Asymmetric synthetic study of macrolactin analogues

We designed two aromatic analogues 1a and 1b of macrolactin A with expectation of enhancing biological activity and metabolical stability. As a result of retrosynthetic analysis of these compounds 1a-b, two synthetic strategies have been examined. The first strategy includes the enantioselective addition of nonadienyl anion, derived from 3, to aldehyde 4 as a key step. The second one includes epimerization of ynone 7 to (E,E)-conjugated dienone 31 and subsequent diastereoselective hydride-reduction of 31. Although the former route furnished no desired target, the latter one was revealed to work well for the synthesis of 1. Unfortunately, the aimed (2Z,4E)-analogue 1a could not be synthesized due to an epimerization of the (2Z)-olefin into the (2E)-olefin. However, these methods could be applied to the total asymmetric synthesis of the (2E,4E)-analogue 1b. Overall, control of all of the four stereocenters was achieved by means of asymmetric and diastereoselective reactions without using any chiral natural sources.     

Ultrasound-assisted convenient synthesis of hypolipidemic active natural methoxylated (E)-arylalkenes and arylalkanones

An ultrasound-assisted convenient method was developed for the conversion of toxic methoxylated cis-isomer of arylalkenes into its hypolipidemic active trans-isomer. Treatment of cis-isomer or mixture of all three isomers (1a-1j) with ammonium formate and 10% Pd/C gave arylalkanes (2a-2j), which upon oxidation with DDQ in anhydrous dioxane containing a little amount of silica gel, provided (E)-arylalkenes (3a-3g) in 42-72% yield depending upon the substituents attached at the aryl ring. The same method, upon addition of a few drops of water, provided hypolipidemic active arylalkanones (3h-3j) in 59-65% yield.     

Isolation and synthesis of N-acyladenine and adenosine alkaloids from a southern Australian marine sponge, Phoriospongia sp.

Chemical fractionation of the southern Australian marine sponge Phoriospongia sp. (CMB-03107) yielded phorioadenine A (1) as a nematocidal agent and the first reported example of a 6-N-acyladenine natural product. The structure of 1 was confirmed by spectroscopic analysis and the chemical synthesis of racemic (1a) and enantiomeric (1b) analogues. HPLC–ESIMS analysis of the crude sponge extract with comparisons to the synthetic 6-N-acyladenosine 2a provided evidence that the biosynthetically related adenosine, phorioadenosine A (2), was present as a trace co-metabolite. The rare starfish metabolite asterubine (3) was also isolated as a co-metabolite, and its structure confirmed by spectroscopic analysis and chemical synthesis. Biological investigations confirmed that natural products 1–3 and synthetic analogues 1a–e and 2a were not cytotoxic to multiple mammalian cancer cell lines, or Gram-positive or -negative bacteria. Nematocidal activity (inhibition of larval development of Haemonchus contortus) detected in the Phoriospongia sp. extract was attributed to 1 (LD₉₉ 31 μg/mL), with preliminary structure–activity relationship investigations confirming the importance of the N-acyl side chain.     

Methylene-2-ethynylcyclopropanes: synthesis and biological activity of (Z)- and (E)-9-{[2-ethynyl-2-(hydroxymethyl)cyclopropylidene]methyl}adenine and -guanine

Synthesis of methylene-2-ethynylcyclopropane analogues of nucleosides 12a, 12b, 13a, and 13b is described. Ethyl methylenecyclopropane carboxylate 14 was hydroxymethylated to give alcohol 15, which was reduced to diol 16. Selective protection with tert-butyldimethylsilyl group gave derivative 17, which was oxidized to aldehyde 18. Wittig reaction with CBr₄ gave dibromoalkene 19. Elimination of both bromine atoms afforded methylene-2-ethynylcyclopropane 20. Bromoselenenylation using N-bromosuccinimide and diphenyldiselenide gave intermediate 21. Alkylation of adenine and 2-amino-6-chloropurine with 21 provided the Z,E-isomeric mixtures 22a and 22c. Oxidation afforded selenoxides 23a and 23c. Mild thermolysis furnished methylenecyclopropanes Z-24a, E-24a, and 24c. Deprotection and separation of Z,E-isomers gave adenine analogues 12a and 13a, and 2-amino-6-chloropurine intermediates 12c and 13c. Hydrolytic dechlorination of 12c and 13c afforded guanine analogues 12b and 13b. Adenine Z-isomer 12a inhibits replication of Epstein-Barr virus through its cytotoxicity. The E-isomer 13a is a substrate for adenosine deaminase.     

Synthesis of the fungal natural product (−)-xylariamide A

The first synthesis of the fungal natural product (−)-xylariamide A 1 is reported. N,O-Bis(trimethylsilyl)acetamide induced coupling of d-tyrosine with (E)-but-2-enedioic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester 5 produced the dechloro natural product 6, which was subsequently monochlorinated using oxone and KCl to yield synthetic 1. (−)-Xylariamide A 1, (+)-xylariamide A 2 and (−)-dechloroxylariamide A 6 displayed no cytotoxic or antimicrobial activity.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Synthesis, structural revision, and biological activities of 4′-chloroaurone, a metabolite of marine brown alga Spatoglossum variabile

4′-Chloroaurone (1a), the only aurone reported from a marine source, Spatoglossum variabile was synthesized from 2-hydroxyacetophenone along with six structural analogs. The products obtained were Z-isomers and these were converted into E-isomers by photoisomerization. The E and Z isomers of aurones showed distinct proton and carbon chemical shifts. However, the spectroscopic data of either Z-4′-chloroaurone (1a) or its E-isomer (2a) did not match with those reported for the natural product and thus requires revision of the structure assigned. The proton NMR spectroscopic data reported for the natural product matches with those reported for a known isocoumarin (5). The synthesized E and Z aurones were evaluated for their antioxidant and antibacterial activities. The aurone, Z-2-[(3,4-dihydroxyphenyl)methylene]benzo[b]furan-3-one exhibited significant antioxidant activity. Interestingly, Z-aurones are active against Gram-positive and Gram-negative bacteria, whereas the corresponding E-aurones were inactive.     

A New Alkylation-Elimination Method for Synthesis of Antiviral Fluoromethylenecyclopropane Analogues of Nucleosides

A new method for the synthesis of fluoromethylenecyclopropane nucleosides by alkylation-elimination procedure is described. Fluorination of methylenecyclopropane carboxylate 6 gave fluoroester 7. Treatment of 7 with phenylselenenyl bromide afforded the desired ethyl (E)-2-bromomethyl-1-fluoro-2-phenylselenenylcyclopropane-1-carboxylate 11 in 85% yield. DIBALH reduction of 11 gave 13, which after acetylation to 14 was reacted with 2-amino-6-chloropurine to give the 9-alkylated product 15 in 87% yield. Se-oxidation of 15 with hydrogen peroxide afforded 16, which underwent smooth elimination in a mixture of THF-DMF at 60 °C giving rise to a Z,E mixture of protected nucleosides 17. Deacetylation gave Z-1a and E-1a which were separated on a silica gel column. Both Z-1a and E-1a were converted into the respective guanine analogues Z-1b and E-1b.     

Determination of the absolute structure of albaconol

The concise synthesis of (8aR)-(−)-albaconol (1) from (8aR)-albicanol (2) obtained from the lipase-assisted asymmetric acetylation of rac-2, was achieved in 45% overall yield (eight steps). By comparison of the sign of specific rotation of between synthetic (8aR)-(−)-albaconol (1) and natural (+)-albaconol (1), the absolute structure of natural (+)-1 was determined to be 1R,2R,4aS,8aS configuration.     

Different recognitions of (E)- and (Z)-1,1′-binaphthyl ketoximes using lipase-catalyzed reactions

Lipase-catalyzed hydrolysis of (E)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1a] and (Z)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1b] yielded optically active (E)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(S)-2a] and (Z)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(R)-2b], respectively, with high enantiomeric excess. Selectivity for the opposite enantiomer of the axial binaphthyl skeleton was shown by (Z)-isomer 1b against (E)-isomer 1a.     

Stereoselective synthesis of 2-methylenepyrrolizidines by tandem cyclization of N-propargylaminyl radicals

Tandem cyclization of N-propargylaminyl radicals, generated by N-chlorination of (E)-alk-4-enylamines 2a-d and 2f followed by treatment with tributyltin radical, afforded 2-methylenepyrrolizidines 3a-d and 3f in a highly stereoselective manner. A similar radical cyclization of (Z)-N-propargyl-1-methyl-5-phenylpent-4-enylamine (2e) gave pyrrolizidine 3b having the same stereochemistry as that obtained from the E isomer 2b.     

Photochemistry of 3,6-bis(styryl)pyridazines in solution and in neat liquid crystalline phase—optical switching and imaging techniques

3,6-Bis(styryl)pyridazines 1a-f with 2-6 alkoxy groups show on irradiation in solution a stereoisomerization which leads to a photostationary state of (E,E)- and (E,Z)-isomer. Sensitizing and quenching experiments reveal that the (E,E)→(E,Z) route is a pure triplet process, whereas the (E,Z)→(E,E) route can have a minor singlet by-reaction.Hexyloxy or dodecyloxy chains on the terminal benzene rings convey the (E,E)-isomers of compounds 1a,b,d-f thermotropic liquid crystalline properties. In particular S_A, S_C, and S_F/I phases were studied with regard to their photochemical behavior. Depending on the system, photodegradation of the smectic phase to the isotropic melt (S→I) or photoinduction of the smectic phase (I→S) can be achieved by alteration of the (E,E)/(E,Z) ratio. These processes represent the basis for imaging techniques (writing and erasing of information).     

Substituted six-membered ring carbenes: the effects of amino and cyclopropyl groups through DFT calculations

DFT calculations are employed to compare and contrast six-membered ring carbenes including 1,3-dimethyltetrahydropyrimidin-2-ylidene (1a), 1-methyl-3-cyclopropyltetrahydropyridine-2-ylidene (2a), and 1,3-dicyclopropylcyclohexane-2-ylidene (3a) as well as their unsaturated analogues 1b, 2b, 3b, and 2c. The amino groups exert singlet-triplet energy separation (?E_s−t) of 60.9 kcal/mol to 1a while cyclopropyls induce a ?E_s−t of 14.8 kcal/mol to 3a. The simultaneous presence of amino and cyclopropyl in 2a leads to a ?E_s−t of 43.3 kcal/mol. Unsaturation slightly increases the ?E_s−t of 1a and 3a but not that of 2a. Our thermodynamic, kinetic, and reactivity results are compared with those of synthetic five-membered ring N-heterocyclic carbenes.     

Base-catalyzed stereoselective intermolecular addition of imidazoles onto alkynes: an easy access to imidazolyl enamines

An efficient transition metal-free approach for the regio- and stereoselective addition of imidazoles 1a–f onto alkynes 2a–l to provide the Z- and E isomers of imidazolyl enamines 3a–q and 4a–d using catalytic amount of KOH is described. Stereoselectivity of the addition products (Z and E isomer) was found to be dependent upon time. Competitive experiments show that imidazole is less reactive than pyrrole and more reactive than aniline towards hydroamination.     

An efficient synthesis of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles and cyanomethyl appended pyrimidines

A series of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles 5a-j and aryl/heteroaryl tethered pyrimidin-4-yl acetonitriles 6a-e has been synthesized in excellent yields through base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 3 using 2-aminopyrazine 4a and arylamidinium salts 4b, separately.     

Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-component domino reaction

An efficient, three-component domino reaction of dimedone 1, aromatic aldehydes (2a–o), and 1,3-cyclohexanedione 1a in the regio-selective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones (3a–o) is reported. The desired product, 3 is efficiently promoted by ascorbic acid as an organo catalyst.     

A non-catalytic regioselective approach to the synthesis of (E)-stilbenes from suitably functionalized 2H-pyran-2-ones

Highly functionalized (E)-stilbenes 3a-m and 4-aryl-6-styryl-pyran-2-ylidineacetonitriles 4a-b have been prepared and delineated through the ring transformation of 6-aryl-3,4-disubstituted-2H-pyran-2-ones 1 with commercially available (E/Z)-4-phenyl-3-buten-2-one 2 without the use of any catalyst.     

An unexpected formation of pyrazolopyrimidines during the attempted to obtain 5-substituted tetrazoles from carbonitriles

In this Letter, we described the synthesis of new 5-(5-amino-1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 2a–c from 5-amino-1-aryl-1H-pyrazole-4-carbonitriles 1a–c as well as the unexpected 1H-pyrazolo[3,4-d]pyrimidine derivatives 6a–c from 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles 4a–c, instead of 5-(5-amino-1-aryl-3-methyl-1H-pyrazole-4-yl)-1H-tetrazoles 5a–c as desired. In an attempt to obtain these tetrazole derivatives containing the methyl group at C3-position in the pyrazole ring, the amino group in 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile 4c was protected by the reaction with sodium hydride and di-tert-butyl-dicarbonate (Boc). The tetrazole derivative 5c was synthesized from the protected compound 7c using analogue methodology to obtain 2a–c and 6a–c.     

Convenient synthesis of 3-fluoro-4,5-diphenylfuran-2(5H)-one from benzoin ethers : Novel and efficient Z-E isomerisation and cyclisation of 2-fluoroalkenoate precursors, substitution of vinylic fluorine

Mixtures of ethyl (E)- and (Z)-4-alkoxy-2-fluoro-3,4-diphenylbut-2-enoates (6-8) prepared from benzoin ethers and ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate were transformed in high yields to the target 3-fluoro-4,5-diphenylfuran-2(5H)-one (14) using bromine in tetrachloromethane at room temperature. The non-cyclisable Z-isomers 6b-8b were gradually isomerised to the cyclisable E-isomers 6a-8a during the process. The reaction of the (E)-butenoates 6a-8a with boron trifluoride led to furanone 14, while in Z-isomers 6b-8b both alkoxy group and vinylic fluorine were substituted with bromine during the reaction. Mechanisms for both complex reactions have been proposed. Furanone 14 was transformed to 2-[tert-butyl(dimethyl)silyloxy]-3-fluoro-4,5-diphenylfuran (18) as a novel building block.     

New reactions and step economy: the total synthesis of (±)-salsolene oxide based on the type II transition metal-catalyzed intramolecular [4+4] cycloaddition

Studies on the viability of the type II nickel-catalyzed intramolecular [4+4] cycloaddition of bis-dienes show that it is influenced by both diene substitution and geometry. Both E- and Z-isomers of 19 and 20 react, albeit at markedly different rates, to afford cycloadducts, whereas only the Z-isomer of 9 (and not the E-isomer) reacts to give 8 and 25. Chemoselective elaboration of 8 to (±)-salsolene oxide (7) was used to confirm the cycloadduct structure while establishing a step economical route to the natural product.