The Zakarian Synthesis of ( + )-Pinnatoxin A

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Claisen Rearrangement ◽  
Aldol Condensation ◽  
Primary Alcohol ◽  
Allylic Alcohol ◽  
University Of California ◽  
Santa Barbara ◽  
Enantiomerically Pure ◽  
Calcium Channel Activator ◽  
The University ◽  
Nabh4 Reduction

( + )-Pinnatoxin A 3, isolated from the shellfish Pinna muricata, is thought to be a calcium channel activator. A key transformation in the synthesis of 3 reported (J. Am. Chem. Soc . 2008, 130, 3774) by Armen Zakarian, now at the University of California, Santa Barbara, was the diastereoselective Claisen rearrangement of 1 to 2. The alcohol portion of ester 1 was derived from the aldehyde 4, prepared from D-ribose. The absolute configuration of the secondary allylic alcohol was established by chiral amino alcohol catalyzed addition of diethyl zinc to the unsaturated aldehyde 5. The acid portion of the ester 1 was prepared from (S)-citronellic acid, by way of the Evans imide 7. Methylation proceeded with high diasterocontrol, to give 8. Functional group manipulation provided the imide 9. Alkylation then led to 10, again with high diastereocontrol. In each case, care had to be taken in the further processing of the α-chiral acyl oxazolidinones. Direct NaBH4 reduction of 8 delivered the primary alcohol. To prepare the acid 10, the alkylated acyl oxazolidinone was hydrolyzed with alkaline hydrogen peroxide. On exposure of the ester 1 to the enantiomerically-pure base 11, rearrangement proceeded with high diastereocontrol, to give the acid 2. This outcome suggests that deprotonation proceeded to give the single geometric form of the enolate, that was then trapped to give specifically the ketene silyl acetal 12. This elegant approach is dependent on both the ester 1 and the base 11 being enantiomerically pure. The carbocyclic ring of pinnatoxin A 3 was assembled by intramolecular aldol condensation of the dialdehyde 11. This outcome was remarkable, in that 11 is readily epimerizable, and might also be susceptible to β-elimination. Note that the while the diol corresponding to 11 could be readily oxidized to 11 under Swern conditions, attempts to oxidize the corresponding hydroxy aldehyde were not fruitful.

The Procter Synthesis of (+)-Pleuromutilin

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Aldol Condensation ◽  
Secondary Alcohol ◽  
Primary Alcohol ◽  
Conjugate Addition ◽  
Alkoxy Group ◽  
Membered Ring ◽  
Allylic Alcohol ◽  
Silyl Ether ◽  
Radical Reduction ◽  
The University

The fungal secondary metabolite (+)-pleuromutilin 3 exerts antibiotic activity by binding to the prokaryotic ribosome. Semisynthetic derivatives of 3 are used clinically. The central step of the first synthesis of (+)-pleuromutilin 3, devised (Chem. Eur. J. 2013, 19, 6718) by David J. Procter of the University of Manchester, was the SmI2-mediated reductive closure of 1 to the tricyclic 2. The starting material for the synthesis was the inexpensive dihydrocarvone 4. Ozonolysis and oxidative fragmentation following the White protocol delivered 5 in high ee. Conjugate addition with 6 followed by Pd-mediated oxidation of the resulting silyl enol ether gave the enone 7. Subsequent conjugate addition of 8 proceeded with modest but useful diastereoselectivity to give an enolate that was trapped as the triflate 9. The Sakurai addition of the derived ester 10 with 11 led to 12 and so 1 as an inconsequential 1:1 mixture of diastereomers. The SmI2-mediated cyclization of 1 proceeded with remarkable diastereocontrol to give 2. SmI2 is a one-electron reductant that is also a Lewis acid. It seems likely that one SmI2 bound to the ester and the second to the aldehyde. Electron transfer then led to the formation of the cis-fused five-membered ring, with the newly formed alkoxy constrained to be exo to maintain contact with the complexing Sm. Intramolecular aldol condensation of the resulting Sm enolate with the other aldehyde then formed the six-membered ring, with the alkoxy group again constrained by association with the Sm. Hydrogenation of 13 gave 14, which could be brought to diastereomeric purity by chromatography. Elegantly, protection of the ketone simultaneously selectively deprotected one of the two silyl ethers, thus differentiating the two secondary alcohols. Reduction of the ester to the primary alcohol then delivered the diol 15. Selective esterification of the secondary alcohol followed by thioimidazolide formation and free radical reduction completed the preparation of 16. Ketone deprotection followed by silyl ether formation and Rubottom oxidation led to the diol 17. Protection followed by the addition of 18 and subsequent hydrolysis and reduction gave the allylic alcohol 19.

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.

C-N Ring Construction: The Synthesis of Decursivine by Mascal and by Jia

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Pyridinium Salt ◽  
University Of California ◽  
Reductive Coupling ◽  
University Of Arkansas ◽  
Santa Barbara ◽  
University Of Illinois ◽  
Enantiomerically Pure ◽  
Du Bois ◽  
Duke University ◽  
The University

Barry M. Trost and Justin Du Bois of Stanford University described (Org. Lett. 2011, 13, 3336) the cyclization of 1 to the activated aziridine 2. Liming Zhang of the University of California, Santa Barbara, rearranged (Angew. Chem. Int. Ed. 2011, 50, 3236) the propergylic amine 3 to the azetidinone 4 by N-H insertion of an intermediate Au carbene. Xiao Zheng and Pei-Qiang Huang of Xiamen University effected (J. Org. Chem. 2011, 76, 4952) reductive coupling of 6 with 7 to deliver the ester 8 . Eiji Tayama of Niigata University found (Tetrahedron Lett. 2011, 52, 1819) that 9 could be alkenylated with 10 with substantial retention of absolute configuration. Duncan J. Wardrop of the University of Illinois at Chicago, en route to a synthesis of (-)-swainsonine, observed (Org. Lett. 2011 , 13, 2376) high diastereocontrol in the cyclization of 12 to 13. Iain Coldham of the University of Sheffield also observed (J. Org. Chem. 2011, 76, 2360) substantial diastereoselection in the cyclization of 14 to 15. Robert E. Gawley of the University of Arkansas established (Org. Lett. 2011, 13, 394) that exposure of metalated 16 to just 5 mol % of a chiral ligand was sufficient to enable enantioselective coupling, to deliver 17. Christian Nadeau of Merck Frosst effected (J. Am. Chem. Soc. 2011, 133, 2878) enantioselective addition to the pyridinium salt 19 to give 20. Jiyong Hong of Duke University observed (Org. Lett. 2011, 13, 796) that enantiomerically pure 21 cyclized to the cis diastereomer of 22. With the Hayashi catalyst, cyclization could be driven toward the trans diastereomer, 22, enabling the synthesis of (+)-myrtine. Dawei Ma of the Shanghai Institute of Organic Chemistry found (Org. Lett. 2011, 13, 1602) that the Hayashi catalyst also directed the relative and absolute outcome in the addition of 24 to 23 , to give the piperidine 25. Donn G. Wishka of Pfizer/Groton devised (J. Org. Chem. 2011, 76, 1937) a practical route to the cis-substituted azepane 27, by Beckmann rearrangement of the enantiomerically pure 26 followed by reduction and oxidative cleavage.

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.

The Williams Synthesis of (–)-Khayasin

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Natural Product ◽  
Claisen Rearrangement ◽  
Aldol Condensation ◽  
Secondary Alcohol ◽  
Alcohol Exposure ◽  
Leaf Beetle ◽  
Allylic Alcohol ◽  
Total Syntheses ◽  
Asymmetric Transformation ◽  
The University

The tetranortriterpenoid (–)-khayasin 3 recently emerged as a potent and selective insecticide against the Coconut leaf beetle Brontispa longissima. In considering a synthetic route to 3, Craig M. Williams of the University of Queensland envisioned (J. Org. Chem. 2012, 77, 8913) the convergent preparation of the allyl vinyl ether 1 and subsequent Claisen rearrangement to the enone 2. To pursue this strategy, the ketone 8 and the allylic alcohol 15 had to be prepared in enantiomerically pure form. To this end, the DIP-Cl-derived enolate of the ketone 7 was added to the aldehyde 6 to give a secondary alcohol, exposure of which to KH led to the enone 8 in high ee. Methyl triflate converted the enone into the enol ether 9. The α-pinene used in the preparation of DIP-Cl was 83% ee. The authors have optimized (Adv. Synth. Catal. 2009, 351, 1148) the Morita-Baylis-Hillman addition of cyclohexenone 10 to formaldehyde to give, after silylation, the enone 11. Methylation followed by DIP-mediated aldol condensation with 13 led to the alcohol 14. Exposure of the derived acetate to lithium diisopropylamide induced cyclization and dehydration. Deprotection completed the preparation (Tetrahedron 2006, 62, 7355) of 15. Fortunately, the enantiomers of 15 could be separated chromatographically. Material having >99% ee was taken onto the next step. Warming of 9 and 15 in the presence of acid delivered the coupled ketone 2 accompanied by the ether 1. Further heating of 1 converted it (Chem. Commun. 2011, 47, 2258) to 2. To form the last ring, the enone 2 was epoxidized to give 16. The reduction of 16 with aluminum amalgam gave preparatively useful amounts of 17. Esterification completed the synthesis of 3. Most total syntheses yield only the target natural product. In this biomimetic project, intermediates 15, 2, and 17 were themselves natural products, and oxidation of 17 delivered an additional natural product, 18. The preparation of 14 and of 8 underscores the importance of the asymmetric transformation of prochiral starting materials, cyclic and acyclic. Although DIP-Cl is used in stoichiometric amounts in both cases, it is not expensive. The preparation of 8, in particular, offers a potentially general approach to high ee-substituted cyclohexenones.

Pacific Ancient and Modern Language Association

PMLA ◽  
1995 ◽  
Vol 110 (4) ◽  
pp. 882-882
Author(s):  
Cyndia Susan Clegg
Keyword(s):  
Comparative Literature ◽  
Annual Meeting ◽  
University Of California ◽  
Modern Language Association ◽  
Santa Barbara ◽  
Modern Language ◽  
Local Committee ◽  
The University ◽  
Slavic Studies

The association's most significant news is its change in name from PAPC to PAMLA to strengthen its identification with the Modem Language Association and to maintain the historic presence of classical languages. The association's ninety-third annual meeting will be held 3-5 November 1995 at the University of California, Santa Barbara, hosted by the College of Letters and Science with its Division of the Humanities, and cosponsored by the Interdisciplinary Humanities Center, the Department of Classics, the Comparative Literature Program, the Department of English, the Department of Germanic, Semitic, and Slavic Studies, and the Department of Spanish and Portuguese. Gerhart Hoffmeister, professor of German, is serving as chair of the local committee.

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.

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