Relative stereochemical assignment of C-33 and C-35 in the antibiotic gladiolin

Gladiolin is a macrolide antibiotic isolated from Burkholderia gladioli BCC0238 with promising activity against Mycobacterium tuberculosis, including several multidrug resistant strains. The configuration of all but one of the stereogenic centers of gladiolin has previously been elucidated using a combination of NOESY NMR experiments and predictive sequence analysis of the polyketide synthase responsible for its assembly. However, it was not possible to assign the configuration of the C-35 methyl group using such methods. Here we report the synthesis of C-33/C-35-syn and C-33/C-35-anti mimics of the C-30 to C-38 fragment of gladiolin from (R) and (S)-citronellol, respectively. Comparison of HSQC NMR data for the mimics and the natural product showed that the C-35 methyl is anti to the C-33 hydroxyl group, indicating that gladiolin has the 35S configuration.     

Direct palladium-catalyzed C-2 and C-3 arylation of indoles: a mechanistic rationale for regioselectivity

We have recently developed palladium-catalyzed methods for direct arylation of indoles (and other azoles) wherein high C-2 selectivity was observed for both free (NH)-indole and (NR)-indole. To provide a rationale for the observed selectivity ("nonelectrophilic" regioselectivity), mechanistic studies were conducted, using the phenylation of 1-methylindole as a model system. The reaction order was determined for iodobenzene (zero order), indole (first order), and the catalyst (first order). These kinetic studies, together with the Hammett plot, provided a strong support for the electrophilic palladation pathway. In addition, the kinetic isotope effect (KIE(H/D)) was determined for both C-2 and C-3 positions. A surprisingly large value of 1.6 was found for the C-3 position where the substitution does not occur (secondary KIE), while a smaller value of 1.2 was found at C-2 (apparent primary KIE). On the basis of these findings, a mechanistic interpretation is presented that features an electrophilic palladation of indole, accompanied by a 1,2-migration of an intermediate palladium species. This paradigm was used to design new catalytic conditions for the C-3 arylation of indole. In case of free (NH)-indole, regioselectivity of the arylation reaction (C-2 versus C-3) was achieved by the choice of magnesium base.     

Stereoselective Functionalization at C-2 and C-3 of the Gibberellin via an Intramolecular Free Radical Cyclization Approach

The gibberellins (GAs) are a group of naturally-occurring tetracyclic diterpenoid plant growth hormones which are widely present in higher plants and some fungal species. To date over one hundred GAs have been identified and found to be involved in almost every aspect and stage of the growth and development of plants1.Among the GAs identified to date, gibberellic acid (GA3) 1 is the most active and widely used naturally occurring gibberellin. However structure-activity relationship studies …     

C-3 to C-2 Carbonyl Transposition via a Vinyl Chloride in Ring-A of Steroids

Transposition of a steroid C-3 ketone to the C-2 position was carried out through the 2-chloro-2-olefin. A convenient synthesis of 5α-androstan-2-on-17β-ol acetate is described.     

Stereochemische untersuchungen an C-10-disubstituierten C-9-hydroxyphäophorbiden der a-reihe

The diastereomeric 9-hydroxy pheophorbides 3a, b-1, 2 and 4a, b-1, 2 were prepared by reduction of the 10-alkoxy pheophorbides 1a, b and 2a, b with NaBH₄. Their absolute configuration at C-10 was determined by NMR- and ORD/CD-measurements as well as chemical correlation, the configuration at C-9 by IR- and mainly NMR-spectroscopy. For this purpose, the NMR-spectra of the 9-hydroxy pheophorbides 3a, b-1, 2 had completely to be assigned with the aid of the selectively deuterated alcohols 5a, b-1, 2. The configuration at C-10 is stable under the conditions of the alkaline reduction while C-9 partially epimerizes. The acidic alcoholysis of 3a, b-1, 2, however, proceeds by equilibration at C-10 and almost complete retention at C-9. The H-bonds between the 9-OH group and the C-10 substituents (-COOCH₃, -OCH₃ were investigated by NMR and IR spectroscopy.     

C-2/c-3 annulation and C-2 alkylation of indoles with 2-alkoxycyclopropanoate esters

The annulation reaction between various indoles and 2-alkoxycyclopropanoate esters is reported. Both high efficiency and complete stereochemical control were observed in some cases with this annulation process. A single stereocenter on the cyclopropane controls the diastereoselective formation of up to four new stereocenters. A different reaction course was observed with 3-substituted indole substrates, and an intervening C-3 to C-2-migration process arose that gives synthetically useful C-2 alkylation indole products.     

Palladium catalysis for the synthesis of hydrophobic C-6 and C-2 aryl 2'-deoxynucleosides. Comparison of C-C versus C-N bond formation as well as C-6 versus C-2 reactivity

Suzuki-Miyaura cross-coupling of haloaromatic compounds with arylboronic acids provides a simple entry to biaryl systems. Despite its ease, to date, there are no detailed investigations of this procedure for deoxynucleoside modification. As shown in this study, a wide variety of C-6 arylpurine 2'-deoxyriboside (C-6 aryl 2'-deoxynebularine analogues) and C-2 aryl 2'-deoxyinosine analogues can be conveniently prepared via the Pd-mediated cross-coupling of arylboronic acids with the C-6 halonucleosides, 6-bromo- or 6-chloro-9[2-deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-beta-D-erythro-pentofuranosyl]purine (1 and 2), and the C-2 halonucleoside, 2-bromo-O(6)-benzyl-3',5'-bis-O-(tert-butyldimethylsilyl)-2'-deoxyinosine (3). Although bromonucleoside 1 proved to be a good substrate for the Pd-catalyzed Suzuki-Miyaura cross-couplings, we have noted that for several C-6 arylations, the chloronucleoside 2 provides superior coupling yields. Also described in this study is a detailed evaluation of catalytic systems that led to optimal product recoveries. Finally, a comparison of the C-C and C-N bond-forming reactions of deoxynucleosides is also reported. On the basis of this comparison, we provide evidence that C-N bond formation at the C-6 position, leading to N-aryl 2'-deoxyadenosine analogues, is more sensitive to the ligand used, whereas C-C bond-forming reactions at the same position are not. In contrast to the ligand dependency exhibited in C-N bond formation at the C-6 position, comparable reactions at the C-2 position of purine deoxynucleosides proceed with less sensitivity to the ligand used.     

Versatile routes to C-2- and C-6-functionalized glucose derivatives of iminodiacetic acid

A series of novel d-glucose derivatives, functionalized at the C-2 or the C-6 position with an iminodiacetic acid moiety for transition-metal complexation, has been prepared. The sugar and the metal-chelating parts are separated by either propyl or octyl chains and were introduced by the reaction of bromoalkylamine. Either N-1-Boc-3-bromopropylamine (17) or N-(8-bromooctyl)phthalimide (19) reacted with methyl 3,5,6-tri-O-benzyl-alpha-beta-d-glucofuranoside (4) (C-2 position) and 1,2:3,5-(O-methylene)-alpha-d-glucose (11) (C-6 position), respectively, in the presence of sodium hydride in DMF at room temperature, affording the desired intermediates. For aminopropyl derivatives, yields varied between 57% and 65%, and for aminooctyl derivatives, yields varied between 40% and 71%. After deprotection of the amine functionality, the metal chelate was built up by dialkylation (6a-c and 13a,b) with methyl bromoacetate in the presence of triethylamine under reflux in THF. Yields varied between 56% and 69% for the glucose modified at the C-2 position and between 58% and 62% for the one modified at the C-6 position. All compounds were characterized by 1H or 13C NMR or both, IR, and mass spectroscopy. Final products were isolated as a mixture of alpha and beta anomers.     

Absolute stereochemistry of amphidinolide C: synthesis of C-1-C-10 and C-17-C-29 segments

Two of each diastereomers of the C-1-C-10 and C-17-C-29 segments of amphidinolide C (1) were synthesized. Comparing the ¹H NMR chemical shifts of its MTPA esters with those of linear methyl ester of 1, the absolute configurations at C-7, C-8, C-20, C-23, and C-24 in amphidinolide C (1) were confirmed to be all R.     

Hydrogen atom transfer methodology for the synthesis of C-22, C-23, and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins

A simple synthesis of all eight C-22, C-23, and C-25 diastereoisomers of the cephalostatin north 1 side chain has been accomplished from (25R)-5α-spirostan-3β-ol (tigogenin). The synthesis involves selective hydroxylations at C-23 and C-25 and reductive opening of the 1,6-dioxaspiro[4.5]decane spirostan system to give a conveniently protected 5α-furostan-3β,23,25,26-tetrol. The construction of the required 1,6-dioxaspiro[4.4]nonane system entailed an intramolecular hydrogen abstraction reaction promoted by the C-25 alkoxyl radical as the key step. Acid-catalyzed isomerization of the spiroketal unit suggested that 22R isomers are the thermodynamic products while the 22S isomers are the result of kinetic control. The acid-catalyzed equilibrium between 1,6-dioxaspiro[4.4]nonane and 1,6-dioxaspiro[4.5]decane systems was also studied. In the 1,6-dioxaspiro[4.4]nonane units, the observed ³J_23,24 coupling constants suggest that the five-membered puckered ring-F undergoes substantial conformational changes on going from 22S to 22R isomers.     

Enantioselective synthesis of the C-14 to C-5 cyclopentane segment of jatrophane diterpenes

The enantioselective synthesis of the C-14 to C-5 cyclopentane segment of jatrophane diterpenes is reported. An Evans aldol addition, a Horner-Wadsworth-Emmons olefination and a thermal intramolecular carbonyl ene reaction of an α-keto ester served as key C/C-connecting transformations.     

Studies on Agarofurans VI. The Introduction of Substituents to C-1 and C-2 Positions of Agarofurans

Agarofurans have been found to be active on the nervous system in our institute. Since no member of natural agarofurans has C-1 or C-2 substituents, we decided to synthesize ketone 1 and 2, for the convenience of further modification.Our synthetic design for ketone 1, outlined in Scheme 1, was to employ β-epoxide 3 as starting material. Reaction of epoxide 3 with CH3MgI cooled with ice-bath afforded alcohol 4 in 50% yield and reductive product 5 in 40% yield. The structure of 5 has been de…     

On the protonation equilibria of sephadex C-25 and C-50

The system H(+)Na(+) has been studied on Sephadex C-25 and C-50 at two ionic strengths by potentiometry. The data have been fitted by the H?gfeldt three-parameter model. For ionic strength 0.100 M (Na)ClO(4) an excellent fit is obtained with a standard deviation of +/-0.013 for both gels. For ionic strength 0.010 M (Na)ClO(4) a satisfactory fit could only be obtained by excluding the lowest and highest pH-value for each gel.     

Synthesis of Sialic Acid Analogues with the Oxime Group at C-4 Or C-5 of KDN 1

Abstract

The readily available methyl (methyl 3-deoxy-5,8:7,9-di-O-isopropylidene-β-D-glycero-D-galacto-2-nonulopyranosid)onate (7) was converted in five synthetic steps into methyl (methyl 4-acetamido-3,4-dideoxy-β-D-glycero-D-talo-2-nonulopyranosid)onate (11). Selective protection of the C-4, C-7, C-8 and C-9 hydroxy groups of methyl (methyl 3-deoxy-8,9-O-isopropylidene-β-D-glycero-D-galacto-2-nonulpyranosid)onate (2) followed by oxidation of the C-5 hydroxy group and then its oximination gave 5-hydroxyimino derivatives (15 and 16).

     

Synthetic studies on (+)-aplasmomycin. 1. Stereoselective synthesis of the C-12˜C-17 segment

The C-12˜C-17 segment of (+)-aplasmomycin ( ) was synthesized stereoselectively starting from (−)-malic acid based on the stereoselective ketone reduction.     

Distinction of absolute configuration at C-22 of C-23-hydroxyspirostane and C-23-hydroxyspirosolane glycosides

It has been revealed that the absolute configurations at C-22 of 23-hydroxyspirostane and 23-hydroxyspirosolane could be unambiguouly judged by the (1)H- and (13)C-NMR spectroscopies.     

Synthesis and biological properties of C-2 triazolylinosine derivatives

O(6)-(Benzotriazol-1H-yl)guanosine and its 2'-deoxy analogue are readily converted to the O(6)-allyl derivatives that upon diazotization with t-BuONO and TMS-N(3) yield the C-2 azido derivatives. We have previously analyzed the solvent-dependent azide·tetrazole equilibrium of C-6 azidopurine nucleosides, and in contrast to these, the O(6)-allyl C-2 azido nucleosides appear to exist predominantly in the azido form, relatively independent of solvent polarity. In the presently described cases, the tetrazole appears to be very minor. Consistent with the presence of the azido functionality, each neat C-2 azide displayed a prominent IR band at 2126-2130 cm(-1). A screen of conditions for the ligation of the azido nucleosides with alkynes showed that CuCl in t-BuOH/H(2)O is optimal, yielding C-2 1,2,3-triazolyl nucleosides in 70-82% yields. Removal of the silyl groups with Et(3)N·3HF followed by deallylation with PhSO(2)Na/Pd(PPh(3))(4) gave the C-2 triazolylinosine nucleosides. In a continued demonstration of the versatility of O(6)-(benzotriazol-1H-yl)purine nucleosides, one C-2 triazolylinosine derivative was converted to two adenosine analogues via these intermediates, under mild conditions. Products were desilylated for biological assays. The two C-2 triazolyl adenosine analogues demonstrated pronounced antiproliferative activity in human ovarian and colorectal carcinoma cell cultures. When evaluated for antiviral activity against a broad spectrum of DNA and RNA viruses, some of the C-2 triazolylinosine derivatives showed modest inhibitory activity against cytomegalovirus.     

Synthesis and structural studies of C-5 aryl- and C-6 alkyl-substituted pyrimidine derivatives

C-5 and C-6 disubstituted pyrimidine derivatives 2–7 were synthesized. Introduction of the aryl rings at C-5 of pyrimidine moiety in 5 and 6 was performed using palladium-catalyzed Stille cross-coupling reaction. The novel C-6 fluorophenylalkylated 5-phenylpyrimidine derivative (7) was prepared by lithiation of 5-phenylpyrimidine (6) and subsequent reaction of thus obtained organolithium intermediate with p-fluoroacetophenone. The structures of 3, 4 and 6 were determined by X-ray crystal structure analysis. Both methoxy groups in these structures adopt a synperiplanar conformation with respect to the N1 and N3 atoms of the pyrimidine ring. The molecules of 3 and 4 are linked through weak Br···Br interactions into zig-zag chains. The molecules of 6 are assembled into layers by one C–H···O hydrogen bond, C–H···π and aromatic π···π stacking interactions.     

Regioselective C-2 and C-6 substitution of (S)-nicotine and nicotine derivatives

[reaction: see text] Regioselective deprotonations of (S)-nicotine and derivatives at the C-2 and C-6 positions of the pyridine ring were performed in good to excellent yields. These methodologies allow the direct introduction of a plethora of functional groups onto the pyridine ring of nicotine.     

Functionalization at C-5 and at the C-6 methyl group of 4-methoxy-6-methyl-2-pyrone

A new entry to C-5 substituted 4-hydroxy-6-methyl-2-pyrones has been achieved. The best conditions to prepare the monobromo and the dibromo derivatives at C-3 and the C-6 methyl group of the title pyrone have been defined. The synthetic applicability of the phosphonium salts at CH₃-C-6 of both 4-methoxy-6-methyl-2-pyrone, 5 , and dehydroacetic acid, 2 , has also been evaluated.