Synthesis of novel exocyclic amino nucleosides by parallel solid-phase combinatorial strategy

A versatile parallel solid-phase combinatorial strategy was developed for the synthesis of large nucleoside libraries. Twelve libraries L1-12 of 1152 novel exocyclic triazinylamino nucleosides and one library L13 of 82 new substituted clitocine derivatives were synthesized in high quality as natural product mimic nucleosides on the semi-automated synthesizer. The polystyrene MMT-Cl resin was selected and utilized. The key intermediate resins 5 and 9 loaded with the corresponding scaffolds were prepared and validated with various amines before parallel synthesis. After a variety of amino building blocks were validated, 56 primary amines in 12 groups (building block set A) and 24 secondary amines in 3 groups (building block set B) were selected and utilized to combinatorialize the first and the second reactive sites on scaffold 5 for the synthesis of libraries L1-12. Eighty-two amines (building block set C) were utilized for the synthesis of clitocine library L13. Thirteen libraries of 1234 novel exocyclic amino nucleosides were all analyzed and characterized by high throughput LC-MS. 81.3-100% of the library members in 13 libraries show more than 60% purity, and 65.7-92.7% of the library members in these libraries show 80-100% purity. The strategy can be widely used for the synthesis of other diverse nucleoside libraries.     

Combinatorial solid-phase synthesis and screening of a diverse tripodal triazacyclophane (TAC)-based synthetic receptor library showing a remarkable selectivity towards a d-Ala-d-Ala containing ligand

A large and diverse library of a TAC-based tripodal synthetic receptor library (6) has been prepared by split-mix synthesis on the solid phase. Each receptor of the 46,656-member TAC-based library (6) is attached to a solid support bead and contains three different dipeptide arms. On-bead screening for binding of a d-Ala-d-Ala containing ligand (7) by the TAC-based library (6) was performed in phosphate buffer (0.2 N, pH=7.0). Remarkable selectivity for particular library members was observed. The best binding members from the screening were manually selected using fluorescence microscopy and subjected to structural analysis by sequencing. The thus determined binding sequences showed a high consensus.     

A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.     

Tandem annulation strategy for the convergent synthesis of benzonaphthopyranones: total synthesis of chartarin and O-methylhayumicinone

A Hauser-initiated tandem annulation has been developed for the rapid regiospecific synthesis of benzonaphthopyranones via formation of two rings in one-pot operation. This strategy has been generalized with benzonaphthopyranones 26, 29, 32, and 35. It has also been employed in a short synthesis of chartarin (3) and O-methylhayumicinone (67).     

Synthesis of external β-turn templates by reaction of protected dehydroamino acids with cyclic enaminoesters

Two external β-turn templates have been synthesised and one of them has been derivatised as a GLDV-tetrapeptide. In the course of the synthesis an interesting dichotomy was observed in the condensation of exocyclic enamines such as 4 and 19 with protected dehydroamino acids using phosphorus trichloride. When dehydroamido acids were condensed with the enamines 4 and 19 then 6/6 and 6/5 fused bicyclic compounds such as 5 and 20, respectively, were obtained, whereas, when dehydroamino acid urethanes were used, the 5/6 and 5/5 fused products 7 and 23 were obtained. The bicyclic template 20 was converted to the GLDV-tetrapeptide derivative 31 but the sensitivity to base of the acyl-enamine system of the template reduced the yield in the synthesis of the external turn 35.     

Synthesis of the marine furanoditerpene (−)-marginatone

A synthesis of the marine labdane furanoditerpene (−)-marginatone 1 has been accomplished by a short sequence of reactions starting from (+)-coronarin E 5. The key step is the stereocontrolled-intramolecular electrophilic cyclisation of the (+)-dihydrocoronarin E 6, to the tetracyclic marginatane skeleton 7, which is subsequently functionalized by allylic oxidation to give 1. As (+)-coronarin E 5 was previously synthesized from (−)-sclareol 10, the herein reported preparation constitutes the first formal total synthesis of (−)-marginatone 1, by which its absolute configuration has been confirmed.     

(R)-2,3-Cyclohexylideneglyceraldehyde, a novel template for facile and simple entry into chiral hydroxy γ-lactones: synthesis of (−)-muricatacin

(R)-2,3-Cyclohexylideneglyceraldehyde 1 has been used in a simple and efficient synthesis of (−)-muricatacin 10. The required chiron, syn-alkanetriol 2a was prepared by the reduction of a ketone 3 derived from 1.     

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.     

Synthesis of ferrocenylarenes and heteroarenes through nucleophile induced ring transformation of 2H-pyran-2-ones

The synthesis of various ferrocenylarenes (3, 5a, 6) and heteroarenes (5b, c, 7) from 6-ferrocenyl-4-methylsulfanyl-2H-pyran-2-one-3-carbonitrile 1 through nucleophile induced ring transformation reactions has been delineated.     

First formal synthesis of (+)-nimbidiol. Synthesis, X-ray structure and anticancer activity of a novel ring C aromatic diterpene: dimethyl (+)-podocarpa-8,11,13-triene-12,13-dicarboxylate

A novel ring C aromatic diterpene (4) has been prepared in three steps from natural (+)-manool (1). The structure and anticancer activity data for 4 has been investigated. This key intermediate (4) was easily transformed into 7-deoxo nimbidiol dimethyl ether (8). The present work represents the first formal synthesis of (+)-nimbidiol (10).     

Toward a synthesis of the antitumor macrolide peloruside A: a chiral pool approach for the C(1)-C(11) segment

Dihydroxylation of the glucose derived α,β-unsaturated lactones 6 and 13 was found to be on the α-face of the pyranolactone ring exclusively. The resulting dihydroxylated compound from 13 has been used in a synthesis of the lactone 4, which corresponds to C(1)-C(11) of peloruside A.     

Convergent synthesis of the IJKLM-ring part of ciguatoxin CTX3C

Convergent synthesis of the IJKLM-ring part (2) of ciguatoxin CTX3C has been achieved from the I-ring and the L-ring parts (4 and 5) in total eight steps in 27% overall yield. The carbanion derived from 4, stabilized by a dimethyldithioacetal S-oxide group, was readily reacted with aldehyde 5 to give an adduct, which was facilely transformed into the corresponding α,ε-dihydroxy ketone 3. The JK-ring formation from 3 under reductive conditions followed by oxidative M-ring cyclization efficiently led to the pentacyclic ether 2. Improved synthesis of 6, a synthetic intermediate for 4, was also established.     

Two-directional total synthesis of efomycine M and formal total synthesis of elaiolide

The anti-inflammatory agent efomycine M (1) has been synthesized from macrodilactone 38 and vinyliodide 42 by a two-directional total synthesis in 17 steps over the longest linear sequence with an overall yield of 7%. The C₂-symmetric macrodiolide 38 has been prepared by Yamaguchi macrolactonization of seco-acid 26. The central stereopentad of 1 was obtained by a highly efficient anti-aldol reaction followed by a diastereoselective ketone reduction. Additionally, we have completed a formal total synthesis of elaiolide (3) by converting macrodiolide 37 into Paterson's methylketone 13.     

Electrochemical synthesis of 5,6-dihydroxy-2-methyl-1-benzofuran-3-carboxylate derivatives

Electrochemical oxidation of catechols (1a-c) has been studied in the presence of methyl acetoacetate (2a) and ethyl acetoacetate (2b) as nucleophiles in aqueous solution using cyclic voltammetry and controlled-potential coulometry. The results indicate that the quinones derived from catechols (1a-c) participate in Michael addition reactions with 2a and 2b to form the corresponding benzofuran derivatives (3a-f). The electrochemical synthesis of 3a-f has been successfully performed in an undivided cell in good yield and purity. The oxidation mechanism was deduced from voltammetric data and by coulometry at controlled potential. The products have been characterized after purification by IR, ¹H NMR, ¹³C NMR, MS, and single crystal X-ray diffraction.     

Integrating chemosensors for amine-containing compounds into cross-linked dendritic hosts

Trifluoroacetylazo dye 1, a known chemosensor for amines, has been integrated into cross-linked dendrimer hosts. Thus, boronic acid 16 was linked to iododye 9 via a Suzuki coupling reaction. In situ deprotection and alkylation with dendrons 3 and 4, containing 8 homoallyl or allyl ether groups, respectively, afforded dendrons 18 and 19 with chemosensor units at their focal point. Conversion of 18 (19) to the bis-imine of butane 1,4-diamine, extensive cross-linking via the ring closing metathesis reaction with Grubbs catalyst 25, and hydrolysis produced dendrimer hosts 28 and 29. Host-guest studies with a small library of amines and alcohols showed 28 and 29 to selectively signal certain diamines but not due to template mediated imprinting.     

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.     

Amberlyst 15 catalyzed synthesis of indole-pyrazole based tri(hetero)arylmethanes

An expedient synthesis of 1,3-diaryl-4-(3,3′-diindolyl)methylpyrazoles 3a-m has been developed using Amberlyst 15 catalyzed condensation of 1,3-diaryl-4-formyl pyrazoles 2 with indoles 1. This reaction was further extended to the synthesis of 4,4′-bis(3,3′-diindolyl)methylphenoxy-alkanes 5a-b by coupling of 4,4′-di(formylphenoxy)alkane 4 with indole 1.     

Iterative two-step strategy for C2-C4′ linked poly-oxazole synthesis using Suzuki-Miyaura cross-coupling reaction

An iterative method for the synthesis of C2-C4′ linked poly-oxazoles has been developed. This efficient two-step repetitive process includes TBS-iodine exchange reaction and Suzuki-Miyaura cross-coupling reaction with oxazolylboronate 8, which allows appending a bis-oxazole moiety per each iteration. The synthesis of bis-, tris-, tetrakis-, pentakis-, and hexakis-oxazoles (10, 14, 22, 18, and 24) was achieved starting from the common intermediate 7 in 1-5 steps.     

The second generation synthesis of (+)-pseudodeflectusin

The second generation synthesis of (+)-pseudodeflectusin (1), a potential antitumor agent, has been achieved. The key synthetic step is the cascade reaction involving Diels-Alder reaction, lactonization, and decarboxylation to give cycloadduct 6 with complete regioselectivity in good yield. We found that NaH is the best base to facilitate the Diels-Alder reaction of hydroxypyrone 7 with alkyne 8. The present synthetic route enables the total synthesis of (+)-1 in only five-steps from the known compounds 7 and 8.