Stereoselective synthesis of (R)-(+)-1-methoxyspirobrassinin, (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether and their enantiomers or diastereoisomers

Stereoselective synthesis of cruciferous indole phytoalexin (R)-(+)-1-methoxyspirobrassinin and its unnatural (S)-(−)-enantiomer was achieved by spirocyclization of 1-methoxybrassinin in the presence of (+)- and (−)-menthol and subsequent oxidation of the obtained menthyl ethers. Methanolysis of menthyl ethers in the presence of TFA afforded (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether as well its unnatural (2S,3S)-, (2R,3S)-, and (2S,3R)-isomers.     

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of common cutworm (Spodoptera litura)

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of Spodoptera litura was carried out. Substrate was converted to three new terpenoids, (+)-(1R,2S)-10-hydroxyfenchol, (+)-(1R,2R,3S)-8-hydroxyfenchol and (−)-(1S,2S,6S)-6-exo-hydroxyfenchol, and one known terpenoid, (−)-(1R,2R,3R)-9-hydroxyfenchol. These structures were established by NMR, IR, specific rotation and mass spectral studies.     

Asymmetric synthesis of (−)-chicanine using a highly regioselective intramolecular Mitsunobu reaction and revision of its absolute configuration

First asymmetric synthesis of (−)-chicanine has been accomplished in 14 steps by employing the Evans asymmetric syn-selective aldol reaction, diastereoselective hydroboration and an regioselective, intramolecular Mitsunobu etherification. The absolute configuration of (+)- and (−)-chicanine has been revised to 2R,3S,4R,5R and 2S,3R,4S,5S, respectively, through CD analysis.     

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.     

Absolute configuration of gomadalactones A, B and C, the components of the contact sex pheromone of Anoplophora malasiaca

Absolute configuration of gomadalactones A (1), B (2) and C (3), the pheromone components of the white-spotted longicorn beetle (Anoplophora malasiaca) was assigned as (1S,4R,5S)-1, (1R,4R,5R)-2 and (1S,4R,5S,8S)-3 by comparing their published CD spectra with those of (1R,5R)-(+)-4,4,8-trimethyl-3-oxabicyclo[3.3.0]oct-7-ene-2,6-dione (4) and (1S,5R,8S)-(+)-4,4,8-trimethyl-3-oxabicyclo[3.3.0]octane-2,6-dione (5) prepared from (R)-(−)-carvone (6).     

δ-Lactone formation from δ-hydroxy-trans-α,β-unsaturated carboxylic acids accompanied by trans-cis isomerization: synthesis of (−)-tetra-O-acetylosmundalin

(±)-(4,5-anti)-4-Benzyloxy-5-hydroxy-(2E)-hexenoic acid 6 was subjected to δ-lactonization in the presence of 2,4,6-trichlorobenzoyl chloride and pyridine to give the α,β-unsaturated-δ-lactone congener (±)-7 (87% yield) accompanied by trans-cis isomerization. This δ-lactonization procedure was applied to the chiral synthesis of (+)-(4S,5R)-7 or (−)-(4R,5S)-7 from the chiral starting material (+)-(4S,5R)-6 or (−)-(4R,5S)-6. Deprotection of the benzyl group in (+)-(4S,5R)-7 or (−)-(4R,5S)-7 by the AlCl₃/m-xylene system gave the natural osmundalactone (+)-(4S,5R)-5 or (−)-(4R,5S)-5 in good yield, respectively. Condensation of (−)-(4R,5S)-5 and tetraacetyl-β-d-glucosyltrichloroimidate 22 in the presence of BF₃·Et₂O afforded the condensation product (−)-8 (97% yield), which was identical to tetra-O-acetylosmundalin (−)-8 derived from natural osmundalin 9.     

Synthesis, resolution and assignment of absolute configuration of trans 3-amino-1-oxyl-2,2,5,5-tetramethylpyrrolidine-4-carboxylic acid (POAC), a cyclic, spin-labelled β-amino acid

Racemic trans 3-(9-fluorenylmethyloxycarbonylamino)-1-oxyl-2,2,5,5-tetramethylpyrrolidine-4-carboxylic acid (Fmoc-POAC-OH), prepared by conventional methods, was resolved upon esterification with (aR)-2,2′-dihydroxy-1,1′-binaphthyl. Separation of the obtained diastereomeric monoesters Fmoc-(±)-trans-POAC-O-(aR)-binaphthol by crystallization/chromatography, and removal of the chiral auxiliary by saponification of the aryl ester function furnished both enantiomers (+)-(3R,4R)-Fmoc-POAC-OH and (−)-(3S,4S)-Fmoc-POAC-OH. The absolute configuration of the asymmetric C³, C⁴ carbons of POAC were assigned from the induced circular dichroism of a flexible biphenyl probe present in the terminally protected dipeptide derivatives Boc-Bip-(+)-POAC-OMe and Boc-Bip-(−)-POAC-OMe (Bip, 2′,1′:1,2;1″,2″:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid). This assignment was confirmed by X-ray diffraction analysis of the diastereomeric monoester Fmoc-(+)-trans-POAC-O-(aR)-binaphthol, shown to be (aR,3R,4R). Solution synthesis of peptides to the hexamer level, based on the (3R,4R)-POAC enantiomer combined with (1S,2S)-2-aminocyclopentane-1-carboxylic acid, was carried out to examine coupling conditions at both C- and N-termini of the POAC residue, in view of further syntheses and 3D-structural investigations.     

Enantioselective syntheses of both enantiomers of cis-pyrrolidine 225H

The efficient and expeditious syntheses of both enantiomers of the amphibian alkaloid cis-225H have been achieved. Utilizing a common cis-2,5-disubstituted pyrrolidine building block derived from (+)-2-tropinone, the enantioselective syntheses have established the absolute configuration of these alkaloids as (+)-(2R,5S) and (−)-(5S,2R).     

Regioselective rearrangement of 7-azabicyclo[2.2.1]hept-2-aminyl radicals: first synthesis of 2,8-diazabicyclo[3.2.1]oct-2-enes and their conversion into 5-(2-aminoethyl)-2,3,4-trihydroxypyrrolidines, new inhibitors of α-mannosidases

Enantiomerically pure 2,8-diazabicyclo[3.2.1]oct-2-ene derivatives (+)-5 and (−)-5 have been obtained from 2-azido-3-tosyl-7-azabicyclo[2.2.1]heptanes (+)-1 and (−)-2 and their enantiomers, by ring expansion under radical conditions. Compounds (+)-5 and (−)-5 were transformed into hemiaminals 9 ((3S,4R,5R)- and 10 ((3R,4S,5S)-5-(2-aminoethyl)-2,3,4-trihydroxypyrrolidine) that are good inhibitors of α-mannosidases.     

Synthesis of (−)- and (+)-8-fluoro-galanthamine

The synthesis of racemic 8-fluorogalanthamine and its separation into (−)- and (+)-8-fluorogalanthamine (= (4aS,6R,8aS)- and (4aR,6S,8aR)-1-fluoro-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol) is described.     

Temporary thio-derivatization in the synthesis of (+)-4-acetylbromoxone

A stereocontrolled synthesis of the marine natural products (+)-bromoxone (1) and (+)-4-acetylbromoxone (2) is reported. The sequence features the enzymatic kinetic resolution of 4-hydroxycyclohexenone (6) via its S-benzyl adduct. Thereafter, a base-mediated elimination-silylation generated an optically active (−)-4S-4-tert-butyldimethylsilyoxycyclohexenone (5), which then underwent diastereoselective epoxidation. Saegusa-Ito oxidation enabled formation of the corresponding α,β-unsaturated ketone 13. Bromination-elimination and subsequent removal of the silicon protecting group afforded (+)-bromoxone (1) which was converted into (+)-(4S,5R,6R)-4-acetoxy-2-bromo-5,6-epoxycyclohex-2-enone (2) [(+)-4-acetylbromoxone]. Using a luciferase gene reporter assay ED₅₀ for NFκB inhibition of 9 μM was determined.     

Synthesis, characterization and nonlinear optical properties in a series of new chiral organotin(IV) Schiff base complexes

Four new chiral organotin derivatives are reported with their crystal structure. They were synthesized by reaction of diphenyltin oxide and four different ligands obtained from the Schiff base condensation of 4-(diethylamino)salicylaldehyde and (1R,2S)-(+)-norephedrine, (R)-(−)-phenylglycinol, (R)-(−)-1-amino-2-propanol and (1S,2R)-2-amino-1,2-diphenylethanol. Their nonlinear optical properties were investigated experimentally in solid state and with the electric field induced second harmonic (EFISH) technique. In particular, the compound obtained with (R)-(−)-phenylglycinol exhibits an efficiency 11 times that of urea in second harmonic generation at 1.907 μm. The properties are discussed in relation with computational studies conducted within the framework of the DFT theory.     

(+)-Cystothiazole G: isolation and structural elucidation

Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpent-4-yne-1,2-diol (6) derived from (2R,3S)-epoxybutanoate 5 followed by methylation gave the tetrahydro-2-furylidene acetate (−)-7, which was converted to the left-half aldehyde (+)-3. A Wittig reaction between (+)-3 and the phosphoranylide derived from the bithiazole-type phosphonium iodide 4 using lithium bis(trimethylsilyl)amide afforded the (+)-cystothiazole G (2), whose spectral data were identical with those of the natural product (+)-2. Thus, the stereochemistry of cystothiazole G (2) was proved to be (4R,5S,6(E)).     

Neat total synthesis of six monoterpenic alkaloids of the actinidine series

A concise enantiopure synthesis of six monoterpenic alkaloids of the actinidine series possessing a cyclopenta[c]pyridine skeleton, (+)-deoxyrhexifoline (4), (+)-boschniakinic acid (5), (+)-boschniakine (6), (−)-plantagonine (7), (−)-indicaine (8) and (−)-tecostidine (9) is reported starting with the chiral precursor 3-bromo-5-((4R)-phenyloxazolin-2-yl)pyridine (10). It involves a C-4 regioselective connection of a butene appendice and an intramolecular 5-exo-trig Heck annulation sequence followed by hydrogenation of the exocyclic alkene. Mixture of (3R)- and (3S)-7-((4R)-phenyloxazolin-2-yl)cyclopenta[c]pyridines was separated by HPLC before being transformed into enantiopure natural products (4-9) by modification of the oxazoline group.     

Total synthesis of (+)-negamycin and its 5-epi-derivative

(+)-Negamycin was prepared in 13 steps in an overall yield of 31% from commercially available ethyl (R)-(+)-4-chloro-3-hydroxybutanoate. The key step in the reaction sequence was a highly stereoselective asymmetric Michael addition of chiral amine (−)-21 [(1S,2R)-(−)-2-methoxybornyl-10-benzylamine] into the α,β-unsaturated carbonyl moiety of key intermediate 8, thus establishing the second chiral center in (+)-negamycin. 5-epi-Negamycin was also prepared in a similar fashion.     

The first asymmetric synthesis of all four isomers of cis- and trans-3,4-dihydroxy-3,4-dihydromollugin

Asymmetric synthesis of all the four stereoisomers of cis-3,4-dihydroxy-3,4-dihydromollugins 4 and 6 and trans-3,4-dihydroxy-3,4-dihydromollugins 5 and 7 was achieved. The O-methoxymethyl mollugin derivatives were dihydroxylated to (−)- and (+)-cis-3,4-dihydroxy-3,4-dihydromollugin derivatives using both AD-mix-α and AD-mix-β. Deprotection of the MOM-ethers of cis-dihydroxy compounds resulted in the targeted stereoisomers (−)-(3R,4R)-cis-3,4-dihydroxy-3,4-dihydromollugin 4, (−)-(3R,4S)-trans-3,4-dihydroxy-3,4-dihydromollugin 5, (+)-(3S,4S)-cis-3,4-dihydroxy-3,4-dihydromollugin 6 and (+)-(3S,4R)-trans-3,4-dihydroxy-3,4-dihydromollugin 7. These routes were paved with difficulties, for example, incompatibility of the substrates with AD-mixes, the unexpected formation of trans-dihydroxy compounds and failures in deprotection protocols.     

Gold catalysis in stereoselective natural product synthesis: (+)-linalool oxide, (−)-isocyclocapitelline, and (−)-isochrysotricine

A stereoselective synthesis of the tetrahydrofuran-containing natural products (2S,5R)-(+)-linalool oxide (1), (−)-isocyclocapitelline (2), and (−)-isochrysotricine (3) is reported. Key steps are the copper-mediated S_N2′-substitution of propargyl oxiranes 7 and the gold-catalyzed cycloisomerization of dihydroxyallenes 8/17, resulting in a highly efficient center-to-axis-to-center chirality transfer. The enantioselective total synthesis of (−)-isocyclocapitelline (2) and (−)-isochrysotricine (3) allowed the elucidation of the absolute configuration of these β-carboline natural products.     

Enantioselective synthesis of axially chiral 1-(1-naphthyl)isoquinolines and 2-(1-naphthyl)pyridines through sulfoxide ligand coupling reactions

Racemic 1-(1′-isoquinolinyl)-2-naphthalenemethanol rac-12 was prepared through a ligand coupling reaction of racemic 1-(tert-butylsulfinyl)isoquinoline rac-7 with the 1-naphthyl Grignard reagent 10. Resolution of rac-12 was achieved through chromatographic separation of the Noe-lactol derivatives 14 and 15, providing (R)-(−)-12 of >99% ee and (S)-(+)-12 of 90% ee. The ligand coupling reaction of optically enriched sulfoxide (S)-(−)-7 (62% ee) with Grignard reagent 10 furnished rac-12, with the absence of stereoinduction resulting from competing rapid racemisation of the sulfoxide 7. Reaction of optically enriched (S)-(−)-7 with 2-methoxy-1-naphthylmagnesium bromide was also accompanied by racemisation of the sulfoxide 7, and furnished optically active (+)-1-(2′-methoxy-1′-naphthyl)isoquinoline (+)-3b in low enantiomeric purity (14% ee). The absolute configuration of (+)-3b was assigned as R using circular dichroism spectroscopy, correcting an earlier assignment based on the Bijvoet method, but in the absence of heavy atoms. Optically active 2-pyridyl sulfoxides were found not to undergo racemisation analogous to the 1-isoquinolinyl sulfoxide 7, with the ligand coupling reactions of (R)-(+)- and (S)-(−)-2-[(4′-methylphenyl)sulfinyl]-3-methylpyridines, (R)-(+)-17 and (S)-(−)-17, with 2-methoxy-1-naphthylmagnesium bromide providing (−)- and (+)-2-(2′-methoxy-1′-naphthyl)-3-methylpyridines, (−)-18 and (+)-18, in 53 and 60% ee, respectively. The free energy barriers to internal rotation in 3b and 18 have been determined, and the isoquinoline (R)-(−)-12 examined as a ligand in the enantioselectively catalysed addition of diethylzinc to benzaldehyde; (R)-(−)-12 was also converted to (R)-(−)-N,N-dimethyl-1-(1′-isoquinolinyl)-2-naphthalenemethanamine (R)-(−)-19, and this examined as a ligand in the enantioselective Pd-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate.     

Rapid access to cis-cyclobutane γ-amino acids in enantiomerically pure form

The (+)-(1R,2S) and (−)-(1S,2R) stereoisomers of 2-(aminomethyl)cyclobutane-1-carboxylic acid have been prepared using a short and efficient strategy, which employs the photochemical [2+2] cycloaddition reaction between ethylene and an unsaturated γ-lactam as the key step.     

Absolute configuration of (-)-biflora-4,10(19),15-triene,a diterpene from a termite soldier,as determined by the synthesis of its (1R, 6S, 7S, 11R)-(+)-isomer

(1R, 6S, 7S, 11R)-(+)-Biflora-4, 10(19),15-triene was synthesized starting from (r)-(+)-citronellic acid. This enabled us to assign (1S), 6R, 7R, (11S)-stereochemistry to the naturally occurring (-)-enantiomer isolated from soldiers of the termite species Cubitermes umbratus.