Excellent Diastereocontrol Research Articles

Chemo- and Diastereoselective Michael-Michael-Acetalization Cascade for the Synthesis of 1,3-Indandione-Fused Spiro[4.5]decan Scaffolds.

A novel, organobase-catalyzed and highly chemoselective Michael-Michael-acetalization cascade is presented for the efficient synthesis of spiro-indandione skeletons. Following this very simple protocol, a broad range of products was obtained in good yields with excellent diastereocontrol. The role of steric factors in the acetalization step was evaluated.

β-Silyl-Assisted Tandem Diels-Alder/Nazarov Reaction of 1-Aryl-3-(trimethylsilyl) Ynones.

A one-pot tandem Diels-Alder/Nazarov reaction of 1-aryl-3-(trimethylsilyl) ynones has been achieved to generate carbo- and heterocyclic fused ring systems in good to excellent yields. The β-silyl effect is instrumental in accessing this otherwise challenging cascade annulation reaction. The tandem reaction proceeds in the presence of BCl3 to generate three new carbon-carbon bonds, a quaternary carbon, and two stereogenic centers with excellent diastereocontrol. A variety of substituted arenes, and even heteroaromatics, are tolerated to provide tricyclic products that are of interest as advanced intermediates toward biologically relevant compounds.

Double Michael addition of nitromethane to divinyl ketones: A remarkably positive effect of additive

An efficient double Michael addition of nitromethane to divinyl ketones was established in good to high yields (75–99%). A wide range of cyclohexanones were obtained with excellent diastereocontrol (up to >20:1 dr) and enantioinduction (91–99% ee) in a one-pot fashion. The involvement of basic additive significantly enhanced the reactivity of this cascade sequence.

ChemInform Abstract: Catalytic Asymmetric Synthesis of Cyclopentyl β‐Amino Esters by [3 + 2] Cycloaddition of Enecarbamates with Electrophilic Metalloenolcarbene Intermediates.

AbstractChiral cyclopentyl β‐amino esters are formed catalytically by [3+2] cycloaddition reactions of enecarbamates with electrophilic metalloenolcarbenes in high yield with up to 98% ee and excellent diastereocontrol.

Copper-Catalyzed Cross-Coupling of Silicon Pronucleophiles with Unactivated Alkyl Electrophiles Coupled with Radical Cyclization.

A copper-catalyzed C(sp3)-Si cross-coupling of aliphatic C(sp3)-I electrophiles using a Si-B reagent as the silicon pronucleophile is reported. The reaction involves an alkyl radical intermediate that also engages in 5-exo-trig ring closures onto pendant alkenes prior to the terminating C(sp3)-Si bond formation. Several Ueno-Stork-type precursors cyclized with excellent diastereocontrol in good yields. The base-mediated release of the silicon nucleophile and the copper-catalyzed radical process are analyzed by quantum-chemical calculations, leading to a full mechanistic picture.

Catalytic Asymmetric Synthesis of Cyclopentyl β‐Amino Esters by [3+2] Cycloaddition of Enecarbamates with Electrophilic Metalloenolcarbene Intermediates

AbstractChiral cyclopentyl β‐amino esters are formed catalytically by [3+2] cycloaddition reactions of enecarbamates with electrophilic metalloenolcarbenes in high yield with up to 98 % ee and excellent diastereocontrol. Use of β‐silyl‐substituted enoldiazoacetates with a chiral dirhodium catalyst and trans‐β‐arylvinylcarbamates are optimal for this transformation, which occurs with hydrogen‐bond association between the vinylcarbamate and the intermediate metalloenolcarbene. Reductive conversion of the protected amino esters forms highly functionalized cyclopentyl β‐amino acids and 3‐aminocyclopentanones.

Catalytic Asymmetric Synthesis of Cyclopentyl β‐Amino Esters by [3+2] Cycloaddition of Enecarbamates with Electrophilic Metalloenolcarbene Intermediates

Chiral cyclopentyl β-amino esters are formed catalytically by [3+2] cycloaddition reactions of enecarbamates with electrophilic metalloenolcarbenes in high yield with up to 98 % ee and excellent diastereocontrol. Use of β-silyl-substituted enoldiazoacetates with a chiral dirhodium catalyst and trans-β-arylvinylcarbamates are optimal for this transformation, which occurs with hydrogen-bond association between the vinylcarbamate and the intermediate metalloenolcarbene. Reductive conversion of the protected amino esters forms highly functionalized cyclopentyl β-amino acids and 3-aminocyclopentanones.

Mild C−H/C−C Activation by Z‐Selective Cobalt Catalysis

AbstractCationic cobalt complexes enable unprecedented cobalt‐catalyzed C−H/C−C functionalizations with unique selectivity features. The versatile cobalt catalyst proved broadly applicable, enabled efficient C−H/C−C cleavage at room temperature, and delivered Z‐alkenes with excellent diastereocontrol.

Mild C-H/C-C Activation by Z-Selective Cobalt Catalysis.

Cationic cobalt complexes enable unprecedented cobalt-catalyzed C-H/C-C functionalizations with unique selectivity features. The versatile cobalt catalyst proved broadly applicable, enabled efficient C-H/C-C cleavage at room temperature, and delivered Z-alkenes with excellent diastereocontrol.

ChemInform Abstract: Regio‐ and Stereospecific 1,3‐Allyl Group Transfer Triggered by a Copper‐Catalyzed Borylation/ortho‐Cyanation Cascade.

A copper-catalyzed borylation/ortho-cyanation/allyl group transfer cascade was developed. Initiated by an unconventional copper-catalyzed electrophilic dearomatization, this process features regio- and stereospecific 1,3-transposition of the allyl fragment enabled by an aromatization-driven Cope rearrangement. This method provides an effective means for the construction of adjacent tertiary and quaternary stereocenters with excellent diastereocontrol.

Asymmetric Alkylation Reactions Using Non‐Cross‐Linked Polystyrene‐supported 2‐Imidazolidinone Chiral Auxiliary Derived from l‐Phenyl Alanine

The non‐cross‐linked polystyrene (NCPS)‐supported 2‐imidazolidinone chiral auxiliary, based on a new anchoring strategy, afforded excellent diastereocontrol and yield in asymmetric alkylation reactions. The cleavage of this soluble, polymer‐supported chiral auxiliary 8 produced highly optical pure carboxylic acids and strong polymer recovery.

Organocatalytic Enantioselective Synthesis of Tetrahydrofluoren-9-ones via Vinylogous Michael Addition/Henry Reaction Cascade of 1,3-Indandione-Derived Pronucleophiles.

An unprecedented organocatalytic enantioselective vinylogous Michael addition/Henry cyclization cascade is presented for the synthesis of highly substituted tetrahydrofluoren-9-ones 3 employing novel 1,3-indandione-derived pronucleophiles 1a-g and nitroalkenes 2. Following a very simple protocol, a wide range of products were obtained in good to excellent yields and with excellent enantioinduction (43-98% yield, up to 98% ee). The reaction proceeded with excellent diastereocontrol despite the simultaneous generation of four stereogenic centers. Surprisingly, when 2-(1-phenylethylidene)-1H-indandione (1h) was used as a pronucleophile, no cyclization was observed, and only Michael addition adducts 4a-x were furnished in very good yields and excellent enantioselectivities.

Regio- and Stereospecific 1,3-Allyl Group Transfer Triggered by a Copper-Catalyzed Borylation/ortho-Cyanation Cascade.

A copper-catalyzed borylation/ortho-cyanation/allyl group transfer cascade was developed. Initiated by an unconventional copper-catalyzed electrophilic dearomatization, this process features regio- and stereospecific 1,3-transposition of the allyl fragment enabled by an aromatization-driven Cope rearrangement. This method provides an effective means for the construction of adjacent tertiary and quaternary stereocenters with excellent diastereocontrol.

Regio‐ and Stereospecific 1,3‐Allyl Group Transfer Triggered by a Copper‐Catalyzed Borylation/ortho‐Cyanation Cascade

AbstractA copper‐catalyzed borylation/ortho‐cyanation/allyl group transfer cascade was developed. Initiated by an unconventional copper‐catalyzed electrophilic dearomatization, this process features regio‐ and stereospecific 1,3‐transposition of the allyl fragment enabled by an aromatization‐driven Cope rearrangement. This method provides an effective means for the construction of adjacent tertiary and quaternary stereocenters with excellent diastereocontrol.

Stereoselective Lewis base catalyzed formal 1,3-dipolar cycloaddition of azomethine imines with mixed anhydrides.

Stereoselective synthesis of pyrazolidinones via dipolar cycloaddition of azomethine imines with active esters under Lewis base catalysis is presented. The active esters are readily generated in situ from the corresponding acids. Products, which are obtained with excellent diastereocontrol and high enantioselectivity, contain along with the pyrazolidinone core also the tetrahydroisoquinoline structural motif. Theoretical studies give insight into the mechanism of the formal cycloaddition reaction.

Stereoselective Lithiation and Carboxylation of Boc-Protected Bicyclopyrrolidine: Synthesis of a Key Building Block for HCV Protease Inhibitor Telaprevir

A stereoselective process for the manufacture of bicyclopyrrolidine 7 to 2 has been developed. The process utilizes a stereoselective lithiation/carboxylation sequence. The achiral diamine ligand DPBP induces excellent diastereocontrol, and resolution with (S)-THNA provides the corresponding salt of 8 in high er and dr. Subsequent processing of 8 gives 2 as the oxalate salt in an overall yield of 27% from 7 (based on total molar charge of 7). Compound 2 was obtained with high chemical and chiral purities. The process was successfully demonstrated on >100 kg scale.

Non-cross-linked polystyrene-supported 2-imidazolidinone chiral auxiliary: synthesis and application in asymmetric alkylation reactions

Asymmetric alkylation reactions using non-cross-linked polystyrene (NCPS)-supported 2-imidazolidinone chiral auxiliaries were successfully investigated with excellent diastereocontrol (>99% de). The recovery and the recycling of this soluble polymer-supported chiral auxiliary were achieved in order to produce highly optical pure carboxylic acids.

ChemInform Abstract: Cationic Bromonium Complex: NBS/P(O‐Ph)3 as an Efficient Catalyst for Nazarov Cyclization.

AbstractThe optimized conditions A) produce the desired target ring system with excellent diastereocontrol.

Catalytic Enantioselective Vinylogous Mukaiyama–Michael Addition of 2-Silyloxyfurans to Cyclic Unsaturated Oxo Esters

The copper-catalyzed asymmetric addition of 2-silyloxyfurans to cyclic unsaturated oxo esters is reported. The reaction proceeds with excellent diastereocontrol (usually dr 99:1) and modest to high enantioselectivity, depending on the nature of the ester group and the substitution of the cyclic oxo ester. We have shown that these substrates can be transformed into a variety of building blocks bearing a γ-butenolide or γ-lactone connected to a cycloalkane or cycoalkene moiety.

Controlling stereochemistry in polyketide synthesis: 1,3- vs. 1,2-asymmetric induction in methyl ketone aldol additions to β-super siloxy aldehydes

The aldol addition of methyl ketones to β-siloxy and α-methyl β-siloxy aldehydes is described. Careful control of mechanistically distinct aldol reactions leverages 1,2- and 1,3-asymmetric induction, selectively forming syn and anti aldol adducts with excellent diastereocontrol. Experimental and theoretical investigations have provided insight to the factors governing diastereoselectivity.