- Toward aplyronine payloads for antibody-drug conjugates: Total synthesis of aplyronines A and D
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The aplyronines are a family of antimitotic marine macrolides that disrupt cytoskeletal dynamics by dual targeting of both actin and tubulin. Given their picomolar cytotoxicity profile and unprecedented mode of action, the aplyronines represent an excellent candidate as a novel payload for the development of next-generation antibody-drug conjugates (ADCs) for cancer chemotherapy. Enabled by an improved second-generation synthesis of the macrolactone core 5, we have achieved the first total synthesis of the most potent congener aplyronine D together with a highly stereocontrolled synthesis of aplyronine A. To facilitate step economy, an adventurous site-selective esterification of the C7 hydroxyl group was performed to install the N,N,O-trimethylserine pharmacophore to directly afford aplyronines A and D. Toward the assembly of ADCs incorporating an aplyronine warhead, the C29-ester derivative 4 featuring an Fmoc-amino substituted linker attached to the actin-binding tail region was also prepared by adapting this flexible endgame.
- An?i?ek, Nika,Williams, Simon,Housden, Michael P.,Paterson, Ian
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supporting information
p. 1343 - 1350
(2018/03/06)
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- Toward the total synthesis of patellazole B: Synthesis of an advanced C1-C25 fragment corresponding to the macrocyclic skeleton
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The patellazoles are a family of complex marine macrolides that exhibit potent cytotoxicity against cancer cell lines. However, despite extensive characterisation efforts, their full stereochemical assignment has remained elusive. We report our approach towards the synthesis-enabled structural elucidation of patellazole B (4), a 24-membered macrolide with 16 stereocentres and a signature thiazole-containing side chain. Our plan hinges upon isolating the unknown stereocentres into a single C20-C25 fragment to facilitate the flexible assembly of various possible diastereomers of an advanced C1-C25 fragment. Towards this end, a highly convergent and modular synthesis of one candidate diastereomer 37, corresponding to the patellazole B macrocyclic skeleton, has been achieved based on the strategic application of stereocontrolled aldol methodology, combined with Suzuki and Heck cross-coupling reactions.
- Phillips, Andrew W.,Anketell, Matthew J.,Balan, Tudor,Lam, Nelson Y. S.,Williams, Simon,Paterson, Ian
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supporting information
p. 6908 - 6913
(2018/10/02)
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- Preparation method of high-purity and high-yield monomethyl 3-methylglutarate
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The invention relates to a preparation method of high-purity and high-yield monomethyl 3-methylglutarate, and belongs to the field of organic synthesis. The preparation method comprises the followingsteps of (1) esterification reaction: performing esterification reaction on beta-methylglutaric acid and methyl alcohol to obtain beta-dimethyl methylglutarate; (2) alkaline hydrolysis reaction: adding a barium hydroxide methyl alcohol solution into the obtained beta-dimethyl methylglutarate to generate barium salt of the monomethyl 3-methylglutarate; (3) finished product preparation: performing hydrochloric acid acidification, diethyl ether extraction and rectification and purification on the barium salt of the monomethyl 3-methylglutarate to obtain the monomethyl 3-methylglutarate. The prepared monomethyl 3-methylglutarate has the advantages of high yield, high purity and high mono-esterification selectivity. The preparation method is scientific and reasonable; simplicity is realized; the implementation is easy; the method is suitable for industrial mass production.
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Paragraph 0032; 0043-0045; 0054; 0055; 0065; 0066
(2018/09/08)
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- Method for synthesizing muscone by utilizing beta-monomethyl methylglutarate
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The invention discloses a method for synthesizing muscone by utilizing beta-monomethyl methylglutarate. According to the method, beta-monomethyl methylglutarate and alpha,omega-dodecanedioic acid monomethyl ester respectively prepared through a heteropoly acid catalytic transesterification method are used as raw materials, and Kolbe electrolysis, acyloin condensation and reduction reaction are performed to prepare the muscone. The method of the present invention has advantages of high raw material utilization rate, mold condition, easy control and environmental protection, and is suitable for industrial production .
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Paragraph 0021; 0022
(2017/12/05)
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- Two potent OXE-R antagonists: Assignment of stereochemistry
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5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is formed by the oxidation of 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE), which is a major metabolite of enzymatic oxidation of arachidonic acid (AA). 5-Oxo-ETE is the most potent lipid chemoattractant for human eosinophils. Its actions are mediated by the selective OXE receptor, which is therefore an attractive target in eosinophilic diseases such as allergic rhinitis and asthma. Recently, we have reported two excellent OXE receptor antagonists that have IC50 values at low nanomolar concentrations. Each of these antagonists has a chiral center, and the isolation of the individual enantiomers by chiral high-performance liquid chromatography (HPLC) revealed that in each case one enantiomer is over 300 times more potent than the other. To unambiguously assign the stereochemistry of these enantiomers and to provide access to larger amounts of the active compounds for biological testing, we report here their total synthesis.
- Patel, Pranav,Reddy, Chintam Nagendra,Gore, Vivek,Chourey, Shishir,Ye, Qiuji,Ouedraogo, Yannick P.,Gravel, Sylvie,Powell, William S.,Rokach, Joshua
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supporting information
p. 815 - 819
(2014/08/05)
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- (4R,6R)-6-(hydroxymethyl)-4-methyltetrahydro-2H-pyran-2-one in the synthesis of polyfunctional compounds with the methyl-branched carbon skeleton
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A simple and efficient asymmetrical synthesis was performed of a convenient bifunctional building block, methyl (R)-5,5-dimethoxy-3-methylpentanoate and its (S)-enantiomer. The possibility was shown of its application to the synthesis of insect pheromones.
- Mineeva
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p. 253 - 258
(2013/07/25)
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- Design, synthesis, and antipicornavirus activity of 1-[5-(4-arylphenoxy) alkyl]-3-pyridin-4-ylimidazolidin-2-one derivatives
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A series of pyridylimidazolidinone derivatives was synthesized and tested in vitro against enterovirus 71 (EV71). On the basis of compound 33 (DBPR103), introduction of a methyl group at the 2- or 3-position of the linker between the imidazolidinone and the biphenyl resulted in markedly improved antiviral activity toward EV71 with IC50 values of 5.0 nM (24b) and 9.3 nM (14a), respectively. Increasing the branched chain to propyl resulted in a progressive decrease in activity, while inserting different heteroatoms entirely rendered the compound only weakly active. The introduction of a bulky group (cyclohexyl, phenyl, or benzyl) led to loss of activity against EV71. The 4-chlorophenyl moiety in 14a was replaced with bioisosteric groups such as oxadiazole (28a-d) or tetrazole (32a,b), dramatically improving anti-EV71 activity and selectivity indices. Compounds 14a, 24b, 28b, 28d, and 32a exhibited a strong activity against lethal EV71, and no apparent cellular toxicity was observed. Three of the more potent imidazolidinone compounds, 14a, 28b, and 32b, were subjected to a large group of picornaviruses to determine their spectrum of antiviral activity.
- Chang, Chih-Shiang,Lin, Ying-Ting,Shih, Shin-Ru,Lee, Chung-Chi,Lee, Yen-Chun,Tai, Chia-Liang,Tseng, Sung-Nien,Chern, Jyh-Haur
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p. 3522 - 3535
(2007/10/03)
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- Chemical compounds
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Compound of formula (I) wherein: A is a bicyclic heteroaryl, optionally substituted with one or more substituents; B is linker group connecting group A to group D and comprising a 3 or 4 atom linker where each atom is independently selected from carbon, oxygen, nitrogen and sulphur and is optionally subsituted with one or more C1-6alkyl groups or two of such adjacent alkyl substituents may form a ring; C is aryl or a mono or bicyclic heteroaryl, each of which can be optionally substituted; D is an aryl or heteroaryl, both of which are optionally substituted R1is hydrogen, C1-5alkyl, C1-3alkanoyl or C1-3alkoxycarbonyl; R2to R5are each independently selected from hydrogen, C1-6alkyl, aryl and heteroaryl containing up to 2 heteroatoms chosen from oxygen, sulphur and nitrogen, the aryl and heteroaryl optionally substituted with C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4alkoxy, C1-4alkanoyl, C1-6alkylamino, C1-4alkylC1-6alkyoxyl, C1-6alkylaminoC1-6alkyl, nitro, cyano, halogeno, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra, and —CONRaRb, where Raand Rbare independently selected from hydrogen and C1-6alkyl or two of R2to R5can be taken together to form a 3 to 7 membered ring; R6is an acidic functional group; r and s are each independently 0 or 1 with the proviso that r and s cannot both be 0; or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof.
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- Ozonolytic decyclization of (R)-4-menthen-3-one
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Ozonolytic decyclization of (R)-4-menthen-3-one is accompanied by fragmentation of the isobutyl group, leading to ω-functionalized 3-methylpentanoic acid derivatives.
- Kharisov,Gazetdinov,Botsman,Muslukhov,Ishmuratov,Tolstikov
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p. 1005 - 1008
(2007/10/03)
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- Bucky ligands: Synthesis, Ruthenium(II) complexes, and electrochemical properties
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The novel tridentate 2,2':6',2-terpyridine ligand (1) in which the metal-binding domain is directly attached to a methanofullerene C60 unit was incorporated into ruthenium-based diads and triads that may undergo photoinduced charge s
- Armspach, Dominique,Constable, Edwin C.,Diederich, Fran?ois,Housecroft, Catherine E.,Nierengarten, Jean-Fran?ois
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p. 723 - 733
(2007/10/03)
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- Regioselectivity in Photochemical Chlorocarbonylation of Carbonyl Compounds
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Photochemical chlorocarbonylation of a series of cyclic and acyclic carbonyl compounds shows remarkable regioselectivity and gives β- or γ-substituted products in reasonable yields.Irradiation of cyclopentanone in oxalyl chloride followed by esterification with methanol gave methyl 3-oxocyclopentanecarboxylate (4).Similarly, photochemical chlorocarbonylation of cyclobutanone yielded methyl 3-oxocyclobutanecarboxylate (6).Application of the chlorpcarbonylation reaction to 3-pentanone gave methyl 4-oxohexanoate (8) and dimethyl 4-oxopimelate (9).When a mixture of 3-methylbutanoic acid and oxalyl chloride was irradiated, dimethyl 3-methylglutarate (11) was obtained after methanolysis.A kinetically-controlled mechanism for the photochemical process was deduced.
- Bashir-Hashemi, A.,Hardee, J. R.
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p. 2132 - 2134
(2007/10/02)
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- 184. Stereoselective Hydrolysis of Substituted Cyclopropanedicarboxylates with Pig Liver Esterase
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The hydrolysis of the meso-cyclopropane-1,2-dicarboxylates 1a-3a, 4, 5a, 6a, and 9, containing various substituents at C(3), and of the rac-3-phenylcyclopropane-1,2-dicarboxylates 7a, 8a, and 10 with pig liver esterase (PLE) is described.The stereoselectivity and absolute configurations of the products were determined.An interpretation of results was attempted on the basis of a recent active-site model for PLE.
- Walser, Paula,Renold, Peter,N'Goka, Victor,Hosseinzadeh, Fatemeh,Tamm, Christoph
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p. 1941 - 1952
(2007/10/02)
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- Clay Montmorillonite: An Efficient Heterogeneous Catalyst for Michael Reactions of Silyl Ketene Acetals and Silyl Enol Ethers with α,β-Unsaturated Carbonyl Compounds
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The Michael addition of silyl ketene acetals to α,β-unsaturated esters (enoates) is investigated.The reaction is catalyzed by clay montmorillonite (solid acid) most effectively among various, homogeneous and heterogeneous acid promoters.The montmorillonite-catalyzed reaction has several prominent features: (1) Not only α- or β-monosubstituted acrylates but also α,β- or β,β-disubstituted acrylates are applicable. (2) The highly regioselective 1,4-addition to a polyenoate is achievable. (3) The michael adduct can be obtained in the form of a labile silyl ketene acetal owing to a simple work-up procedure.The Michael reaction of a silyl enol ether and silyl ketene acetals with α,β-unsaturated ketones (enones) is also described.
- Kawai, Motomitsu,Onaka, Makoto,Izumi, Yusuke
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p. 2157 - 2164
(2007/10/02)
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- SYNTHESES WITH SULFONES XLIX: STEREO- AND ENANTIOSELECTIVE SYNTHESIS OF (S)-(-)-3,9-DIMETHYL 6-(1-METHYLETHYL) (E)-5,8-DECADIEN 1-OL ACETATE, SEXUAL PHEROMONE OF YELLOW SCALE
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The stereo- and enantioselective synthesis of the yellow scale pheromone,(S)-(-)-3,9-dimethyl 6-(1-methylethyl) (E)-5,8-decadien 1-ol acetate, from 3-(R)-(+)-valerolactone 5 and benzene 8 is described.The key step is the in
- Alvarez, E.,Cuvigny, C.,Herve du Penhoat, C.,Julia, M.
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p. 119 - 126
(2007/10/02)
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- CONVENIENT SYNTHETIC ROUTE TO (+)-FARANAL AND (+)-13-NORFARANAL; THE TRAIL PHEROMONE OF PHARAOH'S ANT AND ITS CONGENER
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(+)-Faranal 1a, the trail pheromone of Pharaoh's ant, and its congener, (+)-13-norfaranal 1b were synthetized from chiral building block 4 employing diastereoselective carbon-carbon bond formation.The application of crude pig liver esterase enzyme for the
- Poppe, Laszlo,Novak, Lajos,Kolonits, Pal,Bata, Arpad,Szantay, Csaba
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p. 1477 - 1488
(2007/10/02)
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- SYNTHESIS OF 4-SUBSTITUTED GLUTARIMIDES BY FREE RADICAL ADDITION OF IODOACETAMIDE TO α,β-UNSATURATED ESTERS
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Free radical addition of either methyl bromoacetate or iodoacetamide to an α,β-unsaturated ester gave the 4-substituted glutarate or glutarimide respectively, whereas the radical cyclisation of N-bromoacetyl crotonamide gave the 2-substituted succinimide.
- Sacripante, Guerino,Tan, Charles,Just, George
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p. 5643 - 5646
(2007/10/02)
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