Total synthesis of (-)-xyloketal A

[reaction: see text] The first total synthesis of the C(3)-symmetric and biologically active natural product, (-)-xyloketal A, has been accomplished in one step from phloroglucinol (1,3,5-trihydroxybenzene) and (4R)-3-hydroxymethyl-2,4-dimethyl-4,5-dihydrofuran. This remarkably direct process involved an exceedingly facile and diastereoselective boron trifluoride diethyl etherate-promoted triple electrophilic aromatic substitution reaction that was coupled to three bicyclic acetal formation reactions.     

A concise total synthesis of (-)-cylindricine C through a stereoselective intramolecular aza-[3 + 3] annulation strategy

[reaction: see text] An enantioselective total synthesis of (-)-cylindricine C is described, featuring a diastereoselective intramolecular aza-[3 + 3] annulation strategy and an interesting halohydrin formation of the C4-5 olefin for construction of C4-ketone. This work provides a unique approach to this family of natural products.     

The first total synthesis of (+/-)-ingenol

The first total synthesis of (+/-)-ingenol has been achieved. The key features of the synthesis include the use of a highly diastereoselective Michael reaction to fix the C-11 methyl stereochemistry and the incorporation of the dimethylcyclopropane via diastereoselective carbene addition to the Delta13,14 olefin. The intramolecular dioxenone photoaddition-fragmentation sequence leads to the establishment of the critical C-8/C-10 trans intrabridgehead stereochemistry, a central challenge in the synthesis of ingenanes. The completion of the synthesis proceeds using the C-6alpha hydroxymethyl group as the sole handle for oxidation of seven contiguous carbon centers.     

Spontaneous Nef reaction of 3-aryl-2-(diethoxyphosphoryl)-4-nitroalkanoic acids

Spontaneous Nef reaction of primary and secondary 3-aryl-2-(diethoxyphosphoryl)-4-nitroalkanoic acids has been observed for the first time. The reaction provides a general and effective, highly diastereoselective synthesis of 3-(diethoxyphosphoryl)-1-hydroxysuccinimides and 2-(diethoxyphosphoryl)-4-oxoalkanoic acids.     

Synthesis of the 6-6-6 tricyclic skeleton of the anti-influenza A diterpene wickerol A

A five-step synthesis of the 6-6-6 tricyclic skeleton of the diterpene wickerol A is described. The synthesis features a diastereoselective d-proline-mediated Robinson annulation and N-heterocyclic carbene-catalyzed Stetter reaction as key transformations to give the tricyclic carbon skeleton of this promising anti-influenza A natural product.     

Diastereoselective cationic tandem cyclizations to N-heterocyclic scaffolds: total synthesis of (-)-dysibetaine PP

[reaction: see text] Herein, we report a short and diastereoselective synthesis of the natural product (-)-dysibetaine PP. The key step in the synthetic sequence is a novel highly diastereoselective tandem-cyclization reaction of an enantiomerically pure dipeptide. This cyclization methodology is applied in the synthesis of a broader range of N-heterocyclic scaffolds.     

A concise, enantioselective approach to (-)-quinic acid

[reaction: see text] An expedient, enantioselective synthesis of a key precursor to (-)-quinic acid has been achieved from an ephedrine-derived morpholine-dione. The salient features of this approach are a highly diastereoselective conversion of the dione to a dialkenyl morpholinone and a subsequent ring-closing metathesis reaction. Removal of the ephedrine portion generates an enantiomerically enriched hydroxycyclohexene carboxamide that is readily converted to the quinic acid precursor.     

Highly efficient approach to orthogonally protected (2S,4R)- and (2S,4S)-4-hydroxyornithine

[reaction: see text] A concise stereoselective approach to both orthogonally protected (2S,4R)- and (2S,4S)-4-hydroxyornithine, key constituents of the biphenomycin- and clavalanine-type antibiotics, respectively, has been developed. The approach is based on bis(oxazoline) copper(II)-complex-catalyzed diastereoselective Henry reactions of nitromethane with the homoserine-derived aldehyde 6. The synthesis of this versatile chiral building block has been markedly improved.     

Asymmetric synthesis of (+)-1-epiaustraline and attempted synthesis of australine

A diastereoselective synthesis of the pyrrolizidine alkaloid, (+)-1-epiaustraline has been achieved via a diastereoselective syn-dihydroxylation of a pyrrolo[1,2-c]oxazol-3-one precursor that was readily prepared by a RCM reaction. Attempts to extend this methodology to the synthesis of australine were not successful since the final pyrrolidine ring closure to produce the desired pyrrolizidine of the target molecule was not productive.     

Total synthesis of (+/-)-hapalindole Q

[reaction: see text] The total synthesis of the antibacterial and antimycotic alkaloid hapalindole Q has been achieved in eight steps and 12.4% overall yield. The key step involves a regio- and diastereoselective Diels-Alder reaction to afford a bicyclo[2.2.2]oct-2-ene. This cycloadduct was subsequently dihydroxylated, cleaved, and converted to the natural product.     

Asymmetric total synthesis of (-)-callystatin A and (-)-20-epi-callystatin A employing chemical and biological methods

An efficient asymmetric total synthesis of the potent cytotoxic marine natural product (-)-callystatin A and its 20-epi analogue has been achieved. The synthetic pathway involved the preparation of three fragments to be coupled with each other at the end of the route. The first fragment 3 was obtained using a biocatalytic enantioselective reduction of a 3,5-dioxocarboxylate as the key step. For the second intermediate 4 the asymmetric alpha-alkylation of an O-protected derivative of 4-hydroxybutanal was performed exploiting the SAMP/RAMP hydrazone alkylation methodology, and followed by a highly Z-selective Horner-Wadsworth-Emmons reaction under modified conditions. For the synthesis of the polypropionate fragment 5 a diastereoselective syn-aldol reaction was employed between a chiral ethyl ketone and an alpha-substituted chiral aldehyde, both prepared in enantiopure form again by means of the asymmetric alkylation of their corresponding RAMP hydrazones. Finally, these three building blocks were coupled using highly E-selective Wittig reactions via allyltributylphosphonium ylides to afford the target compounds after a final oxidation/deprotection sequence.     

Synthetic Studies of Didemnaketals Analogue-Construction of the Intermediate (3S,5S,6R)-3,7-Dimethyl-5,6,7-trihydroxy-octanal

TheDidemnaketalsAandBhavebeenreportedtobesignificantinhibitorstoHlV-protease'.Inconnectionwiththetotalsynthesisofthiskindofcompounds,ourrecentresearchinterestisfocusedontheirsyntheticstudiesaswellassynthesisofananaloguel,whichincorPoratedthekeyspiroketalmoietyofthedidemnaketalsAandB.Basedontheretrosyntheticconsideration(Schemcl),thelinearintermediate2wouIdbeconstructedfrom3and4.Furthermore,4wouldbesynthesizedfrom( )-PuIegone5.Wehereinreportedastereoselectivesyntheticprocedureforthe(3S,5S…     

Diastereoselective synthesis of (2S,5R)-5-hydroxypipecolic acid and 6-substituted derivatives

[reaction: see text] Herein, we report a diastereoselective synthesis of the natural product (2S,5R)-5-hydroxypipecolic acid and 6-substituted derivatives thereof. The key step in the synthetic sequence is a novel highly diastereoselective epoxidation reaction of an enantiomerically pure cyclic enamide intermediate.     

Total synthesis and assignment of the double-bond position and absolute configuration of (-)-pyrinodemin A

[structure: see text] The first asymmetric total synthesis of a structurally novel cis-cyclopent[c]isoxazolidine alkaloid, (-)-pyrinodemin A (3), which exhibits potent cytotoxicity, has been accomplished through a highly diastereoselective intramolecular nitrone-olefin cycloaddition reaction as the key step. Thus, it has been found that the hitherto unknown absolute configuration of pyrinodemin A is as indicated in the structural formula 3.     

Studies on the synthesis of (-)-spinosyn a: application of the steric directing group strategy to transannular Diels-Alder reactions

A highly diastereoselective and enantioselective synthesis of the decahydro-as-indacene nucleus 12 of (-)-spinosyn A (1) is reported. By implementing the steric directing group strategy, tricyclic lactone 37 was produced from a remarkably diastereoselective transannular Diels-Alder reaction of lactone 9. The tricyclic core of the natural product was then obtained by using an Ireland-Claisen ring contraction of 37. Reversal of the order of these two steps resulted in an almost complete loss of diastereoselectivity.     

Cover Feature: Stereoselective Domino Semipinacol-Schmidt Reaction: Diastereoselective Synthesis of 7 a-epi-(+)-Lepadiformine C and Formal Synthesis of 7 a-epi-(−)-Lepadiformine A (Eur. J. Org. Chem. 19/2023)

A concise approach has been developed for the diastereoselective synthesis of the azatricyclic core of (−)-7 a-epi-lepadiformine A ( 8 a ) and (−)-7 a-epi-lepadiformine C ( 8 b ) using stereoselective domino semipinacol-Schmidt reaction as a key step. In presence of TiCl₄, the oxaspiropentane-azide derivatives underwent stereoselective domino cyclization to furnish the corresponding angularly fused azatricyclic cores in very good yields. Moreover, azatricyclic core of (−)-7 a-epi-lepadiformine A has also been realized, in a stepwise manner, through the intramolecular Schmidt reaction of azido-spirocyclobutanone intermediate. The synthetic utility of domino semipinacol-Schmidt reaction is further shown in the diastereoselective synthesis of (+)-7 a-epi-lepadiformine C ( 7 ).     

Vinyl quinones as Diels-Alder dienes: concise synthesis of (-)-halenaquinone

A concise asymmetric synthesis of (-)-halenaquinone is described. The synthesis features a diastereoselective Heck cyclization to set a quaternary center as well as a novel intramolecular inverse-electron-demand Diels-Alder reaction involving a vinyl quinone. The synthesis is highly convergent and features a minimal amount of protecting group manipulations.     

N-isopropylsulfinylimines as useful intermediates in the synthesis of chiral amines: expeditive asymmetric synthesis of the calcimimetic (+)-NPS R-568

An efficient and high-yielding approach for the asymmetric synthesis of calcimimetic (+)-NPS R-568 (1) has been developed. The key step of the synthesis is the highly diastereoselective addition of methyl Grignard to the (SS,E)-N-(3-methoxybenzylidene)-2-propanesulfinamide [5(S)], which afforded a single diastereoisomer in high yield in short reaction time.     

Total Synthesis of (+)-7-epi-Tarchonanthuslactone via a Chelation-Controlled Mukaiyama Aldol Reaction

An asymmetric total synthesis of (+)-7-epi-tarchonanthuslactone was achieved from commercially available methyl (R)-3-hydroxybutyrate. The key step employed a diastereoselective chelation-controlled Mukaiyama aldol reaction to construct the chiral hydroxyl group at the C-5 position.     

De novo asymmetric synthesis of homoadenosine via a palladium-catalyzed N-glycosylation

[reaction: see text] A highly stereoselective synthesis of l-2-deoxy-beta-ribo-hexopyranosyl nucleosides from 6-chloropurine and Boc-protected pyranone has been developed. Our approach relies on the iterative application of a palladium-catalyzed N-glycosylation, diastereoselective reduction, and reductive 1,3-transposition. This strategy is amenable to prepare various natural and unnatural hexopyranosyl nucleosides analogues.