Determination of the absolute configuration of marine oxylipin topsentolide A1 by the synthesis of the enantiomer of the natural product

Two possible stereoisomers of topsentolide A₁, a cytotoxic oxylipin against human solid tumor cell lines, were prepared in order to determine the stereochemistry of natural product. That is, the enantiomer of topsentolide A₁, (8S,11S,12R)-isomer, and its diastereomer was efficiently synthesized in a stereoselective manner. The stereochemistry of topsentolide A₁ was determined to be 8R,11R,12S by comparing NMR spectra and specific rotations of the synthetic isomers and the natural product.     

Synthesis of topsentolides A2 and C2, and non-enzymatic conversion of the former to the latter

The first total synthesis of the marine-derived cytotoxin topsentolide A₂, which eventually culminated in its stereochemical determination, was accomplished in 17 steps from a known chiral alcohol. An improved synthesis of its congener, topsentolide C₂, from a synthetic intermediate of topsentolide A₂ was also performed by utilizing the Yamaguchi lactonization to construct its nine-membered lactone ring. Treatment of epoxide ring-containing topsentolide A₂ with HCl/MeOH brought about its quantitative conversion into topsentolide C₂.     

Synthesis of chiral-at-metal half-sandwich ruthenium(II) complexes with the CpH(PNMent) tripod ligand

Treatment of the chiral tripod ligand (L_Ment,S_C)-CpH(PN_Ment) with (Ph₃P)₃RuCl₂ in ethanol afforded the two chiral-at-metal diastereomers (L_Ment,S_C,R_Ru)- and (L_Ment,S_C,S_Ru)-[Cp(PN_Ment)Ru(PPh₃)Cl] (70% de) in which the cyclopentadienyl group and the P atom of the ligand coordinated at the metal center. The (L_Ment,S_C,R_Ru)-diastereomer was isolated by crystallization from ethanol-pentane and its structure was established by X-ray crystallography. The (L_Ment,S_C,R_Ru)-diastereomer epimerized in CDCl₃ solution at 60 °C in a first-order reaction with a half-life of 5.66 h. In alcoholic solution epimerization occurred at room temperature. Substitution of the chloride ligand in (L_Ment,S_C,R_Ru)- and (L_Ment,S_C,S_Ru)-[Cp(PN_Ment)Ru(PPh₃)Cl] by nitriles NCR (R = Me, Ph, CH₂Ph) in the presence of NH₄PF₆ gave mixtures of the diastereomers (L_Ment,S_C,R_Ru)- and (L_Ment,S_C,S_Ru)-[Cp(PN_Ment)Ru(PPh₃)NCR]PF₆. Treatment of (L_Ment,S_C,R_Ru)- and (L_Ment,S_C,S_Ru)-[Cp(PN_Ment)Ru(PPh₃)Cl] with piperidine or morpholine in the presence of NH₄PF₆ led to the chiral-at-metal diastereomers (L_Ment,S_C,R_Ru)- and (L_Ment,S_C,S_Ru)-[Cp(PN_Ment)Ru(PPh₃)NH₃]PF₆ (6% de).     

Chiral memory effects in catalytic hydrogenations with dynamically chiral ligands

The low barrier for interconversion of chiral conformations of the dynamically chiral 2,2′-biphenyl ligand NMe₂C₆H₄C₆H₄PCy₂ is raised upon coordination. The individual enantiomers of the planar chiral arene-tethered complex Ru(η⁶:η¹- NMe₂C₆H₄C₆H₄PCy₂)Cl₂ (1), however, do not undergo racemization readily. A second source of chirality, such as a chiral diamine, can be included by conversion of 1 into a dicationic analogue [Ru(η⁶:η¹-NMe₂C₆H₄C₆H₄PCy₂)((1S,2S)-DPEN)](SbF₆)₂ (2), which is a catalyst precursor for the hydrogenation of aryl ketones. Two epimers of 2, R_Ar,S,S and S_Ar,S,S, are formed when starting from racemic 1; this 1:1 mixture of diastereomers catalyzed the asymmetric hydrogenation of acetophenone. The enantiomerically pure diastereomers were obtained from resolved 1 and used separately to catalyze the reaction. Each diastereomer showed different selectivity, with S_Ar,S,S-2 being the more selective (61% ee for the hydrogenation of acetophenone). Our studies suggest that ruthenium hydride formation is accompanied by a decrease in hapticity of the η⁶-arene and probable detachment of the ring from the metal. Nevertheless, the original conformational chirality of the biphenyl ligand appears to be at least partially retained during the catalysis.     

Biocatalytic and chemical routes to all the stereoisomers of methionine and ethionine sulfoxides

Biotransformations of the N-phthaloyl derivatives of d- and l-methionine and of d- and l-ethionine by Beauveria bassiana ATCC 7159 or Beauveria caledonica ATCC 64970 produce the corresponding (S_S) sulfoxides in good yield and diastereomeric excess. Pure (S_SS_C) diastereomers can be obtained from l-series substrates by crystallisation of the biotransformation extract, and the corresponding (S_SR_C) products obtained from d-series substrates by chromatography of the biotransformation extract. Hydrogen peroxide-catalysed oxidation of the N-phthaloyl derivatives of d- and l-methionine and of d- and l-ethionine gives diastereomeric mixtures from which the (S_SS_C) and (R_SR_C) diastereomers can be obtained by crystallisation, and the (S_SR_C) and (R_SS_C) diastereomers obtained by chromatography. N-Cbz- and N-t-Boc methionines are also converted to sulfoxides with predominant (S_S) configuration by both B. bassiana and B. caledonica, but the isolated yields and d.e. of products were generally lower than those obtained from the N-phthaloyl substrates.Removal of the N-phthaloyl group from diastereomerically pure methionine and ethionine sulfoxides gave the corresponding amino acid sulfoxides in high yield; removal of N-Cbz and N-t-Boc groups from protected methionine sulfoxides was also achieved without loss of configuration at sulfur.     

Preparation of enantiomerically pure α-hydroxyl phosphinates via hydrophosphorylation of aldehydes with H-phosphinate

The hydrophosphorylation of aldehydes with a P-stereogenic H-phosphinate was realized by heating two compounds in a neat state or catalyzed by a base, to afford P-retention α-hydroxyl phosphinates. The (S_P,S_C) and other diastereomers were isolated, and their structures were confirmed by NMR spectroscopy and crystallography.     

Biocatalytic and chemical preparation of all four diastereomers of methionine sulfoxide

Biocatalytic or chemical oxidations can be used in a complementary manner for the preparation of all four diastereomers of methionine sulfoxide with high diastereomeric purity in overall isolated yields of 20–55% from methionine. The N-phthaloyl derivatives of L- and D-methionine were selectively oxidised to the (S_SS_C) and (S_SR_C) sulfoxides respectively by biotransformation using the fungus Beauveria bassiana ATCC 7159. Hydrogen peroxide oxidation of the same materials gave mixtures from which the (S_SS_C) and (R_SR_C) isomers can be readily isolated by crystallisation. Chromatography of the residual material then afforded the (R_SS_C) and (S_SR_C) isomers.     

Efficient enantioselective synthesis of (2R,3R)- and (2S,3S)-3-hydroxyleucines and their diastereomers through dynamic kinetic resolution

(2R,3R)- and (2S,3S)-3-Hydroxyleucines, components of cyclodepsipeptides, papuamides and polyoxypeptins, were efficiently synthesized along with their diastereomers from the corresponding β-keto-α-amino acid ester through dynamic kinetic resolution using RuCl₂(binap)-catalyzed hydrogenation.     

Stereochemical basis for the anti-chlamydial activity of the phosphonate protease inhibitor JO146

JO146, a mixture of two diastereomers of a peptidic phosphonate inhibitor for Chlamydial HtrA (CtHtrA), has reported activity against Chlamydia species in both human and koala. In this study we isolated the individual diastereomers JO146-D1 and JO146-D2 (in ≥90% purity) and assessed their individual inhibitory activity against the serine protease human neutrophil elastase (HNE) which is structurally and functionally related to CtHtrA, as well as in Chlamydia trachomatis cell culture. JO146-D2 [S,S,R-Boc-Val-Pro-Val^P(OPh)₂], the isomer with the physiologically relevant valine at P1, had an approximate 2.5 – fold increase in in vitro HNE inhibition potency over JO146-D1 [S,S,S-Boc-Val-Pro-Val^P(OPh)₂] and greater than 100 – fold increase in cellular anti-chlamydial activity compared to JO146-D1 which possesses the unnatural valine at P1. JO146 and the individual diastereomers had excellent selectivity for the serine protease HNE over the potential off-target serine proteases trypsin and chymotrypsin. Docking studies supported the biological data with a geometrically unfavoured interaction observed between the P1 valine residue of JO146-D1 and the enzyme S1 sub-pocket.     

Stereoselective synthesis of 4-amino-3-hydroxy-2-methylpentanoic acids: stereochemistry of the amino acid occurring in the marine toxin janolusimide

Four diastereomers of 4-amino-3-hydroxy-2-methylpentanoic acid, an amino acid constituent of the hexapeptide portion of the antitumor antibiotic bleomycin A₂, have been stereoselectively synthesized by crotylboration of N-Boc-l-alaninal. The synthesis allowed the assignment of the stereochemistry as 2R,3S,4S to the 4-amino-3-hydroxy-2-methylpentanoic acid occurring in the tripeptide marine toxin janolusimide.     

Intramolecular 1,3-dipolar cycloaddition of unsaturated nitrones derived from methyl α-d-glucopyranoside

The intramolecular 1,3-dipolar cycloaddition of unsaturated nitrones derived from methyl α-d-glucopyranoside with 2-furaldehyde has been studied. This cycloaddition was found to afford three 9-oxa-1-azabicyclo[4.2.1]nonane diastereomers in a 3:1:1 ratio [with the principal isomer possessing a (3S,4R,5S,6S,8S) configuration, determined by NMR spectroscopy]. The effects of different Lewis acid catalysts (MgCl₂, ZnCl₂ and BF₃·OEt₂) on yields and diastereomeric ratios have been examined in detail. The best result (90% yield) was achieved when MgCl₂ was present (in toluene, 120 °C bath temperature, 12 h). The stereoselectivity of the 1,3-dipolar cycloaddition was not significantly altered under the conditions investigated.     

Synthesis of tripeptide hydrolysate from papuamide A: determination of absolute stereostructure of β-methoxytyrosine

Four diastereomers, (2R,3R), (2S,3S), (2S,3R) and (2R,3S) at β-methoxytyrosine (β-OMeTyr), of the tripeptide hydrolysate, H-(S)-N-MeThr-β-OMeTyr-(S)-Hpr-OH, from papuamide A have been synthesized. Comparison of the ¹H NMR data of the natural hydrolysate with the four synthetic diastereomers unambiguously establishes the relative and absolute stereochemistry of the methoxytyrosine as 2R,3R.     

Total synthesis of maremycins A,B, C1/C2, D1, and D2

The total synthesis of maremycins A, B, C₁/C₂, D₁, and D₂ is achieved starting from the natural amino acids l-isoleucine and S-methyl-l-cysteine, in which the total synthesis of maremycins B, C₁/C₂, and D₂ is accomplished for the first time. The synthesis features a position-selective intramolecular bromination process for the synthesis of key chiral building block, a Pd-catalyzed indole synthesis for the preparation of (2S,3S)-β-methyltryptophan and hydroxylation of oxindoles by molecular oxygen. In addition, the protocol for conversion of maremycins A and B to maremycins C and D was improved.     

The absolute configuration of the palmarumycins C9, C10, and C12 by quantum-mechanical calculations of CD spectra

The absolute configurations of the palmarumycins C₉ 1a, C₁₀ 2, and C₁₂ 3 were assigned by comparison of the quantum-mechanically calculated with the experimental CD spectra as (2R,3S,4aS,8aR), (2R,3R,4S,4aS,8aR), and (2R,3R,4R), respectively.     

Synthesis of both RP and SP enantiomers of unsymmetrical methylphosphonates based on a new approach utilizing a P-ester bond with α-hydroxyacids

Condensation of methyl methylphosphonochloridate with the dilithium salt of 2-methyllactic acid gave P-racemic methylphosphonates which unexpectedly contained two units of α-hydroxyacid linked via carboxylic ester bond. The racemic mixture was chromatographically separated via diastereomeric salts with quinine or cinchonine to give, based on the X-ray analysis, pure (R_P)-(+) and (S_P)-(−) enantiomers. Both enantiomers were immobilized on the ArgoGel^®–OH solid support. Condensation of methyl methylphosphonochloridate with α-hydroxyacid methyl esters [2-methyllactate, (S_C)-(−)-lactate, methyl (S_C)-(+) and (R_C)-(−)-mandelates] gave chromatographically inseparable 1:1 mixtures of diastereomers in 63–69% yields. A basic hydrolysis of the latter resulted in a selective and unexpected cleavage of the P–OMe group in a quantitative yield [(S_C)-(+) and (R_C)-(−)-mandelates, (S_C)-(−)-lactate] or simultaneous cleavages of P–OMe and C(O)OMe groups (2-methyllactate).     

Synthesis of (+)-1,3,5,7 -tetrakis[2-(1S,3S,5R,6S,8R,10R)-D3-trishomocubanylbuta-1,3-diynyl]adamantane : The first optically active organic molecule with t symmetry and of known absolute configuration

(-)-(1S,3S,5R,6S,8R,10R)-Trishomocubanethanoic acid (5) of known absolute configuration and absolute rotation was converted into (+)-(1S,3S,5S,6S,8R,10R)-2-bromoethynyl-D₃-trishomocubane (27) of C₃ symmetry. 1,3,5,7-Tetraethynyladamantane (22), with Td symmetry, was prepared from 1,3,5,7-tetrakis(hydroxymethyl)adamantane(13). Coupling of the C₃-component 27 with the Td component 22 was successfully accomplished by Chodkiewicz and Cadiot's procedure providing (+)-1,3,5,7-tetrakis[2-(1S,3S,5R,6S,8R,10R)-D₃-trishomocubanylbuta-1,3-diynyl]adamantane(4) whose highest attainable static and time-averaged dynamic symmetry are T and (C₃)⁴ XXX T,respectively.     

Total synthesis of the proposed structures of hyacinthacines C2, C3, and their C5-epimers

Synthesis and structural confirmation of highly oxygenated pyrrolizidine alkaloids, hyacinthacines C₂ [(1S,2R,3R,5R,7S,7aR)-3,5-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], C₃[(1S,2R,3R,5S,7R,7aR)-3,5-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], and their C5-epimers were achieved on the basis of the highly divergent method employing (S)-(−)-2-pyrrolidone-5-carboxylic acid as the starting material.     

Optically Active Transition Metal Complexes. 128 [1] Synthesis,Characterization and Molecular Structures of Cycloheptatrienyl‐Iminphos‐Molybdenum Complexes Differing Only in the Metal Configuration

The chiral‐at‐metal cycloheptatrienyl‐molybdenum complexes (R_Mo, S_C)‐[(η⁷‐C₇H₇)Mo(iminphos)(CO)]BF₄ ( 2a ) and (S_Mo, S_C)‐[(η⁷‐C₇H₇)Mo(iminphos)(CO)]BF₄ ( 2b ) (iminphos = 2‐[N‐(S)‐1‐phenylethylcarbaldimino]phenyl(diphenyl)phosphane), which only differ in the molybdenum configuration, were prepared and separated by fractional crystallization. The absolute configuration for both diastereomers was determined by X‐ray analysis. ¹H NMR studies demonstrated the configurational lability at the molybdenum centre in solution.     

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.     

Synthesis and application of a new pseudo C2-symmetric tertiary diamine for the enantioselective addition of MeLi to aromatic imines

A new tertiary pseudo C₂-symmetric diamine derived from (1S,2S)-(+)-pseudoephedrine was synthesized and tested in the enantioselective addition of methyllithium on different aromatic imines. A comparative study with a similar C₂-symmetric ligand derived from the cyclohexane diamine showed better reactivity and enantioselectivity up to 91%.