Synthesis Of 1a Research Articles

Synthesis of porphobilinogen via a novel ozonide cleavage reaction.

Porphobilinogen lactam methyl ester (3a) has been prepared in seven steps, and approximately 20-30% overall yield, beginning with furfurylamine (4a).(24) Hydrolysis of 3a following the literature procedure then gave porphobilinogen (1). A key intermediate in our synthesis of 3a is the 7-oxonorbornene derivative 7a, which was derived from 4a utilizing a tandem Johnson ortho ester Claisen rearrangement followed by intramolecular Diels-Alder cyclization (five steps, 55-65%).(24) Interesting steric accelerating effects were observed in this sequence. Conversion of 7a to 3a was then accomplished employing a novel ozonide cleavage/oxidation reaction, which generated tetrahydrofurans 16a, 32, and 33 in the proper oxidation state for direct aminolysis to pyrrole 3a. A mechanism is proposed for the ozonide cleavage/oxidation that accounts for the observed stereoselectivity of this step.

Syntheses of 5a'-homo-vinblastine and congeners designed to establish structural determinants for isolation of atropisomers.

The syntheses of 5a'-homo-vinblastine (3a) and its C-20' methyl congener 62a were achieved. In contrast to vinblastine, these compounds did not allow isolation of atropisomers because of their lower conformational inversion barrier. However, annelation of a six-membered ring to the conformationally mobile D'-piperidine ring provided an isolated atropisomer 81a, which could be converted to its lower energy conformation 65a on heating. The 5a'-homo-vinblastine congeners 3a, 62a, and 65a showed vinblastine-like inhibition of tubulin polymerization and cytotoxicity to L1210 leukemia cells, albeit at lower potency for the latter activity, than that found with the corresponding compounds in the vinblastine series.

Applications of Vinylogous Mannich Reactions. Total Syntheses of the Ergot Alkaloids Rugulovasines A and B and Setoclavine

Concise syntheses of the Ergot alkaloids rugulovasine A (3a), rugulovasine B (3b), and setoclavine (2) have been completed by strategies that feature inter- and intramolecular vinylogous Mannich reactions as the key steps. Thus, the first synthesis of 3a,b commenced with the conversion of the known indole 17 into 24 via the addition of the furan 22 to the iminium ion 21, which was generated in situ from the aldehyde 19. Cyclization of 24 by a novel S(RN)1 reaction followed by removal of the N-benzyl group furnished a mixture (1:2) of 3a and 3b. In an alternative approach to these alkaloids, the biaryl 35 was reduced with DIBAL-H to give an intermediate imine that underwent spontaneous cyclization via an intramolecular vinylogous Mannich addition to provide 36a,b. N-Methylation of the derived benzyl carbamates 37a,b followed by global deprotection gave a mixture (2:1) of rugulovasines A and B (3a,b). Setoclavine (2) was then prepared from the biaryl 41 using a closely related intramolecular vinylogous Mannich reaction to furnish the spirocyclic lactones 42a,b. These lactones were subsequently transformed by hydride reduction and reductive methylation into the ergoline derivatives 43a,b, which were in turn converted into 2 by deprotection and solvolytic 1,3-rearrangement of the allylic hydroxyl group.

ChemInform Abstract: A Practical Synthesis of the Chronic Renal Disease Agent: 4,5‐Dihydro‐3H‐1,4,8b‐triazaacenaphthylen‐3‐one Derivatives Using Regioselective Chlorination of Ethyl 5‐Methylimidazo[1,2‐a]pyridine‐3‐carboxylate with N‐Chlorosuccinimide.

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Design, synthesis, and X-ray crystal structure of a potent dual inhibitor of thymidylate synthase and dihydrofolate reductase as an antitumor agent.

A novel N-¿2-amino-4-methyl[(pyrrolo[2, 3-d]pyrimidin-5-yl)ethyl]benzoyl¿-L-glutamic acid (3a) was designed and synthesized as a potent dual inhibitor of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) and as an antitumor agent. Compound 3b, the N7-benzylated analogue of 3a, was also synthesized as an antitumor agent. The synthesis of 3a was accomplished via a 12-step sequence which involved the synthesis of 2-amino-4-methylpyrrolo[2,3-d]pyrimidine (10) in 5 steps from 2-acetylbutyrolactone. Protection of the 2-amino group of 10 and regioselective iodination at the 5-position followed by palladium-catalyzed coupling afforded intermediate 14 which was converted to 3a by reduction and saponification. Similar synthetic methodology was used for 3b. X-ray crystal structure of the ternary complex of 3a, DHFR, and NADPH showed that the pyrrolo[2, 3-d]pyrimidine ring binds in a "2,4-diamino mode" in which the pyrrole nitrogen mimics the 4-amino moiety of 2,4-diaminopyrimidines. This is the first example of a classical pyrrolo[2,3-d]pyrimidine antifolate shown to have this alternate mode of binding to DHFR. Compounds 3a and 3b were more inhibitory than LY231514 against TS from Lactobacillus casei and Escherichia coli. Analogue 3a was also more inhibitory against DHFR from human, Toxoplasma gondii, and Pneumocystis carinii. Evaluation of 3a against methotrexate (MTX)-resistant cell lines with defined mechanisms indicated that cross-resistance of 3a was much lower than that of MTX. Metabolite protection studies and folylpoly-gamma-glutamate synthetase studies suggest that the antitumor activity of 3a against the growth of tumor cells in culture is a result of dual inhibition of TS and DHFR. Compound 3a inhibited the growth of CCRF-CEM and FaDu cells in culture at ED(50) values of 12.5 and 7.0 nM, respectively, and was more active against FaDu cells than MTX. In contrast, compound 3b was inactive against both cell lines. Compound 3a was evaluated in the National Cancer Institute in vitro preclinical antitumor screening program and afforded IG(50) values in the nanomolar range against a number of tumor cell lines.

A Rationally Designed Prototype of a Molecular Motor.

A proof of principle of the first rationally designed, chemically powered, molecular-scale motor is described. The thermodynamic considerations leading to the choice of 6a and 7a as the initial prototypes are provided, and the synthesis of 6a and 7a and the separation of them from their atropisomers are detailed. The phosgene-powered unidirectional rotation of 6a to its rotamer 6b is demonstrated. It is further established that shortening the length of the tether (→7a) changes the rate-limiting step and accelerates the speed of rotation.

No-carrier-added11C-labelling of benzenoid compounds in ring positions by condensation of nitro-[11C]methane with pyrylium salts

A new synthesis is described for three no-carrier-added nitro-[1-11C]benzenes 3a–c by condensation of nitro[11C]methane (1) with the appropriate pyrylium salts 2a–c in the presence of a base such as t-BuOK in t-BuOH. For synthesizing 4-nitro-[4-11C]anisole (3a), tetrabutylammonium fluoride was successfully used as an auxiliary base. The best results were obtained in the synthesis of 3a. The conversion of 1 with 4-methoxypyrylium perchlorate (2a) yielded 3a of a radiochemical purity of up to 82 % and a mean specific radioactivity of 30 GBq/μmol (0.8 Ci/μmol) within 20 min. Related to 1, the reproducible radiochemical yields of 3a are in the range of 77±5 % (decay-corrected). 2,6-Dimethyl-4-methoxy-nitro-[1-11C]benzene (3b) was prepared by reaction of 1 with 2,6-dimethyl-4-methoxy-pyrylium perchlorate (2b) in radiochemical yields of about 37 % (decay-corrected) within 10 min. 2-Nitro-[2-11C]mesitylene (3c) was obtained by condensation of 1 with 2,4,6-trimethylpyrylium tetrafluoroborate (2c) in radiochemical yields of about 29 % (decay-corrected) within 20 min. 13C/11C Co-labelling experiments were carried out in order to confirm the identity of 3a–c and the position of the label. Copyright © 2000 John Wiley & Sons, Ltd.

Isolation, total synthesis, and relative stereochemistry of a dihydrofurocoumarin from dorstenia contrajerva

The roots of Dorstenia contrajerva afforded the dihydrofurocoumarin 1b whose identity was determined from NMR spectral data of the derived acetate 7b combined with the total syntheses of 1a and 1b, which were carried out in five steps with 19% overall yield, starting from 2,3-dihydro-2-isopropenyl-6-methoxybenzofuran (2). The relative stereochemistry of 7b was determined from a single-crystal X-ray diffraction study as (2S,1'S)-2, 3-dihydro-2-(1'-hydroxy-1'-acetyloxymethylethyl)-7H-furo[3, 2g][1]benzopyran-7-one.

Exchanged ligands on the surface of a giant cluster: [(MoO3)176(H2O)63(CH3OH)17Hn](32 − n)−

The synthesis of 1a·(32 – n)Na+·ca. 600 H2O·ca. 30 CH3OH 1 containing the ring-shaped, mixed-valence (MoV/MoVI) cluster [(MoO3)176(H2O)63(CH3OH)17Hn](32 – n)– 1a as a discrete unit in the crystal lattice is reported, which for the first time yields a compound of this type via a facile synthetic method and without amorphous reaction products; remarkably, H2O ligands can be replaced by CH3OH on the surface of a giant metal-oxide based cluster which has a nanometer sized cavity and, in contrast to zeolites, reducing properties.

Grignard Reactions on Ortho Dicarboxylic Arene Derivatives. Synthesis of 1,3-Dithienylisothianaphthene Compounds

1,3-Dithienylisothianaphthene (10a) is obtained through ring closure of 1,2-dithienoylbenzene (7a). The synthesis of 7a has been accomplished based on a Grignard reaction by adding 2-thiophenemagnesium bromide to 1,2-di(S-(2-pyridinyl)) benzenedithioate (6b) to obtain 7a in a yield of 95%. The use of 6b avoids the formation of the corresponding 3,3-dithienyl-3H-isobenzofuran-1(3H)-one (dithienylphthalide, 8). The same procedure is applied to obtain 1,3-dithienyl-4,5,6,7-tetradeuterioisothianaphthene (10b) and 1,3-dithienyl-4,5,6,7-tetrafluoroisothianaphthene (10c). The synthesis of the 2,3-dithienoylpyridine (12a), 3,4-dithienoylpyridine (12b), and 2,3-dithienoylpyrazine (12c) however fails. The presence of nitrogen in the central ring system influences the result of the Grignard reaction. Possibly the free electron pair of the nitrogen interferes with the formation of a stable six-membered ring intermediate which is essential for the diketone formation.

Novel Synthesis of Vinylcyclopropyl Ketones and Vinylcyclopropanecarboxylic Acids: Application to the Stereoselective Synthesis of trans-Chrysanthemic Acid

Some years ago, we designed1a a stereoselective synthesis of (1RS)-cis-chrysanthemic acid 1a (R1, R2 ) Me)2 from dimethyldimedone 2a (R1, R2 ) Me) which uses cheap reagents compatible with industrial requirements. The key steps of this process are (i) the cyclopropanation of 2a, which produced the bicyclo[3.1.0]hexa-2,4-dione1a,3 3a, and (ii) the Grob fragmentation4 on the mesylate 5a derived from â-hydroxy ketone 4a, itself resulting from the mono-reduction of 3a. The stereochemical outcome of each individual step that is important for the success of the whole process is depicted in Scheme 1.1 Most of the reducing agents used, including sodium borohydride (methanol, -78 °C), efficiently achieved5 monoreduction of the bicyclic dione 3a but delivered, exclusively or mainly, the endo alcohol 4aendo. This alcohol, which results from the attack of the hydride from the least hindered exo face of 3a,1a,b is unsuitable, however, for the synthesis of 1a. This synthesis has been nevertheless successfully achieved from the exo stereoisomer 4aexo, readily available from the reduction of 3a1a,b with sodium borohydride-cerium trichloride (methanol, -78 °C, Luche’s reagent).6 This synthetic approach has been successfully extended to homologous derivatives of 1 bearing one methyl group and one hydrogen or even two hydrogens on the cyclopropane ring. This approach is unsuitable, however, for the synthesis (for example) of derivatives 1 bearing one or two hydrogens on the terminal sp2 carbon, due to competing metalation at the position R to the carbonyl group of 2 and 4 (R1 or/and R2 ) H).

ChemInform Abstract: Remote Functionalization of (‐)‐Menthol ‐ Synthesis of 4a,5,6,7,8,8a‐ Hexahydro‐4H‐benzo(1,3)oxazine Derivatives with the Selectfluor Reagent F‐TEDA‐BF4.

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Rearrangement and Scission of Terminal Alkynes in Dimolybdenum Complexes on Reaction with Ruthenium Carbonyl: Formation of Trinuclear Vinylidene and Hexanuclear Bis(alkylidyne) Clusters

The reaction of the dimolybdenum alkyne complexes Mo2(CO)4(μ-R1C⋮CR2)Cp2 (Cp = η-C5H5; R1= H, R2 = H, Me, Ph, CO2Me; 1a−d) with Ru3(CO)12 in refluxing toluene or heptane affords reasonable yields of the orange μ3-vinylidene clusters [Mo2Ru(μ3-CCHR2)(CO)7Cp2] (2a−d). The crystal structure of Mo2Ru(μ3-CCHMe)(CO)7Cp2 (2b) has been determined and shows that the metal triangle is capped by a vinylidene ligand which is formally σ-bound to the two molybdenum atoms and π-bound to the ruthenium. Low to moderate yields of the blue-turquoise hexanuclear bis(alkylidyne) clusters Mo2Ru4(μ3-CR1)(μ3-CR2)(CO)12Cp2 (3a−d) are formed in addition to the vinylidene clusters, especially if the reaction is carried out in heptane. The synthesis of 3a is particularly noteworthy, as it represents the first example of the scission of ethyne into two methylidyne fragments on a metal cluster. The disubstituted alkyne complex 1e (R1 = R2 = Me) leads to the corresponding hexanuclear cluster 3e in either solvent, but complexes of bulki...

Kinetic isotope effects on metaphosphate generation from fragmentation of 2,3-oxaphosphabicyclo[2.2.2]octene derivatives

Kinetic isotope effects of deuterium and oxygen-18 were measured on fragmentation of syn-3-ethoxy (1a) and syn-3-(N,N-diethylamino) (1b) 2,3-oxaphosphabicyclo[2.2.2]octene derivatives in 1,2-dichloroethane at 100°C. The secondary deuterium isotope effect on hydrogen adjacent to the P(SINGLE BOND)C bond was found to be 1.060 ± 0.008 for 1a and 1.081 ± 0.009 for 1b. The kinetic oxygen isotope effect on the bridge P(SINGLE BOND)O(SINGLE BOND)C is 0.9901 ± 0.0016 for 1a. The data indicate an unsymmetrical transition state for retrocycloaddition extrusion of the metaphosphate moiety, with the breakage of the C(SINGLE BOND)P bond and formation of the P (DOUBLE BOND) O bond more advanced than the C(SINGLE BOND)O breakage. A synthesis of 1a and 1b labeled with deuterium is described. © 1996 John Wiley & Sons, Inc.

ChemInform Abstract: Synthesis of 5a,11b‐Propanonaphtho(1,2‐e) (1,2)oxazepines as Potential Opioid Analgesics.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Design and synthesis of DNA cleaving bleomycin models: 1,2-trans-disubstituted cyclopropane units as novel linkers

The design and synthesis of 1a – e, functional models for bleomycin are described in which AMPHIS, a metal-complexing model of bleomycin, and a distamycin moiety are connected with a series of linkers. Studies on the rates of DNA breakage and a mobility assay of DNA cleavage ability show that trans-1,2-disubstituted cyclopropane units are the best linkers amongst those examined.

Synthesis of antihypertensive agents via coupling reaction of benzothiazepinone and 1,4-dihydropyridine derivatives.

The synthesis of 3a, 3b, 7a and 7b from Benzothiazepinone and 1,4-dihyropyridine derivatives is described. Benzothiazepinone and 1,4-dihydropyridine derivatives were prepared according to literature procedure. The key reactions involve esterification and amidation of benzothiazepinone and 1,4-dihydropyridine derivatives.

Mehrstufige reversible Redoxsysteme. LXI. Synthese von 1,4-Bis(2-methyl-indolizin-1-yl-methyl)-benzol und verwandter Modellverbindungen

Multi-Step Redox Systems. LXI. Synthesis of 1,4-Bis(2-methyl-indolizin-1-yl-methyl)-benzene and Related Model Compounds The synthesis of 1a, in which two 1-indolizine units are connected by a p-xylylene bridge is preformed from its 3,3′bis-acetyl derivative 1b via the precursors 8–11. This route was first tested by the synthesis of benzyl indolizines 2b and 2a via the pyridyl-aminopropanol 3a. 2a can be oxidatively dimerized to the 3,3′-bis-indolizine 6 which forms a perfectly reversible two step redox system with KSEM = 4.7 × 105.

Synthesis and preliminary evaluation of an iodovinyl‐tetrabenazine analog as a marker for the vesicular monoamine transporter

AbstractA derivative of tetrabenazine (TBZ, 1) containing an iodovinyl group (I‐TBZ, 3b) was prepared as a potential radiotracer for the vesicular monoamine transporter. The synthesis of 3a was achieved by ethynylation of TBZ. The ethynyl derivative 4, was converted to the corresponding vinylstannane 5. The vinylstannane intermediate was then treated with I2 in chloroform at room temperature, to afford the iodovinyl compound (3a, I‐TBZ). The no‐carrier‐added [125I]I‐TBZ (3b) was prepared by treating an ethanolic solution of 5 with sodium[125I]iodide in the presence of H2O2. Following i.v. injection, [125I]I‐TBZ (3b) can readily cross the blood brain barrier and localize in the brain (0.92 and 0.36% dose/organ, at 2 min and 30 min, respectively). However, no specific regional uptake of the ligand was observed. Subsequent biodistribution studies performed using two well resolved peaks obtained from chiral HPLC separation of 3b, demonstrated that Fraction I displayed higher brain uptake (0.6% dose/organ, 20 min) than the latter peak (Fraction II, 0.3% dose/organ, 20 min). Fraction I also exhibited a modest degree of specificity for the striatum which could be blocked by pretreatment with tetrabenazine. The high lipophilicity of 3a (Po/b for Fraction 1 and II=1723 and 1395, respectively) may contribute to high nonspecific binding in vivo, and result in the low target/nontarget ratio observed for this compound. Iodovinyl‐TBZ analog 3b is a poor candidate as a SPECT imaging agent for the vesicular monoamine transporter.

An efficient stereoconvergent synthesis of the 4-ethylamino-2,4-dideoxy-l-threo-pentopyranose component of the calicheamicins and esperamicins

A stereconvergent synthesis of the 4-ethylamino-2,4-dideoxy-L-threo-pentopyranose coonponent of calicheamicins γ1, γ1I, α2I, and esperamicin A1b from methyl 2-deoxy-β-D-ribopyranoside is described. The synthesis requires eight steps in each branch. The overall yield is 54%. This synthesis should be adaptable for syntheses of the corresponding 4-methylamino)-2,4-dideoxy- L-threo- and 4-isopropylamino-2.4- dideoxy-L-threo- pentopyranose components of other calicheamicin and esperamicin antibiotics.