不对称羟内酯化合成白三烯A4中间体

为合成白三烯A4的关键中间体, 本文试验了若干7-手性中心-6,5-双键庚酸衍生物的不对称环氧化方法, 发现从D-甘油醛得的顺式烯化合物可选择性地羟内酯化, 游离羟基甲磺酰化后甲醇纳处理可得所需的5S, 6R氧桥, 水解, 过碘酸钠断键后即可顺利得到目标化合物.     

Improved synthesis of key fragments for the preparation of natural product incednine

A shorter and more efficient synthesis of three key fragments that have been previously described for the preparation of the polyenic macrolactam aglycon of natural product incednine isolated from Actinomyces sp. has been developed. These fragments have been prepared with higher levels of selectivity when compared to the already published procedure.     

Highly enantioselective synthesis of terutroban key intermediate via asymmetric hydrogenation

A chiral (R) key intermediate of the biologically active form of terutroban has been prepared by asymmetric hydrogenation. The catalysts are based on very easily accessible ruthenium complexes modified by chiral phosphorous ligands. The use of the chiral catASium^®T ligands family allowed us to realize this transformation efficiently in terms of yield and enantioselectivity (ee up to 92%) with high substrate/catalyst ratios.     

Towards the total synthesis of tonantzitlolone--preparation of key fragments and the complete carbon backbone

The first synthetic advances towards the novel diterpenoid tonantzitlolone 1 are described. The key steps in the synthesis involve a chromium(II) Reformatsky reaction, a diastereoselective C₁ extension and an expeditious aldol coupling step of two advanced precursors.     

Efficient synthesis of 3,4-diarylpyrrole-2-carboxylates,the key fragments of natural antimitotic agents

Russian Chemical Bulletin - Barton-Zard reaction of nitrostilbenes with ethyl isocyanoacetate carried out in EtOH in the presence of K2CO3 allowed us to minimize the formation of side products and...     

A concise enantioselective total synthesis of (+)-epi-muricatacin,using asymmetric hydrogenation/intramolecular iodoetherification as key steps

A concise enantioselective total synthesis of (+)-epi-muricatacin, a potent cytotoxic agent, is described. A key feature of this protocol is a catalytic asymmetric hydrogenation and a chiral auxiliary mediated intramolecular iodoetherification to ensure a high degree of distereo- and enantiocontrol.     

The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments

Due to a combination of their promising anticancer properties, limited supply from the marine sponge source and their unprecedented molecular architecture, spirastrellolides represent attractive and challenging synthetic targets. A modular strategy for the synthesis of spirastrellolide A methyl ester, which allowed for the initial stereochemical uncertainties in the assigned structure was adopted, based on the envisaged sequential coupling of a series of suitably functionalised fragments; in this first paper, full details of the synthesis of these fragments are described. The pivotal C26-C40 DEF bis-spiroacetal was assembled by a double Sharpless asymmetric dihydroxylation/acetalisation cascade process on a linear diene intermediate, configuring the C31 and C35 acetal centres under suitably mild acidic conditions. A C1-C16 alkyne fragment was constructed by application of an oxy-Michael reaction to introduce the A-ring tetrahydropyran, a Sakurai allylation to install the C9 hydroxyl, and a 1,4-syn boron aldol/directed reduction sequence to establish the C11 and C13 stereocentres. Two different coupling strategies were investigated to elaborate the C26-C40 DEF fragment, involving either a C17-C25 sulfone or a C17-C24 vinyl iodide, each of which was prepared using an Evans glycolate aldol reaction. The remaining C43-C47 vinyl stannane fragment required for introduction of the unsaturated side chain was prepared from (R)-malic acid.     

Inorganic asymmetric synthesis: asymmetric synthesis of a two-bladed propeller, octahedral metal complex

A C2 hexadentate, in which two pyridine-2-aldehyde 2'-pyridylhydrazone (PAPHY) groups are linked to a chiral auxiliary derived from (R,R)-tartaric acid, (R,R)-1, reacts with iron(II) benzenesulfonate to give the two-bladed propeller, octahedral complex (P(Fe))-[Fe{(R,R)-1}](PhSO3)2 with complete diastereoselectivity, as determined by 1H NMR spectroscopy and X-ray crystallography. Saponification of the ester linkages and deprotonation of the hydrazone-NH groups in the configurationally pure diastereomer affords the complex (P(Fe))-[Fe(5-HOCH2PAPY)2] with 85% retention of configuration at the iron stereocenter, as determined by reprotonation of the neutral complex with enantiomerically pure (aR)-binaphthyl phosphoric acid and analysis of the 1H NMR spectrum of the mixture of diastereomeric salts produced. This is the first asymmetric synthesis of a two-bladed propeller, octahedral metal complex by the classical organic methodology of chiral auxiliary-directed, asymmetric synthesis.     

Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

In the presence of (R)-SEGPHOS-Pd(OAc)₂ catalyst, the intramolecular N-arylation of ortho-tert-butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89-98% ee) to give optically active atropisomeric lactams having an N-C chiral axis. MPLC purification of the enantio-enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric lactam with various alkyl halides gave α-substituted and α,α-disubstituted lactam products with high diastereoselectivity. α-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.     

Palladium-catalyzed conversion of beta,gamma-unsaturated silyl sulfinates into (E)-alkenes: asymmetric synthesis of polypropionate fragments

At low temperature, 1-alkoxy-1,3-dienes add to sulfur dioxide activated by a Lewis or protic acid generating zwitterionic intermediates that can be quenched by enoxysilanes. The resulting beta,gamma-unsaturated silyl sulfinates can be desilylated by 1:1 Pd(OAc)(2)/PPh(3) catalyst, liberating the corresponding beta,gamma-unsaturated sulfinic acids that undergo smooth and highly stereoselective retro-ene eliminations of sulfur dioxide. The method has been applied to generate enantiomerically pure polypropionate fragments.     

Total synthesis of laulimalide: synthesis of the northern and southern fragments

The first stage in the development of a synthetic route for the total synthesis of laulimalide (1) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product by using a Ru-catalyzed alkene-alkyne coupling. This would be preceded by an esterification of the C19 hydroxyl group, joining together two equally sized synthons, the northern fragment 7 and the southern fragment 8. Our first generation approach to the northern fragment entailed a key sequential Ru/Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, but the inability to achieve a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn-catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct 66 with excellent syn/anti selectivity (10:1), and allowed for the successful completion of the northern fragment 7. The key step for the synthesis of the southern fragment was a chemoselective Rh-catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six-membered ring, over a seven. The use of an electron-deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading.     

Catalytic asymmetric hetero-Diels–Alder route to a key intermediate for the synthesis of calyxin L

A catalytic asymmetric formal synthesis of diarylheptanoid natural product calyxin L has been achieved by incorporating an enantio- and diastereoselective hetero-Diels–Alder (HDA) reaction, a Suzuki–Miyaura coupling, and a stereocontrolled catalytic hydrogenation of 2,4,6-trisubstituted dihydropyran as the key steps. The HDA reaction between 4-(4-benzyloxyphenyl)-2-triethylsilyloxy-1,3-butadiene and (4-benzenesulfonyloxyphenyl)propynal catalyzed by dirhodium(II) tetrakis[(R)-3-(benzene-fused-phthalimido)-2-piperidinonate], Rh₂(R-BPTPI)₄, provided cis-2,6-disubstituted tetrahydropyran-4-one in 91% yield with 91% ee.     

Chemoenzymatic asymmetric synthesis of optically active pentane-1,5-diamine fragments by means of lipase-catalyzed desymmetrization transformations

A novel family of prochiral pentane-1,5-diamines has been efficiently synthesized, possessing stabilities significantly higher than those of corresponding propane-1,3-diamine analogues. Diamines have been later desymmetrized using Pseudomonas cepacia lipase as an efficient biocatalyst for the mono- but also stereoselective protection of one of their amino groups. Reaction parameters such as type and loading of enzyme, temperature, solvent, and acyl donor have been exhaustively analyzed, searching for optimal conditions for the production of interesting optically active nitrogenated compounds. Thus, acylation and alkoxycarbonylation processes have been compared in terms of conversion and enantiomeric excess values. The best results were found in the reaction of prochiral diamines with ethyl methoxyacetate as acyl donor and 1,4-dioxane as solvent, yielding (S)-monoamides in 33-59% isolated yield and 54-99% ee, depending on the aromatic pattern substitution.     

The synthesis of Leishmania major phosphoglycan fragments

The triglycosyl monophosphate 1, heptaglycosyl triphosphates 2 and 3, and octaglycosyl triphosphate 4, which are fragments of the phosphoglycan part of Leishmania major lipo- and proteo-phosphoglycans have been prepared using di- and tri-saccharide H-phosphonates for construction of the phosphodiester bridges.     

Versatile asymmetric synthesis of the kavalactones: first synthesis of (+)-kavain

[reaction: see text] Three asymmetric pathways to the kavalactones have been developed. The first method is chiral auxiliary-based and utilizes aldol reactions of N-acetyl thiazolidinethiones followed by a malonate displacement/decarboxylation reaction. The second approach uses the asymmetric catalytic Mukaiyama additions of dienolate nucleophile equivalents developed by Carreira and Sato. Finally, tin-substituted intermediates, prepared by either of these routes, can serve as advanced general precursors of kavalactone derivatives via Pd(0)-catalyzed Stille couplings with aryl halides.     

Dinuclear asymmetric Zn aldol additions: formal asymmetric synthesis of fostriecin

Direct asymmetric aldol reactions constitute a powerful methodology for the efficient synthesis of complex natural products. Herein we report the first application of our recently reported dinuclear Zn-catalyzed direct aldol addition of alkynyl ketones to aldehydes in a short and efficient formal asymmetric synthesis of fostriecin, a potent cyctotoxic natural product. This work highlights not only the power of the aldol methodology but also the utility of the akynyl silane aldol adducts, as it is subsequently utilized in a vinyl silane cross-coupling reaction which affords the target molecule in 14 steps for the longest linear sequence in 8.5% overall yield.     

Effective asymmetric synthesis of the key chiral building blocks of 20(S)- and 20(R)-camptothecins

Abstract  

An effective diastereoselective synthesis of (S)-N,N-diethyl-2-formyl-2-(methoxymethoxy)butanamide and (S)-2-formyl-2-(methoxymethoxy)butanoic acid ethyl ester, which are two key chiral building blocks for the synthesis of 20(S)-camptothecins, has been developed by employing an asymmetric bromolactonization using (R)-proline. The (R) compounds were also synthesized to obtain 20(R)-camptothecin.