Enantioselective Synthesis of Alcohols and Amines: The Kim Synthesis of (+)-Frontalin

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Imperial College ◽  
Enantioselective Synthesis ◽  
Heinrich Heine ◽  
Max Planck ◽  
Chiral Amine ◽  
P450 Monooxygenase ◽  
Cu Catalyst ◽  
Ready Availability ◽  
The University

Vlada B. Urlacher of the Heinrich-Heine University Düsseldorf showed (Chem. Commun. 2014, 50, 4089) that the P450 monooxygenase CYP154A8 from Nocardia farcinica could monohydroxylate n-octane 1 to 2 with high regioselectivity and ee. Fener Chen of Fudan University used (J. Org. Chem. 2014, 79, 2723) an organocatalyst to open the prochiral anhydride 3 to the monoester 4. Amir H. Hoveyda of Boston College added (Angew. Chem. Int. Ed. 2014, 53, 3387) (pinacolato)borane to the enone 5 to give 6, that was readily oxidized to the tertiary alcohol. Matthias Breuning of the University of Bayreuth designed (Chem. Commun. 2014, 50, 6623) a Cu catalyst for the enantioselective Henry addition of nitromethane to the aldehyde 7 to give 8. Benjamin List of the Max-Planck-Institute für Kohlenforschung optimized (Synlett 2014, 25, 932) the proline-catalyzed formation of the aldol prod­uct 10 from the aldehyde 9. Christian Wolf of Georgetown University devised (Chem. Commun. 2014, 50, 3151) the alkyne 12, that could be added to the aldehyde 11 to give 13 in high ee. Keiji Maruoka of Kyoto University developed (Org. Lett. 2014, 16, 1530) practical conditions for the organocatalyzed addition of an aldehyde 14 to an in situ- generated nitroso urethane, leading, after reduction, to the alcohol 15. Satoko Kezuka of Tokai University added (Tetrahedron Lett. 2014, 55, 2818) the benzyloxyamine 17 to the nitro alkene 16 to give the coupled product 18 in high ee. Xiaohua Liu and Xiaoming Feng of Sichuan University developed (Angew. Chem. Int. Ed. 2014, 53, 1636) a Pd catalyst for the preparation of 20 by the enantioselective amination of the diazo ester 19. Shou-Fei Zhu and Qi-Lin Zhou of Nankai University described (Angew. Chem. Int. Ed. 2014, 53, 2978) related work, not illustrated, on the enantioselective aryloxylation of an α-diazo ester. Alan Armstrong of Imperial College London, taking advantage (J. Org. Chem. 2014, 79, 3895) of the ready availability of enantiomerically secondary selenides such as 21, showed that it could be combined with 22 to give the α-chiral amine 23.

Practical Enantioselective Construction of Arrays of Stereogenic Centers: The Jørgensen Synthesis of the Autoregulator IM-2

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
University Of Pennsylvania ◽  
Gel Chromatography ◽  
Max Planck ◽  
West Virginia University ◽  
Clemson University ◽  
Stereogenic Centers ◽  
Cu Catalyst ◽  
Enantioselective Epoxidation ◽  
Silica Gel Chromatography ◽  
The University

Armando Córdova of Stockholm University found (Angew. Chem. Int. Ed. 2008, 47, 8468) that the enantiomerically-enriched diastereomers from aminosulfenylation of 1 were readily separable by silica gel chromatography. Benjamin List of the Max-Planck-Institut, Mülheim developed (Angew. Chem. Int. Ed. 2008, 47, 8112) what appears to be a general protocol for the enantioselective epoxidation of enones such as 4. Paolo Melchiorre of the Università di Bologna devised (Angew. Chem. Int. Ed. 2008, 47 , 8703) a related protocol for the enantioselective aziridination of enones. Xue-Long Hue of the Shanghai Institute of Organic Chemistry and Yun-Dong Wu of the Hong Kong University of Science and Technology optimized (J. Am. Chem. Soc. 2008, 130 , 14362) a Cu catalyst for enantioselective Mannich homologation of imines such as 6. Guofu Zhong of Nanyang Technological University, Singapore established (Angew. Chem. Int. Ed. 2008, 47, 10187; Organic Lett. 2008 , 10 , 4585) that enantioselective α-aminoxylation of an ω-alkenyl aldehyde such as 9 could lead to defined arrays of stereogenic centers. George A. O’Doherty of West Virginia University devised (Organic Lett. 2008, 10, 3149) a protocol for the enantioselective hydration of 12 to 13 . René Peters, now at the University of Stuttgart, designed (Angew. Chem. Int. Ed. 2008, 47, 5461) an Al catalyst for the enantioselective combination of an acyl bromide 15 with an aldehyde 14 to deliver the β–lactone 16. Hajime Ito and Masaya Sawamura of Hokkaido University established (J. Am. Chem. Soc. 2008, 130, 15774) that the allenyl borane from 17 added to aldehydes such as 18 with high ee. Keiji Maruoka of Kyoto University developed (Tetrahedron Lett. 2008, 49, 5369) an organocatalyst for the Mannich homologation of an aldehyde such as 20 to 21. R. Karl Dieter of Clemson University showed (Organic Lett. 2008, 10, 2087) that 23, readily prepared in high ee, could be displaced sequentially with two different Grignard reagents, to give 24. Jeffrey W. Bode, now at the University of Pennsylvania, found (Organic Lett. 2008, 10, 3817) that bisulfite adducts such as 25 served well for the addition of unstable chloroaldehydes to 26 to give 27.

Enantioselective Synthesis of Alkylated Centers: The Fukuyama Synthesis of (–)-Histrionicotoxin

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Indian Institute ◽  
Enantioselective Synthesis ◽  
Max Planck ◽  
Dimethyl Malonate ◽  
Co Catalyst ◽  
Cu Catalyst ◽  
Enantioselective Addition ◽  
Institute Of Technology ◽  
Enantioselective Alkylation ◽  
Technological University

Vinod K. Singh of the Indian Institute of Technology, Kanpur optimized (Org. Lett. 2011, 13, 6520) an organocatalyst for the enantioselective addition of thiophenol to an imide 1 to give 2 in high ee. Amir H. Hoveyda of Boston College developed (Angew. Chem. Int. Ed. 2011, 50, 7079) a Cu catalyst for the preparation of 4 by the enantioselective hydroboration of a 1,1-disubstituted alkene 3. Yong-Qiang Tu of Lanzhou University effected (Chem. Sci. 2011, 2, 1839) enantioselective bromination of the prochiral 5 to give the bromoketone 6. Song Ye of the Institute of Chemistry, Beijing established (Chem. Commun. 2011, 47, 8388) the alkylated quaternary center of the dimer 8, by condensing a ketene 7 with CS2. Li Deng of Brandeis University added (Angew. Chem. Int. Ed. 2011, 50, 10565) cyanide in a conjugate sense to an acyl imidazole 9 to give 11. Pier Giorgio Cozzi of the Università di Bologna prepared (Angew. Chem. Int. Ed. 2011, 50, 7842) the thioacetal 14 by condensing 13 with an aldehyde 12, followed by reduction. Takahiro Nishimura and Tamio Hayashi of Kyoto University devised (Chem. Commun. 2011, 47, 10142) a Co catalyst for the enantioselective addition of a silyl alkyne 16 to an enone 15 to give the alkynyl ketone 17. Ping Tian and Guo-Qiang Lin of the Shanghai Institute of Organic Chemistry described (Tetrahedron 2011, 67, 10186) improved catalysts for the enantioselective conjugate addition of dimethyl malonate 19 to the nitroalkene 18, to give 20. Keiji Maruoka, also of Kyoto University, established (Chem. Sci. 2011, 2, 2311) conditions for the enantioselective addition of an aldehyde 21 to the acceptor 22 to give, after reduction, an alcohol 23 that could readily be cyclized to the lactone. Jianrong (Steve) Zhou of Nanyang Technological University prepared (J. Am. Chem. Soc. 2011, 133, 15882) the ester 26 by arylation, under Pd catalysis, of a ketene silyl acetal 24 with the triflate 25. Benjamin List of the Max-Planck-Institut, Mülheim employed (Angew. Chem. Int. Ed. 2011, 50, 9471) a system of three catalysts to effect the enantioselective alkylation of an aldehyde 27 with the allyic alcohol 28 to give 29.

Flow Chemistry: The Direct Production of Drug Metabolites

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Organic Synthesis ◽  
Flow Chemistry ◽  
Florida State University ◽  
State University ◽  
Max Planck ◽  
Direct Production ◽  
Reactor Technology ◽  
University Of Cambridge ◽  
The University

Several overviews of flow chemistry appeared recently. Katherine S. Elvira and Andrew J. deMello of ETH Zürich wrote (Nature Chem. 2013, 5, 905) on micro­fluidic reactor technology. D. Tyler McQuade of Florida State University and the Max Planck Institute Mühlenberg reviewed (J. Org. Chem. 2013, 78, 6384) applications and equipment. Jun-ichi Yoshida of Kyoto University focused (Chem. Commun. 2013, 49, 9896) on transformations that cannot be effected under batch condi­tions. Detlev Belder of the Universität Leipzig reported (Chem. Commun. 2013, 49, 11644) flow reactions coupled to subsequent micropreparative separations. Leroy Cronin of the University of Glasgow described (Chem. Sci. 2013, 4, 3099) combin­ing 3D printing of an apparatus and liquid handling for convenient chemical synthe­sis and purification. Many of the reactions of organic synthesis have now been adapted to flow con­ditions. We will highlight those transformations that incorporate particularly useful features. One of those is convenient handling of gaseous reagents. C. Oliver Kappe of the Karl-Franzens-University Graz generated (Angew. Chem. Int. Ed. 2013, 52, 10241) diimide in situ to reduce 1 to 2. David J. Cole-Hamilton immobilized (Angew. Chem. Int. Ed. 2013, 52, 9805) Ru DuPHOS on a heteropoly acid support, allowing the flow hydrogenation of neat 3 to 4 in high ee. Steven V. Ley of the University of Cambridge added (Org. Process Res. Dev. 2013, 17, 1183) ammonia to 5 to give the thiourea 6. Alain Favre-Réguillon of the Conservatoire National des Arts et Métiers used (Org. Lett. 2013, 15, 5978) oxygen to directly oxidize the aldehyde 7 to the car­boxylic acid 8. Professor Kappe showed (J. Org. Chem. 2013, 78, 10567) that supercritical ace­tonitrile directly converted an acid 9 to the nitrile 10. Hisao Yoshida of Nagoya University added (Chem. Commun. 2013, 49, 3793) acetonitrile to nitrobenzene 11 to give the para isomer 12 with high regioselectively. Kristin E. Price of Pfizer Groton coupled (Org. Lett. 2013, 15, 4342) 13 to 14 to give 15 with very low loading of the Pd catalyst. Andrew Livingston of Imperial College demonstrated (Org. Process Res. Dev. 2013, 17, 967) the utility of nanofiltration under flow conditions to minimize Pd levels in a Heck product.

Developments in Flow Chemistry

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Flow Chemistry ◽  
Pharmaceutical Product ◽  
Continuous Control ◽  
Heinrich Heine ◽  
Flow Conditions ◽  
Max Planck ◽  
Direct Renin Inhibitor ◽  
Amino Phenol ◽  
Polymer Bead ◽  
The University

Klavs S. Jensen of MIT showed (Angew. Chem. Int. Ed. 2014, 53, 470) that “batch” kinetics could be developed in flow by online IR analysis and continuous control. Professor Jensen also demonstrated (Org. Process Res. Dev. 2014, 18, 402) the contin­uous flow production of an active pharmaceutical product, the direct renin inhibitor aliskiren, over two steps and two crystallizations, starting from two advanced interme­diates. Michael Werner and Rainer E. Martin of Hoffmann-La Roche AG Basel com­bined (Angew. Chem. Int. Ed. 2014, 53, 1704) flow synthesis with a flow-based bioassay to develop structure–activity relationships for a series of β-secretase inhibitors. Carlos Mateos of Lilly S. A. and C. Oliver Kappe of the University of Graz used (J. Org. Chem. 2014, 79, 223) flow photolysis to promote the bromination of 1 to 2. Alessandro Palmieri of the University of Camerino and Stefano Protti of the University of Pavia added (Adv. Synth. Catal. 2014, 356, 753) the aldehyde 3 to the acceptor 4 to give, after in-flow reduction, the lactone 5. Peter H. Seeberger of the Max Planck Institute Mühlenberg showed (Org. Lett. 2014, 16, 1794) that the tum­bling action of flow photolysis made the production of 7 by the unlinking of 6 from the polymer bead particularly efficient. Enzymes can also be used under flow conditions. Jörg Pietruszka of the Heinrich-Heine-Universität Düsseldorf employed (Adv. Synth. Catal. 2014, 356, 1007) com­mercial laccase to prepare 10 by coupling 8 with 9. Gas–liquid mixing under flow conditions can also be effective. Núria López of ICIQ Catalonia and Javier Pérez-Ramírez of ETH Zurich developed (Chem. Eur J. 2014, 20, 5926) conditions for the selective hydrogenation of an alkyne 11 to the cis alkene 12. Jun-ichi Yoshida of Kyoto University trapped (Chem. Eur J. 2014, 20, 7931) the inter­mediate organolithium from 13 with CO₂ to give a carboxylate that was carried on to the purifiable O-Su ester 14, ready for further coupling. Timothy F. Jamison, also of MIT, prepared (Angew. Chem. Int. Ed. 2014, 53, 3353) the amino phenol 17 by add­ing the chloromagnesium amide from 16 to the intermediate benzyne from 15, then oxidizing the product with air.

Stereocontrolled Carbocyclic Construction: The Trauner Synthesis of the Shimalactones

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Allylic Alcohols ◽  
Max Planck ◽  
Chiral Amine ◽  
Ene Reaction ◽  
Enantiomerically Pure ◽  
University Of Wisconsin ◽  
Single Diastereomer ◽  
Enantioselective Epoxidation ◽  
The University ◽  
Technological University

Benjamin List of the Max Planck Institute, Mülheim devised (J. Am. Chem. Soc. 2008, 130, 6070) a chiral primary amine salt that catalyzed the enantioselective epoxidation of cyclohexenone 1 . Larger ring and alkyl-substituted enones are also epoxidized with high ee. Three- and four-membered rings are versatile intermediates for further transformation. Tsutomu Katsuki of Kyushu University developed (Angew. Chem. Int. Ed. 2008, 47, 2450) an elegant Al(salalen) catalyst for the enantioselective Simmons-Smith cyclopropanation of allylic alcohols such as 3. Kazuaki Ishihara of Nagoya University found (J. Am. Chem. Soc. 2007, 129, 8930) chiral amine salts that effected enantioselective 2+2 cycloaddition of α-acyloxyacroleins such as 5 to alkenes to give the cyclobutane 7 with high enantio- and diastereocontrol. Gideon Grogan of the University of York overexpressed (Adv. Synth. Cat. 2008, 349, 916) the enzyme 6-oxocamphor hydrolase in E. coli . The 6-OCH so prepared converted prochiral diketones such as 8 to the cyclopentane 9 in high ee. Richard P. Hsung of the University of Wisconsin found (Organic Lett. 2008, 10, 661) that the carbene produced by oxidation of the ynamide 10 cyclized to 11 with high de. Teck-Peng Loh of Nanyang Technological University extended (J. Am. Chem. Soc. 2008, 130, 7194) butane-2,3-diol directed cyclization to the preparation of the cyclopentane 15. Note that sidechain relative configuration is also controlled. We established (J. Org. Chem. 2008, 73, 3467) that the thermal ene reaction of 17 delivered the tetrasubstituted cyclopentane 18 as a single diastereomer. Tony K. M. Shing of the Chinese University of Hong Kong devised (J. Org. Chem. 2007, 72, 6610) a simple protocol for the conversion of carbohydrate-derived lactones such as 19 to the highly-substituted, enantiomerically-pure cyclohexenone 21. Hiromichi Fujioka and Yasuyuki Kita of Osaka University established (Organic Lett. 2007, 9, 5605) a chiral diol-mediated conversion of the cyclohexadiene 22 to the diastereomerically pure cyclohexenone 24. Dirk Trauner, now of the University of Munich, reported (Organic Lett. 2008, 10, 149) an elegant assembly of the neuritogenic polyketide shimalactone A 28.

C-C Single Bond Construction

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Aryl Halide ◽  
Allylic Alcohol ◽  
University Of Alabama ◽  
Max Planck ◽  
One Pot ◽  
Single Diastereomer ◽  
Institute Of Technology ◽  
The University ◽  
École Polytechnique

Several remarkable one-carbon homologations have recently appeared. André B. Charette of the Université de Montréal reported (J. Org. Chem. 2008, 73, 8097) the alkylation of diiodomethane with alkyl iodides such as 1, to give the diiodoalkane 2. Carlo Punta and the late Ombretta Porta of the Politecnico di Milano effected (Organic Lett. 2008, 10, 5063) reductive condensation of an amine 3 with an aldehyde 4 in the presence of methanol, to give the amino alcohol 5. Timothy S. Snowden of the University of Alabama showed (Organic Lett. 2008, 10, 3853) that NaBH4 reduced the carbinol 7, easily prepared from the aldehyde 6, to the acid 8. Ram N. Ram of the Indian Institute of Technology, Delhi found (J. Org. Chem. 2008, 73, 5633) that CuCl reduced 7 to the chloro ketone 9. Kálmán J. Szabó of Stockholm University extended (Chem. Commun. 2008, 3420) his elegant work on in situ borinate formation, coupling, in one pot, the allylic alcohol 10 with the acetal 11 (hydrolysed in situ) to deliver the alcohol 12 as a single diastereomer. Samir Z. Zard of the Ecole Polytechnique developed (J. Am. Chem. Soc. 2008, 130, 8898) the 6-fluoropyridyloxy ether of 13 as an effective radical leaving group, enabling efficient coupling with 14, activated by dilauroyl peroxide, to give 15. Shu Kobayashi of the University of Tokyo established (Chem. Commun. 2008, 6354) that the anion of the sulfonyl imidate 17 participated in direct Pd-mediated allylic coupling with the carbonate 16. The product sulfonyl imidate 18 is itself of medicinal interest. It is also easily converted to other functional groups, including the aldehyde 19. Jianliang Xiao of the University of Liverpool found (J. Am. Chem. Soc. 2008, 130, 10510) that Pd-mediated coupling of an aldehyde 21 in the presence of pyrrolidine led to the ketone 22. The reaction is probably proceeding via Heck coupling of the aryl halide with the in situ generated enamine. Alois Fürstner of the Max Planck Institut, Mülheim observed (J. Am. Chem. Soc. 2008, 130, 8773) that in the presence of the simple catalyst Fe(acac)3 a Grignard reagent 24 coupled smoothly with an aryl halide 23 to give 25.

Arrays of Stereogenic Centers: The Yadav Synthesis of Nhatrangin A

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Claisen Rearrangement ◽  
Iron Catalyst ◽  
Aldol Condensation ◽  
State University ◽  
Max Planck ◽  
Chiral Amine ◽  
Cornell University ◽  
University Of Oxford ◽  
Enantioselective Epoxidation ◽  
The University

Miquel Costas of the Universitat de Girona developed (J. Am. Chem. Soc. 2013, 135, 14871) an iron catalyst for the enantioselective epoxidation of the Z-ester 1 to 2. Although the α-chloro aldehyde derived from 3 epimerized under the reaction conditions, Robert Britton of Simon Fraser University showed (Org. Lett. 2013, 15, 3554) that the subsequent aldol condensation with 4 favored one enantiomer, leading to 5 in high ee. Other selective aldol condensations of 4 (not illustrated) have been reported by Zorona Ferjancic and Radomir N. Saicic of the University of Belgrade (Eur. J. Org. Chem. 2013, 5555) and by Tomoya Machinami of Meisei University (Synlett 2013, 24, 1501). Motomu Kanai of the University of Tokyo condensed (Org. Lett. 2013, 15, 4130) D-arabinose 6 with diallyl amine and the alkyne 7 to give the amine 8 as a mixture of diastereomers. Naoya Kumagai and Masakatsu Shibasaki of the Institute of Microbial Chemistry combined (Angew. Chem. Int. Ed. 2013, 52, 7310) 9 and 10 to prepare the α-chiral amine 11. Tomoya Miura and Masahiro Murakami of Kyoto University used (J. Am. Chem. Soc. 2013, 135, 11497) an Ir catalyst to migrate the alkene of 13 to the E allyl boro­nate, that then added to 12 to give 14. Gong Chen of Pennsylvania State University alkylated (J. Am. Chem. Soc. 2013, 135, 12135) the β-H of 15 with 16 to give selec­tively the diastereomer 17. Geoffrey W. Coates of Cornell University devised (J. Am. Chem. Soc. 2013, 135, 10930) catalysts for the carbonylation of the epoxide 18 to either regioisomer of the β-lactone 19. Yujiro Hayashi of Tohoku University combined (Chem. Lett. 2013, 42, 1294) the inexpensive succinaldehyde 20 and ethyl glyoxylate 21 to give the versatile aldehyde 22. Nuno Maulide of the Max-Planck-Institut für Kohlenforschung Mülheim effected (J. Am. Chem. Soc. 2013, 135, 14968) Claisen rearrangement of 23 to give, after reduc­tion and hydrolysis, the aldehyde 24. Stephen G. Davies of the University of Oxford reported (Chem. Commun. 2013, 49, 7037) a related Claisen rearrangement (not illustrated). Ying-Chun Chen of Sichuan University devised (Org. Lett. 2013, 15, 4786) the cascade combination of 25 and 26 to give 27.

Stereocontrolled Construction of Arrays of Stereogenic Centers

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Aldol Condensation ◽  
University Of Minnesota ◽  
Chiral Amine ◽  
University Of Texas ◽  
Crotyl Alcohol ◽  
Alternative Approach ◽  
Stereogenic Centers ◽  
La Jolla ◽  
The University

The Sharpless osmium-catalyzed asymmetric dihydroxylation is widely used. Lawrence Que, Jr. of the University of Minnesota designed (Angew. Chem. Int. Ed. 2008, 47, 1887) a catalyst with the inexpensive Fe that appears to be at least as effective, converting 1 to 2 in high ee. In an alternative approach, Bernd Plietker of the Universität Stuttgart used (J. Org. Chem. 2008, 73, 3218) chiral auxiliary control to direct dihydroxylation. The diastereomers of 4 were readily differentiated. Defined arrays of stereogenic centers can also be constructed by homologation. Armando Córdova of Stockholm University condensed (Tetrahedron Lett. 2008, 49, 803) dihydroxy acetone 6 with an in situ generated imine 5 to give the amino diol 8. In parallel work, Carlos F. Barbas III of Scripps/La Jolla described (Organic Lett. 2008, 10, 1621) a related addition to aldehydes. Magnus Rueping of University Frankfurt found (Organic Lett. 2008, 10, 1731) conditions for the addition of a nitro alkane such as 9 to the imine 10 to give 11. Keiji Maruoka of Kyoto University devised (J. Am. Chem. Soc. 2008, 130, 3728) a chiral amine that mediated the enantioselective iodination of aldehydes such as 12. Direct cyanohydrin formation delivered 13 in high de and ee. The epoxide 14 is readily prepared in high ee from crotyl alcohol. Barry M. Trost of Stanford University found (Organic Lett. 2008, 10, 1893) that 14 could be opened with 15, to give 16 with high regio- and diastereocontrol. Jérôme Blanchet of the Université de Caen Basse-Normandie optimized (Organic Lett. 2008, 10 , 1029) the amine 19 as a catalyst for the condensation of ketones such as 17 with the imine 18, to give 20. Michael J. Krische of the University of Texas has explored (J. Am. Chem. Soc. 2008, 130, 2746) the in situ generation of chiral Rh enolates from enones such as 21, and the subsequent aldol condensation with aldehydes such as 22. Shu Kobayashi of the University of Tokyo found (Organic Lett. 2008, 10, 807) that the conjugate addition of 25 to 24 mediated by a chiral Ca catalyst proceeded with high enantiocontrol at both of the newly formed stereogenic centers, to give 26.

A Short Enantioselective Synthesis of (S)-Levetiracetam Through Direct Pd-Catalyzed Asymmetric N-Allylation of Methyl 4-Aminobutyrate

Synlett ◽  
2021 ◽  
Author(s):  
Dominik Albat ◽  
Jörg-Martin Neudörfl ◽  
Hans-Günther Schmalz
Keyword(s):  
Antiepileptic Drug ◽  
Tartaric Acid ◽  
Enantioselective Synthesis

An exceedingly short and enantioselective synthesis of the antiepileptic drug (S)-levetiracetam was elaborated. As the chirogenic key step a Pd-catalyzed asymmetric N-allylation of methyl 4-aminobutyrate was achieved in the presence of only 1 mol% of a catalyst prepared in situ from [Pd(allyl)Cl]2 and the tartaric acid-derived C2-symmetric diphosphane ligand (S,S)-iPr-MediPhos).

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