- Total synthesis of the virginiamycin antibiotic 14,15-anhydropristinamycin IIB
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A total synthesis of the virginiamycin 14,15-anhydropristinamycin IIB 16 has been achieved from chiral, non-racemic starting materials, and using a route which features an intramolecular Stille coupling reaction, viz. 14→15, as the key stratagem. The virginiamycin 16 was identical with an authentic sample produced from a Streptomyces fermentation process.
- Entwistle, David A.,Jordan, Stuart I.,Montgomery, John,Pattenden, Gerald
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- Total synthesis of oxazole-based virginiamycin antibiotics: 14,15- Anhydropristinamycin II(B)
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A total synthesis of 14,15-anhydropristinamycin II(B) (3), a member of the virginiamycin family of antibiotics (also known as streptogramins, pristinamycins or synergimycins) produced by STreptomyces is described. The synthesis is achieved from chiral, non-racemic starting materials and uses a convergent route involving synthesis of the substituted proline 7 and the 4- oxazole carboxylic acid 8, their coupling to the vinylstannane substituted vinyl bromide 6, and finally an intramolecular sp2-sp2 Stille coupling reaction, i.e. 6 → 22, to elaborate the macrocyclic core of the natural product.
- Entwistle, David A.,Jordan, Stuart I.,Montgomery, John,Pattenden, Gerald
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- AZIRIDINE CONTAINING EPOTHILONE ANALOGS, METHODS OF SYNTHESIS, METHODS OF TREATMENT, AND DRUG CONJUGATES
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In one aspect, the present disclosure provides epothilone analogs of the formula: (I) wherein the variables are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein. Additionally, drug conjugates with cell targeting moieties of the compounds are also provided.
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Page/Page column 107
(2018/11/10)
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- 12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents
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The synthesis and biological evaluation of a series of 12,13-aziridinyl epothilone B analogues is described. These compounds were accessed by a practical, general process that involved a 12,13-olefinic methyl ketone as a starting material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation of the epoxide moiety. The attachment of the aziridine structural motif was achieved by application of the Ess-Kürti-Falck aziridination, while the heterocyclic side chains were introduced via stereoselective phosphonate-based olefinations. In order to ensure high (E) selectivities for the latter reaction for electron-rich heterocycles, it became necessary to develop and apply an unprecedented modification of the venerable Horner-Wadsworth-Emmons reaction, employing 2-fluoroethoxyphosphonates that may prove to be of general value in organic synthesis. These studies resulted in the discovery of some of the most potent epothilones reported to date. Equipped with functional groups to accommodate modern drug delivery technologies, some of these compounds exhibited picomolar potencies that qualify them as payloads for antibody drug conjugates (ADCs), while a number of them revealed impressive activities against drug resistant human cancer cells, making them desirable for potential medical applications.
- Nicolaou,Rhoades, Derek,Wang, Yanping,Bai, Ruoli,Hamel, Ernest,Aujay, Monette,Sandoval, Joseph,Gavrilyuk, Julia
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supporting information
p. 7318 - 7334
(2017/06/06)
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- PYRROLE ANTIFUNGAL AGENTS
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The invention provides compounds of formula (I), and pharmaceutically and agriculturally acceptable salts thereof; wherein: R1, R2, R3, R4, R5, R6, A1, L1 and n are as defined herein. These compounds and their pharmaceutically acceptable salts are useful in prevention or treatment of a fungal disease. Compounds of formula (I), and agriculturally acceptable salts thereof, may also be used as agricultural fungicides.
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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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- Amino-Containing Compounds Which Inhibit Memapsin 2 Beta-Secretase Activity and Methods of Use Thereof
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The present invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer's disease.
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Page/Page column 20
(2008/12/05)
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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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- CASPASE INHIBITORS BASED ON PYRIDAZINONE SCAFFOLD
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The present invention relates to a pyridazinone derivative which can be used as a caspase inhibitor, process for the preparation thereof, and pharmaceutical composition for inhibiting caspase comprising the same.
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Page/Page column 51
(2008/06/13)
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- A stereoselective synthesis of the C20-C32 fragment of the phorboxazoles
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The C20-C32 fragment of the phorboxazoles was realized in a stereoconvergent manner utilizing a desymmetrization approach. This successful strategy involves epimerization and modified Julia olefination as key steps. Georg Thieme Verlag Stuttgart.
- Yadav,Satyanarayana,Srinivasulu,Kunwar
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p. 1577 - 1580
(2008/02/04)
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- BICYCLIC COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF
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The present invention provides bicyclic beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer’s disease.
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Page/Page column 61
(2010/10/20)
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- Studies on the synthesis of phorboxazole B: Stereoselective synthesis of the C28-C46 segment
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A stereoselective synthesis of C28-C46 segment of phorboxazole B is described. Key features of the synthetic route involved the use of 1,3-asymmetric induction of Mukaiyama aldol reaction to construct the stereogenic center at C35, and the employment of m
- Li, De Run,Tu, Yong Qiang,Lin, Guo-Qiang,Zhou, Wei-Shan
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p. 8729 - 8732
(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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- Synthetic Studies Toward Phenoxan Analogs
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We developed two reactions needed for a total synthesis of phenoxan, a naturally occurring compound with anti-HIV activity. In this Note, we farther examined these two issues: metallation of a 2-methyl-oxazole and formation of a pyran-4-one. We employed these methods for the preparation of a phenoxan analog.
- Zhang, Xiaowei,Hinkle, Becky,Ballantyne, Lisa,Gonzales, Sam,Pena, Michael R.
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p. 1061 - 1064
(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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- 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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p. 1039 - 1042
(2007/10/02)
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- Oxazolyl and piperidinyl substituted benimidazolyl compounds
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Oxazolyl derivatives of formula (I) STR1 wherein --A1 =A2 --A3 =A4 -- represents a bivalent radical having the formula --CH=CH--CH=CH-- (a-1), --N=CH--CH=CH-- (a-2), --CH=N--CH=CH-- (a-3), --CH=CH--N=CH-- (a-4),
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