bluuebunny/crossref_metadata_2025 huggingface dataset:
Developments in Alkene Metathesis
Authors: Taber Douglass
Published: November 2020

Hervé Clavier and Steven P. Nolan, now at St. Andrew’s University, found (Adv. Synth. Cat. 2008, 350, 2959) that the indenylidene Ru complex 1 was an excellent pre-catalyst for alkene metathesis. A combination of 1 and the ligand 2 effected cross metathesis of 3 and 4 in just 15 minutes under microwave heating. Robert H. Grubbs of Caltech designed (Organic Lett. 2008, 10, 2693) the Ru catalyst 6 for the preparation of tri- and tetrasubstituted alkenes, as illustrated by the conversion of 7 to 8. The catalyst 6 also worked well for cross metathesis and ring opening metathesis polymerization (ROMP). For some biological applications, it would be desirable to run alkene cross metathesis under aqueous conditions. Benjamin G. Davis of the University of Oxford observed (J. Am. Chem. Soc. 2008, 130, 9642) that allyl sulfides such as 9 were unusually reactive in cross metathesis. Indeed, aqueous cross methathesis with such an allyl sulfide incorporated in a protein worked well, although added MgCl2 was required. The protein, a serine protease, maintained its activity after cross metathesis. α,β-Unsaturated thioesters such as 14 are excellent substrates for, inter alia, enantioselective Cu-catalyzed conjugate addition of Grignard reagents. Adriaan J. Minnaard and Ben L. Feringa of the University of Groningen found (J. Org. Chem. 2008, 73, 5651) that the thioacrylate 13 was an excellent substrate for cross methathesis, allowing ready preparation of 14 . Although alkene metathesis is often run in CH2Cl2 , benzene or toluene, these are not necessarily the optimal solvents. Siegfried Blechert of the TU Berlin established (Tetrahedron Lett. 2008, 49, 5968) that for the difficult cyclization of 16 to 17, hexafluorobenzene worked particularly well. The extended conformation (illustrated for 18) of an ester is more stable than the lactone conformation by about 5 kcal/mol. It is therefore not surprising that SonBinh T. Nguyen of Northwestern University observed (Organic Lett. 2008, 10, 5613) that attempted ring-closing metathesis of 18 gave only the dimer 20. On addition of the bulky Lewis acid 21, which can complex 18 in the lactone conformation, the reaction delivered the desired monomer 19. This should be a generally useful strategy for the cyclization of difficult ester substrates.
Alkene Metathesis: Synthesis of Panaxytriol (Lee), Isofagomine (Imahori and Takahata), Elatol (Stoltz), 5-F2t -Isoprostane (Snapper), and Ottelione B (Clive)
Authors: Taber Douglass
Published: November 2020

Alkene metathesis has been used to prepare more and more challenging natural products. The ﬁrst and second generation Grubbs catalysts 1 and 2 and the Hoveyda catalyst 3 are the most widely used. Daesung Lee of the University of Illinois at Chicago designed (Organic Lett. 2008, 10, 257) a clever chain-walking cross metathesis, combining 4 and 5 to make 6. The diyne 3 was carried on (3R, 9R, 10R )-Panaxytriol 7. Tatsushi Imahori and Hiroki Takahata of Tohoku Pharmaceutical University found (Tetrahedron Lett. 2008, 49, 265) that of the several derivatives investigated, the unprotected alcohol 8 cyclized most efficiently. Selective cleavage of the monosubstituted alkene followed by hydroboration delivered the alkaloid Isofagomine 10. Brian M. Stoltz of Caltech established (J. Am. Chem. Soc. 2008 , 130 , 810) the absolute configuration of the halogenated chamigrene Elatol 14 using the enantioselective enolate allylation that he had previously devised. A key feature of this synthesis was the stereocontrolled preparation of the cis bromohydrin. Marc L. Snapper of Boston College opened (J. Org. Chem. 2008, 73, 3754) the strained cyclobutene 15 with ethylene to give the diene 16. Remarkably, cross metathesis with 17 delivered 18 with high regioselectivity, setting the stage for the preparation of the 5-F2t - Isoprostane 19. Derrick L. J. Clive of the University of Alberta assembled (J. Org. Chem. 2008, 73, 3078) Ottelione B 26 from the enantiomerically-pure aldehyde 20. Conjugate addition of the Grignard reagent 21 derived from chloroprene gave the kinetic product 22, that was equilibrated to the more stable 23. Addition of vinyl Grignard followed by selective ring-closing metathesis then led to 26.
Enantioselective Assembly of Oxygenated Stereogenic Centers
Authors: Taber Douglass
Published: November 2020

Reaction with an enantiomerically-pure epoxide is an efﬁcient way to construct a molecule incorporating an enantiomerically-pure oxygenated stereogenic center. The Jacobsen hydrolytic resolution has made such enantiomerically-pure epoxides readily available from the corresponding racemates. Christopher Jones and Marcus Weck of the Georgia Institute of Technology have now (J. Am. Chem. Soc. 2007, 129, 1105) developed an oligomeric salen complex that effects the enantioselective hydrolysis at remarkably low catalyst loading. Any such approach depends on monitoring the progress of the hydrolysis, usually by chiral GC or HPLC. In a complementary approach, we (J. Org. Chem. 2007, 72, 431) have found that on exposure to NBS and the inexpensive mandelic acid 2, a terminal alkene such as 1 was converted into the two bromomandelates 3 and 4. These were readily separated by column chromatography. Individually, 3 and 4 can each be carried on the same enantiomer of the epoxide 5. As 3 and 4 are directly enantiomerically pure, epoxide 5 of high ee can be prepared reliably without intermediate monitoring by chiral GC or HPLC. Another way to incorporate an enantiomerically-pure oxygenated stereogenic center into a molecule is the enantioface-selective addition of hydride to a ketone such as 6. Alain Burgos and his team at PPG-SIPSY in France have described (Tetrahedron Lett. 2007, 48, 2123) a NaBH4 -based protocol for taking the Itsuno-Corey reduction to industrial scale. In the past, aldehydes have been efficiently α-oxygenated using two-electron chemistry. Mukund P. Sibi of North Dakota State University has recently (J. Am. Chem. Soc. 2007, 129, 4124) described a novel one-electron alternative. The organocatalyst 10 formed an imine with the aldehyde. One-electron oxidation led to an α-radical, which was trapped by the stable free radical TEMPO to give, after hydrolysis, the α-oxygenated aldehyde 11. High ee oxygenated secondary centers can also be prepared by homologation of aldehydes. Optimization of the enantioselective addition of the inexpensive acetylene surrogate 13 was recently reported (Chem. Commun. 2007, 948) by Masakatsu Shibasaki of the University of Tokyo. Note that the free alcohol of 13 does not need to be protected.
Practical Enantioselective Construction of Arrays of Stereogenic Centers: The Jørgensen Synthesis of the Autoregulator IM-2
Authors: Taber Douglass
Published: November 2020

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.
Stereocontrolled C-O Ring Construction: The Fuwa/Sasaki Synthesis of Attenol A
Authors: Taber Douglass
Published: November 2020

Since five-membered ring ethers often do not show good selectivity on equilibration, single diastereomers are best formed under kinetic control. Aaron Aponick of the University of Florida demonstrated (Organic Lett. 2008, 10, 669) that under gold catalysis, the allylic alcohol 1 cyclized to 2 with remarkable diastereocontrol. Six-membered rings also formed with high cis stereocontrol. Ian Cumpstey of Stockholm University showed (Chem. Commun. 2008, 1246) that with protic acid, allylic acetates such as 3 cyclized with clean inversion at the allylic center, and concomitant debenzylation. J. Stephen Clark of the University of Glasgow found (J. Org. Chem. 2008, 73, 1040) that Rh catalyzed cyclization of 5 proceeded with high selectivity for insertion into Ha, leading to the alcohol 6. Saumen Hajra of the Indian Institute of Technology, Kharagpur took advantage (J. Org. Chem. 2008, 73, 3935) of the reactivity of the aldehyde of 7, effecting selective addition of 7 to 8, to deliver, after reduction, the lactone 9. Tomislav Rovis of Colorado State University observed (J. Org. Chem. 2008, 73, 612) that 10 could be cyclized selectively to either 11 or 12. Nadège Lubin-Germain, Jacques Uziel and Jacques Augé of the University of Cergy- Pontoise devised (Organic Lett. 2008, 10, 725) conditions for the indium-mediated coupling of glycosyl fluorides such as 13 with iodoalkynes such as 14 to give the axial C-glycoside 15. Katsukiyo Miura and Akira Hosomi of the University of Tsukuba employed (Chemistry Lett. 2008, 37, 270) Pt catalysis to effect in situ equilibration of the alkene 16 to the more stable regioisomer. Subsequent condensation with the aldehyde 17 led via Prins cyclization to the ether 18. Paul E. Floreancig of the University of Pittsburgh showed (Angew. Chem. Int. Ed. 2008, 47, 4184) that Prins cyclization could be also be initiated by oxidation of the benzyl ether 19 to the corresponding carbocation. Chan-Mo Yu of Sungkyunkwan University developed (Organic Lett. 2008, 10, 265) a stereocontrolled route to seven-membered ring ethers, by Pd-mediated stannylation of allenes such as 21, followed by condensation with an aldehyde.
Synthesis of Dysiherbaine (Hatakeyama), Jerangolid D (Markó) and ( + )-Spirolaxine Me Ether (Trost)
Authors: Taber Douglass
Published: November 2020

Several new developments in enantioselective C-O ring construction have been applied in the syntheses of natural products. To achieve control, the oxygenated quaternary center of dysiherbaine 9 must be established under kinetic conditions. One approach would be SN2 opening, but this would require displacement at a fully-substituted center. Susumi Hatakeyama of Nagasaki University has shown (Chem. Commun. 2007, 4158) that the epoxide 6, prepared by the Sharpless procedure, undergoes just such an opening under mild acid catalysis. Another approach to highly-substituted tetrahydrofurans and tetrahydropyrans is to join two carbons of a preformed chiral ether, such as 18. This is the strategy that István E. Markó employed in his recent (J. Am. Chem. Soc. 2007, 129, 3516) synthesis of jerangolid D 22. The key step was the three-component coupling of 15, 16, and 17, using a protocol recently developed in his group. Again using a procedure his group had developed, the trisubstituted alkene of 21 was prepared by modified Julia coupling of the ketone 19 with the anion of sulfone 20, followed be esterification and reduction. The spiroketal ( + )-spiroxaline methyl ether 31 contains three secondary oxygenated stereogenic centers. In a showcase of current chiral technology, Barry M. Trost of Stanford University constructed (Angew. Chem. Int. Ed. 2007, 46, 7664) the first two of the three alcohols by the enantioselective addition of an alkyne to an aldehyde. The chiral catalyst 25 that directed the alkyne additions was derived from a commercial ligand. The last alcohol center was derived from R -( + )-epoxypropane. Note that the spiroketal was not prepared in the usual way, by acid-catalyzed cyclization of a dihydroxy ketone, but by Pd-catalyzed cyclization of the alkyne diol 30.
Adventures in Alkaloid Synthesis: ( + )-α-Kainic Acid (Jung), 223AB (Ma), Pumiliotoxin 251F (Jamison), Spirotryprostatin B (Trost), (-)-Drupacine (Stoltz)
Authors: Taber Douglass
Published: November 2020

Enantiomerically-pure natural amino acids can serve as starting materials for alkaloid synthesis. In his synthesis (J. Org. Chem. 2007, 72, 10114) of (-)-α-kainic acid 3, Kyung Woon Jung of the University of Southern California prepared the diazo sulfone 1 from (L)-glutamic acid. Rh-mediated intramolecular C-H insertion proceeded with the predicted high diastereoselectivity, to give the lactam 2, containing seven of the ten carbon atoms and two of the three stereogenic centers of (-)-α-kainic acid 3. The absolute configuration of the nitrogen ring system(s) can also be established by chiral catalysis. Dawei Ma of the Shanghai Institute of Organic Chemistry has developed (J. Am. Chem. Soc. 2007, 129, 9300) a chiral Cu catalyst that mediated the addition of alkynyl esters and ketones to the prochiral acylated pyridine 4 in high enantiomeric excess. The dihydro-pyridines (e.g. 5) so produced will be versatile starting materials both for alkaloid synthesis, as illustrated by the preparation of the Dendrobatid alkaloid 223AB 6, and for the production of pharmaceuticals. In his synthesis of the Dentrobatid alkaloid pumiliotoxin 251D 9, Timothy F. Jamison took (J. Org. Chem. 2007, 72, 7451) as his starting material another amino acid, proline. Ni-mediated cyclization of the epoxide 8 proceeded with high geometric and regiocontrol, to give 9. The chemistry to convert 7 into 8 with high diastereocontrol and without racemization is a substantial contribution that will have many other applications. In his synthesis (Organic Lett. 2007, 9, 2763) of spirotryprostatin B 12, Barry M. Trost of Stanford University also started with proline, which was readily elaborated to the oxindole 10. The question was, could the Pd-catalyzed decarboxylation of 10 be induced to provide specifically 11? Counting geometric isomers of the trisubstituted alkene, and allylic regioisomers, as well as diastereomers, there were sixteen possible products from this prenylation. Using chiral Pd control, the rearrangement proceeded with 14:1 regiocontrol, and 16:1 diasterocontrol. Oxidative cyclization of 11 then delivered spirotryprostatin B 12. The Cephalotaxus alkaloid (-)-drupacine 19 has five stereogenic centers, including four of the five positions on the cyclopentane ring.
Synthesis of Heteroaromatics
Authors: Taber Douglass
Published: November 2020

Yasutaka Ishii of Kansai University has developed (J. Org. Chem. 2007, 72, 8820) a novel route to furans, using a mixed-metal catalyst to effect condensation of an aldehyde or 1,3 diketone such as 1 with an acceptor such as 2 to give the 3-furoate 3. In a complementary approach, Yong-Min Liang of Lanzhou University has found (J. Org. Chem. 2007, 72, 10276) that diazoacetate 5 will condense with an alkynyl ketone to give the 2-furoate 6. David W. Knight of Cardiff University has shown (Tetrahedron Lett. 2007, 48, 7709) that an alkynyl diol such as 7, readily available by dihydroxylation of the corrresponding alkenyl alkyne, cyclized to the furan on exposure to AgNO3 on silica gel. Professor Knight has also (Tetrahedron Lett. 2007, 48, 7906) established a route to poly-substituted pyrroles 10, by iodination of alkynyl sulfonamides such as 9. Similarly, Richard C. Larock of Iowa State University found (J. Org. Chem. 2007, 72, 9643) that I-Cl cyclized methoximes such as 11 to the corresponding iodo isoxazole 12, and Stephen L. Buchwald of MIT uncovered (Organic Lett. 2007, 9, 5521) the cyclization of an enamide such as 13 with I2 to the corresponding oxazole 14. In developing a more efficient route to a new class of materials that he has named “triazolamers”, Paramjit S. Arora of New York University was able (J. Org. Chem. 2007, 72, 7963) to effect diazo transfer to the amine 15 and subsequent condensation with 16 to give 17, without isolation of the intermediate azide. C. V. Asokan and E. R. Anabha of Mahatma Gandhi University have described (Tetrahedron Lett. 2007, 48, 5641) the activation of a ketone 18 followed by condensation with malononitrile 19 to give the pyridine 20. Hans-Ulrich Reissig of the Freie Universität Berlin has established (Organic Lett. 2007, 9, 5541) a complementary three-component coupling of a nitrile 21 with the allenyl anion 22, followed by a carboxylic acid 23 to deliver the pyridine 24. Akio Saito and Yuji Hanzawa of the Showa Pharmaceutical University have reported (Tetrahedron Lett. 2007, 48, 6852) the intramolecular Rh-catalyzed cyclization of a methoxime lactone such as 25 to the pyridine 26.
Preparation of Heteroaromatics
Authors: Taber Douglass
Published: November 2020

Masahiro Yoshida of the University of Tokushima described (Tetrahedron Lett. 2008, 49, 5021) the Pt-mediated rearrangement of alkynyl oxiranes such as 1 to the furan 2. Roman Dembinski of Oakland University reported (J. Org. Chem. 2008, 73, 5881) a related zinc-mediated rearrangement of propargyl ketones to furans. The cyclization of aryloxy ketones such as 3 to the benzofuran 4 developed (Tetrahedron Lett. 2008, 49, 6579) by Ikyon Kim of the Korea Research Institute of Chemical Technology is likely proceeding by a Friedel-Crafts mechanism. Sandro Cacchi and Giancarlo Fabrizi of Università degli Studi “La Sapienza”, Roma, observed (Organic Lett. 2008, 10, 2629) that base converted the enamine 5 to the pyrrole 6. Alternatively, oxidation of 5 with CuBr led to a pyridine. Zhuang-ping Zhuan of Xiamen University prepared (Adv. Synth. Cat. 2008, 350, 2778) pyrroles such as 9 by condensing an alkynyl carbinol 7 with a 1,3-dicarbonyl compound. Richard C. Larock of Iowa State University found (J. Org. Chem. 2008, 73, 6666) that combination of an alkynyl ketone 10 with 11 followed by oxidation with I-Cl led to the pyrazole 12. The “click” condensation of azides with alkynes, leading to the 1,4-disubstituted 1,2,3- triazole, has proven to be a powerful tool for combinatorial synthesis. Valery V. Fokin of Scripps/La Jolla and Zhenyang Lin and Guochen Jia of the Hong Kong University of Science and Technology have developed (J. Am. Chem. Soc. 2008, 130, 8923) a complementary approach, using Ru catalysts to prepare 1,5-disubstituted 1,2,3- triazoles. Remarkably, internal alkynes participate, and, as in the conversion of 13 to 15, propargylic alcohols direct the regioselectivity of the cycloaddition. A variety of methods have been put forward for functionalizing pyridines. Sukbok Chang of KAIST described (J. Am. Chem. Soc. 2008, 130, 9254) the direct oxidative homologation of a pyridine N -oxide 16 to give the unsaturated ester 18. Jonathan Clayden of the University of Manchester observed (Organic Lett. 2008, 10, 3567) that metalation of 19 gave an anion that rearranged to 20 with complete retention of enantiomeric excess. Shigeo Katsumura of Kwansei Gakuin University developed (Tetrahedron Lett. 2008, 49, 4349) an intriguing three-component coupling, combining 21, 22, and methanesulonamide 23 to give the pyridine 24.
Transition Metal-Mediated Ring Construction: The Yu Synthesis of 1-Desoxyhypnophilin
Authors: Taber Douglass
Published: November 2020

Both 1 and 3 are inexpensive prochiral starting materials. Tae-Jong Kim of Kyungpook National University devised (Organomet. 2008, 27, 1026) a chiral Cu catalyst that efficiently converted 1 (other ring sizes worked as well) to the enantiomerically pure ester 2. Alexandre Alexakis of the University of Geneva found (Adv. Synth. Cat. 2008, 350, 1090) a chiral Cu catalyst that mediated the enantioselective coupling of 3 with Grignard reagents such as 4 . The π-allyl Pd complex derived from 6 is also prochiral. Barry M. Trost of Stanford University showed (Angew. Chem. Int. Ed. 2008, 47, 3759) that with appropriate ligand substitution, coupling with the phthalimide 7 proceeded to give 8, readily convertible to (-)-oseltamivir (Tamiflu) 9, in high ee. Jonathan W. Burton of the University of Oxford found (Chem Commun. 2008, 2559) that Mn(OAc)3 -mediated cyclization of 10 delivered the lactone 12 with high diastereocontrol. John Montgomery of the University of Michigan observed (Organic Lett. 2008, 10, 811) that the Ni-catalyzed cyclization of 12 also proceeded with high diastereocontrol. Ken Tanaka of the Tokyo University of Agriculture and Technology combined (Angew. Chem. Int. Ed. 2008, 47, 1312) Rh-catalyzed ene-yne cyclization of 14 with catalytic ortho C-H functionalization, leading to 16 in high ee. Eric N. Jacobsen of Harvard University designed (Angew. Chem. Int. Ed. 2008, 47, 1469) a chiral Cr catalyst for the intramolecular carbonyl ene reaction, that converted 17 to 18 in high ee. Using a stoichiometric prochiral Cr carbene complex 20 and the enantiomerically-pure secondary propargylic ether 19, Willam D. Wulff of Michigan State University prepared (J. Am. Chem. Soc. 2008, 130, 2898) a facially-selective Cr-complexed o -quinone methide intermediate, that cyclized to 21 with high ee. A variety of methods have been put forward for the transition metal-mediated construction of polycarbocyclic systems. One of the more powerful is the enantioselective Rh-catalyzed stitching of the simple substrate 22 into the tricycle 23 devised (J. Am. Chem. Soc. 2008, 130, 3451) by Takanori Shibata of Waseda University. Inter alia, ozonolysis of 23 delivered the cyclopentane 24 containing two all-carbon quaternary centers.
Intermolecular and Intramolecular Diels-Alder Reactions: (-)-Oseltamivir (Fukuyama), Platensimycin (Yamamoto) and 11,12-Diacetoxydrimane (Jacobsen)
Authors: Taber Douglass
Published: November 2020

Powerful methods for catalytic, enantioselective intermolecular Diels-Alder reactions have been developed. Ben L. Feringa and Gerard Roelfes of the University of Groningen have shown (Organic Lett. 2007, 9, 3647) that a catalyst prepared by combining salmon testes DNA with a Cu complex directed the absolute sense of the addition of 1 to cyclopentadiene 2 . Mukund P. Sibi of North Dakota State University has reported (J. Am. Chem. Soc . 2007, 129 , 395) related work with achiral pyrazolidinone dienophiles and chiral Cu catalysts. Tohru Fukuyama of the University of Tokyo found (Angew. Chem. Int. Ed . 2007, 46, 5734) that the MacMillan catalyst 5 was effective at mediating the addition of acrolein 4 to the pyridine-derived diene 3, enabling an enantioselective synthesis of the prominent antiviral (-)-oseltamivir (tamiflu) 7. Hisashi Yamamoto of the University of Chicago has demonstrated (J. Am. Chem. Soc . 2007, 129, 9534 and 9536) that the novel catalyst 10 effected addition of methyl acrylate 9 to the diene 8, leading to an elegant enantioselective synthesis of the tetracycle 12, the key intermediate in the Nicolaou synthesis of platensimycin. New illustrations of the power of the intramolecular Diels-Alder reaction have been put forward. Demonstrating the influence of a single subsituent on the tether, William R. Roush of Scripps/Florida found (Organic Lett . 2007, 9, 2243) that cyclization of 13 led to the diastereomer 14, complementary to the result observed with an acyclic triene. Ryo Shintani and Tamio Hayashi of Kyoto University have extended (Angew. Chem. Int. Ed . 2007, 46, 7277) their studies of chiral diene-based Rh catalysts to the enantioselective cyclization of alkynyl dienes such as 16. Jonathan W. Burton of the University of Oxford and Andrew B. Holmes of the University of Melbourne employed (Chem. Commun . 2007, 3954) the MacMillan catalyst 5 for the cyclization of 18 to 19. It is impressive that ent- 5 catalyzed the cyclization of 18 cleanly into the diastereomer of 19 in which both of the newly-created stereogenic centers were inverted.
The Maier Synthesis of Cruentaren A
Authors: Taber Douglass
Published: November 2020

Cruentaren A 3, isolated from the myxobacterium Byssovorax cruenta, is an inhibitor of mitochondrial F-ATPase. The synthesis of 3 (Organic Lett. 2007, 9, 655; Angew. Chem. Int. Ed. 2007, 46, 5209) by Martin E. Maier of the Universität Tübingen illustrates the power of alkyne metathesis as a tool for the synthesis of complex natural products. Very recently, Alois Fürstner of the Max-Planck-Institut, Mülheim, reported (Angew. Chem. Int. Ed. 2007, 46, 9275) an alternative synthesis, also based on alkyne metathesis, of cruentaren A 3. The alcohol portion of 1 was prepared by Marshall homologation of 4 with 5, leading to 6. Homologation of the derived epoxide 7 then gave 8. Note that the homologation of 7 to 8 required three steps. This might have been accomplished more directly with the Li salt of 1-propyne, easily prepared from commercial 1- or 2-bromopropene. Evans auxiliary-controlled homologation of 9 set the relative and absolute configuration of 10, which was carried on to 12. To effect coupling, the acid of 12 was activated with carbonyl diimidazole, then condensed with the bis-alcoholate of 8. This acylation was highly regioselective, giving 1 as the only observed product. Cruentaren A 3 has two Z alkenes, so the authors chose a bis-alkyne strategy, with a partial hydrogenation of both alkynes at the end of the synthesis. To this end, alkyne metathesis was accomplished with the Schrock tungsten carbine catalyst 13. Homologation to 15 followed by deprotection and hydrogenation then gave enantiomerically pure cruentaren A 3.
The Smith Synthesis of ( + )-Lyconadin A
Authors: Taber Douglass
Published: November 2020

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.
The Roush Synthesis of ( + )-Superstolide A
Authors: Taber Douglass
Published: November 2020

( + )-Superstolide A 3, isolated from the New Caledonian sponge Neosiphonia superstes, shows interesting cytotoxicity against malignant cell lines at ~ 4 ng/mL concentration. The key transformation in the synthesis of 3 described (J. Am. Chem. Soc. 2008, 130, 2722) by William R. Roush of Scripps Florida was the transannular Diels-Alder cyclization of 2, which established, in one step with high diastereocontrol, both the cis decalin and the macrolactone of 3. The octaene 1 was assembled from four stereodefined fragments. The first, the linchpin 6, was prepared from the stannyl aldehyde 4. Homologation gave the enyne 5, which on hydroboration and oxidation gave 6. Earlier, Professor Roush had optimized the crotylation of the protected alaninal 7. In this case, the Brown reagent 8 delivered the desired Felkin product 9. Protection followed by ozonolysis gave the aldehyde 10. Crotylation with the Roush-developed tartrate 11 then gave the alkene 12, setting the stage for conversion to the iodide 13. Coupling of 13 with 6 completed the preparation of 14. The third component of (+)-superstolide A 3, the phosphonium salt 21, was assembled by Brown allylation of the aldehyde 15, to give 17. Protecting group interchange followed by ozonolysis delivered 18, which via Still-Gennari homologation was carried on to 21. Condensation with the fourth component, the aldehyde 22 , and esterification with 14 then gave 1. Under high dilution Suzuki conditions 1 was converted to 2. Storage in CDCl3 for five days, or brief warming, cyclized 2 to a single diastereomer of the transannular Diels-Alder product, that was carried on to (+)-superstolide A 3. While acyclic trienes comparable to 2 could be induced to cyclize, the transannular Diels-Alder reaction proceeded with much higher diastereocontrol.
The Paquette Synthesis of Fomannosin
Authors: Taber Douglass
Published: November 2020

The compact sesquiterpene ( + )-fomannosin 3, isolated from the pathogenic fungus Fomes annonsus, presents an interesting set of challenges for the organic synthesis chemist, ranging from the strained cyclobutene to the easily epimerized cyclopentanone. In the synthesis of 3 developed (J. Org. Chem . 2008, 73, 4548) by Leo A. Paquette of Ohio State University, the cyclopentane was constructed by ring-closing metathesis of 1. The real challenge of the synthesis was the enantiospecific preparation of 1 from D-glucose. The starting point for the preparation of 1 was the glucose derivative 4. Selective acetonide hydrolysis followed by oxidative cleavage gave the ester 5, which on base treatment followed by hydrogenation delivered the endo ester 6. Condensation of the enolate of 6 with formaldehyde proceeded with high diastereoselectivity, to give, after protection, the ester 7. Conversion of the ester to the vinyl group, exposure to methanolic acid and ether formation completed the preparation of 9. The construction of the cyclobutane of 1 was effected by an interesting application of the Negishi reagent (Cp2ZrCl2/2 x BuLi). Complexation of Cp2Zr with the alkene followed by elimination generated an allylic organometallic 11, which added to the released aldehyde to give the cyclobutanes 12 and 13 in a 2.4:1 diastereomeric ratio. Homologation of the aldehyde 13 and subsequent oxidation were straightforward, but subsequent methylenation of the hindered carbonyl was not. At last, it was found that Peterson olefination worked well. Metathesis then delivered the cyclopentene 2. The last carbons of the skeleton were added by intramolecular aldol cyclization of the thioester 16. The seemingly simple task of converting the alkene of 17 into a ketone proved challenging. Eventually, dihydroxylation followed by oxidation, and then SmI2 reduction, completed the transformation. This still left the challenge of controlling the cyclopentane stereogenic center. Remarkably, dehydration and epimerization led to (+)-Fomannosin 3 as a single dominant diastereomer.
The Red-headed Stepchild
Authors: Broughton Chad
Published: November 2020

Two Weeks After BusinessWeek lauded Maytag’s remarkable success, the company broke clean from a century-old tradition. On August 12, 1999, Lloyd Ward replaced Leonard Hadley by a vote of the board of directors. Ward was the first executive never to have worked for Maytag. He had not been raised in the idiosyncratic Maytag culture. He was not even an appliance guy. Hadley had been grooming Ward for the CEO’s position since Ward came to the company as president of the home appliance division in 1996. Two internal candidates had been groomed and judged unfit for the CEO’s job; Ward was their last hope. Still, the board’s choice shocked many. Ward was anything but short on confidence though. He had wrestled a childhood of poverty and a career touched often by racism and had won. He had captained the Michigan State basketball team. He had earned a black belt in karate. He was now a star of business on the rise. When Ward became only the second African American to become a CEO at a Fortune 500 company, Black Enterprise declared it a “watershed moment.” It was easy to see why Hadley liked Ward: he brought Maytag a magnetic personality, inspirational leadership, and some badly needed diversity. Hadley said he “drooled” when he saw Ward’s resume and relished bringing in this bold, extroverted marketing man. Even before he became CEO, Ward began to revamp Maytag’s old-fashioned culture with an “unapologetically macho” leadership style. He began to shift Maytag’s focus to brand management, lower-end products, and sophisticated consumer research. Ward also brought in people from outside the appliance industry, from P&G and PepsiCo mainly. Ward’s ascendance won praise, including a fawning cover story in BusinessWeek. Joe Krejci, a Galesburg logistics manager who reported directly to Newton, was taken by Ward’s irresistible charm. Ward, still a diehard Michigan State Spartan, once came into Krejci’s office and stomped on his University of Michigan doormat with a theatrical smile. They then “shot the shit” about Big Ten football and basketball.
Little Detroit, El Cártel, and Aguamiel
Authors: Broughton Chad
Published: November 2020

The Second-Shifters Filed in slowly on a late Thursday afternoon. From the outside, the factory was a long (nearly a third of a mile), nondescript white box, baking silently in the desert sun of the Ramos Arizpe mountain valley. Inside, it was fairly dark and noisy, with long rows of metal-stamping machines, soldering stations, and assembly lines. Neat green pathways edged with yellow lines, stretching as far as the eye could see, marked the safe routes through. Full-sized and colorful cardboard cutouts of a smiling man and woman greeted workers, highlighting appropriate safety gear. The operators, an even mix of men and women, meandered down the green paths like high school students reluctantly heading to class. There were young men with sagging jeans and others with Def Leppard and Metallica T-shirts. One young man sported a fauxhawk. Another had a pony tail and looked slightly hungover. Many of the women wore tight-fitting jeans, some of them bejeweled. A large number appeared to be in their teens. The factory in Ramos Arizpe—a desiccated and spacious industrial valley just southwest of Monterrey, Nuevo León, and just north of Saltillo, Coahuila—was on a refrigerator continental divide. The Whirlpool, Maytag, and KitchenAid refrigerators they assembled here—including the side-by-side, which had been perfected and popularized by Galesburg’s Admiral plant fifty years earlier—flowed north. The hip and colorful Brastemp side-by-sides shipped south to Brazil. The enormous Whirlpool factory was only seven years old in 2013, but it paled in comparison to the massive Dodge Ram truck plant we visited on the other side of Saltillo. Planta Ensamble Saltillo had its own valley, rigorous security, and produced 220,000 trucks a year in nearly infinite combinations of engine sizes, body types, and colors. It sat next to a Chrysler engine factory and a DHL logistics center, which handled some of the highly complicated sequencing for the massive operation. From the back of an electric cart, we saw Dodge trucks start off as metal pieces, pressed out and shaped by hundreds of enormous robotic arms, jerking precisely from position to position, sending up sparks behind tall metal cages.
Fitting Potential Energy Hypersurfaces
Authors: Raff Lionel , Komanduri Ranga , Hagan Martin , Bukkapatnam Satish
Published: November 2020

Molecular dynamics (MD) and Monte Carlo (MC) simulations are the two most powerful methods for the investigation of dynamic behavior of atomic and molecular motions of complex systems. To date, such studies have been used to investigate chemical reaction mechanisms, energy transfer pathways, reaction rates, and product yields in a wide array of polyatomic systems. In addition, MD/MC methods have been successfully applied for the investigation of gas-surface reactions, diffusion on surfaces and in the bulk, membrane transport, and synthesis of diamond using chemical vapor deposition (CVD) techniques. The structure of vapor deposited rare gas matrices has been studied using trajectories procedures. If the chemical reaction of interest contains three atoms or fewer, various types of quantum and semiclassical calculations can be brought to bear on the problem. These methods include wave packet studies, close-coupling calculations at various levels of accuracy, and S-matrix theory. Several excellent review articles have been published describing the principal techniques and problems involved in conducting MD studies; the reader may wish to consult these as background material for this discussion. With the advent of relatively inexpensive, powerful personal computers, MD/MC simulations have become routine. Once the potential-energy hypersurface for the system has been obtained, the computations are straightforward, though time-consuming. In the majority of cases, the computational time required is on the order of hours to a few days. However, the accuracy of these simulations depends critically on the accuracy of the potential hypersurface used. The major problem associated with MD/MC investigations is the development of a potential-energy hypersurface whose topographical features are sufficiently close to those of the true, but unknown, surface that the results of the calculations are experimentally meaningful. Once the potential surface is chosen or computed, all the results from any quantum mechanical, semiclassical, or classical scattering or equilibrium calculation are determined. The only purpose of the MD calculations is to ascertain what these results are. Therefore, the most critical part of any MD/MC study is the development of the potential-energy hypersurface and the associated force field.
Rate Coefficients and Mechanisms for the Atmospheric Oxidation of the Ethers
Authors: Calvert Jack , Mellouki Abdelwahid , Orlando John , Pilling Michael , Wallington Timothy
Published: November 2020

The presence of ethers in the atmosphere is almost entirely the result of direct emissions from anthropogenic sources (e.g., Arif et al., 1997; Intergovernmental Panel on Climate Change, 2001; Johnson and Andino, 2001; http://en.wikipedia.org/wiki/Ethers; and references therein). These sources can be quite varied and species dependent; for example, many ethers are commonly used as industrial solvents; many are formed as combustion intermediates and in the burning of biomass; various branched ethers (e.g., methyl tert-butyl ether) are (or have been) used as fuel additives to increase octane number and reduce CO emissions; dimethyl ether has being proposed as an alternative diesel fuel; many fluorinated species have been manufactured, evaluated and used as possible chlorofluorocarbon (CFC) and hydrochlorofluorocarbon (HCFC) replacement compounds; some halogenated species are used as inhalation anaesthetics or as chlorofluorocarbon replacements; and polybrominated diphenyl ethers (PBDEs) are used as flame retardants. There are no major routes to ether formation in the atmosphere itself. The atmospheric behavior of the simple aliphatic ethers, to a first approximation, mirrors that of the alkanes. Reaction with OH is the dominant removal pathway, and occurs via abstraction of an H-atom. In general, however, the ethers are more reactive than the alkanes, as the ether linkage leads to a weakening of the neighboring C—H bonds, and thus imparts an “activation effect” on the OH reaction. The major oxidation steps occurring subsequent to abstraction are also similar to those occurring in atmospheric alkane chemistry, involving the formation of a peroxy radical and an alkoxy radical prior to end product formation; However, less is know about the quantitative details of these processes than is the case for the alkanes. In general, unimolecular decomposition of the alkoxy radicals [e.g., CH3CH2OCH(O•)CH3 in the above reaction sequence] is more rapid than for an alkane-derived radical of similar structure. The major end product of ether oxidation is quite often an ester, the analog to the carbonyl compounds (aldehydes and ketones) generated from alkane oxidation.
Rate Coefficients and Mechanisms for the Atmospheric Oxidation of the Aldehydes
Authors: Calvert Jack , Mellouki Abdelwahid , Orlando John , Pilling Michael , Wallington Timothy
Published: November 2020

Aldehydes are emitted from a variety of anthropogenic sources associated with natural gas and petroleum combustion (for examples, see tables I-C-2 and I-C-3). Winer et al. (1992) have discussed direct emissions of aldehydes from biogenic sources. They are also important intermediates in the oxidation of directly emitted organic compounds. For example, formaldehyde, CH2O formed in the reaction of CH3O with O2 . . . CH3O + O2 → CH2O + HO2 . . . CH3O is formed in the oxidation of methane, and a number of other compounds. There are also many other sources of CH2O; for example, the Leeds University’s Master Chemical Mechanism (MCM) lists a total of ∼ 140 CH2O precursors: http://mcm.leeds.ac.uk/MCM/. Aldehydes with saturated hydrocarbon chains (termed alkanals or acyclic aldehydes) react mainly with OH during the day and with NO3 at night. The aldehydic C—H bond is weaker than those in the hydrocarbon chain; and, certainly for the shorter carbon chain species, abstraction by both OH and NO3 occurs primarily at the aldehydic center to form an acyl radical which reacts rapidly with O2 to form an acylperoxy radical, e.g., . . . CH3CHO + OH → CH3CO + H2O . . . . . . CH3CO + O2 → CH3C(O)O2 . . . An important reaction of the acylperoxy radical is with NO2 to form an acylperoxy nitrate. In the example shown, the oxidation of acetaldehyde gives acetyl peroxy radicals which can react with NO2 to form peroxyacetyl nitrate, CH3C(O)O2NO2, generally known as PAN: . . . CH3C(O)O2 + NO2 → CH3C(O)O2NO2 . . . Peroxyacyl nitrates dissociate quite quickly at 298 K, to regenerate peroxyacyl radicals. For example, PAN has a lifetime of about 50 min. The lifetime increases rapidly at the lower temperatures experienced at higher altitudes and is several months at the temperatures (∼ 250 K) of the upper troposphere. This long lifetime provides a mechanism for the transport of NOx from polluted areas to less polluted areas, by transfer of peroxyacyl nitrates from the boundary layer to the free troposphere; subsequent subsidence can return them to the boundary layer where they dissociate at the higher temperatures encountered there. The atmospheric reactions of the nitrates are discussed in detail in chapters VIII and IX.
Scales and Chords
Authors: Manzo V. J
Published: November 2020

In this chapter, we will learn to build scales and chords and play them back in a variety of ways. Understanding how to build a scale and diatonic chords from the scale in Max will allow us to expand on these ideas in later projects resulting in the creation of new and accessible musical instruments. By the end of this chapter, you will write a program that allows users to play diatonic chords in a specified key using just the number keys on your computer keyboard. In the last chapter, you created intervals using the + object. Now, let’s create a new patch that takes a note from your MIDI keyboard as a tonic, builds a major scale from it, and displays the scale on a kslider. Can you visualize how to build this in Max? Let’s break down the task into smaller parts: divide and conquer. In order to get data from your MIDI keyboard, you’ll probably want to use notein. 1. Create a new object called notein Next, you’ll want to take the pitch coming from notein and add some intervals to it to form a scale. If you’ll recall, a major scale is a collection of whole steps and half steps. In fact, all major scales have the same whole step and half step pattern: whole whole half whole whole whole half, or, in semitones, 2 2 1 2 2 2 1. If you start on any pitch and go up a whole step to get the next note, then another whole step from that note to get the next tone, and so on, you will have built the major scale from your starting note, the tonic. You know from last chapter that “whole step” is really two semitones which is like adding the number 2 to a note. A half step is like adding 1. What we need for this patch is a series of + objects where whole steps and half steps are added to each note.
Control Interfaces
Authors: Manzo V. J
Published: November 2020

In this chapter, we will examine some premade patches demonstrating a few techniques for designing diatonic musical instruments. We will review some of the basic ins and outs of MIDI, learn some ways to program more efficiently, and discuss a number of control options for your patches. As we examine some working patches and encounter many new objects, please read carefully and, in your mind, follow the flow of data from one object to the next as the process is described in the text. Remember that it will be beneficial to look at the Help file for any objects you may have forgotten about or do not fully understand as you encounter them in this chapter. In the last chapter, you installed the EAMIR SDK (Soft ware Development Kit) which, in addition to putting the Modal Object Library into the Max search path, put a bunch of patches I’ve created into the path as well. In fact, if you select Extras from the top menu, you will see an item marked EAMIR among the other extras. 1. Click on Extras>EAMIR from the top menu to view the main menu of the EAMIR SDK 2. In the umenu labeled Examples, click the first item 1.EAMIR _MIDI_Basics.maxpat If you did a manual install of the EAMIR SDK, you will need to locate the EAMIR_SDK folder on your computer and open the file EAMIR.maxpat. A patch will open containing two rectangular boxes. Unlock the patch to see that these two rectangular boxes have inlets and outlets just like the objects we’ve been working with, except that they, in themselves, contain other objects. These two boxes are called bpatchers. A bpatcher is an object that allows an existing Max patch to be loaded into a viewable window; that window is the bpatcher object itself. 3. Open the Inspector for the upper bpatcher Note that the line Patcher File within the Inspector displays the filename of the Max patch currently loaded in the bpatcher: EAMIR_MIDI_in.maxpat. This is just a Max patch that is being displayed in the bpatcher.