A novel and convenient method for the synthesis of substituted naphthostyrils

3-Pyrrolyl-6-fluoro-naphthostyril 13 was synthesized via a base-catalyzed intramolecular cyclization of oxindole precursor 2 (Y=H). Derivatization of 2 (Y=I) through a one-pot reaction give 5-substituted naphthostyrils. This method allows convenient access to 3,5,6-trisubstituted naphthostyrils which may serve as a new template for CDK2 inhibition.     

Stereospecific route to enantiopure all cis-2,3,6-trisubstituted piperidines. Facile synthesis of (−)-deoxocassine and (+)-azimic acid

Reduction of the enantiopure β-amino esters 10 provides the γ-amnio alcohol 11, which is condensed with 2,4-pentadione to afford 12. Stepwise cyclization of 12 produced the cyclic enamine 13, which is hydrogenated to deliver all cis-2,3,6-trisubstituted piperidine 14. Using this reaction sequence and subsequent Baeyer-Villiger oxidation as the key step (−)-deoxocassine and (+)-azimic acid are synthesized.     

Convergent synthesis of the ABCDE-ring part of ciguatoxin CTX3C

Convergent synthesis of the ABCDE-ring part (2) of ciguatoxin CTX3C (1) has been achieved. A carbanion stabilized by a dimethyldithioacetal S-oxide group in the AB-ring part (4) readily reacted with an aldehyde group in the E-ring part (5). The resulting adduct was facilely converted to the corresponding β,γ-unsaturated α,ε-dihydroxy ketone (3). The subsequent reductive hydroxy-ketone-cyclization reactions constructed the CD-ring part efficiently. Thus, the ABCDE-ring part (2) was concisely synthesized in 10 steps in 11% overall yield from the AB-ring and the E-ring parts (4 and 5).     

New derivatives of trifluoroacetyl acetaldehyde and trifluoroaldol

The reaction of β-ethoxyvinyl trifluoromethyl ketone 1 with O-nucleophiles such as alcohols and diols leads to various derivatives of trifluoroacetyl acetaldehyde, such as β-alkoxyvinyl trifluoromethyl ketones 3 and cyclic keto acetals 4. Several derivatives synthesized contain chiral auxiliaries. Reduction of the compounds 1, 3, 4 under various reaction conditions leads to the trifluoroaldol derivatives 6, 7, 9, 10 containing a protected aldehyde group. The compounds obtained are useful building blocks in fluoroorganic synthesis.     

An expedient route to indoles via a cycloaddition/cyclization sequence from (Z)-1-methoxybut-1-en-3-yne and 2H-pyran-2-ones

The cycloaddition of (Z)-1-methoxybut-1-en-3-yne (2) with 5,6-disubstituted 3-acylamino-2H-pyran-2-ones 1 under microwave-irradiation conditions, with classical heating or at high-pressures (13-15 kbar) affords the benzene derivatives 3 with a strategically positioned 2-methoxyethenyl moiety. In some cases, at high-pressures after long reaction times, 2,2-dimethoxyethyl products 4 were obtained. Adducts 3 and 4 can be cyclized under mild conditions into 1,5,6-trisubstituted indole derivatives 5.     

Face selectivity in the reactions of 2,4-disubstituted adamantanes and their modification by inclusion in β-cyclodextrin solutions

Sodium borohydride reduction reactions on 4-X-adamantan-2-ones (where X=ethyleneketal 11, ethylenethioketal 12, and methylene 15) were studied, which gave Z-alcohols 16 and 17 (from en-face attack) as the predominant products for ketones 11 and 12, but gave 1:1 mixture of Z- and E-18 alcohols for ketone 15. The en/zu face selectivity of 15 in sodium borohydride reduction was enhanced to 32/68 in β-CD solution. Both 1,3-dipolar addition and dichlorocarbene addition reactions on 4-ethyleneketal-2-methyleneadamantane 13 underwent again predominant en-face attack to give products in an E/Z ratio of >99:1 and 92:8, respectively. The exceptional high zu-face selectivity on the dichlorocarbene addition reaction of 15 may be explained by a temporal complexation between the carbene and the C₄-oxo group. In the epoxidation reaction of 13 and 15 the zu-face attack products were favored despite their steric congestions suggesting that hydrogen bonding interaction between the peroxide reagent and the C₄-oxo or 4-ethyleneketal is involved.     

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.     

A facile synthesis of (6S,1′S)-(+)-hernandulcin and (6S,1′R)-(+)-epihernandulcin

A facile total synthesis of (+)-hernandulcin (1) was accomplished from (−)-isopulegol in 6 steps with 15% overall yield. Epoxidation of (−)-isopulegol with m-chloroperbenzoic acid followed by opening of the epoxide 3a with prenyl Grignard afforded the tertiary alcohol 4a with correct C-6 and C-1′ stereochemistry as a major product. Oxidation of the secondary alcohol in compound 4a to the ketone 5a was accomplished in high yield by using TPAP and N-methylmorpholine N-oxide. Conversion of the ketone 5a to α,β-unsaturated ketone via organoselenium intermediate gave (+)-hernandulcin (1). This method was also successfully applied to the synthesis of (+)-epihernandulcin (2).     

ClickEnam. 1. Synthesis of novel 1,4-disubsituted-[1,2,3]-triazole-derived β-aminovinyl trifluoromethylated ketones and their copper(II) complexes

The copper(I) catalyzed cycloaddition reaction of N-Boc propargyl amine (dipolarophile) 1 with benzyl azide (1,3-dipole) 2 was found to proceed smoothly in t-BuOH/H₂O at room temperature, to furnish the corresponding 1,4-disubstituted-[1,2,3]-triazole-derived N-Boc amine 3 in good yield. Deprotection of 3 with trifluoroacetic acid and addition of the trifluoroacetate salt 4 in the presence of triethylamine, with a series of methoxyvinyl(trifluoromethyl)ketones 10-14, gave the corresponding β-aminovinyl trifluoromethylated ketones 15-19 in moderate to good yields. Two copper(II) complexes, one monomer and one dimer with chlorine double bridge, 20 and 21, respectively, were also prepared and their crystal structure determined. β-Aminovinyl trifluoromethylated ketones 15-17 and complexes 20 and 21 have been screened as potential antifungal agents and the antimalarial activity of 15 and 16 were tested against two Plasmodium falciparum strains (3D7 and W2).     

Reaction of 3,3-di-tert-butylthiirane-2-thione S-oxide (α-dithiolactone S-oxide): synthesis of thiolato sulfinato-platinum and palladium complexes

Thermolysis of 3,3-di-tert-butylthiirane-2-thione S-oxide 4 gave di-tert-butyl ketone 5 and carbon disulfide (CS₂). Treatment of α-dithiolactone S-oxide 4 with excess m-CPBA or triphenylphosphine gave di-tert-butylthioketene S-oxide 3 almost quantitatively. Treatment of 4 with (η²-ethylene)bis(triphenylphosphine)platinum(0) 13 or tetrakis(triphenylphosphine) palladium 17 resulted in the formation of thiolato sulfinato-platinum complex 15 or palladium complex 18, respectively. The structure of complex 15 was determined by X-ray crystallographic analysis.     

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.     

Synthetic approach to potential precursors of sclerophytin A

A direct approach to simple bicyclic analogues of the antitumor natural diterpene, sclerophytin A, is described. The readily available bicyclic ketone 8 (prepared from furan and trichloroacetone) was enantioselectively methylated to give the optically active ketone 11. Regioselective allylation using Negishi's method afforded the α,α-dialkyl ketone 12, which was converted to the chloroacetate 15 by hydroboration-oxidation and protection. Regioselective Baeyer-Villiger oxidation afforded the lactone 7a which could be transformed into the silyl ether 7b. Tebbe olefination furnished a mixture of two enol ethers in which the desired product 17 was the minor isomer. Several attempts to use the major endocyclic enol ether 18 to give the tricyclic analogues of sclerophytin proved unsuccessful. Opening of the lactone of 18 and selective protection of the diol afforded the primary alcohol 24 which was oxidized to the keto aldehyde 25. Unfortunately pinacol coupling of 25 did not give any cyclic product. The diene 27 was also prepared from 25 but all attempts at ring-closing metathesis of 27 met with the same fate. The failure of these various cyclization methods underscores the difficulty in forming medium-sized ring systems, especially those cis-fused at the 2- and 5-positions of a tetrahydrofuran ring.     

Synthesis of novel 4′-C-methyl-1′,3′-dioxolane pyrimidine nucleosides and evaluation of its anti-HIV-1 activity

The key glycosyl donor for the target molecule 12 was prepared by two-step sequences; (1) acetalization of tert-butyldimethylsilyloxyacetaldehyde with 3-bromopropanediol, (2) DBN-initiated β-elimination of the resulting 2-(tert-butyldimethylsilyloxy)methyl-4-bromomethyl-1,3-dioxolane 11. Electrophilic glycosidation between 12 and silylated pyrimidine nucleobase proceeded efficiently to provide a mixture of β- and α-anomers of the respective glycosides 14 and 15. Tin radical-mediated reduction of the bromomethyl functional group of 14 and 15 gave protected 4′-C-methyl-dioxorane uracil- 16 and thymine nucleoside 17. The respective cytosine nucleoside 18 was synthesized from 16. De-silylation of 4′-methyl-1′,3′-dioxolane pyrimidine nucleosides 16–18 gave the target molecules. Evaluation of the anti-HIV-1 activity of the β- and α-anomers of the novel 4′-C-methyl-1′,3′-dioxolane nucleosides 22β,α–24β,α revealed that none of the nucleoside derivatives possess anti-viral activity against HIV-1 and show cytotoxicity against MT-4 cells at 100 μM.     

Synthetic studies on reidispongiolide A, an actin-depolymerizing marine macrolide: synthesis of C11-C22 and C23-C35 segments

The C11-C22 and C23-C35 segments 2 and 3 of reidispongiolide A (1), an actin-depolymerizing marine macrolide, were synthesized enantioselectively in 12 steps from (R)-glycidyl trityl ether and in 12 steps from chiral ketone 15, respectively.     

Studies toward the total synthesis of di- and sesterterpenes with a dicyclopenta[a,d]cyclooctane skeleton. Construction of a versatile A/B ring building block via a ring-closing metathesis reaction and carbocationic rearrangement

The cyclopentacyclooctane derivative 1, chosen as the key building block in a synthesis of terpenoid ophiobolates and fusicoccins, has been prepared from 2-methylcyclo-pent-2-en-1-one 5. Cyclization of the intermediate 1,9-diene of l,u configuration 10 under metathesis conditions (Grubbs’ catalyst 15) afforded the eight-membered ring product 13, whereas cyclization of the l,l diastereomer 9 produced a seven-membered ring analog 12. Cationic rearrangement of epoxide 26 occurred with methyl group migration to give ketone 27 as the major product.     

A versatile route to benzocanthinones

Benzocanthinone (1) and five analogs (10, 12-15) were prepared by radical-induced cyclizations of halo N-aroyl derivatives of β-carboline and carbazole.     

Formal total synthesis of aspergillide A

The formal total synthesis of aspergillide A 1 is described. The cross-metathesis of enone 6 with 6-hepten-2-ol derivative 5 provided E-olefin 15 corresponding to the C₄-C₁₄ backbone of 1. The CBS asymmetric reduction of 15 gave allyl alcohol 16, which was transformed into β-alkoxyacrylate 4 which had a formyl group. SmI₂-induced reductive cyclization of 4 gave a 2,6-syn-2,3-trans THP derivative 3 in good yield. After methoxymethylation of 3, the resulting compound 19 was submitted to desilylation and hydrolysis, to afford Fuwa’s key intermediate 2 for the total synthesis of 1.     

Photobehaviour of 2- and 3-heteroaryl substituted o-divinylbenzenes; formation of fused 2,3- and 3,2-heteroareno-benzobicyclo[3.2.1]octadienes and 3-heteroaryl benzobicyclo[2.1.1]hexenes

New β-3-thienyl (8) and β-3-furyl derivatives of o-divinylbenzene (9) have been synthesised and their photochemical behaviour compared with 2-thienyl (7) and 2-furyl derivatives (2). Whereas the β-(2-heteroaryl) substituted o-divinylbenzenes (7 or 2) give only bicyclo[3.2.1]octadiene structure (14 or 1) by 1,6-ring closure of the biradical intermediate, β-(3-heteroaryl) substituted o-divinylbenzenes (8 or 9) give bicyclo[3.2.1]octadiene structure (23 or 24) and bicyclo[2.1.1]hexene structure (25 or 26) by 1,6- and 1,4-ring closure, respectively. This photochemical approach provides a simple method to 2,3- and 3,2-fused thiophene and furan polycyclic compounds.     

Chlorodifluoromethyl aryl ketones and sulfones as difluorocarbene reagents: The substituent effect

We have investigated the different chlorodifluoromethyl aryl ketones 1a-1g and sulfones 2a-2h as difluorocarbene reagents for O- and N-difluoromethylations. It was found that the sulfone reagents 2 were generally more efficient in difluoromethylation than the ketone reagents 1. Furthermore, while the different substituents on ketone reagents 1 did not show a remarkable impact on the difluoromethylation reaction, the substituent effect on the sulfone reagents 2 was much more significant. Finally, we found that p-chlorophenyl chlorodifluoromethyl sulfone 2d and p-nitrophenyl chlorodifluoromethyl sulfone 2h were among the most powerful difluorocarbene reagents in this category for O-difluoromethylations.     

Synthesis and peptide coupling of protected 2-pyrrolylalanine

2-Pyrrolylalanine has been synthesized in two protected forms and applied in the solution-phase synthesis of a dipeptide. (2S)-N-(Boc)-N′-(phenylsulfonyl)- and (2S)-N,N′-bis-(phenylsulfonyl)-3-(2-pyrrolyl)alanines (7 and 9) were obtained, respectively, in 14% and 13% overall yields and six and seven steps from oxazolidine β-methyl ester 1, which was derived from l-aspartic acid. Homoallylic ketone 2 was obtained from a copper-catalyzed cascade addition of vinylmagnesium bromide to 1 and converted into pyrrolylalanines 7 and 9 by a sequence featuring subsequent olefin oxidation and Paal-Knorr condensation. Protected pyrrolylalanine 9 was then introduced into a dipeptide.