Recent Progress in the Synthesis of Silaspiranes.

Silaspiranes bearing a spiro-silicon center are promising ring frameworks for the synthesis of novel spirocyclic molecules possessing unique properties. Development of efficient methods towards these ring structures has therefore attracted considerable attentions of synthetic chemists. This minireview highlights the representative advances in the field, and is categorized into four parts according to the ring formation strategies: cyclization, annulation, ring expansion and cycloaddition.

Towards Axially Chiral Pyrazole-Based Phosphorus Scaffolds by Dipeptide-Phosphonium Salt Catalysis.

Given the comparatively lower rotational barriers, the catalytic asymmetric construction of axially chiral biaryl structures, especially those containing a five-membered heterocycle, still remains a challenge. Herein, we described a general and modular protocol to access atropisomeric arylpyrazole scaffolds containing a phosphorus unit by a dipeptide phosphonium salt catalyzed reaction involving an oxidative central-to-axial chirality conversion. This reaction features excellent yields and enantioselectivities, broad substrate scope, and a low catalyst loading, delivering axially chiral phosphine compounds.

Design, synthesis and biological evaluation of novel procaine derivatives for intravenous anesthesia.

A series of novel procaine derivatives for intravenous anesthesia were prepared and evaluated by physicochemical properties and pharmacodynamic experiments in vivo and in vitro. Systematic optimization of procaine led to the identification of 6f, 6g, 6h, 6o, 6p and 6q with higher TI value and moderate log D. Compared with procaine (TI = 1.65), most procaine derivatives demonstrated better security, among whichcompound 6h (TI = 2.68)was the most notable one and showed fewer adverse events in animals. The result of hNR2B-HEK293 assay indicated that compound 6h suppressed the NMDA receptor 2B subtype channel activity and it showed more than 80% inhibitory effect at the concentration of 500 µM.

Trityl Cation-Catalyzed Hosomi-Sakurai Reaction of Allylsilane with ß,γ-Unsaturated α-Ketoester to Form γ,γ-Disubstituted α-Ketoesters.

(Ph3C)[BPh(F)4]-catalyzed Hosomi-Sakurai allylation of allylsilanes with ß,γ-unsaturated α-ketoesters has been developed to give γ,γ-disubstituted α-ketoesters in high yields with excellent chemoselectivity. Preliminary mechanistic studies suggest that trityl cation dominates the catalysis, while the silyl cation plays a minor role.

Enantioselective Synthesis of Spirosilabicyclohexenes by Asymmetric Dual Ring Expansion of Spirosilabicyclobutane with Alkynes.

Silaspiranes have attracted particular attention due to their chiral spiro-silicon center, which serves as an ideal carbon isostere and can endow spiro-analogs with distinct properties. Distinct from previously reported cyclization or cycloaddition strategies to form 5/5-silaspiranes, we report herein the asymmetric dual ring expansion of spirosilabicyclobutanes with alkynes to synthesize axially chiral spirosilabicyclohexenes bearing a novel 6/6-silaspirane framework. DFT (density functional theory) calculations provide the deep insight into the origin of the high enantioselectivity controlled by the sterically demanding binaphthyl phosphoramidite ligand. Preliminary studies of chiroptical properties indicate that one of the spirosilabicyclohexene analogs exhibit fluorescence emission, Cotton effects and CPL (circularly polarized luminescence) activity.

3-Silaazetidine: An Unexplored yet Versatile Organosilane Species for Ring Expansion toward Silaazacycles.

Small-ring silacycles are important organosilane species in main-group chemistry and have found numerous applications in organic synthesis. 3-Silaazetidine, a unique small silacycle bearing silicon and nitrogen atoms, has not been adequately explored due to the lack of a general synthetic scheme and its sensitivity to air. Here, we describe that 3-silaazetidine can be easily prepared in situ from diverse air-stable precursors (RSO2NHCH2SiR12CH2Cl). 3-Silaazetidine shows excellent functional group tolerance in a palladium-catalyzed ring expansion reaction with terminal alkynes, giving 3-silatetrahydropyridines and diverse silaazacycle derivatives, which are promising ring frameworks for the discovery of Si-containing functional molecules.

The development of an Amber-compatible organosilane force field for drug-like small molecules.

As members of the group IVA elements, silicon and carbon have long been thought of as isosteres of each other in drug design. However, the lack of silicon parameters in current main stream force fields hinders the computational study of this important element in drug discovery. Thus, in this study, we attempted to supplement the parameters of organosilanes in the General Amber Force Field (GAFF2). The parameters have been designed following the principles of GAFF2 to make it compatible with the Amber force field family. The accuracy of the parameters was discussed by comparing the pair interaction energy, the liquid properties, and the structures and alchemical binding free energy differences for a set of protein-ligand complexes.

O2 -Assisted Four-Component Reaction of Vinyl Magnesium Bromide with Chiral N-tert-Butanesulfinyl Imines To Form syn-1,3-Amino Alcohols.

An O2 -assisted, four-component reaction has been developed to synthesize a wide range of syn-1,3-amino alcohols in one step. The reaction proceeds by oxygenation of vinyl magnesium bromide (component-I) with O2 (component-II) to give a magnesium enolate of acetaldehyde, which undergoes addition to a chiral N-tert-butanesulfinyl imine (component-III) followed by a sequential addition with excess vinyl magnesium bromide (component-IV). The approach allows diastereoselective synthesis of anti/syn- and syn/syn-3-amino-1,5-diols in good yields with high diastereoselectivity. The method was illustrated in an efficient, four-step synthesis of piperidine alkaloid (-)-2'-epi-ethylnorlobelol.

Recent Progress in the Transition-Metal-Catalyzed Activation of Si-Si Bonds To Form C-Si Bonds.

Disilanes possessing a Si-Si bond are unique element-element species. Transition-metal-catalyzed activation of the Si-Si bond allows many useful transformations that generate diverse organosilanes. This Minireview highlights impressive developments in this field over the past decade, with an emphasis on the formation of vinyl-, aryl-, and acylsilanes by C(sp2 )-Si bond formation as well as the formation of allyl- and alkylsilanes by C(sp3 )-Si bond formation.

One-Pot Twofold Unsymmetrical C-Si Bond 2,6-Bifunctionalization of Arenes via Sequential [1,4]-Csp2 to O-Silyl Migration.

Twofold unsymmetrical C-Si bond bifunctionalization of 2,6-di(trimethylsilyl) benzyl alcohols has been achieved in one pot via sequential [1,4]-Csp2 to O-silyl migration. The hydroxyl group functions as an "on-off-on" switch to control two successive silyl migrations, and 4,7-dimethyl-o-phenanthroline ligand favors cleavage of the endocyclic C-Si bond. Diverse Csp3/Csp3 or Csp2/Csp3 electrophiles can be installed at the 2- and 6-positions. This approach was used to chemoselectively functionalize the three C-Si bonds of 2,4,6-tri(trimethylsilyl) benzyl alcohol, transforming it into isochroman derivatives. The approach even works as a five-component reaction to construct complex symmetric structures.

exo/endo Selectivity Control in Diels-Alder Reactions of Geminal Bis(silyl) Dienes: Theoretical and Experimental Studies.

The factors controlling the reactivity and exo/ endo selectivity of Diels-Alder reactions of geminal bis(silyl) dienes catalyzed by AlEt2Cl are studied at the B3LYP-D3(BJ)(SMD,CH2Cl2)/6-31++G**//B3LYP-D3(BJ)(SMD,CH2Cl2)/6-31+G* theoretical level. The reaction proceeds via a two-stage one-step mechanism, and the AlEt2Cl as a Lewis acid catalyst enhances the electrophilicity of the carbonyl compound by coordination, consequently accelerating a cycloaddition reaction with a low energy barrier. A geminal bis(silyl) group of the diene and an α-substituent in α,ß-unsaturated carbonyl compounds adjust the interaction energy (Δ Eint) as well as the deformation energy (Δ Estrain) of the diene and dienophile, affecting the barrier height and the diastereochemical outcome accordingly. The steric repulsion between the geminal bis(silyl) group and Al(III) catalyst increases the Pauli repulsion energy (Δ EPauli) and strain energy of dienophile fragment (Δ Estrain(dienophile-LA)) in the endo pathway, ensuring the exo selectivity. The introduction of a halogen atom (Cl or Br) or methyl group at the α-position of α,ß-unsaturated carbonyl compounds increases the deformation energy of the diene fragment. Meanwhile, the noncovalent interactions (that is, dispersion and electrostatic interaction) stabilize the endo transition state, leading to predominant endo products. The theoretical predictions of the exo/ endo selectivity for Diels-Alder reactions of the substituted α,ß-unsaturated carbonyl compound with Cl or Br atoms by the DFT method are also well confirmed by experiment.

Rhodium-Catalyzed Reaction of Silacyclobutanes with Unactivated Alkynes to Afford Silacyclohexenes.

A Rh-catalyzed reaction of silacyclobutanes (SCBs) with unactivated alkynes has been developed to form silacyclohexenes with high chemoselectivity. Good enantioselectivity at the stereogenic silicon center was achieved using a chiral phosphoramidite ligand. The resulting silacyclohexenes are useful scaffolds for synthesizing structurally attractive silacyclic compounds.

Chemoselective Reduction of Sterically Demanding N,N-Diisopropylamides to Aldehydes.

A sequential one-pot process for chemoselectively reducing sterically demanding N,N-diisopropylamides to aldehydes has been developed. In this reaction, amides are activated with EtOTf to form imidates, which are reduced with LiAlH(OR)3 [R = t-Bu, Et] to give aldehydes by hydrolysis of the resulting hemiaminals. The non-nucleophilic base 2,6-DTBMP remarkably improves reaction efficiency. The combination of EtOTf/2,6-DTBMP and LiAlH(O-t-Bu)3 was found to be optimal for reducing alkyl, alkenyl, alkynyl, and 2-monosubstituted aryl N,N-diisopropylamides. In contrast, EtOTf and LiAlH(OEt)3 in the absence of base were found to be optimal for reducing extremely sterically demanding 2,6-disubstituted N,N-diisopropylbenzamides. The reaction tolerates various reducible functional groups, including aldehyde and ketone. 1H NMR studies confirmed the formation of imidates stable in water. The synthetic usefulness of this methodology was demonstrated with N,N-diisopropylamide-directed ortho-metalation and C-H bond activation.

Me3 Si-SiMe2 [oCON(iPr)2 -C6 H4 ]: An Unsymmetrical Disilane Reagent for Regio- and Stereoselective Bis-Silylation of Alkynes.

The air-stable unsymmetrical disilane Me3 Si-SiMe2 [oCON(iPr)2 C6 H4 ] has been developed for bis-silylation of alkynes. This reagent tolerates a range of functional groups, providing Z-vinyl disilanes in high yields. It is proposed that the phenyl-ring-tethered amide group directs oxidative addition of Pd0 into the Si-Si bond, which might facilitate formation of a six-membered Pd cycle, generating products with good to excellent regioselectivity.

Total Synthesis of Bryostatin†8 Using an Organosilane-Based Strategy.

Convergent total synthesis of bryostatin 8 has been accomplished by an organosilane-based strategy. The C ring is constructed stereoselectively through a geminal bis(silane)-based [1,5]-Brook rearrangement, and the B ring through geminal bis(silane)-based Prins cyclization, thus efficiently joining the northern and southern parts of the molecule.

Unique Steric Effect of Geminal Bis(silane) To Control the High Exo-selectivity in Intermolecular Diels-Alder Reaction.

The unique steric effect of geminal bis(silane) [(R3Si)2CH] allows an exo-selective intermolecular Diels-Alder reaction of geminal bis(silyl) dienes with α,ß-unsaturated carbonyl compounds. The approach shows good generality to form ortho-trans cyclohexenes in good yields with high exo-selectivity and high enantioselectivity in some asymmetric cases. The excellent exo-stereocontrol aptitude of (R3Si)2CH group is highlighted by comparing with R3SiCH2 and R3Si groups, which leads to endo-selectivity predominantly. The conformational analysis of dienes suggests that (R3Si)2CH group effectively shields both sides of the diene moiety, ensuring the desired exo-selectivity. Moreover, the geminal bis(silane) can be further functionalized to transform the resulting ortho-trans cycloadducts into useful synthons, which makes the approach hold great potential for organic synthesis.

Regioselective 1,4- over 1,2-addition of 3,3-bis(silyl) allyloxy lithium to enals, enones and enoates. The remarkable α-effect of silicon.

A remarkable α-effect of silicon has been discovered that results in soft nucleophilicity at the Cγ of 3,3-bis(silyl) allyloxy lithium 1. The addition of 1 to α,ß-unsaturated carbonyl compounds, including enals, proceeds in a 1,4- over 1,2-manner with medium to good regioselectivity, whereas the parent allyloxy lithium 4 undergoes complete 1,2-addition. The results from DFT calculations of HMPAcomplexed 1 and 4 provide the rationale to explain this different regioselectivity.

[1,4]-S- to O-silyl migration: multicomponent synthesis of α-thioketones through chemoselective transformation of esters to ketones with organolithium reagents.

A [1,4]-S- to O-silyl migration has been exploited to chemoselectively transform esters into ketones by using organolithium reagents, allowing multicomponent synthesis of α-thioketones. Mechanistic studies reveal that this migration proceeds in an intramolecular manner and is more favorable than the corresponding [1,5]-S- to O- and [1,3]-C- to O-silyl migrations. The resulting α-thioketones are valuable building blocks for the synthesis of cyclic or multifunctionalized organosulfur compounds.

Enantioconvergent construction of stereogenic silicon via Lewis base-catalyzed dynamic kinetic silyletherification of racemic chlorosilanes.

Organosilanes possessing an enantioenriched stereogenic silicon center are important in many branches of chemistry, yet they remain challenging to synthesize in a practical and scalable way. Here we report a dynamic kinetic silyletherification process of racemic chlorosilanes with (S)-lactates using 4-aminopyridine as a Lewis base catalyst. This enantioconvergent approach asymmetrically constructs the stereogenic silicon center in a different manner from traditional resolution or desymmetrization. A range of silylethers have been prepared with high diastereoselectivity on up to 10 g-scale, allowing the practical synthesis of diverse enantioenriched organosilane analogs.