Total asymmetric syntheses of d-lividosamine and 2-acetamido-2,3-dideoxy-d-arabino-hexose derivatives.

The “naked sugar” (+)-(1R, 4R)-7-oxabicyclo[2.2.1]hept-5-en-one((+)-2) has been converted to D-lividosamine ((+)-1: 3-deoxy-D-glucosamine) and derivatives via (+)-2-chloro-2,3-dideoxy-5,6-O-isopropylidene-D-arabino-hexono-1,4-lactone ((+)-33) and (+)-2-azido-2,3-dideoxy-5,6-O-isopropylidene-D-ribo-hexono-1,4-lactone ((+)-34) in a highly stereoselective fashion. Similarly, 2-acetamido-2,3-dideoxy-D-arabino-hexose and derivatives were derived from the “naked sugar” (−)-(1S,4S-7-oxabicyclo[2.2.1]-hept-5-en-2-one ((−)-2) via the double hydroxylation of the C=C double bond in (−)-N-benzyl-N-[(1R,2S,4S)-6-bromo-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl] amine ((−)-40).     

Total, asymmetric synthesis of (1r-1-c-(6′-amino-7′h-purin-8′-yl)-1,4-anhydro-3-azido-2,3-dideoxy-d-erythro-pentitol.

The “naked sugar” (+)-(1R,2R,4R)-2-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((+)-3) was converted in ten synthetic steps into the new C-nucleoside (1R)-1-C-(6′-amino-7′H-purin-8′-yl)-1,4-anhydro-3-azido-2,3-dideoxy- D-erythro-pentitol ((+)-2) in 19% overall yield.     

The electron-releasing homoconjugated carbonyl group. Application to the total syntheses of 3-deoxy-, 4-deoxy-hexose, lividosamine and derivatives

The regioselective electrophilic addition of benzeneselenyl bromide to (−)-(1S,4S)-7-oxabicyclo[2.2.1]-hept-5-en-2-one were exploited to develop efficient syntheses of methyl 3-deoxy--D-arabino-hexofuranoside and 4-deoxy-D-lyxo-hexopyranose. Similarly, D-lividosamine (3-deoxy-D-glucosamine) was derived from (+)-(1R,4R)-7-oxabicyclo[2.2.1]hept-5-en-2-one.     

Synthesis of enantiomerically pure 1,2-diamine derivatives of 7-azabicyclo[2.2.1]heptane. New leads as glycosidase inhibitors and rigid scaffolds for the preparation of peptide analogues

Enantiomerically pure alcohols (-)- and (+)-7-tert-butoxycarbonyl-6-endo-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-en-5-endo-ol ((-)-11 and (+)-11) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrroel and 2-bromo-1-p-toluenesulfonylacetylene, including a resolution method. These two alcohols were converted into (+)- and (-)-5-exo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-18 and (-)-18) and (+)- and (-)-5-endo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-19 and (-)-19) after adequate functionalization and desulfonylation steps. The corresponding conformationally constrained bicyclic 1,2-diamines (+)-4, (-)-4, (+/-)-5, (+/-)-6, (+)-7, and (-)-7 were obtained from the protected precursors 18 and 19 and evaluated as glycosidase inhibitors. Diamines (+)-4, (-)-4, (+)-6, and (-)-6 can be seen as new nonpeptide molecular scaffolds for the design of peptide analogues.     

Synthesis of 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] and derivatives: precursors of long-chain polyketides

Racemic 1,1′-methylene[(1RS,1′RS,3RS,3′RS,5RS,5′RS)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] ((±)-6) derived from 2,2′-methylenedifuran has been resolved kinetically with Candida cyclindracea lipase-catalysed transesterification giving 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] (−)-6 (30% yield, 98% ee) and 1,1′-methylenedi[(1S,1′S,3S,3′S,5S,5′S)-8-oxabicyclo[3.2.1]oct-6-en-3-yl] diacetate (+)-8, (40% yield, 98% ee). These compounds have been converted into 1,1′-methylenedi[(4S,4′S,6S,6′S)- and (4R,4′R,6R,6′R)-cyclohept-1-en-4,6-diyl] derivatives.     

Tris-chelate complexes with chiral ligands: In search of diastereoisomeric selectivity with remote stereogenic centres

The chiral ligands, 4,4′-bis{(1S,2R,4S)-(−)-bornyloxy}-2,2′-bipyridine, (1S,2R,4S)-1, and 4,4′-bis{(1R,2S,4R)-(+)-bornyloxy}-2,2′-bipyridine, (1R,2S,4R)-1, have been prepared and characterized by spectroscopic techniques and, for (1S,2R,4S)-1, by single crystal X-ray diffraction. Despite the use of enantiomerically pure ligands, the formation of the complexes [Fe((1S,2R,4S)-1)₃]²⁺, [Ru((1S,2R,4S)-1)₃]²⁺, [Ru((1S,2R,4S)-1)(bpy)₂]²⁺ and [Ru((1R,2S,4R)-1)(bpy)₂]²⁺ proceeds without preference for either the Δ or Λ-diastereoisomers.     

Acid-Catalyzed Rearrangement of 3-Aza-8-oxatricyclo[3.2.1. 02,4]octan-6-one Acetals. Highly Stereoselective Total Synthesis of 3-Amino-3-deoxy-D-altrose and Derivatives

Ethyl and tert-butyl azidoformate added to 7-oxabicyclo[2.2.1]hept-5-en-2-one dimethyl ( 5 ) and dibenzyl ( 6 ) acetals to give mixtures of regioisomeric triazolines. The latter gave the corresponding aziridines (6,6-dialkoxy-3-aza-8-oxatricyclo[3.2.1.0^2,4]octane-3-carboxylates 15 , 19 , 23 , and 27 and 31 ) on UV irradiation. In the presence of protic acids, the aziridines were rearranged into protected amines ([3-endo-alkoxy-5-oxo-7-oxabicyclo[2.2.1]hept-2-exo-yl]carbamates 16 , 20 , 24 , and 28 and 33 ). Using (+)-(1R, 4R)-5,5-bis(benzyloxy)7-oxabicyclo[2.2.1]hept-2-ene((+)- 6 ) derived from furan and l-cyanovinyl (1S)-camphanate, the method was applied to prepare 2-O-benzyl-3-[(tert-butoxy)carbonyiamino]-5-O-(3-chlorobenzoyl)-3-deoxy-β-D -altrofuranurono-6,1-lactone ((?)- 37 ). This compound was converted to methyl 3-amino-3-deoxy-α-D-altropyranoside hydrochloride ( 44 ) and several derivatives.     

Oligomeric flavanoids. Part 13. Synthesis of profisetinidins based on (−) robinetinidol and (+) -epifisetinidol

Acid-catalyzed condensation of (+)-mollisacacidin-[(2R, 3S, 4R)-2, 3-trans-3, 4-trans-flavan-3,3′,4,4′,7-pentaol] with an excess of (−)-robinetinidol[(2R,3S)-2,3-trans-flavan-3,3′,4′,5′,7-pentaol] afforded a novel series of bi-, tri-, and tetraflavanoid profisetinidins. They are accompanied by (−)-fisetinidol-(4,2′)-(−)-robinetinidol which results from the pyrogallol B-ring of (−)-robinetinidol serving as nucleophile competing with its resorcinol A-ring in coupling with a C-4 carbocationic intermediate. Similar condensation with (+)-epifisetinidol[(2S,3S)-2,3-cis-flavan-3,3′,4′,7-tetraol] led to the exclusive formation of [4,6]-interflavanyl bonds, these units being ‘linearly’ arranged in the tetraflavanoid analogue in contrast to the ‘branched’ nature of the (−)-robinetinidol homologue.     

Asymmetric hydroboration of [E]- and [Z]-2-methoxy-2-butenes. Synthesis of (−)-[2R,3R]-butane-2,3-diol in >97% ee

Asymmetric hydroboration of [E]- and [Z]-2-methoxy-2-butene, using (−)-diisopinocampheylborane at −25°C in THF solvent, followed by oxidation using H₂O₂/NaOH, gave (−)-[2R,3R]- and (+)-[2R,3S]-3-methoxy-2-butanols in >97 and 90% ee, respectively. (−)-[2R,3R]-3-Methoxy-2-butanol was converted to (−)-[2R,3R]-butane-2,3-diol (>97% ee, in an overall yield of 65%).     

Optical resolution of 7-oxabicyclo[2.2.1]hept-21-ene derivatives. Diastereoselectivity in the formation of cyanohydrine-brucine complexes

A new, practical method for the optical resolution of bicyclic ketones if illusttrated by the preparation of (+)-(1R,4R)-7-oxabicyclo[2.2.1]bept-5-en-2-one ((+)- 1 ) and (+)-(1R, 2S,4R)-2-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yul acetate ((+)- 4 ). It involves the diastereoselective formation of a brucine complex with the corresponding cyanhydrine mixture.     

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.     

Stereoselective synthesis of (1R,2S)-2-amino-1,3-diols from (R)-cyanohydrins

Vinyl substituted (1R,2S)-amino alcohols 5 were obtained by addition of vinyl magnesium bromide to the corresponding cyanohydrin O-trimethylsilyl ethers (R)-2. The O- and N-protected vinyl amino alcohols 6 were ozonized at −78°C in methanol yielding (1R,2S)-2-amino-1,3-diols7 in high enantiomeric and diastereomeric excesses. For purification, compounds 7 in some cases were acetylated to give the derivatives (1R,2S)-8. Racemic 6a was converted by oxidative ozonolysis at −78°C in methanolic NaOH solution to the corresponding methyl N-acetyl-β-hydroxy propanoate 9a. The configuration of (1R,2S)-8a was confirmed by x-ray crystallographic analysis.     

Determination of absolute configuration of a metabolite (−)-hydroxyhexamide from acetohexamide, syntheses of (−)- and (+)-hydroxyhexamides and (−)- and (+)-acetoxyhexamides

Enantioselective acetylation of (±)-4-(1-hydroxyethyl)benzenesulfonamide 6 with ‘Acylase I’ (No. A 2156) from Aspergillus melleus in the presence of vinyl acetate gave (R)-4-(1-acetoxyethyl)benzenesulfonamide 7 (98% ee) and (S)-6 (98% ee). Both (S)-6 and (R)-7 were individually converted to the (S)-hydroxyhexamide 2 (>99% ee) and (R)-hydroxyhexamide 2 (>99% ee), respectively. The absolute configuration of a metabolite (−)-hydroxyhexamide 2 from acetohexamide 1 was found to be S based on unequivocal chemical methods including X-ray analysis.     

Enantiodivergent synthesis of 3-amino-4,4-dimethyl-1-phenylpyrrolidin-2-one and derivatives: amino analogues of pantolactone

An enantiodivergent preparation of (+)-(R)- and (−)-(S)-3-amino-4,4-dimethyl-1-phenylpyrrolidin-2-one, (R)- and (S)-9, and several derivatives, from 4,4-dimethyl-1-phenylpyrrolidin-2,3-dione, 4, and (R)- or (S)-1-phenylethylamine, (R)- or (S)-5, as the chirality transfer agents, is described. Amine (S)-9 has also been used as a chiral auxiliary in a diastereoselective Michael reaction.     

Total Syntheses of (−)-Conduritol B ((−)-1L-Cyclohex-5-ene-1,3/2,4-tetrol) and of (+)-Conduritol F((+)-1D-Cyclohex-5-ene-1,2,4/3-tetrol). Determination of the Absolute Configuration of (+)-Leucanthemito

The ‘naked sugar’ (+)-(1R,2R4R)-2-endo-cyano-7-oxabicyclo[2.2.1]hept-5-sn-2-exo-yl acetate ((+)- 4 ) was converted (7 steps, 45% overall) with high stereoselectivity into (?)-(4R,5S,6R)-4,5,6-tris{[(tert-butyl)dimethylsilyl]oxy}cyclohex-2-en-1-one ((?)- 11 ). Reduction of (?)- 1 with NaBH₄- CeCl₃ · 7 H₂O, followed by deprotection of the silyl ether moieties gave (+)-conduritol F ((+)- 1 ; 47%) whose characteristics were identical to those of natural (+)-leucanthemitol. Reduction of (?)- 11 with DIBAH, followed by deprotection of the silyl ether moiety led to (?)-conduritol B ((?)- 3 ; 51 %).     

Asymmetric cyclization of 2-alkenylphenols. A comparative study on the use of palladium(II) and titanium(IV) complexes

The oxidative cyclization of 2-(3-pentenyl)phenol catalyzed by [(η³-pinene)PdOAc]₂ gives optically active (+)-2-vinylchroman (25% e.e.), while (−)-2-(1-hydroxyethyl)chroman (56% e.e.) is formed as a single diastereomer upon treatment with t-BuOOH in the presence of Ti(OⁱPr)₄ and -(+)-diethyl tartrate. 2-(2-Butenyl)phenol also undergoes the Ti-promoted asymmetric cyclization to give (2S,1′R)-(−)-2-(1-hydroxyethyl)-2,3-dihydrobenzofuran (29% e.e.).     

Polyhydroxylated pyrrolizidines. Part 3: A new and short enantiospecific synthesis of (+)-hyacinthacine A2

(1R,2R,3R,7aR)-1,2-Dihydroxy-3-hydroxymethylpyrrolizidine (+)-Hyacinthacine A₂ 1 has been synthesized by Wittig's methodology using [(2′S,3′R,4′R,5′R)-3′,4′-dibenzyloxy-N-tert-butyloxycarbonyl-5′-tert-butyldiphenylsilyloxymethylpyrrolidin-2′-yl]carbaldehyde 3, prepared from a partially protected DMDP 2, and the appropriated ylide, followed by cyclization by an internal reductive amination process of the resulting unsaturated aldehyde 4 and total deprotection.     

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.     

Asymmetric hydroformylation with Pt-phosphine-SnCl2 and Pt-bisphosphine-CuCl2 (or CuCl) catalytic systems

A study has been made of asymmetric hydroformylation of styrene with PtCl₂(PPh₃)₂ + bisphosphine + SnCl₂ (bisphosphine: BDPP = (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane or DIOP = (−)-(4R,5R)-2,2-dimethyl-4,5-bis(diphenylphosphinomethyl)-1,3-dioxolane) and PtCl₂(bisphosphine) + PPh₃ + SnCl₂ catalysts prepared “in situ”. The presence of an excess of the phosphine ligand slightly lowered the reaction rate, but the enantioselectivity of these systems is significantly higher than those involving PtCl(SnCl₃)(bisphosphine) catalysts. Under mild reaction conditions 88.8% enantiomeric excess was achieved. Replacing SnCl₂ in these catalysts by CuCl₂ or CuCl gave a new homogeneous catalytic system which is active at higher reaction temperature (> 100°C), but has a rather moderate enantioselectivity.     

Syntheses of (+)- and (–)-Methyl 8-Epinonactate and (+)- and (–)-Methyl Nonactate

In four synthetic steps, (+)- and (–)-methyl 8-epinonactate ((+)- and (–)− 4 ) have been derived from (+)- and (–)-7-oxabicyclo[2.2.1]heptan-2-one ((+)- and (–)− 9 ), respectively. The (+)- and (–)-methyl nonactate ((+)- and (–)− 3 ) were obtained from (+)- and (–)− 4 , respectively, by Mitsunobu displacement reactions. Optical resolution of (±)− 9 via chromatographic separation of the corresponding N-methyl-S-alkyl-S-phenylsulfoximides 24 and 25 yielded the starting materials (+)- and (–)− 9 , respectively.