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.

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.

The Evans Synthesis of (–)-Nakadomarin A

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Organic Synthesis ◽  
Allyl Alcohol ◽  
First Generation ◽  
Direct Conversion ◽  
Heck Coupling ◽  
Ring Closing Metathesis ◽  
Selective Activation ◽  
Enantiomerically Pure ◽  
Ru Catalyst ◽  
Nakadomarin A

(–)-Nakadomarin A (4), isolated from the marine sponge Amphimedon sp. off the coast of Okinawa, shows interesting cytotoxic and antibacterial activity. David A. Evans of Harvard University prepared (J. Am. Chem. Soc. 2013, 135, 9338) 4 by coupling the enantiomerically pure lactam 2 with the prochiral lactam 1. The preparation of 1 began with the aldehyde 5. Following the Comins protocol, addition of lithio morpholine to the carbonyl gave an intermediate that could be metalated and iodinated. Protection of the aldehyde followed by Heck coupling with allyl alcohol gave the aldehyde 7. Addition of the phosphorane derived from 8 followed by deprotection gave 9 with the expected Z selectivity. Addition of the phosphonate 10 was also Z selective, leading to the lactam 1. The preparation of 2 began with the enantiomerically pure imine 12. The addition of 13 was highly diastereoselective, setting the absolute configuration of 15. Alkylation with the iodide 16 delivered 17, which was closed to 2 under conditions of kinetic ring-closing metathesis, using the Grubbs first generation Ru catalyst. The condensation of 1 with 2 gave both of the diastereomeric products, with a 9:1 preference for the desired 3. Experimentally, acid catalysis alone did not effect cyclization, suggesting that the cyclization is proceeding via silylated intermediates. The diastereoselectivity can be rationalized by a preferred extended transition state for the intramolecular Michael addition. Selective activation of 3 followed by reduction gave 18, which underwent Bischler-Napieralski cyclization to give an intermediate that could be reduced to (–)-nakadomarin A (4). It was later found that exposure of 3 to Tf2O and 19 followed by the addition of Redal gave direct conversion to 4. It is instructive to compare this work to the two previous syntheses of 4 that we have highlighted, by Dixon (OHL May 3, 2010) and by Funk (OHL July 4, 2011). Together, these three independent approaches to 4 showcase the variety and dexterity of current organic synthesis.

Alkene and Alkyne Metathesis: Grandisol (Goess), 8-Epihalosilane (Kouklovsky/Vincent), (+)-Chinensiolide B (Hall)

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Boll Weevil ◽  
Alkyne Metathesis ◽  
Ring Closing Metathesis ◽  
Enantiomerically Pure ◽  
Ru Catalyst ◽  
Complementary Approach ◽  
Terminal Substituent ◽  
Furman University ◽  
The Cost ◽  
The University

The cost of using Grubbs-type catalysts could be reduced dramatically if the turnover could be improved. Richard L. Pederson of Materia found (Organic Lett. 2010, 12, 984) that in MTBE at 50°C, the ring-closing metathesis of 1 proceeded to completion in 8 hours with just 500 ppm of H2 catalyst 2. Jianhui Wang of Tianjin University constructed (Angew. Chem. Int. Ed. 2010, 49, 4425) a modified H2 catalyst 5 tethered to a nitrobenzospiropyran. After the cyclization of 4 to 6 was run in CH2Cl2, the mixture was irradiated with visible light, converting 5 into its ionic form, which could be extracted with glycol/methanol, leaving little Ru residue in the cyclized product. In the dark, the catalyst reverted and could be extracted back into CH2Cl2 and reused. In a complementary approach, David W. Knight of Cardiff University found (Tetrahedron Lett. 2010, 51, 638) that the residual Ru after metathesis could be reduced to < 2 ppm simply by stirring the product with H2O2. Cyclopropenes such as 6 are readily available in enantiomerically pure form by the addition of diazoacetates to alkynes. Christophe Meyer and Janine Cossy of ESPCI ParisTech showed (Organic Lett. 2010, 12, 248) that with a Ti additive, G2 cyclized 7 to 8. Siegfried Blechert of the Technische Universität Berlin devised (Angew. Chem. Int. Ed. 2010, 49, 3972) the chiral Ru catalyst 11, which converted the prochiral 9 to 12 in high ee. Daesung Lee of the University of Illinois, Chicago, explored (J. Am. Chem. Soc. 2010, 132, 8840) the cyclization of the diyne 13 with 14 under G2 catalysis. Depending on the terminal substituent, the cyclization could be directed selectively to 15 or 16. Bran C. Goess of Furman University took advantage (J. Org. Chem. 2010, 75, 226) of alkyne ring-closing metathesis for the conversion of 17 to 18. Selective hydrogenation then delivered the boll weevil pheromone grandisol 19. Cyrille Kouklovsky and Guillaume Vincent of the Université de Paris Sud extended (J. Org. Chem. 2010, 75, 4333) ring-opening/ring-closing metathesis to the nitroso Diels-Alder adduct 20. Reduction led to 8-epihalosilane 22.

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.

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.

Asymmetric synthesis of planar-chiral ferrocenes by Mo- or Ru-catalyzed enantioselective metathesis

2008 ◽  
Vol 80 (5) ◽  
pp. 1109-1113 ◽  
Author(s):  
Masamichi Ogasawara ◽  
Susumu Watanabe ◽  
Kiyohiko Nakajima ◽  
Tamotsu Takahashi
Keyword(s):  
Asymmetric Synthesis ◽  
Kinetic Resolution ◽  
Optically Active ◽  
Ring Closing Metathesis ◽  
Ru Catalyst ◽  
Mo Catalyst ◽  
Metal Catalyzed

Kinetic resolution of planar-chiral 1,1'-diallylferrocene derivatives was realized by Mo- or Ru-catalyzed asymmetric ring-closing metathesis (RCM). The Mo catalyst showed much better performance than the Ru catalyst in the present reactions, and nearly perfect resolution of the racemic ferrocenes was achieved. This is the first example of highly enantioselective metal-catalyzed methods of preparing optically active planar-chiral metallocenes.

Metal-Mediated C–C Ring Construction: (+)-Shiromool (Baran)

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Claisen Rearrangement ◽  
Enantiomeric Excess ◽  
Enantioselective Hydrogenation ◽  
Water Soluble ◽  
University Of Pittsburgh ◽  
Ru Catalyst ◽  
University Of Technology ◽  
La Jolla ◽  
The University ◽  
Medium Rings

Seiji Iwasa of the Toyohashi University of Technology devised (Adv. Synth. Catal. 2012, 354, 3435) a water-soluble Ru catalyst for enantioselective intramolecular cyclopropanation that could be separated from the product and recycled by simple water/ether extraction. Minoru Isobe of the National Tsing Hua University combined (Org. Lett. 2012, 14, 5274) the Nicholas and Hosomi-Sakurai reactions to close the cyclobutane ring of 4. Kazunori Koide of the University of Pittsburgh established (Tetrahedron Lett. 2012, 53, 6637) that the activity of a Ru metathesis catalyst, shut down by the presence of TBAF, could be restored by the inclusion of TMS2O. Jan Streuff of Albert-Ludwigs-Universität Freiburg demonstrated (Angew. Chem. Int. Ed. 2012, 51, 8661) that the enantiomerically pure Brintzinger complex mediated the reductive cyclization of 7 to 8. Huw M.L. Davies of Emory University prepared (J. Am. Chem. Soc. 2012, 134, 18241) the cyclopentenone 11 by the Rh-mediated addition of 10 to 9 followed by elimination. Christophe Meyer and Janine Cossy of ESPCI ParisTech showed (Angew. Chem. Int. Ed. 2012, 51, 11540) that the Rh-mediated rearrangement of 12 to 13 proceeded with substantial diastereocontrol. Jian-Hua Xie and Qi-Lin Zhou of Nankai University observed (Org. Lett. 2012, 14, 6158) that the enantioselective hydrogenation of 14 followed by Claisen rearrangement established the cyclic quaternary center of 17 with high stereocontrol. Ken Tanaka of the Tokyo University of Agriculture and Technology devised (Angew. Chem. Int. Ed. 2012, 51, 13031) the Rh-mediated addition of the enyne 18 to 19 to give the highly substituted cyclohexene 20. Daesung Lee of the University of Illinois at Chicago showed (Chem. Sci. 2012, 3, 3296) that the ring-opening/ring-closing metathesis of 21 delivered 22 with high diastereocontrol. Andreas Speicher of Saarland University cyclized (Org. Lett. 2012, 14, 4548) 23 to 24 with significant atropisomeric induction. Erick M. Carreira of the Eidgenössische Technische Hochschule Zürich effected (J. Am. Chem. Soc. 2012, 134, 20276) the polycyclization of racemic 25 to 26 with high enantiomeric excess. Medium rings are often the most difficult to construct, because of the inherent congestion across the forming ring. Phil S. Baran of Scripps/La Jolla effected (Angew. Chem. Int. Ed. 2012, 51, 11491) the cyclization of 27 to 28 as a single dominant diastereomer.

The Smith Synthesis of (−)-Nodulisporic Acid D

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Functional Group ◽  
University Of Pennsylvania ◽  
Magnesium Bromide ◽  
Ring Closing Metathesis ◽  
Enantiomerically Pure ◽  
Model Study ◽  
Silyl Enol Ether ◽  
Robinson Annulation ◽  
The University ◽  
Stereogenic Center

The nodulisporic acids, isolated from the endophytic fungus Nodulisporium sp., show promising insecticidal activity. Amos B. Smith III of the University of Pennsylvania envisioned (J. Am. Chem. Soc. 2015, 137, 7095) the construction of the central indole of nodulisporic acid D 4 by the convergent coupling of the chloroaniline 1 with the enol triflate 2. The preparation of 2 began (Org. Process Res. Dev. 2007, 11, 19) with the mono­ketal 5 of the Wieland–Miescher ketone, available in enantiomerically-pure form by organocatalyzed Robinson annulation. Condensation with thiophenol and formal­dehyde gave 6, which, under dissolving metal conditions, was reduced to an enolate that was trapped as the silyl enol ether 7. Condensation again with formaldehyde gave 8, that was converted by reduction and protecting group exchange to the ketone 9. Pd-catalyzed formylation of the derived enol triflate led to 10. The Cu-meditated conjugate addition of vinyl magnesium bromide to the unsatu­rated aldehyde 10 was carefully optimized to maximize equatorial addition, away from the angular methyl group. Subsequent C-methylation of the aldehyde was achieved by generating the Li enolate and carrying out the alkylation in diglyme. With 11 in hand, the third carbocyclic ring was assembled by 1,2-addition of vinylmagnesium bromide to the aldehyde followed by ring-closing metathesis and oxidation to give 12. Hydrogenation followed by functional group interconversion then completed the assembly of the enol triflate 2. The stereogenic center of 1 was established by Enders alkylation of 13 with the iodide 14. The ketone 15 was best liberated by ozonolysis under non-epimerizing conditions. The critical Barluenga indole construction that formed 3 also required careful optimization in a model study, the key observation being the value of the Buchwald ligand RuPhos. The conditions developed were found, remarkably, to be compatible with the aldehyde functional group, so subsequent Horner–Wadsworth–Emmons condensation with 16 could be carried out directly, to complete the synthe­sis of (−)-nodulisporic acid D 4.

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