Advances in Alkene Metathesis: The Kobayashi Synthesis of (+)-TMC-151C

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Ethyl Acrylate ◽  
Cascade Process ◽  
Aqueous Mixtures ◽  
University Of Minnesota ◽  
Ring Closing Metathesis ◽  
Ru Catalyst ◽  
Cross Metathesis ◽  
Mo Catalyst ◽  
Institute Of Technology ◽  
The University

Shazia Zaman of the University of Canterbury and Andrew D. Abell of the University of Adelaide devised (Tetrahedron Lett. 2011, 52, 878) a polyethylene glycol-tagged Ru catalyst that is effective for alkene metathesis in aqueous mixtures, cyclizing 1 to 2. Bruce H. Lipshutz of the University of California, Santa Barbara developed (J. Org. Chem. 2011, 76, 4697, 5061) an alternative approach for aqueous methathesis, and also showed that CuI is an effective cocatalyst, converting 3 to 5. Christian Slugovc of the Graz University of Technology showed (Tetrahedron Lett. 2011, 52, 2560) that cross metathesis of the diene 6 with ethyl acrylate 7 could be carried out with very low catalyst loadings. Robert H. Grubbs of the California Institute of Technology designed (J. Am. Chem. Soc. 2011, 133, 7490) a Ru catalyst for the ethylenolysis of 9 to 10 and 11. Thomas R. Hoye of the University of Minnesota showed (Angew. Chem. Int. Ed. 2011, 50, 2141) that the allyl malonate linker of 12 was particularly effective in promoting relay ring-closing metathesis to 13. Amir H. Hoveyda of Boston College designed (Nature 2011, 471, 461) a Mo catalyst that mediated the cross metathesis of 14 with 15 to give 16 with high Z selectivity. Professor Grubbs designed (J. Am. Chem. Soc. 2011, 133, 8525) a Z selective Ru catalyst. Damian W. Young of the Broad Institute demonstrated (J. Am. Chem. Soc. 2011, 133, 9196) that ring closing metathesis of 17 followed by desilylation also led to the Z product, 18. Thomas E. Nielsen of the Technical University of Denmark devised (Angew. Chem. Int. Ed. 2011, 50, 5188) a Ru-mediated cascade process, effecting ring-closing metathesis of 19, followed by alkene migration to the enamide, and finally diastereoselective cyclization to 20. In the course of a total synthesis of (–)-goniomitine, Chisato Mukai of Kanazawa University showed (Org. Lett. 2011, 13, 1796) that even the very congested alkene of 22 smoothly participated in cross metathesis with 21 to give 23. En route to leustroducsin B, Jeffrey S. Johnson of the University of North Carolina protected (Org. Lett. 2011, 13, 3206) an otherwise incompatible terminal alkyne as its Co complex 24, allowing ring closing methathesis to 25.

Functional Group Oxidation and Reduction

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Direct Conversion ◽  
University Of Mississippi ◽  
Ru Catalyst ◽  
Mo Catalyst ◽  
University Of Arizona ◽  
Institute Of Technology ◽  
Diastereoselective Reduction ◽  
The University ◽  
University Of Manchester ◽  
Mediated Reduction

Debabrata Maiti of the Indian Institute of Technology Bombay found (Chem. Commun. 2012, 48, 4253) that the relatively inexpensive Pd(OAc)2 effectively catalyzed the decarbonylation of an aldehyde 1 to the hydrocarbon 2. Hui Lou of Zhejiang University used (Adv. Synth. Catal. 2011, 353, 2577) a Mo catalyst to effect reduction of the ester 3 to the hydrocarbon 4, with retention of all the skeletal carbons. Jon T. Njardarson of the University of Arizona showed (Chem. Commun. 2012, 48, 7844) that the allylic ether 5 could be reduced with high regioselectivity to give 6. José Barluenga and Carlos Valdés of the Universidad de Oviedo effected (Angew. Chem. Int. Ed. 2012, 51, 5950) the direct conversion of a ketone 7 to the azide 8. Although no cyclic ketones were included in the examples, there is a good chance that this will be the long-sought diastereoselective reduction of a cyclohexanone to the equatorial amine. Hideo Nagashima of Kyushu University reduced (Chem. Lett. 2012, 41, 229) the acid 9 directly to the aldehyde 1 using a ruthenium catalyst with the bis silane 10. Georgii I. Nikonov of Brock University described (Adv. Synth. Catal. 2012, 354, 607) a similar Ru-mediated silane reduction of an acid chloride to the aldehyde. Professor Nagashima used (Angew. Chem. Int. Ed. 2012, 51, 5363) his same Ru catalyst to reduce the ester 11 to the protected amine 12. Shmaryahu Hoz of Bar-Ilan University used (J. Org. Chem. 2012, 77, 4029) photostimulation to promote the SmI2-mediated reduction of a nitrile 13 to the amine 14. Bakthan Singaram of the University of California, Santa Cruz effected (J. Org. Chem. 2012, 77, 221) the same transformation with InCl3/NaBH4. David J. Procter of the University of Manchester described (J. Org. Chem. 2012, 77, 3049) what promises to be a general method for activating Sm metal to form SmI2. Mark T. Hamann of the University of Mississippi directly reduced (J. Org. Chem. 2012, 77, 4578) the nitro group of 15 to the alkylated amine 16. Cleanly oxidizing aromatic methyl groups to the level of the aldehyde without overoxidation has been a challenge.

Total Synthesis by Alkene Metathesis: Amphidinolide X (Urpí/Vilarrasa), Dactylolide (Jennings), Cytotrienin A (Hayashi), Lepadin B (Charette), Blumiolide C (Altmann)

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
First Generation ◽  
Allylic Alcohols ◽  
Silyl Ether ◽  
Ring Closing Metathesis ◽  
Enantiomerically Pure ◽  
Ru Catalyst ◽  
Mo Catalyst ◽  
Metathesis Catalysts ◽  
The University ◽  
Medium Rings

To assemble the framework of the cytotoxic macrolide Amphidinolide X 3, Fèlix Urpí and Jaume Vilarrasa of the Universitat de Barcelona devised (Organic Lett. 2008, 10, 5191) the ring-closing metathesis of the alkenyl silane 1. No Ru catalyst was effective, but the Schrock Mo catalyst worked well. In the course of a synthesis of (-)-Dactylolide 6, Michael P. Jennings of the University of Alabama offered (J. Org. Chem. 2008, 73, 5965) a timely reminder of the particular reactivity of allylic alcohols in ring-closing metathesis. The cyclization of 4 to 5 proceeded smoothly, but attempted ring closing of the corresponding bis silyl ether failed. Polyenes such as ( + )-Cytotrienin A 8 are notoriously unstable. It is remarkable that Yujiro Hayashi of the Tokyo University of Science could (Angew. Chem. Int. Ed. 2008, 47, 6657) assemble the triene of 8 by the ring-closing metathesis of the highly functionalized precursor 7. Bicyclo [2.2.2] structures such as 9 are readily available by the addition of, in this case, methyl acrylate to an enantiomerically-pure 2-methylated dihydropyridine. André B. Charette of the Université de Montréal found (J. Am. Chem. Soc. 2008, 130, 13873) that 9 responded well to ring-opening/ring-closing metathesis, to give the octahydroquinoline 10. Functional group manipulation converted 10 into the Clavelina alkaloid ( + )-Lepadin B 11. The construction of trisubstituted alkenes by ring-closing metathesis can be difficult, and medium rings with their transannular strain are notoriously challenging to form. Nevertheless, Karl-Heinz Altmann of the ETH Zürich was able (Angew. Chem. Int. Ed. 2008, 47, 10081), using the H2 catalyst, to cyclize 12 to cyclononene 13, the precursor to the Xenia lactone ( + )-Blumiolide C 14. It is noteworthy that these fi ve syntheses used four different metathesis catalysts in the key alkene forming step. For the cyclization of 7, the use of the Grubbs first generation catalyst G1, that couples terminal alkenes but tends not to interact with internal alkenes, was probably critical to success.

Alkene and Alkyne Metathesis: (+)-Anamarine (Sabitha), ( ± )-Pseudotabersonine (Martin), Lactimidomycin (Fürstner)

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Indian Institute ◽  
Alkyne Metathesis ◽  
Max Planck ◽  
Ring Closing Metathesis ◽  
University Of Texas ◽  
Ru Catalyst ◽  
Cross Metathesis ◽  
University Of Zurich ◽  
Indian Institute Of Science ◽  
The University

Masato Matsugi of Meijo University showed (J. Org. Chem. 2010, 75, 7905) that over five iterations, the fluorous-tagged Ru catalyst 1b was readily recovered and reused for the cyclization of 2 to 3. Hengquan Yang of Shanxi University reported (Chem. Commun. 2010, 46, 8659) that the Hoveyda catalyst 1a encapsulated in mesoporous SBA-1 could also be reused several times. Jean-Marie Basset of KAUST Catalysis Center, Régis M. Gauvin of Université Lille, and Mostafa Taoufik of Université Lyon 1 described (Chem. Commun. 2010, 46, 8944) a W catalyst on silica that was also active for alkene metathesis. Reto Dorta of the University of Zurich, exploring several alternatives, found (J. Am. Chem. Soc. 2010, 132, 15179) that only 4c cyclized cleanly to 5. Karol Grela of the Polish Academy of Sciences showed (Synlett 2010, 2931) that 3-nitropropene (not illustrated) participated in cross-metathesis when catalyst 1c was used. Shawn K. Collins of the Université de Montré al complexed (J. Am. Chem. Soc. 2010, 132, 12790) 6 with a quinolinium salt to direct paracyclophane formation. Min Shi of the Shanghai Institute of Organic Chemistry incorporated (Org. Lett. 2010, 12, 4462) the cyclopropene 8 in cross-metathesis, to give 10. A. Srikrishna of the Indian Institute of Science (Bangalore) constructed (Synlett 2010, 3015) the cyclooctenone 12 by ring-closing metathesis. LuAnne McNulty of Butler University established (J. Org. Chem. 2010, 75, 6001) that a cyclic boronic half acid 15, prepared by ring-closing metathesis, coupled with an iodoalkene 16 to deliver the diene 17 with high geometric control. Gowravaram Sabitha of the Indian Institute of Chemical Technology, Hyderabad, en route to (+)-anamarine 21, observed (Tetrahedron Lett. 2010, 51, 5736) that the tetraacetate 18b would not participate in cross-metathesis. Fortunately, 18a , an earlier intermediate in the synthesis, worked well. Stephen F. Martin of the University of Texas prepared (Org. Lett. 2010, 12, 3622) (±)-pseudotabersonine 24 by way of a spectacular metathesis that converted 22 to 23. Ring-closing alkyne metathesis was a key step in the total synthesis of lactimidomycin 27 reported (J. Am. Chem. Soc. 2010, 132, 14064) by Alois Fürstner of the Max-Planck- Institut Mülheim.

Advances in Alkene Metathesis: The Hoveyda Synthesis of (+)-Quebrachamine

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
University Of Iowa ◽  
Enantiomerically Pure ◽  
Ru Catalyst ◽  
Cross Metathesis ◽  
Mo Catalyst ◽  
Conformational Effects ◽  
Ru Complexes ◽  
Metathesis Catalysts ◽  
La Rioja ◽  
The University

There are two major impediments to scaling up alkene metathesis: reducing the amount of the expensive Ru catalyst required, and minimizing residual Ru in the product. Robert H. Grubbs of Caltech developed (Organic Lett. 2009, 11, 1261) a family of silica-supported Ru complexes, exemplified by 1. At 0.75 mol % of 1, the rate of cyclization of 2 to 3 was maintained over eight cycles. The solution of product 3 showed < 5 ppb Ru. Hassan S. Bazzi and David E. Bergbreiter of the Texas A&M campuses in Qatar and College Station also reported (Organic Lett. 2009, 11, 665) a durable polymer-bound Ru metathesis catalyst that maintained its activity over many cycles. Most metathesis catalysts are strongly E selective. Amir H. Hoveyda of Boston College designed (J. Am. Chem. Soc. 2009, 131, 3844) a chiral Mo catalyst that was both highly enantioselective and strongly Z selective, converting the prochiral 4 into the alkene 6. Professor Hoveyda also took advantage (J. Am. Chem. Soc. 2009, 131, 8378) of the known propensity of Ru metathesis catalysts for H bonding, showing that metathesis of the prochiral cyclopropene 7 proceeded with remarkable diastereocontrol. This appears to be a generally useful protocol for assembling enantiomerically pure alkylated quaternary stereogenic centers. It is also possible to encapsulate the Ru catalyst. Ned B. Bowden of the University of Iowa pioneered the use of PDMS thimbles for this purpose. He has now shown (Organic Lett. 2009, 11, 33) that by subsequently adding AD-mix, cross-metathesis can be followed directly by enantioselective dihydroxylation. Ring-opening cross-metathesis of an unsymmetrical alkene such as 13 could give two different products. Alberto Avenoza and Jesús H. Busto of the Universidad de La Rioja established (J. Org. Chem. 2009, 74, 1736) that by tuning the electronic nature of the participating alkene, either product can be obtained with high selectivity. Metathesis can be used to close larger rings. Conformational effects are important. Motoo Tori of Tokushima Bunri University observed (Tetrahedron Lett. 2009, 50, 2225) that although 18 cyclized efficiently, the other three precursors that were diastereomeric on the cyclopentane ring did not undergo ring-closing metathesis.

Developments in Alkene and Alkyne Metathesis

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Pyridinium Salt ◽  
University Of Pittsburgh ◽  
Ru Catalyst ◽  
University Of Utah ◽  
Temple University ◽  
Cross Metathesis ◽  
University Of Wisconsin ◽  
Institute Of Technology ◽  
Ru Species ◽  
The University

Jon D. Rainier of the University of Utah has put forward (J. Am. Chem. Soc. 2007 , 129 , 12604) an elegant alternative to Ru-catalyzed alkene metathesis, demonstrating that an ω-alkenyl ester such as 1 will cyclize to the enol ether 2 under Tebbe conditions. The particular reactivity of free alcohols in Ru-catalyzed alkene metathesis is underscored by the observation (Tetrahedron Lett. 2007, 48, 6905) by Javed Iqbal of Dr. Reddy’s Laboratories, Ltd., Miyapur that attempted metathesis of the ether 4a failed, but metathesis of the diol 4b proceeded efficiently. Kazunori Koide of the University of Pittsburgh has demonstrated (Organic Lett. 2007, 9, 5235) that the yields of cross-metathesis with an alkenyl alcohol could be enhanced by binding it to a trityl resin. He observed that the Grela catalyst 8 was particularly effective in this application. Residual Ru species do not interfere with some subsequent transformations. Rodrigo B. Andrade of Temple University has demonstrated (Tetrahedron Lett. 2007, 48, 5367) that metathesis with an α, β-unsaturated aldehyde such as 11 can be followed directly by phosphonate condensation to give the doubly-homologated product 12. Philip J. Parsons of the University of Sussex has found (Organic Lett. 2007, 9, 2613) that the nitro functional group is compatible with the Ru catalyst. The product nitro alkene 15 could be cyclized (intramolecular Michael addition) to the cyclopentane 16, or (intramolecular dipolar cycloaddition) to the cyclopentane 17. There has been much interest in carrying out the several alkene metathesis transformations (cross metathesis, ring closing metathesis, ring-opening metathesis polymerization) in water. Robert H. Grubbs of the California Institute of Technology has designed (Angew. Chem. Int. Ed. 2007, 46, 5152) the ammonium salt 18 for this purpose, and Karol Grela of the Polish Academy of Sciences in Warsaw and Marc Mauduit of ENSC Rennes have jointly(Chem. Commun. 2007, 3771) put forward the pyridinium salt 19. Remarkably, Ronald T. Raines of the University of Wisconsin has shown (Organic Lett. 2007, 9, 4885) that the Hoveyda catalyst 20 is sufficiently stable in aqueous acetone and aqueous DME to function efficiently.

Advances in Alkene and Alkyne Metathesis

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Acetic Acid ◽  
Diels Alder ◽  
Alkyne Metathesis ◽  
Santa Barbara ◽  
Ring Closing Metathesis ◽  
Enol Ethers ◽  
Cross Metathesis ◽  
Simple Filtration ◽  
The University ◽  
Academy Of Sciences

As alkene metathesis is extended to more and more challenging substrates, improved catalysts and solvents are required. Robert H. Grubbs of Caltech developed (Organic Lett. 2008, 10, 441) the diisopropyl complex 1, that efficiently formed the trisubstituted alkene 6 by cross metathesis of 4 with 5. Hervé Clavier and Stephen P. Nolan of ICIQ, Tarragona, and Marc Mauduit of ENSC Rennes found (J. Org. Chem. 2008, 73, 4225) that after cyclization of 7 with the complex 2b, simple filtration of the reaction mixture through silica gel delivered the product 8 containing only 5.5 ppm Ru. The merit of CH2Cl2 as a solvent for alkene metathesis is that the catalysts (e.g. 1 - 3) are very stable. Claire S. Adjiman of Imperial College and Paul C. Taylor of the University of Warwick established (Chem. Commun. 2008, 2806) that although the second generation Grubbs catalyst 3 is not as stable in acetic acid, for the cyclization of 9 to 10 it is a much more active catalyst in acetic acid than in CH2Cl2 . Bruce H. Lipshutz of the University of California, Santa Barbara observed (Adv. Synth. Cat . 2008, 350, 953) that even water could serve as the reaction solvent for the challenging cyclization of 11 to 12, so long as the solubility- enhancing amphiphile PTS was included. Ernesto G. Mata of the Universidad Nacional de Rosario explored (J. Org. Chem. 2008, 73, 2024) resin isolation to optimize cross-metathesis, finding that the acrylate 13 worked particularly well. Karol Grela of the Polish Academy of Sciences, Warsaw optimized (Chem. Commun. 2008, 2468) cross-metathesis with a halogenated alkene 16. Jean-Marc Campagne of ENSC Montpellier extended (J. Am. Chem. Soc. 2008, 130, 1562) ring-closing metathesis to enynes such as 19. The product diene 20 was a reactive Diels-Alder dienophile. István E. Markó of the Université Catholique de Louvain applied (Tetrahedron Lett. 2008, 49, 1523) the known (OHL 20070122) ring-closing metathesis of enol ethers to the cyclization of the Tebbe product from 23. The ether 24 was oxidized directly to the lactone 25.

Metal-Mediated Carbocyclic Construction: The Simpkins Synthesis of Ialibinones A and B

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Gold Catalyst ◽  
Conjugate Addition ◽  
South Florida ◽  
Pt Catalyst ◽  
General Strategy ◽  
Ru Catalyst ◽  
University Of Technology ◽  
Rh Catalyst ◽  
Institute Of Technology ◽  
The University

Adriaan J. Minnaard and Ben L. Feringa of the University of Groningen devised (J. Am. Chem. Soc. 2010, 132, 14349) what promises to be a general strategy for the construction of enantiomerically pure cyclopropanes, based on conjugate addition to acceptors such as 1 . X. Peter Zhang of the University of South Florida developed (J. Am. Chem. Soc. 2010, 132, 12796) a Co catalyst for the enantioselective cyclopropanation of α-olefins such as 3. Seiji Iwasa of Toyohashi University of Technology designed (Angew. Chem. Int. Ed. 2010, 49, 8439) a resin-bound Ru catalyst that could be used repeatedly for the enantioselective cyclization of the ester 6. Rai-Shung Lin of National Tsing-Hua University showed (Angew. Chem. Int. Ed. 2010, 49, 9891) that a gold catalyst could expand the alkyne 8 to the cyclobutene 9. Takao Ikariya of the Tokyo Institute of Technology reported (J. Am. Chem. Soc. 2010, 132, 16637) a detailed study of the enantioselective conjugate addition of malonate 11 to cyclopentenone 10. Vladimir A. D’yakonov of the Russian Academy of Sciences, Ufa, showed (Tetrahedron Lett. 2010, 51, 5886) that a cyclic alkyne 13 could be annulated to the cyclopentenone 14. Shunichi Hashimoto of Hokkaido University also designed (Angew. Chem. Int. Ed. 2010, 49, 6979) a resin-bound Rh catalyst that could also be used repeatedly for the enantioselective cyclization of the ester 15. Tushar Kanti Chakraborty of the Central Drug Research Institute used (Tetrahedron Lett. 2010, 51, 4425) Ti(III) to mediate the diastereoselective cyclization of 17 to 18. Alexandre Alexakis of the University of Geneva extended (Synlett 2010, 1694) enantioselective conjugate addition of isopropenyl to the more difficult enone 19. Joseph P. A. Harrity of the University of Sheffield showed (Org. Lett. 2010, 12, 4832) that Pd could catalyze the rearrangement of 21 to 22. Strategies for the controlled construction of polycyclic ring systems are also important. Günter Helmchen of the Universität Heidelberg showed (J. Org. Chem. 2010, 75, 7917) that 23 was efficiently cyclized to the diene with Pt catalyst. The reaction could be carried out in the presence of the dienophile 24 to give 25 directly.

Metal-Mediated C–C Ring Construction: The Carreira Synthesis of (+)-Asperolide C

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Conjugate Addition ◽  
Ring Expansion ◽  
Ethyl Acrylate ◽  
Heck Cyclization ◽  
University Of Oxford ◽  
Silyl Enol Ether ◽  
Emory University ◽  
Institute Of Technology ◽  
The University ◽  
Technological University

Djamaladdin G. Musaev and Huw M. L. Davies of Emory University effected (Chem. Sci. 2013, 4, 2844) enantioselective cyclopropanation of ethyl acrylate 2 with the α-diazo ester 1 to give 3 in high ee. Philippe Compain of the Université de Strasbourg used (J. Org. Chem. 2013, 78, 6751) SmI2 to cyclize 4 to the cyclobutanol 5. Jianrong (Steve) Zhou of Nanyang Technological University effected (Chem. Commun. 2013, 49, 11758) enantioselective Heck addition of 7 to the prochiral ester 6 to give the cyclopentene 8. Liu-Zhu Gong of USTC, Hefei added (Org. Lett. 2013, 15, 3958) the Rh enolate from the enantioselective ring expansion of the α-diazo ester 9 to the nitroalkene 10, to give 11 in high de. Stephen P. Fletcher of the University of Oxford set (Angew. Chem. Int. Ed. 2013, 52, 7995) the cyclic quaternary center of 14 by the enantioselective conjugate addition to 12 of the alkyl zirconocene derived from 13. Alexandre Alexakis of the University of Geneva reported (Chem. Eur. J. 2013, 19, 15226) high ee from the conjugate addition of alkenyl Al reagents (not illustrated) to 12. Paultheo von Zezschwitz of Philipps-Universität Marburg prepared (Adv. Synth. Catal. 2013, 355, 2651) the silyl enol ether 17 by trapping the intermediate from the conjugate addition of 16 to 15. Stefan Bräse of the Karlsruhe Institute of Technology effected (Eur. J. Org. Chem. 2013, 7110) conjugate addition to the prochiral dienone 18 to give the highly substi­tuted cyclohexenone 19. Ping Tian and Guo-Qiang Lin of the Shanghai Institute of Organic Chemistry cyclized (J. Am. Chem. Soc. 2013, 135, 11700) 20 to the kinetic, less stable epimer of the diketone 21. Rh-mediated intramolecular C–H insertion has been a powerful tool for the con­struction of cyclopentane derivatives. Douglass F. Taber of the University of Delaware found (J. Org. Chem. 2013, 78, 9772) that the Rh carbene derived from 22 was dis­criminating enough to target the more nucleophilic C–H bond, leading to the cyclohexanone 23. Kozo Shishido of the University of Tokushima observed (Org. Lett. 2013, 15, 3666) high diastereoselectivity in the intramolecular Heck cyclization of 24 to 25.

The Kozmin Synthesis of Spirofungin A

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Absolute Configuration ◽  
Journal Article ◽  
Ring System ◽  
Spatial Proximity ◽  
Silyl Ether ◽  
Secondary Alcohols ◽  
Ring Closing Metathesis ◽  
Cross Metathesis ◽  
The University ◽  
Flexible Ring

Often, 6,6-spiroketals such as Spirofungin A 3 have a strong anomeric bias. Spirofungin A does not, as the epimer favored by double anomeric stabilization suffers from destabilizing steric interactions. In his synthesis of 3, Sergey A. Kozmin of the University of Chicago took advantage (Angew. Chem. Int. Ed. 2007, 46, 8854) of the normally-destablizing spatial proximity of the two alkyl branches of 3, joining them with a siloxy linker to assure the anomeric preference of the spiroketal. The assembly of 1 showcased the power of asymmetric crotylation, and of Professor Kozmin’s linchpin cyclopropenone ketal cross metathesis. To achieve the syn relative (and absolute) configuration of 6, commercial cis-2-butene was metalated, then condensed with the Brown (+)-MeOB(Ipc)2 auxiliary. The accompanying Supporting Information, accessible via the online HTML version of the journal article, includes a succinct but detailed procedure for carrying out this homologation. For the anti relative (and absolute) configuration of 9, it is more convenient to use the tartrate 8 introduced by Roush. Driven by the release of the ring strain inherent in 10, ring opening cross metathesis with 6 proceeded to give the 1:1 adduct 11 in near quantitative yield. The derived cross-linked silyl ether 12 underwent smooth ring-closing metathesis to the dienone 1. On hydogenation, the now-flexible ring system could fold into the spiro ketal. With the primary and secondary alcohols bridged by the linking silyl ether, only one anomeric form, 2, of the spiro ketal was energetically accessible. A remaining challenge was the stereocontrolled construction of the trisubstituted alkene. To this end, the aldehyde 13 was homologated to the dibromide 14. Pd-mediated coupling of the alkenyl stannane 15 with 14 was selective for the E bromide. The residual Z bromide was then coupled with Zn(CH3)2 to give 16. These steps, and the final steps to complete the construction of spirofungin A 3 , could be carried out without exposure to equilibrating acid, so the carefully established spiro ketal confi guration was maintained.

Alkene Metathesis: Synthesis of Panaxytriol (Lee), Isofagomine (Imahori and Takahata), Elatol (Stoltz), 5-F2t -Isoprostane (Snapper), and Ottelione B (Clive)

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Grignard Reagent ◽  
Conjugate Addition ◽  
Ring Closing Metathesis ◽  
University Of Illinois ◽  
Enantiomerically Pure ◽  
University Of Alberta ◽  
Cross Metathesis ◽  
Grubbs Catalysts ◽  
The University ◽  
First And Second Generation

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.

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