High Diastereoselectivity Research Articles

Diastereoselective Polypseudorotaxane Formation with Planar Chiral Pillar[5]arenes via Co-crystallization Processes.

As the number of chiral ring molecules in chiral polyrotaxane increases, the number of possible stereoisomers exponentially increases. Consequently, the selective synthesis of a specific stereoisomer becomes much more challenging. To address this problem, we co-crystallized poly(ethylene glycol) and a diastereomeric ring molecule, pillar[5]arene, in the solid state. The co-crystallization formed polypseudorotaxanes with a high diastereomeric excess (ca. 88% de), meaning that polypseudorotaxanes containing (S, pS) stereoisomer pillar[5]arene rings were synthesized selectively. By contrast, in a solution and evaporation systems, the selectivity remained low (ca. 10% de). The results suggested that the packing effect by the co-crystallization contributed to the denser assembly of ring molecules on the polymeric chain, resulting in the diastereoselective formation. High diastereoselectivity was also observed even in higher-molecular-weight poly(ethylene glycol)s. These selectivities arose from the cooperative effects of the ring molecules on the polymeric chain, which were supported by calculating the stabilization energy.

Diastereoselective Polypseudorotaxane Formation with Planar Chiral Pillar[5]arenes via Co‐crystallization Processes

As the number of chiral ring molecules in chiral polyrotaxane increases, the number of possible stereoisomers exponentially increases. Consequently, the selective synthesis of a specific stereoisomer becomes much more challenging. To address this problem, we co‐crystallized poly(ethylene glycol) and a diastereomeric ring molecule, pillar[5]arene, in the solid state. The co‐crystallization formed polypseudorotaxanes with a high diastereomeric excess (ca. 88% de), meaning that polypseudorotaxanes containing (S, pS) stereoisomer pillar[5]arene rings were synthesized selectively. By contrast, in a solution and evaporation systems, the selectivity remained low (ca. 10% de). The results suggested that the packing effect by the co‐crystallization contributed to the denser assembly of ring molecules on the polymeric chain, resulting in the diastereoselective formation. High diastereoselectivity was also observed even in higher‐molecular‐weight poly(ethylene glycol)s. These selectivities arose from the cooperative effects of the ring molecules on the polymeric chain, which were supported by calculating the stabilization energy.

Enzymatic Upgrading of Biomass-Derived Aldoses to Rare Deoxy Ketoses Catalyzed by Transketolase Variants.

A sustainable, convenient, scalable, one-step method for the two-carbon chain elongation of cheap and biomass-derived pentoses (l-arabinose, and 2-deoxy-d-ribose) and hexose l-rhamnose was developed to produce Cn+2 deoxy ketoses (C-7 and C-8) using transketolase, an enzyme catalyzing the quasi-irreversible transfer of a ketol group from an α-keto acid to an aldehyde. Deoxygenated ketoses - commonly obtained by chemical synthesis - were afforded through a suitable combination of both nucleophile and electrophile substrates in the presence of rationally designed TK variants. Pyruvate as nucleophile with pentose l-arabinose (C-5) as electrophile gave 1-deoxy-L-gluco-heptulose (C-7), while ß-hydroxypyruvate (HPA) as nucleophile with acceptors 2-deoxy-d-ribose (C-5) and 6-deoxy-l-mannose (l-rhamnose) (C-6) led to formation of 4-deoxy-d-altro-heptulose (C-7) and 8-deoxy-l-glycero-l-galacto-octulose (C-8), respectively. These three deoxy ketoses were easily obtained with efficient TK variants under mild conditions with complete or high substrate conversions, good to excellent yields and high diastereoselectivities. This strategy offers interesting prospects to study the biological activities of these three rare and valuable deoxy ketoses on various cellular targets.

Synthesis of Functionalized Benzo[f]chromanes and Hydroxyalkyl Naphthols: Catalytic Coupling of Naphthols and Allylic Alcohols

AbstractCatalytic dearomatization of arenols is an uphill task that can serve as a powerful method to construct C−C bonds with unsaturated coupling partners. Herein, a simple and efficient strategy for coupling naphthols with allylic alcohols is reported. A single Ru(II) pincer catalyzed coupling of naphthols with primary allylic alcohols led to the formation of benzo(f)chromanes, whereas the use of secondary alcohols delivered the hydroxyalkyl naphthols. Broad substrate scope and good functional group tolerance are demonstrated. Notably, a high diastereoselectivity is attained on chromanes. Hydroxyalkyl naphthols are synthetically transformed into spiroethers, and dearomative bromination is achieved on chromanes. Mechanistic studies revealed the involvement of tandem reactions, a formal O−H bond activation of allylic alcohols by an active catalyst via amine‐amide metal‐ligand cooperation provided α‐β, unsaturated carbonyl intermediates, which further underwent 1,4 conjugate addition with dearomatized naphthols. One of the crucial intermediates, naphthyl radical, is elucidated by EPR studies and trapped using a radical scavenger. Liberated hydrogen and water molecules are the only byproducts in these transformations.

Regio‐ and Diastereoselective One‐pot Double Cascade Hybrid Formation/[3+3] Spirocyclization for the Synthesis of 3‐Spiropiperidines Under Phase Transfer Conditions

AbstractHerein, we report an efficient approach to synthesizing hybrid 3‐spiropiperidine heterocycles that incorporate both 3‐isochromanone and 3‐isoindolinone units through a one‐pot, double cascade reaction facilitated by an economical K2CO3/TBAB catalytic system. By examining the nucleophilicity of the lactone 3‐isochromanone, we developed a cascade reaction pathway that first generates a bi‐nucleophilic hybrid intermediate, which then undergoes [3+3] spirocyclization with α,β‐unsaturated aldehydes. The regioselectivity of the spirocyclization strongly depends on the substitution pattern of lactam ring.The process exhibits high diastereoselectivity, even with the formation of three or four stereocenters, including two contiguous tetra‐substituted carbons. These sequential cascade reactions were successfully scaled up, and the subsequent reactivity was readily analyzed, enabling the transformation of existing functional groups into valuable new functionalities.

Enantioselective Alkylation of Primary C(sp3)-H Bonds in N-Methyl Tertiary Amine Enabled by Iridium Complex of Axially Chiral β-Aryl Porphyrins.

A fine-tuning of enantioselective carbene insertion into primary C(sp3)-H bonds has been realized in challenging substrates, such as N-methyl unblocked aromatic and non-deactivated aliphatic tertiary amines, in which sterically demanding β-axially chiral iridium porphyrin catalysts play a crucial role. This primary C(sp3)-H alkylation with diazo compounds affords a series of β-chiral tertiary amines in high yields with excellent enantioselectivities. Notably, the protocol was successfully applied to the postmodification of chiral bicuculline, yielding the desired derivative with high diastereoselectivity. This approach paves a facile way for the stereodivergent derivation of chiral alkaloid natural products featuring an N-methyl handle. In addition, a mechanism for the reaction was proposed based on deuterium experiments and an identified cationic iridium species via HRMS analysis.

Total Synthesis of (-)-Cordycicadin D and 3,4-trans-Cordycicadins A and B: Entry to the 3,4-trans-Fused Cordycicadin Framework.

Lost in post-translation. Cordycicadins A-D are four C20polyketides, all containing ag-lactonefused to a 10-membered lactone. The proposed biosynthetic pathway for the cordycicadins anticipates the formation of two more natural products which are unknown. We report the total synthesis of (-)-cordycicadin D and the two anticipated natural products 3,4-trans-cordycicadins A and B. The targets were convergently assembled, in a biomimetic fashion,viaan efficient ketene trapping-intramolecular Michael addition sequence that delivered the requisite 3,4-trans-fused framework with high diastereoselectivity, enabled by the synthesis of complex dioxenones that serve asin situketene precursors. Recognition of the embedded polyketide symmetry enabled the use of a divergent-convergent syntheticstrategy, based on the use of two products from an early-stage enzymatic resolution. The synthetic routes afforded (-)-cordycicadin D in 14 steps and 3,4-trans-cordycicadins A and B in 13 steps (longest linear sequence). This work confirms the structure of (-)-cordycicadin D and the observed instability of the anticipated natural product 3,4-trans-cordycicadin B during purification may explain why it is yet to be isolated.

Total Synthesis of Tipranavir Based on Iridium-Catalyzed Asymmetric Allylic Substitution of Dihydropyranone.

An efficient and highly enantioselective synthesis of tipranavir is realized based on an iridium-catalyzed asymmetric allylic substitution. High yield and diastereoselectivity (>20:1), as well as excellent enantioselectivity (99% ee), were obtained for the key intermediate through direct asymmetric alkylation reaction of dihydropyranone with allylic tert-butyl carbonate. Anti-AIDS drug of tipranavir was finally accomplished in 8 steps and 6 pots starting from commercially available 1-phenyl-3-hexanone in 20.7% overall yield with 99% ee and >20:1 dr.

Nitrogenation of Alkynes with Nitrones to Prepare Functionalized [1,4]Oxazinones through Csp-Csp2 Bond Cleavage.

Herein, we report a novel strategy of hypervalent iodine(III) compound-mediated selective Csp-Csp2 bond cleavage of alkynes and C═N/N-O bond cleavage of nitrones and recombination of C-C/C-O/C-N multiple bonds to access various functionalized [1,4]oxazinones bearing a vicinal carbon stereocenter in good yields and high diastereoselectivity. Mechanistic studies revealed that the reaction undergoes a domino [4 + 3] cycloaddition, 1,3-rearrangement of N-O bond, intramolecular cyclization, dearomatization, and rearomatization over four steps in a single flask. The present method features good functional group tolerance, broad substrate scope, and C-C/C═N/N-O multiple bonds cleavage and recombination.

Synthesis of Bicyclo[3.2.0]heptanes by Organophotoredox Catalytic Diastereoselective Anion Radical [2+2] Photocycloadditions of Arylenones under Batch and Flow Conditions

AbstractIn this study, the anion radical [2+2] photocycloaddition of aryl‐enones was investigated under batch and flow conditions. The reaction was promoted by LiBr as a Lewis acid and catalyzed by Eosin Y under visible light irradiation. Symmetrical enones and asymmetrical unsaturated ketoesters were effectively cyclized to yield substituted bicyclo[3.2.0]heptanes in high yield and diastereoselectivity. Through the exploration of different experimental setups and reaction conditions, a precise control over the diastereoselectivity of the process was achieved, favoring the formation of either cis or trans substituted bicyclo[3.2.0]heptanes. In‐flow experiments allowed to further improve the efficiency of the methodology, leading to higher productivity and space time yields. Furthermore, DFT investigations were conducted in order to elucidate the reaction mechanism.

Synthesis of Mono‐ and Bis‐Thiourea Organocatalysts and Their Application in Stereoselective Glycosylation Reactions

AbstractTwo new mono‐thiourea, four bis‐thiourea and one squaramide organocatalysts were synthesised from L‐tartaric acid. These organocatalysts were able to activate glycosyl phosphates for stereoselective nucleophilic substitution reactions with broad functional group compatibility under mild conditions. The influence of the number and position of the thiourea groups and the proximity of the asymmetric centre to the catalytic important atoms for the stereoselective outcome of the glycosylation reactions was studied. 1,2‐cis Glycosides were obtained in up to 85 % yield and high diastereoselectivity (up to α:β 83 : 17).

Diastereoselective Homocoupling of Benzylic C(sp3)-H Bonds Enabled by Halogen Transfer.

A transition-metal- and harsh-oxidant-free strategy for diastereoselective homocoupling of benzylic α-boryl carbanions has been developed. Central to this methodology is the ability of the halogen transfer reagent to seamlessly integrate halogenation and substitution within a compatible process. Additionally, this methodology is also applicable to the homocoupling of diarylmethanes and alkylheteroarenes. Substrates bearing oxidatively sensitive functional groups were well-tolerated. Preliminary studies suggest that the hydrogen bond between two boryl groups contributes to the high diastereoselectivities.

Convenient Synthesis of Dihydrobenzofuran‐Fused Spirocyclopentane‐1,2‐Diindolinone Scaffolds

AbstractThe diverse functionalized dihydrobenzofuran‐fused spirocyclopentane‐1,2‐diindolin‐one scaffolds were conveniently synthesized by base promoted domino cyclization reaction of MBH (Morita‐Baylis‐Hillmann) carbonates of isatins and 3‐(o‐hydroxybenzylidene)indolin‐2‐ones. The base promoted reactions of MBH maleimides of isatins and MBH formates of isatins with 3‐(o‐hydroxybenzylidene)indolin‐2‐ones afforded polycyclic dispiro[indoline‐3,4′‐benzofuro[2′,3′:1,5]cyclopenta[1,2‐c]pyrrole‐5′,3′′‐indolines] and dispiro[indoline‐3,1′‐cyclopenta[b]benzofuran‐2′,3′′‐indolines] in good yields and with high diastereoselectivity. More importantly, DMAP facilitated annulation reaction of MBH nitriles of isatins and 3‐(o‐hydroxybenzylidene)indolin‐2‐ones selectively resulted in dispiro[indoline‐3,1′‐cyclopentane‐2′,3′′‐indolines], while Cs2CO3 promoted reaction gave dispiro[indoline‐3,1′‐cyclopenta[b]benzofuran‐2′,3′′‐indolines] in high yields and with high diastereoselectivity. The relative configurations of the various polycyclic compounds were clearly elucidated by determination several single crystal structures.

N-Halosuccinimide enables cascade oxidative trifluorination and halogenative cyclization of tryptamine-derived isocyanides

Both the pyrroloindoline core and N–CF3 moiety hold significant importance in medicinal chemistry. However, to date, no instances of constructing N–CF3-containing pyrroloindolines have been reported. Herein, we present a robust and operationally simple approach to assembling such intriguing skeletons from tryptamine-derived isocyanides through a cascade sequence, which includes an oxidative trifluorination and a subsequent halogenative cyclization. Key to the success lies in the development of a facile conversion of isocyanides to N–CF3 moiety with commercially available reagents N-halosuccinimide and Et3N·HF. The protocol features mild reaction conditions, broad functional group tolerance, good to excellent yields, and high diastereoselectivities. In addition, we demonstrate that the halide substituent within the products serves as a versatile functional handle for accessing diverse C3-quaternary-substituted N–CF3-pyrroloindolines.

Spirophosphine-Catalyzed Enantioselective [3 + 2] Cycloaddition of Allenoates and Unsaturated α-Ketimine Esters.

A novel chiral spiro-monophosphine, OUC-Phos, was synthesized and utilized for the first time in the asymmetric Lu's [3 + 2] cycloaddition reaction of β,γ-unsaturated α-ketimine ester with allenoate. OUC-Phos, featuring a 3,3'-diphenyl-modified spirobiindane skeleton, demonstrated exceptional catalytic efficiency in the [3 + 2] cycloaddition to achieve high yields, enantioselectivities, and diastereoselectivities for the targeted products. The broad substrate scope encompassing diverse functional groups demonstrated the versatility of this methodology. Furthermore, the reaction was successfully scaled up, and the products were easily converted into their corresponding functionalized derivatives.

Selenium-Catalyzed Regioselective Intermolecular Diamination of Dienes and Dienolate Derivatives.

We report a selenium-catalyzed diamination of dienes using sulfamates as a convenient nitrogen source. This reaction proceeds regioselectively for 1,2-addition at the less substituted alkene, without the need for a tethered diamine. We also report the first diamination of dienyl phosphates and tosylates, affording synthetically useful α,β-diaminoketone derivatives with high syn diastereoselectivity. Density functional theory calculations support a mechanism proceeding via [4+2] cycloaddition of the diene with a selenium bis(imide), followed by ring-opening aminolysis and [2,3]-sigmatropic rearrangement.

Direct asymmetric synthesis of β-branched aromatic α-amino acids using engineered phenylalanine ammonia lyases

β-Branched aromatic α-amino acids are valuable building blocks in natural products and pharmaceutically active compounds. However, their chemical or enzymatic synthesis is challenging due to the presence of two stereocenters. We design phenylalanine ammonia lyases (PAL) variants for the direct asymmetric synthesis of β-branched aromatic α-amino acids. Based on extensive computational analyses, we unravel the enigma behind PAL’s inability to accept β-methyl cinnamic acid (β-MeCA) as substrate and achieve the synthesis of the corresponding amino acids of β-MeCA and analogs using a double (PcPAL-L256V-I460V) and a triple mutant (PcPAL-F137V-L256V-I460V). The reactions are scaled-up using an optimized E. coli based whole-cell biotransformation system to produce ten β-branched phenylalanine analogs with high diastereoselectivity (dr > 20:1) and enantioselectivity (ee > 99.5%) in yields ranging from 41-71%. Moreover, we decipher the mechanism of PcPAL-L256V-I460V for the acceptance of β-MeCA and converting it with excellent stereoselectivity by computational simulations. Thus, this study offers an efficient method for synthesizing β-branched aromatic α-amino acids.

Recent advances in the synthesis of highly substituted imidazolidines.

Imidazolidine is a saturated heterocycle with a cyclic aminal core that can be found in natural products and biologically active molecules. Additionally, these heterocyclic compounds have been utilized as chiral ligands, N-heterocyclic carbene precursors, and catalysts in organic synthesis. This review is an attempt to compile the literature of various synthetic procedures of highly substituted imidazolidines, chiral imidazolidines with high diastereoselectivities and enantioselectivities, bis-imidazolidines, and spiro-imidazolidines, as well as their pharmacological properties during the period from 1949 to 2023.

Photocatalyzed Direct C(sp3)-H Alkenylation of Unactivated Alkanes via Tandem C-C Activation of Cyclopropenes.

A highly adaptable method has been developed for the alkenylation of a broad spectrum of inert alkanes, employing milder reaction conditions. Tetrabutylammonium decatungstate (TBADT) serves as a photocatalyst for hydrogen atom transfer (HAT), instigating the formation of transient alkyl radicals through C(sp3)-H functionalization. These radicals exhibit regioselective addition to cyclopropenes, followed by the subsequent activation of C-C bonds, forming the corresponding vinylated derivatives. This methodology accommodates diverse unreactive C(sp3)-H bond motifs and multisubstituted cyclopropenes, enabling the efficient synthesis of highly functionalized olefins with high diastereoselectivity.

Phosphomolybdic Acid‐Catalyzed One‐Pot Multicomponent Synthesis of 1,2,5,6‐Tetrahydropyridine Derivatives

AbstractWe report the synthesis of alkyl 1,2,6‐triaryl‐4‐arylaminopiperidine‐3‐ene‐3‐carboxylates in acceptable yields (42%–71%) and high trans‐diastereoselectivity (69:31 to 100:0) through a one‐pot multicomponent reaction of aromatic aldehydes, aromatic amines, and β‐ketoesters catalyzed by phosphomolybdic acid in methanol at room temperature. The structure and stereochemistry of tetrahydropyridines were confirmed by X‐ray crystallography. This protocol stands out for its operational simplicity, the use of an inexpensive and commercially available heteropolyacid catalyst, low catalyst loading, and purification via simple filtration, resulting in acceptable yields and high diastereoselectivity.