Efficient syntheses of (±)-hydrangenol, (±)-phyllodulcin and (±)-macrophyllol

In this paper we report on a efficient and flexible synthetic route towards the total syntheses of the dihydrocoumarine derivatives hydrangenol (1), phyllodulcin (1a) and macrophyllol (6b). The syntheses started with a readily available phosphonium salt 2 and suitable modified benzaldehydes 3/3a/3b resulting in 46 to 61% overall yields in three to four-steps sequences. The racemic products could be separated by chiral HPLC. The evidence of the (R)-enantiomer for sweetness could be demonstrated for 1a.     

Chemoenzymatic total syntheses of the linear triquinane-type natural products (+)-hirsutic acid and (−)-complicatic acid from toluene

Total syntheses of title natural products, 1 and 2, have been achieved using the cis-1,2-dihydrocatechol 7 as starting material. Compound 7 is readily obtained in large quantity and enantiomerically pure form through the whole-cell biotransformation of toluene using the genetically engineered micro-organism Escherichia coli JM109 (pDTG601) that over-expresses the enzyme toluene dioxygenase (TDO). Three key chemical steps were employed in these syntheses, the first of which was a high-pressure-promoted Diels-Alder cycloaddition reaction between diene 8 and cyclopentenone to give adduct 9. The second key step was the photochemically promoted oxa-di-π-methane rearrangement of the bicyclo[2.2.2]octenone derivative, 18, of 9 to give 20 while the third key step was the reductive cleavage of the last compound so as to afford the linear triquinane 22. Elaboration of compound 22 to targets 1 and 2 followed conventional and/or established procedures. Single-crystal X-ray analyses were carried out on compounds 10-13, 15, 18, 24, and 34.     

Cycloadditions of NS functions to cyclopentadienones

Cyclopentadienones react with EtO₂CNSO and related NS reagents to provide ready syntheses of 1,2,5-thiadiazolidines (8, 12, 17), diaminosulfanes (11, 13), an aminocyclopentenone (10) and the first unoxidised 1,2,3-oxathiazolidine (16), all in a mechanistically rational manner.     

Photolysis of dicarbonyl(cyclopentadiene)rhodium complexes with a pendent alkyne unit

The syntheses of dicarbonyl[1-(5,5-dimethylhex-3-inyl)-3-phenylcyclopentadienyl]rhodium (7) and its congeners 8 and 9 are reported. Photolysis of 8 and 9 leads to a replacement of one CO ligand by the tethered alkyne unit, yielding 16, and to the dirhodium complexes 17 and 18. The structural assignment of 17 and 18 is based on X-ray studies. The photolysis of 9 leads to 19 and 20.     

Amphiphilic perfluoroalkylated sulfones and sulfonate betaines

Two types of perfluoro alkyl-containing amphiphilic sulfones 7-9 and 13-15, respectively, and sulfonate betaines 23-32 were prepared using 2-[(perfluoroalkyl)methyl]oxiranes (1-3, R_F = C₄F₉, C₆F₁₃, C₈F₁₇) or 3-(perfluoroalkyl)propyl iodides (16 and 17, R_F = C₆F₁₃, C₈F₁₇) as the starting compounds. The overall yields of two-step syntheses were above 90%. The compounds 7-9 were prepared by the reaction of oxiranes 1-3 with 2-sulfanylethan-l-ol and subsequent oxidation of intermediate sulfides. Similarly, the amphiphiles 13-15 were obtained by analogous reaction of oxiranes 1-3 with thiomorpholine and subsequent oxidation of the sulfur atom in the morpholine ring. In the syntheses of betaines 23-32, the starting compounds 1-3 or 16 and 17 were first reacted with dimethylamine followed by the ring-opening reaction of the intermediate fluoroalkyl(dimethyl)amines with propane-1,3- or butane-1,4-sultones.     

Stereoselective total syntheses of (±)-1,14-herbertenediol and (±)-tochuinyl acetate and facile total syntheses of (±)-α-herbertenol, (±)-β-herbertenol and (±)-1,4-cuparenediol

Stereoselective total syntheses of (±)-1,14-herbertenediol (7) and (±)-tochuinyl acetate (10) and facile total syntheses of (±)-α-herbertenol (2), (±)-β-herbertenol (3) and (±)-1,4-cuparenediol (8) have been successfully accomplished involving intramolecular cyclisation of 3-aryl-3-methyl-6-bromohexanoates and in situ methylation of the resulting cyclopentanecarboxylates as the key reactions.     

The enantioselective syntheses of bisabolane sesquiterpenes Lepistirone and Cheimonophyllon E

The synthetic approach to the bisabolane sesquiterpenes Lepistirone 1 and Cheimonophyllon E 2 involves the transformation of (+)-2-carene (5) into the p-menthane furans 8 and 11. Regio- and stereoselective alkylation, and standard reactions complete the enantioselective syntheses.     

Syntheses of 2-arylbenzothiazoles from flash vacuum pyrolyses and photolyses of 2-methylthio-N-(arenylidene)anilines

Flash vacuum pyrolyses and photolyses of 2-methylthio-N-(arenylidene)anilines 2a-h are new and convenient methods for the syntheses of 2-arylbenzothiazoles 1a-h.     

(2-Halogeno-5-pyridyl)dimethyl(oxiran-2-ylmethyl)silanes: New potential building blocks for the synthesis of silicon-containing drugs

(2-Fluoro-5-pyridyl)dimethyl(oxiran-2-ylmethyl)silane (1a) and (2-chloro-5-pyridyl)dimethyl(oxiran-2-ylmethyl)silane (1b) were prepared in two-step syntheses, starting from allylchlorodimethylsilane. Compounds 1a and 1b were characterized by elemental analyses and NMR studies. With the synthesis of 1a and 1b, new potential building blocks for the synthesis of silicon-containing drugs have been made accessible.     

Asymmetric synthesis of (+)-1-deoxynojirimycin and (+)-castanospermine

Asymmetric total syntheses of (+)-1-deoxynojirimycin (1) and (+)-castanospermine (2) are described. Starting from diene 3, the required absolute stereochemistry is introduced by an asymmetric hydroxylation followed by epoxidation. An intramolecular cyclization of amine 17 gives access to the corresponding tetrasubstituted piperidine 18, which is a precursor to compounds 1 and 2. (+)-Deoxynojirimicyn (1) was obtained in 36% yield over 11 steps from diene 3, while (+)-castanospermine (2) was achieved in 13% after 19 steps from the same starting material.     

Enantioselective syntheses of poison-frog alkaloids: 219F and 221I and an epimer of 193E

Enantioselective syntheses of indolizidines (−)-219F and (−)-221I have been achieved and the relative stereochemistries of natural 219F and 221I were determined by the present synthesis. A levorotatory indolizidine, corresponding to one proposed structure for 193E, was also synthesized, but was found to differ from 193E. It seems likely that natural 193E is the 8-epimer of the synthesized indolizidine.     

Stereospecific synthesis of 2,2,3-trisubstituted tetrahydroquinolines: application to the total syntheses of benzastatin E and natural virantmycin

An efficient methodology for the synthesis of 2,2,3-trisubstituted tetrahydroquinolines has been developed, which involves the triphenylphosphine-CCl₄-mediated stereospecific rearrangement of α,α-disubstituted indoline-2-methanols 15 to 2,2,3-trisubstituted tetrahydroquinolines 26. The rearrangement precursors 15 are readily prepared by the diastereoselective Grignard addition to 2-acylindolines 13. The total syntheses of (+)-benzastatin E (1) and natural virantmycin (2a) were accomplished utilizing this methodology. This rearrangement reaction might afford some chemical precedent for the biogenetic pathway of the benzastatin family.     

Asymmetric syntheses of 6-deoxyfagomin, d-deoxyrhamnojirimycin, and d-rhamnono-1,5-lactam

N-Allyl protected 3-O-benzyloxglutarimide 11 was synthesized as a useful variant of the chiral building block 10. This modification allowed a high-yielding deprotection of the allyl group from the lactam intermediate 14. Starting from this building block, the asymmetric syntheses of aza-sugars 6-deoxyfagomine (2), d-rhamnono-1,5-lactam (6), as well as d-deoxyrhamnojirimycin (5) have been achieved in high regio- and/or diastereo-controlled manner.     

Total syntheses of hyacinthacine A2 and 7-deoxycasuarine by cycloaddition to a carbohydrate derived nitrone

Practical syntheses of nitrone 8 by two different approaches from sugars are reported. Its use as a versatile intermediate in highly selective 1,3-dipolar cycloaddition reactions constitutes the key step for novel total syntheses of hyacinthacine A₂ (3) and 7-deoxycasuarine (20) by simple transformations of a common isoxazolidine adduct.     

Methyl 3-bromomethyl-3-butenoate as an isopentane building block for the stereoselective preparation of (S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde and (+)-faranal

(S)-4-Methyl-3,6-dihydro-2H-pyran-2-carbaldehyde (3), the common intermediate in the syntheses of the C17-C27 subunit of laulimalide (4) and (+)-faranal (5), the trail pheromone of the pharaoh ant, Monomorium pharaonis, were obtained via transformation of methyl 3-bromomethyl-3-butenoate (1) into allylstannane 2 and subsequent allylation of (benzyloxy)acetaldehyde (6) in accordance with the Keck procedure as the key steps.     

Structure elucidation by synthesis of four metabolites of the antitumor drug ENMD-1198 detected in human plasma samples

ENMD-1198 is a biologically active analogue of the antitumor drug 2-methoxyestradiol. Four human metabolites of ENMD-1198 were identified through synthesis and liquid chromatography/mass spectrometry comparisons of the metabolites with the synthetic standards. Two metabolites (3 and 4) are epimers resulting from benzylic hydroxylation at C-6. Two additional metabolites (5 and 6) are formed by epimeric hydroxylation at C-6 and α-epoxidation of the 16,17-alkene. The syntheses provided sufficient quantities of the metabolites for cytotoxicity studies to proceed. The 6-β-ol 4 was moderately less cytotoxic than the parent drug, while the remaining three metabolites (3, 5, and 6) were significantly less cytotoxic.     

Stereochemical studies—XIII: Cyclic aminoalcohols and related compounds—VI synthesis of the four 2-amino-4-t-butylcyclopentanol isomers

From diethyl 3-t-butyladipate (5), via cis- and trans-4-t-butylcyclopentene-1,2-oxide (31, 32) as key compounds, the syntheses of cis-2-amino-cis-4-t-butylcyclopentanol (1), cis-2-amino-trans-4-t-butylcyclopentanol (2), trans-2-amino-cis-4-t-butylcyclopentanol (3) and trans-2-amino-trans-4-t-butylcyclopentanol (4) have been achieved. 1, 3 and 4 were also synthesized from the corresponding 2-hydroxy-4-t-butylcarboxylic acids by Curtius degradation of the hydrazides (11, 18, 19). The steric course of process leading to the above compounds is discussed.     

Synthesis of the C9-C29 fragments of ajudazols A and B

The syntheses of both C9-C29 fragments 3 and 4 of the myxobacteria metabolites ajudazols A (1) and B (2) are described. The key steps were a cyclodehydration to form the oxazole, Sonogashira coupling to form the C18-C19 bond and a P-2 Ni mediated partial alkyne hydrogenation to install the C17-C18 Z-alkene. The C15 alkene in the ajudazol A fragment 3 was introduced in the final steps by elimination of the corresponding primary alcohol.     

An efficient electrochemical method for a unique synthesis of new derivatives of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one

The electrochemical oxidation of catechols (1a-c) has been studied in the presence of 6-methyl-1,2,4-triazine-3-thion-5-one 3 in aqueous sodium acetate, using cyclic voltammetry and controlled-potential coulometry. A plausible mechanism for the oxidation of catechols and their reaction with 3 is presented. All the catechol derivatives (1a-c) were converted into 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives (6a-c) through a Michael-type addition reaction of 3 to anodically generated o-quinones. The electrochemical syntheses of 6a-c were successfully performed in one pot in an undivided cell using an environmentally friendly method with high atomic economy.