Origin Of Diastereoselectivity Research Articles

Pd/Cu-Cocatalyzed Enantio- and Diastereodivergent Wacker-Type Dicarbofunctionalization of Unactivated Alkenes.

The Wacker and Wacker-type reactions are some of the most fundamental and powerful transformations in organic chemistry for their ability to efficiently produce valuable chemicals. Remarkable progress has been achieved in asymmetric oxy/aza-Wacker-type reactions; however, asymmetric Wacker-type dicarbofunctionalization remains underdeveloped, especially for the concurrent construction of two stereocenters. Herein, we report a Pd/Cu-cocatalyzed enantio- and diastereodivergent Wacker-type dicarbofunctionalization of alkene-tethered aryl triflates with imino esters. A series of 2-indanyl motifs bearing adjacent carbon stereocenters could be easily synthesized in moderate to excellent yields and with good to excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). Density functional theory calculations revealed that the origin of diastereoselectivity in this Pd/Cu synergistic catalytic system is jointly determined by both the intermolecular anti-carbopalladation of alkenes and the reductive elimination processes, in accordance with the Curtin-Hammett principle.

Origins of Diastereoselectivity in the Addition of Enoxysilanes to Vinyl Diazonium Salts.

The addition of enoxysilanes to vinyl diazonium ions occurs with varying levels of diastereoselectivity. To understand the origins of the stereoselectivity, we studied these transformations using density functional theory (DFT) calculations. The selectivity stems from a stabilizing cation-π interaction that orients the nucleophile and the diazonium ion.

Elucidating the mechanism and origin of diastereoselectivity in scandium-catalyzed β-C(sp3)–H activation and transformation of an aliphatic aldimine

The mechanism and origin of regio- and diastereoselectivity in the reaction of divergent [3 + 2] annulation of aliphatic aldimines with alkenes by scandium-catalyzed β-C(sp3)–H activation have been revealed in detail using DFT calculations.

Molecular Reconstruction with Stereochemical Relay: An Investigation into the Rearrangement of Spiro[4.5]decadienone to Benzoxepane.

Herein, we report the unusual skeletal rearrangement of spiro[4.5]decadienone to benzoxepane. In particular, Lewis acid-promoted epoxide-opening ipso-cyclization of aryl epoxides afforded spiro[4.5]decadienone intermediates. Subsequent thermal activation assembled a benzoxepane core via rearomative molecular reorganization. The sequence was high-yielding and highly diastereoselective but sensitive to the aromatic substitution pattern and the epoxide side chain. Mechanistic studies suggested that the rearrangement proceeded via an uncommon intramolecular enolate attack onto the electrophilic O of p-quinone oxonium zwitterion. DFT calculations helped rationalize the product distribution and the origin of diastereoselectivity. Initial investigation into the application of this chemical transformation is also presented.

Syn-Selective Difunctionalization of Bicyclobutanes Enabled by Photoredox-Mediated C-S σ-Bond Scission.

Given the importance of cyclic frameworks in molecular scaffolds and drug discovery, it is intriguing to precisely forge and manipulate ring systems in synthetic chemistry. In this field, the intermolecular synthesis of densely substituted cyclobutanes with precise diastereocontrol under simple reaction conditions remains a challenge. Herein, a photoredox strategy for the difunctionalization of bicyclo[1.1.0]butanes (BCBs) under high regio- and syn-selectivity is disclosed. C-S σ-bond cleavage of partially unsaturated sulfur-containing bifunctional reagents in an overall strain-release-driven process enables the thio-alkynylation, -alkenylation, and -allylation of BCBs under mild conditions and demonstrates the generality of this protocol. Mechanistic studies suggest that the intermediacy of cyclic distonic radical cations might be key for the efficient scission of C-S σ-bonds and the origin of diastereoselectivity.

Origin of High Diastereoselectivity in Reactions of Seven-Membered-Ring Enolates.

Unlike many reactions of their six-membered-ring counterparts, the reactions of chiral seven-membered-ring enolates are highly diastereoselective. Diastereoselectivity was observed for a range of substrates, including lactam, lactone, and cyclic ketone derivatives. The stereoselectivity arises from torsional and steric interactions that develop when electrophiles approach the diastereotopic π-faces of the enolates, which are distinguished by subtle differences in the orientation of nearby atoms of the ring.

Formal [4+1] Cyclization of ortho‐ or para‐Quinone Methides with 3‐Chlorooxindoles: Synthesis of 3,2′‐Tetrahydrofuryl Spirooxindoles

AbstractA base promoted formal [4+1] cycloaddition of ortho‐ and para‐quinone methides with 3‐chlorooxindoles is reported to afford various functionalized 3,2′‐tetrahydrofuryl spirooxindoles in high yields under mild conditions. An unexpected reversal in diastereoselectivity was observed from these two types of reactions. Computational studies have provided insight into the origin of diastereoselection, and different configurations of 1,4‐addition and 1,6‐addition at the oxindole carbanionic center are found to give rise to different diastereomers. The anti‐tumor activity of these structurally unique spirooxindole derivatives is reported.

Asymmetric Diels–Alder reaction between furans and propiolates

We report the first asymmetric Diels–Alder reaction between furan and propiolates. Propiolate, a dienophile, was equipped with an Evans’ auxiliary and a sulfonyl group to control and facilitate diastereoselective cycloaddition. Treatment with furan as a diene and aluminium Lewis acid afforded a 7-oxabicyclo[2.2.1]heptadiene skeleton diastereoselectively. The origin of diastereoselectivity can be explained by chelation of aluminium center to carbonyl groups and oxygen of furan. Friedel–Crafts-type products were obtained when pyrrole was used as diene.

Origin of diastereoselectivity and catalytic efficiency on Isothiourea-mediated cyclization of carboxylic acid with alkenyl ketone

Asymmetric synthesis plays an important role in organic chemistry. To this end, a theoretical study of the possible mechanisms, origin of diastereoselectivity, and efficiency of catalysts on isothiourea-catalyzed asymmetric cyclization of carboxylic acids and alkenyl ketones was performed by using density functional theory (DFT). The calculated results show that the diastereoselectivity can be induced in the CC bond formation step involved in the [4 + 2] cycloaddition. The atoms-in-molecules (AIM) analysis shows that bonding interaction and hydrogen bonds contribute significantly for the favorability of SS-configured product. The catalytic efficiency of isothioureas was explored and predicted by nucleophilic atom energy Ea-.

Mechanism, origin of diastereoselectivity and factors affecting reaction efficiency of serine/threonine ligation: A computational study

The mechanism of serine/threonine ligation was investigated by density functional theory. The reaction sequentially proceeds through imine capture, 5-endo-trig cyclization and [1,5] O-to-N acyl transfer steps, all of which occur with the assistance of pyridinium. The imine capture and 5-endo-trig cyclization steps are reversible whereas the [1,5] O-to-N acyl transfer step is irreversible. The [1,5] O-to-N acyl transfer step proceeds through a stepwise addition-elimination mechanism with the C–O bond cleavage as the rate-determining step of the overall reaction. The diastereoselectivity for the exclusive formation of the S-configured N,O-benzylidene acetal-linked peptide originates from the disfavored steric repulsion between the leaving phenolic oxygen and the side chain of the C-terminal peptide in the R-configured C–O bond cleavage transition state in the acyl transfer step. A suitable ring size as well as a good leaving group in acyl transfer are responsible for the high efficiency of the serine/threonine ligation reaction.

Stereoselective synthesis of alicyclic ketones: A hydrogen borrowing approach

A highly diastereoselective annulation strategy for the synthesis of alicyclic ketones from diols and pentamethylacetophenone is described. This process is mediated by a commercially available iridium(III) catalyst, and provides efficient access to a wide range of cyclopentane and cyclohexane products with high levels of stereoselectivity. The origins of diastereoselectivity in the annulation reaction have been explored by a series of control experiments, which provides an explanation for how each stereocentre around the newly forged ring is controlled.

Practical, asymmetric route to sitagliptin and derivatives: development and origin of diastereoselectivity.

The development of a practical and scalable process for the asymmetric synthesis of sitagliptin is reported. Density functional theory calculations reveal that two noncovalent interactions are responsible for the high diastereoselection. The first is an intramolecular hydrogen bond between the enamide NH and the boryl mesylate S=O, consistent with MsOH being crucial for high selectivity. The second is a novel C–H···F interaction between the aryl C5-fluoride and the methyl of the mesylate ligand.

Origins of diastereoselectivity in Lewis acid promoted ketene-alkene [2 + 2] cycloadditions.

A detailed analysis of a Lewis acid promoted ketene-alkene [2 + 2] cycloaddition is reported. The studies have led to a rationalization for an observed inversion of diastereoselectivity between thermally induced and Lewis acid promoted ketene-alkene [2 + 2] cycloadditions. The model is supported with both experimental and computational results.

Mechanism and diastereoselectivity of the prebiotic synthesis of deoxyribonucleotide precursors C5-thiazoline: A DFT study

The prebiotic synthesis of deoxyribonucleotide precursor C5-thiazoline has been studied by performing density functional theory calculations. Two possible reaction pathways are explored and the results indicate that it prefers stepwise nucleophilic addition and ring-closure processes rather than concerted pathway. Four possible channels associated with four diastereoisomers have been explored in detail. Our calculations show that the C–C bond-forming step can be regarded as the rate-determining step and thiazole addition to the Si-face of iminium represents an energetically preferred pathway. In addition, the origin of diastereoselectivity is also investigated and the steric hindrance is considered to play a very important role. The current theoretical study provides very important information for in-depth understanding of other prebiotic nucleotides synthesis.

Total synthesis of d-fagomine and 6-deoxyfagomine

Total synthesis of d-fagomine and 6-deoxyfagomine from readily available d-lyxose is described. The key steps included regioselective and diastereoselective amination, hydroboration–oxidation, and Appel reaction. The reaction of 3,4-anti-tribenzyl ether with chlorosulfonyl isocyanate in toluene at 0 °C afforded 3,4-anti-amino alcohol, an essential compound for the preparation of d-fagomine and 6-deoxyfagomine, with a high diastereoselectivity (dr=26:1) in 74% yield. The origin of diastereoselectivity can be explained by the neighboring group effect, which leads to retention of the stereochemistry.

Highly Diastereoselective Construction of Fused Carbocycles from Cyclopropane‐1,1‐dicarboxylates and Cyclic Enol Silyl Ethers: Scope, Mechanism, and Origin of Diastereoselectivity

Cyclopropane rings true: By selecting the appropriate substituents on the ester and silyl groups, fused cyclopentane derivatives with multiple contiguous stereocenters can be synthesized with excellent diastereoselectivity through Cu(II)/bisoxazoline-catalyzed intermolecular [3+2] cycloaddition reactions of cyclopropane-1,1-dicarboxylates and cyclic enol silyl ethers (see scheme).

On the origins of diastereoselectivity in the conjugate additions of the antipodes of lithium N-benzyl-(N-α-methylbenzyl)amide to enantiopure cis- and trans-dioxolane containing α,β-unsaturated esters

"Matching" and "mismatching" effects in the doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-(N-α-methylbenzyl)amide to enantiopure cis- and trans-dioxolane containing α,β-unsaturated esters have been investigated. High levels of substrate control were established first upon conjugate addition of achiral lithium N-benzyl-N-isopropylamide to both tert-butyl (S,S,E)-4,5-O-isopropylidene-4,5-dihydroxyhex-2-enoate and tert-butyl (4R,5S,E)-4,5-O-isopropylidene-4,5-dihydroxyhex-2-enoate. However, upon conjugate addition of lithium (R)-N-benzyl-(N-α-methylbenzyl)amide and lithium (S)-N-benzyl-(N-α-methylbenzyl)amide to these substrates, neither reaction pairing reinforced the apparent sense of substrate control. These reactions do not, therefore, conform to the classical doubly diastereoselective "matching" or "mismatching" pattern usually exhibited by this class of reaction. A comparison of these reactions with the previously reported doubly diastereoselective conjugate addition reactions of lithium amide reagents to analogous substrates is also discussed.

Origins of the diastereoselectivity in hydrogen bonding directed Diels–Alder reactions of chiral dienes with achiral dienophiles: a computational study

In this study, the origins of diastereoselectivity in the hydrogen bonding assisted Diels-Alder reactions of chiral dienes with achiral dienophiles have been investigated with density functional methods. The distortion/interaction model has been applied to shed light on the origins of selectivity. C9-Substituted chiral anthracene templates (R = (CH(3))(OCH(3))(H), R = (CH(3))(OH)(H), R = (CH(3))(CH(2)CH(3))(H) and R = (-CH(2)-C(CH(3))(OCH(3))(H)) are used to rationalize the role of a stereogenic center and H-bonding on the product distribution ratio. Even though hydrogen bonding increases the reactivity of the diene, the stereoselectivity is reduced because of the hydrogen bonding capacity of both diastereomeric transition states. The interaction energies of the studied anthracene templates with N-methyl maleimide at the transition state correlate linearly with an increase in reactivity. The selectivity is determined by both favorable distortion and interaction energies. The π-facial selectivity induced by the presence of a chiral auxiliary in 1-substituted 1,3-pentadienes (R1 = (CH(3))(OCH(3))(H) and R1 = (CH(3))(OH)(H)) has also been modeled in order to rationalize the role of the stereogenic center and H-bonding on the stereoselectivity of an aliphatic diene. In both parts, the product distribution ratios calculated from Boltzmann distributions based on Gibbs free energies are in reasonable agreement with the experimental results. Finally the role of OH-substituted five-membered pyrrolidine on C9 of anthracene is investigated since the successful usage of the conformationally rigid pyrrolidines in asymmetric synthesis is well known. Overall, both in the acyclic system and in anthracene, the facilitation due to H-bonding is reflected in the interaction energies: the higher the difference in interaction energies in the transition structures of the two diastereomers, the more selective the H-bonding assisted Diels-Alder reaction is.

The origin of diastereoselectivity in the Michael addition reaction: a computational study of the interaction between CH-acidic Schiff base and α,β-unsaturated ketones

Theoretical quantum chemical computations were applied in answering a question set from the experiment: why the Michael addition to chalcones is a highly diastereoselective process? Density functional theory methods were used to examine the mechanistic pathways for the Michael reaction of [(diphenylmethylene)amino]acetonitrile—CH-acidic Schiff base with α,β-unsaturated ketones (enones). Transition state structures, prereactive complexes and reaction path energetics for different channels of the reaction are determined. The theoretical predictions reveal that the difference in the stabilization of the prereactive complex explains adequately the experimental findings for diastereoselectivity of the addition to benzylideneacetophenone (chalcone), compared to the nonselective process in the case of 4,4-dimethyl-1-phenyl-1-pentene-3-one.

On the Origins of Diastereoselectivity in the Alkylation of Enolates Derived fromN-1-(1′-Naphthyl)ethyl-O-tert-butylhydroxamates: Chiral Weinreb Amide Equivalents

The stereochemical outcome observed upon alkylation of enolates derived from N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxamates (chiral Weinreb amide equivalents) may be rationalized by a chiral relay mechanism. Deprotonation with KHMDS leads to a nonchelated (Z)-enolate in which the oxygen atoms adopt an anti-periplanar conformation. The configuration of the N-1-(1'-naphthyl)ethyl group dictates the conformation of the O-tert-butyl group and the configuration adopted by the adjacent pyramidal nitrogen atom. Highly diastereoselective enolate alkylation then proceeds anti to both the bulky tert-butyl group (sterically driven) and the N-lone pair (stereoelectronically driven).