Synthesis of Naturally Occurring Cyclic Ethers: Boivivianin B (Murakami), SC- Δ 13 -9-IsoF (Taber), Brevisamide (Panek, Lindsley,Ghosh), Gambierol (Mori)

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Absolute Configuration ◽  
Cyclic Ether ◽  
Diels Alder ◽  
Synthetic Methods ◽  
Hydroxy Ketone ◽  
Total Syntheses ◽  
Enantiomerically Pure ◽  
Boston University ◽  
Gambierdiscus Toxicus ◽  
The University

The challenge of controlling the relative and absolute configuration of highly substituted cyclic ether-containing natural products continues to stimulate the development of new synthetic methods. Masahiro Murakami of Kyoto University showed (J. Org. Chem. 2009, 74, 6050) that Rh-mediated addition of an aryl boronic acid to 1 proceeded with high syn diastereocontrol, giving 3. This set the stage for Au-mediated rearrangement, leading to 4. We found (J. Org. Chem. 2009, 74, 5516) that asymmetric epoxidation of 5 followed by exposure to AD-mix could be used to prepare each of the four diastereomers of 6. We carried 6 on the isofuran 7, using a stereodivergent strategy that allowed the preparation of each of the 32 enantiomerically pure diastereomers of the natural product. Following up on the synthesis of brevisamide 16 described (Organic Highlights, November 16, 2009) by Kazuo Tachibana of the University of Tokyo, three groups reported alternative total syntheses. James S. Panek of Boston University prepared (Organic Lett. 2009, 11, 4390) the cyclic ether of 16 by addition of the enantiomerically pure silane 9 to 8. Craig W. Lindsley of Vanderbilt University used (Organic Lett. 2009, 11, 3950) SmI2 to effect the cyclization of 11 to 12. Arun K. Ghosh of Purdue University employed (Organic Lett. 2009, 11, 4164) an enantiomerically pure Cr catalyst to direct the absolute configuration in the hetero Diels-Alder addition of 14 to 13. Rubottom oxidation of the enol ether so formed led to the α-hydroxy ketone 15. Yuji Mori of Meijo University described (Organic Lett. 2009, 11, 4382) the total synthesis of the Gambierdiscus toxicus ladder ether gambierol 19. A key strategy, used repeatedly through the sequence, was the exo cyclization of an epoxy sulfone, illustrated by the conversion of 17 to 18. The epoxy sulfones were prepared by alkylating the anions derived from preformed epoxy sulfones such as 20.

Diels–Alder Cycloaddition: Sarcandralactone A (Snyder), Pseudopterosin (−)-G-J Aglycone (Paddon-Row/Sherburn), IBIR-22 (Westwood), Muironolide A (Zakarian), Platencin (Banwell), Chatancin (Maimone)

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Absolute Configuration ◽  
Alder Reaction ◽  
Diels Alder ◽  
University Of California ◽  
Enantiomerically Pure ◽  
Protein Protein Interaction ◽  
South Wales ◽  
National University ◽  
The Absolute ◽  
The University

En route to sarcandralactone A 3, Scott A. Snyder of Scripps Florida effected (Angew. Chem. Int. Ed. 2015, 54, 7842) Diels–Alder cycloaddition of the activated enone 1 to the Danishefsky diene. On exposure to trifluoroacetic acid, the adduct was unraveled to the ene dione 2. Michael N. Paddon-Row of the University of New South Wales and Michael S. Sherburn of the Australian National University prepared (Nature Chem. 2015, 7, 82) the allene 4 in enantiomerically-pure form. Sequential cycloaddition with 5 followed by 6 gave an adduct that was decarbonylated to 7. Further cycloaddition with nitro­ethylene 8 led to the pseudopterosin (−)-G-J aglycone 9. The protein–protein interaction inhibitor JBIR-22 12 contains a quaternary α-amino acid pendant to a bicyclic core. Nicholas J. Westwood of the University of St. Andrews set (Angew. Chem. Int. Ed. 2015, 54, 4046) the absolute configuration of the core 11 by using an organocatalyst to activate the cyclization of 10. Metal catalysts can also be used to set the absolute configuration of a Diels–Alder cycloaddition. In the course of establishing the structure of the marine natural prod­uct muironolide A 15, Armen Zakarian of the University of California, Santa Barbara cyclized (J. Am. Chem. Soc. 2015, 137, 5907) the enol form of 13 preferentially to the diastereomer 14. Unactivated intramolecular Diels–Alder cycloadditions have been carried out with more and more challenging substrates. A key step in the synthesis (Chem. Asian. J. 2015, 10, 427) of (−)-platencin 18 by Martin G. Banwell, also of the Australian National University, was the cyclization of 16 to 17. In another illustration of the power of the unactivated intramolecular Diels–Alder reaction, Thomas J. Maimone of the University of California, Berkeley cyclized (Angew. Chem. Int. Ed. 2015, 54, 1223) the tetraene 19 to the tricycle 20. Allylic chlo­rination followed by reductive cyclization converted 20 to chatancin 21.

C-O Ring Construction: The Theodorakis Synthesis of (-)-Englerin A

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Ring Expansion ◽  
Propargyl Alcohol ◽  
Oxidative Cyclization ◽  
University Of California ◽  
Hydroxy Ketone ◽  
Santa Barbara ◽  
University Of Pittsburgh ◽  
Enantiomerically Pure ◽  
Boston University ◽  
The University

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.

Complex Cyclic Ethers: (+)-Conocarpan (Hashimoto), (-)-Brevisamide (Satake/ Tachibana), (+)-Bruguierol A (Fañanás/ Rodríguez), (-)-Berkelic Acid (Snider), and (-)-Aigialomycin D (Harvey)

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Absolute Configuration ◽  
Cyclic Ether ◽  
Membered Ring ◽  
Open Pit ◽  
Relative Configuration ◽  
Enantiomerically Pure ◽  
Berkelic Acid ◽  
The Absolute ◽  
Berkeley Pit ◽  
The University

( + )-Conocarpan 3, isolated from the wood of Conocarpus erectus , exhibits insecticidal, antifungal and antitrypanosomal activity. Shunichi Hashimoto of Hokkaido University developed (J. Org. Chem. 2009, 74 , 4418) a chiral Rh (II) carboxylate that effected the cyclization of 1 to 2, setting the absolute configuration of 3. The dinoflagellate Karenia brevis produces the brevetoxins, a family of complex polyethers. Recently, the first N-containing cyclic ether, (-)-Brevisamide 6, was isolated from K. brevis . Masayuki Satake and Kazuo Tachibana of the University of Tokyo, in their synthesis of 6 (Organic Lett. 2009, 11, 217) found it convenient to set the relative configuration around the six-membered ring by double hydroboration/oxidation of the diene 4. ( + )-Bruguierol A 9, isolated from the mangrove Bruguiera gymmorrhiza, has an unusual bridged structure. Francisco J. Fañanás and Félix Rodríguez of the Universidad de Oviedo conceived (J. Org. Chem. 2009, 74, 932) an elegant approach to the construction of 9, based on the Pt-mediated addition of the alcohol of 7 to the alkyne to give a transient enol ether. It is not clear whether the subsequent intramolecular electrophilic addition to the aromatic ring is mediated by the Pt, or by a trace of adventitious acid. The overall transformation was remarkably efficient. The Berkeley Pit in Butte, Montana, is an abandoned open-pit copper mine filled with 30 billion gallons of pH = 2.5 water heavily contaminated with, inter alia , copper, cadmium, arsenic and zinc. Remarkably, microorganisms can be cultured from that water. (-)-Berkelic Acid 13 , isolated from a Penicillium fungus, showed selective activity against OVCAR-3 ovarian cancer. Barry B. Snider of Brandeis University set (Angew. Chem. Int. Ed. 2009, 48, 1283) the absolute configuration of the central five-membered ring ether of 13 by conjugate addition of the enantiomerically-pure reagent 11 to the prochiral lactone 10. (-)-Aigialomycin D 17, isolated from the mangrove fungus Aigialus parvus , was found to be a selective inhibitor of the kinases CDK1, CDK5 and GSK3.

Diels-Alder Cycloaddition: (+)-Armillarivin (Banwell), Gelsemiol (Gademann), (+)-Frullanolide (Liao), Myceliothermophin A (Uchiro), Peribysin E (Reddy), Caribenol A (Li/Yang)

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Elevated Pressure ◽  
Diels Alder ◽  
Cope Rearrangement ◽  
National Chemical Laboratory ◽  
Chemical Laboratory ◽  
Enantiomerically Pure ◽  
Peking University ◽  
National University ◽  
Diastereoselective Addition ◽  
The University

Martin G. Banwell of the Australian National University prepared (Org. Lett. 2013, 15, 1934) the enantiomerically pure diol 1 by fermentation of the aromatic precursor. Diels-Alder addition of cyclopentenone 2 proceeded well at elevated pressure to give 3, the precursor to (+)-armillarivin 4. Karl Gademann of the University of Basel found (Chem. Eur. J. 2013, 19, 2589) that the Diels-Alder addition of 6 to 5 proceeded best without solvent and with Cu catalysis to give 7. Reduction under free radical conditions led to gelsemiol 8. Chun-Chen Liao of the National TsingHua University carried out (Org. Lett. 2013, 15, 1584) the diastereoselective addition of 10 to 9. A later oxy-Cope rearrangement established the octalin skeleton of (+)-frullanolide 12. D. Srinivasa Reddy of CSIR-National Chemical Laboratory devised (Org. Lett. 2013, 15, 1894) a strategy for the construction of the angularly substituted cis-fused aldehyde 15 based on Diels-Alder cycloaddition of 14 to the diene 13. Further transformation led to racemic peribysin-E 16. An effective enantioselective catalyst for dienophiles such as 14 has not yet been developed. Hiromi Uchiro of the Tokyo University of Science prepared (Tetrahedron Lett. 2012, 53, 5167) the bicyclic core of myceliothermophin A 19 by BF3•Et2O-promoted cyclization of the tetraene 17. The single ternary center of 17 mediated the formation of the three new stereogenic centers of 18, including the angular substitution. En route to caribenol A 22, Chuang-Chuang Li and Zhen Yang of the Peking University Shenzen Graduate School assembled (J. Org. Chem. 2013, 78, 5492) the triene 20 from two enantiomerically pure precursors. Inclusion of the radical inhibitor BHT sufficed to suppress competing polymerization, allowing clean cyclization to 21. Methylene blue has also been used (J. Am. Chem. Soc. 1980, 102, 5088) for this purpose.

Diels–Alder Cycloaddition: Pancratistatin (Cho), Nootkatone (Reddy), Platensimycin (Zhang/Lee), Scabronine G (Nakada), Isoglaziovianol (Trauner)

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Aldol Condensation ◽  
Diels Alder ◽  
Cancer Center ◽  
Columbia University ◽  
National Chemical Laboratory ◽  
Chemical Laboratory ◽  
Intramolecular Cycloaddition ◽  
Enantiomerically Pure ◽  
Peking University ◽  
The University

Samuel J. Danishefsky of Columbia University and the Memorial Sloan-Kettering Cancer Center made (Proc. Natl. Acad. Sci. 2013, 110, 10904) the unexpected obser­vation that methylation of the enolate derived from conjugate addition to the readily-prepared 1 followed by intramolecular alkene metathesis led to the trans fused ketone 2. This can be contrasted to the diastereo- and regioisomer 3, the product from Diels-Alder cycloaddition of 2-methylcyclohexenone to isoprene. The trans ring fusion of 2 is particularly significant because ozonolysis followed by aldol condensation would deliver the angularly-methylated trans-fused 6/5 C–D ring system of the steroids and related natural products. Cheon-Gyu Cho of Hanyang University added (Org. Lett. 2013, 15, 5806) the activated dienophile 4 to the dienyl lactone to give, after oxidation, the dibro­mide 5. Debromination followed by oxidation led to the antineoplastic lactam pancratistatin 6. D. Srinivasa Reddy of CSIR-National Chemical Laboratory Pune devised (J. Org. Chem. 2013, 78, 8149) a cascade protocol of Diels-Alder cycloaddition of 8 to the diene 7, followed by intramolecular aldol condensation, to give the enone 9. Oxidative manipulation followed by methylenation completed the synthesis of the commercially important grapefruit flavor nootkatone 10. Xinhao Zhang and Chi-Sing Lee of the Peking University Shenzen Graduate School uncovered (J. Org. Chem. 2013, 78, 7912) another cascade transformation, intermolecular addition of 11 to 12 followed by intramolecular Conia-ene cyclization, to give the tricyclic 13. Further manipulation led to an established intermediate for the total synthesis of platensimycin 14. Masahisa Nakada of Waseda University prepared (Angew. Chem. Int. Ed. 2013, 52, 7569) the enantiomerically-pure allene 15. Oxidation of the phenol to the monoketal of the cyclohexadienone set the stage for intramolecular cycloaddition to give 16. Oxidative cleavage followed by intramolecular alkene metathesis led to (+)-scabronine G 17. Dirk Trauner of the University of Munich assembled (Org. Lett. 2013, 15, 4324) the enantiomerically-pure alcohol 18. Oxidation gave the quinone, leading to intra­molecular Diels–Alder cycloaddition. The free alcohol then added to the exocyclic alkene of that product, to give, after further oxidation, the ether 19. Deprotection fol­lowed by reduction then completed the synthesis of (−)-isoglaziovianol 20.

Stereoselective C-N Ring Construction

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Organic Chemistry ◽  
Diels Alder ◽  
Wolff Rearrangement ◽  
Enantiomerically Pure ◽  
Amino Esters ◽  
Shanghai Institute ◽  
Single Diastereomer ◽  
Peking University ◽  
Convenient Route ◽  
The University

Ryoichi Kuwano of Kyushu University showed (J. Am. Chem. Soc. 2008, 130, 808) that diastereomerically and enantiomerically pure pyrollidines such as 2 could be prepared by hydrogenation of the corresponding pyrrole. Victor S. Martín of Universidad de la Laguna found (Organic Lett. 2008, 10, 2349) that the stereochemical outcome of the pyrrolidine-forming Nicholas cyclization could be directed by the protecting group on the N. Jianbo Wang of Peking University established (J. Org. Chem. 2008, 73, 1971) a convenient route to diazo esters such as 6. N-H insertion led to the pyrrolidine, which Zhen-Jiang Xu of the Shanghai Institute of Organic Chemistry and Chi-Ming Che of the University of Hong Kong showed (Organic Lett. 2008, 10, 1529) could be reduced with high diastereoselectivity to the hydroxy ester 7. Alternatively, Professor Wang found that photochemical Wolff rearrangement of 6 delivered the pyrrolidone 8 . Martin J. Slater and Shiping Xie of GlaxoSmithKline optimized (J. Org. Chem. 2008, 73, 3094) the hydroquinine catalyzed enantioselective 3+2 cycloaddition of 9 and 10, leading to the pyrrolidine 11 with high diastereocontrol. Shu Kobayashi of the University of Tokyo developed (Adv. Synth. Cat. 2008, 350, 647) a practical protocol for the aza Diels-Alder construction of enantiomerically-pure piperidines such as 14 . Biao Yu of the Shanghai Institute of Organic Chemistry cyclized (Tetrahedron Lett. 2008, 49, 672) the product from the proline-catalyzed enantioselective aldol of 15 and 16, leading to the substituted piperidine 17 . Michael Shipman of the University of Warwick described (Tetrahedron Lett. 2008, 49, 250) the cyclization of the aziridine derived from 18, that proceeded to give 19 as a single diastereomer, apparently via kinetic side-chain protonation. Takeo Kawabata of Kyoto University found (J. Am. Chem. Soc. 2008, 130, 4153) that intramolecular alkylation to form four, five and six-membered rings from amino esters such as 21 proceeded with remarkable enantioretention. Géraldine Masson and Jieping Zhu of CNRS, Gif-sur-Yvette, condensed (Organic Lett. 2008, 10, 1509) cinnamaldehyde 23 with cyanide and an ω-alkenyl amine to give the intramolecular aza-Diels-Alder substrate 24. Hongbin Zhai of the Shanghai Institute of Organic Chemistry acylated (J. Org. Chem. 2008, 73, 3589) 26 with 27, leading to the ring-closing metathesis precursor 28.

Diels-Alder Cycloaddition: Fawcettimine (Williams), Apiosporic Acid (Helmchen), Marginatone (Abad- Somovilla), Okilactomycin (Hoye), Vinigrol (Barriault), Plakotenin (Bihlmeier/Klopper)

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Natural Product ◽  
Diels Alder ◽  
State University ◽  
University Of Minnesota ◽  
Enantiomerically Pure ◽  
Colorado State University ◽  
Institute Of Technology ◽  
La Jolla ◽  
The University ◽  
Stereogenic Center

Highly substituted dienes and dienophiles are often reluctant participants in intermolecular Diels-Alder cycloaddition. Nevertheless, Robert M. Williams of Colorado State University, in the course of a synthesis of fawcettimine 4, was able (J. Org. Chem. 2012, 77, 4801) to prepare 3 by combining the enone 1 with the diene 2. Günter Helmchen of the Universität Heidelberg set (J. Org. Chem. 2012, 77, 4491) the single stereogenic center of 5 by Ir-catalyzed allylic alkylation. The Lewis acid that promoted the cycloaddition also conveniently removed the trityl protecting group, leading to 6, that was saponified to apiosporic acid 7. Antonio Abad-Somovilla of the Universidad de Valencia prepared (J. Org. Chem. 2012, 77, 5664) the triene 8 in enantiomerically pure form from carvone. Despite the additional substitution on the diene, cycloaddition proceeded smoothly to give 9, which was carried on to marginatone 10. One could envision that okilactomycin 13 could be formed by an intramolecular Diels-Alder cycloaddition. Thomas R. Hoye of the University of Minnesota observed (Org. Lett. 2012, 14, 828) that the tetraene tetronic acid corresponding to 11 was inert, but that the methyl ether 11 cyclized smoothly to 12. Demethylation then gave the natural product The complex polycyclic structure of vinigrol 16 challenged organic synthesis chemists for many years, until a route was established by Phil Baran of Scripps/La Jolla (Highlights September 6, 2010). Louis Barriault cyclized (Angew. Chem. Int. Ed. 2012, 51, 2111) 14 to 15 en route to a late intermediate in the Baran synthesis It had been hypothesized that the natural product plakotenin 19 was formed naturally from a tetraene corresponding to 17. The tetraene 17 was prepared and the cyclization was successful, “confirming” both the structure of the natural product and the biosynthetic hypothesis. Angela Bihlmeier and Wim Klopper of the Karlsruhe Institute of Technology calculated (J. Am. Chem. Soc. 2012, 134, 2154) the relative energies of the four competing transition states for the cyclization, leading to a correction of the structure of 18, and so of the natural product 19.

Stereocontrolled Construction of C-N Rings: The Vanderwal Synthesis of Norfluorocurarine

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Absolute Configuration ◽  
Enantiomeric Excess ◽  
Silver Catalyst ◽  
West Virginia University ◽  
Science And Engineering ◽  
Enantiomerically Pure ◽  
The Absolute ◽  
Asymmetric Transformation ◽  
The University ◽  
Stereogenic Center

Forrest E. Michael of the University of Washington described (Organic Lett. 2009, 11, 1147) the Pd-catalyzed aminative cyclization of 1 to the differentially-protected diamine 3. Peter Somfai of KTH Chemical Science and Engineering observed (Organic Lett. 2009, 11, 919) that [1,2]-rearrangement of 4 proceeded to deliver 5 with near-perfect maintenance of enantiomeric excess. Tushar Kanti Chakraborty of the Central Drug Research Institute, Lucknow applied (Tetrahedron Lett. 2009, 50, 3306) the Ti(III) reduction of epoxides to the Sharpless-derived ether 6, leading to the pyrrolidine 7. Chun-Jiang Wang of Wuhan University devised (Chem. Commun. 2009, 2905) a silver catalyst that directed the absolute sense of the dipolar addition of 9 to 8 to give 10. Homoallyic azides such as 11 are readily prepared in high enantiomeric excess from the corresponding alcohol. Bernhard Breit of Albert-Ludwigs-Universität, Freiburg and André Mann of the Faculté de Pharmacie, Illkirch showed (Organic Lett. 2009, 11, 261) that Rh-mediated hydroformylation could be effected in the presence of the azide. Subsequent reduction delivered the piperidine 12. Jan-E. Bäckvall of Stockholm University applied (J. Org. Chem. 2009, 74, 1988) the protocol for dynamic kinetic asymmetric transformation (DYKAT) that he had developed to the cyanodiol 13. Remarkably, a single enantiomerically- pure diasteromer emerged, which he carried on to 14. Xiaodong Shi of West Virginia University found (Organic Lett. 2009, 11, 2333) that the stereogenic center of 17, even though it ended up outside the ring, directed the absolute configuration of the other centers of 18 as they formed. Jan Vesely of Charles University and Albert Moyano and Ramon Rios of the Universitat de Barcelona established (Tetrahedron Lett. 2009, 50, 1943) that an organocatayst directed the absolute configuration in the addition of 19 to 20 to give 21. Osamu Tamura of Showa Pharmaceutical University effected (Organic Lett. 2009, 11, 1179) cyclization of the malic acid-derived amide 22 to give 23 with high diastereocontrol.

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