A concise stereoselective synthesis of pterosin B

Pterosin B is a naturally occurring indanone found in bracken fern (Pteridium aquilinum) that displays a variety of interesting pharmacological properties, but for which few stereoselective syntheses exist. Herein we describe a 7-step stereoselective synthesis of (2R)-pterosin B via 6-bromo-5,7-dimethylindan-1-one whose structure was confirmed by NOE analysis and structure determination by X-ray crystallography. The hydroxyethyl chain was introduced via a Suzuki-Miyaura cross-coupling reaction. The 2-methyl group was introduced stereoselectively by methylation of a SAMP [(S)-1-amino-2-methoxymethyl)pyrrolidine] hydrazone and the chiral auxiliary was removed to produce (2R)-pterosin B. The structure of pterosin B was confirmed by specific rotation and structural determination by X-ray crystallography.     

Stereoselective epoxidation of 4-fluoro-4-nitrocyclohexenes

Novel fluorinated α-epoxycyclohexanes were synthesized in up to 96% yields by epoxidation of the Diels–Alder adducts of β-fluoro-β-nitrostyrenes and 2,3-dimethylbuta-1,3-diene. The epoxidation with m-chloroperoxybenzoic acid and subsequent hydrolysis into diols were found to proceed in a highly stereoselective manner.     

Stereoselective synthesis of tetrahydronaphthocyclobuta[1,2-d]pyrimidinediones from 5-fluoro-1,3-dimethyluracil and naphthalenes

Upon UV-irradiation in the presence of piperylene, 5-fluoro-1,3-dimethyluracil (5-FDMU) couples with naphthalenes having either an electron-withdrawing group or an electron-donating group by way of 1,2-cycloaddition via mode selectivity to give the corresponding naphthocyclobutapyrimidines regio- and stereo-selectively.     

Synthesis and cross coupling of a highly substituted 2-pyridylboronate: application to the large scale synthesis of a mineralocorticoid antagonist

The large scale synthesis of functionalized 2-pyridylboronate 8 and optimization of its Suzuki-Miyaura coupling to chloropyrazoline (R)-7 to provide a scalable synthesis of mineralocorticoid antagonist (R)-1 is described.     

Facile stereoselective synthesis of 1,3-disubstituted-4-trichloromethyl azetidin-2-ones

The highly stereoselective synthesis of 1,3-disubstituted-4-trichloromethyl azetidin-2-ones by the [2+2] cycloaddition of ketenes with imines derived from chloral is described.     

Stereoselective generation of (E)- and (Z)-2-fluoroalkylidene-type carbenoids from (2-fluoro-1-alkenyl)iodonium salts and their application for stereoselective synthesis of fluoroalkenes

Alkylidene-type carbenoids, generated from (Z)- or (E)-(2-fluoro-1-alkenyl)iodonium salts by treatment with LDA, reacted with trialkylboranes to give (E)- or (Z)-(fluoroalkenyl)boranes stereoselectively. The resulting (fluoroalkenyl)borane can be used for the selective synthesis of (E)- or (Z)-fluoroalkenes, (E)- or (Z)-fluoroiodoalkenes, and alpha-fluoroketones. [reaction: see text]     

Stereoselective synthesis of 3-mono- and 1,3-disubstituted 4-phenyl-1,2,3,4-tetrahydroisoquinolines

(1S,2S)-(+)-Thiomicamine was transformed in high yield and with high diastereoselectivity into (3R,4R)-4-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and enantiomerically pure (3R,4R)-3-hydroxymethyl-4-phenyl- and (1R,3R,4R)-3-hydroxymethyl-1-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline derivatives.     

Palladium-catalyzed cross-coupling of vinylic tellurides and potassium vinyltrifluoroborate salt: synthesis of 1,3-dienes

Here we report an ultrasound-assisted synthesis of stereodefined 1,3-dienes by Suzuki-Miyaura cross-coupling reactions of vinylic tellurides and potassium β-styryl trifluoroborate salt.     

Highly stereoselective total synthesis of fully hydroxy-protected mycolactones A and B and their stereoisomerization upon deprotection

Unprecedentedly efficient and highly (≥98 %) stereoselective syntheses of mycolactones A and B side chains relied heavily on Pd‐catalyzed alkenylation (Negishi version) and were completed in 11 longest linear steps from ethyl (S)‐3‐hydroxybutyrate in 12 % and 11 % overall yield, respectively, roughly corresponding to an average of 82 % yield per step. The synthesis of mycolactone core was realized by using Pd‐catalyzed alkenyl? allyl coupling and an epoxide‐opening reaction with a trialkylalkenylaluminate as key steps. Fully hydroxy‐protected mycolactones A and B of ≥98 % isomeric purity were synthesized successfully for the first time. However, unexpected 4:3–5:4 inseparable mixtures of mycolactones A and B were obtained upon deprotection.     

A one-pot,multi-component reaction cascade for the rapid synthesis of diversely functionalized heteroaryl methyl substrates

A novel one-pot, “green” protocol to rapidly access pharmaceutically relevant heteroaryl methyl substrates is described. This process allows for a tandem S_N2/Suzuki-Miyaura reaction or Sonogashira reaction across a breadth of chemical diversity with yields ranging between 31 and 87% for the tandem Suzuki-Miyaura process and 50–66% for the tandem Sonogashira process. This procedure tolerates S, N, and O heteroatom linkers and is amenable for both rapid and robust lead development screening. In addition, T-type and N-type calcium channel blocker (15) was synthesized in 43% yield using this methodology which stands as an improvement in both yield and reaction time of the previously reported synthesis. The one-pot protocol also allows for the inclusion of greater chemical diversity within the scaffold of 15.     

Stereoselective synthesis and transformations of pinane-based 1,3-diaminoalcohols

A library of pinane-based 1,3-diaminoalcohols and 5-aminomethyloxazolidin-2-ones was developed from commercially available (1R)-(?)-myrtenol which was transformed to N-trichloroacetyl protected allyl amine via Overmann rearrangement followed by stereoselective epoxidation with mCPBA resulting in key intermedier epoxy-amine. In order to obtain the diaminoalcohol moiety, aminolysis and azidolysis of the oxirane ring was performed. The cleavage of the oxirane ring proceeded regioselectively, affording N-trichloroacetyl protected 1,3-diaminoalcohols and oxazolidin-2-ones, which were obtained also via a thermal cyclisation. Since N deprotection of diaminoalcohols was unsuccessful under varied conditions, the protecting group was changed and Boc-protected analogues were synthesised. In this case, removal of the Boc protecting group was successful resulting in the planned diamino alcohols. An unexpected extreme δ Me_α-9 value (0.11 ppm) was measured for the dibenzylaminomethyl-substituted oxazolidine-2-one, and the stereostructure was refined by means of DFT geometry optimization. The obtained potential catalysts were applied in the test reaction of benzaldehyde and diethylzinc with low to moderate enantioselectivities (up to 74% ee).     

Cascade iodination-fluorination synthesis of 2-fluorothiophene and 5-fluoro-2-thienyliodonium salts

The first synthesis of fluorine-containing 2-thienyliodonium salts was accomplished using cascade iodination-fluorination. According to this methodology, thiophene is first converted to bis(2-thienyl)iodonium hexafluorophosphate using an electrophilic iodination reaction. Upon heating with potassium fluoride, this salt undergoes regioselective fluorination producing 2-fluorothiophene. 2-Fluorothiophene is then iodinated again to yield fluorothienyliodonium salts.     

Regio- and stereoselective microwave-assisted synthesis of 5-alkyl-4-alkenyl-4-phenyl-1,3-oxazolidin-2-ones

Chiral symmetrical alk-2-yne-1,4-diols have been stereoselectively transformed into 5-alkyl-4-alkenyl-4-phenyl-1,3-oxazolidin-2-ones, which are precursors of quaternary α-amino β-hydroxy acids. The key step was the cyclization of the bis(tosylcarbamates) of 2-phenylalk-2-yne-1,4-diols, easily obtained from the starting chiral diols. These cyclizations were accomplished with complete regioselectivity and up to 92:8 dr in the presence of catalytic amounts of Ni(0) or Pd (II) derivatives under microwave heating.     

Total synthesis of mycestericin A and its 14-epimer

The total synthesis of mycestericin A (1) and its 14-epimer 34 is described herein. The Overman rearrangement of an allylic trichloroacetimidate derived from l-tartrate generated a tetra-substituted carbon with nitrogen and subsequent stereoselective transformations afforded the highly functionalized left-half segment, vinyl iodide. Cross-coupling of the vinyl iodide with a chiral organometallic species synthesized from d-tartrate under the Negishi or Suzuki-Miyaura coupling conditions, followed by deprotection, completed the total synthesis of 1. The 14-epimer of mycestericin A was also synthesized, and a comparison of [α]_D values of peracetyl γ-lactone derivatives of mycestericin A and its 14-epimer as well as degradation studies of 1 and 34 fully confirmed the proposed absolute structure of mycestericin A.     

Methodology for the synthesis of 1,2-disubstituted arylnaphthalenes from α-tetralones

α-Tetralones were initially converted into 1-bromo-dihydronaphthalene-2-carbaldehydes and 1-bromo-naphthalene-2-carbaldehydes. These precursors were then subjected to Suzuki coupling reactions to afford 1,2-disubstituted aryldihydronaphthalenes and 1,2-disubstituted arylnaphthalenes, respectively. The former products were oxidized with DDQ to give 1,2-disubstituted arylnaphthalenes.     

Total synthesis of lamellarins D, L, and N

Total synthesis of cytotoxic marine alkaloids, lamellarins D, L, and N, has been achieved by using Hinsberg-type pyrrole synthesis and palladium-catalyzed Suzuki-Miyaura coupling of the 3,4-dihydroxypyrrole bistriflate 6 as the key reactions. The total yields of lamellarins D, L, and N from the common intermediate 6 are 54, 58, and 50%, respectively.     

Synthesis and characterization of 1-phenyl-3-alkylbenzimidazol-2-ylidene salts and their catalytic activities in the Heck and Suzuki cross-coupling reactions

The synthesis and characterization of 1-phenyl-3-alkyl-substituted carbene precursors that were prepared from 1-phenyl substituted benzimidazole and various alkyl halides are reported. The new benzimidazolium salts (1a–e) were characterized by ¹H NMR, ¹³C NMR, FT-IR spectroscopic methods and elemental analyses. New in situ generated palladium-benzimidazolium complexes were tested for catalytic activity in the Mizoroki-Heck and Suzuki-Miyaura cross-coupling reactions.     

Diastereoselective synthesis of 6-functionalized 4-aryl-1,3-oxazinan-2-ones and their application in the synthesis of 3-aryl-1,3-aminoalcohols and 6-arylpiperidine-2,4-diones

Halocyclocarbamation of benzyl N-(1-phenyl-3-butenyl)carbamates afforded 6-functionalized 4-aryl-1,3-oxazinan-2-ones with moderate to excellent diastereoselectivity depending on the N-substituent. Importantly, in contrast to reported cyclocarbamations of homoallylic carbamates, which are generally trans-diastereoselective, cyclization of N-unsubstituted Cbz-protected homoallylamines led to cis-1,3-oxazinan-2-ones, predominantly. The use of N-benzylated and in situ prepared N-silylated derivatives resulted however in trans-selectivity. Transition states are proposed to explain the stereochemical influence of the N-substituent on the cyclocarbamations. The functionalized 1,3-oxazinan-2-ones could be further elaborated towards biologically or synthetically important 6-arylpiperidine-2,4-diones and 3-aryl-1,3-aminoalcohols.     

A short synthesis of lennoxamine via ynamides

Lennoxamine was synthesized in eight steps from 2,3-dimethoxybenzoic acid via an intermediate ynamide by using palladium-catalyzed Heck-Suzuki-Miyaura domino reactions.