Synthetic studies on homophymine A: stereoselective synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid

An efficient and highly stereocontrolled synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid, the β-hydroxy acid unit that acylates the N-terminus of homophymine A, has been devised starting from iodoethane and (S,S)-pseudoephedrine propionamide in 9 steps and 36% average overall yield. Comparison of the ¹H and ¹³C NMR and optical rotation data of the resulting β-hydroxy acid with the natural fragment unambiguously verifies the configurational assignment as (2R,3R,4R,6R).     

Anti-inflammatory cyclopeptides from the marine sponge Theonella swinhoei

DCCC chromatography followed by HPLC purification on the polar extract of marine sponge Theonella swinhoei resulted in the isolation of five new cyclopeptides, perthamides G–K. The new structures, featuring unprecedented amino acid units, were determined by interpretation of extensive spectroscopic and spectrometric data (MS, ¹H and ¹³C NMR, COSY, HSQC, HMBC, and ROESY). Pharmacological analysis demonstrated that these natural cyclopeptides are endowed with anti-inflammatory potential as assessed by their ability to reduce carrageenan-induced mouse paw oedema.     

Structure and absolute configuration of new acidic metabolites from Stachys ehrenbergii

Two novel metabolites have been isolated from the aerial parts of Stachys ehrenberiigii. Their structures and stereochemistry were elucidated using a combination of ¹³C and ¹H homo and heteronuclear 2D NMR experiments and mass analysis. The development of an enantioselective synthesis of 3-(2′-acetoxy-4-phenylbut-3′-enoylamino)propionic acid allowed to confirm the structure and assign the (R) absolute configuration at C-2′ of the natural product.     

Perthamides C and D, two new potent anti-inflammatory cyclopeptides from a Solomon Lithistid sponge Theonella swinhoei

Two new metabolites, perthamides C and D, have been isolated from the marine sponge Theonella swinhoei. Their structures were determined by interpretation of NMR and ESIMS data. All compounds exhibited in vivo potent anti-inflammatory activity. Biological activity and structural elucidation are reported.     

Configurational analysis of the natural product passifloricin A by quantum mechanical C NMR GIAO chemical shift calculations

Quantum chemical calculations at mPW1PW91 level, with full geometry optimization, using the 6-31g(d) basis set, and GIAO (gauge including atomic orbitals) ¹³C NMR chemical shifts using the 6-31g(d,p) basis set, are here utilized as a support to define the configurational features of the natural product passifloricin A, whose previously proposed relative configuration has been recently shown, by synthetic studies, to be incorrect. This study suggests that the relative stereostructure for passifloricin A corresponds to the δ-lactone of the (5R,7R,9S,11R)-tetrahydroxyhexacos-2-enoic acid.     

Synthesis of the structures proposed for natural butanolides piliferolides A and C

The structures proposed for natural butanolides piliferolides A and C have been synthesized. The allylic and lactone stereogenic centers in the target structures were derived from d-mannitol, while that near the side-chain terminal was taken from (R)-propylene oxide. The synthetic samples helped to reveal that a signal at around δ 2.0 ppm was missing in the ¹H NMR data listing for the structures proposed for natural piliferolides, whereas the δ 29.7 ppm signal in the ¹³C NMR reported for the structure proposed for natural piliferolide C most likely stemmed from the impurities in the chromatography solvent.     

Structure elucidation and stereoselective total synthesis of pavettamine, the causal agent of gousiekte

The structure elucidation of a novel natural product pavettamine (1), the causal agent of the plant toxicosis gousiekte, is reported. The structure was defined by analysis of NMR and MS data and the relative configuration followed from the ¹³C NMR data of the acetonide derivative. The absolute stereochemistry was established by total synthesis from (2S)-malic acid using chiral sulfoxide methodology as (2S,4R,8R,10S)-1,11-diamino-6-aza-undecane-2,4,8,10-tetraol.     

Synthesis of mono- and dihydroxy-substituted 2-aminocyclooctanecarboxylic acid enantiomers

(1R,2S,6R)-2-Amino-6-hydroxycyclooctanecarboxylic acid (?)-10 was synthesized from (1R,2S)-2-aminocyclooct-5-enecarboxylic acid (+)-2 via an iodolactone intermediate, while (1R,2S,3R,4S)-2-amino-5,6-dihydroxycyclooctanecarboxylic acid (?)-12 was prepared by using the OsO₄-catalyzed oxidation of Boc-protected amino ester (?)-5. The stereochemistry and relative configurations of the synthesized compounds were determined by 1D and 2D NMR spectroscopy (based on 2D NOE cross-peaks and ³J(H,H) coupling constants) and X-ray crystallography.     

C13-Methylation of methyl pheophorbide a and stereoselective preparation of methyl (13R)-methylpyropheophorbide a

The (13²R)-methoxycarbonyl group of methyl pheophorbide a, one of the chlorophyll-a derivatives, was converted to a methyl group through methylation at the C13² position followed by removal of the methoxycarbonyl group. The methylation of the C13² carboanion gave a 4:1 mixture of methyl 13²-methyl-pheophorbide a and its 13²-epimer. The successive pyrolysis of the major methylated product afforded methyl (13²R)-methyl-pyropheophorbide a with a small amount of its (13²S)-epimer. The substitution effects at the C13² position including stereochemistry were discussed on the basis of 1D/2D NMR, UV–vis absorption, and circular dichroism spectroscopic analyses as well as molecular modeling simulation.     

Two Unusual Methylidenecyclopropane Glucosides from Metaxya rostrata C.Presl

Two new natural compounds, (1R,2E)‐2‐(6‐hydroxyhexylidene)cyclopropyl‐β‐D ‐glucopyranoside ( 1 ) and (6E)‐6‐[(2R)‐2‐(β‐D ‐glucopyranosyloxy)cyclopropylidene]hexanoic acid ( 2 ), glucosides of a very rare methylidenecyclopropane alcohol, as well as two known glycosides of phenolic acids, namely 4‐O‐β‐D ‐glucopyranosylcaffeic acid ( 3 ) and (E)‐4‐O‐β‐D ‐glucopyranosylcoumaric acid ( 4 ), and methyl α‐fructofuranoside ( 5 ) were isolated for the first time from the rhizomes of the tree fern Metaxya rostrata C.Presl . The structures were elucidated on the basis of detailed spectroscopic data analysis, and the structure of 1 was additionally confirmed by X‐ray crystal‐structure analysis.     

Synthetic studies directed toward amphidinol 2: elucidation of the relative configuration of the C1-C10 fragment

Model compounds (11 and 12) for the C1-C10 tetrahydropyran fragment of amphidinol 2 were prepared from (2S)-benzyloxypropanal in 9 steps. The synthetic route relied on diastereoselective diene-aldehyde cycloaddition, stereoselective C-allylation, and reagent based enantioselective aldehyde allylation. Comparison of the NMR spectra for models 11 and 12 with that for amphidinol 2 indicated that the C1-C10 segment of the natural product possesses the 2R^∗,4R^∗,6R^∗,7S^∗,8R^∗,10S^∗relative configuration.     

Total Synthesis and Absolute Configuration of Epicoccamide D,a Naturally Occurring Mannosylated 3‐Acyltetramic Acid

The endofungal metabolite epicoccamide D was synthesised in eighteen steps and 17 % yield as the first member of the family of natural glycotetramic acids. The modular character of the synthesis opens access also to analogues featuring different sugars and spacers. It comprises several high‐yielding key steps. The β‐D ‐mannosyl group was introduced by using an α‐D ‐glucosyl imidate donor with subsequent oxidative‐reductive epimerisation at C‐2′. The pyrrolidine ring was closed quantitatively by a Lacey‐Dieckmann condensation of an N‐(β‐ketoacyl)‐N‐methyl alaninate. The resulting 3‐[ω‐(β‐D ‐mannosyl)octadec‐2‐enoyl]tetramic acid was hydrogenated in the presence of the rhodium catalyst (R,R)‐[Rh(Et‐DUPHOS)][BF₄] to establish the (7S)‐stereocentre. This was possible only after blocking the acyltetramic acid as a BF₂‐chelate to prevent capture of the metal catalyst. We also assigned the hitherto unknown configuration of the natural product as being 5S,7S by comparison of its ¹³C NMR spectroscopic and optical rotation data with those of our two synthetic 5S,7R/S‐diasteromers.     

Total synthesis of the potent anti-inflammatory lipid mediator Protectin D1

The total synthesis of the potent anti-inflammatory lipid mediator Protectin D1 derived from docosahexaenoic acid, has been achieved. The chiral hydroxy-groups at C10 and C17 were obtained via a chiral pool strategy from (4R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane and 3,4-O-isopropylidene-2-deoxy-d-ribose, respectively. Wittig reactions, Takai olefination, Pd⁰/Cu^I Sonogashira coupling, and Zn(Cu/Ag) reduction completed the total synthesis of Protectin D1.     

13C, 15N and 29Si nuclear magnetic resonance studies of some aminosilanes and aminodisilanes

¹³C, ¹⁵N (at natural abundance) and ²⁹Si NMR data (chemical shifts and coupling constants) are reported for aminosilanes R₂R′SiNHR¹ (1), bis(silyl)amines Me₂R′SiNHSiMe₃ (2), 1,2-bis(amino)-ethanes (3), bis(amino)silanes RR′Si(NHR¹)₂ (4), 1,2-bis(amino)tetramethyldisilanes (5) and 1,1,2,2-tetrakis(amino)dimethyldisilanes (6). The δ¹⁵N values depend more on the nature of the substituents R¹(H, alkyl, aryl) at the nitrogen atom (in the same way as for other amines) than on different substituents at the silicon atom. A linear correlation between ¹J(²⁹Si¹⁵N) and ¹J(²⁹Si¹³C) is proposed for silanes in which the SiN unit is replaced by the SiCH unit. This correlation comprises all ¹J(²⁹Si¹⁵N) values for aminosilanes R_4-nSi(N)n (n = 1–4) and—most likely—also for aminodisilanes, and it predicts ¹J(²⁹Si¹⁵N)>0 if the corresponding value |¹J(²⁹Si¹³C)|>25 Hz. For the first time a two-bond coupling across Si, ²J(²⁹Si ¹⁵N) = 6.9 Hz, has been observed for 6a. In the case of 6b (R¹ = ^sBu) all resonances for the diastereomers are resolved in the ¹⁵N and ²⁹Si NMR spectra in contrast to the ¹H and ¹³C NMR spectra.     

Diastereoselective synthesis of 3-tert-butyl-3,4-dihydropyrazolo[5,1-c][1,2,4]triazine-3,4-diyl dicarboxylates

The reactions of 3-tert-butyl-7-R¹-8-R²-pyrazolo[5,1-c][1,2,4]triazines (R¹ = H, Br; R² = Me, n-Bu) with N-bromosuccinimide in the presence of R³CO₂H (R³ = Me, t-Bu, Ph) afforded novel diastereomerically pure 3-tert-butyl-7-R¹-8-R²-3,4-dihydropyrazolo[5,1-c][1,2,4]triazine-3,4-diyl dicarboxylates. The structures of the isolated products were established on the basis of IR, ¹H, ¹³C, 2D NOESY NMR, high resolution mass spectrometry and X-ray single-crystal analysis. The steric and mechanistic origins of the observed regio- and stereoselectivity were also discussed.     

In vitro antitumor and antibacterial assay of organotin(IV) complexes of 2,3-methylenedioxybenzoic acid; X-ray crystal structure of [(C2H5)2Sn(C8H5O4)2]

New organotin(IV) compounds containing the carboxylate ligand 2,3-methylenedioxybenzoic acid (HL) have been synthesized with the general formula R₂SnL₂ (R = Me, Et, n-Bu, Ph and n-Oct) and R₃SnL (R = n-Bu). All compounds have been studied in the solution state by multinuclear NMR (¹H, ¹³C and ¹¹⁹Sn) by using the non-coordinating solvent and also in solid sate by FTIR, mass spectrometry and X-ray crystallography. Spectroscopic data have shown that methylenedioxy moiety does not coordinate with tin atom and the coordination site is actually -COO group, as is proved by X-ray structure determination. The solid state structure of compound (2) has been determined by X-ray crystallography which shows that the complex (2) has distorted octahedral geometry. These complexes have been evaluated in vitro against crown gall tumor and antibacterial activity. Interesting results were noticed during the bio-activity screenings, which proved their in vitro biological potential and possible use as drugs.     

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.     

Chiral self-assembly of triorganotin complexes: Syntheses, characterization, crystal structures and antitumor activity of organotin(IV) complexes containing (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid ligands

Six new chiral triorganotin(IV) complexes, {(R₃Sn)₂[C₃H₆(COO)₂]}_n (R = Me: 1; Bu: 2), {(R₃Sn)₂[C₄H₈(COO)₂]}_n (R = Me: 3; Bu: 4), and {(R₃Sn)₂[C₂H₄O(COO)₂]}_n (R = Me: 5; Bu: 6) have been prepared by treatment of (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid, with the corresponding R₃SnCl (R = Me, Bu) and sodium ethoxide in methanol. All the complexes were characterized by elemental analysis, FT-IR, NMR (¹H, ¹³C, ¹¹⁹Sn) spectroscopy and TGA. Except for 3, all of the complexes were also characterized by X-ray crystallography. The structural analyses reveal that complexes 1 and 5 have 2D network structures in which (R)-(+)-methylsuccinic acid and l-(−)-malic acid act as tetradentate ligands coordinated to trimethyltin(IV) ions. Complexes 2 and 4 have 3D metal-organic framework structures in which the deprotoned acids serve as tetradentate ligands. Complex 6 adopts a 1D zigzag chain structure and forms a 2D supramolecular framework through intermolecular C-H?O interactions. In addition, the antitumor activities of complexes 1-6 have been studied. We also have measured the specific rotation of the chiral dicarboxylic acids and the organotin derivatives.     

Les cations ammoniums chiraux de type [R1R2R3R4N]+, de nouveaux templates pour les réseaux bimétalliques à pont oxalate

Chiral ammonium cations of the type [R¹R²R³R⁴N]⁺, new templates for a new family of bimetallic oxalate bridged networks. This work deals with the obtention of a new family of bimetallic [R¹R²R³R⁴N][MnCr(C₂O₄)₃] oxalate bridged 2D networks templated by chiral ammonium cations of the type [R¹R²R³R⁴N]⁺, in which R stands for n-alkyl groups from methyl to dodecyl. To cite this article: M. Gruselle et al., C. R. Chimie 6 (2003).     

Synthesis of the Macrocyclic Spermidine Alkaloid (±)‐(2R*,3R*)‐3‐Hydroxycelacinnine

The macrocyclic lactam alkaloid (±)‐(2R*,3R*)‐3‐hydroxycelacinnine ( 1 ) derived from spermidine was synthesized via stereoselective epoxide‐ring opening with magnesium azide and cesium carbonate promoted macrocyclization of the ditosylated diamino precursor 12 with 1,4‐dibromobutane in the two key steps (Scheme 2). ¹H‐ and ¹³C‐NMR Signal assignments from COSY, HSQC, and HMBC 2D NMR data of the synthesized 1 were compared with the earlier‐described data of the natural 3‐hydroxycelacinnine. The similarity of their ¹³C‐NMR spectra point to the correctness of the proposed constitutional formula for natural 3‐hydroxycelacinnine; however, different ¹H‐NMR chemical shifts and coupling constants (J(2,3)=9.0 vs. 1.2 Hz, resp.) in the α‐hydroxy‐β‐amino lactam moiety suggest that natural 3‐hydroxycelacinnine is the 2,3‐cis‐epimer of one synthetic (±)‐ 1 .