Prostaglandin Total Synthesis Enabled by the Organocatalytic Dimerization of Succinaldehyde

Prostaglandins have been attractive targets in total synthesis for over 50 years, resulting in the development of new synthetic strategies and methodologies that have served the broader chemical community. However, these molecules are not just of academic interest, a number of prostaglandin analogues are used in the clinic, and some are even on the WHO list of essential medicines. In this personal account, we describe our own approach to the family of prostaglandins, which centers around the synthesis of a key enal intermediate, formed from the l ‐proline catalysed dimerization of succinaldehyde. We highlight the discovery and further optimization of this key reaction, its scale up, and subsequent application to a range of prostaglandins.     

Ni-Catalyzed Regio- and Enantioselective Homoallylic Coupling: Synthesis of Chiral Branched 1,5-Dienes Featuring a Quaternary Stereogenic Center and Mechanistic Analysis

Asymmetric synthesis of small molecules comprising quaternary stereogenic carbon centers represents a challenging objective. Here regio- and enantioselective synthesis of chiral 1,5-dienes featuring quaternary stereocenters is reported via nickel-promoted by reductive homoallylic coupling. The developed methodology features an atypical preference for the formation of unusual branched regioisomers (rr >20 : 1) in a sterically challenging allylic substitution event and furnishes the products with enantiomeric ratios of up to 98 : 2 and with high chemo- and E-selectivity. A range of experimental evidences suggest that zinc plays a dual role to generate electrophilic and nucleophilic Ni(II)-allyl intermediates empowering a unique formal bimetallic cross-electrophile manifold in two separate kinetic regimes.     

L-苏式二氢鞘氨醇的立体选择性合成

二氢鞘氨醇（ＤＨＳ）是２－氨基－１，３－二羟基的饱和长链氨基醇化合物，是构成鞘脂类（包括鞘磷脂和糖鞘脂）的主链部分．由于鞘脂类在自然界中来源稀少，又很难得到纯品．因此，作为鞘脂类主链部分的二氢鞘氨醇的合成有重要的意义［１］．二氢鞘氨醇有两个手性碳，共...     

Asymmetric Synthesis of Chiral 1,2-Bis(Boronic) Esters Featuring Acyclic,Non-Adjacent 1,3-Stereocenters

The construction of acyclic, non-adjacent 1,3-stereogenic centers, prevalent motifs in drugs and bioactive molecules, has been a long-standing synthetic challenge due to acyclic nucleophiles being distant from the chiral environment. In this study, we successfully synthesized highly valuable 1,2-bis(boronic) esters featuring acyclic and nonadjacent 1,3-stereocenters. Notably, this reaction selectively produces migratory coupling products rather than alternative deborylative allylation or direct allylation byproducts. This approach introduces a new activation mode for selective transformations of gem-diborylmethane in asymmetric catalysis. Additionally, we found that other gem-diborylalkanes, previously challenging due to steric hindrance, also successfully participated in this reaction. The incorporation of 1,2-bis(boryl)alkenes facilitated the diversification of the alkenyl and two boron moieties in our target compounds, thereby enabling access to a broad array of versatile molecules. DFT calculations were performed to elucidate the reaction mechanism and shed light on the factors responsible for the observed excellent enantioselectivity and diastereoselectivity. These were determined to arise from ligand-substrate steric repulsions in the syn-addition transition state.     

Diastereoselective Biomimetic Synthesis of Dimeric Tetrahydrocarbazoles via a Copper(II)-Catalyzed Cycloisomerization-[3+2] Cyclodimerization Cascade

The cyclodimerization (homochiral- and heterochiral−) of monomeric units for the construction of stereodefined polycyclic systems is a powerful strategy in both biosynthesis and biomimetic synthesis. Herein we have discovered and developed a Cu^II- catalyzed, biomimetic, diastereoselective tandem cycloisomerization-[3+2] cyclodimerization of 1-(indol-2-yl)pent-4-yn-3-ol. This novel strategy operates under very mild conditions, providing access to structurally unprecedented dimeric tetrahydrocarbazoles fused to a tetrahydrofuran unit in excellent yields of the products. Several fruitful control experiments, isolation of the monomeric-cycloisomerized products and their subsequent conversion into the corresponding cyclodimeric products supported their intermediacy and the possible mechanism as a cycloisomerization-diastereoselective [3+2] cyclodimerization cascade. The cyclodimerization involves a substituent controlled, highly diastereoselective homochiral [3+2] annulation or heterochiral [3+2] annulation of in situ generated 3-hydroxytetrahydrocarbazoles. The key and important features of this strategy are: a) construction of three new C−C bonds & one new C−O bond; b) creation of two new stereocenters, and c) construction of three new rings, in a single operation; d) low catalyst loading (1–5 mol %); e) 100 % atom economy; and f) rapid construction of structurally unprecedented natural product like polycyclic frameworks. A chiral pool version using an enantio- and diastereopure substrate was also demonstrated.     

Enantioselective Total Synthesis of (+)-Incargranine A Enabled by Bifunctional Iminophosphorane and Iridium Catalysis

Herein we report the first enantioselective total synthesis of (+)-incargranine A, in nine steps. The total synthesis was enabled by an enantioselective intramolecular organocatalysed desymmetrising Michael addition of a malonamate ester to a linked dienone substrate that established pivotal stereocentres with excellent enantio- and complete diastereoselectivity. Furthermore, a key hemiaminal intermediate was accessed by developing an iridium-catalysed reductive cyclisation, and the scope of this transformation was explored to produce a range of bicyclic hemiaminal motifs. Once installed, the hemiaminal motif was used to initiate a biomimetic cascade to access the natural product directly in a single step.     

Organocatalytic Enantioselective Synthesis of Pyrazoles Bearing a Quaternary Stereocenter

An efficient one‐pot asymmetric synthesis of pyrazoles bearing a chiral quaternary stereocenter has been developed. Quinine‐derived thiourea catalyzed the enantioselective addition of pyrazolones to isatin‐derived ketimines, providing the corresponding acetylated pyrazoles after in situ treatment with Ac₂O/Et₃N. The corresponding pyrazoles were afforded in high yields and excellent enantioselectivities.     

Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations

Monothiomalonates (MTM s) are surrogates of thioester enolates that allow for stereoselective C–C bond formations under mild conditions and thereby afford access to synthetically versatile thioester derivatives. Here we present a straightforward synthetic route to MTM s that proceeds through nucleophilic ring‐opening of Meldrum 's acid derivatives followed by O‐alkylation of the resulting malonic acid half thioesters with alkyl triflates or acetimidates as electrophiles. The method affords MTM s in overall yields of 34 – 92% and allows for variations of the oxo‐ and thioester moieties as well as the substituent at the C(α ) position.     

Synthesis of highly decorated chiral 2-nitro-cyclohexane carboxylic esters through microwave-assisted organocatalyzed cascade reactions

Starting from (E)-β-substituted-β-nitroacrylates and α,β-unsaturated ketones, a stereoselective organocatalyzed one-pot methodology allowed to synthesize highly decorated chiral 2-nitro-cyclohexane carboxylic esters. The reaction is promoted by Cinchona alkaloid-derived primary amines in the presence of an acidic co-catalyst and affords two diastereoisomers, in good yields and high enantiomeric excess (often higher than 90% ee). By replacing conventional heating with microwave irradiation, cleaner reactions in shortened times (from 48 h to 30 min) were obtained, with improved dr (80:20) and high ee (up to 94%). The application of microwave technology to this organocatalytic methodology allowed also employing C1 substituted enones, leading to cyclohexanones with four contiguous stereocenters in two isomers only, and up to 99% enantioselectivity.     

含双蒽基团酰胺受体分子的合成及阴离子识别研究

合成了一种新型的带有双蒽基团的酰胺阴离子受体B.用荧光光谱、紫外-可见吸收光谱以及核磁共振氢谱研究了B与Cl^-,Br^-,I^-及对硝基酚氧阴离子的相互作用.结果表明,B与Cl^-,Br^-,I^-等阴离子无识别作用,而与对硝基酚氧阴离子有较好的选择性识别能力,其络合比为1∶1.利用荧光发射强度和吸光度的变化分别计算出主体B与客体相互作用的络合常数KS分别为(1.24±0.07)×10⁵和(1.27±0.18)×10⁵,并对主体分子B与客体之间的相互作用进行了讨论.     

Asymmetric Synthesis of Stereogenic Phosphorus P(V) Centers Using Chiral Nucleophilic Catalysis

Organophosphates have been widely used in agrochemistry, as reagents for organic synthesis, and in biochemistry. Phosphate mimics possessing four unique substituents, and thereby a chirality center, are useful in transition metal catalysis and as nucleotide therapeutics. The catalytic, stereocontrolled synthesis of phosphorus-stereogenic centers is challenging and traditionally depends on a resolution or use of stochiometric auxiliaries. Herein, enantioenriched phosphorus centers have been synthesized using chiral nucleophilic catalysis. Racemic H-phosphinate species were coupled with nucleophilic alcohols under halogenating conditions. Chiral phosphonate products were synthesized in acceptable yields (33–95%) and modest enantioselectivity (up to 62% ee) was observed after identification of an appropriate chiral catalyst and optimization of the solvent, base, and temperature. Nucleophilic catalysis has a tremendous potential to produce enantioenriched phosphate mimics that could be used as prodrugs or chemical biology probes.     

Structural Diversity-Oriented Synthesis of Orthogonally Protected Cyclic Amino Acid Derivatives with Multiple Stereogenic Centers

The synthesis of three-dimensional cyclopentane amino acid derivatives with multiple stereocenters and with high regiochemical and diastereochemical diversity has been achieved starting from cyclopentadiene-derived β-aminocyclopentenecarboxylic acid. The small-molecular design was based on stereo- and regiocontrolled functionalization of the starting cyclopentene β-amino acid through stereoselective oxirane formation/regioselective oxirane opening and resulted in regio- and diastereoisomers of novel orthogonally protected aminocyclopentanecarboxylates.     

Organocatalytic strategy for hydrophenolation of gem-difluoroalkenes

Gem-difluoroalkenes are an easily accessed fluorinated functional group, and a useful intermediate for elaborating into more complex fluorinated compounds. Currently, most functionalization reactions of gem-difluoroalkenes, with or without a transition metal-based catalyst system, involve the addition or removal of a fluorine atom to generate trifluorinated or monofluorinated products, respectively. In contrast, we present a complementary “fluorine-retentive” reaction that exploits an organocatalytic strategy to add phenols across gem-difluoroalkenes to deliver β,β-difluorophenethyl arylethers. The products are produced in good to moderate yields and selectivities, thus providing a range of compounds that are underrepresented in the synthetic and medicinal chemistry literature.     

Synthesis of Enantioenriched Vicinal Tertiary and Quaternary Carbon Stereogenic Centers within an Acyclic Chain

Overcoming the inherent difficulty to prepare quaternary carbon stereogenic centers, the diastereo‐ and enantioselective preparation of acyclic carbon backbones possessing vicinal quaternary and tertiary stereogenic centers (i.e. in a 1,2‐relationship) causes distorted geometries and represents a very acute problem in organic synthesis. Several approaches are discussed in this minireview underlining the challenges illustrated by the rather limited number of approaches available to practitioners.     

Organocatalytic enantioselective Friedel-Crafts alkylation of simple phenols with trifluoropyruvate

Enantioselective Friedel-Crafts alkylation of simple phenols (4a-j) with 3,3,3-trifluoropyruvate (3) was accomplished by using chiral cinchona alkaloid catalyst 2h (10 mol %). High yields and enantioselectivities (71-94% ee) of the Friedel-Crafts alkylation products were obtained.     

Facile Synthesis of Cyclic Tetrapeptides from Nonactivated Peptide Esters on Metal Centers

The cyclization of dipeptide esters of α-, β-, γ-, and δ-amino acids can be achieved by using Ni^II, Pd^II, or Cu^II templates. The structure of one of the complexes ( 1 ) obtained, which was determined by X-ray crystallography, reveals that the anions form layers and are linked to water molecules by hydrogen bonds.