N-cyclopropylation of indoles and cyclic amides with copper(II) reagent

Copper-mediated coupling reactions of cyclopropylboronic acid with indoles and cyclic amides are described. The process utilizes catalytic or stoichiometric amounts of copper(II) acetate, DMAP, and NaHMDS at 95 degrees C under an atmosphere containing oxygen. A variety of functional groups remain intact throughout the reaction.     

Resolution of (4RS,5RS)-4,5-diphenylimidazolidine-2-thione using pentafluorophenyl active esters

(4RS,5RS)-4,5-Diphenylimidazolidine-2-thione is resolved efficiently by treatment with NaHMDS and an enantiomerically pure pentafluorophenyl active ester. The levels of diastereocontrol were excellent (up to 90% de).     

Anionic versus photochemical diastereoselective deconjugation of diacetone d-glucose α,β-unsaturated esters

Deconjugation of diacetone d-glucose α,β-unsaturated esters has been conducted by deprotonation using NaHMDS with HMPA as co-solvent followed by stereoselective protonation at low temperature. High selectivities (>95%) were obtained with α-methyl linear compounds.     

Microwave-Assisted N-Cyclopropylation of Pyridinols with Cyclopropyl Boronic Acid

Copper(II)-mediated N-cyclopropylation of pyridinols involving copper(II) acetate, pyridine, and NaHMDS under microwave conditions in a dry air atmosphere is described.     

Introducing a Hydrogen‐Bond Donor into a Weakly Nucleophilic Brønsted Base: Alkali Metal Hexamethyldisilazides (MHMDS,M=Li,Na, K,Rb and Cs) with Ammonia

Alkali metal 1,1,1,3,3,3‐hexamethyldisilazide (MHMDSs) are one of the most utilised weakly nucleophilic Brønsted bases in synthetic chemistry and especially in natural product synthesis. Like lithium organics, they aggregate depending on the employed donor solvents. Thus, they show different reactivity and selectivity as a function of their aggregation and solvation state. To date, monomeric LiHMDS with monodentate donor bases was only characterised in solution. Since the first preparation of LiHMDS in 1959 by Wannagat and Niederprüm, all efforts to crystallise monomeric LiHMDS in the absence of chelating ligands failed. Herein, we present ammonia adducts of LiHMDS, NaHMDS, KHMDS, RbHMDS and CsHMDS with unprecedented aggregation motifs: 1) The hitherto missing monomeric key compound in the LiHMDS aggregation architectures. Monomeric crystal structures of trisolvated LiHMDS ( 1 ) and NaHMDS ( 2 ), showing unique intermolecular hydrogen bonds, 2) the unprecedented tetrasolvated KHMDS ( 3 ) and RbHMDS ( 4 ) dimers and 3) the disolvated CsHMDS ( 5 ) dimer with very close intermolecular Si?CH₃???Cs s‐block “agostic” interactions have been prepared and characterised by single‐crystal X‐ray structure analysis.     

Desymmetrisation of (4R,5S)-4,5-diphenylimidazolidine-2-thione using pentafluorophenyl active esters

(4R,5S)-4,5-Diphenylimidazolidine-2-thione is efficiently desymmetrised by stereorandom deprotonation with NaHMDS, followed by kinetic resolution of the resulting racemic intermediate with an enantiomerically pure pentafluorophenyl active ester. The levels of diastereocontrol were found to be excellent (86-92% de at ∼30% conversion). This desymmetrisation reaction is an example of a masked resolution.     

Alpha-heteroarylation of esters, lactones, amides, and lactams by nucleophilic aromatic substitution

[reaction: see text] A mild and efficient alpha-heteroarylation of simple esters and amides was developed via nucleophilic aromatic substitution. The choice of NaHMDS in toluene gave the best results. A tandem alpha-heteroarylation and hydroxylation protocol using air as the oxidant afforded tertiary alcohols in good yields.     

Regio-selective synthesis of 1,2-aminoalcohols from epoxides and chlorohydrins

A simple and efficient procedure for the regio-selective synthesis of 1,2-aminoalcohols from terminal epoxides and chlorohydrins by using NaHMDS as the source of amine is reported. The wider scope and utility of this method is demonstrated.     

(R)-2-甲基半胱氨酸盐酸盐的合成方法改进

以L-半胱氨酸甲酯盐酸盐为起始原料,经4步反应合成了(R)-2-甲基半胱氨酸盐酸盐.在关键中间体(2R, 4R)-2-叔丁基-3-甲酰基-4-甲基-1,3-噻唑烷-4-甲酸甲酯(4)的合成中,采用Self-regeneration of stereocenters原理,用六甲基二硅胺钠取代文献方法中的二异丙基胺基锂,4的收率由文献的56%提高至90%.化合物的结构经1H NMR和MS表征.     

Total Synthesis of Marinomycin A Based on a Direct Dimerization Strategy

The asymmetric total synthesis of (+)‐marinomycin A, a 44‐membered macrodiolide antitumor agent and antibiotic isolated from a marine actinomycete, Marinispora strain CNQ‐140, is reported. The key features of the synthesis include the highly convergent stereocontrolled construction of the monomeric hydroxy salicylate starting from asymmetric epoxidation of the σ‐symmetrical dialkenyl carbinol, and an unprecedented direct dimerization through NaHMDS‐promoted double transesterification.     

Versatile stereocontrol in kinetic resolution of a diphenylphosphinyl-protected α-amino aldehyde by reaction with chiral phosphonates

In kinetic resolutions of the racemic aldehyde 1 by reaction with chiral phosphonates of type 2, all of which contain the same chiral auxiliary in the same enantiomeric form, any of the four diastereomers 3a, 3b, 4a or 4b can be obtained as the main product by an appropriate choice of reaction parameters (geometric selectivities from 66:34 to 98:2, diastereomer ratios between 93:7 and ≥99:1). The switch in stereoselectivity observed when KHMDS or NaHMDS is used as base instead of KHMDS/18-crown-6 is rationalized as resulting from a change in influence of the aldehyde α-stereocenter from Felkin-Anh-Eisenstein to chelation control.     

Non-reductive decyanation reactions of disubstituted malononitrile derivatives promoted by NaHMDS

A new method for achieving the decyanation of disubstituted malononitrile derivatives without using reducing agents has been developed. Treatment of a six-membered malononitrile derivative with NaHMDS followed by methanol afforded the corresponding acetonitrile derivative in high yield. The present method was applicable to the decyanation reactions of a variety of malononitriles including four- and five-membered compounds as well as acyclic ones.     

Cobalt-mediated, enantioselective synthesis of C(2) and C(1) dienes

The asymmetric C-H functionalization of norbornene and norbornadiene with five-, six-, and seven-membered cyclic enones mediated by the reactive intermediate [{η(5)-((t)BuMe(2)Si)C(5)H(4)}Co(NO)(2)] is reported. A novel base mixture derived from enantiopure ammonium salts and NaHMDS was used as a source of chirality, and this enantioselective desymmetrization of C(s) alkenes has been applied to the asymmetric synthesis of C(2)- and C(1)-symmetric diene ligands in high regioselectivity (3.7-20:1 anti/syn), near perfect diastereoselectivity (>99:1 dr), and high enantioselectivity (90-96% ee).     

Improved Julia-Kocienski conditions for the methylenation of aldehydes and ketones

[reaction: see text] The scope of the methylenation of aldehydes and ketones under optimized Julia-Kocienski conditions is broadened by using 1-tert-butyl-1H-tetrazol-5-ylmethyl sulfone. Two different Barbier-type procedures are applied with NaHMDS at -78 degrees C or Cs2CO3 at 70 degrees C. The latter conditions are also adapted for the preparation of 1,2-disubstituted olefins and intramolecular olefination reactions.     

Asymmetric synthesis of orthogonally protected trans-cyclopropane gamma-amino acids via intramolecular ring closure

The synthesis of enantiomerically-enriched trans-cyclopropane amino- and hydroxy-acids can be achieved by intramolecular ring closure in moderate to good yields. The optically active cyclopropane precursors are easily prepared in a short sequence from inexpensive, commercially available olefins and tert-butyl acetate. Several leaving groups and bases were compared for the cyclopropanation step, showing that the diphenylphosphinate and tosyl leaving groups give the best results when used in combination with either LDA or NaHMDS.     

Toward the synthesis of γ-pyrone-containing natural products: diastereoselective aldol-type reaction of a γ-pyrone

The diastereoselective aldol-type reaction of a γ-pyrone via a sodium anion has been developed. This reaction is useful for synthesizing γ-pyrone-containing natural products. Also, we applied the Mukaiyama aldol-type reaction of silyl enol ether of γ-pyrone by using TiCl₄. This Mukaiyama aldol-type reaction of γ-pyrone indicated higher anti-aldol selectivity than the aldol-type reaction of a γ-pyrone with NaHMDS.     

Chemoselective intramolecular alkylation of the Blaise reaction intermediates: tandem one-pot synthesis of exo-cyclic enaminoesters and their applications toward the synthesis of N-heterocyclic compounds

The intramolecular alkylative reactivity and N/C selectivity of the various Blaise reaction intermediates, which are formed from the reaction of the Reformatsky reagents with ω-chloroalkyl nitriles, did not reach the synthetic potential as an entry to exo-cyclic enaminoesters. To circumvent this issue, various additives were investigated, among which the addition of NaHMDS dramatically enhanced the reactivity and N/C selectivity. This modification provided a highly efficient route for the synthesis of various N-fused heterocyclic compounds, as it requires only two steps from nitriles.     

Chemoselective reactions of amidines: selective formation of iminopyrimidine regioisomers

The dramatic effect of base on the chemoselectivity of the reaction of amidines with substituted 3-phenyl-2-propynylnitriles is demonstrated. Amidine 1 can be added to cyanoalkyne 2 to give iminopyrimidine isomer 3 with high selectivity. The addition of 2 equiv of NaHMDS completely reverses the selectivity of the reaction, yielding isomer 4 almost exclusively. This method has been used to prepare a variety of substituted 4-iminopyrimidines.     

Synthesis of 2'-O-methoxyethylguanosine using a novel silicon-based protecting group

A short and efficient synthesis of 2'-O-methoxyethylguanosine (8) is described. Central to this strategy is the development of a novel silicon-based protecting group (MDPSCl(2), 2) used to protect the 3',5'-hydroxyl groups of the ribose. Silylation of guanosine with 2 proceeded with excellent regioselectivity and in 79% yield. Alkylation of the 2'-hydroxyl group of 6 proceeded with methoxyethyl bromide and NaHMDS and afforded compound 7 in 85% yield, without any noticeable cleavage of the silyl protecting group and without the need to protect the guanine base moiety. Finally, deprotection of 7 was achieved using TBAF and produced 8 in 97% yield.     

The first example of racemization of the sulfur stereogenic center of α-sulfinyl carbanions at low temperatures

The treatment of enantiopure aryl dichloromethyl sulfoxides in THF with strong bases such as LDA, LiHMDS, NaHMDS, and KHMDS resulted in racemization of the sulfur stereogenic center of the sulfoxides even at ?78 °C. The rate of the racemization was found to be dependent on the alkali metal of the bases used. This is the first example of the racemization of the sulfur stereogenic center of α-sulfinyl carbanions at low temperatures.