bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction of Alkylated Stereogenic Centers
Authors: Taber Douglass F.
Published: November 2020

Andreas Pfaltz of the University of Basel and Keisuke Suzuki of the Tokyo Institute of Technology showed (Angew. Chem. Int. Ed. 2010, 49, 881) that the iodohydrin of 1 did not interfere with the enantioselective hydrogenation. J. R. Falck of UT Southwestern developed (J. Am. Chem. Soc. 2010, 132, 2424) a procedure for coupling arene boronic acids with a cyano triflate 3, readily available in high ee from the corresponding aldehyde. Anita R. Maguire of University College Cork devised (J. Am. Chem. Soc. 2010, 132, 1184) a Cu catalyst for the enantioselective C-H insertion cyclization of 5 to 6. Jin-Quan Yu of Scripps/La Jolla established (J. Am. Chem. Soc. 2010, 132, 460) a complementary enantioselective C-H functionalization protocol, converting the prochiral 7 into 8 in high ee. Xumu Zhang of Rutgers University effected (Angew. Chem. Int. Ed. 2010, 49, 4047) enantioselective branching hydroformylation of 9 to give 10. T. V. RajanBabu of Ohio State University established (J. Am. Chem. Soc. 2010, 132, 3295) the enantioselective hydrovinylation of a diene 11 to the diene 12. Gregory C. Fu extended (J. Am. Chem. Soc. 2010, 132, 1264, 5010) Ni-mediated cross-coupling, both with alkenyl and aryl nucleophiles, to the racemic bromoketone 13. Hyeung-geun Park and Sang-sup Jew of Seoul National University used (Organic Lett. 2010, 12 , 2826) their asymmetric phase transfer protocol to effect the enantioselective alkylation of the amide 15. Kyung Woon Jung of the University of Southern California showed (J. Org. Chem. 2010, 75, 95) that the oxidative Pd-mediated Heck coupling of arene boronic acids to 17 could be effected in high ee. Nicolai Cramer of ETH Zurich observed (J. Am. Chem. Soc. 2010, 132, 5340) high enantioinduction in the cleavage of the prochiral cyclobutanol 19. Alexandre Alexakis of the University of Geneva achieved (Organic Lett. 2010, 12, 1988) the long-sought goal of efficient enantioselective conjugate addition of a Grignard reagent to an unsaturated aldehyde 21. Professor Alexakis also established (Organic Lett. 2010, 12, 2770) conditions for enantioselective conjugate addition to a nitrodiene 23. This procedure worked equally well for β-alkynyl nitroalkenes.
Enantioselective Construction of Arrays of Stereogenic Centers: The Breit Synthesis of (+)-Bourgeanic Acid
Authors: Taber Douglass F.
Published: November 2020

Kyungsoo Oh of Indiana University Purdue University Indianapolis devised (Organic Lett. 2009, 11, 5682) a new ligand that with Cu delivered predominantly one diastereomer of the Henry adduct 3, and with Zn delivered the other. Liu-Zhu Gong of the University of Science and Technology of China reported (Angew. Chem. Int. Ed. 2009, 48, 6503) the Darzens condensation of the diazoacetamide 5 with a variety of aldehydes to give the corresponding epoxy amides with high diastereo- and enantiocontrol. Michael J. Krische of the University of Texas, Austin, applied (Organic Lett. 2009, 11, 3108, 3112) his asymmetric allylation to a variety of primary diols including 7, leading to the homologated product 9. M. Christina White of the University of Illinois showed (J. Am. Chem Soc. 2009, 131, 11707) that Pd-mediated oxidative amination of carbamate 10 delivered the protected 1,3-amino alcohol 11 with high diastereocontrol. James P. Morken of Boston College devised (J. Am. Chem Soc. 2009, 131, 9134) a Pt catalyst for the asymmetric bis-boration of dienes. The allyl borane prepared from 12 added with high stereocontrol to benzaldehyde, to give, after oxidation, the diol 13. Carlos F. Barba III of Scripps/La Jolla optimized (Angew. Chem. Int. Ed. 2009, 48, 9848) an organocatalyst for the enantioselective conjugate addition of an alkoxy aldehyde 15 to a nitroalkene. Do Hyun Ryu of Sungkyunkwan University found (Chem. Commun. 2009, 5460) that an organocatalyst could also mediate the dipolar cycloaddition of a diazo ester 18 to an unsaturated aldehyde, giving 19 with high diastereo- and enantiocontrol. Francesco Fini and Luca Bernardi of the University of Bologna developed (J. Am. Chem Soc. 2009, 131, 9614) an organocatalyst that effected enantioselective dipolar cycloaddition of the nitrone derived from 20 to the unsaturated ester 21. Kevin Burgess of Texas A&M optimized (J. Am. Chem Soc. 2009, 131, 13236) an Ir catalyst for the enantioselective hydrogenation of trisubstituted alkenes such as 23. In the course of a synthesis of (+)-faranal, Varinder K. Aggarwal of the University of Bristol described (Angew. Chem. Int. Ed. 2009, 48, 6317) a one-pot procedure for the conversion of the allyl borane 25 into 27.
C-O Ring Construction: The Theodorakis Synthesis of (-)-Englerin A
Authors: Taber Douglass F.
Published: November 2020

Liming Zhang of the University of California, Santa Barbara, described (J. Am. Chem. Soc. 2010, 132, 8550) the remarkable transformation of a propargyl alcohol 1 into the oxetanone 2. The transformation proceeded without loss of ee, as did the ring expansion of 3 to 5 reported (J. Org. Chem. 2010, 75, 6229) by Peter R. Schreiner of Justus-Liebig University, Giessen, and Andrey A. Fokin of the Kiev Polytechnic Institute. Takeo Taguchi of the Tokyo University of Pharmacy and Life Sciences developed (Chem. Commun. 2010, 46, 8728) a catalyst for the stereoselective conjugate addition of 7 to 6. Mitsuru Shindo of Kyushu University devised (Org. Lett. 2010, 12, 5346) the thioester 10, which condensed smoothly with an α-hydroxy ketone 9 to deliver the lactone 11. Zili Chen of the Renmin University of China and Lin Guo of the Beijing University of Aeronautics and Astronautics developed (Org. Lett. 2010, 12, 3468) the diastereoselective double addition of propargyl alcohol 13 to 12 to give 14. Jian-Wu Xie of Zhejiang Normal University uncovered (J. Org. Chem. 2010, 75, 8716) the catalyzed enantioselective addition of 16 to 15 to give the dihydrofuran 17. James S. Panek of Boston University extended (Org. Lett. 2010, 12, 4624) the utility of the enantiomerically pure allenic nucleophile 19, adding it to the acceptor 18 to give 20 with both ring and sidechain stereocontrol. Biswanath Das of the Indian Institute of Chemical Technology, Hyderabad, showed (Tetrahedron Lett. 2010, 51, 6011) that the epoxide of the tartrate-derived acetonide 21 could be rearranged to the fully substituted, differentially protected tetrahydrofuran 22. Paul E. Floreancig of the University of Pittsburgh uncovered (Angew. Chem. Int. Ed. 2010, 49, 5894) the highly stereocontrolled oxidative cyclization of 22 to 23. Dirk Menche of the University of Heidelberg found (Angew. Chem. Int. Ed. 2010, 49, 9270) that the Pd-mediated addition of 24 to 25 also proceeded with high diastereocontrol. Dipolar cycloaddition to a furan is of increasing importance in target-directed synthesis. Emmanuel A. Theodorakis of the University of California, San Diego, added (Org. Lett. 2010, 12, 3708) the diazo ester 27, prepared from the inexpensive chiral auxiliary pantolactone, to the furan 28.
Synthesis of C-N Natural Products: (-)-α-Kainic Acid (Helmchen), (+)-Tylophorine (Opatz), (-)-Lycoperine A (Rychnovsky), Fluvirucidine A2 (Suh), Complanidine A (Sarpong)
Authors: Taber Douglass F.
Published: November 2020

Günter Helmchen of the Ruprecht-Karls-Universität Heidelberg set (Organic Lett. 2010, 12, 1108) the absolute configuration of 3 by Ir*-mediated coupling of 1 with 2. Diastereoselective Pauson-Khand cyclization then led to (-)-α-kainic acid 5. Till Opatz, now at the Johannes Gutenberg-Universität Mainz, showed (Organic Lett. 2010, 12, 2140) that the product from the Dibal reduction of 6 could be condensed with the amine 7 without epimerization. Kim cyclization then directly delivered the pentacyclic alkaloid (+)-tylophorine 9. The interesting dimeric alkaloid lycoperine A 13 was recently isolated from the Japanese club moss Lycopodium hamiltonii. Scott D. Rychnovsky of the University of California, Irvine, prepared (Organic Lett. 2010, 12, 72) 12 by double alkylation of the bis-nitrile 11 with the enantiomerically pure allylic bromide 10. Although the projected reductive decyanation of 12 failed, hydrolysis followed by diastereoselective reductive amination successfully gave 13. Retrosynthetic analysis of fluvirucinine A2 16 could lead to an acyclic amino acid, which could be cyclized to the macrolactam. Young-Ger Suh of Seoul National University took (Organic Lett. 2010, 12, 2040) a different approach, building up the 14-membered ring system by two four-carbon ring expansions, beginning with an enantiomerically pure piperidine precursor. The second of these enolate-based aza-Claisen ring expansions is illustrated in the conversion of 14 to 15. Richmond Sarpong of the University of California, Berkeley, faced (J. Am. Chem. Soc. 2010, 132, 5926) a different sort of challenge in the synthesis of the dimeric Lycopodium alkaloid complanadine A 19. Even with established access to monomers such as 17 and its precursors, it was not clear how the 5-position of the pyridine ring could be selectively activated for bond formation. The solution to this dilemma was found in the work of Hartwig. Following that precedent, Ir-catalyzed activation of 17 converted it cleanly into the borinate 18, which could then be coupled with a pyridone triflate to complete the synthesis of 19.
Alkaloid Synthesis: Mearsine (Taylor), Cephalotaxine (Li), Cocaine (Shing), Quinine (Hatakeyama), Cleavamine (Bennasar), Strychnine(Vanderwal)
Authors: Taber Douglass F.
Published: November 2020

Richard J. K. Taylor of the University of York employed (Tetrahedron Lett. 2011, 52, 2024) the Jørgensen protocol to add 2 to 1, to give the enantiomerically enriched cyclohexenone 3. Condensation of 3 with aqueous ammonia led directly to (-)-mearsine 4. Wei-Dong Z. Li of Nankai University found (Org. Lett. 2011, 13, 3538) that the intermediate from Dibal reduction of the lactone 5 underwent Nazarov cyclization, giving the α-hydroxy cyclopentenone 6. After acetylation, deprotection gave an amine that cyclized with high diastereocontrol, leading to (±)-cephalotaxine 7. Tony K. M. Shing of the Chinese University of Hong Kong cyclized (Org. Lett. 2011, 13, 2916) the aldehyde 8 by exposure to 9. The product 10 was carried on to (-)-cocaine 11, as well as several hydroxylated cocaine derivatives. Susumi Hatakeyama of Nagasaki University found (Tetrahedron Lett. 2011, 52, 923) that exposure of the simple prochiral aldehyde 12 to catalytic proline transformed it, after reduction, into the cyclized diol 13 in high ee. The diol 13 was readily carried on to quinine 14. M.-Lluïsa Bennasar of the University of Barcelona devised (Org. Lett. 2011, 13, 2042) Pd-catalyzed conditions for the cyclization of 15 that selectively delivered the unstable kinetic product 18. Selective hydrogenation of the more reactive bridgehead alkene then led to cleavamine 17. The alkene 16 is also prochiral, so it is possible that a catalyst could be found that would deliver 17 in high ee. The synthesis of the heptacyclic alkaloid strychnine 23 would, in the past, have been a major undertaking. Christopher D. Vanderwal of the University of California, Irvine, prepared (Chem. Sci. 2011, 2, 649) 23 in just six linear steps. The dienyl aldehyde 18 was available in two steps from tryptophyl bromide. Exposure to t -BuOK cyclized 18 to 19. N-deallylation followed by alkylation with 20 provided 21, setting the stage for a truly spectacular Brook rearrangement/conjugate addition, to give the Wieland-Gumlich aldehyde 22. The known condensation with malonic acid completed the preparation of 23.
Substituted Benzenes: The Saikawa/Nakata Synthesis of Kendomycin
Authors: Taber Douglass F.
Published: November 2020

Jianbo Wang of Peking University described (Angew. Chem. Int. Ed. 2010, 49, 2028) the Au-promoted bromination of a benzene derivative such as 1 with N-bromosuccinimide. In a one-pot procedure, addition of a Cu catalyst followed by microwave heating delivered the aminated product 2. Jian-Ping Zou of Suzhou University and Wei Zhang of the University of Massachusetts, Boston, observed (Tetrahedron Lett. 2010, 51, 2639) that the phosphonylation of an arene 3 proceeded with substantial ortho selectivity. Yonghong Gu of the University of Science and Technology, Hefei, showed (Tetrahedron Lett. 2010, 51, 192) that an arylpropanoic acid 6 could be ortho hydroxylated with PIFA to give 7. Louis Fensterbank, Max Malacria, and Emmanuel Lacôte of UMPC Paris found (Angew. Chem. Int. Ed. 2010, 49, 2178) that a benzoic acid could be ortho aminated by way of the cyano amide 8. Daniel J. Weix of the University of Rochester developed (J. Am. Chem. Soc. 2010, 132, 920) a protocol for coupling an aryl iodide 10 with an alkyl iodide 11 to give 12. Professor Wang devised (Angew. Chem. Int. Ed. 2010, 49, 1139) a mechanistically intriguing alkyl carbonylation of an iodobenzene 10. This is presumably proceeding by way of the intermediate diazo alkane. Usually, benzonitriles are prepared by cyanation of the halo aromatic. Hideo Togo of Chiba University established (Synlett 2010, 1067) a protocol for the direct electrophilic cyanation of an electron-rich aromatic 15. Thomas E. Cole of San Diego State University observed (Tetrahedron Lett. 2010, 51, 3033) that an alkyl dimethyl borane, readily prepared by hydroboration of the alkene with BCl3 and Et3 SiH, reacted with benzoquinone 17 to give 18. Presumably this transformation could also be applied to substituted benzoquinones. When a highly substituted benzene derivative is needed, it is sometimes more economical to construct the aromatic ring. Joseph P. A. Harrity of the University of Sheffield and Gerhard Hilt of Philipps-Universität Marburg showed (J. Org. Chem. 2010, 75, 3893) that the Co-catalyzed Diels-Alder cyloaddition of alkynyl borinate 21 with a diene 20 proceeded with high regiocontrol, to give, after oxidation, the aryl borinate 22.
Heteroaromatic Construction: The Fukuyama Synthesis of Tryprostatin A
Authors: Taber Douglass F.
Published: November 2020

Alessandro Palmieri of the University of Camerino developed (Synlett 2010, 2468) the condensation of a nitro acrylate 1 with a 1,3-dicarbonyl partner 2 to give the furan 3. Chaozhong Li of the Shanghai Institute of Organic Chemistry showed (Tetrahedron Lett. 2010, 51, 3678) that an alkenyl halide 4 could be cyclized to the furan 5. Ayhan S. Demir of Middle East Technical University established (Chem. Commun. 2010, 46, 8032) that a Au catalyst could catalyze the addition of an amine 7 to a cyanoester 6 to give the pyrrole 8 . Bruce A. Arndtsen of McGill University effected (Org. Lett. 2010, 12, 4916) the net three-component coupling of an imine 9, an acid chloride 10, and an alkyne 11 to deliver the pyrrole 12. Bernard Delpech of CNRS Gif-sur-Yvette prepared (Org. Lett. 2010, 12, 4760) the pyridine 15 by combining the diene 13 with the incipient carbocation 14. Max Malacria, Vincent Gandon, and Corinne Aubert of UPMC Paris optimized (Synlett 2010, 2314) the internal Co-mediated cyclization of a nitrile alkyne 5 to the tetrasubstituted pyridine 17. Yoshiaki Nakao of Kyoto University and Tamejiro Hiyama, now at Chuo University, effected (J. Am. Chem. Soc. 2010, 132, 13666) selective substitution of a preformed pyridine 18 at the C-4 position by coupling with an alkene 19. We showed (J. Org. Chem. 2010, 75, 5737) that the anion from deprotonation of a pyridine 21 could be added in a conjugate sense to 22 to give 23. Other particularly useful strategies for further substitution of preformed pyridines have been described by Olafs Daugulis of the University of Houston (Org. Lett. 2010, 12, 4277), by Phil S. Baran of Scripps/La Jolla (J. Am. Chem. Soc. 2010, 132, 13194), and by Robert G. Bergmann of the University of California, Berkeley, and Jonathan A. Ellman of Yale University (J. Org. Chem. 2010, 75, 7863). K. C. Majumdar of the University of Kalyani developed (Tetrahedron Lett. 2010, 51, 3807) the oxidative Pd-catalyzed cylization of 24 to the indole 25. Nan Zheng of the University of Arkansas showed (Org. Lett. 2010, 12, 3736) that Fe could be used to catalyze the rearrangement of the azirine 26 to the indole 27.
Heteroaromatic Construction: The Wipf Synthesis of Cycloclavine
Authors: Taber Douglass F.
Published: November 2020

Wesley J. Moran of the University of Huddersfield cyclized (Tetrahedron Lett. 2011, 52, 2605) a propargylated ketone 1 with Au to give the furan 2. Shengming Ma of the Shanghai Institute of Organic Chemistry found (Synlett 2011, 931) that tri(2-furyl)phosphine catalyzed the rearrangement of cyclopropene diesters, prepared by the addition of diazomalonate to alkynes, to the corresponding alkoxy furan 4. Xihe Bi and Qian Zhang of Northeast Normal University established (Chem. Commun. 2011, 47, 809) that a simple Fe catalyst effected the condensation of 5 with 6 to give the pyrrole 7. Gianfranco Favi of the Università degli Studi di Urbino showed (J. Org. Chem. 2011, 76, 2860) that the three-component coupling of 8 with an amine 9 and a ketone 10 proceeded without catalyst to deliver the pyrrole 11. Timothy J. Donohoe of the University of Oxford homologated (Org. Lett. 2011, 13, 1036) 12 by cross-metathesis with methyl vinyl ketone, to give, after oxidation and condensation with NH4OAc, the substituted pyridine 13. Dale L. Boger of Scripps/La Jolla condensed ( Org. Lett. 2011, 13, 2492) the unsubstitued 1,2,3-triazine 15 with an enamine 14 to give 16. Shunsuke Chiba of Nanyang Technological University prepared (J. Am. Chem. Soc. 2011, 133, 6411) the pyridine 19 by oxidizing the cyclopropanol 17 in the presence of the alkenyl azide 18. Limin Wang of the East China University of Science and Technology prepared (Tetrahedron Lett. 2011, 52, 509) the 2-aminopyridine 23 by the four-component coupling of the aldehyde 20 and the ketone 22 with NH4OAc and malononitrile 21. Taking advantage of the Knochel protocol for aryl Grignard formation, Christopher J. Moody of the University of Nottingham combined (Chem. Commun. 2011, 47, 788) the adduct from 24 with the ketone 25 to give the indole 26. Carsten Bolm of RWTH Aachen extended (Org. Lett. 2011, 13, 2012) the Fe catalysis reported by Zheng to the azide 27 to give 28. Sang-gi Lee of Ewha Womans University found (Org. Lett. 2011, 13, 1350) that the Blaise adduct from the addition of 29 to the nitrile could be cyclized to the indole 30.
Organocatalysis of Carbocyclic Construction: The MacMillan Synthesis of (+)-Frondosin B
Authors: Taber Douglass F.
Published: November 2020

One of the more powerful applications of organocatalysis has been the enantioselective transformation of preformed prochiral rings. In the five-membered ring series, Nobuyuki Mase of Shizuoka University effected (Synlett 2010, 2340) enantioselective addition of malonate to cyclopentenone 1, and Eric N. Jacobsen of Harvard University devised (Angew. Chem. Int. Ed. 2010, 49, 9753) a guanidinium catalyst for the Claisen rearrangement of 4 to 5. Jacek Mlynarski of Jagiellonian University accomplished (Tetrahedron Lett. 2010, 51, 4088) the enantioselective hydroxymethylation of 6. This worked equally well for cyclopentanone and cycloheptanone. The dynamic kinetic resolution/reductive amination of 8 described (Angew. Chem. Int. Ed. 2010, 49, 4612) by Benjamin List of the Max-Planck-Institut Mülheim worked best with cyclohexanones such as 8. Organocatalysts can also be effective for the construction of carbocyclic rings. Teck-Peng Loh of Nanyang Technological University found (Chem. Sci. 2010, 1, 739) a commercial phosphine catalyst that efficiently mediated the condensation of 10 with 11. David W. C. MacMillan of Princeton University used (J. Am. Chem. Soc. 2010, 132, 10015) a SOMO catalyst to combine 13 with 14 to make 15. Dawei Ma of the Shanghai Institute of Organic Chemistry employed (Org. Lett. 2010, 12, 3634) the Hayashi catalyst in the double Michael condensation of 16 with 17. Daniel Romo of Texas A&M University showed (Org. Lett. 2010, 12, 3764) that the appropriate organocatalyst could direct 19 to either diastereomer of the β-lactone 20. Professor Romo also reported (Angew. Chem. Int. Ed. 2010, 49, 9479) the desymmetrization of 2-alkyl cyclohexane-1,3-diones using a similar approach. In the six-membered ring series, José Alemán and José Luis García Ruano of the Universidad Autónoma de Madrid carried out (Eur. J. Org. Chem. 2010, 4482) Robinson annulation of 17 with 21. Ying-Chun Chen of Sichuan University, again using the Hayashi catalyst, reported (Angew. Chem. Int. Ed. 2010, 49, 6418) the addition of 17 to 23 to give 24. In another elegant application of visible light–mediated organocatalysis, Professor MacMillan described (Chem. Sci. 2010, 1, 37) the addition of the commercial boronic acid 25 to 17.
Transition-Metal Catalyzed Ring Construction: The Yu Synthesis of α-Agorafuran
Authors: Taber Douglass F.
Published: November 2020

Valery V. Fokin of Scripps/La Jolla extended (J. Am. Chem. Soc. 2010, 132, 2510) enantioselective Rh-mediated intermolecular cyclopropanation to α-olefins such as 1. Takahiro Nishimura and Tamio Hayashi of Kyoto University developed (Angew. Chem. Int. Ed. 2010, 49, 1638) a procedure for enantioselective intramolecular cyclopropanation, beginning with a propargyl sulfonamide 4. Gerhard Hilt of Philipps-Universität Marburg established (Organic Lett. 2010, 12, 1536) that an aryl alkyne 6 could add to cyclopentene to give the cyclobutene 7. Hajime Ito of Hokkaido University devised (J. Am. Chem. Soc. 2010, 132, 5990) a protocol for the borylation of an alkenyl silane 8 to give an intermediate α-lithio silane, which cyclized to the cyclobutane 9 with high diastereoconrol. Aryl alkenes worked as well. This same approach could be used to construct cyclopentanes and cyclohexanes. Zhi-Xiang Yu of Peking University showed (J. Am. Chem. Soc. 2010, 132, 4542) that the triene 10 cyclized to the cyclopentane 11 with high diastereocontrol. Yong Tang of the Shanghai Institute of Organic Chemistry optimized (Angew. Chem. Int. Ed. 2010, 49, 4463) a Cu catalyst for the enantioselective Nazarov cyclization of 12 to 13. The meso bis-carbonates 14 and 16 were prepared by singlet oxygenation of the inexpensive cyclopentadiene. Mark Lautens of the University of Toronto developed (J. Org. Chem. 2010, 75, 4056) a protocol for the enantioselective coupling of 14 to an arene boronic acid, giving the carbonate 15 with high enantiocontrol. Professor Ito devised (Angew. Chem. Int. Ed. 2010, 49, 560) a complementary procedure, coupling 16 with bis-pinacolatoborane to give an intermediate allylborinate, that then added to the aldehyde 18 to give 19 with high stereocontrol. It would be interesting to know if these procedures worked as well with the meso bis-carbonates derived from cyclohexadiene. Saim Özkar of Middle East Technical University prepared (J. Am. Chem. Soc. 2010, 132, 6541) Ru nanoclusters stabilized by a zeolite framework that effected hydrogenation of 20 at near ambient conditions, in contrast to the high pressure and temperature usually required.
Metal Mediated C-C Ring Construction:The Nevado Route to (-)- Frondosin A
Authors: Taber Douglass F.
Published: November 2020

Barry M. Trost of Stanford University generated (J. Am. Chem. Soc. 2011, 133, 4766) a β-keto carbene from the propargyl alcohol 1, leading to the cyclopropane 2. Tsutomu Katsuki of Kyushu University devised (J. Am. Chem. Soc. 2011, 133, 170) an Ir catalyst for the enantioselective cyclopropenation of a terminal alkyne 3 to give 5. David J. Procter of the University of Manchester showed (Org. Lett. 2010, 12, 5446) that the SmI2 -mediated cyclization of 6 proceeded with high diastereocontrol. F. Dean Toste of the University of California, Berkeley, developed (J. Am. Chem. Soc. 2011, 133, 5500) a gold catalyst for the enantioselective cyclization of 8 to 9. Jon D. Rainier of the University of Utah found (Org. Lett. 2011, 13, 700) that the readily prepared diazo ester 10 cyclized smoothly to 11. Brian M. Stoltz of Caltech rearranged (Angew. Chem. Int. Ed. 2011, 50, 2756) 12, prepared by enantioselective allylation, to the cyclopentene 13. Tushar Kanti Chakraborty of the Indian Institute of Chemical Technology cyclized (Tetrahedron Lett. 2011, 52, 1709) the epoxy ester 14 to the cyclopentanol 15. Zhi-Xiang Yu of Peking University found (Angew. Chem. Int. Ed. 2011, 50, 2144) that a BINOL-derived catalyst cyclized 16 to 17. Related transition metal-mediated cyclizations (not illustrated) have been reported (Org. Lett. 2011, 13, 1517, 2630). Pher G. Andersson of Uppsala University reduced (Chem. Commun. 2011, 47, 3989) the inexpensive Birch reduction product 18 to give, after hydrolysis, the cyclohexanone 19 in high ee. Silas P. Cook of the University of Indiana found (Org. Lett. 2011, 13, 1904) conditions for the allylation of the Zn enolate resulting from enantioselective conjugate addition to cyclohexenone 20. This approach worked for other ring sizes as well. Weiping Tang of the University of Wisconsin effected (Angew. Chem. Int. Ed. 2011, 50, 1346) regioselective cyclocarbonylation of 22 to give the cyclohexanone 23. Ken Tanaka of the Tokyo University of Agriculture and Technology devised (Angew. Chem. Int. Ed. 2011, 50, 1664) a spectacular three-component coupling leading, after oxidative coupling, to the cyclohexane 26. Cristina Nevada of the University of Zurich condensed (Angew. Chem. Int. Ed. 2011, 50, 911) 27 with 28 to give, after methanolysis, the cycloheptanone 29 in high ee.
Tethered Diels-Alder Cycloaddition: (±)-Neovibsanin B (Imagawa, Nishizawa), Valerenic Acid (Mulzer), (-)-Himandrine (Movassaghi), (±)-Pallavicinolide A (Wong), (+)-Phomopsidin (Nakada)
Authors: Taber Douglass F.
Published: November 2020

It has generally been observed that prospective intramolecular Diels-Alder cycloadditions that would form a γ-lactone are reluctant to proceed. In the course of a synthesis of (±)-neovibsanin B 4, Hiroshi Imagawa and Mugio Nishizawa of Tokushima Bunri University reversed (Organic Lett. 2009, 11, 1253) the usual connectivity and found that the dienyl ester 1 could be induced to cyclize to 3. The solvent 2 improved both the yield and the diastereoselectivity of the cycloaddition. It was not surprising that Johann Mulzer of the University of Vienna could see (Organic Lett. 2009, 11, 1151) no evidence of cyclization on heating the acrylate 5. In contrast, following the lead of Barriault, they found that MgBr2 -tethered cycloaddition of methyl acrylate 7 with the alcohol 6 proceeded smoothly, to give 8, which they carried on to valerenic acid 9. Intramolecular Diels-Alder reactions to form 6,6-systems are often facile. Mohammad Movassaghi of MIT, en route to (-)-himandrine 12, showed (J. Am. Chem. Soc. 2009, 131, 9648) that the tetraene 10 cyclized to 11 at 95°C with 5:1 dr. In this case the solvent was the more typical acetonitrile with 10% diethyl aniline. The intramolecular Diels-Alder reaction is concerted but nonsynchronous (Tetrahedron Lett. 1981, 22, 5141), with β-bond formation preceding α-bond formation. This contributes to the reluctance of 8 to cyclize. In contrast, Henry N. C. Wong of the Chinese University of Hong Kong observed (Angewandte Chem. Int. Ed. 2009, 48, 2351) that the tetraene 13, which is polarity matched, cyclized to 14 spontaneously as soon as it was formed. Functional group conversion completed the synthesis of (±)-pallavicinolide A 15. The transannular Diels-Alder (TADA) reaction can proceed with high diastereocontrol, but the factors directing these cyclizations are not completely understood. In the course of a synthesis of (+)-phomopsidin 18, Masahisa Nakada of Waseda University found (Tetrahedron 2009, 65, 888) that 16 led to 17 with 16:1 dr. In contrast, the triene epimeric to 16 at the silyloxy group cyclized with only 2:1 dr.
The Nicolaou Synthesis of (+)-Vannusal
Authors: Taber Douglass F.
Published: November 2020

The correct assignment of relative configuration for portions of a complex structure that are remote one from another can present substantial difficulties. This was brought home in the course of the synthesis of (+)-vannusal 3 described (Angew. Chem. Int. Ed. 2009, 48, 5642, 5648) by K. C. Nicolau of Scripps/La Jolla. In fact, they prepared several alternative diastereomers, including the originally assigned structure, before finally coming to 3, the spectra of which matched those of the natural product. Their synthetic strategy was based on the late-stage convergent coupling of the aldehyde 13 with the iodide 19, leading to 1. The preparation of 13 began with conjugate addition of the 1-propenyl Grignard reagent 5 to the cyclohexenone 4. Deprotection, oxidation, and acetal formation led to 6, which cyclized with high diastereocontrol to 7. Carbomethoxylation of the ketone followed by Mn(OAc)3 cyclization delivered the highly strained norbornane 8 as a single diastereomer. Condensation of the derived ketone 9 with acetone 10 followed by reduction set the three remaining ternary stereogenic centers of 13. O-Alkylation of the aldehyde 11 followed by Claisen rearrangement established the alkylated quaternary center. Functional group manipulation then converted 12 into 13. The preparation of the iodide 19 began with the diene 14. Hydroboration followed by acetylation provided the meso diol. Enzymatic hydrolysis proceeded with high enantioselectivity, giving 15. Opening of the epoxide 16 with 2-propenyl lithium gave the trans alcohol, which was converted to the requisite cis alcohol 17 by Mitsunobu esterification followed by hydrolysis. Shapiro iodination of 18 then delivered 19. The iodide 19 was enantiomerically pure, but the aldehyde 13 was racemic, so coupling of the two led to 1 and its diastereomer. The cyclization of 1 with SmI2 proceeded with remarkable diastereocontrol, to give the desired 2 directly. Deprotection and oxidation then completed the synthesis of (+)-vannusal B 3. It is noteworthy that throughout this synthesis, the radicals AZADO 20 and 1-Me-AZADO 21, developed by Yoshiharu Iwabuchi (Organic Highlights, March 8, 2010), more efficient than the traditional TEMPO, were used to effect selective catalytic oxidation.
The Rawal Synthesis of N-Methylwelwitindolinone D Isonitrile
Authors: Taber Douglass F.
Published: November 2020

The complex polycyclic structure of N-methylwelwitindolinone D isonitrile 3 was assigned in 1999. The welwitinines show an intriguing range of biological activity, including reversal of P-glycoprotein-mediated multidrug resistance in human carcinoma cells. Viresh H. Rawal of the University of Chicago described (J. Am. Chem. Soc. 2011, 133, 5798) the first synthesis of 3, using as a key step the Pd-catalyzed cyclization of 1 to 2. The ketone 1 was assembled by the convergent coupling of 7 with 11. The indole 7 was readily available by Batcho-Leimgruber cyclization of commercial 4 to 5. The expected 3-acylation followed by N -methylation delivered the stable ketone 6. The unstable 7 was prepared as needed. The anisole 8 was the starting material for the preparation of the alicyclic diene 11. Although this synthesis was carried out in the racemic series, enantiomerically enriched 9 could be prepared by Shi epoxidation of the β,γ-unsaturated ketone from Birch reduction The alcohol 7 was not stable to silica gel chromatography. The mixture of 11 with the crude alcohol 7 was therefore activated by the addition of TMSOTf, then added via cannula to aqueous HClO4 in THF to deliver the coupled product 1 as a single diastereomer. The remarkable cyclization of 1 to 2 required extensive screening. Eventually it was found that a combination of ( t -Bu)3 P with Pd(OAc)2 as the Pd source worked well. This concise convergent synthetic strategy makes the welwitinine core 2 available in gram quantities. There were two problems to be solved in the conversion of 2 to 3. The first was the installation of the oxy bridge. Indoles are notoriously sensitive to overoxidation. Nevertheless, addition of an acetone solution of dimethyl dioxirane to the bromo ketone 12 over 24 hours gave clean conversion to 13. The remaining challenge was the conversion of the aldehyde of 13 to the isonitrile. Kim had described the inversion of an oxime to the isothiocyanate. Optimization of this protocol led to the thiourea 14 as the best for this transformation. Mild desulfurization then delivered N -methylwelwitindolinone D isonitrile 3.
Aiming for Excellence
Authors: Tansey Michael
Published: November 2020

Clinical trial processes are what we repeatedly do in clinical research, but, unfortunately, the habit of excellence is not as prevalent as it might be. Processes are only as good as the ways in which they are carried out, so this aspect is worth looking at before examining the processes themselves. Excellence means the very best that is achievable in a given situation with the knowledge and resources available, and it is not to be confused with perfection, which is rarely attainable, and trying to achieve it is a waste of time. Although the rational implementation of the various approaches described later can help to make the clinical development process significantly more efficient, this will not in itself achieve excellence. Implementation needs to take place in a cultural, intellectual, and operational environment that lends the necessary support. There are many possible components of such an environment, but one can go far by • instituting some basic behavioral elements; • doing things as well as they can be done all the time; • simplifying processes; • not allowing regulations to develop into liabilities. I have included this section risking that it might be considered unnecessary and patronizing by some. After all, everybody believes that their behavior is impeccable, just as everybody is a perfect driver. It only takes a few people to behave badly to poison an organization (or to injure others). . . . Laws control the lesser man. Right conduct controls the greater one. . . . . . .—Chinese proverb. . . . . .Good behavior is the last refuge of mediocrity.. . . . . . —Henry S. Haskins, stockbroker who was expelled for alleged misconduct and published his aphorisms anonymously. . . Can principles be applied that encourage positive, ethical, complex, and intelligent behavior without retreating into the lowest common denominator of mediocrity? One can argue the extent to which principles can help to achieve these objectives, but what is undeniable is that, in their absence, the results can be extremely damaging. This is exemplified not only by the poor performance metrics but also by the poor reputation of the pharmaceutical industry in the public’s view.
Redistillation: Eliminating Impurities by Carrying out Protocol Feasibility
Authors: Tansey Michael
Published: November 2020

The main objective is to make sure that a protocol designed by a committee can be carried out in the real world. Protocol feasibility is the process for determining whether or not a proposed protocol is practicable from ethical, patient, and medical practice perspectives. If not, the next step is to determine which parts need to be amended to make it practicable without undermining the objective of the proposed study. Once the operational core of the protocol has been drafted, the next essential step is to find out if there are any aspects that are either completely impracticable or impede the conduct of the study unnecessarily. Finding the balance between the fully loaded protocol that could, if the study were ever finished, provide the perfect answer for a tightly defined population, and the minimalist protocol that, although easy to carry out, might be too nonspecific and even put patients at risk, is largely an art dependent on experience. There are, however, many objective measures that can be taken to reduce uncertainty to the minimum possible. This process is called “protocol feasibility.” The term means exactly what it says (finding out if it is possible to carry out the study described in the protocol), but it has frequently become confused with or combined with other study startup activities that have nothing to do with protocol feasibility, to the detriment of all of them. Even when the term is understood, the process for determining feasibility is rarely performed rigorously in practice. Protocol feasibility includes the collection of all relevant information to determine whether or not the protocol can be carried out as planned, with subsequent modification of the protocol to bring it more in line with reality. Although most of the effort of protocol feasibility is concentrated at the site level, because the major factor is whether or not patients conforming to the protocol selection criteria actually exist in numbers large enough to make the study possible, country-specific aspects are also important and should be included in the feasibility process.
The Brain-Scrambling, Fit-Inducing, Mind-Numbing Technicolor Laser Show
Authors: Tansey Michael
Published: November 2020

The main objective is to make presentations less painful and more presentable. Presentations are made in order to provide information to an audience in such a way as to achieve a desired objective, whatever that may be. The objective is unlikely to be achieved unless the audience • wants to listen; • remains interested; • understands; • is convinced. A natural talent for presenting material effortlessly in an informative, entertaining, and engrossing way is shared by few, so most of us put disproportionate reliance on props. The most commonly used props are slides and pointers. Unfortunately, the use of slides and pointers has almost become an end in itself, often obscuring the message. As with all the processes described in this book, the aim here is to apply a core of common sense. This will not address every aspect of the use of slides and pointers or result in the perfect presentation every time (something even the most comprehensive manuals and training courses rarely achieve). What should result with consistency is more clarity and comprehensibility, and less frustration and confusion, all of which should serve to keep an audience from losing interest and fiddling with their cell phones after five minutes. Why use slides? After all, the greatest orators of all time managed to keep audiences spellbound with long recitations (just think of Homer and the Iliad) without using any props or prompts. Okay, so their audiences didn’t have TV or many other alternatives for entertainment, but that does not detract from the underlying principle, namely that audiences are generally primarily interested in what the speaker has to say, not in the props. After all, why else go to a presentation when information is so widely available today in many forms, especially electronically? The question may be answered by thinking about the good reasons for using slides. This is a common reason for most presenters, especially in situations when there is new, lengthy, detailed, or complicated information. Just as presenters have difficulty remembering detailed information, so audiences need time and different types of input (visual, as well as auditory) in order to assimilate new details.
Hallucinations and Delusions
Authors: Ahlskog J. Eric
Published: November 2020

Defining terms is an appropriate introduction to this chapter. Hallucinations imply seeing things that are not truly present, or hearing illusory voices or music. In DLB and PDD, hallucinations are nearly always visual and manifest as seeing nonexistent people or objects, such as strangers in the house or yard. The affected individual may realize that he or she is experiencing a hallucination, but some people may not recognize that these are not real. In other disorders auditory hallucinations may be present, such as hearing voices. However, such auditory hallucinations are rare in Lewy disorders. Delusions are defined as false, often irrational beliefs. Frequently, these will have a theme, such as the conviction that someone is spying, or paranoia about friends or neighbors. A common theme is spousal infidelity, sometimes nonsensical, such as an older adult’s accusations of their mate starting an extramarital affair after 50 years of marriage. Capgras syndrome is an uncommon but striking example of delusional thinking in which the spouse or other immediate family member is accused of being an impostor. Hallucinations or delusions may occur in Parkinson’s disease in the absence of frank dementia. However, dementia is the usual setting for these problems. Hallucinations are much more common than delusions. Sometimes they are very limited, perhaps only present at night. Hallucinations are a contraindication to driving a motor vehicle, for obvious reasons. The fundamental cause of hallucinations and delusions in DLB and PDD is the Lewy neurodegenerative process. The precise region of the brain that is responsible is not known, however. These often occur in the absence of any external provocative factors. However, medications are notorious for inciting such problems in susceptible people. Chapter 7 focused on simplifying medications especially for this reason. Drugs for parkinsonism are well-known culprits, in particular two classes: (1) the dopamine agonists: pramipexole (Mirapex), ropinirole (Requip) and rotigotine (Neupro patch); and (2) anticholinergic drugs: trihexyphenidyl (Artane) and benztropine (Cogentin). Carbidopa/levodopa by itself may provoke hallucinations, but that is not very common unless combined with other drugs for parkinsonism.
Pathologic Behaviors Provoked by Dopamine Agonist Drugs: Gambling, Sex, Eating, and Spending
Authors: Ahlskog J. Eric
Published: November 2020

Dopamine agonists are synthetic medications that stimulate dopamine receptors. They are commonly used for treatment of Parkinson’s disease and in lower doses for restless legs syndrome. This drug class includes pramipexole (Mirapex), ropinirole (Requip), and the rotigotine patch (Neupro). These drugs have special properties, with unique adverse effects that are not intuitively associated with the drug. Hence, a brief chapter is devoted to these side effects. If the patient is not taking one of these medications, this chapter may be skipped. Several years ago clinicians recognized that pramipexole and ropinirole were associated with the development of pathologic gambling. Insidiously, a minority of people who were prescribed these medications began experiencing the desire to gamble, such as at casinos or online. For some, this was an exacerbation of prior tendencies, but for others this desire came out of the blue, with no prior gambling history. Other types of compulsive pathologic behaviors soon were also recognized in some people treated with these drugs. This included inappropriate hypersexual behavior (extramarital affairs, pornography) and compulsive spending, eating, drinking, or smoking. In many people, this behavior was completely out of character. The common element was the initiation of pramipexole or ropinirole. The behaviors did not develop immediately, but insidiously became apparent after the medication was slowly escalated into the therapeutic range. Patients and family were often oblivious to the behavior or relation to the drug until specifically asked about it in the doctor’s office. The common theme among these compulsive behaviors is that they are inherently rewarding human experiences. It became recognized that use of these dopamine agonist drugs by some people was associated with a pathologic drive to excessively engage in such activities as gambling, sex, eating, or spending. For affected people, this began to dominate their thoughts and actions. Who would think that a drug could drive specific hedonistic or rewarding behaviors? Experience in the clinic and published evidence, however, corroborates this risk. The two primary agents that have been implicated are pramipexole (Mirapex) and ropinirole (Requip). The rotigotine patch has also been associated with such behaviors, but apparently less frequently.
Dementia: Impaired Thinking and Judgment; Confusion
Authors: Ahlskog J. Eric
Published: November 2020

Dementia implies problems with cognition (thinking), and this is a fundamental component of DLB and PDD. Dementia also implies that the cognitive problems are sufficiently troublesome to affect activities of daily living. Less severe impairment of memory or thinking that does not interfere with daily activities is classified as mild cognitive impairment (MCI). MCI may be a prelude to dementia. If MCI accompanies parkinsonism, then the treatment strategies outlined in this text are appropriate. Dementia does not necessarily mean that a rapid progression to an advanced state is inevitable. Dementia may be relatively mild and well compensated, especially with the help of the spouse and family; it may remain that way for years. The cognitive profile of DLB and PDD was described in Chapter 4. To review, this impairment affects several major components of intellect. This includes executive function, localized to the frontal lobes of the brain. Visuospatial conceptualization is similarly affected, which reflects problems in the posterior brain (i.e., parietal and occipital lobes). Memory declines in DLB and PDD, but less than in Alzheimer’s disease. Fluctuations in mental clarity are often noted in these Lewy disorders, where near-normal thinking may be followed hours later by confusion. In Chapter 4, the process of diagnosing DLB and PDD was also discussed. Before clinicians consider such a diagnosis, however, they must be certain that they have not overlooked any other treatable causes or contributors. Sometimes the DLB or PDD diagnosis is correct but the dementia is exacerbated by some other factor. In this chapter, those factors and the appropriate workup are considered. One should not arrive at the final diagnosis of a neurodegenerative dementia before considering treatable factors, including medical conditions, brain lesions (e.g., bleeds), and medication effects. This is especially relevant if there has been a rapid decline or recent onset. Prescription drugs are a common cause of cognitive impairment. Before ordering tests, it is appropriate to go over all medications that the patient is taking. Commonly prescribed drugs that can impair cognition include those shown in Table 12.1. This is not an exhaustive list. The primary clinician should decide what, if any, medication should be eliminated.