The enantioselective synthesis of poison-frog alkaloids (−)-203A, (−)-209B, (−)-231C, (−)-233D, and (−)-235B″

The enantioselective synthesis of indolizidines (−)-203A, (−)-209B, (−)-231C, (−)-233D, and (−)-235B″ has been achieved and the absolute stereochemistry of both indolizidines 203A and 233D was established as 5S,8R,9S. The relative stereochemistry of natural 231C was established by the present asymmetric synthesis.     

Determination of the absolute structure of albaconol

The concise synthesis of (8aR)-(−)-albaconol (1) from (8aR)-albicanol (2) obtained from the lipase-assisted asymmetric acetylation of rac-2, was achieved in 45% overall yield (eight steps). By comparison of the sign of specific rotation of between synthetic (8aR)-(−)-albaconol (1) and natural (+)-albaconol (1), the absolute structure of natural (+)-1 was determined to be 1R,2R,4aS,8aS configuration.     

Gold catalysis in stereoselective natural product synthesis: (+)-linalool oxide, (−)-isocyclocapitelline, and (−)-isochrysotricine

A stereoselective synthesis of the tetrahydrofuran-containing natural products (2S,5R)-(+)-linalool oxide (1), (−)-isocyclocapitelline (2), and (−)-isochrysotricine (3) is reported. Key steps are the copper-mediated S_N2′-substitution of propargyl oxiranes 7 and the gold-catalyzed cycloisomerization of dihydroxyallenes 8/17, resulting in a highly efficient center-to-axis-to-center chirality transfer. The enantioselective total synthesis of (−)-isocyclocapitelline (2) and (−)-isochrysotricine (3) allowed the elucidation of the absolute configuration of these β-carboline natural products.     

An enantioselective total synthesis of (S)-(−)-licochalcone E: determination of the absolute configuration

The absolute configuration of (−)-licochalcone E (1) was determined to be (S) via the first enantioselective total synthesis of the compound. The chirality in (S)-(−)-licochalcone E (1) was installed by asymmetric methylation of the Evans' oxazolidinone derivatives.     

δ-Lactone formation from δ-hydroxy-trans-α,β-unsaturated carboxylic acids accompanied by trans-cis isomerization: synthesis of (−)-tetra-O-acetylosmundalin

(±)-(4,5-anti)-4-Benzyloxy-5-hydroxy-(2E)-hexenoic acid 6 was subjected to δ-lactonization in the presence of 2,4,6-trichlorobenzoyl chloride and pyridine to give the α,β-unsaturated-δ-lactone congener (±)-7 (87% yield) accompanied by trans-cis isomerization. This δ-lactonization procedure was applied to the chiral synthesis of (+)-(4S,5R)-7 or (−)-(4R,5S)-7 from the chiral starting material (+)-(4S,5R)-6 or (−)-(4R,5S)-6. Deprotection of the benzyl group in (+)-(4S,5R)-7 or (−)-(4R,5S)-7 by the AlCl₃/m-xylene system gave the natural osmundalactone (+)-(4S,5R)-5 or (−)-(4R,5S)-5 in good yield, respectively. Condensation of (−)-(4R,5S)-5 and tetraacetyl-β-d-glucosyltrichloroimidate 22 in the presence of BF₃·Et₂O afforded the condensation product (−)-8 (97% yield), which was identical to tetra-O-acetylosmundalin (−)-8 derived from natural osmundalin 9.     

Asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine

An asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine (1R and 1S) is presented. Trifluoromethylation involves nucleophilic aromatic substitution of halobenzene 4 most likely via a copper mediated CF₃ anion equivalent generated in situ. The asymmetric step involves conversion of 3,4-dimethoxy-2-trifluoromethylbenzaldehyde (5) to silyl cyanohydrin (6R and 6S) using a chiral salen catalyst in the presence of titanium. 1R and 1S are potential alternatives to currently used vasoconstrictors in local anesthetic formulations.     

New synthesis of (−)- and (+)-actinobolin from d-glucose

The total synthesis of (−)-actinobolin 2, an antipode of the natural product starting from d-glucose is described. A three-component coupling reaction of a functionalized cyclohexenone (+)-6, derived from d-glucose by way of Ferrier's carbocyclization, with vinyl cuprate and an aldehyde (R)-5 effectively constructed the carbon framework of 2 in a highly stereoselective manner. The formal synthesis of the natural enantiomer 1 from d-glucose was also achieved.     

Stereoselective synthesis of tetrahydroisoquinoline alkaloids: (−)-trolline, (+)-crispin A, (+)-oleracein E

Tetrahydroisoquinoline alkaloids, (S)-(−)-trolline, (R)-(+)-crispin A, and (R)-(+)-oleracein E, have been synthesized stereoselectively from the both enantiomers of common intermediate (S)-4 and (R)-4. The key step in the synthesis include a stereoselective Bi(OTf)₃-catalyzed intramolecular 1,3-chirality transfer reaction of chiral non-racemic amino allylic alcohols (S)-6 and (R)-6 to construct both enantiomers of (E)-1-propenyl tetrahydroisoquinoline 4.     

Total synthesis of (+)-epiepoformin, (+)-epiepoxydon and (+)-bromoxone employing a useful chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate

Enantioselective total synthesis of (+)-epiepoformin 1, (+)-epiepoxydon 2 and (+)-bromoxone 3 using a chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25, it accomplished a formal synthesis of (−)-theobroxide 19, (−)-phyllostine 22, (+)-herveynone 27 and (−)-asperpentyn 28. The usefulness of 6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated.     

Enantioselective synthesis of axially chiral 1-(1-naphthyl)isoquinolines and 2-(1-naphthyl)pyridines through sulfoxide ligand coupling reactions

Racemic 1-(1′-isoquinolinyl)-2-naphthalenemethanol rac-12 was prepared through a ligand coupling reaction of racemic 1-(tert-butylsulfinyl)isoquinoline rac-7 with the 1-naphthyl Grignard reagent 10. Resolution of rac-12 was achieved through chromatographic separation of the Noe-lactol derivatives 14 and 15, providing (R)-(−)-12 of >99% ee and (S)-(+)-12 of 90% ee. The ligand coupling reaction of optically enriched sulfoxide (S)-(−)-7 (62% ee) with Grignard reagent 10 furnished rac-12, with the absence of stereoinduction resulting from competing rapid racemisation of the sulfoxide 7. Reaction of optically enriched (S)-(−)-7 with 2-methoxy-1-naphthylmagnesium bromide was also accompanied by racemisation of the sulfoxide 7, and furnished optically active (+)-1-(2′-methoxy-1′-naphthyl)isoquinoline (+)-3b in low enantiomeric purity (14% ee). The absolute configuration of (+)-3b was assigned as R using circular dichroism spectroscopy, correcting an earlier assignment based on the Bijvoet method, but in the absence of heavy atoms. Optically active 2-pyridyl sulfoxides were found not to undergo racemisation analogous to the 1-isoquinolinyl sulfoxide 7, with the ligand coupling reactions of (R)-(+)- and (S)-(−)-2-[(4′-methylphenyl)sulfinyl]-3-methylpyridines, (R)-(+)-17 and (S)-(−)-17, with 2-methoxy-1-naphthylmagnesium bromide providing (−)- and (+)-2-(2′-methoxy-1′-naphthyl)-3-methylpyridines, (−)-18 and (+)-18, in 53 and 60% ee, respectively. The free energy barriers to internal rotation in 3b and 18 have been determined, and the isoquinoline (R)-(−)-12 examined as a ligand in the enantioselectively catalysed addition of diethylzinc to benzaldehyde; (R)-(−)-12 was also converted to (R)-(−)-N,N-dimethyl-1-(1′-isoquinolinyl)-2-naphthalenemethanamine (R)-(−)-19, and this examined as a ligand in the enantioselective Pd-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate.     

(+)-Cystothiazole G: isolation and structural elucidation

Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpent-4-yne-1,2-diol (6) derived from (2R,3S)-epoxybutanoate 5 followed by methylation gave the tetrahydro-2-furylidene acetate (−)-7, which was converted to the left-half aldehyde (+)-3. A Wittig reaction between (+)-3 and the phosphoranylide derived from the bithiazole-type phosphonium iodide 4 using lithium bis(trimethylsilyl)amide afforded the (+)-cystothiazole G (2), whose spectral data were identical with those of the natural product (+)-2. Thus, the stereochemistry of cystothiazole G (2) was proved to be (4R,5S,6(E)).     

Temporary thio-derivatization in the synthesis of (+)-4-acetylbromoxone

A stereocontrolled synthesis of the marine natural products (+)-bromoxone (1) and (+)-4-acetylbromoxone (2) is reported. The sequence features the enzymatic kinetic resolution of 4-hydroxycyclohexenone (6) via its S-benzyl adduct. Thereafter, a base-mediated elimination-silylation generated an optically active (−)-4S-4-tert-butyldimethylsilyoxycyclohexenone (5), which then underwent diastereoselective epoxidation. Saegusa-Ito oxidation enabled formation of the corresponding α,β-unsaturated ketone 13. Bromination-elimination and subsequent removal of the silicon protecting group afforded (+)-bromoxone (1) which was converted into (+)-(4S,5R,6R)-4-acetoxy-2-bromo-5,6-epoxycyclohex-2-enone (2) [(+)-4-acetylbromoxone]. Using a luciferase gene reporter assay ED₅₀ for NFκB inhibition of 9 μM was determined.     

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.     

Enantioselective synthesis of (2R,3R)- and (2S,3S)-β-hydroxyornithine

An efficient and short synthesis of (2R,3R)- and (2S,3S)-β-hydroxyornithine 1a-b is described using Sharpless asymmetric dihydroxylation and regioselective nucleophilic opening of a cyclic sulfite as the key steps.     

Formal synthesis of (−)-anisomycin based on stereoselective nucleophilic substitution along with 1,2-aryl migration

The stereoselective conversion of (4R)-5-hydroxy-4-(4′-methoxyphenyl)-2(E)-pentenoate 4 into the (4S)-4-hydroxy-5-(4′-methoxyphenyl)-2(E)-pentenoate 5 using the AgNO₃/MS 4 Å/MeNO₂ system was accomplished along with complete inversion at the C₄-position, and the synthesis of the intermediate (4S)-7 for the chiral synthesis of (−)-anisomycin 6 from (4S)-7 based on osmium tetroxide-catalyzed stereoselective hydroxylation was achieved.     

An efficient approach to 2-substituted N-tosylpiperdines: asymmetric synthesis of 2-(2-hydroxy substituted)piperidine alkaloids

We have developed an efficient and a general approach to chiral 2-substituted N-tosylpiperidines starting from chiral α-substituted-N-tosylaziridines. Using this approach, we have synthesized (+)-coniine. The synthesis of chiral N-tosyl-2-piperidinylethanol 15 and ent-15, was achieved from l- and d-aspartic acids, respectively in few steps. Piperidine 15 was converted into 2-(2-hydroxysubstituted)piperidines of type 2 in optically active form. By applying this strategy, asymmetric syntheses of halosaline (R,R)-2a, (+)- and (−)-sedamine 2b, (+)- and (−)-allosedamine 2c, (+)- and (−)-sedridine 2d, (+)- and (−)-allosedridine 2e, (+)-tetraponerine T-3 3a, T-4 3c, T-7 3b, and T-8 3d have been achieved in high yields. These stereoisomers can be interconverted via Mitsunobu inversion in excellent yields.     

Synthesis of the C(1)-C(16) fragment of bryostatins using an ‘ene’ reaction between an allylsilane and an alkynone

The zinc(II) iodide mediated ‘ene’ reaction between (4R)-4,5-bis-(tert-butyldimethylsilyloxy)-2-(trimethylsilylmethyl)pent-1-ene (43) and (5S,7R,9S)-5,11-dibenzyloxy-4,4-dimethyl-7,9-dihydroxy-7,9-O-isopropylideneundec-1-yn-3-one (53) gave the (E)-vinylsilane 54 with excellent stereoselectivity. Simultaneous deprotection and cyclisation via a stereoselective oxy-Michael reaction gave the bicyclic acetal 57 after treatment with trimethyl orthoformate. A synthesis of the ester 60 corresponding to the C(1)-C(16) fragment of the bryostatins was then completed by O-silylation, oxidative cleavage of the methylene group and a stereoselective condensation of the resulting ketone 59 with the chiral phosphonate 61.     

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.     

Application of chiral tetrahydropentalene ligands in rhodium-catalyzed 1,4-addition of (E)-2-phenylethenyl- and (Z)-propenylboronic acids to enones

Chiral tetrahydropentalenes (3aR,6aR)-1 have been prepared and used as ligands in the Rh-catalyzed 1,4-addition of 1-alkenylboronic acids to cyclic enones 5. It has been discovered that the stereochemistry of the reaction was controlled by the steric properties of the aryl groups in 1 rather than their electronic nature. In the vinylation with (E)-2-phenylethenylboronic acid 5, ligands (3aR,6aR)-1 provided enantioselectivity up to 87% ee and gave high yields of ethenylketones 6 in the presence of 1 (6.6 mol %). The configuration of all ketone products obtained with (3aR,6aR)-1 is (S). Rh-catalyzed reaction of cyclopentenone 4a and (Z)-propenylboronic acid 7 in the presence of ligands (3aR,6aR)-1 yielded at 50 °C an inseparable mixture of (Z)- and (E)-ketones 8 with (Z)-8 as the major product and both in only moderate enantiomeric excess.     

The first stereoselective total synthesis of (3S,4R)-dihydroxy-(6S)-undecyl-α-pyranone and total synthesis of (2S,3R,5S)-(−)-2,3-dihydroxytetradecan-5-olide

The first total synthesis of (3S,4R)-dihydroxy-(6S)-undecyl-α-pyranone 1 and total synthesis of (2S,3R,5S)-(−)-2,3-dihydroxytetradecan-5-olide 2 have been achieved in five steps in a highly stereoselective manner using Maruoka allylation, olefin cross-metathesis, and Sharpless asymmetric dihydroxylation as key steps.