Michael addition-based cyclization strategy in the total synthesis of Lycopodium alkaloids

Lycopodium alkaloids, a unique family of biologically important natural products isolated and characterized from various species of Lycopodium(sensu lato), have attracted extensive attention from chemists and pharmacists in the past three decades. Michael addition-based cyclization has been successfully employed as an elegant and efficient ring-construction protocol of constructing key cyclohexanone intermediates in the total synthesis of Lycopodium alkaloids. This mini-review chooses and summarizes several representative total syntheses of various Lycopodium alkaloids in which intramolecular Michael addition severed as the key methodology.

A gram-scale laboratory synthesis of Annonaceous acetogenin mimic AA005

AA005(1),a potent anticancer mimicking molecule of natural Annonaceous acetogenin,features a central C_(2)-symmetric triglycol moiety and three stereogenic centers.To support ongoing animal studies,a scalable 10-step synthesis of AA005(1) has been studied,optimized and accomplished in this work,starting from commercially available economic materials ethylene glycol and(R)-epichlorohydrin.A regio-and stereo-controlled BF_(3)·Et_(2)O-promoted epoxide opening of(R)-epichlorohydrin with ethylene glycol was investigated,optimized and successfully applied to the scalable preparation of the crucial fragment 6 a with C_(2)-symmetry.Further successive epoxide openings elaborated both two side chains and the whole skeleton with proper nucleophiles and electrophiles.Comparison and optimization of the reaction sequences finally led to completion of a new multi-gram synthesis ofAA005(1) with satisfactory enantiomeric and diastereomeric purity.

Scalable Cu(Ⅱ)-mediated intramolecular dehydrogenative phenol-phenol coupling:Concise synthesis of enantiopure axially chiral homo-and hetero-diphenols

An intramolecular dehydrogenative homo-and hetero-coupling of phenols has been successfully developed for quick preparation of enantiopure axial diphenols under mild Cu(Ⅱ)-mediated conditions,using((4 S,5 S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol as the chiral auxiliary.The commercially available(R)-α-met hylbenzy la mine was identified as the best amine ligand for Cu(Ⅱ) in the reactions.A variety of homo/hetero bis-dihydroxylbenzoate substrates were examined,affording the corresponding axially chiral diphenols with satis factory to excellent diastereomeric ratios,and a representative scalable preparation was also attempted.A formal synthesis of natural product(+)-deoxyschizandrin has been achieved in this work using one axially chiral diphenol as the synthetic intermediate.

An Eight-Step Total Synthesis of Pyrroloquinolone-Type LycopodiumAlkaloid via a Tandem Annulation Approach

Summary of main observation and conclusion A total synthesis of 6,7,9,10,12,12o-hexahydro-2-methyl-(2R/4αS,12α5)-2H,5H-benzo[e]pyrrolo-[3,2;l-ij]quinolone-4;ll(1H,3H)-dione(1),a unique pyrroloquinolone-type Lycopodium alkaloid containing a complex 6/6/6/5 tetracyclic core,has been disclosed in eight steps and 38%overall yield.The reported synthesis features a short,efficient synthesis of the crucial multi-substituted cyclohexanone intermediate with three stereogenic centers,and one-pot generation of the complex 6/6/6/5 tetracyclic core in a single tandem step.

An Artemisinin Derivative ART1 Induces Ferroptosis by Targeting the HSD17B4 Protein Essential for Lipid Metabolism and Directly Inducing Lipid Peroxidation

Artemisinin and its derivatives,commonly known as antimalarial drugs,have gradually come to be regarded as potential antitumor agents,although their cytotoxic efficacy and mechanisms of action remain to be settled.Herein,we report that an artemisinin analog,ART1,can potently induce ferroptosis in a subset of cancer cell lines.Structure–activity relationship(SAR)analysis reveals that both the endoperoxide moiety and the artemisinin skeleton are required for the antitumor activity of ART1.Aided with ART1-based small-molecule tools,chemical proteomic analysis identified the HSD17B4 protein as a direct target of ART1.HSD17B4 resides in peroxisomes and is an essential enzyme in the catabolism of very-long-chain fatty acids.Our results demonstrate that ART1 initiates ferroptosis through selective oxidation of the fatty acids in peroxisomes by hijacking the HSD17B4 protein without disturbing its enzymatic function,providing a promising mechanism to develop therapeutics for cancer treatment.

Recent advances in direct dehydrogenative biphenyl couplings

Biphenyl moiety represents a unique structural motif of many natural and unnatural products with biological interests, and dehydrogenative couplings of two aryl C–H bonds under oxidative conditions is unambiguously the most efficient and direct preparation of these compounds. However, higher oxidation potential of benzene derivatives makes such oxidative couplings much more difficult than other arenes. Only very limited advances have been achieved on direct formation of the crucial C–C bond between two phenyl derivatives by dehydrogenative phenyl coupling in the last two decades. This article briefly summarized and commented a number of representative recent achievements in this attractive field, including homo-, cross-and intramolecular rearrangement and couplings, as well as their applications in organic synthesis.