- Research and development of an efficient synthesis of hexahydrofuro[2,3-b] furan-3-ol moiety - a key component of the HIV protease inhibitor candidates
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A highly efficient method for synthesizing racemic hexahydrofuro[2,3-b] furan-3-ol has been developed utilizing a lanthanide catalyst, such as Yh(fod)3, to promote condensation of 23-dihydrofuran and glycolaldehyde dimer. Access to either optically enriched enantiomer of bisfuran alcohol can be obtained by using this method employing chiral ligands with the lanthanide catalyst In support of Gilead Sciences' protease inhibitor project, this method has been demonstrated to be a robust and scalable process with potential application for the construction of a variety of furo[2,3-b]furan derivatives.
- Yu, Richard H.,Polniaszek, Richard P.,Becker, Mark W.,Cook, Charles M.,Yu, Lok Him L.
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Read Online
- CHEMICAL COMPOUNDS
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The present invention relates to highly functionalized 1,3-diamino-propan-2-ols and pharmaceutically acceptable salts thereof. More specifically, the invention relates to highly functionalized 1,3-diamino-propan-2-ols that are derivatives of the HIV prote
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- Towards aflatoxins: a formal synthesis of aflatoxin B2
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The development of a formal synthesis of aflatoxin B2 is described, which utilizes a D?tz benzannulation reaction as a key step.
- Eastham, Stephen A.,Ingham, Steven P.,Hallett, Michael R.,Herbert, John,Modi, Andrea,Morley, Timothy,Painter, James E.,Patel, Prakash,Quayle, Peter,Ricketts, Dean C.,Raftery, James
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p. 936 - 948
(2008/09/16)
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- FITNESS ASSAY AND ASSOCIATED METHODS
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The present invention provides an assay for determining the biochemical fitness of a biochemical species in a mutant replicating biological entity relative to its predecessor. The present invention further provides a continuous fluorogenic assay for measuring the anti-HIV protease activity of protease inhibitor. The present invention also provides a method of administering a therapeutic compound that reduces the chances of the emergence of drug resistance in therapy. The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, a prodrug, a composition, or an ester thereof, wherein A is a group of formulas (A), (B), (C) or (D); R1, R2, R3, R5 or R6 is H, or an optionally substituted and/or heteroatom-bearing alkyl, alkenyl, alkynyl, or cyclic group; Y and/or Z are CH2, O, S, SO, SO2, amino, amides, carbamates, ureas, or thiocarbonyl derivatives thereof, optionally substituted with an alkyl, alkenyl, or alkynyl group; n is from 1 to 5; X is a bond, an optionally substituted methylene or ethylene, an amino, O or S; Q is C(O), C(S), or SO2; m is from 0 to 6; R4 is OH, ═O (keto), NH2, or alkylamino, including esters, amides, and salts thereof; and W is C(O), C(S), S(O), or SO2. Optionally, R5 and R6, together with the N—W bond of formula (I), comprise a macrocyclic ring.
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Page/Page column 17; 18; Sheet 2
(2010/11/30)
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- PROCESS FOR PREPARATION OF HIV PROTEASE INHIBITORS
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A process for the synthesis of bisfuran intermediates useful for preparing antiviral HIV protease inhibitor compounds is hereby disclosed.
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Page/Page column 29-30
(2008/06/13)
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- A formal synthesis of aflatoxin B2: a Doetz benzannulation approach
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A Doetz benzannulation reaction has been utilized in the synthesis of the furo[2,3-b]furan core of aflatoxin B2.
- Eastham, Stephan A.,Ingham, Steven P.,Hallett, Michael R.,Herbert, John,Quayle, Peter,Raftery, James
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p. 2299 - 2304
(2007/10/03)
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- Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation.
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Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.
- Ghosh,Kincaid,Walters,Chen,Chaudhuri,Thompson,Culberson,Fitzgerald,Lee,McKee,Munson,Duong,Darke,Zugay,Schleif,Axel,Lin,Huff
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p. 3278 - 3290
(2007/10/03)
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- SINTHESIS AND OPTICAL RESOLUTION OF HIGH AFFINITY P2-LIGANDS FOR HIV-1 PROTEASE INHIBITORS
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Racemic bis-tetrahydrofuran ligand 6 was efficiently synthesized utilizing catalytic cobaloxime 10 mediated radical cyclization as the key step.Optical resolution of the racemic alcohol with immobilized-Amano lipase, afforded optically pure ligands.
- Ghosh, Arun K.,Chen, Yan
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p. 505 - 508
(2007/10/02)
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- A NEW ROUTE TO PERHYDRO- AND TETRAHYDRO- FURO-2,3b FURANS VIA RADICAL CYCLISATION
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Perhydrofuro-2,3b furans have been prepared in high yield by radical cyclisation of unsaturated bromo acetals.Their transformation into tetrahydro derivatives is described along with a radical anneltion to 2,3- dihydrofurans by tributyltin iodoacetate.
- Pezechk, M.,Brunetiere, A. P.,Lallemand, J. Y.
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p. 3715 - 3718
(2007/10/02)
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