kinetic resolution of racemic sulfoxides provides access to both aryl-alkyl and dialkyl sulfoximines in highly enantioenriched forms.

N-Alkynylated sulfoximines have been obtained by copper-catalyzed cross-coupling reactions starting from NH-sulfoximines and bromoacetylenes in moderate to good yields. The reaction conditions are mild, and the substrate scope is wide.

SummaryFor the first time, chiral sulfoximine derivatives have been applied as asymmetric organocatalysts. In combination with a thiourea-type backbone the sulfonimidoyl moiety leads to organocatalysts showing good reactivity in the catalytic desymmetrization of a cyclic meso-anhydride and moderate enantioselectivity in the catalytic asymmetric Biginelli reaction. Straightforward synthetic routes provide the newly designed thiourea-sulfoximine catalysts in high overall yields without affecting the stereohomogeneity of the sulfur-containing core fragment.