- Versatile Photochemical Reactivity of Diverse Substituted 2-, 4- and 5-(o-Vinylstyryl)oxazoles
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To study the effects of the position of the hexatrienyl moiety on the oxazole ring, novel substituted cis/trans-2/4/5-(2-vinylstyryl)oxazoles have been synthesized. These novel compounds were prepared by Wittig reaction from the diphosphonium salt of α,α′-o-xylenedibromide, formaldehyde and the corresponding 2-methyl-4-, 4-methyl-2-, 2-pheny-5- and 4-methyl-5-oxazolecarbaldehyde, respectively. Aldehydes were synthesized by using several synthetic approaches. By applying intramolecular photocycloaddition, 2-methyl-4-(2-vinylstyryl)oxazole afforded, as major product, fused oxazoline-benzobicyclo[3.2.1]octene with small quantities of 4-(1,2-dihydronaphthalen-2-yl)-2-methyloxazole, as electrocyclization product. Upon irradiation of 4-methyl-5-(2-vinylstyryl)oxazole, endo- and exo-benzobicyclo[2.1.1]hexene products were formed by [2+2] cycloaddition; this was the first instance of the 1,4-closure to the bicyclo[2.1.1]hexene skeleton in the 2-, 4-, and 5-oxazole-stilbene derivatives studied so far. Derivatives 2-phenyl-5- and 4-methyl-2-(2-vinylstyryl)oxazole did not react and gave only high-weight molecular products but were crucial as a comparison in the overall mechanistic study. We have found that, depending on the position of the hexatrienyl moiety in the oxazole ring, as well as on the position of the methyl/phenyl substituents, these new vinylstyryl-2/4/5-oxazole derivatives show diverse photochemical behavior.
- ?agud, Ivana,?indler-Kulyk, Marija,Vojnovi?-Jandri?, Dragana,Marini?, ?eljko
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- Utilization of alternate substrates by the first three modules of the epothilone synthetase assembly line
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The epothilones, a family of macrolactone natural products produced by the myxobacterial species Sorangium cellulosum, are of current clinical interest as antitumor agents. Inspection of the structure of the epothilones suggests a hybrid polyketide/nonribosomal peptide biosynthetic origin, and the recent sequencing of the epothilone biosynthetic gene cluster has validated this proposal. Here we have examined unnatural substrates with the first two enzymes of the biosynthetic pathway, EpoA and EpoB, to investigate the enzymatic construction of alternate heterocyclic structures and the subsequent elongation of these products by the third enzyme of the pathway, EpoC. The epothilone biosynthetic machinery can utilize serine to install an oxazole in place of a thiazole in the epothilone structure and will tolerate functionalized donor groups from the EpoA-ACP domain to produce epothilone fragments modified at the C21 position. These studies with the early enzymes of the epothilone biosynthesis cluster suggest that combinatorial biosynthesis may be a viable means for producing a variety of epothilone analogues that incorporate diversity into the heterocycle starter unit. Copyright
- Schneider, Tanya L.,Walsh, Christopher T.,O'Connor, Sarah E.
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- The first total synthesis of the antitumor macrolide, rhizoxin
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The first total synthesis of the antitumor macrolide, rhizoxin in a highly stereocontrolled manner is described.
- Nakada,Kobayashi,Shibasaki,Iwasaki,Ohno
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- Large-scale preparation of 2-methyloxazole-4-carboxaldehyde
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The large-scale preparation of 2-methyloxazole-4-carboxaldehyde presents a significant challenge due to the physical characteristics of the molecule. A method for the preparation of 10-kg batches of 2-methyloxazole-4-carboxaldehyde is described. The key reaction is the reduction of the corresponding N-methoxy-N-methyl amide using lithium aluminium hydride, followed by workup and isolation by crystallization.
- Benoit, Georges-Emmanuel,Carey, John S.,Chapman, Alan M.,Chima, Ranjit,Hussain, Nigel,Popkin, Matthew E.,Roux, Guillaume,Tavassoli, Bahareh,Vaxelaire, Carine,Webb, Michael R.,Whatrup, David
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- Synthesis of 4-arylethynyl-2-methyloxazole derivatives as mGluR5 antagonists for use in the treatment of drug abuse
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In structure-activity relationship studies directed toward the use of mGluR5 antagonists in the treatment of drug abuse, we sought a convenient means for gaining access to the oxazole analogues of MTEP. Toward this end, the aldehyde group in 2-methyloxazo
- Iso, Yasuyoshi,Kozikowski, Alan P.
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- Total synthesis of the marine toxin phorboxazole A using palladium(ii)-mediated intramolecular alkoxycarbonylation for tetrahydropyran synthesis
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The potent antitumor agent phorboxazole A was synthesized from six subunits comprising C1-C2 (115), C3-C8 (98), C9-C19 (74), C20-C32 (52), C33-C41 (84) and C42-C46 (85). Tetrahydropyrans B and C containing cis-2,6-disubstitution were fabricated via palladium(ii)-mediated intramolecular alkoxycarbonylation which, in the case of tetrahydropyran C, was carried out with catalytic palladium(ii) and p-benzoquinone as the stoichiometric re-oxidant. Tetrahydropyran D was obtained by a stereoselective tin(iv)-catalyzed coupling of a C9 aldehyde with an allylsilane, and the C19-C20 connection was made using a completely stereoselective Wittig-Schlosser (E) olefination. Coupling of the oxazole C32 methyl substituent with the intact C33-C46 δ-lactone 3 was accompanied by elimination of the vinyl bromide to a terminal alkyne, but the C32-C33 linkage was implemented successfully with 83 and C33-C41 lactone 84. The C42-C46 segment of the side chain was then appended via Julia-Kocienski olefination. The macrolide portion of phorboxazole A was completed by means of an Ando-Still-Gennari intramolecular (Z)-selective olefination at C2-C3 which required placement of a (dimethoxyphosphinyl)acetate moiety at C24. Final deprotection led to phorboxazole A via a route in which the longest linear sequence is 37 steps and the overall yield is 0.36%.
- Kuntiyong, Punlop,Lee, Tae Hee,Kranemann, Christian L.,White, James D.
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supporting information
p. 7884 - 7899
(2013/07/05)
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- Oxidative rearrangements of isobenzofurans: Studies toward the synthesis of the ajudazols
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(Chemical Equation Presented) We present a new facet of isobenzofuran chemistry which allows for its efficient manipulation to generate biologically relevant entities. This methodology has been successfully applied toward the synthesis of ajudazol A.
- Hobson, Stephen J.,Parkin, Andrew,Marquez, Rodolfo
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supporting information; experimental part
p. 2813 - 2816
(2009/05/27)
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- 6-Alkenyl -, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations
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This invention describes the new 6-alkenyl- and 6-alkinyl-epothilone derivatives of general formula (I) in which R1a, R1b, R2a, R3a, R3b, R4, R5, R6, R7, A,
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Page/Page column 44-45
(2008/06/13)
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- Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol- 4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications
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Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype 5 (mGluR5) may represent a druggable target in identifying new therapeutics for the treatment of various central nervous system disorders including drug abuse. In particular, considerable attention in the mGluR5 field has been devoted to identifying ligands that bind to the allosteric modulatory site, distinct from the site for the primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogue 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have been shown to be selective and potent noncompetitive antagonists of mGluR5. Because of results presented in this study showing that MTEP prevents the reinstatement of cocaine self-administration caused by the presentation of environmental cues previously associated with cocaine availability, we have prepared a series of analogues of MTEP with the aim of gaining a better understanding of the structural features relevant to its antagonist potency and with the ultimate aim of investigating the effects of such compounds in blunting the self-administration of cocaine. These efforts have led to the identification of compounds showing higher potency as mGluR5 antagonists than either MPEP or MTEP. Two compounds 19 and 59 exhibited functional activity as mGluR5 antagonists that are 490 and 230 times, respectively, better than that of MTEP.
- Iso, Yasuyoshi,Grajkowska, Ewa,Wroblewski, Jarda T.,Davis, Jared,Goeders, Nicholas E.,Johnson, Kenneth M.,Sanker, Subramaniam,Roth, Bryan L.,Tueckmantel, Werner,Kozikowski, Alan P.
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p. 1080 - 1100
(2007/10/03)
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- Enantioselective total synthesis of the antitumor macrolide rhizoxin D
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The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from γ-butyrolactone. The central core of rhizoxin D was prepared via a chiral resolution/asymmetric aldol protocol. Several methods for the generation of the polyene fragment were explored, and the side-chain was ultimately prepared from serine in six steps. The unification of the left and right wings of the molecule was achieved using a one-step olefination protocol, and the macrocyclization was carried out using a Horner-Emmons olefination at the C(2)-C(3) olefin.
- Lafontaine, Jennifer A.,Provencal, David P.,Gardelli, Cristina,Leahy, James W.
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p. 4215 - 4234
(2007/10/03)
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- BENZAZEPINE DERIVATIVES, PROCESS FOR THE PREPARATION OF THE SAME AND USES THEREOF
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Compounds of the general formula (I): or salts thereof, which exhibit CCR5 antagonism and exert preventive and therapeutic effects against HIV infections: wherein R1 is a 5- to 6-membered aromatic ring which bears a substituent represented by the general formula: R-Z1-X-Z2- (wherein R1 is hydrogen or optionally substituted hydrocarbyl; X is optionally substituted alkylene; and Z1 and Z2 are each a heteroatom) and may be further substituted, with R being optionally bonded to the aromatic ring to form another ring; Y is optionally substituted imino; and R2 and R3 are each optionally substituted aliphatic hydrocarbyl or an optionally substituted hetero-alicyclic group.
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- Atropisomers of 3-heteroaryl-4(3H)-quinazolinones for the treatment of neurodegenerative and CNS-trauma related conditions
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The present invention relates to novel atropisomers of 3-heteroaryl-4(3H)-quinazolinones of the formula Ia, and their pharmaceutically acceptable salts, and pharmaceutical compositions and methods of treating neurodegenerative and CNS-trauma related conditions.
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- Atropisomers of 3-aryl-4(3H)-quinazolinones and their use as AMPA-receptor antagonists
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The present invention relates to novel atropisomers of 2-(aryl or heteroaryl)-3-aryl-4(3H)-quinazolinones of the formula I, and their pharmaceutically acceptable salts, and pharmaceutical compositions and methods of treating neurodegenerative and CNS-trau
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- Intramolecular palladium(II)-mediated alkoxy carbonylation as a route to functionalized tetrahydropyrans. synthesis of the C9-C32 segment of phorboxazole A
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matrix presented Hydroxy alkene 12, synthesized stereoselectively from 2-methyloxazole-4-carboxaldehyde, underwent intramolecular methoxy carbonylation in the presence of palladium(II) acetate to give 13 in which all five stereogenic centers around the tetrahydropyran correspond to those in ring C of phorboxazole A. Aldehyde 15, derived from 13, was linked to hydroxy alkene 23 via a Wittig coupling, and the composite 25 was subjected to a second palladium(II) acetate mediated methoxy carbonylation to yield 26, accompanied by acetoxy ester 27.
- White, James D.,Kranemann, Christian L.,Kuntiyong, Punlop
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p. 4003 - 4006
(2007/10/03)
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- Rhizoxin synthetic studies. 2. Synthesis of the left hand [C(10) to C(19)] and polyene fragments
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The syntheses of the central core and the polyene fragments of the antitumor macrolide rhizoxin have been achieved in an efficient manner. The core has been prepared in enantiopure form via a asymmetric allylation/aldol protocol. The selective oxidation o
- Provencal, David P.,Gardelli, Cristina,Lafontaine, Jennifer A.,Leahy, James W.
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p. 6033 - 6036
(2007/10/02)
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- Synthesis of the Lower Subunit of Rhizoxin
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Full details of a study leading to a synthesis of the optically active C13-C26 lower subunit of rhizoxin including the side-chain chromophore characteristic of the full class of antimitotic agents are described.A key element of the synthesis is the stereoselective introduction of the C18-C19 trisubstituted olefin through use of a Wadsworth-Horner-Emmerson condensation of 3 with β-keto phosphonate 38 bearing resident functionality suitable for the diastereoselective introduction of C15-C17 employing a hydroxyl-directed reduction of the resultant β-hydroxy ketone.
- Boger, Dale L.,Curran, Timothy T.
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p. 2235 - 2244
(2007/10/02)
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