(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in Diels–Alder reactions

A study of the Diels–Alder reactions of the esters derived from acrylic, methacrylic, trans-crotonic and trans-cinnamic acid and the chiral auxiliaries (R)- and/or (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone (4, 17, 25 and 26, respectively) with different dienes [cyclopentadiene 5, isoprene 8, 11,12-dimethylene-9,10-dihydro-9,10-ethanoanthracene 9 and anthracene 10], catalyzed by titanium tetrachloride, is described. Cyclopentadiene gave adducts with esters (R)- or (S)-4 and (R)-25 with high endo- and facial-diastereoselectivities. Diene 5 reacted with (±)-17 without endo-diastereoselectivity and failed to give a cycloadduct with (±)-26. Isoprene reacted only with ester (S)-4 with high facial-diastereoselectivity. The reaction of 9 with (R)-4 failed, because the diene was not stable under the acid reaction conditions. Adducts derived from 10 and esters (S)-4 and (R)-17 could be obtained with high facial-diastereoselectivity. LiOH-hydrolysis of the adducts derived from esters (R)- or (S)-4 and (R)-25 gave the corresponding enantiopure acids, the chiral auxiliaries being completely recovered unchanged. However, hydrolysis of the adduct derived from 10 and (R)-17, required more drastic basic conditions which partially epimerized the chiral auxiliary. X-Ray diffraction analysis of the adducts derived from 10 and esters (S)-4 and (R)-17, let us establish their relative configurations and, taking into account the absolute configuration of the starting chiral auxiliary, their absolute configurations.     

Stereoselective production of (S)-1-aralkyl- and 1-arylethanols by freshly harvested and lyophilized yeast cells

Substituted (S)-1-phenyl- 2a–h and (S)-1-benzyl-propan-2-ols 4a and b, and (S)-1-phenylethanol 6 were produced from prochiral ketones 1a–h, 3a,b and 5 by reductions with freshly harvested Zygosaccharomyces rouxii and Debaryomyces hansenii cells. The bioreductions were also performed by lyophilized cells. Comparison of the secondary alcohols from the bioreductions 2b–e,g,h and 4a and authentic (S)-alcohols (S)-2b–e,g,h and (S)-4a synthesized from enantiopure (S)-methyloxirane 7 proved the absolute configuration of the products.     

Tri- and tetrasubstituted α-fluorocyclohexanones with enantiomeric excesses in the range of 97–100%

The α-fluorinated trisubstituted ketones (2S,5R)-(−)-7-Ia, (2R,5R)-(+)-7-IIe, (2S,5R)-(−)-8-Ia and (2R,5R)-(+)-8-IIe were synthesised from (+)-dihydrocarvone (99% (R)-configuration at C-5) and fully characterised. α-Fluorinated tetrasubstituted ketones (−)-9-Ia, (+)-9-Ia, (+)-9-IIa and (+)-10-Ia having e.e.s of ≥97% were synthesised as racemates from 3-methyl cyclohexenone then resolved into the pure enantiomers using chiral HPLC and fully characterised.     

Asymmetric hydrolysis,esterfication catalyzed by esterases from porcine pancreas in the synthesis of both enantiomers of cyclopentanoid building blocks

The asymmetric synthesis of the cyclopentanoid building blocks 5 and ent-5 from the easily accessible meso-diacetates 4 and meso-diols 7, respectively by crude PPL and a carboxyl esterase from crude PPL is described. Enzymatic esterfication of 8 by crude PPL gave the cyclohexanoid monoacetate 9, whereas by hydrolysis of 10 the cyclobutenoid monoacetate 11 was obtained.     

New phenylpyridone derivatives from the Penicillium sumatrense GZWMJZ-313, a fungal endophyte of Garcinia multiflora

Citridones E-G (1-3), three new phenylpyridone derivatives together with two known curvularins (4 and 5) were isolated from the solid culture of the endophytic fungus Penicillium sumatrense GZWMJZ-313 in Garcinia multiflora. The structures of new compounds were determined in the light of spectroscopic data,X-ray and ECD calculation. Compounds 1 and 3 are racemates, while compound 2 is optically pure.Compounds 1 and 4 showed antibacterial and antifungal activities against Staphylococcus aureus,Pseudomonas aeruginosa, Clostridium perfringens, Escherichia coli and Candida albicans with MIC values ranging from 8 μg/mL to 64 μg/mL.     

New pentacyclic ring systems: intramolecular cyclization of o,o′-disubstituted bibenzothiazoles

Efficient methods for the preparation of isomeric o,o′-diaminobibenzothiazoles (8a and 11a) and o,o′-diamino-2,2′-dimethylbibenzothiazoles (8b and 11b), potentially valuable building blocks for construction of hitherto unknown dithiazolo annulated pentacyclic heterocycles, have been developed. The dithiazolo annulated benzo[c]cinnolines 9a, 9b, and 12a were prepared from the corresponding diamines by oxidation with PhI(OAc)₂ in good yield. The dithiazolo annulated carbazoles 13 and 14 were efficiently prepared from the corresponding diamines by thermal cyclization in H₃PO₄. The unusual course of reduction and product formation of o,o′-dinitrosubstituted bibenzothiazoles 6a and 6b with SnCl₂ under acidic conditions was rationalized by DFT quantum-mechanical calculations. It was suggested that cyclic products are formed from dinitroso derivatives and open-shell species immediately following on a reduction path.     

Isolation of amoenamide A and five antipodal prenylated alkaloids from Aspergillus amoenus NRRL 35600

A new prenylated alkaloid, Amoenamide A (6), was isolated from the fungus Aspergillus amoenus NRRL 35600. Previously, 6 was postulated to be a precursor of Notoamide E4 (21) converted from Notoamide E (16), which was a key precursor of the prenylated indole alkaloids in the fungi of the genus Aspergillus. We previously succeeded in the isolation of two pairs of antipodes, Stephacidin A (1) and Notoamide B (2), from A. amoenus and A. protuberus MF297-2 and expected the presence of other antipodes in the culture of A. amoenus. We here report five new antipodes (7–11) along with a new metabolite (12), which was isolated as a natural compound for the first time, from A. amoenus.     

Isolation of a new indoxyl alkaloid,Amoenamide B,from Aspergillus amoenus NRRL 35600: Biosynthetic implications and correction of the structure of Speramide B

A new prenylated indoxyl alkaloid, Amoenamide B (1), was isolated from Aspergillus amoenus NRRL 35600 along with Asperochramide A (2). Although many prenylated oxindole alkaloids, containing bicyclo[2.2.2]diazaoctane cores, have been isolated from the fungus of the genera Aspergillus and Penicillium to date, 1 is the fourth compound with the indoxyl unit containing the cores. During the structure elucidation of 1, we found that the planar structure matched to that of Speramide A (3), isolated from A. ochraceus KM007, but the reported structure of 3 was incorrect and turned out to be that of Taichunamide H (4), recently isolated from A. versicolor HDN11-84.     

Sesterterpenes and phenolic alkenes from the Thai sponge Hyrtios erectus

Sesterterpene, erectusolide A (1), six phenolic alkenes, erectuseneols A?F (2–7) and nine known compounds, luffalactone (8), luffariolide E (9), (6E)- and (6Z)-neomanoalide 24,25-diacetates (10 and 11), 6,6-dimethylundecane-2,5,10-trione (12), threo- and erythro-cavernosines (13 and 14), (4E,6E)-dehydromanoalide (15), echinoclerodane A (16), were isolated from the marine sponge Hyrtios erectus. Compound 13 was isolated for the first time from a natural source. The structures of these compounds were elucidated on the basis of spectroscopic analysis. The phenolic alkenes 3 and 7, the sesterterpenes 8–11 and 15, and compounds 12–14 were evaluated for cytotoxic activities against six cancer cell lines, MOLT-3, HepG2, HeLa, HuCCA-1, A549, and MDA-MB-231.     

Asymmetric synthesis of (S)-(−)-tetrahydropalmatine and (S)-(−)-canadine via a sulfinyl-directed Pictet–Spengler cyclization

(S)-(?)-Tetrahydropalmatine 2 and (S)-(?)-canadine 4 were synthesized in three steps from (S)-6, in 33% and 34% overall yield, respectively. Thus, condensation of the (S)-(E)-sulfinylimines 10 and 11 with the carbanion derived from (S)-6 gave the tetrahydroisoquinolines 12 and 13, respectively, which upon TFA induced N-desulfinylation, and subsequent microwave assisted Pictet–Spengler cyclization effected both cyclization and C-desulfinylation producing (S)-(?)-tetrahydropalmatine 2 and (S)-(?)-canadine 4 in optically pure form.     

Enantioselective hydrolysis of (RS)-2-fluoroarylacetonitriles using nitrilase from Arabidopsis thaliana

The enzymatic resolution of 2-fluoroarylacetonitriles (RS)-3 using nitrilase from the plant Arabidopsis thaliana is described. Racemic 2-fluoronitriles 3 are easily accessible from O-silylated aromatic cyanohydrins 2 by reaction with DAST. The nitriles (RS)-3 were hydrolysed with the nitrilase as a catalyst, not to the expected 2-fluoroarylacetic acids but to the corresponding (R)-2-fluoroarylacetamides (R)-5 as the main products. After optimization of reaction conditions (pH 9, 7°C), the enantiomeric excesses of (R)-5a,c and f (R=H, 3-Me, 3-OMe) could be improved to >99% by one recrystallization. The acid catalysed hydrolysis of (R)-5a,5c and 5f afforded the corresponding (R)-2-fluoroarylacetic acids (R)-4a,4c and 4f without racemization.     

Synthesis of (1R,cis,αS)-cypermethrine via lipase catalyzed kinetic resolution of racemic m-phenoxybenzaldehyde cyanohydrin acetate

A technical scale preparation of optically active (1R,cis,αS)-cypermethrine 4 from racemic m-phenoxybenzaldehyde cyanohydrin acetate (RS)-1 and (1R,cis)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (1R,cis)-3 is described. Key steps of the new procedure are a lipase catalyzed enantioselective transesterification of (RS)-1 with n-butanol and direct acylation of the mixture of (R)-1 and (S)-cyanohydrin (S)-2 with (1R,cis)-3 to give enantiomerically pure (1R,cis,αS)-4. The unchanged (R)-1 is removed from (1R,cis,αS)-4 by distillation, and is racemized with triethylamine to give (RS)-1 which is returned to the process. The total yield of (1R,cis,αS)-4 referred to (RS)-1 is 80%.     

Inclusion and selectivity of amides by p-terphenyl derivative bearing adamantanecarboxylic acid

Hydrogen-bonding compound (1), which is composed of p-terphenyl and adamantanecarboxylic acid, acted as a host molecule for three amides, respectively, forming crystals. Crystals containing the amides (1a and 1b) were produced from N,N-dimethylformamide (DMF) and N,N-diethylformamide (DEF) in 1:2 host:guest complexation stoichiometry, respectively, whereas guest-free crystals (1c) were generated from N-methylformamide (NMF). In the crystal structures of 1a and 1b, carboxylic acids of 1 interact with oxygen atoms of the amide guests through hydrogen bonds to afford network and layer architectures. Crystals 1a and 1b were given from equimolar binary mixtures of DMF or DEF and NMF, respectively. Further, from a mixture of DMF and DEF, guest-inclusion crystals 1d different from 1a and 1b were formed, where DMF was preferentially accommodated. Competition experiments revealed that the selectivity order of 1 for the amide guests was DMF?>?DEF???NMF.     

Enantiopure erythro- and threo-1-aryl-1-[2-pyrrolidyl]-methanols: synthesis from l-proline

Enantiopure (1R,2S)-erythro- and (1S,2S)-threo-isomers of four new aryl-pyrrolidyl alcohols 5aH, 5aMe, 5bH and 5bMe have been obtained in five steps from (−)-(S)-proline and fully characterized. The oxidation of alcohol 8 into aldehyde 9 was the most difficult step and racemization occurs during Swern oxidation but this difficulty can be overcome by using SO₃/pyridine as oxidant. Diastereomer I of the protected amino alcohol 10a crystallized and was shown to be the (1R,2S)-erythro-isomer (e-10a-I) using X-ray crystallography. Therefore the (1R,2S)-erythro structure was assigned to all compounds obtained from e-10a-I, and, as a consequence, the (1S,2S)-threo structure was assigned to diastereomers II.     

Stereochimie de la cycloaddition sur les ethers butadienyliques d'alcools chiraux. Derives en 4 et 6 de glucosides perbenzylés

Two partially protected derivatives of α-D-glucose with one free OH group function, benzyl 2,3,6-tri-O--α-D-glucopyranoside 2 and benzyl-2,3,4-tri-$\text{O}$-benzyl-α-D-glucopyranoside 4 were prepared. Base-catalysed addition of the diyne-diol 5 onto these sugars gave trans-cis mixtures of enynyl ethers, 6 and 8 from compound 2, and 7 and 9 from compound 4. Catalytic partial hydrogenation gave the corresponding butadienyl ethers 10 and 12 from 6 and 8, and 11 and 13 from 7 and 9. All trans-cis mixtures obtained could be readily separated by fractionnal crystallisation or column chromatography, thus making for the first time pure trans and cis enynyl ethers readily available in quantity. The cycloaddition of butyl glyoxylate onto the trans dienes led to mixtures of dia-stereoisomeric, dihydropyrannyl ethers, 14 (β-L) 18 (α-D) and 22 (β-D) from diene 10, and 16 (β-L), 20 (α-D) and 24 (β-D) from diene 11. Configurations were ascribed by the use of already described methods. This study brings to a number of five all examined reactions of cycloaddition onto butadienyl ethers of chiral alcohols. In each case a strong preference is observed for one of the faces of the prochiral butadienyl ether, but no great preference for the endo path of cycloaddition.     

Synthesis of new chiral N-arylsulfonyl-1,3-oxazolidin-2-ones from α-amino acids

A variety of new chiral N-arylsulfonyl-1,3-oxazolidin-2-ones were prepared in three steps starting from (d)- and (l)-amino acid. N-Arylsulfonyl amino alcohols, derived from amino acids, were carbonylated with the bis-(trichloromethyl) carbonate (BTC), in the presence of triethylamine, to provide optically pure N-phenylsulfonyloxazolidin-2-ones 3a–f, N-naphthylsulfonyloxazolidin-2-ones 3g–j and N-tosylsulfonyloxazolidin-2-ones 3k–p in good yields.     

The 7,8-epoxy-2,3,5,6-tetrakis(methylene) bicyclo[2.2.2]octane; synthesis and diels-alder reactivity

The preparation of 7,8-epoxy-2,3,5,6-tetrakis(methylene)bicyclo[2,2,2] octane (5) is described. Evidence for transannular interaction between the homoconjugated s-cis-butadiene functions in 5 is found in the UV absorption spectrum. The Diels-Alder addition of 5 to tetracyanoethylene (TCE) is syn-regioselective and leads to the monoaducts 16:17 (85:15). The dienes 16,17 are less reactive than 5 toward TCE. anti-regioselectivity (leading to exo-2, endo-3-bis(chloromethyl)-5,6-bis(methylene)-syn-7,8-epoxybicyclo[2.2.2]octaves (25) is observed in the double elimination of HCl from the syn-7,8-epoxy-exo-2,endo-3,exo-5,endo-6-tetrakis(chloromethyl)bicyclo[2.2.2]octane (11), precursor of 5. The structures of the regioisomers 16,17 were confirmed spectroscopically and chemically. Elimination of HCl from the chloromethyl groups in 26 (TCE adduct of 25) and HCN from the TCE adducts 16, 17 and 26 can be induced by CsF in DMF.     

A radical version of the bromine cyclization of alkenols

The scope of an alkoxyl radical version of the classical bromine cyclization was explored. Oxygen-centered radicals were generated in photochemically initiated radical chain reactions from N-alkenoxy-4-(p-chlorophenyl)thiazole-2(3H)-thiones 5a–c, N-alkenoxy-4-methylthiazole-2(3H)-thiones 13, 14, 21, rac-23, and N-alkenoxypyridine-2(1H)-thiones 6d–f, 16, rac-25. Thus, 2-(2-bromopropyl)-substituted tetrahydrofurans 4a–c, which are minor compounds (< 10 %) in NBS-mediated bromine cyclizations of corresponding alkenols 1a–c, were prepared in 87–90 % yield and with good to excellent diastereoselectivities. Further, photochemical conversions of O-alkyl thiohydroxamates 14, 16 and 21 in benzene and BrCCl₃ afforded β-oxy-functionalized bromomethyl substituted tetrahydrofurans 29, 34, and 36. The results of this study indicate, that efficient 5-exo-trig cyclizations of β-oxy-substituted 4-penten-1-oxyl radical require an electronwithdrawing substituent at the β-heteroatom substituent. In the third part of the study a synthetically useful new access to oxabicyclo〚4.3.0〛nonanes rac-38 and rac-40 is reported which takes profit from highly diastereoselective 5-exo-trig-ring closures and, in case of the formation of rac-40, stereoselective bromine atom transfer.     

Conformational study of α-arylethylamides of (−)-camphanic acid

The absolute conformation and configuration of diastereomeric amides (4A,B–6A,B) of (1S,3R)-camphanic acid (lactone of 1-hydroxy-2,2,3-trimethylcyclopentan-1,3-dicarboxylic acid, (−)-camphanic acid 9) with α-arylethylamines 1–3 are deduced from ¹H NMR data and MM2 calculations. The α-arylethyl group in diastereomers A and B adopt nearly opposite absolute conformations, stabilized by hydrogen bonding in the syn-oriented O–C(1)–C(6)–N–H unit, and repulsive interaction between the 1′C–Me group and the amide CO group. The absolute configuration (1′S) is assigned to the 4A–6A diastereomers, and the (1′R)-configuration to the 4B–6B diastereomers; this assignment is confirmed by the preparation of 4A and 5A from enantiomerically pure (1′S)-α-arylethylamines 1 and 2, respectively. These results also enabled the assignment of pro-R (H_R) and pro-S (H_S) protons in the benzyl derivative 7.     

Regio- and stereospecific models for the biosynthesis of the indole alkaloids—III : The Aspidosperma-Iboga-secodine relationship

In vitro transformation of the Aspidosperma alkaloid (?) tabersonine (1) to (±)-pseudocatharanthine (7) via (+) allocatharanthine (6) and dehydrosecodine A (3) is described as a model for the biochemical interconversion of Aspidosperma and Iboga alkaloids. Facile conversion of 1, 2 and 7 in xylene solution to the carbazole (9) suggests the intermediacy of dehydrosecodines (as 8) in these reactions. In methanol solution the racemic salt (12) is formed in 50% yield from catharanthine at 175°. Further pyrolysis of the salt yields the carbazole (9). Reduction of the salt (12) with NaBH₄ affords (±) dihydrosecodine (16) identical with the natural alkaloid from Rhazya stricta.