Tertiary Stereogenic Centers Research Articles

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: Organocatalytic Asymmetric Conjugate Addition of α‐Substituted Cyanoacetates to Maleimides.

AbstractChiral succinimides with two adjacent quaternary and tertiary stereogenic carbon centers are formed with good diastereo‐ and enantioselectivities in most cases using Takemoto′s thiourea catalyst.

基于分子识别的脯氨酸酰肼催化剂催化丙酮和α-酮酸的不对称aldol 反应

On the basis of molecular recognition, a series of proline hydrazide derived organocatalysts have been designed and synthesized. They have been effectively used in the direct aldol reaction between acetone and α-keto acid, which afforded α-hydroxyl carboxylic acids with a tertiary stereogenic center in excellent yields (up to 99% yield) and high enantioselectivities (up to 90% ee).

Enantio- and diastereoselective Michael additions of C-succinimidyl esters to nitro olefins using cinchonine-derived bifunctional organocatalysts

A novel bifunctional organocatalytic Michael addition of a succinimide-derived pronucleophile to nitro olefins is described. The use of a range of nitro olefins afforded Michael adducts containing contiguous quaternary and tertiary stereogenic centres in high enantioselectivities and moderate diastereoselectivities.

Efficient and enantioselective total syntheses of heliannuols A and K

The second-generation enantioselective synthesis of heliannuol A and the first enantioselective total synthesis of heliannuol K (via two routes) have both been accomplished efficiently; (heliannuol A, nine steps and 25% yield; heliannuol K, seven steps and 47% yield). Highlights of our synthetic strategy include a substrate-controlled chirality transfer in the Lewis acid mediated Claisen rearrangement of the allyl aryl ether for the key construction of a tertiary stereogenic center at the benzylic position followed by, for heliannuol A, ring-closing metathesis, diastereoselective epoxidation, and regioselective cleavage of the epoxide; and for heliannuol K, ring-closing metathesis and conjugate reduction of the eight-membered enone.

Enantioselective syntheses of the assigned structures of the helibisabonols A and B

The enantioselective syntheses of the compounds with the assigned structures of the helibisabonols A and B have been accomplished. Using an enzymatic desymmetrization of the σ-symmetrical diol (route a) and a diastereoselective conjugate addition of the methyl to the enone with a chiral auxiliary (route b) we constructed the key tertiary stereogenic center at the benzylic position (C7) and then used an asymmetric dihydroxylation for assembling the C10 stereogenic center. In addition, possible diastereoisomers of the natural products were prepared and detailed comparisons of the 1H and 13C NMR spectra were conducted. As a result, the structure originally assigned to helibisabonol A may be revised to (7 R,10 R)- 1. In the case of helibisabonol B, the (7 R,10 R)- 2 would be reasonable based on a comparison of the NMR data and the biogenetic parallelism with helibisabonol A.

Enantioselective Construction of Quaternary Stereogenic Centers from Tertiary Boronic Esters: Methodology and Applications

Pin it down: A range of substrates that bear versatile functional groups with quaternary stereogenic centers have been prepared with very high enantioselectivity from tertiary boronic esters (see scheme; Cb=N,N-diisopropylcarbamoyl, pin=pinacolato). The preparation of allylboronic esters bearing contiguous quaternary and tertiary stereogenic centers, and applications to natural product synthesis are also reported.

Organocatalytic asymmetric conjugate addition of α-substituted cyanoacetates to maleimides

The asymmetric conjugate addition of α-substituted cyanoacetates to N-substituted maleimides has been developed. A number of cinchona alkaloids and amine thioureas were evaluated as catalysts. Takemoto’s catalyst was found to be the most efficient for the transformation. Chiral succinimides with two adjacent quaternary and tertiary stereogenic carbon centers were obtained in good yields, enantioselectivities, and diastereoselectivities. The products were converted to chiral γ-lactams conveniently without a loss in the enantioselectivity.

Asymmetric Synthesis of Tertiary Stereogenic Centers

Boronic esters represent a versatile class of synthetic intermediates in organic synthesis since they can be easily prepared in an enantio-selective fashion. Their transformation into other functional groups like alcohols and amines or their use in C-C coupling reactions under retention of configuration is well known. Herein, the authors present an efficient protocol for the protodeboronation of tertiary diarylalkyl and aryldialkyl boronic esters of type 2 into the corresponding products 3 with full retention of configuration and excellent yields. Furthermore, the applicability of this methodology has been proved in a short total synthesis of the small natural product (S)-­turmerone.

Highly efficient construction of spirocyclic chromanone–pyrrolidines via Cu(i)/TF–BiphamPhos-catalyzed asymmetric 1,3-dipolar cycloaddition

A facile synthesis of highly functional spiro-[4-chromanone-3,3'-pyrrolidine] bearing one unique spiro quarternary and three tertiary stereogenic centers is developed in excellent stereoselectivity for the first time.

An efficient total synthesis of (+)-heliannuol D

An efficient total synthesis of (+)-heliannuol D was accomplished in 14 steps and in 12% overall yield by employing a diastereoselective conjugate addition reaction to create a tertiary benzylic stereogenic center and simple assembly of the functionalized oxepane framework by an efficient one-pot transformation procedure as the key steps.

A Simple Primary Amine Thiourea Catalyzed Highly Enantioselective Conjugate Addition of α,α‐Disubstituted Aldehydes to Maleimides

Branch point: A simple primary amine thiourea catalyzed highly enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides has been developed. The biologically useful chiral disubstituted α-branched succinimides are attained with the generation of two contiguous quaternary and/or tertiary stereogenic centers in one step with excellent enantioselectivities and in high yields under mild reaction conditions (see scheme).

Enantioselective Aldol Reaction of α‐Ketoester and Cyclopentaone Catalyzed by L‐Proline

AbstractA concise and enantioselective synthesis of (S)‐ethyl 2‐cyclopentyl‐2‐hydroxy‐2‐arylacetate, a key intermediate for the muscarinic receptor, is reported. The tertiary stereogenic center was constructed with good stereoselectivity through the L‐proline‐catalyzed direct asymmetric aldol reaction of ethyl arylglyoxylate and cyclopentanone. The carbonyl of the condensation product was reduced using a modified Clemmensen reaction which provided an easier workup and was more environmentally acceptable. The enantioselectivity of the aldol reactions was between 58.3%–93.2%, which means that the stereoselective is efficient in controlling configuration of reaction product.

Stereoselective Synthesis of α-Alkyl-β-keto Imides via Asymmetric Redox C−C Bond Formation between α-Alkyl-α-diazocarbonyl Compounds and Aldehydes

Asymmetric redox C-C bond formation between alpha-alkyl-alpha-diazocarbonyl compounds and aldehydes was developed as a practical and general method for the construction of alpha-alkyl-beta-keto imides having a chiral nonracemic tertiary stereogenic center.

Enantio- and regioselective CpRu-catalyzed Carroll rearrangement

Abstract The addition of unstabilized carbonyl nucleophiles to allyl-metal fragments still represents a challenge for generating stereoselectively tertiary (and quaternary) stereogenic centers. In this context, the decarboxylative Carroll rearrangement of secondary and tertiary allyl β-ketoesters is particularly interesting since chiral γ,δ-unsaturated ketones are obtained. Herein, we show that CpRu half-sandwich complexes can, in the presence of selected enantiopure diimine ligands, catalyze this transformation and afford complete conversions and decent level of enantiomeric excess. Zwitterionic adducts of a hexacoordinated phosphorus anion and CpRu moieties were also associated and shown to generate air-, moisture-, and microwave-stable catalysts that can be readily purified and recycled. Carroll rearrangements of allylic β-ketoesters performed with these zwitterionic species occur with better regio- and enantioselectivity.

Enantioselective Catalytic Formation of Quaternary Stereogenic Centers

AbstractEnantioselective catalytic formation of tertiary stereogenic centers has nowadays reached an impressive level of maturity, as is reflected in the large variety of available methods that afford high yields and high stereoselectivities. However, the development of stereoselective approaches for the formation of quaternary stereogenic centers still represents an enormous challenge for synthetic chemists. On the other hand, biologically active molecules containing quaternary stereogenic centers provide an incentive for the development of new, selective, and useful processes. Over the last few years, breakthrough work relating to the formation of fully substituted carbon centers has appeared in the literature. In this review we discuss recent highlights of this new direction in catalysis research: the formation of quaternary stereogenic centers by enantioselective catalytic methodologies.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Design of Highly Enantioselective Organocatalysts Based on Molecular Recognition

[reaction: see text] Various organocatalysts have been designed based on molecular recognition to catalyze the asymmetric direct aldol reaction of ketones with aryl and alkyl alpha-keto acids, affording beta-hydroxyl carboxylic acids with a tertiary stereogenic center with excellent enantioselectivities of up to 98% ee. A linear effect was observed for the reaction, demonstrating a single molecule of the catalyst involved in the catalysis.

Diastereoselective Synthesis of the 19‐epi‐C18—C25 Segment of (‐)‐Lasonolide A and an Unusual Inversion at C19.

Abstract Diastereoselective construction of the 19- epi -C 18 –C 25 segment of (−)-lasonolide A was achieved using a 5- exo -trigonal mode of radical cyclization for the creation of the contiguous quaternary and tertiary stereogenic centers at C 22 and C 23 as the key reaction step. During the dehydration stage, it was found that an unusual inversion of configuration took place.

Diastereoselective synthesis of the 19- epi-C 18–C 25 segment of (−)-lasonolide A and an unusual inversion at C 19

Diastereoselective construction of the 19- epi-C 18–C 25 segment of (−)-lasonolide A was achieved using a 5- exo-trigonal mode of radical cyclization for the creation of the contiguous quaternary and tertiary stereogenic centers at C 22 and C 23 as the key reaction step. During the dehydration stage, it was found that an unusual inversion of configuration took place.

Utilization of molybdenum- and palladium-catayzed dynamic kinetic asymmetric transformations for the preparation of tertiary and quaternary stereogenic centers: a concise synthesis of tipranavir.

Tipranavir, an important antiviral agent in clinical development for the treatment of HIV, is synthesized in 15 linear steps from readily available starting materials in 25% overall yield by utilizing Pd- and Mo-catalyzed DYKAT reactions to control the quaternary and tertiary stereogenic centers, respectively.