Synthesis and biological evaluation of tetrahydroisoquinoline derivatives as potential multidrug resistance reversal agents in cancer

Tetrahydroisoquinoline derivatives were synthesized and their multidrug resistance reversal activities were evaluated in vitro. The results showed that some of the synthetic compounds had higher multidrug resistance （MDR） reversal activities than verapamil.     

Atom-economic and stereoselective syntheses of the ring a and B subunits of the bryostatins

This article describes chemoselective and atom-economic methods for the stereoselective assembly of the ring A and B subunits of bryostatins. A Ru-catalyzed tandem alkene-alkyne coupling/Michael addition reaction was developed and applied to the synthesis of bryostatin ring B. We explored an acetylide-mediated epoxide-opening/6-exo-dig cyclization route to access the bryostatin ring A, although ring A was eventually furnished through an acid-catalyzed tandem transketalization/ketalization sequence. In addition, a dinuclear zinc-catalyzed methyl vinyl ketone (MVK) aldol strategy was evaluated for the construction of the polyacetate moiety. Utilization of these methods ultimately led to the rapid assembly of the northern bryostatin fragment containing both the ring A and B subunits.     

Studies directed toward the synthesis of rhizopodin: stereoselective synthesis of the C1-C15 fragment

A stereoselective synthesis of the C1-C15 fragment of a G-actin binding natural macrodiolide, rhizopodin was achieved using, as key steps, highly stereoselective acetate aldol reactions to build the C1-C7 fragment, one pot oxazole synthesis and an asymmetric Keck allylation reaction to build the C8-C15 fragment and finally, a Stille reaction to couple both the fragments.     

The fluoride ion-induced intramolecular conjugate addition of propargylsilanes to dihydropyridones. A novel method for the stereoselective construction of azabicyclic ring systems

The fluoride ion-induced intramolecular conjugate addition of propargylsilanes to dihydropyridones is reported. Our results revealed that tetrabutylammonium triphenyldifluorosilicate (TBAT), an air-stable, non-hygroscopic fluoride ion source, catalyzes cyclocondensation to provide the corresponding 1-vinylidene indolizidines in a high yield as single isomers, while Lewis acid catalysts were ineffective. The scope of this method was further investigated in the reactions leading to compounds with larger ring size. In these cases dihydropyridones with the propargylsilane located in the side-chain underwent cyclization to give 9-vinylidene quinolizidines with significantly lower yields.     

Studies on the total synthesis of sanglifehrin A: stereoselective synthesis of the C(29)-C(39) fragment

A highly stereoselective synthesis of the C(29)-C(39) fragment of the potent immunosuppressant sanglifehrin A has been accomplished by a sequence involving 16 steps (18% overall yield) from N-propionyloxazolidinone 9. Key steps are a diastereoselective hydroboration, and a diastereoselective epoxidation of an allylic alcohol followed by a 1,5-anti boron-mediated aldol reaction of methyl ketone 4 with chiral aldehyde 5.     

Nucleophilic addition to nitroacrylates: application towards the synthesis of 2,3-dehydroamino acids and 2,3-diamino acids

The addition of the N-pronucleophiles to 2- or 3-nitro-2-alkenoates in the presence of base provided Michael addition products. In the case of 3-nitro compounds, reaction occurred via the formation of α-adducts and the subsequent elimination of nitrous acid to produce olefins with high Z stereoselectivity. 3-Phthalimido-2-nitrocinnamate adduct 8a was converted into 2,3-diamino ester 11a.     

MCASE study of the multidrug resistance reversal activity of propafenone analogs

A database containing 130 propafenone type chemicals which have been tested for their multidrug resistance (MDR) reversal activity was compiled. Using the Multiple Computer-Automated Structure Evaluation (MCASE) program to analyze this database, an underlying relationship between MDR reversal activity and octanol/water partition coefficient was found. An MDR reversal model was created based on this database by the baseline activity identification algorithm (BAIA) of the MCASE program. The main phamacophores relevant to MDR reversal activity were identified.     

Synthetic study of yonarolide: stereoselective construction of the tricyclic core

Stereoselective construction of the tricyclic core of yonarolide (1), a marine norditerpenoid, was achieved. This synthetic route includes a Diels-Alder reaction and an intramolecular aldol condensation. It also involves efficient epimerization through a retro-Michael reaction-Michael addition and will be applicable to the total synthesis of 1.     

Convergent synthesis of the FGHI ring system of yessotoxin: stereoselective construction of the G ring

A convergent synthetic route to the FGHI ring system of yessotoxin, a marine ladder polyether, has been developed. The synthesis features convergent coupling of the diol and the aldehyde to form α-cyano ethers via acetal formation followed by ring closing metathesis and reductive etherification to construct the oxocane ring G and tetrahydropyran ring H, respectively. The β-methyl group on the G ring was stereoselectively introduced by alkylation of the corresponding ketone.     

Enantioselective total synthesis of octalactin a using asymmetric aldol reactions and a rapid lactonization to form a medium-sized ring

Octalactin A, an antitumor agent containing an eight-membered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn(II) complex. The medium-sized lactone part was effectively constructed by way of a new and rapid mixed-anhydride lactonization using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine 1-oxide (DMAPO). The use of only 5 mol % of DMAP or 2 mol % of DMAPO rapidly promoted formation of the medium-sized ring of the octalactin, demonstrating the remarkable efficiency of the new lactonization protocol.     

A stereoselective approach to bioactive secolignans: synthesis of peperomin C and its analogues

A stereoselective approach to secolignans is described. The key synthetic strategy involves an asymmetric aldol reaction to control the creation of the stereogenic center at the β-carbon of the target secolignans. In the present work, peperomin C and its analogues, i.e., 2,6-didehydropeperomin C and 2-epi-peperomin C were successfully synthesized in good yields with high stereoselectivities.     

Studies directed toward the total synthesis of pinnatoxin A: synthesis of the 6,5,6-dispiroketal (BCD ring) system by double hemiketal formation/hetero-Michael addition strategy

An efficient, highly stereoselective synthesis of the C10–C26 portion of pinnatoxin A has been achieved, wherein the key step is a highly stereoselective construction of the 6,5,6-dispiroketal (BCD ring) system by an intramolecular hetero-Michael addition of a hemiketal alkoxide reversibly formed under the influence of lithium methoxide.     

Synthesis of the core ring system of awajanomycin from N-Boc-3-methoxycarbonyl-2-pyridinone

Awajanomycin, which was isolated from marine-derived fungus, possesses unique structural features and cytotoxic activity against A549 cells. Due to its unique structure, no total synthesis has yet been reported, and neither the relative stereochemistry nor the absolute configuration has been determined. We report the synthesis of the core ring system of awajanomycin, which includes: (i) regioselective addition of the acetate unit onto C4-position of N-Boc-3-methoxycarbonyl-2-pyridinone; (ii) stereoselective installation of a hydroxyl group on C3-position; and (iii) stereo- and regioselective epoxide-opening reaction by Me₃Al.     

Rapid access to the synthesis of polysubstituted δ-lactones via tandem stereoselective conjugate addition/α-alkylation of unsaturated 7,3-lactone-α-d-xylofuranose derivative

α-d-xylo-7,3-Unsaturated lactone, a versatile chiral building block, undergoes Cu-catalyzed conjugated addition with high yield and stereoselectivity. When the conjugated reaction is quenched with a suitable alkyl halide, a tandem stereoselective conjugated/α-alkylation reaction is achieved. Further, selective hydrolysis of the 1,2-O-isopropylidene moiety followed by oxidative cleavage and reduction reaction, afforded the title compounds.     

Scope and limitations of the synthesis of functionalized quinolizidinones and related compounds by a simple precursor approach via addition of lithium allylmagnesates to 2-pyridones and RCM as key steps

The scope and limitations of the simple synthesis of functionalized quinolizidin-4-ones by chemoselective N-alkenylation of NH pyridin-2(1H)-ones (2-pyridones), regioselective addition of lithium allyl(di-n-butyl)magnesates(1-) to N-alkenylpyridin-2(1H)-ones, followed by ring closing metathesis (RCM) is described. A number of functionalizations introduced into quinolizidin-4-one rings demonstrated the high prospect of the strategy proposed in scaffold synthesis. Their extension to the syntheses of pyrido[1,2-a]azepin-4-one and pyrido[1,2-a]azocin-4-one derivatives as well as to spiro-fused compounds is also presented.     

Studies on the synthesis of phorboxazole B: stereoselective synthesis of the C28-C46 segment

A stereoselective synthesis of C28-C46 segment of phorboxazole B is described. Key features of the synthetic route involved the use of 1,3-asymmetric induction of Mukaiyama aldol reaction to construct the stereogenic center at C35, and the employment of metalated oxazole chemistry to prepare the ketal 6.     

Studies on the total synthesis of lactonamycin: synthesis of the CDEF ring system

A concise and efficient synthesis of the tetracyclic CDEF ring system of lactonamycin (1) is described. The key step involved the Lewis acid mediated, intramolecular Friedel-Crafts acylation of carboxylic acid 6 to produce the tetracyclic CDEF core structure of target 1. The synthesis of 6 was carried out using a high-yielding Negishi coupling of benzyl bromide 7 with triflate 8, which was accessible in 11 steps and 31% overall yield on a multigram scale starting from trihydroxy acid 9.     

The synthesis and catalytic activity of the iridium(I) hydroquinone complex [(H2Q)Ir(COD)]

The η⁶-hydroquinone iridium complex [(η⁶-H₂Q)Ir(COD)]BF₄ undergoes facile double deprotonation to the η⁴-quinone anionic analogue. The latter has been shown to be the first example of an iridium complex that catalyzes 1,4 conjugate addition reactions of aryl boronic acids to electron deficient olefins.     

Studies on the synthesis of durhamycin A: stereoselective synthesis of a model aglycone

A stereoselective synthesis of the model aglycone corresponding to the anti-HIV aureolic acids durhamycins A (1) and B (2) is described.