Organocatalytic C-C Ring Construction: (+)-Ricciocarpin A (List) and (-)-Aromadendranediol (MacMillan)

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Aldol Condensation ◽  
Catalytic Amount ◽  
Heterocyclic Carbenes ◽  
University Of Pennsylvania ◽  
State University ◽  
Max Planck ◽  
Mannich Condensation ◽  
The University ◽  
Oregon State University ◽  
Prochiral Ketone

Yoshiji Takemoto of Kyoto University designed (Organic Lett. 2009, 11, 2425) an organocatalyst for the enantioselective conjugate addition of alkene boronic acids to γ-hydroxy enones, leading to 1 in high ee. Attempted Mitsunobu coupling led to the cyclopropane 2, while bromoetherification followed by intramolecular alkylation delivered the cyclopropane 3. Jeffrey W. Bode of the University of Pennsylvania demonstrated (Organic Lett. 2009, 11, 677) a remarkable dichotomy in the reactivity of N-heterocyclic carbenes. A triazolium precatalyst combined 4 and 5 to give 6, whereas an imidazolium precatalyst combined 4 and 5 to give 7. Xinmiao Liang of the Dalian Institute of Chemical Physics and Jinxing Ye of the East China University of Science and Technology devised (Organic Lett. 2009, 11, 753) a Cinchona -derived catalyst that converted the prochiral cyclohexenone 8 into the diester 10 in high ee. Rich G. Carter of Oregon State University found (J. Org. Chem. 2009, 74, 2246) a simple sulfonamide-based proline catalyst that effected the Mannich condensation of the prochiral ketone with ethyl glyoxalate 12 and the amine 13, leading to the amine 14. In the first pot of a concise, three-pot synthesis of (-)-oseltamivir, Yujiro Hayashi of the Tokyo University of Science combined (Angew. Chem. Int. Ed. 2009, 48, 1304) 15 and 16 in the presence of a catalytic amount of diphenyl prolinol TMS ether to give an intermediate nitro aldehyde. Addition of the phosphonate 17 led to a cyclohexenecarboxylate, that on the addition of the thiophenol 18 equilibrated to the ester 19. Ying-Chun Chen of Sichuan University used (Organic Lett. 2009, 11, 2848) a related diaryl prolinol TMS ether to direct the condensation of the readily-prepared phosphorane 20 with the unsaturated aldehyde 21 to give the cyclohexenone 22. Armando Córdova of Stockholm University also used (Tetrahedron Lett. 2009, 50, 3458) diphenyl prolinol TMS ether to mediate the addition of 24 to 23. The subsequent intramolecular aldol condensation proceeded with high diastereocontrol, leading to 25. Benjamin List of the Max-Planck Institut, Mülheim employed (Nat. Chem. 2009, 1, 225) a MacMillan catalyst for the reductive cyclization of 26.

Organocatalyzed C–C Ring Construction: The Mihovilovic Synthesis of Piperenol B

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
State University ◽  
Air Oxidation ◽  
Microbial Oxidation ◽  
Max Planck ◽  
National Chemical Laboratory ◽  
Chemical Laboratory ◽  
Northwestern University ◽  
National University ◽  
The University ◽  
Oregon State University

M. Kevin Brown of Indiana University prepared (J. Am. Chem. Soc. 2015, 137, 3482) the cyclobutane 3 by the organocatalyzed addition of 2 to the alkene 1. Karl Anker Jørgensen of Aarhus University assembled (J. Am. Chem. Soc. 2015, 137, 1685) the complex cyclobutane 7 by the addition of 5 to the acceptor 4, followed by conden­sation with the phosphorane 6. Zhi Li of the National University of Singapore balanced (ACS Catal. 2015, 5, 51) three enzymes to effect enantioselective opening of the epoxide 8 followed by air oxidation to 9. Gang Zhao of the Shanghai Institute of Organic Chemistry and Zhong Li of the East China University of Science and Technology added (Org. Lett. 2015, 17, 688) 10 to 11 to give 12 in high ee. Akkattu T. Biju of the National Chemical Laboratory combined (Chem. Commun. 2015, 51, 9559) 13 with 14 to give the β-lactone 15. Paul Ha-Yeon Cheong of Oregon State University and Karl A. Scheidt of Northwestern University reported (Chem. Commun. 2015, 51, 2690) related results. Dieter Enders of RWTH Aachen University constructed (Chem. Eur. J. 2015, 21, 1004) the complex cyclopentane 20 by the controlled com­bination of 16, 17, and 18, followed by addition of the phosphorane 19. Derek R. Boyd and Paul J. Stevenson of Queen’s University Belfast showed (J. Org. Chem. 2015, 80, 3429) that the product from the microbial oxidation of 21 could be protected as the acetonide 22. Ignacio Carrera of the Universidad de la República described (Org. Lett. 2015, 17, 684) the related oxidation of benzyl azide (not illustrated). Manfred T. Reetz of the Max-Planck-Institut für Kohlenforschung and the Philipps-Universität Marburg found (Angew. Chem. Int. Ed. 2014, 53, 8659) that cytochrome P450 could oxidize the cyclohexane 23 to the cyclohexanol 24. F. Dean Toste of the University of California, Berkeley aminated (J. Am. Chem. Soc. 2015, 137, 3205) the ketone 25 with 26 to give 27. Benjamin List, also of the Max-Planck-Institut für Kohlenforschung, reported (Synlett 2015, 26, 1413) a parallel investigation. Philip Kraft of Givaudan Schweiz AG and Professor List added (Angew. Chem. Int. Ed. 2015, 54, 1960) 28 to 29 to give 30 in high ee.

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.

The Carter Synthesis of (-)-Lycopodine

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Aldol Condensation ◽  
Enantioselective Synthesis ◽  
State University ◽  
X Ray Crystallography ◽  
Racemic Form ◽  
Lycopodium Alkaloid ◽  
Silyl Enol Ether ◽  
Mannich Condensation ◽  
Oppenauer Oxidation ◽  
Oregon State University

Rich G. Carter of Oregon State University described (J. Am. Chem. Soc. 2008, 130, 9238) the first enantioselective synthesis of the Lycopodium alkaloid (-)-lyopodine 3. A key step in the assembly of 3 was the diastereoselective intramolecular Michael addition of the keto sulfone of 1 to the enone, leading to the cyclohexanone 2. The key cyclization substrate 1 bore a single secondary methyl group. While that could have been derived from a natural product, it was operationally easier to effect chiral auxiliary controlled conjugate addition to the crotonyl amide 4, leading, after methoxide exchange, to the ester 5. The authors reported that double deprotonation with LiTMP gave superior results, vs. LDA or BuLi, in the condensation of 6 with 5 to give 7. Metathesis with pentenone 8 gave the intramolecular Michael substrate 1. The authors thought that they would need a chiral catalyst to drive the desired stereocontrol in the cyclization of 1 to 2. As a control, they tried an achiral base first, and were pleased to observe the desired diastereomer crystallize from the reaction mixture in 89% yield. The structure of 2 was confirmed by X-ray crystallography. To prepare for the intramolecular Mannich condensation, the azide was reduced to give the imine, and the methyl ketone was converted to the silyl enol ether. Under Lewis acid conditions, the sulfonyl group underwent an unanticipated 1,3-migration, to give 11. Cyclization of 12 then delivered the crystalline 14. Reduction converted 14 to the known (in racemic form) ketone 15. To complete the synthesis, the amine 15 was alkylated with 16 to give the alcohol 17. Oppenauer oxidation followed by aldol condensation delivered the cyclized enone, that was reduced with the Stryker reagent to give (-)-Lycopodine 3. Both the cyclization of 1 to 2 and the cyclization of 9 to 14 are striking. It may be that the steric demand of the phenylsulfonyl group destabilizes the competing transition state for the cyclization of 1.

scholarly journals Why Age Matters to Higher Education: Age-Friendly Tools and Techniques for Culture Change

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 551-551
Author(s):  
David Burdick ◽  
Karen Rose ◽  
Dana Bradley
Keyword(s):  
University Presidents ◽  
Steering Committee ◽  
State University ◽  
Community Members ◽  
University Leadership ◽  
Drexel University ◽  
College Of Nursing ◽  
Tools And Techniques ◽  
The University ◽  
Oregon State University

Abstract Momentum is growing for the Age-Friendly University Network as proponents, primarily gerontology educators, have successfully encouraged university presidents to sign nonbinding pledged to become more age-friendly in programs and policies, endorsing 10 Age-Friendly University Principles. While this trend is inspiring, more is needed to fully achieve benefits for universities, students, communities, and older adults. Four presentations discuss innovative ways of deepening university commitment, weaving the principles into the fabric of the university. The first paper describes thematic content analysis from five focus groups with admissions and career services staff at Washington University in St. Louis and the recommendations that emerged for the provision of programs and services for post-traditional students. The second paper describes efforts to utilize community-impact internships and community partnerships to build support for Age-Friendly University initiatives at Central Connecticut State University, particularly in the context of the university’s recent Carnegie Foundation Engaged Campus designation. The third paper describes how Drexel University became Philadelphia’s first Age-Friendly University and current efforts in the Drexel College of Nursing and Heatlh Care Profession’s AgeWell Collaboratory to convene university-wide leadership for an AFU Steering Committee working on four mission-driven efforts to ensure AFU sustainability. The fourth paper describes steps taken by AFU proponents at Western Oregon State University to gain endorsement from university leadership and community, including mapping the 10 AFU Principles to the university’s strategic plan, faculty senate endorsement, and survey/interview results of older community members’ use of the university, which collectively have enhanced deeper and broader campus buy-in of AFU.

C-O Ring Containing Natural Products: Paeonilactone B (Taylor), Deoxymonate B (de la Pradilla), Sanguiin H-5 (Spring), Solandelactone A (White), Spirastrellolide A (Paterson)

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Oxidative Coupling ◽  
Claisen Rearrangement ◽  
Cyclic Carbonate ◽  
Membered Ring ◽  
State University ◽  
Enantiomerically Pure ◽  
University Of Cambridge ◽  
Spirastrellolide A ◽  
The University ◽  
Oregon State University

Richard J. K. Taylor of the University of York has developed (Angew. Chem. Int. Ed. 2008, 47, 1935) the diasteroselective intramolecular Michael cyclization of phosphonates such as 2. Quenching of the cyclized product with paraformaldehyde delivered ( + )-Paeonilactone B 3. Roberto Fernández de la Pradilla of the CSIC, Madrid established (Tetrahedron Lett. 2008, 49, 4167) the diastereoselective intramolecular hetero Michael addition of alcohols to enantiomerically-pure acyclic sulfoxides such as 4 to give the allylic sulfoxide 5. Mislow-Evans rearrangement converted 5 into 6, the enantiomerically-pure core of Ethyl Deoxymonate B 7. The ellagitannins, represented by 10, are single atropisomers around the biphenyl linkage. David R. Spring of the University of Cambridge found (Organic Lett. 2008, 10, 2593) that the chiral constraint of the carbohydrate backbone of 9 directed the absolute sense of the oxidative coupling of the mixed cuprate derived from 9, leading to Sanguiin H-5 10 with high diastereomeric control. A key challenge in the synthesis of the solandelactones, exemplified by 14, is the stereocontrolled construction of the unsaturated eight-membered ring lactone. James D. White of Oregon State University found (J. Org. Chem. 2008, 73, 4139) an elegant solution to this problem, by exposure of the cyclic carbonate 11 to the Petasis reagent, to give 12. Subsequent Claisen rearrangement delivered the eight-membered ring lactone, at the same time installing the ring alkene of Solandelactone E 14. AD-mix usually proceeds with only modest enantiocontrol with terminal alkenes. None the less, Ian Paterson, also of the University of Cambridge, observed (Angew. Chem. Int. Ed. 2008, 47, 3016, Angew. Chem. Int. Ed. 2008, 47, 3021) that bis-dihydroxylation of the diene 17 proceeded to give, after acid-mediated cyclization, the bis-spiro ketal core 18 of Spirastrellolide A Methyl Ester 19 with high diastereocontrol.

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.

Establishing Arrays of Stereogenic Centers: The Sato/Chida Synthesis of (-)-Kainic Acid

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Catalyst System ◽  
Allylic Alcohol ◽  
University Of Pennsylvania ◽  
Ni Catalyst ◽  
Max Planck ◽  
Stereogenic Centers ◽  
University College London ◽  
Enantioselective Addition ◽  
La Jolla ◽  
The University

Benjamin List of the Max-Planck-Institut, Mülheim, devised (J. Am. Chem. Soc. 2010, 132, 10227) a catalyst system for the stereocontrolled epoxidation of a trisubstituted alkenyl aldehyde 1. Takashi Ooi of Nagoya University effected (Angew. Chem. Int. Ed. 2010, 49, 7562; see also Org. Lett. 2010, 12, 4070) enantioselective Henry addition to an alkynyl aldehyde 3. Madeleine M. Joullié of the University of Pennsylvania showed (Org. Lett. 2010, 12, 4244) that an amine 7 added selectively to an alkynyl aziridine 6. Yutaka Ukaji and Katsuhiko Inomata of Kanazawa University developed (Chem. Lett. 2010, 39, 1036) the enantioselective dipolar cycloaddition of 9 with 10. K. C. Nicolaou of Scripps/La Jolla observed (Angew. Chem. Int. Ed. 2010, 49, 5875; see also J. Org. Chem. 2010, 75, 8658) that the allylic alcohol from enantioselective reduction of 12 could be hydrogenated with high diastereocontrol. Masamichi Ogasawara and Tamotsu Takahashi of Hokkaido University added (Org. Lett. 2010, 12, 5736) the allene 14 to the acetal 15 with substantial stereocontrol. Helen C. Hailes of University College London investigated (Chem. Comm. 2010, 46, 7608) the enzyme-mediated addition of 18 to racemic 17. Dawei Ma of the Shanghai Institute of Organic Chemistry, in the course of a synthesis of oseltamivir (Tamiflu), accomplished (Angew. Chem. Int. Ed. 2010, 49, 4656) the enantioselective addition of 21 to 20. Shigeki Matsunaga of the University of Tokyo and Masakatsu Shibasaki of the Institute of Microbial Chemistry developed (Org. Lett. 2010, 12, 3246) a Ni catalyst for the enantioselective addition of 23 to 24. Juthanat Kaeobamrung and Jeffrey W. Bode of ETH-Zurich and Marisa C. Kozlowski of the University of Pennsylvania devised (Proc. Natl. Acad. Sci. 2010, 107, 20661) an organocatalyst for the enantioselective addition of 27 to 26. Yihua Zhang of China Pharmaceutical University and Professor Ma effected (Tetrahedron Lett. 2010, 51, 3827) the related addition of 27 to 29. There have been scattered reports on the stereochemical course of the coupling of cyclic secondary organometallics. In a detailed study, Paul Knochel of Ludwig-Maximilians- Universität München showed (Nat. Chem. 2020, 2, 125) that equatorial bond formation dominated, exemplified by the conversion of 31 to 33.

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.

Congratulations! The Second JDR Award

2017 ◽  
Vol 12 (2) ◽  
pp. 222-222
Author(s):  
Editors-in-Chief ◽  
Haruo Hayashi
Keyword(s):  
State University ◽  
Award Winner ◽  
Award Ceremony ◽  
Future Success ◽  
The University ◽  
Oregon State University

The second JDR Award ceremony was held in Kasumigaseki, Japan, at November 22, 2016 and the certificate was given to the JDR award winner, Prof. Harry Yeh of Oregon State University (Prof. Shinji Sato of the University of Tokyo received it as a dupty). We congratulate the winner and sincerely wish for future success.

The Smith Synthesis of ( + )-Lyconadin A

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Total Synthesis ◽  
Aldol Condensation ◽  
Primary Alcohol ◽  
Selective Reduction ◽  
Axial Direction ◽  
In Vitro Cytotoxicity ◽  
University Of Pennsylvania ◽  
Enantiomerically Pure ◽  
The University

The pentacyclic alkaloid ( + )-lyconadin A 3, isolated from the club moss Lycopodium complanatum, showed modest in vitro cytotoxicity. A key step in the first reported (J. Am. Chem. Soc. 2007, 129, 4148) total synthesis of 3, by Amos B. Smith III of the University of Pennsylvania, was the cyclization of 1 to 2. The pentacyclic alkaloid (+)-lyconadin A 3, isolated from the club moss Lycopodium complanatum, showed modest in vitro cytotoxicity. A key step in the first reported (J. Am. Chem. Soc. 2007, 129, 4148) total synthesis of 3, by Amos B. Smith III of the University of Pennsylvania, was the cyclization of 1 to 2. The pentacyclic skeleton of 3 was constructed around a central organizing piperidine ring 9. This was prepared from the known (and commercial) enantiomerically-pure lactone 4. The akylated stereogenic center of 9 was assembled by diastereoselective hydroxy methylation of the acyl oxazolidinone 5 with s-trioxane, followed by protection. Reduction of the imide to the alcohol led to the mesylate 7, which on reduction of the azide spontaneously cyclized to give, after protection, the piperidine 8. Selective desilylation of the primary alcohol then enabled the preparation of 9. The plan was to assemble the first carbocyclic ring of 3 by intramolecular aldol condensation of the keto aldehyde 15. The enantiomerically-pure secondary methyl substituent of 15 derived from the commercial monoester 10. Activation as the acid fluoride followed by selective reduction led to the volatile lactone 11. Opening of the lactone with H3CONHCH3HCl gave, after protection, the Weinreb amide 12. Alkylation of the derived hydrazone 13, selectively on the methyl group, led, after deprotection, to 15. The intramolecular aldol condensation of 15 did deliver the unstable cyclohexenone 1. Under the acidic conditions of the aldol condensation, the enol derived from the piperidone added in a Michael sense, from the axial direction on the newly-formed ring, to give the trans-fused bicyclic diketone 2.

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