- A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates
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Ligand-controlled reactivity plays an important role in transition-metal catalysis, enabling a vast number of efficient transformations to be discovered and developed. However, a single ligand is generally used to promote all steps of the catalytic cycle (e.g., oxidative addition, reductive elimination), a requirement that makes ligand design challenging and limits its generality, especially in relay asymmetric transformations. We hypothesized that multiple ligands with a metal center might be used to sequentially promote multiple catalytic steps, thereby combining complementary catalytic reactivities through a simple combination of simple ligands. With this relay catalysis strategy (L/L?), we report here the first highly regio- and enantioselective remote hydroarylation process. By synergistic combination of a known chain-walking ligand and a simple asymmetric cross-coupling ligand with the nickel catalyst, enantioenriched α-aryl alkylboronates could be rapidly obtained as versatile synthetic intermediates through this formal asymmetric remote C(sp3)-H arylation process.
- Chen, Jian,Liang, Yong,Ma, Jiawei,Meng, Lingpu,Zhang, Yao,Zhu, Shaolin
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supporting information
p. 3171 - 3188
(2021/11/16)
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- Indirect Tertiary Alcohol Enantiocontrol by Acylative Organocatalytic Kinetic Resolution
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The stereocontrol of tertiary alcohols represents a recurrent challenge in organic synthesis. In the present paper, we describe a simple, efficient, and indirect method to enantioselectively prepare tertiary alcohols through a chiral isothiourea catalyzed
- Amalian, Jean-Arthur,Bressy, Cyril,Charles, Laurence,Desrues, Titouan,Liu, Xueyang,Monnier, Valérie,Pons, Jean-Marc,Quintard, Adrien
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supporting information
p. 4332 - 4336
(2021/06/27)
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- Enantioselective Total Synthesis of the Putative Biosynthetic Intermediate Ambruticin J
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The family of anti-fungal natural products known as the ambruticins are structurally distinguished by a pair of pyran rings adorning a divinylcyclopropane core. Previous characterization of their biosynthesis, including the expression of a genetically modified producing organism, revealed that the polyketide synthase pathway proceeds via a diol intermediate, known as ambruticin J. Herein, we report the first enantioselective total synthesis of the putative PKS product, ambruticin J, according to a triply convergent synthetic route featuring a Suzuki-Miyaura cross-coupling and a Julia-Kocienski olefination for fragment assembly. This synthesis takes advantage of synthetic methodology previously developed by our laboratory for the stereoselective generation of the trisubstituted cyclopropyl linchpin.
- Trentadue, Kathryn,Chang, Chia-Fu,Nalin, Ansel,Taylor, Richard E.
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supporting information
p. 11126 - 11131
(2021/06/01)
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- Synthesis of α-Borylated Ketones by Regioselective Wacker Oxidation of Alkenylboronates
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As part of a program aimed at metal-catalyzed oxidative transformations of molecules with carbon-metalloid bonds, the synthesis of α-borylated ketones is reported via regioselective TBHP-mediated Wacker-type oxidation of N-methyliminodiacetic acid (MIDA)-protected alkenylboronates. The observed regioselectivity correlates with the hemilabile nature of the B-N dative bond in the MIDA boronate functional group, which allows boron to guide selectivity through a neighboring group effect.
- Corless, Victoria B.,Holownia, Aleksandra,Foy, Hayden,Mendoza-Sanchez, Rodrigo,Adachi, Shinya,Dudding, Travis,Yudin, Andrei K.
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supporting information
p. 5300 - 5303
(2018/09/12)
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- Synthesis of enantiopure cyclic amino acid derivatives via a sequential diastereoselective Petasis reaction/ring closing olefin metathesis process
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A novel approach to the synthesis of enantiopure cyclic amino esters is reported. The utilization of allylboronic acid together with (S)-α-methylbenzylamine as a chiral auxiliary in the Petasis/Mannich reaction led to the formation of allylglycine derivatives in good yield and with high diastereoselectivity. Subsequent esterification, N-allylation followed by ring-closing metathesis (RCM) reaction enabled the preparation of enantiomerically pure cyclic α-amino acid derivatives.
- Morozova, Veronika A.,Beletskaya, Irina P.,Titanyuk, Igor D.
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p. 349 - 354
(2017/02/18)
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- Copper-Catalyzed Oxy-Alkenylation of Homoallylic Alcohols to Generate Functional syn-1,3-Diol Derivatives
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A novel method for the synthesis of a wide range of functionalized 1,3-diol derivatives is reported. Employing a copper-catalyzed oxy-alkenylation strategy, a range of readily available, substituted homoallylic alcohol derivatives and alkenyl(aryl) iodonium salts combine to form syn-1,3-carbonates in excellent yield and with high selectivity. Furthermore, the products formed are amenable to an iterative reaction sequence, thus affording highly complex polyketide-like fragments. Polyols: The reported copper-catalyzed oxy-alkenylation strategy works well for a range of readily available, substituted homoallylic alcohol derivatives and alkenyl(aryl) iodonium salts to form syn-1,3-carbonates in excellent yield and high selectivity. Furthermore, the products formed are amenable to an iterative reaction sequence, thus affording highly complex polyketide-like fragments.
- Holt, Dean,Gaunt, Matthew J.
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supporting information
p. 7857 - 7861
(2015/06/30)
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- Enantioselective syn and anti homocrotylation of aldehydes: Application to the formal synthesis of spongidepsin
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Whereas crotylboration has been a useful method for synthesis of stereochemically complex products, we have shown that homocrotylboration can be achieved with cyclopropanated crotylation reagents, and that the stereoselectivity of the reaction can be predicted by analogous models. This paper presents a full account of this work, including the first examples of asymmetric anti homocrotylation. The scope of this reaction is demonstrated with highly enantioselective homocrotylation of both aliphatic and aromatic aldehydes, as well as double diastereoselection studies. An application of the synthesis of the marine natural product spongidepsin is presented, as well as streamlined syntheses of homocrotylation reagents.
- Lin, Hongkun,Tian, Leiming,Krauss, Isaac J.
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supporting information
p. 13176 - 13182
(2015/10/28)
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- Construction of multiple, contiguous quaternary stereocenters in acyclic molecules by lithiation-borylation
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Lithiation of carbamates followed by borylation provides a powerful method for the homologation of boron reagents. However, when applied to hindered systems (secondary carbamates with tBu-boronic esters) for the construction of two quaternary centers, thi
- Watson, Charlotte G.,Balanta, Angelica,Elford, Tim G.,Essafi, Stphanie,Harvey, Jeremy N.,Aggarwal, Varinder K.
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supporting information
p. 17370 - 17373
(2015/02/05)
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- Enantioselective homocrotylboration of aliphatic aldehydes
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A practical route to optically pure syn-homocrotylation reagents is described, including highly diastereo- and enantioselective preparation of numerous syn-homocrotyl products, as well as several matched mismatched pairs. NMR experiments suggest that the active homocrotylating species is a cyclopropylcarbinyldichloroborane generated by chloride exchange from the PhBCl2 activator. Computational studies support the intermediacy of chloroboranes and suggest that homoallyl/homocrotyl transfers occur through Zimmerman-Traxler transition states.
- Lin, Hongkun,Pei, Wenbo,Wang, Hao,Houk, Kendall N.,Krauss, Isaac J.
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supporting information
p. 82 - 85
(2013/02/25)
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- SYNTHESIS OF BORONIC ESTERS AND BORONIC ACIDS USING GRIGNARD REAGENTS
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Boronic esters and boronic acids are synthesized at ambient temperature in an ethereal solvent by the reaction of Grignard reagents with a boron-containing substrate. The boron-containing substrate may be a boronic ester such as pinacolborane, neopentylglycolborane, or a dialkylaminoborane compound such as diisopropylaminoborane. The Grignard reagents may be preformed or generated from an alkyl, alkenyl, aryl, arylalkyl, heteroaryl, vinyl, or allyl halide compound and Mg°. When the boron-containing substrate is a boronic ester, the reactions generally proceed at room temperature without added base in about 1 to 3 hours to form a boronic ester compound. When the boron-containing substrate is a dialkylaminoborane compound, the reactions generally proceed to completion at 0°C in about 1 hour to form a boronic acid compound.
- -
-
Paragraph 0114; 0118
(2013/03/26)
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- Mechanistic insights into the BINOL-derived phosphoric acid-catalyzed asymmetric allylboration of aldehydes
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BINOL-derived phosphoric acids catalyze the asymmetric allylboration of aldehydes. DFT and QM/MM hybrid calculations showed that the reaction proceeds via a transition state involving both a hydrogen-bonding interaction from the catalyst hydroxyl group to
- Grayson, Matthew N.,Pellegrinet, Silvina C.,Goodman, Jonathan M.
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supporting information; experimental part
p. 2716 - 2722
(2012/03/22)
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- AUTOMATED SYNTHESIS OF SMALL MOLECULES USING CHIRAL, NON-RACEMIC BORONATES
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Provided are methods for making and using chiral, non-racemic protected organoboronic acids, including pinene-derived iminodiacetic acid (PIDA) boronates, to direct and enable stereoselective synthesis of organic molecules. Also provided are methods for purifying PIDA boronates from solution. Also provided are methods for deprotection of boronic acids from their PIDA ligands. The purification and deprotection methods may be used in conjunction with methods for coupling or otherwise reacting boronic acids. Iterative cycles of deprotection, coupling, and purification can be performed to synthesize chiral, non-racemic compounds. The methods are suitable for use in an automated chemical synthesis process. Also provided is an automated small molecule synthesizer apparatus for performing automated stereoselective synthesis of chiral, non-racemic small molecules using iterative cycles of deprotection, coupling, and purification.
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Page/Page column 143
(2012/11/13)
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- Reaction of grignard reagents with diisopropylaminoborane. Synthesis of alkyl, aryl, heteroaryl and allyl boronic acids from organo(diisopropyl)- aminoborane by a simple hydrolysis
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Diisopropylaminoborane (BH2-N(iPr)2) is prepared by reacting lithium diisopropylaminoborohydride (iPr-LAB) with trimethylsilyl chloride (TMSCl). Aliphatic, aromatic, and heteroaromatic (diisopropylamino) boranes are readily synthesiz
- Bailey, Christopher L.,Murphy, Chris L.,Clary, Jacob W.,Eagon, Scott,Gould, Naomi,Singaram, Bakthan
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p. 331 - 341
(2013/08/23)
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- Pinene-derived iminodiacetic acid (PIDA): A powerful ligand for stereoselective synthesis and iterative cross-coupling of C(sp3) boronate building blocks
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Efficient access to chiral C(sp3) boronates in stereochemically pure form is critical for realizing the substantial potential of such building blocks in complex-molecule synthesis. We herein report that a pinene-derived iminodiacetic acid (PIDA) ligand enables the highly diastereoselective synthesis of a wide range of oxiranyl C(sp3) boronates from the corresponding olefins. These oxiranyl PIDA boronates, in turn, can be readily transformed into unprecedented stable α-boryl aldehydes via a novel 1,2-migration of the boronate group that proceeds with complete maintenance of stereochemical purity. B-Protected haloboronic acids containing dual sp3-hybridized C centers are readily accessible via this platform, and the herein demonstrated capacity for stereocontrolled iterative C(sp3) cross-coupling with this novel type of bifunctional reagent to access a medicinally important chiral small-molecule target in highly enantioenriched form represents a substantial advance for the building-block-based approach to synthesis.
- Li, Junqi,Burke, Martin D.
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supporting information; experimental part
p. 13774 - 13777
(2011/10/09)
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- A concise synthesis of natural benzofuran neolignans and analogues
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The first total synthesis of four naturally occurring benzofuran neolignans and two analogues was achieved in four steps in 44-51% overall yield. Key steps involved a two-step construction of benzofuran nucleus and a Suzuki coupling. This synthesis has been proven straightforward and efficient, and more related analogues can be prepared for structure-activity relationship explorations. Georg Thieme Verlag Stuttgart New York.
- Duan, Xin-Fang,Shen, Gang,Zhang, Zhan-Bin
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experimental part
p. 2547 - 2552
(2010/09/08)
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- Cyclic alkenyl boronic half acid synthesis and applications
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The synthesis of cyclic alkenyl boronic half acids from vinyl and propenyl boronic esters and homoallylic alcohols by ring-closing metathesis is reported. The method is compatible with both conventional and microwave heating and comparable yields are obta
- McNulty, Luanne,Kohlbacher, Kris,Borin, Katie,Dodd, Bryan,Bishop, Jeni,Fuller, Lindsey,Wright, Zach
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experimental part
p. 6001 - 6004
(2010/11/16)
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- Efficient hydrolysis of organotrifluoroborates via silica gel and water
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(Chemical Equation Presented) A general, mild, and efficient method for the hydrolysis of organotrifluoroborates to unveil boronic acids using silica gel and H2O was developed. This method proved to be tolerant of a broad range of aryl-, heteroaryl-, alkenyl-, and alkyltrifluoroborates as well as structurally diverse aminomethylated organotrifluoroborates.As anticipated, electron-rich substrates provided the corresponding boronic acids more readily than electron-poor substrates, owing to the resonance-stabilized difluoroborane intermediate. The method developed was expanded further for the conversion of organotrifluoroborates to the corresponding boronate esters. 2009 American Chemical Society.
- Molander, Gary A.,Cavalcanti, Livia N.,Canturk, Belgin,Pan, Po-Shen,Kennedy, Lauren E.
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supporting information; experimental part
p. 7364 - 7369
(2010/01/16)
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- Diastereoselective addition of zincated hydrazones to alkenylboronates and stereospecific trapping of boron/zinc bimetallic intermediates by carbon electrophiles
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Zincated hydrazones possessing a tert-butyl group on the zinc atom undergo addition to (E)- or (Z)-alkenylboronic acid pinacol esters to produce α-alkylated-γ-boryl-γ-zinciohydrazone intermediates with good to excellent diastereoselectivity (ds). The 1,1 -organodimetallic intermediate possessing a boron atom and a zinc atom in the position γ to the hydrazone group undergoes further C-C bond formation with a carbon electrophile to give a γ-boryl hydrazone possessing several contiguous stereogenic centers with up to 99% ds. The (S)-1-amino-2-methoxymethylpyrrolidine hydrazone shows a high level of asymmetric induction in the addition/trapping sequence. Density functional theory calculations on the pathways of the addition reaction revealed a metallo-ene mechanism consisting of the formation of a π complex between a zincated hydrazone and a vinylborane followed by a six-centered bond reorganization of a highly ordered boat conformation transition state. The calculations indicated that the use of the zinc atom together with the imine or hydrazone is the key for the success of the olefinic variant of the aldol reaction that has long been considered not to take place because of the endothermicity of the reaction and has never been examined with any seriousness by chemists. The steric repulsion caused by the bulky tert-butyl ligand on the zinc atom and the pinacol moiety of the vinylboronate substrates in the highly ordered transition structures gives rise to the observed high ds of the present carbozincation reaction.
- Hatakeyama, Takuji,Nakamura, Masaharu,Nakamura, Eiichi
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supporting information; experimental part
p. 15688 - 15701
(2009/03/12)
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- Pyrrolo(oxo)isoquinolines as 5HT ligands
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The present application describes compounds according to Formula I, pharmaceutical compositions, comprising at least one compound according to Formula I and optionally at least one additional therapeutic agent and methods of treating various diseases, conditions and disorders associated with modulation of serotonin receptors such as, for example: metabolic diseases, which includes but is not limited to obesity, diabetes, diabetic complications, atherosclerosis, impared glucose tolerance and dyslipidemia; central nervous system diseases which includes but is not limited to, anxiety, depression, obsessive compulsive disorder, panic disorder, psychosis, schizophrenia, sleep disorder, sexual disorder and social phobias; cephalic pain; migraine; and gastrointestinal disorders using compounds according to Formula I or pharmaceutically acceptable salt forms thereof, wherein A, B, D, E, m, n, R3, R7, R8, R9, R10, R11 and X are described herein.
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Page/Page column 33
(2008/06/13)
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- Catalytic enantioselective and catalyst-controlled diastereofacial- selective additions of allyl- and crotylboronates to aldehydes using chiral Bronsted acids
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(Chemical Equation Presented) Towards the ideal: A chiral diol-SnCl 4 complex is applied to the allylboration of aldehydes (see scheme). This approach highlights the use of chiral Bronsted acid catalysis in the development of an ideal method for the allylation of aldehydes which would display high diastereo- and enantioselectivity, wide substrate scope, and high practicality (ease of use, low cost, and low environmental impact).
- Rauniyar, Vivek,Hall, Dennis G.
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p. 2426 - 2428
(2007/10/03)
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- Synthesis of functionalized vinyl boronates via ruthenium-catalyzed olefin cross-metathesis and subsequent conversion to vinyl halides
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Functionalized vinyl pinacol boronates suitable for Suzuki cross-coupling reactions are synthesized using ruthenium-catalyzed olefin cross-metathesis of 1-propenyl pinacol boronate and various alkenes, including functionalized and 1,1-disubstituted alkenes. The resultant boronate cross products are stereoselectively transformed into predominantly Z-vinyl bromides and E-vinyl iodides. The vinyl bromides may be synthesized in a two-step, one-pot synthesis from a variety of olefins, resulting in a Z-selective formal vinyl bromide cross-metathesis reaction.
- Morrill, Christie,Grubbs, Robert H.
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p. 6031 - 6034
(2007/10/03)
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- Diastereoselective allylation and crotylation reactions of aldehydes with potassium allyl- and crotyltrifluoroborates under Lewis acid catalysis
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Potassium allyl- and crotyltrifluoroborates react with aldehydes in a process catalyzed by a variety of Lewis acids, to give the corresponding homoallylic alcohols. Of the Lewis acids examined, BF3·OEt2, used either stoichiometrically or catalytically, was found to most efficiently catalyze this reaction. The air and moisture stable potassium organotrifluoroborate salts react with a variety of alkyl, α- or β- substituted alkyl, and aryl aldehydes, and lead to the adducts in high yield and with high diastereoselectivity.
- Batey, Robert A.,Thadani, Avinash N.,Smil, David V.,Lough, Alan J.
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p. 990 - 998
(2007/10/03)
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- Potassium allyl- and crotyltrifluoroborates: Stable and efficient agents for allylation and crotylation
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Potassium allyl- and crotyltrifluoroborates react rapidly with aldehydes in the presence of BF3 · Et2O. These salts are stable to air and moisture, and lead to adducts in high yield and with high diastereoselectivity. The stereochemistry of the crotylated products is consistent with the reaction via allylboron difluoride and a Zimmerman-Traxler like transition state.
- Batey, Robert A.,Thadani, Avinash N.,Smil, David V.
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p. 4289 - 4292
(2007/10/03)
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- Diastereo- and Enantioselective Aldehyde Addition Reactions of 2-Allyl-1,3,2-dioxaborolane-4,5-dicarboxylic Esters, a Useful Class of Tartrate Ester Modified Allylboronates
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The preparation and aldehyde addition reactions of the title compounds (1a-c) are described.These tartrate ester based reagents are the most highly enetioselective group of allylboronate esters reported to date.Reagent 1b prepared from diisopropyl tartrate reacts with achiral aldehydes to give homoallylic alcohols in good yield and high enantioselectivity (71-87percent ee).Interestingly, the greatest selectivity is obtained with α-branched aldehydes such as pivaldehyde (82percent ee) and cyclohexanecarboxaldehyde (87percent ee).These reagents also exhibit useful levels of matched and mismatched diastereoselection in reactions with chiral aldehydes.For example, the reaction of glyceraldehyde acetonide (4) and 1b is selective either for erythro alcohol 6 (96:4) or the threo diastereomer 7 (92:8) depending on the chirality of 1b and the reaction solvent.The asymmetric induction in these reactions appears to originate from a novel stereoelectronic effect involving n/n repulsive interactions between the aldehydic oxygen atom and an ester carbonyl in the disfavored transition state B.
- Roush, William R.,Walts, Alan E.,Hoong, Lee K.
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p. 8186 - 8190
(2007/10/02)
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- Lithium bis(ethylenedioxyboryl)methide and its reactions with carbonyl compounds and with the chlorotriphenyl derivatives of germanium, tin and lead
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Transesterification of tris(dimethoxyboryl)methane, HC[B(OCH3)2]3, with ethylene glycol yielded tris(ethylenedioxyboryl)methane (I), HC(BO2C2H4)3 which with methyllithium in THF at -70°C precipitated lithium bis(ethylenedioxyboryl)methide (II), Li+ HC(BO2C2H4)2-. Reaction of II with Ph3MCl, where M = Ge, Sn, or Pb, gave Ph3MCH(BO2C2H4)2. The analogous 1,3-propanediol ester, Li+HC(BO2C3H6)2-, yielded Ph3MCH(BO2C3H6)2. Treatment of Ph3SnCH(BO2C2H4)2 with MeLi followed by Ph3SnCl gave (Ph3Sn)2CHBO2C2H4, showing that one B and one Sn atom are sufficient to stabilize a carbanion. Reaction of II with aldehydes gave high yields of 1-alkene-1-boronic esters, RCHCHBO2C2H4, with unexpectedly high stereoselectivity, 90-100% trans by NMR analysis. Aqueous work-up of these boronic esters yielded the boronic acids, RCHCHB (OH)2, which crystallized as the pure trans isomers. Ketones react with II in an analogous manner. The reaction with acetophenone was not stereospecific. Functional group compatibility has been demonstrated in condensations of II with 1,3-dichloroacetone, cinnamaldehyde, p-nitrobenzaldehyde, and p-dimethylaminobenzaldehyde. The trans geometry of the major isomer of CH3CHCHBO2C2H4 was proved by B-butylation with butyllithium followed by rearrangement with iodine and base to form cis-2-heptene, a sequence of known stereochemistry, and analogous structure proofs were carried out with cis-CH3CHCHBO2C2H4 and trans-C6H5CHCHBO2C2H4.
- Matteson, Donald S.,Jesthi, Pradipta K.
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