Stereoselective synthesis of (1R,3S)- -chrysanthemic acid through microbiological reduction of 2,2,5,5-tetramethyl 1,4-cyclohexanedione.

An efficient, highly stereoselective synthesis of (1 ,3 )- -chrysanthemic acid 6 is described. The crucial step of this synthesis was the microbiological reduction of dione 1 into ( )-ketol 2.     

Synthesis of 5-(trifluoromethyl)cyclohexane-1,3-dione and 3-amino-5-(trifluoromethyl)cyclohex-2-en-1-one: new trifluoromethyl building block

A simple synthesis of 5-(trifluoromethyl)cyclohexane-1,3-dione and 3-amino-5-(trifluoromethyl)cyclohex-2-en-1-one from the sodium salt of methyl or ethyl-4-hydroxy-2-oxo-6-(trifluoromethyl)cyclohex-3-en-1-oate is demonstrated. The compounds represent highly functionalized reactive intermediates for the synthesis of organic and heterocyclic compounds containing a trifluoromethyl group.     

Total synthesis of asimicin via highly stereoselective [3 + 2] annulation reactions of substituted allylsilanes

A highly stereoselective total synthesis of (+)-asimicin (1) is reported. The synthesis features two chelate-controlled [3 + 2] annulation reactions-one of which (e.g., 2 + 3) constitutes a key, convergent fragment assembly step-that establish all of the stereochemistry of the bis-tetrahydrofuran unit of the natural product.     

Palladium-catalyzed regioselective arylation of imidazo[1,2-b][1,2,4]triazine: synthesis of an alpha 2/3-selective GABA agonist

A convergent, practical, and efficient synthesis of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABA(A) alpha(2/3)-selective agonist, is described. The seven-step, chromatography-free synthesis was demonstrated on a multi-kilogram scale and utilized biaryl bromide 6 and imidazotriazine 22 as key intermediates. Biaryl bromide 6 was prepared via a highly selective aromatic bromination. The regioselective condensation of aminotriazine 15 with chloroacetaldehyde provided the desired imidazotriazine intermediate 22. A highly regioselective palladium-catalyzed arylation in the final step highlights the efficiency of the route.     

Enantiospecific Synthesis of Trisubstituted Butyrolactone Natural Products and Their Analogs

A general methodology for the synthesis of highly substituted butyrolactones in enantiomerically pure form has been developed. The application of this process in a highly efficient synthesis of lactone natural products blastmycinone (1), NFX-2 (2), antimycinone (3), and NFX-4 (4) and two lipid metabolites (5, 6) are described. Additionally, the total synthesis of 5-epi-blastmycinone (22), 5-epi-NFX-2 (21b), 5-epi-NFX-4 (21c), and lipid metabolite analogs (19, 20) are also described. The overall yields for the target molecules are the highest reported so far in the literature.     

Synthesis of a muscarinic receptor antagonist via a diastereoselective Michael reaction, selective deoxyfluorination and aromatic metal-halogen exchange reaction

An efficient synthesis of a structurally unique, novel M(3) antagonist 1 is described. Compound 1 is conveniently disconnected retrosynthetically at the amide bond to reveal the acid portion 2 and the amine fragment 3. The synthesis of key intermediate 2 is highlighted by a ZnCl(2)-MAEP complex 19 catalyzed diastereoselective Michael reaction of dioxolane 7 with 2-cyclopenten-1-one (5) to establish the contiguous quaternary-tertiary chiral centers and a subsequent geminal difluorination of ketone 17 using Deoxofluor in the presence of catalytic BF(3).OEt(2). The synthesis of the amine moiety 3 is highlighted by the discovery of a novel n-Bu(3)MgLi magnesium-halogen exchange reaction for selective functionalization of 2,6-dibromopyridine. This new and practical metalation protocol obviated cryogenic conditions and upon quenching with DMF gave 6-bromo-2-formylpyridine (26) in excellent yield. Further transformations afforded the amine fragment 3 via reductive amination with 35, Pd-catalyzed aromatic amination, and deprotection. Finally, the highly convergent synthesis of 1 was accomplished by coupling of the two fragments. This synthesis has been used to prepare multi-kilogram quantities of the bulk drug.     

Total synthesis of formamicin

The enantioselective total synthesis of the cytotoxic plecomacrolide natural product formamicin (1) is described. Key aspects of this synthesis include the efficient transacetalation reactions of MOM ethers 28 and 38 to form the seven-membered formyl acetals 29 and 39, a late-stage Suzuki cross-coupling reaction of the highly functionalized vinyl boronic acid 6 and vinyl iodide 7, a highly beta-selective glycosidation reaction of beta-hydroxy ketone 4 with 2,6-dideoxy-2-iodoglucopyranosyl fluoride 3, and the global desilylation of penultimate intermediate 77 mediated by in situ generated Et(3)N.2HF.     

Efficient solid-phase synthesis of 2-substituted-3-hydroxy-4(1H)-quinolinone-7-carboxamides with two diversity positions

A highly efficient solid-phase synthesis of 2-substituted-3-hydroxy-4(1H)-quinolinone-7-carboxamides was developed using anthranilates and bromoketones as the key synthons. Primary amines immobilized to an acid-cleavable BAL linker were acylated with 1-methyl-2-aminoterephtalate. After cleavage of the methyl ester, bromoketones were used to form resin-bound phenacyl esters. Acid-mediated cleavage and subsequent cyclization in solution afforded 3-hydroxy-4(1H)-quinolinones in high purity and yield. Highly efficient solid-phase synthesis (purity>90%, yield>80%, synthetic time=2 days using commercially available synthons) is amenable to high-throughput/combinatorial synthesis to match the high-throughput screening capability.     

Total synthesis of phorboxazole B

An efficient and highly convergent total synthesis of the potent antitumor agent phorboxazole B has been achieved. The synthetic strategy of this synthesis features: 1) a highly efficient substrate-controlled hydrogenation to construct the functionalized cis-tetrahydropyrane unit; 2) iterative crotyl addition to synthesize the segment that contains alternating hydroxyl and methyl substituents; 3) Hg(OAc)2/I2-induced cyclization to establish the cis-tetrahydropyrane moiety; 4) 1,3-asymmetric induction in the Mukaiyama aldol reaction to afford the stereogenic centers at C9 and C3; and 5) the exploration of the Still-Gennari olefination reaction to complete the macrolide ring of phorboxazoloe B.     

A short,three-component total synthesis of 12-hydroxyeicosa-5,8,14(Z), 10(E)-tetraenoic acid (12-HETE) via the corresponding ketone

A highly effective synthesis of (±)-12-HETE (1) from the components 2, 3 and 6 is described which employs a new class of cuprate reagents.     

Efficient synthesis of 2-(pyrazol-3-yl)benzimidazoles from 3-arylacylidene-3,4-dihydroquinoxalin-2(1H)-ones and hydrazine hydrate via a novel rearrangement

A highly efficient method for the synthesis of 2-(pyrazol-3-yl)benzimidazoles has been developed on the basis of the novel ring contraction of 3-arylacylidene-3,4-dihydroquinoxalin-2(1H)-ones with hydrazine hydrate.     

Synthetic applications of Baylis-Hillman chemistry: an efficient and solely stereoselective synthesis of (E)-alpha-methylcinnamic acids and potent hypolipidemic agent LK-903 from unmodified Baylis-Hillman adducts

An efficient and solely stereoselective synthesis of (E)-alpha-methylcinnamic acids has been accomplished in single pot by reduction of the unmodified Baylis-Hillman adducts, methyl-3-hydroxy-3-aryl-2-methylenepropanoates with I(2)/NaBH(4) reagent system at room temperature followed by hydrolysis. The efficacy of this method has been proved in the total synthesis of 1-[p-(myristyloxy)-alpha-methylcinnamoyl]glycerol, LK-903, a highly active hypolipidemic agent.     

A straightforward stereoselective synthesis of D- and L-5-hydroxy-4-hydroxymethyl-2-cyclohexenylguanine.

A novel and facile synthesis of 5-hydroxy-4-hydroxymethyl-2-cyclohexenylguanine 1 is described. The key steps involve a Diels-Alder reaction of ethyl (2E)-3-acetyloxy-2-propenoate 2 as dienophile with Danishefsky's diene 3 to build up the six-membered ring skeleton, a Fraser-Reid reductive rearrangement of the adduct using LiAlH(4), and base-moiety introduction using a Mitsunobu reaction. Optically pure D- and L-1 were obtained via resolution of intermediate 7 with (R)-(-)-methylmandelic acid. The synthetic procedure toward racemic 1 consists of only five steps and has proven to be highly efficient toward the synthesis of cyclohexenyl nucleosides.     

Studies on the Model Synthesis of the Brassinolide and Dolicholide‘s Side Chains

A highly stereoselective synthesis of the side Chain enantiomers of brassinolide and dolicholide through an aldol reaction of 2-(4-methoxy benzyloxyl) proplonylaldehyde (5) with the anion of 1- ( tert -butyldimethylsiloxy )-3-methyl-2-butanone ( 6 ) is described.     

PMO[KIT-5]-n: synthesis of highly ordered three-dimensional periodic mesoporous organosilicas with Fm3m symmetry

Divalent surfactant [CH3(CH2)15N(CH3)2(CH2)3N(CH3)3]2+ - 2Br- (C16-3-1) was used as a structure directing agent (SDA) for the synthesis of highly ordered periodic mesoporous organosilicas (PMOs) with cubic Fm3m symmetry from 1,2-bis(triethoxylsilyl)ethane (BTEE) under basic conditions.     

Highly stereoselective and efficient total synthesis of (+)-laurencin

A highly stereoselective and efficient asymmetric total synthesis of (+)-laurencin (1) has been accomplished from the known oxazolidinone 5 in 15 steps. The route features an efficient internal alkylation to form oxocene 3 from 4 and a novel use of acetonitrile anion as a two-carbon acetaldehyde equivalent for direct synthesis of ketone 2 from alpha-alkoxy amide 3.     

A highly efficient asymmetric synthesis of optically active α,β-epoxyaldehydes from α,β-unsaturated acids

The bromolactones(3) prepared from α,β-unsaturated acids(1) were converted to optically active α,β-epoxyaldehydes(2(R),3(S)-6)(84–98% ee) by successive epoxide formation and reductive cleavage of the proline moiety. The overall process constitutes a highly efficient asymmetric synthesis of 2(R),3(S)-6 from 1.     

PdCl2-catalyzed oxidative cycloisomerization of 3-cyclopropylideneprop-2-en-1-ones

A novel PdCl(2)-catalyzed oxidative cycloisomerization of 3-cyclopropylideneprop-2-en-1-ones, providing a facile synthesis of highly strained functionalized 2-alkylidenecyclobutanones via furan-fused cyclobutene intermediates, is reported. An interesting route to 2(3H)-furanones with a spiro-cyclopropane unit from the obtained 2-alkylidenecyclobutanones via a ring-contraction rearrangement reaction is also realized.     

Synthesis of methyl epijasmonate and cis-3-(2-oxopropyl)-2-(pent-2Z-enyl)-cyclopentan-1-one

A novel and efficient synthesis of both (±)-methyl epijasmonate and (±)-cis-3-(2-oxopropyl)-2-(pent-2Z-enyl)-cyclopentan-1-one is described. The key step to establish the cis-stereochemistry on the 5-membered ring is an ionic Diels–Alder reaction, which is high yielding and highly regioselective. Subsequent key steps include oxidative cleavage of the six-membered ring, Wittig coupling and for the synthesis of epijasmonate, the haloform reaction.     

Spontaneous Nef reaction of 3-aryl-2-(diethoxyphosphoryl)-4-nitroalkanoic acids

Spontaneous Nef reaction of primary and secondary 3-aryl-2-(diethoxyphosphoryl)-4-nitroalkanoic acids has been observed for the first time. The reaction provides a general and effective, highly diastereoselective synthesis of 3-(diethoxyphosphoryl)-1-hydroxysuccinimides and 2-(diethoxyphosphoryl)-4-oxoalkanoic acids.