Total synthesis of epoxyquinols A, B, and C and epoxytwinol A and the reactivity of a 2H-pyran derivative as the diene component in the Diels-Alder reaction

Full details of two versions of the total synthesis of epoxyquinols A, B, and C and epoxytwinol A (RKB-3564D) are described. In the first-generation synthesis, the HfCl(4)-mediated diastereoselective Diels-Alder reaction of furan with Corey's chiral auxiliary has been developed. In the second-generation synthesis, a chromatography-free preparation of an iodolactone, by using acryloyl chloride as the dienophile in the Diels-Alder reaction of furan, and the lipase-mediated kinetic resolution of a cyclohexenol derivative have been developed. This second-generation synthesis is suitable for large-scale preparation. A biomimetic cascade reaction involving oxidation, 6pi-electrocyclization, and then Diels-Alder dimerization is the key reaction in the formation of the complex heptacyclic structure of epoxyquinols A, B, and C. Epoxytwinol A is synthesized by the cascade reaction composed of oxidation, 6pi-electrocyclization, and formal [4 + 4] cycloaddition reactions. A 2H-pyran, generated by oxidation/6pi-electrocyclization, acts as a good diene, reacting with several dienophiles to afford polycyclic compounds in one step. An azapentacyclic compound is synthesized by a similar cascade reaction composed of the four successive steps: oxidation, imine formation, 6pi-azaelectrocyclization, and Diels-Alder dimerization.     

Synthesis of the core structure of cruentaren A

The core structure of the macrolactone cruentaren A (1) was prepared via a ring-closing alkyne metathesis reaction. The corresponding ester 33 was constructed from the benzoic acid derivative 14 and the diol 30. As a key step in the synthesis of acid 14, an aldol reaction resulted in the required anti-OH/Me pattern. The anti-configuration in the stereotetrad of diol 30 was established by a Marshall reaction. [reaction: see text].     

A convenient asymmetric synthesis of the octalactin lactone

A facile asymmetric synthesis of the octalactin lactone was developed staring from (R)-cyclohexylideneglyceraldehyde (1). The key step of the synthesis is an In-mediated diastereoselective crotylation of 1 in water, which furnished the building blocks with the required stereochemistry under operationally simple conditions. Their conversion to the appropriate intermediates, invertive esterification and a ring closing metathesis reaction furnished the target compound.     

Total Synthesis of (−)‐Glaucocalyxin A

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃‐mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (?)‐glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.     

Use of a tandem Prins/Friedel-Crafts reaction in the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids: formal synthesis of (-)-haouamine A

A tandem Prins/Friedel-Crafts reaction useful for the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids and a formal synthesis of (-)-haouamine A are described.     

Total synthesis of (-)-fusarisetin A and reassignment of the absolute configuration of its natural counterpart

The first total synthesis of (-)-fusarisetin A, the enantiomer of naturally occurring acinar morphogenesis inhibitor (+)-fusarisetin A, was accomplished in 13 steps, leading to the reassignment of the absolute configuration of the natural product. The synthesis featured a Lewis acid-promoted intramolecular Diels-Alder reaction, a Pd-catalyzed O→C allylic rearrangement, a chemoselective Wacker oxidation, and a Dieckmann condensation/hemiketalization cascade.     

Total synthesis of spirotenuipesines A and B

Spirotenuipesines A and B, isolated from the entomopathogenic fungus Paecilomyces tenuipes by Oshima and co-workers, have been synthesized. The synthesis features the highly stereoselective construction of two vicinal all-carbon quaternary centers (C(5) and C(6)) via an intramolecular cyclopropanation/radical initiated fragmentation sequence and a diastereoselective intermolecular Diels-Alder reaction between alpha-methylenelactone dienophile 20 and synergistic diene 6a. Installation of the C(9) tertiary alcohol occurred via nucleophilic methylation. An RCM reaction to produce a tetrasubstituted double bond in the presence of free allylic alcohol and homoallylic oxygenated functional group is also described. This route shortened the synthesis of 11 from 9 steps to 3 steps. We have further developed a strategy to gain access to optically active spirotenuipesines A and B through the synthesis of enantioenriched 10 from commercially available R-(-)-epichlorohydrin.     

Tandem oxidative dearomatization/intramolecular Diels-Alder reaction for construction of the tricyclic core of palhinine A

A concise construction of the 6/6/5 tricyclic core of Lycopodium alkaloid palhinine A (1) has been accomplished. The developed synthetic strategy featured a tandem oxidative dearomatization/intramolecular Diels-Alder reaction to construct C/D rings and an intramolecular 5-exo-trig radical cyclization to install the B ring of palhinine A (1). The developed approach paves the way for the total synthesis of palhinine A (1).     

Total synthesis of the cyanolide A aglycon

The synthesis of the potent molluscicide cyanolide A has been achieved in 10 steps without the use of protecting groups. The synthesis features a key Sakurai macrocyclization/dimerization reaction that simultaneously forms both tetrahydropyran rings and the macrocycle of the natural product.     

A highly convergent cascade cyclization to cis-hydrindanes with all-carbon quaternary centers and its application in the synthesis of the aglycon of dendronobiloside A

An efficient and versatile ZnBr(2)-catalyzed Diels-Alder/carbocyclization cascade reaction has been developed for construction of highly functionalized cis-hydrindanes (70-96% yields with high diastereoselectivity), and it has been successfully utilized in the synthesis of the aglycon of dendronobiloside A.     

Nature-inspired total synthesis of (-)-fusarisetin A

A concise, protecting group-free total synthesis of (-)-fusarisetin A (1) was efficiently achieved in nine steps from commercially available (S)-(-)-citronellal. The synthetic approach was inspired by our proposed biosynthesis of 1. Key transformations of our strategy include a facile construction of the decalin moiety that is produced via a stereoselective IMDA reaction and a one-pot TEMPO-induced radical cyclization/aminolysis that forms the C ring of 1. Our route is amenable to analogue synthesis for biological evaluation.     

A facile one-pot protocol for the synthesis of tetrazolyl-tetrahydroisoquinolines via novel domino intramolecular cyclization/Ugi-azide sequence

A facile one-pot, four-component domino reaction between 2-(2-bromoethyl)benzaldehyde, isocyanide, amine, and azide for the synthesis of tetrazolyl-tetrahydroisoquinoline derivatives has been developed. The reaction sequence involves intramolecular replacement of halide by iminium nitrogen followed by Ugi-azide reaction. The reaction is catalyst/additive free and takes place under ambient conditions with short reaction times to furnish products in good to excellent yields.     

A chemoenzymatic total synthesis of the phytotoxic undecenolide (-)-cladospolide A

An eleven-step synthesis of the title compound (1) from biocatalytically-derived and enantiomerically pure 'building blocks' alcohol (R)-(-)-9 and ester 13 is described. Attempts to construct the twelve-membered lactone ring of cladospolide A in a direct manner by using a ring-closing metathesis (RCM) reaction failed. However, a ten-membered lactone 19, could be constructed by such means and this was then subject to a two-carbon homologation sequence involving, inter alia, Wadsworth-Horner-Emmons and Yamaguchi lactonisation reactions in the closing stages of the synthesis. The impact of substituent stereochemistries and protecting groups on the RCM reaction leading to various ten-membered lactones is also described.     

Concise formal synthesis of (+)-pyripyropene A

A concise enantioselective synthesis of A/B bicyclic segment of naturally occurring α-pyrone meroterpenoid pyripyropene A is achieved in 9 steps (LLS) and 7.5% yield starting from R-(?)-carvone. The significant points of the synthesis include: (1) an intramolecular 1, 3-dipolar cycloaddition reaction to construct the A ring and assemble C4 quaternary carbon stereocenter as well; (2) reductive cleavage of the oxazole motif utilized Raney Ni/B(OCH₃)₃.     

A novel strategy for the synthesis of medium-sized lactams

[reaction: see text] A novel method for the synthesis of medium-sized lactams based on an auxiliary-mediated combined tethered/templated strategy is presented. Cyclization by a tethered ring-closing metathesis reaction was followed by a templated transannular aminolysis reaction to give seven- to ten-membered lactams in good yields.     

Total synthesis of (+/-)-deoxypenostatin A. Approaches to the syntheses of penostatins A and B

A short synthesis of (+/-)-deoxypenostatin A (28) has been carried out using the convergent coupling of dienal 11, epoxide 13, and methylenetriphenylphosphorane (17) to prepare trienol 19 in only two steps. The key step is the Yb(OTf)(3)-catalyzed intramolecular Diels-Alder reaction of hydrated trienyl glyoxylate 23, which gives lactone 24 stereoselectively. Elaboration of lactone 24 to enone 27 by an intramolecular Horner-Emmons Wittig reaction and epimerization completes the synthesis of 28. Modest yields of Diels-Alder adducts 45a and 46a could be prepared analogously from MEM ether 44c, but the sensitivity of several of the intermediates precluded the elaboration of 45a to penostatin A (1).     

Asymmetric Synthesis of the Ring A Substructure of Genkwadane A

A practical approach to the asymmetric synthesis of the ring A substructure of genkwadane A, a daphnane diterpenoid, was developed. This synthesis features the Mukaiyama aldol reaction to introduce the quaternary stereogenic center at C4 and VO(acac)₂‐catalyzed Jackson‐Ellman‐Bolm sulfoxidation to deliver the corresponding sulfoxide. The Dieckmann‐type condensation was efficiently promoted by KHMDS and the ring A substructure was finally accomplished through Barton iodination condition.     

A modular, one-pot, four-component synthesis of polysubstituted 1,3-oxazolidines

A modular, one-pot, two-step, four-component synthesis of polysubstituted 1,3-oxzolidines is described. The method comprises two linked domino processes: an organocatalyzed domino reaction of alkyl propiolate and an aliphatic aldehydes and a microwave-assisted amine addition cyclization domino process. An alternative modular, one-pot, three-step, four-component synthesis has also been developed by linking the organocatalyzed domino process to a sequential amine addition/Yb(OTf)(3)-catalyzed enamine cyclization reaction.     

Apoptolidinone A: synthesis of the apoptolidin A aglycone

An efficient stereocontrolled synthesis of apoptolidinone A, the aglycone of apoptolidin A is described. The synthetic strategy relies on a cross coupling between C11/C12 of a northern half (C1-C11) and a southern part (C12-C28) followed by a ring-size selective macrolactonization. Key steps for the introduction of the southern half stereocenters are a stereoselective aldol reaction, a substrate controlled dihydroxylation and a chelation-controlled Grignard/aldehyde addition. The conjugated triene of the northern half was built up successively by E-selective Wittig reactions. L-Malic acid was chosen as the chiral pool source for the C8/C9 stereocenters. The final cleavage of the silyl ethers and the conversion of the C21 methyl ketal into the hemiketal was achieved by HF.pyridine.     

A novel double deprotection-peptide cyclisation procedure and its application to the synthesis of analogues of the cyclic tetrapeptide HC-toxin.

A hydroxide-mediated Fmoc/methyl ester double deprotection procedure followed by an improved bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) cyclisation reaction are reported. This novel methodology was applied to the synthesis of three new HC-toxin analogues.