Stereoselective synthesis of (+)-lauthisan

Stereoselective synthesis of (+)-lauthisan has been accomplished starting from d-glyceraldehyde acetonide by combination of diastereoselective alkylation and ring-closing metathesis. High degree of 1,3-asymmetric induction has been realized in ether system.     

Enantioselective synthesis of Fmoc-l-3-(2-benzothienyl)alanine (2-BtAla) via diastereoselective alkylation of a glycine equivalent

Stereoselective alkylation of the anion derived from (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with 2-chloromethylbenzothiophene afforded the corresponding trans-monosubstituted product, (2S,5R)-2-((1-benzo[b]thiophen-2-yl)methyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihyropyrazine in 88% yield. Hydrolysis of the alkylated product using 40% TFA/H₂O at 0?°C and subsequent protection of the α-amino functional group with Fmoc-OSu afforded Fmoc-l-3-(2-benzothienyl)alanine methyl ester in 88% yield. Hydrolysis of the methyl ester with aqueous LiOH gave Fmoc-l-3-(2-benzothienyl)alanine in 62% overall yield.     

The first stereoselective total synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one

Iterative asymmetric allylations and ring-closing metathesis have been effectively performed for the first stereoselective total synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one, a novel α,β-unsaturated-δ-lactone having antifungal activity, isolated from Ravensara crassifolia.     

Synthesis of (2S,7S)-dibutyroxynonane, the sex pheromone of the orange wheat blossom midge, Sitodiplosis mosellana (Géhin) (Diptera: Cecidomyiidae), by diastereoselective silicon-tethered ring-closing metathesis

The sex pheromone of Sitodiplosis mosellana, (2S,7S)-dibutyroxynonane, has been synthesised using a mixed di-t-butylsilaketal prepared from (S)-5-hexen-2-ol and prochiral 1,4-pentadiene-3-ol. Ring-closing metathesis occurs diastereoselectively and after the removal of the silyl group and the reduction of the double bonds, generates (2S,7S)-nonanediol with a diastereoisomeric excess of 94% as measured by gas chromatographic analysis of the diacetylated product.     

Highly regioselective Pd-catalyzed allylic alkylation of fluorobis(phenylsulfonyl)methane

A highly regioselective palladium-catalyzed allylic alkylation of fluorobis(phenylsulfonyl)methane has been studied. Using different allylic carbonates, a variety of terminal mono-fluoromethylated compounds were achieved in 85-99% yields with high regioselectivities.     

Total synthesis of (-)-diversifolin

First total synthesis of biologically active germacrane-type sesquiterpene (−)-diversifolin has been achieved. The features of the synthesis involve (i) ring-closing metathesis to give a 10-membered carbocycle, (ii) regioselective Mukaiyama aldol reaction of silyl dienol ether with formaldehyde at the α-position, and (iii) lactone transposition of the fully functionalized 11-oxabicyclo[6.2.1]undecane system.     

Studies on the diastereoselective reductive alkylation of (R)-phenylglycinol derived phthalimide: observation of stereoelectronic effects

Full details of a flexible approach to N-protected (R)-3-alkyl-isoindolin-1-ones 13 via diastereoselective reductive-alkylation are described, with emphasis on the stereochemical outcome of the key diastereoselective reactions. Additional experiments allowed finding remarkable stereoelectronic effects on the reductive ring-opening reactions.     

Enantioselective synthesis of (L)-Fmoc-α-Me-Lys(Boc)-OH via diastereoselective alkylation of oxazinone as a chiral auxiliary

Benzyl (2R,3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (4) was successively alkylated with methyl iodide and 1,4-diiodobutane using a base. In each alkylation step anti-alkylated product formed exclusively. The iodo group was displaced with azide, which served as a precursor for the side-chain amino function. Catalytic hydrogenation with concomitant cleavage of the chiral auxiliary afforded (L)-α-Me-Lys-OH (9) in a total of four steps in good yield. (L)-Fmoc-α-Me-Lys(Boc)-OH (16) was obtained from 9 via regioselective benzyloxycarbonylation. Alternately, (L)-Fmoc-α-Me-Lys(Boc)-OH (16) was obtained via Staudinger reduction of azide (8) in a total of six steps in good yield.     

Diels-alder reactions of 2- and 3-vinyl-1-(phenylsulfonyl)pyrroles

Regioselectively produced 2- and 3-acetyl-1-(phenylsulfonyl)pyrroles can be reduced to the corresponding alcohols and subsequently dehydrated to afford N-protected vinylpyrroles. These remarkably stable vinylpyrroles can then serve as heterodienes in [4 + 2] cycloaddition reactions with electron deficient dienophiles to afford tetrahydroindole derivatives.     

Ca(II)-catalyzed diastereoselective formal [4+2] annulation of a 3-component solvent-free povarov reaction

Diastereoselective, three-component annulation reaction involving glyoxals, anilines and dienophiles is developed under calcium catalysis. When indene is the dienophile, the reaction gave excellent diastereoselectivity to yield tetrahydro-indenoquinolines, these were further aromatized to get indenoquinolines in one-pot. Aryl acetylenes are used as dienophiles to get 2-acyl quinolines in good yields.     

Highly diastereoselective synthesis of 2-substituted-1,3-diols catalyzed by ketoreductases

The stereoselective reduction of α-substituted-β-hydroxy ketones for the preparation of the corresponding optically pure 2-monosubstituted or 2-disubstituted-1,3-diols is described. These transformations proceed in high optical purities and yields. Ketoreductases were able to catalyze the formation of either the syn or the anti diol, depending on the enzyme. By replacing the α-alkyl substituent for an OAc moiety, in low conversion time (≤24 h), ketoreductases catalyzed the formation of the OAc-protected 1,2,3-triol, in high yield and with high optical purity (>99% de, >99% ee). This is a simple and highly stereoselective method for the synthesis of different diastereomers of chiral diols.     

Synergic effect of hydrogen bonding and dipole repulsion in the ring-closing metathesis of N-homoallyl-2-(hydroxymethyl)acrylamides

This study reveals that the Ru-catalyzed ring-closing metathesis of N-homoallyl-2-(hydroxymethyl)acrylamides is promoted by substrate-catalyst hydrogen bonding as well as dipole repulsion between the electron-rich side-chain and the carbonyl group, providing clues for designing effective synthetic routes towards 5,6-dihydro-2(1H)-pyridinones.     

Influence of microemulsions on enantioselective synthesis of (R)-cyclopent-2-enol catalyzed by vitamin B12

The influence of microemulsions on the vitamin B12-catalyzed enantioselective isomerization of 1,2-epoxycyclopentane (1) to form (R)-cyclopent-2-enol (2) has been examined. The reaction was initiated by a reduction of vitamin B12 to the Co(I) form by Zn/NH4Cl. The largest enantiomeric excess (e.e.) in the products was 52% for (R)-2 obtained in a bicontinuous sodium dodecyl sulfate (SDS) microemulsion. A water-in-oil SDS microemulsion gave a poorer percent e.e. probably because of limited catalyst utilization in the water droplets. The influence of the pH of the water phase, the amount of water, and the concentration of vitamin B12 on the enantioselectivity and yield of the reaction was also explored. Results suggest that factors such as higher water content and bicontinuous fluid structure facilitated efficient intermixing of catalyst with reactant to form a key organocobalt intermediate, thus improving enantioselectivity.     

A diastereoselective synthesis 1-trimethylsilyl-(E)-1,3-alkenynes and a simple synthesis of alkyl trimethylsilylethynyl ketones via organoboranes

A convenient, novel diastereoselective synthesis of 1-trimethylsilyl-(E)-1,3-alkenynes and a convenient synthesis of alkyl trimethylsilylethynyl ketones based on Z-1-bromo-1-alkenylboronate esters are developed. α-Bromo-(Z)-1-alkenylboronate esters readily available using literature procedures smoothly undergo a reaction with trimethylsilylethynyllithium (derived from the deprotonation of trimethylsilylethyne with n-butyllithium) in tetrahydrofuran to provide the corresponding ‘ate’ complexes. These ‘ate’ complexes undergo intramolecular nucleophilic substitution reactions to afford the corresponding (E)-1-alkenylboronate esters containing trimethylsilylethynyl moiety which upon protonolysis with acetic acid provide the corresponding 1-trimethylsilyl-(E)-1,3-alkenynes in good yields (70-82%) and in high stereochemical purities (>98%). These intermediates upon oxidation with hydrogen peroxide and sodium acetate afford the corresponding alkyl trimethylsilylethynyl ketones in good yields (66-78%).     

First total syntheses and absolute configuration of rugulactone and 6(R)-(4′-oxopent-2′-enyl)-5,6-dihydro-2H-pyran-2-one

The first efficient total syntheses of rugulactone and 6(R)-(4′-oxopent-2′-enyl)-5,6-dihydro-2H-pyran-2-one have been achieved in six steps with 51% and 48% overall yield, respectively. The key steps are Jacobsen’s hydrolytic kinetic resolution (HKR), Horner-Wadsworth-Emmons (HWE) homologation, and ring-closing metathesis reaction.     

C(3)-alkylation and cyclization of pyrazino[1,2-b]isoquinolin-4-ones

To avoid the epimerization of the C(11a)-stereocenter previously observed in 6,11a-cis-pyrazino[1,2-b]isoquinolin-1,4-diones, we present in this paper the C(3)-alkylation of 1-methoxy-pyrazino[1,2-b]isoquinolin-4-ones to obtain all-cis derivatives through a very reliable protocol. The success of the acid-promoted cyclization to get pentacyclic (R₃=arylmethyl) or tetracyclic (R₃=2-bromo-2-propenyl) compounds is dependent on the nature of the C(3)-unsaturated chain and of the N-substituent, but these limitations have been overcome by using trifluoromethanesulfonic as a superacid catalyst. The C-(3)-alkylation of pyrazino[1,2-b]isoquinolin-4-one is also studied.     

The use of d-mannitol-derived C2-symmetric trienes in tandem metathesis reactions towards valuable lactones

Chiral lactones were synthesized from d-mannitol. C₂-symmetric triene precursors were constructed with a central relay-olefin allowing the key domino ring-closing metathesis to be achieved. It led to the symmetrical cleavage of the substrate and to the formation of 2 mol of the desired 5- or 6-membered lactone. Attempts to form 7-membered lactones thus far only led to 14-membered macrodiolides instead.     

First synthesis of 4a-carba-β-d-galactofuranose

The synthesis of 4a-carba-β-d-galactofuranose is described starting from diacetone glucose. The key ring-closure step was carried out by metathesis to form a cyclopentene. Catalytic hydrogenation of the CC double bond gave the galacto configured saturated carbahexofuranose with excellent diastereoselectivity.     

Stereocontrolled total synthesis and biological evaluation of (−)- and (+)-petrosin and its derivatives

Total synthesis of (−)- and (+)-petrosin was accomplished. Stereocontrolled construction of the quinolizidine ring was achieved through a diastereoselective Mannich reaction and an aza-Michael reaction. Head-to-tail dimerization was performed by assembly of the two monomers using Suzuki–Miyaura cross coupling and subsequent ring-closing metathesis to construct the 16-membered ring. Biological evaluation of synthetic (−)- and (+)-petrosin and its derivatives indicated that the bispiperidine structure was necessary for the inhibition of syncytium formation.     

Total synthesis of (−)-diospongin A and (+)-cryptofolione via asymmetric aldol reaction

Stereoselective synthesis of two distinctive pyranone skeletons diospongin A and cryptofolione has been described based on an asymmetric aldol reaction starting from Chan’s diene. The synthetic strategy involves the enantioselective Mukaiyama aldol, diastereoselective reduction of δ-hydroxy-β-keto ester, a tandem sequence of deprotection, and intramolecular oxa-Michael reaction to obtain diospongin A and an asymmetric allylation and lactone formation using ring-closing metathesis reaction to obtain cryptofolione.