Enantioselective Total Syntheses of (−)‐Rhazinilam, (−)‐Leucomidine B,and (+)‐Leuconodine F

A divergent total synthesis of three structurally distinct natural products from imine 9 was accomplished through an approach featuring: 1) a Pd‐catalyzed decarboxylative cross‐coupling, and 2) heteroannulation of 9 with bromoacetaldehyde and oxalyl chloride to give tetrahydroindolizine 6 and dioxopyrrole 7 , respectively. The former was converted into (−)‐rhazinilam, while the latter was converted into (−)‐leucomidine B and (+)‐leuconodine F. A substrate‐directed highly diastereoselective reduction of a sterically unbiased double bond by using a homogeneous palladium catalyst was developed. A self‐induced diastereomeric anisochronism (SIDA) phenomenon was observed for leucomidine B.     

Total Synthesis of a Dimeric Thymol Derivative Isolated from Arnica sachalinensis

The total synthesis of a dimeric thymol derivative (thymarnicol) isolated from Arnica sachalinensis was accomplished in 6 steps. A key biomimetic Diels–Alder dimerization was found to occur at ambient temperature and the final oxidative cyclization occurs when the substrate is exposed to air and visible light. These results indicate that this natural product is likely the result of spontaneous (non‐enzyme‐mediated) reactivity.     

Enzymatic Synthesis of Homogeneous Chondroitin Sulfate Oligosaccharides

Chondroitin sulfate (CS) is a sulfated polysaccharide that plays essential physiological roles. Here, we report an enzyme‐based method for the synthesis of a library of 15 different CS oligosaccharides. This library covers 4‐O‐sulfated and 6‐O‐sulfated oligosaccharides ranging from trisaccharides to nonasaccharides. We also describe the synthesis of unnatural 6‐O‐sulfated CS pentasaccharides containing either a 6‐O‐sulfo‐2‐azidogalactosamine or a 6‐O‐sulfogalactosamine residue. The availability of structurally defined CS oligosaccharides offers a novel approach to investigate the biological functions of CS.     

Biomimetic and Biocatalytic Synthesis of Bruceol

The first total synthesis of bruceol has been achieved using a biomimetic cascade cyclization initiated by a stereoselective Jacobsen–Katsuki epoxidation (and kinetic resolution) of racemic protobruceol‐I. A bacterial cytochrome P450 monooxygenase was also found to catalyze the conversion of protobruceol‐I into bruceol. The first full analysis of the NMR data of natural bruceol suggested that “isobruceol” was a previously unrecognized natural product also isolated from Philotheca brucei. This was confirmed by the re‐isolation, synthesis, and X‐ray analysis of isobruceol. In total, eight stereoisomers and structural isomers of bruceol have been synthesized in a highly divergent approach.     

Access to Chiral Hydropyrimidines through Palladium‐Catalyzed Asymmetric Allylic C−H Amination

A palladium‐catalyzed asymmetric intramolecular allylic C−H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N ‐sulfonyl amides bearing an arylethene‐1‐sulfonyl group underwent a sequential allylic C−H amination and intramolecular Diels–Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.     

Stereoselective Direct Chlorination of Alkenyl MIDA Boronates: Divergent Synthesis of E and Z α‐Chloroalkenyl Boronates

The individual molecules of α‐chloroalkenyl boronates include both an electrophilic C−Cl bond and a nucleophilic C−B bond, which makes them intriguing organic synthons. Reported herein is a stereodivergent synthesis of both E and Z α‐chloroalkenyl N ‐methyliminodiacetyl (MIDA) boronates through the direct chlorination of alkenyl MIDA boronates using t BuOCl and PhSeCl reagents, respectively. Both reaction processes are stereospecific and the use of sp³‐B MIDA boronate is the key contributor to the reactivity. The synthetic value of the boronate products was also demonstrated.     

A Divergent Synthetic Route to the Vallesamidine and Schizozygine Alkaloids: Total Synthesis of (+)‐Vallesamidine and (+)‐14,15‐Dehydrostrempeliopine

The total synthesis of representative members of the schizozygine alkaloids, (+)‐vallesamidine and (+)‐14,15‐dehydrostrempeliopine, were completed from a late‐stage divergent intermediate. The synthesis took advantage of efficient nitro‐group reactions with the A/B/C ring skeleton constructed concisely on a gram scale through an asymmetric Michael addition, nitro‐Mannich/lactamisation, Tsuji–Trost allylation, and intramolecular C?N coupling reaction. Other key features of the synthesis are a novel [1,4] hydride transfer/Mannich‐type cyclisation to build ring E and a diastereoselective ring‐closing metathesis reaction to construct ring D. This approach gave access to a late‐stage C14,C15 alkene divergent intermediate that could be simply transformed into (+)‐vallesamidine, (+)‐14,15‐dehydrostrempeliopine, and potentially other schizozygine alkaloids and unnatural derivatives.     

Organocatalytic,Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa‐Michael Addition Sequence

An unprecedented enantioselective oxa‐Michael reaction of α‐tertiary alcohols using cinchona‐alkaloid‐based chiral bifunctional squaramide catalysts is reported. An oxidative dearomatization of phenol followed by an enantioselective oxa‐Michael addition sequence provided a broad array of chiral sterically hindered tetrahydrofurans and tetrahydropyrans attached to a cyclohexadienone moiety in spiro fashion. In general, good yields and excellent enantioselectivities (up to 99 %) were observed. The chiral oxo‐cycles obtained have easily been transformed into chromans without disturbing the enantioselectivity.     

A Bioinspired Synthesis of (±)‐Rubrobramide, (±)‐Flavipucine,and (±)‐Isoflavipucine

A biomimetic synthesis of naturally occurring lactams rubrobramide, flavipucine, and isoflavipucine is described. The key step is a regioselective Darzens reaction between isobutyl glyoxal and an α‐bromo‐β‐ketoamide. The construction of the core tricyclic ring system of rubrobramide was achieved by a cascade reaction in a single step from an α,β‐epoxy‐γ‐lactam. Furthermore, the absolute configuration of naturally occurring (+)‐rubrobramide was determined by vibrational circular dichroism. (±)‐Flavipucine and (±)‐isoflavipucine were synthesized from an epoxyimide, which was prepared by reaction of isobutyl glyoxal with a protected α‐bromo‐β‐ketoamide. Deprotection of the epoxyimide and formation of the pyridone ring gave (±)‐flavipucine, which was converted into (±)‐isoflavipucine by thermal isomerization.     

Synthesis of γ‐Boryl‐Substituted Homoallylic Alcohols with anti Stereochemistry Based on a Double‐Bond Transposition

The stereoselective synthesis of anti isomers of γ‐boryl‐substituted homoallylic alcohols is disclosed. (E)‐1,2‐Di(boryl)alk‐1‐enes undergo Ru‐catalyzed double‐bond transposition with control of the geometry. The in situ generated (E)‐1,2‐di(boryl)alk‐2‐enes add to aldehydes in a stereospecific manner. The alkenylboron group within the product is amenable to a variety of synthetic derivatizations.     

Precise Synthesis of Poly(thioester)s with Diverse Structures by Copolymerization of Cyclic Thioanhydrides and Episulfides Mediated by Organic Ammonium Salts

The precise synthesis of poly(thioester)s with diverse structures is still a significant challenge in the polymeric materials field. Herein, we report a novel approach to the synthesis of well‐defined poly(thioester)s by the controlled alternating copolymerization of cyclic thioanhydrides and episulfides induced by simple organic ammonium salts. Both the cation and anion have strong effects on the copolymerization. [PPN]OAc ([PPN]=bis(triphenylphosphine)iminium) with a bulky cation was proven to be efficient in initiating this polymerization, yielding poly(thioester)s with a completely alternating structure, controlled molecular weight, and narrow polydispersity. The poly(thioester) obtained from succinic thioanhydride and propylene sulfide is a typical semicrystalline material, possessing a high refractive index of up to 1.78. Because it uses readily available monomers, this method is expected to open up a new route to poly(thioester)s with diverse structures and properties.     

One‐Step Multigram‐Scale Biomimetic Synthesis of Psiguadial B

A gram‐scale synthesis of psiguadial B, a purported inhibitor of human hepatoma cell growth, has been achieved in one step by a biomimetic three‐component coupling of caryophyllene, benzaldehyde, and diformylphloroglucinol. This cascade reaction is catalyzed by N,N′‐dimethylethylenediamine, and proceeds at ambient temperature to generate four stereocenters, two rings, one C−O bond, and three C−C bonds. Combined computational and experimental investigations suggest the biosynthesis of the natural product is non‐enzyme mediated, and is the result of a Michael addition between caryophyllene and a reactive ortho‐quinone methide, followed by two sequential intramolecular cationic cyclization events.     

Enantioselective Synthesis of 3,3′‐Diaryl‐SPINOLs: Rhodium‐Catalyzed Asymmetric Arylation/BF3‐Promoted Spirocyclization Sequence

The enantioselective synthesis of a series of C₂‐symmetric 3,3′‐diarylated 1,1′‐spirobiindane‐7,7′‐diols (3,3′‐diaryl‐SPINOLs) was developed by sequential Rh‐catalyzed twofold asymmetric conjugate arylation/BF₃‐promoted diastereoselective spirocyclization (>20:1 d.r. and >99 % ee for all examples). Some phosphoramidite ligands were prepared from the 3,3′‐Ph‐SPINOL and applied to several catalytic asymmetric reactions, and the 3,3′‐diarylated ligands showed higher enantioselectivities than the privileged nonsubstituted ligands.     

Electronically Activated Organoboron Catalysts for Enantioselective Propargyl Addition to Trifluoromethyl Ketones

A broadly applicable, practical, scalable, efficient and highly α‐ and enantioselective method for addition of a silyl‐protected propargyl moiety to trifluoromethyl ketones has been developed. Reactions, promoted by 2.0 mol % of a catalyst that is derived in situ from a readily accessible aminophenol compound at ambient temperature, were complete after only 15 minutes at room temperature. The desired tertiary alcohols were isolated in up to 97 % yield and 98.5:1.5 enantiomeric ratio. Alkyl‐, alkenyl‐, alkynyl‐, aryl‐ or heteroaryl‐substituted trifluoromethyl ketones can be used. Utility is highlighted by application to a transformation that is relevant to enantioselective synthesis of BI 653048, a compound active against rheumatoid arthritis.     

Cobalt‐Catalyzed Enantio‐ and Diastereoselective Intramolecular Hydroacylation of Trisubstituted Alkenes

Enantio‐ and diastereoselective synthesis of trans ‐2,3‐disubstituted indanones is achieved by intramolecular hydroacylation of 2‐alkenylbenzaldehydes bearing trisubstituted alkenyl groups under cobalt‐chiral diphosphine catalysis. Notably, a high level of enantioselectivity is induced regardless of the stereochemistry (E /Z ratio) of the alkenyl group of the starting material. Deuterium‐labeling experiments shed light on the productive reaction pathways of the E ‐ and Z ‐isomers.     

Catalytic Atropenantioselective Heteroannulation between Isocyanoacetates and Alkynyl Ketones: Synthesis of Enantioenriched Axially Chiral 3‐Arylpyrroles

We report herein the first examples of catalytic enantioselective synthesis of axially chiral 3‐arylpyrroles. Reaction of α‐isocyanoacetates with β‐aryl‐α,β‐alkynic ketones in the presence of silver oxide and a phosphine ligand derived from Cinchona alkaloid occurred chemoselectively to afford enantioenriched 3‐arylpyrroles in high yields with excellent enantiomeric excesses. The pyrrole ring was constructed de novo in this process.     

Sustainable Synthesis of Pure Silica Zeolites from a Combined Strategy of Zeolite Seeding and Alcohol Filling

Currently, the synthesis of pure silica zeolites always requires the presence of organic structure‐directing agents (OSDAs), which direct the assembly pathway and ultimately fill the pore space. A sustainable route is now reported for synthesizing pure silica zeolites in the absence of OSDAs from a combined strategy of zeolite seeding and alcohol filling, where the zeolite seeds direct crystallization of zeolite crystals from amorphous silica, while the alcohol is served as pore filling in the zeolites. Very importantly, the alcohol could be fully washed out from zeolite pores by water at room temperature, which completely avoids calcination at high temperature for removal of OSDAs in the synthesis of pure silica zeolites.     

Short,Enantioselective Total Synthesis of Chatancin

An enantioselective total synthesis of the polycyclic diterpene (+)‐chatancin, a potent PAF antagonist, is reported. Proceeding in seven steps from dihydrofarnesal, this synthetic route was designed to circumvent macrocyclization‐based strategies to complex, cyclized cembranoids. The described synthesis requires only six chromatographic purifications, is high yielding, and avoids protecting‐group manipulations. An X‐ray crystal structure of this fragile marine natural product was obtained.     

Pot Economy in the Total Synthesis of Estradiol Methyl Ether by Using an Organocatalyst

Enantioselective total synthesis of estradiol methyl ether has been accomplished in a pot‐economical manner using five reaction vessels and four purifications. The key reaction is a diphenylprolinol silyl ether mediated domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane derivatives, containing the A, C, and D rings of steroids, as a single isomer with excellent enantioselectivity. Six reactions such as oxidation, hydrogenation, formation of acid chloride, Friedel–Crafts reaction, deprotection, and reduction can be carried out in the last one‐pot sequence.     

Organocatalytic and Scalable Synthesis of the Anti‐Influenza Drugs Zanamivir,Laninamivir, and CS‐8958

Zanamivir, laninamivir, and CS‐8958 are three neuraminidase inhibitors that have been clinically used to combat influenza. We report herein a novel organocatalytic route for preparing these agents. Only 13 steps are needed for the assembly of zanamivir and laninamivir from inexpensive D ‐araboascorbic acid by this synthetic route, which relies heavily on a thiourea‐catalyzed enantioselective Michael addition of acetone to tert‐butyl (2‐nitrovinyl)carbamate and an anti‐selective Henry reaction of the resulting Michael adduct with an aldehyde prepared from D ‐araboascorbic acid. The synthetic procedures are scalable, as evident from the preparation of more than 3.5 g of zanamivir.