Enantioselective Protonation of Enolates and Enols

Enantioselective protonation, until recently a largely overlooked reaction, has, in the last five years, developed into a field of intense research activity. The progress achieved parallels or complements that obtained in the understanding of enolate structures and reactivities. The conceptual simplicity and attractiveness of enantioselective protonation results from the fact that after reaction, the chiral proton donor is regenerated in its original protonated form by an extractive workup. Enantioselective protonation has been applied to the synthesis of amino acids, antiinflammatory agents (2-arylpropanoic acids), and fragrance compounds such as (S)-α-damascone, for which its industrial feasibility has been demonstrated.     

Stereoselective Formation of Fully Substituted Ketone Enolates

The application of stereochemically defined acyclic fully substituted enolates of ketones to the enantioselective synthesis of quaternary carbon stereocenters would be highly valuable. Herein, we describe an approach leading to the formation of several new stereogenic centers through a combined metalation–addition of a carbonyl–carbamoyl transfer to reveal in situ stereodefined α,α‐disubstituted enolates of ketone as a single stereoisomer. This approach could produce a series of aldol and Mannich products from enol carbamate with excellent diastereomeric ratios.     

Stereoselective Aminoxylation of Biradical Titanium Enolates with TEMPO

A highly efficient and straightforward aminoxylation of titanium(IV) enolates from (S)‐N‐acyl‐4‐benzyl‐5,5‐dimethyl‐1,3‐oxazolidin‐2‐ones with TEMPO has been developed. A wide array of functional groups on the acyl moiety, including alkyl and aryl substituents, olefins, esters, or α‐cyclopropyl, as well as α‐trifluoromethyl groups, are well tolerated. This transformation can therefore produce the α‐aminoxylated adducts in excellent yields with high diastereomeric ratios (d.r.). In turn, parallel additions to the α,β‐unsaturated N‐acyl counterparts give the corresponding γ‐adducts with complete regioselectivity in moderate to good yields. Removal of the piperidinyl moiety or the chiral auxiliary converts the resultant adducts into enantiomerically pure α‐hydroxy carboxyl derivatives, alcohols, or esters in high yields under mild conditions. Finally, a new mechanistic model based on the biradical character of the titanium(IV) enolates has been proposed.     

Stereoselective Synthesis of Trisubstituted Vinylboronates from Ketone Enolates Triggered by 1,3‐Metalate Rearrangement of Lithium Enolates

An unprecedented stereoselective synthesis of trisubstituted vinylboronates is reported to proceed by direct borylation of lithium ketone enolates under transition‐metal‐free conditions. The stereospecific C?O borylation of lithium enolates was triggered by a carbonyl‐induced 1,3‐metalate rearrangement via a C‐bound boron enolate. DFT calculations and control experiments revealed that the stereoselectivity is controlled by sterics. A variety of stereospecific trisubstituted vinylboronates, together with several tetrasubstituted vinylboronates, were conveniently synthesized with the newly developed methodology. Based on the transformation of stereospecific vinylboronate, a single isomer of Dienestrol was efficiently obtained.     

Stereoselective Aldol Reactions with α-Unsubstituted Chiral Enolates

The aldol reaction is among the most important methods of forming carbon-carbon bonds. The addition of an enolate to an aldehyde leads to the formation of at least one chiral center. In the case of α-substituted enolates it has to a large extent been possible to control the product stereochemistry, while the aldol reaction of α-unsubstituted chiral enolates was for many years a “problem child” for synthetic chemists because of its insufficient stereoselectivity. Progress in this area has only been made in the last few years using either new chiral auxiliaries or alternatives to the aldol reaction.     

Palladium(II)‐Catalyzed Dehydroboration via Generation of Boron Enolates

The Pd^II‐catalyzed dehydroboration of boron enolates generated from ketones and 9‐iodo‐9‐borabicyclo[3.3.1]nonane was achieved, providing a synthetically versatile protocol from ketones to α,β‐unsaturated ketones. The Pd^II compound employed in this reaction worked catalytically in the presence of Cu(OAc)₂. The high trans‐selectivity of the olefinic moiety was observed. Aryl halide moieties (‐Br and ‐Cl) remained intact for this reaction in spite of the presence of a Pd species. An ester substrate could also be applied when a stoichiometric amount of Pd^II was used. The crossover reactions using boron and silyl enolates revealed that the oxidation reaction is much faster than the Saegusa‐Ito reaction.     

New Chromium Enolates

Three new (η²‐acrylate)(η⁶‐arene)dicarbonylchromium complexes are reported. They were obtained either by CO/acrylate exchange in [Cr(η⁶‐benzene)(CO)₃] ( 1 ) via the photolytically generated η²‐cyclooctene intermediate or by arene exchange in [Cr(η²‐methyl acrylate)(η⁶‐benzene)(CO)₂] ( 3 ) (Scheme 1). On crystallization, [Cr(η²‐methyl acrylate)(η⁶‐o‐xylene)(CO)₂] ( 5 ) underwent partial resolution. The degree of this resolution was analyzed via X‐ray crystal‐structure determination (Fig. 1) and was correlated to the CD spectra in solution (Fig. 6), thus allowing the assignment of the absolute configuration. The reaction of [Cr(η²‐acrylate)(η⁶‐benzene)(CO)₂] complexes with cyclopentad‐1,3‐diene or 1H‐indene afforded new (η⁶‐cyclopenta‐2,4‐dien‐1‐yl)‐ or (η⁶‐1H‐inden‐1‐yl)(η³‐oxaallyl)chromium complexes (Scheme 2). A mechanism is proposed that involves arene‐ligand substitution by the diene ligand, initiated by haptotropic rearrangement of the acrylate from a η²‐ to a η⁴‐coordination mode, followed by hydride migration from the diene to the acrylate (Scheme 3). An X‐ray crystal‐structure determination of [Cr(CO)₂(η⁵‐1H‐inden‐1‐yl){η³‐CH(CH₂CF₃)C(O)OEt}] ( 8 ) reveals a metal enolate that is best described as η³‐oxaallyl species (Fig. 2). A shorter, more‐efficient route to the [Cr(η⁵‐1H‐inden‐1‐yl)(η³‐oxaallyl)] complexes was devised via the reaction of [Cr(CO)₂(η²‐cyclooctene)(η⁶‐1H‐indene)] with methyl acrylate (Scheme 4).     

立体选择性还原的硼试剂及其在手性药物合成中的应用

硼试剂在药物化学合成中广泛应用. 综述了可参与立体选择性还原反应的手性硼试剂、烷基硼试剂和硼氢化钠衍生物在手性药物合成中的应用, 并讨论这些试剂用于工业化生产的潜力.