Contiguous Stereocenters Research Articles

Lewis Acid Catalyzed Stereoselective Dearomative Coupling of Indolylboron Ate Complexes with Donor-Acceptor Cyclopropanes and Alkyl Halides.

Indolylboron ate complexes readily generated from 2-lithioindoles and boronic esters underwent multicomponent dearomative coupling with D-A cyclopropanes and alkyl halides in the presence of Sc(OTf)3 as a catalyst. The reactions proceeded with complete diastereoselectivity and excellent stereospecificity to provide indolines containing three contiguous stereocenters. The valuable boronic ester moiety remains in the product and allows for subsequent functionalization.

Lewis Acid Catalyzed Stereoselective Dearomative Coupling of Indolylboron Ate Complexes with Donor–Acceptor Cyclopropanes and Alkyl Halides

AbstractIndolylboron ate complexes readily generated from 2‐lithioindoles and boronic esters underwent multicomponent dearomative coupling with D‐A cyclopropanes and alkyl halides in the presence of Sc(OTf)3 as a catalyst. The reactions proceeded with complete diastereoselectivity and excellent stereospecificity to provide indolines containing three contiguous stereocenters. The valuable boronic ester moiety remains in the product and allows for subsequent functionalization.

Asymmetric Organocatalytic Sulfa-Michael Addition to Enone Diesters.

An asymmetric sulfa-Michael addition of alkyl thiols to enone diesters is reported. The reaction is catalyzed by a bifunctional triaryliminophosphorane-thiourea organocatalyst and provides a range of α-sulfaketones in high yields and enantioselectivities. Leveraging the gem-diester functional handle via a subsequent diastereotopic group discrimination generates functionalized lactones with three contiguous stereocenters.

Diastereo- and Enantioselective Synthesis of Spirooxindoles with Contiguous Tetrasubstituted Stereocenters via Catalytic Coupling of Two Tertiary Radicals.

The oxidative N-heterocyclic carbene-catalyzed [3 + 2] annulation of β,β-disubstituted enals and dioxindoles was developed, giving the spirocyclic oxindole-γ-lactones bearing two contiguous tetrasubstituted stereocenters in good yields with excellent diastereoselectivities and good enantioselectivities.

Zinc‐Catalyzed Enantioselective Dearomative [3+2] Cycloaddition Reaction of 3‐Nitrobenzothiophenes and 3‐Nitrothieno[2,3‐b]yridine with 3‐Isothiocyanato Oxindoles

AbstractA highly diastereo‐ and enantioselective dearomative [3+2] cycloaddition reaction of 3‐nitrobenzothiophenes and 3‐nitrothieno[2,3‐b]with 3‐isothiocyanato oxindoles is developed. The reaction is catalyzed by the chiral Zn(OTf)2/bis(oxazoline, and is the second example of a catalytic asymmetric dearomative cycloaddition reaction of 3‐nitrobenzothiophene derivatives. A range of complex heterocyclic compounds containing three contiguous stereocenters, one of which is spirocyclic center, can be obtained in quantitative yields with excellent stereoselectivities.magnified image

Electrophile-Dependent Alkylations of Lithiated 4-Alkoxyalk-4-enenitriles.

Alkylations of acyclic, lithiated 4-alkoxyalk-4-enenitriles are highly diastereoselective with an unusual electrophile-dependent preference. Alkyl halides, sulfur, chlorine, and acyl cyanide electrophiles intercept a series of lithiated 4-alkoxyalk-4-enenitriles to install contiguous tertiary-quaternary stereocenters with high diastereoselectivity, whereas acylations with ester and carbonate electrophiles are modestly selective. The diastereoselectivity is consistent with electrophilic attack on the most accessible face of the lithated nitrile for most electrophiles except ester and carbonate electrophiles, which likely precoordinate the lithiated nitrile before acylation. Intercepting the lithiated 4-alkoxyalk-4-enenitriles with a range of electrophiles provide insight into the criteria for otherwise challenging diastereoselective alkylations and acylations of acyclic nitriles.

Concise and efficient synthesis of eliglustat

ABSTRACTEliglustat, a ceramide glucosyltransferase inhibitor, was synthesized in six steps with 28.4% overall yield. The key features include the use of a diastereoselective aldol reaction to construct two contiguous stereocenters and a selective sulfonylation of a 1,3-diol catalyzed by dibutyltin oxide.

Rhodium-Catalyzed Asymmetric Conjugate Alkynylation/Aldol Cyclization Cascade for the Formation of α-Propargyl-β-hydroxyketones.

A rhodium-catalyzed conjugate alkynylation/aldol cyclization cascade was developed. Densely functionalized cyclic α-propargyl-β-hydroxyketones were synthesized with simultaneous formation of a C(sp)-C(sp3) bond, a C(sp3)-C(sp3) bond, as well as three new contiguous stereocenters. The transformation was achieved with excellent enantio- and diastereoselectivities using BINAP as the ligand. The synthetic utility of the newly installed alkynyl moiety was exhibited by subjecting the products to an array of derivatizations.

Enantioselective Polyene Cyclization Catalyzed by a Chiral Brønsted Acid

AbstractThe first enantioselective polyene cyclization initiated by a BINOL‐derived chiral N‐phosphoramide (NPA) catalyzed protonation of an imine is described. The ion‐pair formed between the iminium ion and chiral counter anion of the NPA plays an important role for controlling the stereochemistry of the overall transformation. This strategy offers a highly efficient approach to fused tricyclic frameworks containing three contiguous stereocenters, which are widely found in natural products. In addition, the first catalytic asymmetric total synthesis of (−)‐ferruginol was accomplished with an NPA catalyzed enantioselective polyene cyclization, as the key step for the construction of the tricyclic core, with excellent yield and enantioselectivity.

Enantioselective Polyene Cyclization Catalyzed by a Chiral Brønsted Acid.

The first enantioselective polyene cyclization initiated by a BINOL-derived chiral N-phosphoramide (NPA) catalyzed protonation of an imine is described. The ion-pair formed between the iminium ion and chiral counter anion of the NPA plays an important role for controlling the stereochemistry of the overall transformation. This strategy offers a highly efficient approach to fused tricyclic frameworks containing three contiguous stereocenters, which are widely found in natural products. In addition, the first catalytic asymmetric total synthesis of (-)-ferruginol was accomplished with an NPA catalyzed enantioselective polyene cyclization, as the key step for the construction of the tricyclic core, with excellent yield and enantioselectivity.

Regioselective and Stereoselective Heck-Matsuda Arylations of Trisubstituted Allylic Alkenols and Their Silyl and Methyl Ether Derivatives To Access Two Contiguous Stereogenic Centers: Expanding the Redox-Relay Process and Application in the Total Synthesis of meso-Hexestrol.

Novel palladium-catalyzed redox-relay Heck arylation reactions of trisubstituted allylic alkenols were developed employing silyl and methyl ethers. The reactions proceeded under mild conditions in moderate to high yields in an excellent anti diastereoselectivity to form α,β-disubstituted methyl ketones containing two contiguous stereocenters. The new redox-relay arylations using silyl and methyl ethers of the starting alkenols demonstrate that the presence of a free hydroxyl group is not a sine qua non condition for an effective redox-relay process as previously thought. Deuterium-labeled alkenols 2-d-10a, 2-d-10b, and 2-d-10c permitted tracking the palladium-hydride reinsertion steps in the conversion of the starting free alcohols, silyl, and methyl ethers into the corresponding methyl ketone 3-d-11a, with >98% deuterium retention. Moreover, the synthetic potential of the method was demonstrated with a straightforward synthesis of the meso-hexestrol in 4 steps, in 41% overall yield from alkenol 10a.

Diastereo- and Enantioselective Dearomative [3 + 2] Cycloaddition Reaction of 2-Nitrobenzofurans with 3-Isothiocyanato Oxindoles.

Enantioselective dearomative [3 + 2] cycloaddition reaction of 2-nitrobenzofurans with 3-isothiocyanato oxindoles was developed. The reaction employs a chiral bis(oxazoline)/Zn(OTf)2 catalyst, allowing a practical, straightforward access to structurally diverse spirooxindoles containing a 2,3-dihydrobenzofuran motif and three contiguous stereocenters with excellent diastereo- and enantioselectivities. The synthetic potentials of the method have been demonstrated by the scale-up experiment and transformations of the products. The preliminary mechanism was investigated with experimental observations, nonlinear effects studies, and MS experiments.

Synthesis of Kaitocephalin Facilitated by Three Stereoselective Allylic Transposition Reactions

A stereoselective synthesis of kaitocephalin is described. The central strategy is based on chirality transfer reactions of three secondary alcohols derived from l-arabinose. The Overman rearrangement of an α,β-unsaturated ester, and intramolecular anti-type SN2′ reaction constructed a β-hydroxy-α,α-disubstituted amino acid moiety. The third chirality transfer reaction is the Ichikawa rearrangement. These stereoselective reactions successfully established the three contiguous stereocenters embedded in kaitocephalin.

Stereoselective Construction of Halogenated Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2] Cycloaddition of α‐Haloaldehydes

AbstractAsymmetric construction of halogenated quaternary carbon centers under mild reaction conditions remains challenging. Reported here is an unprecedented and highly stereoselective Brønsted base catalyzed [4+2] cycloaddition between either α‐chloro‐ or α‐bromoaldehydes and cyclic enones. The key intermediate, an α‐halogenated enolate, is susceptible to dehalogenation and can be stabilized and stereochemically controlled using bifunctional tertiary amines. This method provides facile access to a collection of optically pure bicyclic dihydropyrans having three contiguous stereocenters, including a halogen‐bearing quaternary carbon center. Of note, the product can be transformed in situ into densely functionalized spirocyclopropanes in a highly efficient and stereoselective manner.

Stereoselective Construction of Halogenated Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2] Cycloaddition of α-Haloaldehydes.

Asymmetric construction of halogenated quaternary carbon centers under mild reaction conditions remains challenging. Reported here is an unprecedented and highly stereoselective Brønsted base catalyzed [4+2] cycloaddition between either α-chloro- or α-bromoaldehydes and cyclic enones. The key intermediate, an α-halogenated enolate, is susceptible to dehalogenation and can be stabilized and stereochemically controlled using bifunctional tertiary amines. This method provides facile access to a collection of optically pure bicyclic dihydropyrans having three contiguous stereocenters, including a halogen-bearing quaternary carbon center. Of note, the product can be transformed in situ into densely functionalized spirocyclopropanes in a highly efficient and stereoselective manner.

Multicomponent, Enantioselective Michael-Michael-Aldol-β-Lactonizations Delivering Complex β-Lactones.

Optically active, tertiary amine Lewis bases react with unsaturated acid chlorides to deliver chiral, α,β-unsaturated acylammonium salts. These intermediates participate in a catalytic, enantioselective, three-component process delivering bi- and tricyclic β-lactones through a Michael-Michael-aldol-β-lactonization. In a single operation, the described multicomponent, organocascade process forms complex bi- and tricyclic β-lactones by generating four new bonds, two rings, and up to four contiguous stereocenters. In the racemic series, yields of 22-75% were achieved using 4-pyrrolidinopyridine as Lewis base. In the enantioselective series employing isothiourea catalysts, a kinetic resolution of the initially formed racemic Michael adduct appears operative, providing yields of 46% to quantitative (based on 50% max) with up to 94:6 er. Some evidence for a dynamic kinetic asymmetric transformation for tricyclic-β-lactone 1d was obtained following optimization (yields up to 61%, 94:6 er) through a presumed reversible Michael.

Solid acid-catalyzed domino cyclization reaction: regio- and diastereoselective synthesis of pyrido[2,3-d]pyrimidine derivatives bearing three contiguous stereocenters

A highly efficient, operationally simple, green method using a solid acid for regio- and diastereoselective synthesis of pyrido[2,3-d]pyrimidines.

3-Homoacyl coumarin: an all carbon 1,3-dipole for enantioselective concerted (3+2) cycloaddition.

A new type of all-carbon 1,3-dipole precursor, 3-homoacylcoumarin, was employed for the stereoselective (3+2) cycloaddition with indandione alkylidenes to generate a series of coumarin/indandione-fused spirocyclopentanes bearing four contiguous stereogenic centers. While two reaction pathways progressed simultaneously, detailed mechanistic investigation revealed that the highly efficient stereoselective concerted route dominated the extremely slow stepwise pathway.

Asymmetric synthesis of highly functionalized spirothiazolidinone tetrahydroquinolines via a squaramide-catalyzed cascade reaction.

A bifunctional squaramide-catalyzed asymmetric cascade aza-Michael/Michael addition reaction for the synthesis of chiral spirothiazolidinone tetrahydroquinolines with three contiguous stereocenters has been developed. This cascade reaction proceeded well under mild conditions, and afforded the desired products in high to excellent yields (up to >99% yield) with excellent diastereoselectivities (>25 : 1 dr) and high enantioselectivities (up to 96% ee). More importantly, both the amplification and the derivation experiments do not affect the stereoselectivity.

An uncommon multicomponent reaction involving nucleophilic heterocyclic carbenes: facile synthesis of fully substituted cyclopentanones

An unprecedented three component reaction involving arylidene oxazolone, enal and NHC, leading to the synthesis of fully substituted cyclopentanone derivatives with three contiguous stereocenters, is reported.