Highly selective synthesis of 4(5)-aryl-, 2,4(5)-diaryl-, and 4,5-diaryl-1H-imidazoles via Pd-catalyzed direct C-5 arylation of 1-benzyl-1H-imidazole

Highly selective, practical, and efficient protocols for the preparation of 4(5)-aryl-1H-imidazoles 2, 2,4(5)-diaryl-1H-imidazoles 3, and 4,5-diaryl-1H-imidazoles 1 are described. A key step of these protocols is the regioselective synthesis of 5-aryl-1-benzyl-1H-imidazoles 9 by Pd-catalyzed direct C-5 arylation of commercially available 1-benzyl-1H-imidazole (8) with aryl halides. The three-step synthesis of compounds 3 from 8 also involves the Pd-catalyzed and Cu-mediated direct C-2 arylation of imidazoles 9 with aryl halides under base-free and ligandless conditions. On the other hand, the four-step synthesis of imidazoles 1 from 8 also involves the regioselective bromination of compounds 9 and a Suzuki reaction of the resulting 5-aryl-1-benzyl-4-bromo-1H-imidazoles 11 with arylboronic acids 5 under phase-transfer conditions, followed by N-debenzylation.     

Synthesis of unnatural pentahydroxylated pyrrolizidines: 5-epi- and 5,7a-di-epi-hyacinthacine C1

Stereocontrolled synthesis of 5-epi- and 5,7a-di-epi-hyacinthacine C₁ (7 and 8), two potential glycosidase inhibitors are described using α,β-unsaturated ketone 9 as homochiral starting material. The key step in the synthesis is the highly diastereoselective dihydroxylation reaction of 9, that allows the obtention of a single bis-hydroxylated ketone (10). Further derivatization into two epimeric mesylate esters followed by internal cyclization form the pyrrolizidinic compounds 7 and 8. This type of compounds can be useful in glycobiology due to their ability to inhibit carbohydrate-processing enzymes.     

Asymmetric synthesis of 1-deoxynojirimycin and its congeners from a common chiral building block

A new, promising chiral building block 9 for the synthesis of 1-deoxy-4,5-trans-oriented azasugars such as 1-deoxynojirimycin (1) was prepared in only four steps from the Garner aldehyde 10 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring. In practical test, the first synthesis of all four isomers (1 and 6-8) of trans-4,5-orientated 1-deoxyiminosugars using 9 as a common chiral building block was demonstrated.     

Synthesis of 5-alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones by denitrocyclisation of N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides. Evidence of a Smiles rearrangement

An efficient method for the synthesis of hitherto unknown alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones 8a-g, 16 and 17 has been established. The method is based on the synthesis of the corresponding N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides 3a-c and 7a-c,e which undergo denitrocyclisation with NaH in DMF in 4.5 or 2 h. When 3a was treated with NaH in DMF for 30 min the product of a Smiles rearrangement, 9, was isolated. Under similar conditions but for 4.5 h 9 was converted into 8a. This confirms the involvement of a Smiles rearrangement during the denitrocyclisation process. Conversion of 3b into isomeric pyrroloquinoxalinones 12 and 13 confirms a process involving two pathways, direct denitrocylisation of 3b and Smiles rearrangement of 3b followed by denitrocylisation, respectively. Furthermore, denitrocylisation of 7d into pyrroloquinoxalinones 16 and 17 suggests that similar cyclisation pathways are followed by N-arylcarboxamides.     

Total Synthesis of Amphidinolide E and Amphidinolide E Stereoisomers

Four amphidinolide E stereoisomers, amphidinolide E (1), 2-epi-amphidinolide E (2), 19-epi-amphidinolide E (3), and 2-epi-19-epi-amphidinolide E (4), have been synthesized via the judicious union of aldehyde 5, allylsilanes 7 or 8, acids 9 or 10, and vinylstannane 6. The C19 stereocenters of the C19 epimeric allylsilanes 7 and 8 were introduced via crotylboration reactions early in the synthesis. [3+2] Annulation reactions of aldehyde 5 with allylsilanes 7 and 8 were employed to set the core tetrahydrofuran units of 1-4. Finally, the C2 stereocenter was installed by esterification using acid 9, without incident, or with acid 10, in which case an unexpected and completely stereoselective inversion of C2 occurs.     

A convenient enantioselective synthesis of 3-asymmetrically substituted oxindoles as progesterone receptor antagonists

A convenient enantioselective synthesis of 3-asymmetrically substituted oxindoles is reported. Compound (2) prepared by radical cyclisation of (1) was used for the synthesis of racemic and enantiomerically pure 3-asymmetrically substituted oxindoles. Desulfurisation of (2) using Raney Ni yielded the racemate (5). Addition of (S)-1-phenylethanol to compound (2) yielded the diastereoisomer (21) the structure of which was determined using X-ray crystallography. Using a sequence of steps (21) was converted to the enantiomer (8). The enantiomer (9) was similarly prepared from (2) using (R)-1-phenylethanol.     

Organofluorine compounds and fluorinating agents : Part 28. New perfluoroalkyl substituted chiral mesogens

The perfluorohexyl-aryl-thioethers 3 and 4, building blocks for the synthesis of the chiral target mesogens 12-15, were prepared by dithionite-mediated S-perfluoroalkylation of the p-substituted thiophenols 1 and 2. The phenolic HO group of 3 was O-glucosylated with pentaacetyl-d-glucopyranose to 5 followed by deacetylation forming the tetrol 6 and by acetalizing with 4-(4-perfluorohexylsulfanyl-benzoyloxy)-benzaldehyde-dimethylacetal (8) generating the dihydroxy-intermediate 9. The latter contains two perfluorohexylthio chains. Alternatively, the dimethylacetal 8 was linked to p-octylphenyl-β-d-glucopyranoside (10) giving the mixed octyl/perfluorohexyl substituted p-octylphenyl-4,6-O-[4′-(4″-perfluorohexylsulfanyl)-benzoyloxy]-benzylidene-β-d-glucopyranoside (11). Compound 8 was obtained via esterification of 4 with p-hydroxy-benzaldehyde to 4-(4-perfluorohexylsulfanyl-benzoyloxy)-benzaldehyde (7). Finally, the diols 9 and 11 were dehydroxylated to 12 and 13 followed by hydrogenation yielding 14 and 15, respectively. Tetrol 6, diols 9, 11 and the non-amphiphilic compounds 7, 12-15 are thermotropic liquid crystals.     

The enantioselective synthesis of poison-frog alkaloids (−)-203A, (−)-209B, (−)-231C, (−)-233D, and (−)-235B″

The enantioselective synthesis of indolizidines (−)-203A, (−)-209B, (−)-231C, (−)-233D, and (−)-235B″ has been achieved and the absolute stereochemistry of both indolizidines 203A and 233D was established as 5S,8R,9S. The relative stereochemistry of natural 231C was established by the present asymmetric synthesis.     

An efficient substituent dependent synthesis of congested pyridines and pyrimidines

An efficient and versatile synthesis of various congested pyridines 3a-h, 6a,b, 8a-n, 10a-g, and 16a,b, and (pyrimidin-4-yl)acetonitriles 13a-g has been delineated by base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 1a-h, 5, 7, and 15 by formamidine acetate 2a, acetamidine hydrochloride 2b, S-methylisothiourea 9a, pyrazol-1-yl-carboxamidine 9b, and arylamidine hydrochloride 12 separately in the presence of powdered KOH in dry DMF.     

Total synthesis of (+)-Z-deoxypukalide, a furanobutenolide-based cembranoid isolated from the pacific octocoral Leptogorgia spp.

A total synthesis of (+)-Z-deoxypukalide 3 using a combination of Stille and Nozaki-Hiyama-Kishi(NHK) coupling reactions as key steps, is described. During this study a new practical synthesis of the substituted butenolide intermediate 10, based on a combination of RCM and CM reactions from the cyclobutene ester 21 in the presence of 2-methylpropenol was also developed. Attempts to apply the intramolecular NHK reaction to the substrates 8a and 8b containing an ester group adjacent to the reacting aldehyde functionality gave disappointing low yields (<6%) of the corresponding coupled products 9. The synthetic (+)-Z-deoxypukalide 3 was correlated with naturally derived material, and also with pukalide 1, the first member of the furanobutenolide-based cembranoids to be isolated from corals.     

Total synthesis of (−)-2-epi-lentiginosine by use of chiral 5-hydroxy-1,5-dihydropyrrol-2-one as a building block

We have developed a practical synthesis of the chiral lactam as a new chiral building block for alkaloid synthesis. Lipase-catalyzed kinetic resolution of hydroxylactam 8, followed by isolation-racemization of the chiral acetoxylactam 9 provided the optically pure hydroxylactam 8 in 96.0% yield with >99% ee after five cycles of kinetic resolution-racemization process. Chemical transformation of (S)-hydroxylactam 8 furnished chiral (−)-2-epi-lentiginosine (1) in 20% yield in 10 steps with no loss of enantiomeric excess.     

Stereoselective synthesis of nucleoside monophosphate HepDirect™ prodrugs

Synthesis of HepDirect™ prodrugs of nucleoside monophosphates via phosphorylation with a chiral reagent forms a new asymmetric center at phosphorus and produces two diastereomers. Coupling of chiral phosphoramidite 6 derived from (S)-diol 5 with ara-A followed by oxidation of the intermediate phosphite gave ara-AMP prodrugs 8 (4S,2S isomer) and 9 (4S,2R isomer). Several methods were explored to identify routes for the selective synthesis of each diastereomer. Two successful stereoselective approaches to ara-AMP prodrugs 8 and 9 are described.     

Studies in symmetry-driven synthesis of ryanodol: application of nucleophilic alkynylation for regio- and stereoselective desymmetrization

We developed a simple and novel desymmetrization strategy toward the total synthesis of ryanodol. The advanced intermediate 1 with six contiguous tetrasubstituted carbons was synthesized from the previously reported 3 by employing two key nucleophilic reactions. The first nucleophilic reaction to C₂-symmetric tetraketone 2 installed the C6-tetrasubstituted carbon in a regio- and stereoselective fashion, leading to desymmetrized mono-alkynylated 8 without forming C₂-symmetric bis-alkynylated 9. The second addition to triketone 8 also proceeded regio- and stereoselectively to construct the C2-tetrasubstituted stereocenter of 10.     

New synthesis of glycolipid immunostimulants RC-529 and CRX-524

An efficient and scalable synthesis of the potent vaccine adjuvant RC-529 (3) and TLR4 agonist CRX-524 (4) is described in eight steps from 1,3,4,6-tetra-O-acetyl-2-amino-2-benzyloxycarbonyl-2-deoxy-β-d-glucopyranose (10c) in ca. 25% overall yield. The synthesis features the strategic use of the N-Cbz group for β-glycosylation and the selective N,N,O-triacylation of common advanced intermediate 15 with (R)-3-tetradecanoyloxy or decanoyloxytetradecanoic acid (8, 9) late in the synthesis. A new method for preparing and enhancing the enantiopurity of (R)-3-hydroxytetradecanoic acid (6), a key component of 3 and 4 as well as bacterial lipid A, is also described.     

Synthesis of pyrrolo[3,2-b]benzofurans and pyrrolo[3,2-b]naphthofurans via addition of a silyloxypyrrole to activated quinones

The uncatalyzed reaction of N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 with 1,4-quinones bearing an electron withdrawing group at C-2 has been studied. Use of 1,4-quinones 4, 5 bearing an ester group at C-2 provided an efficient synthesis of the respective pyrrolidinobenzofuran adduct 9 or pyrrolidinonaphthofuran adduct 10 whereas use of 1,4-quinones 6, 7 and 8 bearing an acetyl group at C-2 afforded silyloxypyrroles 11, 12 and 13 resulting from direct electrophilic substitution of the silyloxypyrrole by the electrophilic quinone. Addition of Eu(fod)₃ to the reaction of 2-acetyl-1,4-naphthoquinone 7 and 3-acetyl-5-methoxy-1,4-naphthoquinone 8 with N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 provided a method for obtaining the pyrrolidinonaphthofuran adducts 14 and 15 together with silyloxypyrroles 12 and 13. Oxidative rearrangement of pyrrolidinonaphthofuran adduct 15 to pyrrolidino pyranonaphthoquinone 16 using ceric ammonium nitrate in acetonitrile provided a novel approach for the synthesis of an aza-analogue of the pyranonaphthoquinone antibiotic kalafungin.     

Addition of 2-tert-butyldimethylsilyloxythiophene to activated quinones: an approach to thia analogues of kalafungin

The uncatalyzed reaction of 2-tert-butyldimethylsilyloxythiophene 2 with 1,4-quinones bearing either an electron withdrawing acetyl or a carbomethoxy group at C-2, was investigated. No reaction was observed using 1,4-quinones 8 and 9 bearing an ester group at C-2 whereas use of 1,4-quinones 10 and 11 bearing an acetyl group at C-2 only provided low yields of the silyloxythiophenes 15 and 16 resulting from electrophilic substitution of the silyloxythiophene by the 1,4-quinone. Use of the Lewis acids InCl₃, Cu(OTf)₂ and BF₃·Et₂O were investigated in an effort to improve the yield of the desired annulation reaction. BF₃·Et₂O proved to be the optimum catalyst for the synthesis of thiolactone naphthofuran adducts 14 and 18 from 1,4-naphthoquinones 9 and 11, respectively. Reaction of 2-tert-butyldimethylsilyloxythiophene 2 with 1,4-benzoquinones 8 and 10 bearing a carbomethoxy or an acetyl group at C-2, respectively, afforded thiolactone benzofuran adducts 13 and 17, respectively, catalyzed by either InCl₃ or Cu(OTf)₂. Addition of 2-tert-butyldimethylsilyloxythiophene 2 to 3-acetyl-5-methoxy-1,4-naphthoquinone 12 afforded adduct 19 that underwent oxidative rearrangement to thiolactone pyranonaphthoquinone 20 using ceric ammonium nitrate in acetonitrile, thus providing a novel approach for the synthesis of a thia analogue of the pyranonaphthoquinone antibiotic kalafungin.     

New pinene-derived pyridines as bidentate chiral ligands

A synthesis of new bidentate pyridines 8a-d, 9, and 10 has been developed, starting from triflate 14, readily available from β-pinene 11. A copper complex of the pyridine-oxazoline ligands 8a has been found to catalyze asymmetric allylic oxidation of cyclic olefins 36a-c with good conversion rates and acceptable enantioselectivity (≤67% ee). The imidazolium salt 10 has been identified as a precursor of the corresponding N,N′-unsymmetrical N-heterocyclic carbene ligand, whose complex with palladium catalyzed the intramolecular amide enolate α-arylation leading to oxindole 45 in excellent yield but with low enantioselectivity.     

Synthetic studies of kampanols, novel p21 farnesyltransferase inhibitors: an efficient synthesis of the tetracyclic ABCD ring system of kampanols

An enantioselective synthesis of the tetracyclic ABCD ring system (4) of kampanols, novel Ras farnesyltransferase inhibitors from a microorganism, was efficiently achieved for the first time starting from the known trans-decalone derivative 9. The synthetic method involves the following two key steps: (i) a conjugate addition reaction between the α-methylene ketone 6 and the Grignard reagent (7) of the ortho-disubstituted bromobenzene derivative 8 to deliver the coupling product 21 with stereoselectivity at the C9 position and (ii) a phenylselenium-mediated cyclization reaction of the phenol derivative 5 to stereoselectively construct the requisite tetracyclic intermediate 25 possessing the cis-fused connectivity of the B/C rings.     

Formal synthesis of (+)-lactacystin based on a novel radical cyclisation of an α-ethynyl substituted serine

A diastereoselective 5-exo-dig radical cyclisation of the bromoamide 7 produced from the enantiopure α-ethynyl substituted amino alcohol 5 led to the pyrrolidinone 8 (2:1 α:β epimers) in 70% yield. Oxidative cleavage of the alkene bond in 8, followed by a stereoselective α-methylsulfanylation of the resulting 4-keto derivative 9, next led to the methylsulfanyl derivative 10. Finally, the pyrrolidinone derivative 10 was converted into the key intermediate 12 used previously in an enantioselective synthesis of (+)-lactacystin.     

Aromatics to bis-triquinane: a tandem oxidative dearomatization of bis-phenol,cycloaddition, photorearrangement and a rapid entry into carbocyclic framework of Xeromphalinone E

A novel approach for the synthesis of a bird-shaped bis-triquinane 3, a fascinating carbocyclic framework closely related to the skeleton of Xeromphalinone E 1 from readily available 2,6-dimethyl phenol 8 has been reported. The synthesis of bis-cyclohexadienones 6, 22a–e by oxidative acetylation of tetramethyl bisphenols 7, 20a–e has been investigated using two different reagents under varying reaction conditions. The cycloaddition of bis-cyclohexadienone 6 gives two carbocycles, bis-adduct 4b and mono-adduct 5d in a stereocontrolled manner. The photochemical sigmatropic 1,2-acyl shift in 4b furnished 3 and monotriquinane 9 linked with a 9-acetoxy-9-methyl-endo-tricyclo[5,2,2,0^2,6]undeca-4,10-diene-8-one system. Two different pentasubstituted phenols 13 and 14 were also isolated during an attempted oxa-di-π-methane (ODPM) rearrangement of mono-adduct 5d via aromatisation of the cyclohexadienone ring. The photochemical behaviour of bis-cyclohexadienones 6, 22a–e has also been investigated under UV irradiation and two different aromatized products were isolated for each bis-cyclohexadienone by migration and elimination of acetate groups.