Synthesis of the aglycone of 26-O-deacetyl pavoninin-5

The aglycone of 26-O-deacetyl pavoninin-5, (25R)-cholest-5-en-3β,15α,26-triol, 5a, was synthesized in 10 steps in 17% overall yield from diosgenin, 3. Removing mercury from the Clemmensen reduction of diosgenin 3, gave a higher yield of (25R)-cholest-5-en-3β,16β,26-triol, 4, by a method, that is also more environmentally friendly. Attempted methods for the transposition of the C-16β hydroxyl to the 15α position are described. A successful method for this transposition via the 15α-hydroxy-16-ketone, 13, using the Barton deoxygenation reaction on the 16-alcohol, 15, is reported.     

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).     

Practical method for the synthesis of (R)-homopipecolinic acid and (R)-homoproline esters from ω-chloroalkanoic acids and available chiral amines

A practical synthesis of (R)-homopipecolinic acid methyl ester 1 and (R)-homoproline methyl ester 2 was performed utilizing (i) a direct intramolecular cyclization of ω-chloro-β-enamino esters 11 and 12, which were prepared from available (S)-1-phenylethylamine or (S)-1-(1-naphthyl)ethylamine and ω-chloro-β-keto esters 5 and 10, respectively and (ii) a highly diastereoselective NaBH₄ reduction followed by hydrogenolysis. The present method is a short-step process using inexpensive and readily available substrates and reagents with fewer wasted materials.     

Chemoenzymatic synthesis and HPLC analysis of the stereoisomers of miyakosyne A [(4E,24E)-14-methyloctacosa-4,24-diene-1,27-diyne-3,26-diol], a cytotoxic metabolite of a marine sponge Petrosia sp., to determine the absolute configuration of its major component as 3R,14R,26R

Six samples [(3R,14R,26R)-, (3R,14S,26R)-, (3S,14R,26S)-, and (3S,14S,26S)-1, a mixture of (3R,14R,26S)- and (3S,14R,26R)-1, and a mixture of (3R,14S,26S)- and (3S,14S,26R)-1] of miyakosyne A [1, (4E,24E)-14-methyloctacosa-4,24-diene-1,27-diyne-3,26-diol] were synthesized starting from the enantiomers of citronellal (2), employing olefin cross metathesis and R-selective asymmetric acetylation of a stereoisomeric mixture of acetylenic alcohols with vinyl acetate and lipase PS as key reactions. Separation of the eight stereoisomer of 1 by reversed phase HPLC at −56 °C was achieved after their esterification with (1R,2R)-2-(anthracene-2,3-dicarboximido)cyclohexanecarboxylic acid (16), and the natural miyakosyne A was found to be a mixture of 95.7% of (3R,14R,26R)-1 and 4.3% of (3R,14S,26R)-1. This is different from the (3R,14S,26R)-configuration of 1 as tentatively assigned by X-ray analysis.     

The transannular interaction germanium-nitrogen in germocanes: The influence of substituents

The reaction of RN(CH₂CH₂OH)CHR¹CR²R³OH (1-8) with a stoichiometric amount of tetrachloro(bromo)germane leads to the corresponding RN(CH₂CH₂O)(CHR¹CR²R³O)GeHal₂ (9-21). Difluorenylgermocane 22 was prepared by treatment of diethoxydifluorenylgermane with N-methyldiethanolamine. Different dialkanolamines were found to be successive precursors of dimethylgermocanes, RN(CH₂CH₂O)(CHR¹CR²R³O)GeMe₂ (23-26). The chemical properties of simple and easy to access germocanes RN(CH₂CH₂O)₂GeX₂ [X = OH, Br (28), Cl (29)] were studied and the difluoro (27), haloalkoxy (30-32), and dialkoxy (33, 34) derivatives were prepared. The structures of the compounds 16, 20-22, and 26 were confirmed by X-ray diffraction and the structural features in solution of 23 and 26 were studied by NMR spectroscopy (NOEs). The relationship between the nature of substituents at different positions of the germocane skeleton and the strength of the intramolecular Ge ← N bond is discussed.     

Regio- and stereoselective cycloadditions of (1Z,4R,5R)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides to methyl methacrylate

[3+2] Cycloadditions of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides 1a-e to methyl methacrylate gave the 1-CO₂Me regioisomers 3/3′, exclusively, in 1-67% yields. Stereocontrol was dependent on the ortho-substituents at the 1′-aryl group in dipole 1: ortho-unsubstituted dipoles 1a-c gave the major (1R^∗,3R^∗,5R^∗,6R^∗)-isomers 3a-c, whilst ortho-disubstituted dipoles gave the major (1R^∗,3S^∗,5R^∗,6R^∗)-isomers 3′d,e. The structures of cycloadducts were determined by NMR and X-ray diffraction.     

Synthesis and structural revision of eurypamides isolated from the Palauan sponge Microciona eurypa

Eurypamides A and B, 1 and 2, were successfully synthesized by employing Tl(NO₃)₃ (TTN) oxidation of the corresponding halogenated phenols, 9, 16, and 26. This investigation revealed that the dihydroxyarginine residue of 1 should be revised to possess (2S,3R,4S)-configuration. In addition, the synthesis of 2 provided a pure sample, which was previously characterized in a mixture.     

Polyhydroxylated pyrrolizidines. Part 8. Enantiospecific synthesis of looking-glass analogues of hyacinthacine A5 from DADP

(1R,2S,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine[(−)-3-epihyacinthacine A₅, 1a] and (1S,2R,3R,5S 7aS)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine[(+)-3-epihyacinthacine A₅, 1b] have been synthesized either by Wittig's or Horner-Wadsworth-Emmond's (HWE's) methodology using aldehydes 4 and 9, both prepared from (2S,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (2, partially protected DADP), and the appropriate ylides, followed by cyclization through an internal reductive amination process of the resulting α,β-unsaturated ketones 5 and 10, respectively, and total deprotection.     

Synthesis of (−)-lentiginosine, its 8a-epimer and dihydroxylated pyrrolizidine alkaloid from d-glucose

The d-glucose derived α,β-unsaturated ester 5 on 1,2-acetonide deprotection, oxidative diol cleavage followed by treatment with N-benzylamine in the presence of NaBH₃CN undergoes reductive amination and a concomitant intramolecular conjugate addition reaction leading to the formation of dihydroxypyrrolidine-ester 6a and monohydroxypyrrolidine-γ-lactone 6b. Intermediates 6a and 6b were efficiently converted to (−)-lentiginosine 3a, its 8a-epimer 3b, and pyrrolizidine azasugar 4 in good overall yield.     

Autoxidation of isotachysterol

Isotachysterol, the acid-catalyzed isomerization product of vitamin D₃, produces seven previously unknown oxygenation products in a self-initiated autoxidation reaction under atmospheric oxygen in the dark at ambient temperature. They are (5R)-5,10-epoxy-9,10-secocholesta-6,8(14)-dien-3β-ol (6a), (5S)-5,10-epoxy-9,10-secocholesta-6,8(14)-dien-3β-ol (6b), (10R)-9,10-secocholesta-5,7,14-trien-3β,10-diol (7a), (10S)-9,10-secocholesta-5,7,14-trien-3β,10-diol (7b), (7R,10R)-7,10-epoxy-9,10-secocholesta-5,8(14)-dien-3β-ol (8), 5,10-epidioxyisotachysterol (9) and 3,10-epoxy-5-oxo-5,10-seco-9,10-secocholesta-6,8(14)-dien-10-ol (10). The formation of these products is explained in terms of free radical peroxidation chemistry.     

Synthetic access to optically active isoflavans by using allylic substitution

A general approach to the (S)- and (R)-isoflavans was invented, and efficiency of the method was demonstrated by the synthesis of (S)-equol ((S)-3), (R)-sativan ((R)-4), and (R)-vestitol ((R)-5). The key step is the allylic substitution of (S)-6a (Ar¹=2,4-(MeO)₂C₆H₃) and (R)-6b (Ar¹=2,4-(BnO)₂C₆H₃) with copper reagents derived from CuBr·Me₂S and Ar²-MgBr (7a, Ar²=4-MeOC₆H₄; 7b, 2,4-(MeO)₂C₆H₃; 7c, 2-MOMO-4-MeOC₆H₃), furnishing anti S_N2′ products (R)-8a and (S)-8b,c with 93-97% chirality transfer in 60-75% yields. The olefinic part of the products was oxidatively cleaved and the Me and Bn groups on the Ar¹ moieties was then removed. Finally, phenol bromide 9a and phenol alcohols 9b,c underwent cyclization with K₂CO₃ and the Mitsunobu reagent to afford (S)-3 and (R)-4 and -5, respectively.     

Acid-catalyzed rearrangement of α-hydroxytrialkylsilanes

Cationic rearrangement of several α-hydroxysilanes is described. Treatment of both (1R,1′R,2′S)-α-hydroxycyclopropylsilane syn-9 and (1S,1′R,2′S)-anti-9 under aqueous H₂SO₄ underwent rearrangement via a common α-silyl cation intermediate A to give a mixture of the ring-opened (R)-vinylsilane 13, the tandem [1,2]-CC bond migration product (1R,2S,1′R)-14, and its 1′S isomer 15. On the other hand, the acidic treatment of (R,E)-α-hydroxyalkenylsilane 8 or (R,Z)-8 was each accompanied with partial racemization to give an enantiomeric isomer of allylic alcohol 23 via a preferential syn-facial S_N2′ reaction, respectively. Both α-hydroxyalkynylsilane 6 and α-hydroxyalkylsilane 12 were inert to the acidic conditions; however, treatment of (R)-α-mesyloxyalkynylsilane 26 under aqueous H₂SO₄ gave a mixture of the optically active rearranged allene 27, α,β-unsaturated ketone 28, and (S)-α-hydroxyalkynylsilane 6 with partial racemization. Comparisons of the reactivities of these α-hydroxysilanes under acidic conditions are also disclosed.     

Influence of multidentate N-donor ligands on highly electrophilic zinc initiator for the ring-opening polymerization of epoxides

A set of multidentate ligands have been synthesized and used to stabilize the putative highly electrophilic zinc species initiating ring-opening polymerization (ROP) of cyclohexene oxide (CHO) and propylene oxide (PO). Reaction of the bidentate C₂-chiral bis(oxazoline) ligand (^R2,R3BOX: R₂ = (4S)-tBu, R₃ = H (a); R₂ = (4S)-Ph, R₃ = H (b); R₂ = (4R)-Ph, R₃ = (5S)-Ph (c)) with Zn(R₁)₂ (R₁ = Et (1), Me (2)) led to the heteroleptic three-coordinate complexes (^R2,R3BOX)ZnR₁, 1a-c and 2a, which were isolated in 92-96% yield. Next, two pyridinyl-functionalized N-heterocyclic carbene (NHC) ligands have been designed and synthesized: the 1,3-bis(2-pyridylmethyl)imidazolinium salt (d) and the protected NHC adduct 2-(2,3,4,5,6-pentafluorophenyl)-1,3-bis(2-pyridylmethyl)imidazolidine (e). The reaction of ligands d and e with ZnEt₂ led directly to the formation of (NHC)ZnEt(Cl) 3d complex with ethane elimination and the adduct (NHC-C₆F₅(H))ZnEt₂4e, respectively, in high yield. In situ combinations of selected complexes 1a-c, 3d and 4e with B(C₆F₅)₃ (1 or 2 equivalents) give active systems for ROP, with high productivity (3.3-5.9 10⁶ g_polym. mol_Zn⁻¹ h⁻¹) and high molecular weight (M_n up to 132 10³ g mol⁻¹) for CHO polymerization. Although the in situ B(C₆F₅)₃-activated zinc species were not isolated, the sterically demanding BOX ligands (1c > 1b > 1a) and functionalized NHC ligands seem to enhance the stability of highly electrophilic zinc complexes over ligand redistribution, allowing a better control of the cationic ROP as reflected particularly for 3d and 4e complexes by their respective efficiency (42-88%).     

Polyhydroxylated pyrrolidines: synthesis from d-fructose of new tri-orthogonally protected 2,5-dideoxy-2,5-iminohexitols

The readily available 3-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (2) was transformed into its 5-O- (3) and 4-O-benzoyl (4) derivative. Compound 4 was straightforwardly transformed into 5-azido-4-O-benzoyl-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (7) via the corresponding 5-deoxy-5-iodo-α-l-sorbopyranose derivative 6. Cleavage of the acetonide in 7 to give 8, followed by regioselective 1-O-silylation to 9 and subsequent catalytic hydrogenation gave a mixture of (2S,3R,4R,5R)- (10) and (2R,3R,4R,5R)-4-benzoyloxy-3-benzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (12) that was resolved after chemoselective N-protection as their Cbz derivatives 11 and 1a, respectively. Stereochemistry of 11 and 1a could be determined after total deprotection of 11 to the well known DGDP (13). Compound 2 was similarly transformed into the tri-orthogonally protected DGDP derivative 18.     

Some new DTPA-N,N″-bis(amides) functionalized by alkyl carboxylates: Synthesis,complexation and stability properties

A new series of DTPA-N,N″-bis(amide) ligands functionalized by alkyl carboxylates on the amide side-arms (1a–1l) and their Gd(III) complexes of the type [Gd(1)(H₂O)] · xH₂O (2a–2l) were synthesized and characterized by analytical and spectroscopic techniques. Potentiality of 2a–2l as contrast agent for magnetic resonance imaging (MRI CA) was investigated by measuring some relevant physicochemical properties such as (i) the protonation constants of 1a–1l, (ii) thermodynamic and conditional stability constants of 2a–2l, (iii) the selectivity (pGd) of 1a–1l for the Gd(III) ion over the endogenous metal ions such as Zn(II), Ca(II), and Cu(II), and (iv) the relaxivities (R₁ and R₂) of 2a–2l in aqueous and aqueous HP-β-CD solutions. Comparative studies reveal that most of new Gd(III) complexes show enhanced thermodynamic stability and selectivity as compared with those of [Gd(DTPA-BMA)(H₂O)] (DTPA-BMA = N,N″-di(methylcarbamoylmethyl)diethylenetriamine-N,N′,N″-triacetate). Also enhanced with 1a–1l (except 1f and 1h) is affinity for Gd(III) as compared with [DTPA-BMA]³⁻ under physiological conditions. The relaxivities (R₁ and R₂) of aqueous solutions of 2a–2l, on the other hand, drop significantly as compared with [Gd(DTPA-BMA)(H₂O)] although they increase dramatically (6–10 fold) in aqueous hydroxypropyl-β-cyclodextrin (HP-β-CD) solutions.     

Synthesis of trimethyl (2S,3R)- and (2R,3R)-[2-H1]-homocitrates and the corresponding dimethyl ester lactones—towards elucidating the stereochemistry of the reaction catalysed by homocitrate synthase and by the Nif-V protein

Trimethyl (2S,3R)- and (2R,3R)-[2-²H₁]-homocitrates, 10b and 10c respectively, and dimethyl (2S,3R)- and (2R,3R)-[2-²H₁]-homocitric lactones, 11b and 11c respectively, have been synthesised from shikimic acid and [2-²H]-shikimic acid by a route which defines the stereochemistry of the two chiral centres in each compound. The NMR spectra of these products will enable the stereochemistry of the biological reaction catalysed by homocitrate synthase and by the protein from the nifV gene to be elucidated.     

Preparation of both enantiomers of β-(3,4-dihydroxybenzyl)-β-alanine, higher homologues of Dopa

β²-(3,4-Dihydroxybenzyl)-β-alanine [β²-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.     

Polyhydroxylated pyrrolidines, III. Synthesis of new protected 2,5-dideoxy-2,5-iminohexitols from d-fructose

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (6) was straightforwardly transformed into 5-azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (8), after treatment under modified Garegg's conditions followed by reaction of the resulting 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-l-sorbopyranose (7) with lithium azide in DMF. O-debenzoylation at C(3) in 8, followed by oxidation and reduction caused the inversion of the configuration to afford the corresponding β-d-psicopyranose derivative 11 that was transformed into the related 3,4-di-O-benzyl derivative 12. Cleavage of the acetonide of 12 to give 13 followed by O-tert-butyldiphenylsilylation afforded a resolvable mixture of 14 and 15. Compound 14 was transformed into (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-dibenzyloxy-2′,5′-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (18) either by a tandem Staudinger/intramolecular aza-Wittig process and reduction of the resulting intermediate Δ²-pyrroline (16), or only into 18 by a high stereoselective catalytic hydrogenation. When 15 was subjected to the same protocol, (2S,3S,4R,5R)- (21) and (2R,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22) were obtained, respectively.     

Cyclopalladation of enantiopure oxazolines having the prochiral CMe2 moiety at position 2 of the heterocycle

(R)-4-Ethyl-2-(1,1-dimethylpropyl)-2-oxazoline (1) and (S)-4-tert-butyl-2-(1,1-dimethylbutyl)-2-oxazoline (2) were synthesized in two steps from the corresponding enantiopure amino alcohols and acid chlorides in a total yield of 95% and 72%, respectively. (S)-2-(1-Adamantyl-1-methylethyl)-4-isobutyl-2-oxazoline (3) was obtained from adamantyl bromide and l-leucinol in five steps in a total yield of 82%. Reactions of oxazolines 1–3 with Pd(OAc)₂ in AcOH or CH₂Cl₂ followed by treatment with LiCl afforded the corresponding μ-Cl dimeric cyclopalladated complexes 15, 17, and 20 in good yield. Compounds 15, 17, and 20 reacted with PPh₃ to furnish the corresponding mononuclear complexes 16, 19, and 21. The ³¹P NMR spectra of trans(N,P) adducts 16, 19, and 21 contained signals of two diastereomers in a ratio of ca. 1.3:1.     

Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin

A convergent synthesis of (4R,15R,16R,21S)-rollicosin (1) and (4R,15S,16S,21S)-rollicosin (2) was accomplished. Hydroxy lactone 6a and/or 6b were synthesized from 4-pentyn-1-ol, and α,β-unsaturated lactone 7 was synthesized from γ-lactone 8 and 5-hexen-1-ol. Inhibitory activity of these compounds was examined with bovine heart mitochondrial complex I.