Open Transition State Research Articles

Diastereoselective addition of 2-alkoxy-2-fluoroacetate to N-(tert‑butylsulfinyl)imines: Synthesis of α-alkoxy-α-fluoro-β-amino acids

A diastereoselective Mannich-type reaction of 2-alkoxy-2-fluoroacetate and N-(tert‑butylsulfinyl)imines is reported. This protocol provides a straightforward route to α-alkoxy-α-fluoro-β-amino acids in good yields and moderate to high diastereoselectivities. This approach uses readily accessible starting materials and is operationally simple. Additionally, the stereochemistry of the current reaction was different from that of the known addition of comparable nonfluorinated 2-alkoxycarboxylic esters to N-sulfinyl imines. An open transition state (rather than a closed one) is proposed to explain the stereochemical outcome.

Diazo Strategy for Intramolecular Azirine Ring Expansion: Rh(II)-Catalyzed Synthesis of 2-Hydroxy-3-oxo-2,3-dihydro-1H-pyrrole-2-carboxylates.

A diazo strategy for the intramolecular azirine ring expansion was developed. Azirinyl-substituted diazodicarbonyl compounds, prepared from diazoacetylazirines, were converted in excellent yields to 2-hydroxy-3-oxo-2,3-dihydro-1H-pyrrole-2-carboxylates under Rh catalysis in the presence of water. According to DFT calculations, the formation of only pyrrolinone derivatives and the absence of O-H insertion products of Rh carbene into water are due to the low Gibbs free energy of the transition state for the concerted opening of the azirine ring and recyclization to pyrrolone in intermediate Rh complexes.

Asymmetric Addition of Allylsilanes to Aldehydes: A Cr/Photoredox Dual Catalytic Approach Complementing the Hosomi–Sakurai Reaction

The allylation of aldehydes is a fundamental transformation in synthetic organic chemistry. Among the multitude of available reagents, allylsilanes especially have been established as a preferred allyl source. As initially reported by Hosomi and Sakurai, these non-toxic and highly stable reagents add to carbonyls via an open transition state upon Lewis acid activation. Herein, we report a general strategy to access a variety of valuable homoallylic alcohols in opposite chemo- and diastereoselectivity to the established Hosomi–Sakurai conditions by switching to photocatalytic activation in combination with a closed transition state (chromium catalysis). Moreover, this dual catalytic approach displays a straightforward way to introduce excellent levels of enantioselectivity and its mild conditions allow for a broad substrate scope including chiral boron-substituted products as a highlight. To emphasize the synthetic utility, our method was applied as the key step in the synthesis of a bioactive compound and in the late-stage functionalization of steroid derivatives. Detailed mechanistic studies and DFT calculations hint toward an unprecedented photo-initiated chain being operative.

Cooperative Palladium/Brønsted Acid Catalysis toward the Highly Enantioselective Allenylation of β-Keto Esters.

We report the first enantioselective allenylation of Pd enolates enabled by cooperative Pd/Brønsted acid catalysis employing β-keto esters and propargyl alcohols. The enantioselectivity originates solely from an in-situ-generated chiral metal enolate in an open transition state with no additional binding of the propargyl component to the catalyst. Thus a broad substrate scope was established, furnishing hitherto inaccessible products in very good yields with excellent enantioselectivities (up to >99:1 e.r.).

Conformational dynamics of the Beta and Kappa SARS-CoV-2 spike proteins and their complexes with ACE2 receptor revealed by cryo-EM

The emergence of SARS-CoV-2 Kappa and Beta variants with enhanced transmissibility and resistance to neutralizing antibodies has created new challenges for the control of the ongoing COVID-19 pandemic. Understanding the structural nature of Kappa and Beta spike (S) proteins and their association with ACE2 is of significant importance. Here we present two cryo-EM structures for each of the Kappa and Beta spikes in the open and open-prone transition states. Compared with wild-type (WT) or G614 spikes, the two variant spikes appear more untwisted/open especially for Beta, and display a considerable population shift towards the open state as well as more pronounced conformational dynamics. Moreover, we capture four conformational states of the S-trimer/ACE2 complex for each of the two variants, revealing an enlarged conformational landscape for the Kappa and Beta S-ACE2 complexes and pronounced population shift towards the three RBDs up conformation. These results implicate that the mutations in Kappa and Beta may modify the kinetics of receptor binding and viral fusion to improve virus fitness. Combined with biochemical analysis, our structural study shows that the two variants are enabled to efficiently interact with ACE2 receptor despite their sensitive ACE2 binding surface is modified to escape recognition by some potent neutralizing MAbs. Our findings shed new light on the pathogenicity and immune evasion mechanism of the Beta and Kappa variants.

Catalytic Chemo- and Enantioselective Transformations of gem-Diborylalkanes and (Diborylmethyl)metallic Species.

Chemo- and stereoselective transformations of polyborylalkanes are powerful and efficient methods to access optically active molecules with greater complexity and diversity through programmed synthetic design. Among the various polyborylalkanes, gem-diborylalkanes have attracted much attention in organic chemistry as versatile synthetic handles. The notable advantage of gem-diborylalkanes lies in their ability to generate two key intermediates, α-borylalkyl anions and (gem-diborylalkyl) anions. These two different intermediates can be applied to various enantioselective reactions to rapidly access a diverse set of enantioenriched organoboron compounds, which can be further manipulated to generate various chiral molecule libraries via stereospecific C(sp3)-B bond transformations.In this Account, we summarize our recent contributions to the development of catalytic chemo- and stereoselective reactions using gem-diborylalkanes as versatile nucleophiles, which can be categorized as follows: (1) copper-catalyzed enantioselective coupling of gem-diborylalkanes with electrophiles and (2) the design and synthesis of (diborylmethyl)metallic species and their applications to enantioselective reactions. Since Shibata and Endo reported the Pd-catalyzed chemoselective Suzuki-Miyaura cross-coupling of gem-diborylalkanes with organohalides in 2014, Morken and Hall subsequently developed the first enantioselective analogous reactions using TADDOL-derived chiral phosphoramidite as the supporting ligand of a palladium catalyst. This discovery sparked interest in the catalytic enantioselective coupling of gem-diborylalkanes with electrophiles. Our initial studies focused on generating chiral (α-borylmethyl)copper species by enantiotopic-group-selective transmetalation of gem-diborylalkanes with chiral copper complexes and their reactions with various aldimines and ketimines to afford syn-β-aminoboronate esters with excellent enantio- and diastereoselectivity. Moreover, we developed the enantioselective allylation of gem-diborylalkanes that proceeded by reaction of in situ-generated chiral (α-borylalkyl)copper and allyl bromides. Mechanistic investigations revealed that the enantiotopic-group-selective transmetalation between gem-diborylalkanes and the chiral copper complex occurred through the open transition state rather than the closed transition state, thereby effectively generating chiral (α-borylmethyl)copper species. We also utilized (diborylmethyl)metallic species such as (diborylmethyl)silanes and (diborylmethyl)zinc halides in catalytic enantioselective reactions. We succeeded in developing the enantiotopic-group-selective cross-coupling of (diborylmethyl)silanes with aryl iodides to afford enantioenriched benzylic 1,1-silylboronate esters, which could be used for further consecutive stereospecific transformations to afford various enantioenriched molecules. In addition, we synthesized (diborylmethyl)zinc halides for the first time by the transmetalation of isolated (diborylmethyl)lithium and zinc(II) halides and their utilization to the synthesis of enantioenriched gem-diborylalkanes bearing a chiral center at the β-position via an iridium-catalyzed enantioselective allylic substitution process. In addition to our research efforts, we also include key contributions by other research groups. We hope that this Account will draw the attention of the synthetic community to gem-diboryl compounds and provide guiding principles for the future development of catalytic enantioselective reactions using gem-diboryl compounds.

Stereodivergent Total Syntheses of (+)‐Monomorine I and (+)‐Indolizidine 195B

AbstractA simple and efficient stereoselective total syntheses of two natural products (+)‐monomorine I and (+)‐indolizidine 195B in high yields starting from a readily available alcohol is described. The key step in this synthetic route exploits the judicious use of solvent to enable a closed or open transition state in a nucleophilic addition of Grignard reagent to sulfinimine, giving selective access to two distinct diastereomers required for the formation of the two target natural products.

Stereoselective Sc(OTf)3‐Catalyzed Aldol Reactions of Disubstituted Silyl Enol Ethers of Aldehydes with Acetals

AbstractFacile and modular access to stereodefined disubstituted aldehyde‐derived silyl enol ethers allowed their successful application in a stereoselective aldol reaction affording the products with excellent yields and diastereomeric ratios. The counter‐intuitive stereochemical behavior of this Mukaiyama‐aldol reaction is accounted for by a non‐classical open transition state.

Stereoselective Sc(OTf)3 -Catalyzed Aldol Reactions of Disubstituted Silyl Enol Ethers of Aldehydes with Acetals.

Facile and modular access to stereodefined disubstituted aldehyde-derived silyl enol ethers allowed their successful application in a stereoselective aldol reaction affording the products with excellent yields and diastereomeric ratios. The counter-intuitive stereochemical behavior of this Mukaiyama-aldol reaction is accounted for by a non-classical open transition state.

Mechanism and Origins of Product Selectivity of Au‐Catalyzed Coupling Benzisoxazoles with Ynamides: A Computational Study

AbstractAu(I)‐catalyzed coupling of benzisoxazoles and ynamides was recently reported to synthesize challenging indoloquinoline core structures. In this report, we employed DFT methods to elucidate the mechanistic details of this reaction. The results reveal that the catalytic cycle involves initial coupling of ynamide with benzisoxazole, simultaneous ring opening of the isoxazole unit and attack of the dimethoxybenzene (DMOB) unit to gold carbenoid, proton transfer from the DMOB group to hydroxyl group, thioether migration, ring closure, and proton transfer. The experimentally observed ligand‐controlled product selectivity is reproduced well by the calculations. The product selectivity‐determining step is the ring opening of the isoxazole unit. The flexible P(t‐Bu)2(o‐biphenyl) ligand facilitates the approach of the DMOB group to gold carbenoid, which brings about significant C−H/π interactions in the transition state for ring opening, and thus leads to the indoloquinoline product. The rigid 1,3‐bis(diisopropylphenyl)imidazol‐2‐ylidene ligand prefers keeping the DMOB group away from the gold carbenoid, which can cause strong orbital interaction in the transition state for ring opening, and thus results in indole product.

Benzylation of Imines with Activated Boronate Nucleophiles.

Benzylation reactions of N-tosyl imines and N-tert-butanesulfinyl imines using benzylboronic acid pinacol ester are reported. s-Butyllithium was used to activate the boronic ester, rendering it nucleophilic. The reaction was compatible with electronically diverse substituents on the imine in both substrate classes. Good diastereoselectivity was observed in additions to N-tert-butylsulfinylaldimines. The diastereoselectivity observed in these reactions is consistent with an open transition state for the addition. Examples of a secondary alkylboronic ester nucleophile and an N-tert-butanesulfinyl trifluoromethylketimine electrophile are also included.

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

Abstractα‐Oxygen‐functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α‐fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn‐ and anti‐aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2‐dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.

Direct Catalytic Asymmetric Aldol Reaction of α-Alkoxyamides to α-Fluorinated Ketones.

α-Oxygen-functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α-fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn- and anti-aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2-dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.

Direct and Asymmetric Nickel(II)-Catalyzed Construction of Carbon-Carbon Bonds from N-Acyl Thiazinanethiones.

A wide array of new N-acyl thiazinanethiones are employed in a number of direct and enantioselective carbon-carbon-bond-forming reactions catalyzed by nickel(II) complexes. The electrophilic species are mostly prepared in situ from ortho esters, methyl ethers, acetals, and ketals, which makes the overall process highly efficient and experimentally straightforward. Theoretical calculations indicate that the reactions proceed through an open transition state in a SN1-like mechanism. The utility of this novel procedure has been demonstrated by the asymmetric preparation of synthetically useful intermediates and the total synthesis of peperomin D.

Stereochemistry and reactivity of the HPA-imine Mannich intermediate

Homophthalic anhydride (HPA) typically reacts rapidly with benzalimines to afford the formal [4+2] adduct, a 1,2,3,4-tetrahydroisoquinolin-1-one-4-carboxylic acid. The stereochemical outcome of this reaction is consistent with an open transition state comprising an iminium species and enolized HPA, leading to a short-lived amino-anhydride intermediate. In the case of N-tert-butylbenzalimine, this Mannich-type intermediate, which would normally cyclize at low temperature to a single isomer of the delta-lactam, is intercepted by base treatment to afford beta-lactam products. A pathway featuring ketene formation followed by ring closure is implicated.

Stereospecific, Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Allylic Pivalates To Deliver Quaternary Stereocenters.

Recognizing the importance of all-carbon, quaternary stereocenters in complex molecule synthesis, a stereospecific, nickel-catalyzed cross-coupling of allylic pivalates with arylboroxines to deliver products equipped with quaternary stereocenters and internal alkenes was developed. The enantioenriched allylic pivalate starting materials are readily prepared, and a variety of functional groups can be incorporated on both the allylic pivalate and the arylboroxine. Additional advantages include the use of a commercially available and air-stable Ni(II) salt and BISBI ligand, mild reaction conditions, and high yields and ee's. The observed stereoinversion of this reaction is consistent with an open transition state in the oxidative addition step.

Stereoselective Mannich Reaction of N‐(tert‐Butylsulfinyl)imines with 3‐Fluorooxindoles and Fluoroacetamides

AbstractA diastereoselective Mannich reaction has been developed for the construction of stereogenic C−F units by the reaction of α‐fluoro‐substituted amides, including highly activated 3‐fluoro‐oxindoles, and simple linear fluoroacetamides with N‐tert‐butylsulfinylimines. This method provides a concise route to a variety of structurally diverse α‐fluoro‐β‐amino amides containing stereogenic fluorinated carbon centers. This protocol has the benefit of using readily accessible starting materials and is operationally simple. The Mannich reactions of cyclic and linear α‐fluoro‐substituted amides resulted in different stereochemical outcomes, suggesting that these substrates reacted via closed and open transition states, respectively.magnified image

Zinc‐Mediated syn‐Selective Crotylation of N‐Unsubstituted Imines

AbstractThe first example of a zinc‐mediated diastereoselective crotylation of N‐unsubstititued imines is described. The use of Et3B as an additive was of crucial importance to achieve high yield and diastereoselectivity. Notably, a high level of syn‐selectivity was observed. A mechanism involving an open transition state is suggested to explain this unique selectivity.

New insights into the electroreduction of ethylene sulfite as an electrolyte additive for facilitating solid electrolyte interphase formation in lithium ion batteries.

To help understand the solid electrolyte interphase (SEI) formation facilitated by electrolyte additives of lithium-ion batteries (LIBs) the supermolecular clusters [(ES)Li+(PC)m](PC)n (m = 1-2; n = 0, 6 and 9) were used to investigate the electroreductive decompositions of the electrolyte additive ethylene sulfite (ES) as well as the solvent propylene carbonate (PC) with density functional theory. The results show that ES can be reduced prior to PC, resulting in a reduction precursor that will then undergo a ring opening decomposition to yield a radical anion. A new concerted pathway (path B) was located for the ring opening of the reduced ES, which has a much lower energy barrier than the previously reported stepwise pathway (path A). The transition state for the ring opening of PC induced by the reduced ES (path C, indirect path) is closer to that of path A than path B in energy. The direct ring opening of the reduced PC (path D) has a lower energy barrier than paths A, B and C, yet it is less favorable than the latter paths in terms of thermodynamics (vertical electron affinity or reduction potential and dissociation energy). The overall rate constant including the initial reduction and the subsequent ring opening for path B is the largest among the four paths, followed by paths A > C > D, which further signifies the importance of the concerted new path in facilitating the SEI formation. The hybrid models, the supermolecular clusters augmented by a polarized continuum model, PCM-[(ES)Li+(PC)2](PC)n (n = 0, 6 and 9), were used to further estimate the reduction potential by taking into account both explicit and implicit solvent effects. The second solvation shell of Li+ in [(ES)Li+(PC)2](PC)n (n = 6 and 9) partially compensates the overestimation of solvent effects arising from the PCM for the naked (ES)Li+(PC)2, and the theoretical reduction potential of PCM-[(ES)Li+(PC)2](PC)6 (1.90-1.93 V) agrees very well with the experimental one (1.8-2.0 V).

TfOH Catalyzed [3+2] Cycloaddition of Cyclopropane 1,1‐Diesters with Nitriles: A Density Functional Study

AbstractThe mechanistic pathways for TfOH catalyzed [3+2] cycloaddition reaction between cyclopropane 1, 1 diesters and MeCN has been investigated using density functional theory. The study sheds light on selective synthesis of 1‐pyrroline or γ‐lactone derivatives in two different reaction conditions. Analysis of global reactivity descriptors in the solvent free medium predicts the protonated cyclopropane 1,1 diesters and MeCN as strong electrophile and nucleophile respectively, favoring intermolecular reaction to give 1‐pyrroline derivative as the product. On the other hand, the presence of solvent environment with DCM solvent significantly supresses this nature of the two molecules to undergo intermolecular reaction. Protonated cyclopropane 1,1 diester, therefore, prefers intramolecular rearrangement to yield γ‐lactone. While the synthesis of 1‐pyrroline derivative follows pathway involving a transition state showing weak interaction between two reactants, γ‐lactone synthesis undergo mechanism preferring initial cyclopropane ring opening transition state. Molecular electron density topography yield support to the proposed mechanism.