Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. Part 6: synthesis and incorporation into peptides of the first reported 2,3-dihydroxycyclopentanecarboxylic acid

Herein we report the intramolecular alkylation of nitronates of methyl-5-O-benzyl-3,6-deoxy-6-nitro-β-d-glucofuranoside and methyl-5-O-benzyl-3,6-deoxy-6-nitro-α-d-glucofuranoside into the corresponding 2-oxabicyclo[2.2.1]heptane derivatives. Similarly, methyl-3-O-benzyl-5-deoxy-5-nitromethyl-β-d-xylofuranoside and methyl-3-O-benzyl-5-deoxy-5-nitromethyl-α-d-xylofuranoside were cyclized to (1R,3R,4S,5R,7R)-7-benzyloxy-3-methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane and (1R,3S,4S,5R,7R)-7-benzyloxy-3-methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane, respectively. These 2-oxabicyclo[2.2.1]heptane derivatives were eventually transformed into enantiopure methyl (1S,2S,3R,4S,5R)-2-amino-2,3-dihydroxycyclopentanecarboxylate and this novel β-amino acid was incorporated into peptides.     

Efficient,scalable kinetic resolution of cis-4-benzyloxy-2,3-epoxybutanol

A new enzyme catalysed kinetic resolution of cis-4-benzyloxy-2,3-epoxybutanol has been reported. Efficient, scalable separation of the optically active alcohol from its ester derivative has been solved with liquid–liquid and solid–liquid extraction methods using commercial organic solvents and supercritical carbon dioxide. cis-4-Benzyloxy-2,3-epoxy-1-butanol enantiomers were applied for the enantioselective synthesis of (2S,3S,1′S)- and (2R,3R,1′R)-3-[2′-(dibenzylamino)-1′-hydroxyethyl]-2-phenyloxetane.     

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F 3 was achieved from the chiral bithiazole-type primary alcohols [(S)- and (R)-4-ethoxycarbonyl-2′-(1-hydroxymethylethyl)-2,4′-bithiazoles 8], which were obtained based on the enzymatic resolution of racemic alcohol 8 and its acetate 9. From a direct comparison by means of chiral HPLC between natural cystothiazole F 3 and synthetic compounds [(4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles 3], natural cystothiazole F 3 was found to be a 33:67 diastereomeric mixture [(4R,5S,6E,14S)-3:(4R,5S,6E,14R)-3 = 33:67].     

Highly Stereoselective Total Syntheses of 2,5-Anhydro-4-deoxy-D-ribo-hexonic Acid and of (1S)-1-C-(6-amino-7H-purin-8-yl)-1,4-anhydro-3-deoxy-D-erythro-pentitol (= cordycepin C)

Highly regio- and stereoselective monohydroxylation of the C?C bond of (+)-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 8 ) was achieved via LiAlH₄ reduction of the corresponding 5,6-exo-epoxy dimethyl acetal 9 . The reaction gave exclusively (–)-(1R, 2R, 4S)-6,6-dimethoxy-7-oxabicyclo[2.2.1]heptan-2-exo-ol ( 10 ) which was transformed into 2,5-anhydro-3-O-benzyl-4-deoxy-D -ribo-hexonic acid ( 15 ) and 2,5-anhydro-4-deoxy-D -ribo-hexonic acid ( 6 ) via ozonolysis of (–)-(1R, 4S, 6R)-6-exo-benzyloxy-2-{[(tert-butyl)dimethylsilyl]oxy}-7-oxabicyclo[2.2.1]hept-2-ene ( 14 ). Cordycepin C ( 5 ) was derived from 6 and 4,5,6-triaminopyrimidine using CsF/DMF to generate the adenine heterocycle.     

Total synthesis of 2-(β-D-ribofuranosyl)thiazole-4-carboxamide (Tiazofurin) and of precursors of ribo-C-nucleosides

(1R,2S,4R)-2-Cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl (1S′)-camphanate ( 5 ) was transformed into (?)-methyl 2,5-anhydro-3,4,6-O-tris[(tert-butyl)dimethylsilyl]-D -allonate ( 2 ), (+)-1,3-diphenyl-2-{2′,3′,5′-O-tris[(tert-butyl)dimethylsilyl]-β-D -ribofuranosyl}imidazolidine ( 3 ), and the benzamide 20 of 1-amino-2,5-anhydro-1-deoxy-3,4,6-O-tris-[((tert-butyl)dimethylsily)]-D -allitol. Compound 2 was converted efficiently into optically active tiazofurin ( 1 ).     

Synthesis of (+)-1,3:2,5-dianhydroviburnitol ((+)-(1R,2R,3S,5R,6S)-4,7-dioxatricyclo[3.2.1.03,6]octan-2-ol)

Epoxidation of (?)-(1R,2R,4R)-2-endo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((?)-5) followed by saponification afforded (+)-(1R,4R,5R,6R)-5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ((+)-7). Reduction of (+)-7 with diisobutylaluminium hydride (DIBAH) gave (+)-1,3:2,5-dianhydroviburnitol ( = (+)-(1R,2R,3S,4R,6S)-4,7-dioxatricyclo[3.2.1.0^3,6]octan-2-ol; (+)-3). Hydride reductions of (±)-7 were less exo-face selective than reductions of bicyclo[2.2.1]heptan-2-one and its derivatives with NaBH₄, AlH₃, and LiAlH₄ probably because of smaller steric hindrance to endo-face hydride attack when C(5) and C(6) of the bicyclo-[2.2.1]heptan-2-one are part of an exo oxirane ring.     

Studies towards the synthesis of (1R,2S)- and (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonates and (1S,2S)- and (1R,2S)-2,3-epoxy-1-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised by the intramolecular Williamson reaction of diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate. The cis-analogue was obtained as O-ethyl or O,O-diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphosphonates, when (1R,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate or its 3-O-trityl derivative were used as starting materials, respectively. The intramolecular Williamson cyclisations of diethyl (1S,2R)- and (1R,2S)-1-benzyloxy-3-hydroxy-2-mesyloxypropylphosphonates led to diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, respectively, with the concomitant formation of diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phosphonate. From diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, enantiomerically pure diethyl (1S,2S)- and (1R,2S)-1,2-dihydroxypropylphosphonates were obtained by catalytic hydrogenation, while diethyl (1S,2S)- and (1R,2S)-3-acetamido-1,2-dihydroxypropylphosphonates were produced after epoxide ring opening with dibenzylamine, acetylation and hydrogenolysis.     

Asymmetric Total Synthesis of (11R, 12S, 13S, 9Z, 15Z)-9, 12, 13-Trihydroxyoctadeca-9, 15-dienoic Acid,a self-defensive agent against rice-blast disease

The Diels-Alder adduct of furan and 1-cyanovinyl (1′R)-camphanate was converted into methyl [(tert-butyl)-dimethylsilyl 5-deoxy-2, 3-O-isopropylidene-β-L -ribo-hexofuranosid] uronate ((+)- 4 ). Reduction with diisobutyl-aluminium hydride gave the corresponding aldehyde which was condensed with the ylide derived from triphenyl-(propyl)phosphonium bromide to give (1R, 2S, 3S, 4S)-1-[(tert-butyl)dimethylsilyloxy]tetrahedro-2, 3-(isopropyl-idenedioxy)-4-[(Z)-pent-2′ -enyl]furan ((+)- 7 ). Removal of the silyl protective group gave a mixture of the corresponding furanose that underwent Wittig reaction with the ylide derived from [8-(methoxycarbonyl)-octyl]triphenylphosphonium bromide to yield methyl (11R, 12S, 13S, 9Z, 15Z)-13-hydroxy-11, 12-(isopropylidene-dioxy)octadeca-9, 15-dienoate ((?)- 9 ). Acidic hydrolysis, then saponification afforded (11R, 12S, 13S, 9Z, 15Z)-11, 12, 13-trihydroxyoctadeca-9, 15-dienoic acid ( 1 ).     

A Convenient Stereoselective Synthesis of (1R,2S,3R,4S)-3-(Neopentyloxy)isoborneol

A convenient preparation of (1R,2S,3R,4S)-3-(neopentyloxy)isoborneol (= (1R,2S,3R,4S)-3-(2,2-dimethyl-propoxy)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 1a ), a valuable chiral auxiliary, is described. The synthesis involves six steps starting from the readily available camphorquinone ( 5 ) and gives 1a in 48% overall yield. The key step is the chemoselective hydrolysis of the less hindered 1,3-dioxolane moiety in the camphorquinone di-acetal 4 .     

Carotinoide mit 7-Oxabicyclo[2.2.1]heptyl-Endgruppen. Teil II. Synthese von (2S,5R,6S,2′S,5′R,6′S)-2,5:2′5′-Diepoxy-5,6,5′,6′-tetrahydro-β,β-carotin

Carotenoids mit 7-Oxabicyclo[2.2.1]heptyl-End Groups. Synthesis of (2S,5R,6S,2′S,5′R,6′S)-2,5:2′5′-Diepoxy-5,6,5′,6′-tetrahydro-β,β-carotene Mukayama's ester 6 (methyl (1S,2R,5S)-2,5-epoxy-2,6,6-trimethylcyclohexane-1-carboxylate) was transformed in a few conventional steps into the title compound 14 . Its CD curve was found to be significantly different from that of the analogous 3,6-epoxide, a fact we tentatively lake as an indication of a (weak) electronic interaction between the ring O-atom and the π-orbitals of the polyene chain.     

Exploration of chiral induction on epoxides in lipase-catalyzed epoxidation of alkenes using (2R,3S,4R,5S)-(–)-2,3:4,6-di-O-isopropylidiene-2-keto-l-gulonic acid monohydrate

Epoxidation of alkenes by peracid, generated in situ from (2R,3S,4R,5S)-(?)-2,3:4,6-di-O-isopropylidiene-2-keto-l-gulonic acid monohydrate [(?)-DIKGA] and hydrogen peroxide by lipase catalysis induces chirality on the product epoxides with moderate to good enantioselectivity (35–71%). Alkoxy/aralkyloxy styrenes however did not undergo any epoxidation. (R)-(+)-4-Hydroxy styrene-7,8-oxide was formed and isolated with moderate enantiomeric excess (57%) but was found to have poor stability.     

Syntheses of (2R,4'R,8'R)-alpha-tocopherol and (2R,3'E,7'E)-alpha-tocotrienol.

Reaction of trimethyl-hydroquinone with methyl vinyl ketone in acidic methanol gave rac.-2-methoxy-2,5,7,8-tetramethyl-chroman-6-ol ( 8 ). This acetal was converted in four steps to rac.-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)acetic acid ( 13 ). Acid 13 was readily resolved with α-methyl-benzylamine to give the (S)-enantiomer 14 . Treatment of the unwanted (2 R)-isomer with acid regenerated 13 , thus leading to an efficient use of this compound. Employing a side chain derived from phytol, 14 was converted to (2R, 4′R, 8′R)-α-tocopherol ( 1d , ‘natural’ vitamin E). A reaction sequence from 14 involving two highly stereoselective Claisen rearrangements has provided the first total synthesis of (2R,'E,7′E)-α-tocotrienol ( 2d ).     

The Synthesis of the 2′′- and 2′′′-Monodeoxygenated Analogues of β-Maltosyl-(1→4)-Trehalose

Abstract

Two derivatives of β-maltosyl-(1→4)-trehalose monodeoxygenated at C-2′′ or C-2′′′ have been synthesized in [2+2] block syntheses. O-(2,3,4,6-Tetra-O-benzyl-α-D-glucopyranosyl)-(1→4)-3,6-di-O-benzyl-1,2-di-O-acetyl-β-D-glucopyranose (6), prepared from the respective orthoester, was coupled to the glycosyl acceptor 2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranosyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside. In the resulting tetrasaccharide 8, the only ester group was removed and replaced by a xanthate which was reduced in a Barton-McCombie reaction to afford the 2′′-deoxygenated tetrasaccharide 12. For the synthesis of a 2′′′-deoxygenated derivative, a maltose building block was assembled from two monosaccharides. The key building block was ethyl 2,3,6-tri-O-benzyl-1-thio-β-D-glucopyranoside (14) which was used i) as a glycosyl acceptor in a phenylselenyl chloride mediated coupling reaction with tri-O-benzyl-glucal and ii) after the first coupling as a glycosyl donor to react with glycosyl acceptor 7 to give tetrasaccharide 18. The phenylselenyl group was reduced with tributyltin hydride on the disaccharide level. Deprotection of 18 furnished the 2′′′-deoxy-maltosyl-(1→4)-trehalose 20.     

Uncommon transformations of methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate initiated by bases

Methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate prepared in two stages from D-ribose acetonide underwent a series of uncommon transformations under the treatment with bases providing the following different products depending on the base applied: methyl 3-(5-acetyl-2,2-dimethyl-1,3-dioxol-4-yl)propionate (DBU), methyl 2,3-isopropylidenedioxy-7-oxabicyclo[2.2.1]heptane-6-carboxylate (t-BuOK), methyl {(5R)-2,2-dimethyl-5-[(2R)-oxiranyl]-1,3-dioxolan-4-ylidene}propionate and methyl-(E)-3-{(4S,5R)-2,2-dimethyl-5-[(1R)-(2-oxiranyl)]-1,3-dioxolan-4-yl}-2-propenoate (t-BuOK and LDA).     

Studies on the transformation of nitrosugars into iminosugars III: synthesis of (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol and (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol

A divergent synthesis of the two novel polyhydroxylated azepanes (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol and (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol from d-mannose is described. The method involves a Henry reaction between dimethyl-tert-butylsilyl 2,3-O-isopropylidene-α-d-lyxo-pentodialdo-1,4-furanoside and 2-nitroethanol followed by a reductive ring closure of the resulting epimeric nitro aldols. Glycosidase inhibition tests showed that (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol exhibits a weak but selective inhibition against α-l-fucosides.     

Synthesis of Polypropionate Fragments Containing Tertiary-Alcohol Moieties. Cross-aldolisations with lithium enolates of 7-oxabicyclo[2.2.1]heptan-2-one derivatives

The Diels-Alder adduct of 2,4-dimethylfuran to 1-cyanovinyl (1′R)-camphanate ((+)-(1R,2S,4R)-2-exo-cyano-1,5-dimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl (1′R)-camphanate ((+)- 1 )) was converted into (+)-2,7-dideoxy-2,4-di-C-methyl-L -glycero- ((+)- 6 ) and -D -glycero-L -altro-heptono-1,4-lactone ((+)- 7 ), into (?)-(3R,4R,5R,6S)-3,4:5,7-bis(isopropylidenedioxy)-4,6-dimethylheptan-2-one ((?)- 22 ), and into (+)-(2R,3R,4R,5S,6S)-3,4:5,6-bis(isopropylidenedioxy)-2,4-dimethylheptanal ((+)- 34 ). Condensation of ((+)- 34 with the lithium enolate of (?)-(1R,4R,5S,6R)-6-exo-[(tert-butyl)dimethylsilyloxy]-1,5-endo-dimethyl-7-oxabicyclo[2.2.1] heptan-2-one ((?)- 38 ; derived from (+)- 1 ) gave a 3:2 mixture of aldols (+)- 39 and (+)- 40 (mismatched pairs of a α-methyl-substituted aldehyde and (E)-enolate) whereas the reaction of (±)- 34 with (±)- 38 gave a 10:1 mixture of aldols (±)- 41 and (±)- 39 . A single aldol, (?)- 44 , was obtained to condensing (+)- 34 with the lithium enolate of (+)-(1S,4S,5S,6S)-5-exo-(benzyloxy)-1,5-endo-dimethyl-7-oxabicyclo[2.2.1]heptan-2-one ((+)- 43 ; derived from (?)-(1S,2R,4S)-2-exo-cyano-1,5-dimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl (1′S)-camphanate ((?)- 3 )). All these cross-aldolisations are highly exo-face selective for the bicyclic ketones. The best stereochemical matching is obtained when the lithium enolates and α-methyl-substituted aldehydes can realize a ‘chelated transition state’ that obeys the Cram and Felkin-Anh models (steric effects). Polypropionate fragments containing eleven contiguous stereogenic centres and tertiary-alcohol moieties are thus prepared with high stereoselectivity in a convergent fashion. The chiral auxiliaries ((1R)- and (1S)-camphanic acid) are recovered at the beginning of the syntheses.     

Eine Suche nach 3′-Epilutein ( = (3R,3′S,6′R)-β,ε-Carotin-3,3′-diol) und 3′, O-Didehydrolutein (=(3R, 6′R)-3-Hydroxy-β,ε-carotin-3′-on) in Eigelb,in Blüten von Caltha palustris und in Herbstblättern

Search for the Presence in Egg Yolk, in Flowers of Caltha palustris and in Autumn Leaves of 3′-Epilutein ( =(3R,3′S,6′R)-β,ε-Carotene-3,3′-diol) and 3′,O-Didehydrolutein ( =(3R,6′R)-3-Hydroxy-β,ε-carotene-3′-one) 3′.O-Didehydrolutein ( =(3R, 6′R)-3-hydroxy-β,ε-carotene-3′-one; 2) has been detected in egg yolk and in flowers of Caltha palustris. This is the first record for its occurrence in a plant. The compound shows a remarkable lability towards base; therefore, it may have been overlooked til now, because it is destroyed under the usual conditions of saponification of the carotenoid-esters. One of the many products formed from 2 with 1% KOH in methanol has been purified and identified as the diketone 3 ( =(3R)-3-hydroxy-4′, 12′-retro-β,β-carotene-3′,12′-dione). The identification of this transformation product from lutein might throw a new light on the metabolism of this important carotenoid in green plants. 3′-Epilutein ( =(3R,3′S,6′R)-β,ε-carotene-3,3′-diol; 1) was not detected in egg yolk, but is present besides lutein in flowers of C. palustris, thus confirming an earlier report of the occurrence of an isomeric (possibly epimeric) lutein (‘calthaxanthin’) in that plant [21]. We were not able to detect even traces of 1 or 2 in the carotenoid fraction from autumn leaves of Prunus avium (cherry), Parrotia persica, Acer montanum (maple) and yellow needles of Larix europaea (larch). α-Cryptoxanthin (4) , a very rare carotenoid, was isolated in considerable quantity for the first time from flowers of C. palustris.     

Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. IV: Synthesis of enantiopure methyl (1S,2R,3R,4R,5S)-5-benzyloxycarbonylamino-2,3-isopropylidenedioxy-4-methoxycyclopentanecarboxylate

The first total synthesis of a new enantiopure polyhydroxylated cyclopentyl β-amino acid [methyl (1S,2R,3S,4R,5S)-2-benzyloxy-5-benzyloxycarbonylamino-3-hydroxy-4-methoxycyclopentanecarboxylate] was achieved according to our recent novel strategy for the transformation of nitrohexofuranoses into cyclopentylamines. This approach is based on an intramolecular cyclization leading to 2-oxabicyclo[2.2.1]heptane derivatives. Epimerization of this amino acid derivative to methyl (1S,2R,3R,4R,5S)-2-benzyloxy-5-benzyloxycarbonylamino-3-hydroxy-4-methoxycyclopentanecarboxylate constitutes the first example of the preparation of one of the members of this family of amino acids with a stereochemistry that is not compatible with the above key cyclization step.     

A 2,4-O-[(Z)-2-butenylene]-bridged glucopyranose: efficient construction of the bicyclic skeleton and its axial-rich twist-boat conformation

Synthesis and conformational analyses of 1-O-acetyl-3,6-di-O-benzyl-2,4-O-[(Z)-2-butenylene]-β-d-glucopyranose are described. The construction of the trioxabicyclo[6.3.1]dodecane skeleton of the compound was initiated from a ring-opened glucose, followed by the successive cyclization of first the nine-membered ring and then the six-membered ring. The pyranose of the compound was in ³S₁, an axial-rich twist-boat conformation. This result demonstrated an alternative method for the restriction of the pyranose into the axial-rich twist-boat conformation in contrast to the procedures that use bulky silyl protecting groups.     

Isolierung von (2S, 4S)-(+)-γ-Hydroxynorvalin und (2S, 4R)-(−)-γ-Hydroxynorvalin aus Boletus satanas Lenz

We have isolated from the carpophores of Boletus satanas Lenz (Basidiomycetae) (2S,4S)-(+)-γ-hydroxynorvaline ( 1 ) and (2S,4R)-(?)-γ-hydroxynorvaline ( 2 ). The chirality of each diastereomer has been determined by chemical synthesis starting from optically active precursors and by application of different chiroptical methods. Gaschromatographic separation of the derived diastereomeric N-[(S)-α-methoxypropionyl]-lactones reveals that the optical purity of natural 2 is 88% whereas 1 exists as a partial racemate: (2S,4S): (2R,4R) = 3:2. Muscarine could not be detected in the carpophores of B. satanas, contrary to some literature data but basic substances of unknown structure are present in low concentration.