Absolute configuration of (−)-4-methylheptan-3-ol,a pheromone of the smaller european elm bark beetle,as determined by the synthesis of its (3R,4R)-(+)- and (3S,4R)-(+)-isomers

Nerol and geraniol were stereoselectively converted to (±)-threo- and (±)-erythro-4-methylheptan-3-ol respectively. (R)-(+)-Citronellic acid was converted to a mixture of (3R,4R)-(+)-threo- and (3S,4R)-(+)-erythro-isomers which was separable by GLC. These syntheses established the absolute configuration of the naturally occurring (?)-4-methylheptan-3-ol to be 3S,4S.     

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.     

An efficient approach to d-threo-3-hydroxyaspartic acid for the synthesis of novel l-threo-oxazolines as selective blockers of glutamate reversed uptake

An efficient, stereoselective synthetic strategy to d-threo-3-hydroxyaspartic acid was developed. Starting from l-(2S,3S)-N-benzoyl-3-hydroxyaspartic acid dimethyl ester by a Deoxo-fluor-catalyzed cyclization reaction, an inversion of configuration at the β-center (erythro isomer), was observed. A base-induced epimerization reaction led to the d-trans-isomer, which was hydrolyzed to give d-threo-3-hydroxyaspartic acid with excellent stereoselectivity and overall yield. Starting from d-threo-3-hydroxyaspartic acid, l-threo-oxazolines can be stereoselectively synthesized.     

Photochemische Umsetzung von optisch aktiven 2-(1′-Methylallyl)anilinen mit Methanol

Photochemical Reaction of Optically Active 2-(1′-Methylallyl)anilines with Methanol It is shown that (?)-(S)-2-(1′-methylallyl)aniline ((?)-(S)- 4 ) on irradiation in methanol yields (?)-(2S, 3R)-2, 3-dimethylindoline ((?)-trans- 8 ), (?)-(1′R, 2′R)-2-(2′-methoxy-1′-methylpropyl)aniline ((?)-erythro- 9 ) as well as racemic (1′RS, 2′SR)-2-(2′-methoxy-1′-methylpropyl) aniline ((±)-threo- 9 ) in 27.1, 36.4 and 15.7% yield, respectively (see Scheme 3). By deamination and chemical correlation with (+)-(2R, 3R)-3-phenyl-2-butanol ((+)-erythro- 13 ; see Scheme 4) it was found that (?)-erythro- 9 has the same absolute configuration and optical purity as the starting material (?)-(S)- 4 . Comparable results are obtained when (?)-(S)-N-methyl-2-(1′-methylallyl)aniline ((?)-(S)- 7 ) is irradiated in methanol, i.e. the optically active indoline (+)-trans- 10 and the methanol addition product (?)-erythro- 11 along with its racemic threo-isomer are formed (cf. Scheme 3). These findings demonstrate that the methanol addition products arise from stereospecific, methanol-induced ring opening of intermediate, chiral trans, -(→(?)-erythro-compounds) and achiral cis-spiro [2.5]octa-4,6-dien-8-imines (→(±)-threo-compounds; see Schemes 1 and 2).     

An efficient and stereodivergent synthesis of threo- and erythro-β-methylphenylalanine. Resolution of each racemic pair by semipreparative HPLC

threo and erythro diastereoisomers of the constrained amino acid (βMe)Phe can be obtained separately on a multigram scale through a three-step synthesis from the corresponding Z and E isomers of 2-phenyl-4(α-phenylethylidene)-5(4H)-oxazolone. The 5(4H)-oxazolones are readily available from acetophenone and hippuric acid. The four enantiomerically pure isomers of β-methylphenylalanine, (2R,3R)-(βMe)Phe, (2S,3S)-(βMe)Phe, (2R,3S)-(βMe)Phe and (2S,3R)-(βMe)Phe, have been prepared by HPLC resolution of the racemic precursors methyl threo (or erythro)-2-benzamide-3-phenylbutanoates.     

Simultaneous determination of enantiomeric purity and erythro/threo relationship in chiral 1,2-aminoalcohols by NMR using (R)-(+)-t-butylphenylphosphinothioic acid

The rapid simultaneous determination of enantiomeric purity and erythro/threo relationship for a series of chiral 1,2-aminoalcohols is reported. Complexation with 1 equivalent (R)-(+)-t-butylphenylphosphinothioic acid results in a preferred conformation of the aminoalcohol which in turn causes the interproton dihedral angle to assume either large (threo) or small (erythro) J values. Measurement of the resulting vicinal coupling constant allows easy and rapid assignment of erythro versus threo.     

Stereospezifische Synthese von (+)-(3R, 4R)-4-Methyl-3-heptanol,das Enantiomere eines Pheromons des kleinen Ulmensplintkäfers (Scolytus multistriatus)

Stereospecific Synthesis of (+)-(3R, 4R)-4-Methyl-3-heptanol, the Enantiomer of a Pheromone of the Smaller European Elm Bark Beetle (Scolytus multistriatus) Reduction of 2 with actively fermenting baker's yeast gave (?) -3. Stereospecific alkylation [3] of (?) -3 with propyl iodide furnished ethyl (+)-(2R, 3R)-2-propyl-3-hydroxypentanoate ((+) -4 , 58%) which was converted to the tetrahydropyranyl ether (?) -5 , then the alcohol 6 , the p-toluenesulfonate 7 and the thiophenyl ether 8 to give the title compound (+) -1. The latter consisted of 97% of the threo- and 3% of the erythro-isomer. The above synthesis also correlates the absolute configuration of (?)-(R) -3 with that of (+)-(R)-citronellic acid (see [2]).     

The crystal structure and molecular conformation of threo 5-methylmetadone in relation to opioid receptor binding

Crystals of the hydrochloride salt of the biologically inactive threo isomer of 5-methylmethadone, C₂₂H₃₀ONCl, are monoclinic space group P2₁ with unit cell dimnsionsa = 11.019 Å, b = 8.6153Å, c = 10.680Å and β = 93.026°. The observed conformation is one in which the nitrogen bearing chain is extended with the substituents on C(5) and C(6) nearly eclipsed, a feature compatible with NMR studies and molecular mechanics calculations. The very potent agonist (5S, 6S)-erythro-5-methylmethadone has a solid state conformation in which the N atom is rotated back toward the phenyl rings [C(4)-C(5)-C(6)-N = 97°]in agreement with molecular mechanics calculations. The fact that the more potent enantiomers, (6R)-methadone and (5S)-isomethadone, and the inactive threo isomer are observed in the extended solid state conformation in contrast to (5S, 6S)-erythro-5-methylmethadone is consistent with three different models for their interaction with opioid receptors. It is proposed that the more likely of these involves a receptor bound conformation of (6R)-methadone and (5S)-isomethadone that resembles the conformation of (5S, 6S)-erythro-5-methylmethadone or that opioid receptors recognize both gauche-like and extended conformations.     

Chemo-enzymatic short-step total synthesis of symbioramide

A concise synthesis of symbioramide, a marine-origin ceramide from a common starting material, methyl (±)-trans-2,3-epoxyoctadecanoate, in a convergent manner was achieved. The key step is the direct lipase-catalyzed coupling reaction between methyl (2R,3E)-2-hydroxy-3-octadecenoate and non-protected (±)-erythro-dihydrosphingosine, giving natural (2S,3R,2′R)-symbioramide and its (2R,3S,2′R)-isomer in 38% and 37% yield, respectively. The optically active β,γ-unsaturated α-hydroxyester was prepared by Mg(ClO₄)₂-mediated isomerization of epoxide and the subsequent lipase PS-catalyzed kinetic resolution.     

Revidierte Struktur des Makrodiolids Colletodiol

Revised Structure of the Macrodiolide Colletodiol An X-ray analysis shows that the vicinal glycol unit of colletodiol has the threo-rather than the previously assigned erythro-configuration (see 1 , Fig. 1 and Fig. 3). Together with the correlative assignments of (2R)- and (8R)-absolute configurations by MacMillan & Simpson the centers of chirality of colletodiol 1 are now established to be (2R, 8R, 10R, 11R).     

The synthesis of 3,6-diamino-2,3,4,6-tetradeoxy-dl-threo-hexopyranose derivatives,substrates for the synthesis of negamycin

Three synthetic routes to derivatives of 3,6 - diamino - 2,3,4,6 - tetradeoxy - DL - threo - hexopyranose were investigated. Addition of sodium azide in acetic acid to 6 - phthalimido - 5,6 - dihydro - 2 - pyrone gave 4-azido compound (7) of the erythro configuration. From methyl 2,4 - dideoxy - β -dl- erythro - hexopyranoside threo 4 - phthalimido - 6 - phthalimidomethyl - tetrahydro - 2 - pyrone (17) was obtained in three steps in low overall yield. Addition of sodium azide in acetic acid to butyl 6 - oxo - 2 - hydroxy - hex - 4 - enoate followed by methylation, amonolysis of the ester group, and reduction gave methyl 3,6 - diacetamido - 2,3,4,6 - tetradeoxy - α - DL - threo - hexopyranoside (26).     

Iodocyclization/base-induced hydrodeiodination reaction of 5-substituted 4-alkenols. The influence of substituent on the stereoselective pathway

The electrophilic iodocyclization reaction of (Z)- and (E)-5-n-alkylsubstituted 4-alken-1-ols followed by base-induced hydrodeiodination reaction stereoselectively gave, respectively, (Z)- and (E)-alkylidentetrahydrofurans in high yield. Completely different outcomes were observed with (Z)- and (E)-6,6-dimethylhept-4-en-1-ol: their iodocyclization furnished, respectively, threo- and erythro-2-(1-iodo-2,2-dimetylpropyl)tetrahydrofuran with high stereoselectivity. The threo isomer gave clean formation of 6-tert-butyl-3,4-dihydro-2H-pyran by base-induced ring expansion, while erythro isomer underwent a base-induced ring contraction to 1-cyclopropyl-3,3-dimethylbutan-1-one. Moreover, (Z)- and (E)-5-cyclopropylpent-4-en-1-ol underwent a 6-endo-iodocyclization to threo- and erythro-2-cyclopropyl-3-iodotetrahydro-2H-pyran, respectively, that under the same basic treatment, gave two isomeric 6-cyclopropyldihydro-2H-pyrans in a stereoselective fashion.     

Asymmetric synthesis of the natural erythro-(1R,2S)-8-O-4′-neolignan myrislignan

Abstract  

An efficient and practical asymmetric synthesis of erythro-(1R,2S)-8-O-4′-neolignan myrislignan was achieved by using vanillin and pyrogallic acid as the starting materials. Two key steps are involved: preparation of an enantiopure threo alcohol of predictable stereochemistry by dihydroxylation with AD-mix-β, and inversion of the absolute configuration from the threo to the erythro isomer using a Mitsunobu reaction. The route illustrates a new methodology for the synthesis of erythro-8-O-4′-neolignan.     

Diastereoselective addition of organozinc reagents to 2-alkyl-3-(arylsulfanyl)propanals

The preparation of compounds incorporating the 3-hydroxy-2-methyl-1-alkyl moiety of high diastereomeric purity is described. Such compounds can serve as potential building blocks for the preparation of several kinds of natural products. Diastereoselective synthesis of two potential pine sawfly pheromone components, one the pure racemic threo-isomer of 3-methylpentadecan-2-ol and the other the racemic erythro-isomer of 3-methyltridecan-2-ol are described. The diastereoselective addition of R₂Zn (R=Me, Et and n-Bu) to several 2-alkyl-3-(arylsulfanyl)propanals in the presence of a Lewis acid and CH₂Cl₂ as solvent was studied. An excellent diastereomeric ratio (95/5 anti-Cram/Cram) was obtained with 2-[(phenylsulfanyl)methyl]pentanal, 2-[(phenylsulfanyl)methyl]decanal and 2-[(phenylsulfanyl)methyl]dodecanal and Me₂Zn in the presence of TiCl₄.     

An efficient large scale resolution of (±)-threo-methylphenidate hydrochloride (Ritalin® hydrochloride)

An efficient and large scale preparation of (2R,2′R)-(+)-threo-methylphenidate hydrochloride (3) by the resolution of (±)-threo-methylphenidate hydrochloride (1) salt with O,O′-dibenzoyl-d-(+)-tartaric acid in the presence of 4-methylmorpholine is described.     

Composés propargyliques et alléniques du Si,Ge, Sn chiraux possédant en α un carbone asymétrique mise en évidence des diastéréoisomères

The propargylic R¹R²R³MCH(CH₃)CCH and allenic R¹R²R³MCHCCHCH₃ compounds (M = Si, Ge, Sn) with two neighbouring asymmetric centres exist in two diastereotopic erythro and threo forms observable in NMR.     

An unexpected high erythro-selection in the Grignard reaction with an N,O-acetal: a concise asymmetric synthesis of indolizidine alkaloid (−)-2-epi-lentiginosine

Starting from commercially available lactone 10, a concise and highly diastereoselective synthesis of (?)-(lS,2R,8aS)-2-epi-lentiginosine (2) is described. The synthesis featured an unexpected highly erythro-selective reaction of Grignard reagent 7 with the protected N,O-acetal 8. The stereochemical outcome of this reaction is contrary to the known results involving the reactions with O-benzyl protected aminofuranosides and aminoglycosides. Thus, this method constitutes an extension of the threo-diastereoselective C–C bond formation methodology.     

Zur Stereochemie der aromatischen Claisen-Umlagerung. Thermische Umlagerung von erythroiden und threoiden ortho-Dienonen

On the Stereochemistry of the Aromatic Claisen Rearrangement. Thermal Rearrangement of erythroid and threoid ortho-Dienones. Erythro- and threo-1-methyl-1-(1′-methyl-2′-propynyl)-2-oxo-1,2-dihydronaph-thalene (erythro- and threo- 6 ) as well as erythro- and threo-2,6-dimethyl-6-(1′-methyl-2′-propynyl)-cyclohexa-2,4-dien-1-one (erythro- and threo- 8 ) were obtained together with the corresponding aromatic ethers 5 and 7 by alkylation of 1-methyl-2-naphthol and 2,6-dimethyl-phenol, respectively in alcoholic potassium hydroxide solution with 1-methyl-2-propynyl p-toluenesulfonate (Scheme 2). The diastereoisomeric dienones 6 and 8 were easily separated by column chromatography on silica gel and its relative configuration at C(1) or C(6) and C(1′) deduced from the chemical shifts in their ¹H-NMR.-spectra (Table 1). Hydrogenation of 6 and 8 using Lindlar catalyst yielded the corresponding erythro- and threo-configurated (1′-methyl-2′-propenyl)-dienones 10 and 13 , respectively (Scheme 3) the thermal rearrangement of which were studied. The following results were obtained: threo- 10 rearranged in benzene at 85–105° preferentially via a chair-like (C) transition state to yield 99,5% (E)- and 0,5% (Z)-(2′-butenyl) 1-methyl-2-naphthyl ether ((E)- and (Z)- 14 ; ΔΔG (C/B) = ?4,0 kcal/mol). On the other hand, erythro- 10 when heated at 105-125° in benzene gave 84,7% (E)- and 15,3% (Z)- 14 , i.e. in this case a boat-like (B) transition state is favoured (G (C/B) = + 1,3 kcal/mol) (Scheme 5 and Table 2). The thermal rearrangement of dienones 13 led to the corresponding ethers 12 as well as p-allyl-phenols 11 . Thus, heating of threo- 13 at 20–42° in cyclohexane resulted in the formation of 2,5% of ether 12 , consisting of 98% of the (E)- and 2% of the (Z)-isomer, and 97,5% of (E)- 11 which contained, at a maximum, 0,5% of the (Z)-isomer, (Scheme 6 and Table 3). This means that both rearrangements occurred with a strong preference of the C transition state (G ( C/B , phenol) = ?3,3 kcal/mol). On the contrary, erythro- 13 when heated at 42–68° in cyclohexane yielded a 3:2 mixture of ether 12 and phenol 11 (Scheme 6). The ethereal part consisted of 88,0% of the (E)- and 12,0% of the (Z)-isomer which again shows that the B geometry predominated in the erythro transition state leading to the ether (G ( C / B )= + 1,3 kcal/mol). In the phenolic part 36–40% of the (E)-isomer and 64–60% of (Z)-isomer were found which means that in the para-Claisen rearrangement of erythro- 13 the C arrangement is only slightly favoured (ΔΔG ( C / B )= ?0,36 kcal/mol).     

Catalytic dissymmetrization of meso-2-imidazolidinones: alternative route to chiral synthons for 1,2-diamines

The chiral functionalization of a simple heterocycle, 1,3-dihydro-2-imidazolone, was achieved by the highly enantioselective monodeacylation of meso-1,3-diacetyl-2-imidazolidinones via an oxazaborolidine-catalyzed borane reduction. This kinetically controlled dissymmetrization is sufficiently effective to provide a synthetic route to either enantiomer of (4S, 5S)- or (4R, 5R)-4,5-dimethoxy-2-imidazolidinone derivatives, which serve as chiral synthons for threo-1,2-diamines.     

A convenient synthesis of new diamine,amino alcohol and aminophosphines chiral auxiliaries based on limonene oxide

A strategy for the synthesis of new chiral auxiliaries based upon vicinal diamines, amino alcohols and aminophosphines, obtained from limonene oxide, has been developed. The methodology allows the preparation of (1R,2R,4S)-1-methyl-4-(prop-1-en-2-yl)cyclohexane-1,2-diamine starting from a commercially available mixture of cis/trans (4S)-(?)-limonene oxides, through a stereoconvergent synthetic sequence. The process starts from an inexpensive naturally occurring material, is amenable to scale-up and allows easy access to highly useful enantiopure building blocks and ligands, employed in asymmetric catalysis.