Lewis acid-mediated reactions of 1-cyclopropyl-2-arylethanone derivatives with allenic ester, ethyl acetoacetate, and methyl acrylate

TMSOTf-mediated reactions of 2-aryl-1-(1-phenylcyclopropyl)ethanones 1 with allenic esters afford a novel method for the synthesis of 6-methyl-3a,7-diaryl-3,3a-dihydro-2H-benzofuran-4-one derivatives 2 in moderate yields. In addition, we also found that TMSOTf-mediated reactions of 1-cyclopropyl-2-arylethanones with ethyl acetoacetate can provide the corresponding 2,3-dihydrobenzofuran-4-ol and dihydrofuro[2,3-h]chromen-2-one in moderate yields via a sequential reaction involving a nucleophilic ring-opening reaction of the cyclopropane by H2O, one intermolecular aldol type reaction and two intramolecular aldol type reactions, a cyclic transesterification, dehydration, and aromatization. Moreover, by using methyl acrylate to replace allenic ester, the corresponding 7-aryl-3,5,6,7-tetrahydro-2H-benzofuran-4-one and 5-aryl-3,5,6,7-tetrahydro-2 H-benzofuran-4-one can be formed in moderate to high yields in the presence of Bi(OTf)2Cl. Plausible reaction mechanisms have also been provided on the basis of control experiments.     

A highly stereoselective TMSOTf-mediated catalytic carbocupration of alkynoates

The TMSOTf-mediated catalytic carbocupration of ynoates has been investigated. It has been shown that catalyst loadings as low as 5 mol % readily allow for high yields and diastereoselectivities for a series of aromatic Grignard reagents. In addition, we have been successful in vicinally functionalizing 1a via initial TMSOTf-mediated catalytic carbocupration followed by a secondary electrophilic capture of the TMS allenoate intermediate.     

Lewis acid-mediated reactions of 1-cyclopropyl-2-arylethanone derivatives with diethyl 2-oxomalonate and ethyl 2-oxoacetate

TMSOTf-mediated reactions of 2-aryl-1-(1-phenylcyclopropyl)ethanones 1 with diethyl 2-oxomalonate 2 afford a novel method for the synthesis of spiro-γ-lactone derivatives 3 in good to excellent yields via a sequential reaction involving a nucleophilic ring-opening reaction of the cyclopropane by H₂O, an aldol-type reaction and a cyclic transesterification mediated by Lewis acid. On the other hand, we found that TMSOTf-mediated reactions of 1-cyclopropyl-2-arylethanones 1 with ethyl 2-oxoacetate 4 could also provide the corresponding spiro-γ-lactone derivatives 5 in moderate yields along with another spiro-γ-lactone derivatives 6 derived from the reaction of 1 with two molecules of ethyl 2-oxoacetate. The plausible reaction mechanisms have also been provided on the basis of control experiments.     

Synthesis of 1-azaxanthones by condensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-(cyano)benzopyrylium triflates and subsequent domino ‘retro-Michael/nitrile-addition/heterocyclization’ reaction

Functionalized 1-azaxanthones (5-oxo-5H-[1]-benzopyrano[2,3-b]pyridines) were prepared by TMSOTf-mediated condensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-cyanochromones and subsequent base-mediated domino ‘retro-Michael/nitrile-addition/heterocyclization’ reaction.     

Lewis acid mediated reactions of 1-cyclopropyl-2-arylethanones with allenic esters: a facile synthetic protocol for the preparation of dihydrofuro[2,3-h]chromen-2-one derivatives

TMSOTf-mediated reactions of 1-cyclopropyl-2-arylethanones with allenic esters afford a novel method for the synthesis of dihydrofuro[2,3-h]chromen-2-one derivatives in moderate to good yields. This process is a sequential reaction involving a nucleophilic ring-opening reaction of the cyclopropane by H(2)O, two intermolecular aldol-type reactions and one intramolecular aldol-type reaction, a cyclic transesterification, dehydration, and aromatization mediated by Lewis acid.     

Synthesis and configurational assignment of the amino alcohol in the eastern fragment of the GE2270 antibiotics by regio- and stereoselective addition of 2-metalated 4-bromothiazoles to alpha-chiral electrophiles

A synthesis of the eastern fragment of the thiazole peptide GE2270 A (1) has been developed. The synthetic approach relies on the regioselective functionalization of 2,4-dibromothiazole (5) via metalation and nucleophilic addition (at C2) or palladium-mediated cross-coupling (at C2 or C4). The stereochemistry at the N-bearing stereocenter was established by coupling of 2-metalated 4-bromothiazoles (4) to enantiomerically pure mandelic acid derivatives. Both the erythro (2) and threo (3) configurated amino alcohols were prepared with high diastereoselectivities depending on the electrophile employed. More specifically, the threo-configurated (S,R)-4-bromothiazolyl beta-amino alcohol 6 was synthesized from O-TBS protected (R)-mandelonitrile in 62% yield. Its N-PMB protected (R,S)-enantiomer 20 was obtained from O-TBS protected (S)-mandelic aldehyde in 67% yield. The erythro-configurated (S,S)-4-bromothiazolyl beta-amino alcohol 29 was prepared from O-TBS protected (S)-ethyl mandelate in four steps and 33% overall yield. The bithiazole moiety in the desired products 2 and 3 was finally established by the regioselective Negishi coupling of 2,4-dibromothiazole (5) and the 4-zincated, N-Boc protected thiazole derivatives of the diastereomeric 4-bromothiazolyl beta-amino alcohols 6 and 29.     

Isosteres of natural phosphates. 11. Synthesis of a phosphonic acid analogue of an oligonucleotide

The synthesis of an isosteric phosphonic acid analogue of UpUpU has been accomplished. In this analogue each of the normal 3'-phosphate esteric oxygen atoms has been replaced with a methylene group. The synthesis began with diacetone-D-glucose which was converted in a series of reactions to a 3'-deoxy-3'-dihydroxyphosphinylmethyluridine derivative, which bore protection as a 3-benzoylpropionate at the 5'-hydroxyl and as an acetate at the 2'-hydroxyl. This critical intermediate (A) was condensed with 2',3'-O-isopropylidene uridine to generate a protected analogue of a dinucleoside phosphate. Selective removal of the 3-benzoylpropionate followed by condensation with another unit of (A) yielded the protected oligonucleotide. Deprotection was accomplished in two steps.     

Synthese von selektiv N- funktionalisierten Polyamin-Derivaten

Synthesis of Selectively N-Functionalized Polyamine Derivatives A threefold differently protected derivative 8 of the triamine spermidine ( 2 ) has been prepared in three steps starting from propane-1,3-diamine ( 1 ). The protected spermidine derivative 8 was converted to its spermine analogue 12 , a useful polyamine intermediate. In a convergent way, the fourfold differently protected derivative 18 of the tetraamine spermine ( 3 ) has been obtained by coupling the two different and separately prepared propane-1,3-diamine units 15 and 17 . Spermidine derivative 19 and spermine derivative 20 , both selectively protected at both primary amino groups, have been Prepared from the free polyamines 2 and 3 , respectively, in a direct approach.     

保护的预酯化紫杉醇侧链的合成

以市场可购得的（2R,3S）-苯基异丝氨酸盐酸盐为起始原料,通过在甲醇的氯化亚砜溶液中进行酯化反应,及随后对氨基进行苯甲酰化,氨基羟基的环化保护,最后对其酯进行水解,合成得到保护的预酯化的紫杉醇侧链．整个过程无需柱层析操作,适于工业化生产．为制备保护的预酯化紫杉醇侧链提供了一种有效而又实用的合成方法．     

Synthesis of rhamnosylated diosgenyl glucosides as mimetics of cytostatic steroidal saponins from Ornithogalum saindersiae and Galtonia candicans

The synthesis of mimetic of the steroid saponins 1 and 2 was investigated. As a substitute for the complex 22-homo-23-nor-steroid moieties A and B in 1 and 2 diosgenin was introduced. The silyl protected thioorthoester 20 was successfully employed for glucosylation. After selective 2--deacetylation, the glucosylated diosgenyl acceptor 23 was rhamnosylated. The 4---methoxybenzoylated donor 12 gave only minor yields. By using the tri--benzoyl protected donor 15 the [small alpha]--rhamnopyranosyl-(1[rightward arrow]2)-[small beta]--glucopyranosyl-(1[rightward arrow]3[small beta])-diosgenin derivative 25 was obtained.     

Addition of difluorocarbene to 3',4'-unsaturated nucleosides: synthesis of 2'-deoxy analogues with a 2-oxabicyclo[3.1.0]hexane framework

Treatment of protected 2'-deoxy-3',4'-unsaturated nucleosides derived from adenosine and uridine with difluorocarbene [generated from bis(trifluoromethyl)mercury and sodium iodide] gave fused-ring 2,2-difluorocyclopropane compounds. Stereoselective alpha-face addition to the dihydrofuran ring resulted from hindrance by the protected beta-anomeric nucleobases. A protected uracil compound was converted smoothly into the cytosine derivative via a 4-(1,2,4-triazol-1-yl) intermediate. Removal of the protecting groups gave new difluorocyclopropane-fused nucleoside analogues. The solid-state conformation of the nearly planar furanosyl ring in the uracil compound had a shallow 2E pucker, and a more pronounced 1E conformation was present in the furanosyl ring of the cytosine derivative.     

Nucleosides and Nucleotides. Part 17. A simple preparation of protected deoxynucleoside-3'-phosphates

A simple method for the preparation of fully protected 2′-deoxynucleoside-3′-phosphates is described. The main step, phosphorylation of partially protected deoxynucleosides, is performed with the monofunctional reagent p-chlorophenyl (2-cyanoethyl) phosphochloridate³) ( 2 ) in dioxane. This reagent is quickly prepared from readily accessible p-chlorophenyl phosphodichloridate by reaction with 3-hydroxypropionitrile and triethylamine in dioxane or ether. The crude reagent is used directly for phosphorylation. After chromatography, protected deoxynucleoside-3′-phosphates were isolated in yields of 80–87%. The method described here, which has been optimized in detail, represents a simple alternative to published methods.     

Chemical Synthesis of a 5'-Terminal TMG-Capped Triribonucleotide m(3)(2,2,7)G(5)(')pppAmpUmpA of U1 RNA

The 5'-terminal TMG-capped triribonucleotide, m(3)(2,2,7)G(5)(')pppAmpUmpA, has been synthesized by condensation of an appropriately protected triribonucleotide derivative of ppAmpUmpA with a new TMG-capping reagent. During this total synthesis, it was found that the regioselective 2'-O-methylation of 3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-N-(4-monomethoxytrityl)adenosine was achieved by use of MeI/Ag(2)O without affecting the base moiety. A new route to 2-N,2-N-dimethylguanosine from guanosine via a three-step reaction has also been developed by reductive methylation using paraformaldehyde and sodium cyanoborohydride. These key intermediates were used as starting materials for the construction of a fully protected derivative of pAmpUmpA and a TMG-capping reagent of Im-pm(3)(2,2,7)G. The target TMG-capped tetramer, m(3)(2,2,7)G(5)(')pppAmpUmpA, was synthesized by condensation of a partially protected triribonucleotide 5'-terminal diphosphate species, ppA(MMTr)mpUmpA, with Im-pm(3)(2,2,7)G followed by treatment with 80% acetic acid. The structure of m(3)(2,2,7)G(5)(')pppAmpUmpA was characterized by (1)H and (31)P NMR spectroscopy as well as enzymatic assay using snake venom phosphodiesterase, calf intestinal phosphatase, and nuclease P1.     

Stereoselective synthesis of the alpha-allyl C-glycoside of 3-deoxy-D-manno-2-octulosonic acid (KDO) by use of radical chemistry.

Methyl 2-C-allyl-2,6-anhydro-3-deoxy-4,5:7,8-di-O-isopropylidene-D-glycero- D-talo-octonate (9a), the protected alpha-allyl C-glycoside of 3-deoxy-D-manno-2-octulosonic acid (KDO), has been synthesized using a photochemically initiated radical reaction. A phenyl thioglycoside (8) was used as the substrate and allyltributyltin as the acceptor. The stereoselectivity of the reaction was 90:10 in favour of the talo-isomer (alpha-).     

Synthesis of beta-cyclopropylalanines by photolysis of diacyl peroxides

[reaction: see text] Photolysis at 254 nm of neat (no solvent) unsymmetrical diacyl peroxides derived from cyclopropane carboxylic acids and l-aspartic acid generates protected beta-cyclopropylalanines in reasonable yields. Orthogonally protected 3-(trans-2-aminocyclopropyl)alanine (21), a key constituent of the antitumor agent belactosin A, as well as protected hypoglycin A (26), a causative agent of Jamaican vomiting sickness, is synthesized by this approach with coupling of the intermediate substituted cyclopropyl radicals proceeding predominantly with retention of configuration (dr >or= 95:5).     

Building blocks for the solution phase synthesis of oligonucleotides: regioselective hydrolysis of 3',5'-Di-O-levulinylnucleosides using an enzymatic approach

A short and convenient synthesis of 3'- and 5'-O-levulinyl-2'-deoxynucleosides has been developed from the corresponding 3',5'-di-O-levulinyl derivatives by regioselective enzymatic hydrolysis, avoiding several tedious chemical protection/deprotection steps. Thus, Candida antartica lipase B (CAL-B) was found to selectively hydrolyze the 5'-levulinate esters, furnishing 3'-O-levulinyl-2'-deoxynucleosides 3 in >80% isolated yields. On the other hand, immobilized Pseudomonas cepacia lipase (PSL-C) and Candida antarctica lipase A (CAL-A) exhibit the opposite selectivity toward the hydrolysis at the 3'-position, affording 5'-O-levulinyl derivatives 4 in >70% yields. A similar hydrolysis procedure was successfully extended to the synthesis of 3'- and 5'-O-levulinyl-protected 2'-O-alkylribonucleosides 7 and 8. This work demonstrates for the first time application of commercial CAL-B and PSL-C toward regioselective hydrolysis of levulinyl esters with excellent selectivity and yields. It is noteworthy that protected cytidine and adenosine base derivatives were not adequate substrates for the enzymatic hydrolysis with CAL-B, whereas PSL-C was able to accommodate protected bases during selective hydrolysis. In addition, we report an improved synthesis of dilevulinyl esters using a polymer-bound carbodiimide as a replacement for dicyclohexylcarbodiimide (DCC), thus considerably simplifying the workup for esterification reactions.     

Chemical synthesis of a pentaribonucleoside tetraphosphate constituting the 3'-acceptor stem sequence of E. coli tRNAIle using 2'-O-(3-methoxy-1,5-dicarbomethoxypentan-3-yl)-ribonucleoside building blocks. Application of a new achiral and acid-labile 2'-hydroxyl protecting group in tRNA synthesis

A synthesis of a pentaribonucleotide fragment constituting the residues 59-63 of 3'-terminus of E. coli tRNAIle, 5'-ApGpUpCpC-3', has been carried out using a new, easily accessible and achiral 2'-ketal protecting group. The new 2'-ketal group has an additional advantage in that it is easily functionalized to the diamide with aqueous ammonia in the penultimate step of deblocking of fully protected oligoribonucleotides. Such a functionalization of the 2'-ketal group at the penultimate step of deblocking of the fully protected tRNA molecule enhances its relative rate of removal under an acidic condition with a minimum of damage of the target tRNA molecule.     

Synthesis of the unnatural amino acid AGDHE,a constituent of the cyclic depsipeptides callipeltins A and D

[reaction: see text] The novel amino acid residue (2R,3R,4S)-4-amido-7-guanidino-2,3-dihydroxyheptanoic acid (AGDHE, 3), a constituent of the cyclic depsipeptides callipeltins A and D, and its (2S,3S,4S) diastereomer were synthesized from a protected L-ornithine derivative in 13 steps (15% overall yield), and its configurational assignment was reexamined by (1)H NMR.     

Synthesis and crystal structures of ring A modified glycyrrhetinic acid derivatives derived from 2,3-oxirane and 2,3-thiirane intermediates

A general method for the introduction of thiol groups at positions 1, 2, and 3 of glycyrrhetinic acid has been developed starting from a protected 2α,3α-oxido-derivative. Conversion into the corresponding 2β,3β-epithio-derivative was followed by ring-opening leading to either 2- or 3-substituted thio derivatives. Conversely, 3α-configured allylic alcohol intermediates derived from the 2,3-epoxide provided efficient access to both diastereoisomeric 3-thio derivatives as well as 1α-thio derivatives. The stereochemistry of the newly formed stereogenic centers was rigorously proven using X-ray crystallography.     

Stereoselective synthesis of protected (2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid: a novel amino acid of callipeltins A and D

An orthogonally protected derivative 1 of (2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid, the unusual amino acid residue of the biologically active marine peptides such as callipeltins A and D and neamphamide A, was efficiently prepared in 10 steps and 30% overall yield from a commercially available L-ornithine derivative 2. The key step includes the N-diphenylmethylene-controlled diastereoselective dihydroxylation of (Z)-ester 3 with >13:1 selectivity for the desired isomer.