- An Olefin Cross-Metathesis Approach to Depudecin and Stereoisomeric Analogues
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A new total synthesis of the natural product (?)-depudecin, a unique and unexplored histone deacetylase (HDAC) inhibitor, is reported. A key feature of the synthesis is the utilization of an olefin cross-metathesis strategy, which provides for an efficient and improved access to natural depudecin, compared with our previous linear synthesis. Featured by its brevity and convergency, our developed synthetic strategy was applied to the preparation of the 10-epi derivative and the enantiomer of depudecin, which represent interesting stereoisomeric analogues for structure-activity relationship studies.
- Cheng-Sánchez, Iván,García-Ruiz, Cristina,Guerrero-Vásquez, Guillermo A.,Sarabia, Francisco
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- Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids
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Synthesis of 14S,21R- and 14S,21S-dihydroxy-DHA (diHDHA) among the four possible stereoisomers of 14,21-diHDHA was studied. Methyl (R)-lactate (>97% ee), selected as a C20-C22 fragment (DHA numbering), was converted to the C17-C22 phosphonium salt, which was subjected to a Wittig reaction with racemic C16-aldehyde of the C12-C16 part with the TMS and TBS-oxy groups at C12 and C14, yielding the C12-C22 derivative with 14R/S and 21R chirality. Kinetic resolution using Sharpless asymmetric epoxidation of the TBS-deprotected allylic alcohol with l-(+)-DIPT/Ti(O-i-Pr)4 afforded 14S-epoxy alcohol and 14R-allylic alcohol with >99% diastereomeric excess (de) for both. The CN group was introduced to the epoxy alcohol by reaction with Et2AlCN. The 14R-allylic alcohol was also converted to the nitrile via Mitsunobu inversion. Reduction of the nitrile with DIBAL afforded the key aldehyde corresponding to the C11-C22 moiety. The Wittig reaction of this aldehyde with a phosphonium salt of the remaining C1-C10 part followed by functional group manipulation gave 14S,21R-diHDHA. Similarly, ethyl (S)-lactate (>99% ee) was converted to 14S,21S-diHDHA. The chiral LC-UV-MS/MS analysis demonstrated that each of these two 14,21-diHDHAs synthesized using the presented total organic synthesis was highly stereoselective and identical to the macrophage-produced counterpart.
- Nishimura, Keita,Sakaguchi, Tsuyoshi,Nanba, Yutaro,Suganuma, Yuta,Morita, Masao,Hong, Song,Lu, Yan,Jun, Bokkyoo,Bazan, Nicolas G.,Arita, Makoto,Kobayashi, Yuichi
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- Ambruticins: tetrahydropyran ring formation and total synthesis
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The ambruticins are a family of polyketide natural products which exhibit potent antifungal activity. Gene knockout experiments are in accord with the proposal that the tetrahydropyran ring of the ambruticins is formedviathe AmbJ catalysed epoxidation of the unsaturated 3,5-dihydroxy acid, ambruticin J, followed by regioselective cyclisation to ambruticin F. Herein, a convergent approach to the total synthesis of ambruticin J is described as well as model studies involving epoxidation and cyclisations of unsaturated hydroxy esters to give tetrahydropyrans and tetrahydrofurans. The total synthesis involves preparation of three key fragments which were unitedviaa Suzuki-Miyaura cross-coupling and Julia-Kocienski olefination to generate the required carbon framework. Global deprotection to a triol and selective oxidation of the primary alcohol gave, after hydrolysis of the lactone, ambruticin J.
- Bowen, James I.,Crump, Matthew P.,Wang, Luoyi,Willis, Christine L.
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supporting information
p. 6210 - 6215
(2021/07/28)
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- MEAYAMYCIN ANALOGUES AND METHODS OF USE
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Compounds according to formula (I), where R is as defined herein, have anti-cancer properties.
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Page/Page column 8; 24
(2021/10/15)
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- Total Synthesis of Meayamycin and O-Acyl Analogues
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A short, scalable total synthesis of meayamycin is described by an approach that entails a longest linear sequence of 12 steps (22 steps overall) from commercially available chiral pool materials (ethyl l-lactate, BocNH-Thr-OH, and d-ribose) and introduces the most straightforward preparation of the right-hand subunit detailed to date. The use of the approach in the divergent synthesis of a representative series of O-acyl analogues is exemplified.
- Boger, Dale L.,Chanda, Prem B.,Chowdari, Naidu S.,Gangwar, Sanjeev,Gartshore, Christopher,Momirov, Jelena,Sarkar, Anindya,Tadano, Shinji,Vite, Gregory D.,Zhang, Qian
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supporting information
(2020/11/18)
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- Antifungal water-soluble compound as well as preparation method and application thereof (by machine translation)
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The invention provides an antifungal water-soluble compound, a preparation method thereof and application, of the compound as I shown in formula. The compound has good antifungal effect and water solubility, can be used for treating and preventing,configuration optical isomers of the optical isomer SRSS obtained by chiral synthesis. (by machine translation)
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Paragraph 0095; 0098-0099
(2020/06/02)
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- An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: Generality, applications and mechanistic investigations
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The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.
- Richmond, Edward,Ling, Kenneth B.,Duguet, Nicolas,Manton, Lois B.,elebi-?lcüm, Nihan,Lam, Yu-Hong,Alsancak, Sezen,Slawin, Alexandra M. Z.,Houk,Smith, Andrew D.
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supporting information
p. 1807 - 1817
(2015/02/19)
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- A short and facile stereoselective total synthesis of cryptocarya diacetate
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A short, simple, and efficient stereoselective total synthesis of cryptocarya diacetate using benzylidene acetal as a key intermediate is described. The synthesis proceeded with overall yield of 10 % starting from commercially available (S)-ethyl lactate.
- Yadav, Jhillu S.,Reddy, P. Murali Krishna,Gupta, Manoj K.,Reddy, Basi V. Subba
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p. 1583 - 1587
(2013/10/22)
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- First stereoselective total synthesis of isoaspinonene through a Baylis-Hillman/olefin cross-metathesis protocol
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The first stereoselective and efficient total synthesis of isoaspinonene by using Baylis-Hillman reaction, chelation-controlled vinyl Grignard reaction, Wittig olefination, and olefin cross-metathesis reaction of a hitherto unreported substrate as the key
- Radha Krishna, Palakodety,Alivelu, Munagala,Prabhakar Rao, Tadikamalla
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scheme or table
p. 616 - 622
(2012/03/10)
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- Synthetic access to optically active isoflavans by using allylic substitution
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A general approach to the (S)- and (R)-isoflavans was invented, and efficiency of the method was demonstrated by the synthesis of (S)-equol ((S)-3), (R)-sativan ((R)-4), and (R)-vestitol ((R)-5). The key step is the allylic substitution of (S)-6a (Ar1=2,4-(MeO)2C6H3) and (R)-6b (Ar1=2,4-(BnO)2C6H3) with copper reagents derived from CuBr·Me2S and Ar2-MgBr (7a, Ar2=4-MeOC6H4; 7b, 2,4-(MeO)2C6H3; 7c, 2-MOMO-4-MeOC6H3), furnishing anti SN2′ products (R)-8a and (S)-8b,c with 93-97% chirality transfer in 60-75% yields. The olefinic part of the products was oxidatively cleaved and the Me and Bn groups on the Ar1 moieties was then removed. Finally, phenol bromide 9a and phenol alcohols 9b,c underwent cyclization with K2CO3 and the Mitsunobu reagent to afford (S)-3 and (R)-4 and -5, respectively.
- Takashima, Yuji,Kaneko, Yuki,Kobayashi, Yuichi
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experimental part
p. 197 - 207
(2010/03/03)
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- Asymmetric total synthesis of pyranicin
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The asymmetric total synthesis of pyranicin (1) is reported. The butenolide ring was constructed via an asymmetric alkylation/ring-closing metathesis strategy. The three stereocenters in the left-hand tetrahydropyran ring were installed by sequential chir
- Crimmins, Michael T.,Jacobs, Danielle L.
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supporting information; experimental part
p. 2695 - 2698
(2009/10/10)
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- New general method for regio- and stereoselective allylic substitution with aryl and alkenyl coppers derived from grignard reagents
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Allylic substitution with sp2-carbon reagents (aryl and alkenyl anions) was realized by using allylic picolinates and copper reagents derived from RMgBr and CuBr-Me2S to afford anti SN2 products regioand stereoselectively. Steric and electronic factors in the reagents and the size of the methylene substituents around the allylic moiety marginally affected the selectivity. The reaction system was compatible with alkyl reagents as well. Furthermore, the substitution was applied to construction of a quaternary center and synthesis of (-)-sesquichamaenol. Electron-withdrawing nature of the pyridyl group and chelation of the C(=O)-C5H4N to MgBr2 generated in situ were found to be responsible for the high efficiency of the substitution.
- Kiyotsuka, Yohei,Katayama, Yuji,Acharya, Hukuni P.,Hyodo, Tomonori,Kobayashi, Yuichi
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supporting information; experimental part
p. 1939 - 1951
(2009/08/07)
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- Synthesis of C13-C23 fragment of Iriomoteolide-1a
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Highly efficient asymmetric conjugate addition of MeMgBr to α,β-unsaturated esters catalyzed by CuI/To1-BINAP, Paterson aldol, organocatalytic aldol, and cross-metathesis reactions were applied in the synthesis of C13-C23 fragment of Iriomoteolide-la.
- Wang, Shun-Yi,Chin, Yen-Jin,Loh, Teck-Peng
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experimental part
p. 3557 - 3564
(2010/03/03)
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- The effects of sulfur substitution for the nucleophile and bridging oxygen atoms in reactions of hydroxyalkyl phosphate esters
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(Graph Presented) The effects of sulfur substitution on the reactions of hydroxyalkyl phosphate esters are examined. These compounds are models for the intramolecular phosphoryl transfer reaction involved in the cleavage of the internucleotide bond in RNA. The models studied here lack the ribose ring and their conformational flexibility results in greater stability and the availability of different reaction pathways. Sulfur in the nucleophilic position shows no nucleophilic reaction at phosphorus, instead rapidly attacking at the beta carbon atom, forming thiirane with departure of a phosphomonoester. Sulfur substitution at either of the two bridging positions leads to cleavage of the diester via formation of a cyclic intermediate, but with significant rate acceleration when compared to the oxygen analogues. The bridge-substituted models react substantially slower than the analogous ribose compounds with sulfur substitution at comparable positions. Kinetic isotope effects reveal significant differences in the transition state depending on which bridging position sulfur occupies. When sulfur is in the scissile bridging position, a highly associative transition state is indicated, with a largely formed bond to the nucleophile and the scissile P-S bond is little changed. When sulfur occupies the other bridging position, the isotope effects imply a very early transition state in a concerted reaction.
- Iyer, Subashree,Hengge, Alvan C.
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p. 4819 - 4829
(2008/12/20)
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- New synthetic route to (S)-(-)-equol through allylic substitution
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Allylic substitution of allylic picolinate 5 with a copper reagent derived from p-MeOC6H4MgBr (6) and CuBr·Me2S produced the anti SN2′ product 7 with high regioselectivity and efficient chirality transfer. Oxidative cleavage of the olefinic function to the alcohol followed by bromination afforded bromide 16, which upon demethylation and intramolecular ether ring formation furnished (S)-(-)-equol (3).
- Takashima, Yuji,Kobayashi, Yuichi
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p. 5156 - 5158
(2008/12/20)
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- Altered transition state for the reaction of an RNA model catalyzed by adinuclear zinc(II) catalyst
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The cyclization of 2-(hydroxypropyl)-4-nitrophenyl phosphate (HpPNP) catalyzed by the dinuclear zinc complex of 1,3-bis(1,4,7-triazacyclonon-1-yl)-2- hydroxypropane (1) proceeds by a transition state that is different from that of the uncatalyzed reaction. Kinetic isotope effects (KIEs) measured in the nucleophilic atom and in the leaving group show that theuncatalyzed cyclization has a transition state (TS) with little phospho rus-oxygen bond fission to the leaving group 18klg= 1.0064 ± 0.0009 and 15k = 1.0002 ± 0.0002) a nd that nucleophilic bond formation occurs in the rate-determining step (18knuc ) 1.0326 ( 0.0008). In the catalyzed reaction, larger leaving group isotope effects ( 18klg ) 1.0113 ± 0.0005 and 15k = 1.0015 ± 0.0005) and a smaller nucleophile isotope effect (18k nuc = 1.0116 ± 0.0010) indicate a later TS with greater leaving group bond fission and greater nucleophilic bond formation. These observed nucleophile KIEs are the combined effect of the equilibrium effect on deprotonation of the 2′-hydroxyl nucleophile and the KIE on the nucleophilic step. An EIE of 1.0245 for deprotonation of the hydroxyl group of HPpNP was obtained computationally. The different KIEs for the two reactions indicate that the effective catalysis by 1 is accompanied by selection for an altered transition state, presumably arising from the preferential stabilization by the catalyst of charge away from the nucleophile and toward the leaving group. These results demonstrate the potential fora catalyst using biologically relevant metal ions to select for an alte red transition state for phosphoryl transfer.
- Morrow, Janet R.,Richard, John P.,et al.,Humphry, Tim,Iyer, Subashree,Iranzo, Olga
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experimental part
p. 17858 - 17866
(2009/08/08)
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- A concise asymmetric route to the antibiotic macrolides patulolide A and pyrenophorin
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In this letter, we describe an enantiospecific route to patulolide A and pyrenophorin through the synthesis of known protected seco acid precursors starting from commercially available (S)-ethyl lactate.
- Rao, K. Srinivasa,Reddy, D. Srinivasa,Mukkanti,Pal, Manojit,Iqbal, Javed
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p. 6623 - 6626
(2007/10/03)
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- Synthesis of 7-oxa-phomopsolide e and its C-4 epimer
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A flexible, enantioselective route to highly functionalized α,β-unsaturated δ-lactones has been applied to the synthesis of 7-oxa-phomopsolide E and its C-4 epimer. This approach relies on the application of the Noyori asymmetric hydrogenation of furyl ke
- Li, Miaosheng,Scott, Jana,O'Doherty, George A.
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p. 1005 - 1009
(2007/10/03)
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- Enantioselective synthesis of the carbocyclic moiety of (-)-carbovir
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Enantioselective construction of the protected carbocycle moiety of the anti-HIV drug carbovir was achieved in 11 steps from (S)-(-)-ethyl lactate. The two key steps are a Claisen [3+3] sigmatropic rearrangement of (3S,4E)-3-(4-methoxy-phenoxymethyl)-hex-
- Roulland, Emmanuel,Monneret, Claude,Florent, Jean-Claude
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p. 4125 - 4128
(2007/10/03)
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- An enantioselective total synthesis of phomopsolide C
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A flexible enantioselective route to highly functionalized α,β-unsaturated δ-lactones, has allowed for the synthesis of phomopsolide C. This approach derives its asymmetry from (S)-lactic acid and by applying the Sharpless catalytic asymmetric dihydroxylation to vinylfuran. The resulting diols are produced in high enantioexcess and can be stereoselectively transformed into α,β-unsaturated-δ-lactones via a short highly diastereoselective oxidation and reduction sequence. A Wittig olefination reaction was used to introduce the side chain in either cis or trans form that was further elaborated into phomopsolide C.
- Harris, Joel M.,O'Doherty, George A.
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p. 8195 - 8199
(2007/10/03)
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- Synthesis of (7S,15S)- and (7R,15S)-dolatrienoic acid
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The stereospecific synthesis of (7S,15S)- and (7R,15S)-dolatrienoic acids (2) was achieved using an approach consisting of 16 linear steps. The C-11-C-16 unit was prepared in seven steps from ethyl (S)lactate and coupled using a trans-selective Wittig - Schlosser reaction to the C-7-C-10 fragment. Chirality at the C-7 position was introduced using an Evan's-type chiral auxiliary in a cobalt-mediated Reformatsky reaction to give the (3S,11S)-aldehyde 24. Subsequent Wittig reaction with a phosphonium salt derived in three steps from tiglic acid gave (7S,15S)-dolatrienoic acid, one of the four possible diastereoisomers of the nonpeptide portion of the strong Cancer cell growth inhibitory cyclodepsipeptide dolastatin 14 (1). A second diastereoisomer, (7R,15S)-dolatrienoic acid, was synthesized employing chiral oxazolidinone 21 by an analogous synthetic route.
- Duffield, Jonathan J.,Pettit, George R.
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p. 472 - 479
(2007/10/03)
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- Studies directed towards the total synthesis of the antibiotic macrodiolide tartrolon: EPC synthesis of the protected seco acid
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An efficient synthesis of the protected seco acid 2 of the antibiotic macrodiolide tartrolon 1 is described. Key steps are a substrate controlled aldol-reaction, a Johnson-Claisen rearrangement, and a Horner-Wadsworth-Emmons olefination with subsequent Co
- Mulzer, Johann,Berger, Markus
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p. 803 - 806
(2007/10/03)
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- A 1,2-O-O-SILYL-MIGRATION-CLAISEN-REARRANGEMENT-SN2'-DISPLACEMENT SEQUENCE IN THE STEREOSELECTIVE SYNTHESIS OF 5-OXAPROSTANOID DERIVATIVES
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A novel stereocontrolled route to 5-oxaprostaglandin and PGF intermediates is described, which starts from the ene-diols (6/7) and uses a sequence of Claisen rearrangement, 1,2-O-O-silyl migration and SN2'-cyclization reactions (9b10a/b via
- Mulzer, Johann,Greifenberg, Stefan
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- Stereocontrolled preparation of tetrahydrofurans from acid-promoted rearrangements of allylic acetals
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A new method for constructing substituted tetrahydrofurans from readily available allylic did and carbonyl components is reported (eq 1). This synthesis is highly stereocontrolled and allows carbon side chains to be incorporated at each carbon. Enantiomer
- Hopkins, Mark H.,Overman, Larry E.,Rishton, Gilbert M.
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p. 5354 - 5365
(2007/10/02)
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- De novo synthesis of carbohydrates by stereoselective aldol reaction: L-cladinose.
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Aldol reactions of methyl 2-methoxypropanoate (4), the corresponding ester of 2-methoxypropanoic acid with 4-methyl-2,6-di-(tert-butyl)phenol (13), and silylketene acetals 14 and 15 with (S)-2-(phenyl-methoxy)propanal (17) have been investigated. The lith
- Montgomery,Pirrung,Heathcock
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- Asymmetric α-Amino Acid Synthesis: Synthesis of (+)-Polyoxamic Acid using a Allylic Trifluoroacetimidate Rearrangement
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The stereoselective rearrangement of allylic trifluoroacetimidate (15) has been used in a synthesis of (+)-polyoxamic acid (1).
- Savage, Ian,Thomas, Eric J.
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p. 717 - 719
(2007/10/02)
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- STEREOSELECTIVE CONDENSATION OF BIS-p-TOLYLTHIOMETHANE WITH LACTIC ACID DERIVATIVES THROUGH AN ACYLATION-REDUCTION STRATEGY: SYNTHESIS OF PROTECTED 4-DEOXY-L-THREOSE AND 4-DEOXY-L-ERYTHROSE
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The condensation of lithium bis-p-tolylthiomethanide with protected ethyl-L-lactates gave a series of 3-alkoxy- (or 3-hydroxy-) 1,1-bis-p-tolylthiobutan-2-ones, which were stereoselectively reduced to the corresponding syn- or anti-alcohols with diastereo
- Guanti, Giuseppe,Banfi, Luca,Guaragna, Alberto,Narisano, Enrica
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p. 2369 - 2376
(2007/10/02)
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