- Iridium-catalyzed diborylation of benzylic C-H bonds directed by a hydrosilyl group: Synthesis of 1,1-benzyldiboronate esters
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We describe a regioselective diborylation of primary benzylic C-H bonds catalyzed by [Ir(COD)OMe]2 and 4,4′-di-tert-butyl-2,2′- bipyridine (dtbpy). The hydrosilyl group acts as a traceless directing group, providing access to a range of 1,1-benzyldiboronate esters in good yields. Transformations of the 1,1-benzyldiboronate ester products include chemoselective Suzuki-Miyaura cross-couplings and synthesis of tetrasubstituted alkenyl boronate esters.
- Cho, Seung Hwan,Hartwig, John F.
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- Regioselective Metallation of Propylbenzene with Superbase: A Convenient Route to Stilbene Derivatives
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The benzylic metallation of propylbenzene has been elaborated with LIC-KOR superbase; the method has been applied in a new synthesis of stilbene derivatives.
- Thurner, Angelika,Agai, Bela,Faigl, Ferenc
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- Opportune gem-Silylborylation of Carbonyl Compounds: A Modular and Stereocontrolled Entry to Tetrasubstituted Olefins
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An easy access to highly versatile gem-silylboronate synthons is achieved by means of a new olefination reagent, HC(Bpin)2(SiMe3). Subsequent silicon or boron-based selective functionalization allows for the modular and stereocontrolled synthesis of all-carbon tetrasubstituted alkenes. A particular attraction of this approach is the iododesilylation reaction, which becomes a pivotal tool for C?Si functionalization.
- La Cascia, Enrico,Cuenca, Ana B.,Fernández, Elena
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- An atom efficient synthesis of tamoxifen
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The direct carbolithiation of diphenylacetylenes and their cross-coupling procedure taking advantage of the intermediate alkenyllithium reagents are presented. By employing our recently discovered highly active palladium nanoparticle based catalyst, we were able to couple an alkenyllithium reagent with a high (Z/E) selectivity (10:1) and good yield to give the breast cancer drug tamoxifen in just 2 steps from commercially available starting materials and with excellent atom economy and reaction mass efficiency.
- Heijnen, Dorus,Van Zuijlen, Milan,Tosi, Filippo,Feringa, Ben L.
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- Stereospecific Synthesis of (Z)-Tamoxifen via Carbometalation of Alkynylsilanes
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A sterospecific synthesis of (Z)-tamoxifen, a tetrasubstituted alkene with antiestrogenic activity, is described.The key reaction that establishes the olefin stereochemistry is a carbometalation of phenyl(trimethylsilyl)acetylene with diethylaluminum chloride-titanocene dichloride.A key intermediate that would lead to (E)-tamoxifen was also prepared in an analogous stereospecific manner.
- Miller, R. Bryan,Al-Hassan, Mohammed I.
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- Stereoselective synthesis of trisubstituted alkenylboranes by palladium-catalysed reaction of alkynyltriarylborates with aryl halides
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The palladium-catalysed reaction of alkynyltriarylborates with aryl halides afforded trisubstituted alkenylboranes, in which two different aryl groups were installed across the carbon-carbon double bond in a cis arrangement. The Royal Society of Chemistry.
- Ishida, Naoki,Miura, Tomoya,Murakami, Masahiro
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- Rh-Catalyzed Coupling of Aldehydes with Allylboronates Enables Facile Access to Ketones
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We present herein a novel strategy for the preparation of ketones from aldehydes and allylic boronic esters. This reaction involves the allylation of aldehydes with allylic boronic esters and the Rh-catalyzed chain-walking of homoallylic alcohols. The key to this successful development is the protodeboronation of alkenyl borylether intermediate via a tetravalent borate anion species in the presence of KHF2 and MeOH. This approach features mild reaction conditions, broad substrate scope, and excellent functional group tolerance. Mechanistic studies also supported that the tandem allylation and chain-walking process were involved.
- Zhang, Kezhuo,Huang, Jiaxin,Zhao, Wanxiang
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supporting information
(2022/02/21)
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- Stereoconvergent and -divergent synthesis of tetrasubstituted alkenes by nickel-catalyzed cross-couplings
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We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura cross-couplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the kraken library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 Z/E and 93:7 E/Z observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the cross-coupling.
- Zell, Daniel,Kingston, Cian,Jermaks, Janis,Smith, Sleight R.,Seeger, Natalie,Wassmer, Jana,Sirois, Lauren E.,Han, Chong,Zhang, Haiming,Sigman, Matthew S.,Gosselin, Francis
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supporting information
p. 19078 - 19090
(2021/11/22)
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- NOVEL TRIBORYLALKENE, PRODUCTION METHOD THEREOF, AND PRODUCTION METHOD OF MULTISUBSTITUTED ALKENE
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PROBLEM TO BE SOLVED: To provide a compound as a synthetic intermediate for a tetraarylalkene useful as medicaments and electronic materials. SOLUTION: The invention provides a triborylalkene represented by the general formula (I) in the figure, where Ra represents an optionally substituted aryl group. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
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- Pd-catalyzed cross-coupling of highly sterically congested enol carbamates with grignard reagents via c-o bond activation
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The palladium-catalyzed cross-coupling reaction of enol carbamates to construct highly sterically congested alkenyl compounds is presented for the first time. This protocol demonstrates the potential of using thermally stable and highly atom-economic enol electrophiles as building blocks in bulky alkene synthesis. This reaction accommodates a broad substrate scope with excellent Z/E isomer ratios, which also provides a new synthetic pathway for accessing Tamoxifen.
- Chen, Zicong,So, Chau Ming
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p. 3879 - 3883
(2020/06/08)
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- Divergent Synthetic Access to E- and Z-Stereodefined All-Carbon-Substituted Olefin Scaffolds: Application to Parallel Synthesis of (E)- and (Z)-Tamoxifens
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A highly substrate-general synthesis of all-carbon-substituted E- and Z-stereodefined olefins is performed. The method comprises two sets of parallel and stereocomplementary preparations of (E)- and (Z)-α,β-unsaturated esters involving two robust and distinctive reactions: 1) stereocomplementary enol tosylations using readily available TsCl/diamine/(LiCl) base reagents, and 2) stereoretentive Negishi cross-coupling using the catalysts [Pd(dppe)Cl2] (for E) and [Pd(dppb)Cl2] (for Z). The present parallel approach is categorized as both type I (convergent approach: 16 examples, 56–87 % yield) and type II (divergent approach: 18 examples, 70–95 % yield). The obtained (E)- and (Z)-α,β-unsaturated ester scaffolds are successfully transformed into various E- and Z-stereodefined known and novel olefins (8×2 derivatization arrays). As a demonstration, application to the parallel synthesis of both (E)- and (Z)-tamoxifens, a representative motif of all-carbon-substituted olefins, is accomplished in a total of eight steps with an overall yield of 58 % (average 93 %) and 57 % (average 93 %), respectively.
- Ashida, Yuichiro,Honda, Atsushi,Sato, Yuka,Nakatsuji, Hidefumi,Tanabe, Yoo
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- Photoredox-Catalyzed C-H Arylation of Internal Alkenes to Tetrasubstituted Alkenes: Synthesis of Tamoxifen
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Visible-light-induced direct C-H arylation of S,S-functionalized internal alkenes, that is, α-oxo ketene dithioacetals and analogues, has been efficiently realized with aryldiazonium salts (ArN2BF4) as coupling partners and Ru(bpy)s
- Wang, Quannan,Yang, Xiaoge,Wu, Ping,Yu, Zhengkun
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supporting information
p. 6248 - 6251
(2017/11/24)
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- Synthesis of Highly Stereodefined Tetrasubstituted Acyclic All-Carbon Olefins via a Syn-Elimination Approach
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An efficient synthesis of stereodefined tetrasubstituted acyclic all-carbon olefins has been developed via a bis(2,6-xylyl)phosphate formation of stereoenriched tertiary alcohols, followed by in situ syn-elimination of the corresponding phosphates under mild conditions. This chemistry tolerates a wide variety of electronically and sterically diverse substrates and generates the desired tetrasubstituted olefins in high yields and stereoselectivities (>95:5) in most cases. This stereocontrolled olefin synthesis has been applied to the synthesis of anticancer drug tamoxifen in three steps from commercially available 1,2-diphenylbutan-1-one in 97:3 stereoselectivity and 78% overall yield.
- Lim, Ngiap-Kie,Weiss, Patrick,Li, Beryl X.,McCulley, Christina H.,Hare, Stephanie R.,Bensema, Bronwyn L.,Palazzo, Teresa A.,Tantillo, Dean J.,Zhang, Haiming,Gosselin, Francis
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p. 6212 - 6215
(2017/11/24)
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- Photochemical Activation of Tertiary Amines for Applications in Studying Cell Physiology
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Representative tertiary amines were linked to the 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group (PPG) to create photoactivatable forms suitable for use in studying cell physiology. The photoactivation of tamoxifen and 4-hydroxytamoxifen, which can be used to activate Cre recombinase and CRISPR-Cas9 gene editing, demonstrated that highly efficient release of bioactive molecules could be achieved through one- and two-photon excitation (1PE and 2PE). CyHQ-protected anilines underwent a photoaza-Claisen rearrangement instead of releasing amines. Time-resolved spectroscopic studies revealed that photorelease of the tertiary amines was extremely fast, occurring from a singlet excited state of CyHQ on the 70 ps time scale.
- Asad, Naeem,Deodato, Davide,Lan, Xin,Widegren, Magnus B.,Phillips, David Lee,Du, Lili,Dore, Timothy M.
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supporting information
p. 12591 - 12600
(2017/09/23)
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- Pd(OAc)2-Catalyzed Desulfinative Cross-Coupling of Sodium Sulfinates with β-Bromostyrenes: Synthesis of Tamoxifen
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A Pd(OAc)2-catalyzed desulfinative cross-coupling of (Z)-β-halostyrenes with sodium sulfinates in the presence of PPh3 and Na2CO3 at reflux in good yields is reported. The stereocontrolled cross-coupling process provides a series of sulfonylmethyl (Z)-stilbenes. A synthesis of tamoxifen was studied.
- Chang, Meng-Yang,Cheng, Yu- Chieh,Sun, Pei- Pei
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p. 2411 - 2422
(2017/05/22)
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- Aluminum Chloride Promoted Cross-Coupling of Trisubstituted Enol Phosphates with Organozinc Reagents En Route to the Stereoselective Synthesis of Tamoxifen and Its Analogues
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A new method for the stereoselective cross-coupling reaction of arylzinc chlorides with trisubstituted enol phosphates is described. The developed method requires aluminum chloride as a promoter, and the reaction conditions tolerate various functional groups. The observed reactivity pattern of trisubstituted enol phosphates was used for the stereoselective preparation of tamoxifen and its analogues.
- Kotek, Vladislav,Polák, Peter,Dvo?áková, Hana,Tobrman, Tomá?
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p. 5037 - 5044
(2016/10/26)
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- Nickel-Catalyzed Regioselective Cleavage of Csp2-S Bonds: Method for the Synthesis of Tri- and Tetrasubstituted Alkenes
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We describe here an efficient route for the synthesis of (Z)-vinylic sulfides 3 via the highly regio- and stereoselective coupling of (Z)-1,2-bis(aryl(alkyl)thio)alkenes and Grignard reagents over a Ni catalyst under mild conditions. (Z)-Vinylic sulfides 3 are important intermediates in the synthesis of tri- and tetrasubstituted alkenes that are important construction blocks for drugs and natural products. The directing organosulfur groups (SR) can be converted to diaryl(alkyl) disulfides (RSSR) using H2O2 as oxidant, hence avoiding the waste of sulfur resources. The protocol provides a general method that is highly regio- and stereoselective for the synthesis of a diversity of tri- and tetrasubstituted alkenes.
- Chen, Jinyang,Chen, Sihai,Xu, Xinhua,Tang, Zhi,Au, Chak-Tong,Qiu, Renhua
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p. 3246 - 3255
(2016/05/19)
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- SnCl4-Zn: A novel reductive system for deoxygenative coupling of aliphatic, aromatic, chalcone epoxide, and indanone carbonyl compounds to olefins
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SnCl4-Zn complex provided a novel reductive system in the deoxygenative cross-coupling of aliphatic, aromatic, chalcone epoxide and indanone carbonyl compounds to olefins in high yield (55-86%) at reflux temperature in THF. The advantage of this reagent is inexpensive, short reaction time, and high yield compared to the reagents used in the McMurry cross-coupling reaction.
- Pathe, Gulab Khushalrao,Ahmed, Naseem
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supporting information
p. 1555 - 1561
(2015/03/14)
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- PROCESS FOR CREATING CARBON-CARBON BONDS USING CARBONYL COMPOUNDS
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The present invention concerns a process for preparing a compound of formula (I) by reaction between a compound of formula (II) and a compound of formula (III) in the presence of a copper-containing catalyst, a ligand and base. The invention also concerns the implementing of this process for the preparation of building blocks to prepare molecules of interest in particular in the pharmaceutical, agro-chemical fields, etc.
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Paragraph 0434-0440
(2015/06/24)
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- Transition-Metal-Free α-Arylation of Enolizable Aryl Ketones and Mechanistic Evidence for a Radical Process
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The α-arylation of enolizable aryl ketones can be carried out with aryl halides under transition-metal-free conditions using KOtBu in DMF. The α-aryl ketones thus obtained can be used for step- and cost-economic syntheses of fused heterocycles and Tamoxifen. Mechanistic studies demonstrate the synergetic role of base and solvent for the initiation of the radical process.
- Pichette Drapeau, Martin,Fabre, Indira,Grimaud, Laurence,Ciofini, Ilaria,Ollevier, Thierry,Taillefer, Marc
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p. 10587 - 10591
(2015/09/02)
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- Nickel-catalyzed three-component domino reactions of aryl grignard reagents, alkynes, and aryl halides producing tetrasubstituted alkenes
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Three-component reaction of aryl Grignard reagents, alkynes, and aryl halides in the presence of 1 mol % of NiCl2 proceeded sequentially through carbomagnesiation of the alkyne followed by cross-coupling of the resulting alkenyl Grignard reagent with aryl halide to give tetrasubstituted alkenes in high yields.
- Xue, Fei,Zhao, Jin,Hor, T. S. Andy,Hayashi, Tamio
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supporting information
p. 3189 - 3192
(2015/03/30)
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- Efficient synthesis of polysubstituted olefins using stable palladium nanocatalyst: Applications in synthesis of tamoxifen and isocombretastatin A4
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A phosphine-free stable palladium nanocatalyst was used for an efficient synthesis of polysubstituted olefins from N-tosylhydrazones and aryl iodides. This methodology was successfully utilized in the synthesis of biologically important tamoxifen and isocombretastatin A4. The nanocatalyst was easily recovered and reused without any apparent loss in size and catalytic activity.
- Ganapathy, Dhandapani,Sekar, Govindasamy
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supporting information
p. 3856 - 3859
(2014/08/18)
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- Stereoselective synthesis of triarylethylenes via copper-palladium catalyzed decarboxylative cross-coupling: Synthesis of (Z)-tamoxifen
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The first Cu/Pd-catalyzed decarboxylative cross-coupling of 3,3-diarylacrylic acids with aryl bromides is described. Triarylethylenes were obtained in high yields with excellent stereoselectivities. This methodology was successfully applied to the stereos
- Cahiez, Gérard,Moyeux, Alban,Poizat, Ma?l
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p. 8982 - 8984
(2014/08/05)
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- Copper-catalyzed cross-coupling of boronic esters with aryl iodides and application to the carboboration of alkynes and allenes
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Copper-catalyzed Suzuki-Miyaura-type cross-coupling and carboboration processes are reported. The cross-couplings function well with a variety of substituted aryl iodides and aryl boronic esters and allows for orthogonal reactivity compared to palladium-catalyzed processes. The carboboration method includes both alkynes and allenes and provides access to highly substituted and stereodefined vinyl boronic esters. The alkyne carboboration method is highlighted in the simple one-pot synthesis of Tamoxifen. Cross-Cu-pling: The title cross-couplings function well with a variety of substituted aryl iodides and aryl boronic esters and allows for reactivity orthogonal to that of the palladium-catalyzed processes. The title carboboration method includes both alkynes and allenes and provides access to highly substituted and stereodefined vinyl boronic esters. The alkyne carboboration method is highlighted in a simple one-pot synthesis of Tamoxifen.
- Zhou, Yiqing,You, Wei,Smith, Kevin B.,Brown, M. Kevin
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supporting information
p. 3475 - 3479
(2014/04/03)
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- Continuous flow-processing of organometallic reagents using an advanced peristaltic pumping system and the telescoped flow synthesis of (E/Z)-tamoxifen
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A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal-halogen exchange, addition, addition-elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.
- Murray, Philip R. D.,Browne, Duncan L.,Pastre, Julio C.,Butters, Chris,Guthrie, Duncan,Ley, Steven V.
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p. 1192 - 1208
(2013/10/08)
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- Copper-catalyzed three-component borylstannylation of alkynes
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Regio- and stereoselective installation of boryl and stannyl moieties into a carbon-carbon triple bond of various alkynes has been achieved based on a three-component coupling reaction by using a diboron and a tin alkoxide with the aid of a copper(II) acetate-tricyclohexylphosphine complex, giving diverse vic-borylstannylalkenes in a straightforward manner. Carbon-tin and carbon-boron bonds of the resulting borylstannylation product are successively transformed into carbon-carbon bonds by a Migita-Kosugi-Stille and a Suzuki-Miyaura coupling, leading to the formation of (Z)-tamoxifen with anti-breast cancer activity. Borylstannylation: A copper-tricyclohexylphosphine complex was found to catalyse the three-component borylstannylation of alkynes with a diboron and a tin alkoxide to afford vic-borylstannylalkenes in a regio- and stereoselective manner. Synthetic utility of the resulting borylstannylation product was demonstrated by a three-step synthesis of (Z)-tamoxifen from commercially available substrates by successive Migita-Kosugi-Stille and Suzuki-Miyaura couplings (see scheme). Copyright
- Takemoto, Yuki,Yoshida, Hiroto,Takaki, Ken
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p. 14841 - 14844
(2013/01/15)
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- Direct copper-catalyzed α-arylation of benzyl phenyl ketones with aryl iodides: Route towards tamoxifen
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No activation needed: The first efficient method for direct α-arylation of non-activated or non-protected family of enolizable ketones with simple aryl iodides employs a catalytic copper system. The method shows potential for the easy and step-economical synthesis of tamoxifen, the most commonly administrated drug for the management of breast cancer. R, R′, R′′ = electron-donating or electron-withdrawing groups. Copyright
- Danoun, Grégory,Tlili, Anis,Monnier, Florian,Taillefer, Marc
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supporting information
p. 12815 - 12819
(2013/02/22)
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- Oxidative heck arylation for the stereoselective synthesis of tetrasubstituted olefins using nitroxides as oxidants
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One, two, and three! Nitroxides and dioxygen serve as oxidants in highly stereoselective oxidative Pd-catalyzed Heck arylations in which aryl boronic acids are used to synthesize triarylalkyl-substituted olefins. The reactions occur under very mild conditions at room temperature. As an example, the threefold sequential arylation of methyl acrylate is the crucial step in the stereoselective synthesis of Z-Tamoxifen.
- He, Zhiheng,Kirchberg, Sylvia,Froehlich, Roland,Studer, Armido
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supporting information; experimental part
p. 3699 - 3702
(2012/05/20)
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- Palladium-catalyzed fluoride-free cross-coupling of intramolecularly activated alkenylsilanes and alkenylgermanes: Synthesis of tamoxifen as a synthetic application
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We have demonstrated that intramolecular hypercoordination of a carboxylic acid is a powerful activation strategy for the palladium-catalyzed cross-coupling reaction of trialkyl(vinyl)silanes and trialkyl(vinyl)germanes under fluoride-free conditions. Z-β-Trialkylsilyl- and Z-β- trialkylgermylacrylic acids, synthesized stereoselectively by olefination with ynolates, are highly stable and useful reagents for cross-coupling with a variety of aryl iodides to provide tetrasubstituted olefins possessing different carbon substituents in a stereocontrolled and diversity-oriented manner. An application to a stereoselective synthesis of (Z)-tamoxifen is also reported. Copyright
- Matsumoto, Kenji,Shindo, Mitsuru
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p. 642 - 650
(2012/05/04)
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- Copper-catalyzed synthesis of β-haloalkenyl chalcogenides by addition of dichalcogenides to internal alkynes and its application to synthesis of (Z)-tamoxifen
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A copper-catalyzed synthesis of β-haloalkenyl sulfides or selenides was carried out by addition of dichalcogenides and tetrabutylammonium halides to internal alkynes. The present reaction anti- and regio-selectively afforded the corresponding alkenyl chal
- Taniguchi, Nobukazu
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experimental part
p. 2782 - 2790
(2009/08/15)
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- Stereoselective synthesis of (E)-(trisubstituted alkenyl)borinic esters: Stereochemistry reversed by ligand in the palladium-catalyzed reaction of alkynylborates with aryl halides
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"Chemical Equation Presented" The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively gave (E)-(trisubstituted alkenyl)-9-BBNs, in which two different aryl groups were installed trans to each other.
- Ishida, Naoki,Shimamoto, Yasuhiro,Murakami, Masahiro
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supporting information; experimental part
p. 5434 - 5437
(2010/02/28)
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- Trans-stilbene as a starting material for the synthesis of tamoxifen based on palladium-catalyzed cross-coupling reactions
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(Z)-Tamoxifen was synthesized from a simple olefin (trans-stilbene) in 5 steps and 40% overall yield (Z/E = 74:26). The phenyl substituted group (4-Me2NCH2CH2OC6H4) was attached by a bromination-dehydrobromination-Suzuki reaction sequence. Subsequently, the ethyl group was attached to the triarylated olefin by a bromination-Negishi reaction sequence. Both the Suzuki and Negishi cross-coupling processes are stereospecific, and the stereo-selectivity depends only on the bromination-dehydrobromination reactions. (Z)-Tamoxifen was also obtained from trans-stilbene in only 3 steps by using Heck reaction-bromination- Negishi reaction sequence in 57% overall yield (Z/E = 65:35). Georg Thieme Verlag Stuttgart.
- Nunes, Carolina M.,Limberger, Jones,Poersch, Silvia,Seferin, Marcus,Monteiro, Adriano L.
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experimental part
p. 2761 - 2765
(2010/01/21)
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- An expeditious synthesis of tamoxifen, a representative SERM (selective estrogen receptor modulator), via the three-component coupling reaction among aromatic aldehyde, cinnamyltrimethylsilane, and β-chlorophenetole
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Two new synthetic pathways to the anti-cancer agent tamoxifen and its derivatives were developed. The first route involved the aldol reaction of benzyl phenyl ketone with acetaldehyde followed by Friedel-Crafts substitution with anisole in the presence of Cl2Si(OTf)2 to produce 1,1,2-triaryl-3-acetoxybutane, a precursor of the tamoxifen derivatives. The second one utilized the novel three-component coupling reaction among aromatic aldehydes, cinnamyltrimethylsilane, and aromatic nucleophiles using HfCl4 as a Lewis acid catalyst to produce 3,4,4-triarylbutene, that is also a valuable intermediate of the tamoxifen derivatives. The former strategy requires a total of 10 steps from the aldol formation to the final conversion to tamoxifen, whereas the latter needs only three or four steps to produce tamoxifen and droloxifene including the installation of the side-chain moiety and the base-induced double-bond migration to form the tetra-substituted olefin structure. This synthetic strategy seems to serve as a new and practical pathway to prepare not only the tamoxifen derivatives but also the other SERMs (selective estrogen receptor modulators) including estrogen-dependent breast cancer and osteoporosis agents.
- Shiina, Isamu,Sano, Yoshiyuki,Nakata, Kenya,Suzuki, Masahiko,Yokoyama, Toshikazu,Sasaki, Akane,Orikasa, Tomoko,Miyamoto, Tomomi,Ikekita, Masahiko,Nagahara, Yukitoshi,Hasome, Yoshimune
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p. 7599 - 7617
(2008/03/14)
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- Zirconocene-mediated highly regio- and stereoselective synthesis of multisubstituted olefins starting from 1-alkynylboronates
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Multisubstituted olefins are efficiently prepared by the zirconocene-mediated regio- and stereoselective coupling between 1-alkynylboronates and ethylene, followed by sequential transformation in moderate to high yields. The proper combination of substrates and reaction conditions is important for high yields. The synthesis of various tetrasubstituted alkenes in a regio- and stereocontrolled manner is described. This methodology has been applied to the synthesis of (Z)-tamoxifen in a concise, regio- and stereoselective manner. This multicomponent coupling strategy involves the characteristics of 1-alkynylboronates toward high selectivities followed by palladium(0)-mediated cross-coupling with aryl halides. Copyright
- Nishihara, Yasushi,Miyasaka, Mitsuru,Okamoto, Masanori,Takahashi, Hideki,Inoue, Eiji,Tanemura, Kenki,Takagi, Kentaro
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p. 12634 - 12635
(2008/03/13)
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- Carbolithiation of diphenylacetylene as a stereoselective route to (Z)-tamoxifen and related tetrasubstituted olefins
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(Chemical Equation Presented) Carbolithiation of diphenylacetylene can be exploited to generate (E)-1-lithio-1,2-diphenylalkyl-1-enes which can be reacted in situ with triisopropylborate to stereoselectively provide (E)-1,2-diphenyl-1-alkylene boronic acids. These tetrasubstituted vinylboronic acids served as versatile intermediates for the generation of tetrasubstituted olefins with retention of stereochemistry. The application of this method for the stereoselective synthesis of (Z)-tamoxifen and related analogues is described.
- McKinley, Neola F.,O'Shea, Donal F.
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p. 9552 - 9555
(2007/10/03)
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- Effective synthesis of tamoxifen using nickel-catalyzed arylative carboxylation
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Tamoxifen was synthesized using a nickel-catalyzed arylative carboxylation developed by our group. The key compound, tetrasubstituted alkene, was synthesized from disubstituted alkyne using a catalytic amount of Ni(0) and DBU in the presence of Ph2Zn under an atmosphere of carbon dioxide. The reaction proceeded smoothly in a regio- and stereoselective manner, and the resultant tetrasubstituted alkene was converted into tamoxifen. Georg Thieme Verlag Stuttgart.
- Shimizu, Kazuya,Takimoto, Masanori,Mori, Miwako,Sato, Yoshihiro
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p. 3182 - 3184
(2008/02/13)
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- Regio- and stereoselective route to tetrasubstituted olefins by the palladium-catalyzed three-component coupling of aryl iodides, internal alkynes, and arylboronic acids
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The Pd-catalyzed three-component coupling of readily available aryl iodides, internal alkynes, and arylboronic acids provides a convenient, one-step, regio- and stereoselective route to tetrasubstituted olefins in good to excellent yields, although electron-poor aryl iodides and dialkylalkynes normally afford only low yields under our standard reaction conditions. The proper combination of substrates and reaction conditions is important for high yields. The presence of water generally substantially increases the yields of the desired tetrasubstituted olefins. The reaction involves cis-addition of the aryl group from the aryl iodide to the less hindered or more electron-rich end of the alkyne, while the aryl group from the arylboronic acid adds to the other end. A modified, room-temperature procedure has also been successfully developed, which works very well for some substrates. Tamoxifen and its derivatives are synthesized in a concise, regio- and stereoselective manner by applying our synthetic protocol.
- Zhou, Chengxiang,Larock, Richard C.
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p. 3765 - 3777
(2007/10/03)
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- Wittig-Horner approach for the synthesis of tamoxifen
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A stereoselective synthesis of Z-tamoxifen, a tetra-substituted alkene with antiestrogenic activity, is described. The Wittig-Horner reaction has been employed as the key step to establish the olefin stereochemistry. Copyright Taylor & Francis, Inc.
- Pandey, Rajesh K.,Wakharkar,Kumar, Pradeep
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p. 2795 - 2800
(2007/10/03)
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- Stereoselective cross-coupling reaction of 1,1-diboryl-1-alkenes with electrophiles: A highly stereocontrolled approach to 1,1,2-triaryl-1-alkenes
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Palladium-catalyzed cross-coupling reaction of 1,1-diboryl-1-alkenes with aryl and alkenyl iodides was found to proceed stereoselectively, giving rise to the corresponding mono-coupled product as a single diastereomer with E-configuration. Second coupling of the initial product with another aryl iodide affords diverse triarylalkenes in their stereochemically pure form. This highly stereoselective approach for triarylalkenes allows one to synthesize both diastereomers in one pot from 1,1-diboryl-1-alkenes. Copyright
- Shimizu, Masaki,Nakamaki, Chihiro,Shimono, Katsuhiro,Schelper, Michael,Kurahashi, Takuya,Hiyama, Tamejiro
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p. 12506 - 12507
(2007/10/03)
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- Facile synthesis of multisubstituted buta-1,3-dienes via Suzuki-Miyaura and Kumada cross-coupling strategy of 2,4-diiodo-buta-1-enes with arylboronic acids and Grignard reagents
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One-pot Suzuki-Miyaura-type and Kumada-type cross-coupling reactions of 2,4-diiodo-buta-l-enes with arylboronic acids and alkyl/aryl magnesium bromides were carried out in the presence of accessibly simple catalysts under mild conditions. As a result, some 1,1,2-trisubstituted buta-1,3-dienes were obtained including the Tamoxifen-type, which have potential adjuvant therapy in women who have suffered from breast cancer and cyclooxygenase-2-type (COX-2-type) inhibitors, some of which have been proved to elicit efficient anti-inflammatory analgesic activities and less adverse gastrointestinal side effects and to be very useful in the prophylactic treatment of a wide variety of cancers and neurodegenerative disorders. The Royal Society of Chemistry 2005.
- Shao, Li-Xiong,Shi, Min
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p. 1828 - 1831
(2007/10/03)
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- Catalytic carbometalation/cross-coupling sequence across alkynyl(2-pyridyl)silanes leading to a diversity-oriented synthesis of tamoxifen-type tetrasubstituted olefins
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A general synthetic scheme for tamoxifen-type tetrasubstituted olefins based on the novel Cu-catalyzed carbomagnesation across alkynyl(2-pyridyl)silane has been developed. A wide array of electronically and structurally diverse tetrasubstituted olefins can be prepared in a regiocontrolled, stereo-controlled, and diversity-oriented manner. Noteworthy features are that (i) the three aryl groups, which are believed to be important (essential) for anti-estrogenic activity, can be varied at will because they all stem from readily available aryl iodides, and (ii) any stereo- and regioisomers can, in principle, be prepared by simply changing the order use of the aryl iodides in the sequence.
- Kamei, Toshiyuki,Itami, Kenichiro,Yoshida, Jun-Ichi
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p. 1824 - 1835
(2007/10/03)
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- Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells
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A treatment solution used to prevent posterior capsular opacification is applied or introduced into the lens capsular bag before, during, or after cataract surgery. The treatment solution comprises an ion transport mechanism interference agent, which either alone or in combination with other treatment agents such as an osmotic stress agent and an agent to establish a suitable pH, selectively induces detachment and/or death of lens epithelial cells such that posterior capsular opacification is prevented. While the ion transport mechanism interference agent is capable of interfering with the cellular mechanisms and cell ion distribution of a broad range of cells, a concentration of agent is selected such that the treatment solution interferes selectively with the cellular mechanisms of lens epithelial cells while leaving other ocular cells substantially unharmed. The treatment solution selectively induces cellular death and/or detachment of lens epithelial cells while other ocular cells and tissue remain substantially unharmed and without lengthy preoperative pre-treatment.
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- Short-step synthesis of tamoxifen and its derivatives via the three-component coupling reaction and migration of the double bond
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The anti-tumor agent, tamoxifen, is easily synthesized by the successive allylation of benzaldehyde and the Friedel-Crafts alkylation reaction of anisole with the intermediary homoallyl silyl ethers, followed by the migration of the double bond to form the desired tetra-substituted ethylenes. Several derivatives of tamoxifen are also produced according to a similar synthetic strategy.
- Shiina, Isamu,Suzuki, Masahiko,Yokoyama, Kazutoshi
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p. 965 - 967
(2007/10/03)
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- Diversity-Oriented Synthesis of Tamoxifen-type Tetrasubstituted Olefins
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A general synthetic scheme for tamoxifen-type tetrasubstituted olefins based on the novel Cu-catalyzed carbomagnesation across alkynyl(2-pyridyl)silane has been developed. A wide array of electronically and structurally diverse tetrasubstituted olefins can be prepared in a regiocontrolled, stereocontrolled, and diversity-oriented manner. Noteworthy features are that (i) the three aryl groups, which are believed to be important (essential) for anti-estrogenic activity, can be varied at will because they all stem from readily available aryl iodides, and (ii) any stereo- and regioisomers can, in principle, be prepared by simply changing the applying order of aryl iodides into the sequence. Copyright
- Itami, Kenichiro,Kamei, Toshiyuki,Yoshida, Jun-Ichi
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p. 14670 - 14671
(2007/10/03)
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- (Z)-tamoxifen and tetrasubstituted alkenes and dienes via a regio- and stereospecific three-component magnesium carbometalation palladium(O) cross-coupling strategy
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(Matrix presented) The synthesis of various tetrasubstituted alkenes and dienes in a regio- and stereocontrolled manner is described. This three-component coupling strategy involves the addition of Grignard reagents to propargyl alcohols followed by palladium(O)-mediated cross-coupling with aryl or vinyl halides. This protocol has been applied to the synthesis of (Z)-Tamoxifen and related mimics.
- Tessier, Pierre E.,Penwell, Andrea J.,Souza, Fabio E. S.,Fallis, Alex G.
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p. 2989 - 2992
(2007/10/03)
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- Preparation of α,n-dilithiotoluene equivalents. Synthesis of tamoxifen
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The successive reaction of chlorobenzyl alcohols with n-butyllithium and lithium powder in the presence of a substoichiometric amount of 4,4′-di-tert-butylbiphenyl (DTBB) at -78°C yields the expected (lithiooxymethyl)phenyllithium derivative, which is trapped by reaction with different ketones. The subsequent arene-catalysed lithiation at 25°C permits the one-pot chemoselective lithiation of the primary benzyl alcoholate in the presence of a tertiary one. These new functionalised benzyllithium derivatives react with different electrophilic compounds, such as aldehydes, ketones and chlorotrimethylsilane, to give after hydrolysis the expected functionalised benzyl alcohols. Some of these alcohols are successfully transformed into mono- or di-olefins by acidic treatment. This whole strategy is applied to the preparation of anti-cancer drug tamoxifen.
- Yus, Miguel,Ramón, Diego J.,Gómez, Inmaculada
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p. 3219 - 3225
(2007/10/03)
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- Development of a microwave-enhanced isotopic labelling procedure based on the Eschweiler-Clarke methylation reaction
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A number of primary and secondary amines have been rapidly methylated under microwave-enhanced conditions using formic acid-formaldehyde mixtures, providing a route to 2H(D)-containing compounds and the potential for 3H(T), 11C, 13C and 14C labelling.
- Harding, John R.,Jones, John R.,Lu, Shui-Yu,Wood, Robin
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p. 9487 - 9488
(2007/10/03)
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- Method of using deuterated calcium channel blockers
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Therapeutic methods and compositions using deuterated enriched 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester and other deuterated dihydropyridine compounds are described. The deuterated compounds exhibit enhanced efficacy in blocking calcium channels over non-deuterated dihydropyridines.
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- Tamoxifen and analogues thereof
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A method of preparing a first geometric isomer of tamoxifen or an analogue comprises allowing the first isomer to crystallize in hexanol and the product thereof to crystallize in methanol and then derivatising the product of the methanol crystallization to prepare said first isomer in very high purity.
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- Enhanced anti-angiogenic activity of permanently charged derivatives of steroid hormones
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The present invention discloses the use of permanently charged steroid agonists or antagonists as potent anti-angiogenic compositions comprising as an active ingredient a compound of the general formulae I, II or III: STR1 wherein DRUG is any steroid agonist or antagonist, a mixed agonist-antagonist, or a partial agonist and the substituents are as defined in the specification.
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