Adjacent Stereogenic Centers Research Articles

ChemInform Abstract: Organocatalytic Asymmetric Domino Michael/Henry Reaction of Indolin‐3‐ones with o‐Formyl‐β‐nitrostyrenes.

A highly diastereo- and enantioselective domino Michael/ Henry reaction of 1-acetylindolin-3-ones with o-formyl-(E)-β-nitrostyrenes catalyzed by low loading of a quinine-derived amine-squaramide provides the corresponding indolin-3-one derivatives bearing four adjacent stereogenic centers in good to high yields and with excellent stereo­selectivities.

Chiral Squaramide‐Catalyzed Michael/­Alkylation Cascade Reaction for the Asymmetric Synthesis of Nitro‐Spirocyclopropanes

AbstractA new diastereoselective and enantioselective cyclopropanation reaction has been developed by employing a Michael/alkylation cascade reaction between (E)‐3‐arylenechroman‐4‐one or (E)‐2‐arylideneindan‐1‐one derivatives and a bromonitroalkane with a chiral squaramide catalyst. This reaction constitutes a facile asymmetric synthesis for nitro‐spirocyclopropanes that have three adjacent stereogenic centers, including one quaternary center, in moderate to good yields (up to 90 %) with excellent enantio‐ [up to >99 % ee (enantiomeric excess)] and diastereoselectivities [up to >99:1 dr (diastereomeric ratio)].

Synthesis of β-alkynyl α-amino acids via palladium-catalyzed alkynylation of unactivated C(sp3)-H bonds

β-Di-substituted α-amino acids (AAs) contain adjacent carbon stereogenic centers and pose considerable synthetic challenge. Complementary to the conventional synthesis strategies based on the transformation of existing functional groups, we envisioned these molecules could be quickly accessed via selective functionalization of sp3 hybridized C-H bonds on the side chains of common α-AA precursors. We report a readily applicable method to prepare β-alkynyl α-amino acids via Pd-catalyzed diastereoselective C(sp3)-H alkynylation of common α-amino acids precursors with acetylene bromide.

Diastereoselective Synthesis of 1-Deoxygalactonojirimycin, 1-Deoxyaltronojirimycin, and N-Boc-(2S,3S)-3-Hydroxypipecolic Acid via Proline Catalyzed α-Aminoxylation of Aldehydes.

An efficient synthesis of deoxygalactonojirimycin and deoxyaltronojirimycin through the use of proline catalyzed asymmetric α-aminoxylation of a higher homologue of Garner's aldehyde, derived from l-aspartic acid, is reported. The method is also used for a highly diastereoselective synthesis of the N-Boc derivative of (2S,3S)-3-hydroxypipecolic acid. The configuration of the proline catalyst used for the asymmetric aminoxylation step ultimately controls the absolute configuration of three adjacent stereogenic centers in the final products.

Open-close: an alternative strategy to α-functionalization of lactone via enamine catalysis in one pot under mild conditions.

An open-close strategy in asymmetric catalysis is newly developed. With this powerful strategy, lactols are directly applied as potential precursors of lactones in enamine-based asymmetric Michael reactions providing a facile access to α-functionalized lactones containing two adjacent stereogenic centers as a single diastereomer in good to excellent yields (up to 99%) and with excellent enantioselectivities (most cases >99%). Moreover, the reaction products are shown to give highly functionalized derivatives by stepwise systematic transformations.

Catalytic asymmetric inverse-electron-demand oxa-Diels-Alder reaction of in situ generated ortho-quinone methides with 3-methyl-2-vinylindoles.

The first catalytic asymmetric inverse-electron-demand (IED) oxa-Diels-Alder reaction of ortho-quinone methides, generated in situ from ortho-hydroxybenzyl alcohols, has been established. By selecting 3-methyl-2-vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho-hydroxybenzyl alcohols as precursors of dienes and 3-methyl-2-vinylindoles as dienophiles, as well as the hydrogen-bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa-Diels-Alder reaction.

Catalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction of In Situ Generated ortho‐Quinone Methides with 3‐Methyl‐2‐Vinylindoles

AbstractThe first catalytic asymmetric inverse‐electron‐demand (IED) oxa‐Diels–Alder reaction of ortho‐quinone methides, generated in situ from ortho‐hydroxybenzyl alcohols, has been established. By selecting 3‐methyl‐2‐vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho‐hydroxybenzyl alcohols as precursors of dienes and 3‐methyl‐2‐vinylindoles as dienophiles, as well as the hydrogen‐bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa‐Diels–Alder reaction.

Organocatalytic Asymmetric Domino Michael/Henry Reaction of Indolin-3-ones with o-Formyl-β-nitrostyrenes.

A highly diastereo- and enantioselective domino Michael/Henry reaction of 1-acetylindolin-3-ones with o-formyl-(E)-β-nitrostyrenes catalyzed by low loading of a quinine-derived amine-squaramide provides the corresponding indolin-3-one derivatives bearing four adjacent stereogenic centers in good to high yields and with excellent stereoselectivities.

Synthesis of virtually enantiopure aminodiols with three adjacent stereogenic centers by epoxidation and ring-opening.

A virtually complete enantioselective synthesis of 3-amino-1,2-diols with three consecutive stereocenters was accomplished by a sequential cascade of two kinetic resolutions, which features a Sharpless or Hafnium-catalyzed asymmetric epoxidation and a subsequent W-catalyzed aminolysis. Enantiopure products with up to >99.9% ee and >99.9 : 0.1 dr were obtained and could serve as potential building blocks for pharmaceutical or biological significant molecules.

Construction of multiple, contiguous quaternary stereocenters in acyclic molecules by lithiation-borylation.

Lithiation of carbamates followed by borylation provides a powerful method for the homologation of boron reagents. However, when applied to hindered systems (secondary carbamates with tBu-boronic esters) for the construction of two quaternary centers, this methodology fails. Instead, using mixed boranes (tBuBMe2), the synthesis of adjacent quaternary stereogenic centers with full stereocontrol was successful. The process can be repeated two or three times in one pot leading to carbon chains bearing multiple contiguous quaternary stereogenic centers. The boranes were converted into tertiary alcohols or C-tertiary amines using chloramine. The origin of the high selectivity for alkyl over Me group migration was determined computationally.

ChemInform Abstract: Pd‐Catalyzed Highly Regio‐, Diastereo‐, and Enantioselective Allylic Alkylation of α‐Fluorophosphonates.

AbstractThe resulting allylic alkylation products (III) contain two adjacent stereogenic centers and three functional groups that can be easily elaborated into more complex compounds such as oxazine (V).

Multistereogenic Phosphine Ligand‐promoted Palladium‐Catalyzed Allylic Alkylation of Cyanoesters

AbstractA palladium‐catalyzed allylic alkylation of unsubstituted 2‐cyanoacetates using a 1,1′‐bi‐2‐naphthol‐derived multifunctional N,O,P ligand is reported. A number of chiral monosubstituted 2‐cyanoacetates with two adjacent stereogenic carbon centers are obtained in this Pd‐catalyzed asymmetric allylic alkylation reaction, in which the multistereogenic and multifunctional 1,1′‐bi‐2‐naphthol‐derived N,O,P ligand‐promoted Pd‐catalyzed asymmetric allylic alkylation reaction proceeds smoothly in high diastereo‐ and enantioselectivity (up to >99:1 dr and up to 96 % ee).

Highly stereoselective construction of adjacent tetrasubstituted carbon stereogenic centres via an organocatalytic Mukaiyama-aldol reaction of monofluorinated silyl enol ethers to isatins

We report the first organocatalytic activation of monofluorinated silyl enol ethers 1, by nucleophilic tertiary amine catalysis, to develop asymmetric reactions for the construction of fully substituted chiral carbons featuring a C–F bond. Accordingly, a highly stereoselective Mukaiyama-aldol reaction of isatins to furnish hydroxyoxindoles bearing two adjacent tetrasubstituted carbon stereocenters is developed.

Catalytic, Asymmetric Synthesis of Phosphonic γ‐(Hydroxyalkyl)butenolides with Contiguous Quaternary and Tertiary Stereogenic Centers

A procedure that enables high yielding access to phosphonic γ-(hydroxyalkyl)butenolides with excellent regio-, diastereo- and enantiocontrol is reported. The simultaneous construction of up to two adjacent quaternary stereogenic centers by a catalytic asymmetric vinylogous Mukaiyama aldol reaction unites biologically and medicinally relevant entities, namely α-hydroxy phosphonates and γ-(hydroxyalkyl)butenolides. This is achieved by utilizing a readily available chiral copper-sulfoximine catalyst showing a broad functional group tolerance for both the electrophilic and nucleophilic reactants. A discussion about potential factors affecting the observed level of enantioselectivity, which stems from the enantiopure sulfoximine ligand, is also included.

Diastereoselective Synthesis of β‐Lactam–Oxindole Hybrids Through a Three‐Component Reaction of Azetidine‐2,3‐diones, α‐Diazo‐oxindoles, and Alcohols Catalyzed by [Rh2(OAc)4

Abstractβ‐Lactam–oxindole hybrids have been synthesized in good yields in a one‐pot procedure through efficient and stereoselective capture of an oxonium ylide with azetidine‐2,3‐diones. The reaction allows high to moderate control of stereoselectivity, depending on the 3‐diazo‐oxindole precursor and the hydroxylic compound used. Two new quaternary stereogenic centers were formed; the stereochemistry at the C‐3 quaternary center was controlled by a bulky substituent at C‐4, whereas the stereoselectivity in the adjacent second quaternary stereogenic center was controlled by the α‐diazo‐oxindole. The stereochemistry of both quaternary centers has been unambiguously assigned by single‐crystal X‐ray diffraction.

Sc(OTf)3-catalyzed diastereoselective Friedel–Crafts reactions of arenes and hetarenes with 3-phenylglycidates

Five different para-substituted 3-phenylglycidates (3-phenyloxirane-2-carboxylates) were prepared and subjected to reactions with arenes and hetarenes under Lewis acid catalysis. Sc(OTf)(3) was found to effectively (5 mol%) promote a Friedel-Crafts reaction in nitromethane as the solvent. The reaction was shown to proceed stereoconvergently, which makes the intermediacy of a benzylic cation likely. The diastereoselectivities varied depending on the choice of the nucleophile and 3-arylglycidate. Best results were obtained with tert-butyl 3-anisylglycidate, which delivered the respective products with high syn-preference in diastereomeric ratios (d.r.) between 82 : 18 and >95 : 5. The observed selectivity can be explained by a model, according to which the intermediate benzylic cations adopt a preferred conformation, which allows for diastereoface-differentiation by the adjacent stereogenic center.

Conjugate Addition Approach Towards Unnatural Amino Acid Derivatives

Unnatural α-amino acids play important roles in peptide-based drugs and iso­steres. The preparation of unnatural amino acids in high stereochemical purity is a challenging and important task. In the present work, β-substituted bisphosphonates are explored as Michael acceptors. Utilizing azomethine ylid nucleophiles, unnatural α-amino acids containing two adjacent tertiary stereogenic centers are produced in excellent yield, diastereoselectivity, and enantioselectivity.

ChemInform Abstract: Dramatic Lithium Chloride Effect on the Reaction Stereocontrol in Zn‐Mediated Asymmetric Cinnamylation: Highly Practical Synthesis of β‐Aryl Homoallylic Amines.

AbstractAn extremely mild and practical route for the synthesis of enantiomerically enriched β‐aryl substituted homoallylic amines bearing two adjacent stereogenic centers is developed using the Zn‐mediated highly stereoselective cinnamylation of N‐sulfinyl imines.

A tandem reaction of organozinc reagent prepared from palladium-catalyzed umpolung method: diastereoselective formation of cyclohexene derivatives bearing three adjacent stereocenters

In the presence of a palladium catalyst, treatment of γ-acyloxy-α,β-unsaturated ketone with bis(iodozincio)methane caused umpolung of π-allylpalladium to give a zinc dienolate. Thus formed zinc species afforded a cyclohexene derivative via a self-condensation reaction. It is noteworthy that the three adjacent stereogenic centers were created in a single process with quite high diastereoselectivity.

Stereoselective Construction of Adjacent Quaternary Chiral Centers by the Ireland-Claisen Rearrangement: Stereoselection with Esters of Cyclic Alcohols

This work describes a study of the Ireland-Claisen rear- rangement of a,a-disubstituted enolates derived from esters of cy- clic alcohols. Highly stereoselective enolizaitions could be generally achieved using N-benzyl Koga-type bases by matching chirality of the ester and the base. The (3,3)-sigmatropic rearrange- ment took place in good yields and moderate diastereoselectivity forming two adjacent quaternary stereogenic centers, and generally proceeding through a chairlike transition state.