The Evans Synthesis of (–)-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.

The Carreira Synthesis of (+)-Daphmanidin E

(+)-Daphmanidin E 3, isolated from the leaves of Daphniphyllum teijsmanni, shows moderate vasorelaxant activity on the rat aorta. Considering the curiously compact structure of 3, Erick M. Carreira of ETH Zürich chose (Angew. Chem. Int. Ed. 2011, 50, 11501) to start the synthesis from the enantiomerically pure bicyclic diketone 2. The mono enolate of 2 was readily prepared, but the steric bulk of the ketal of 4 was needed to direct the subsequent hydroboration. Indeed, the alkene of 5 was so congested that excess BH3 at elevated temperature was required. Under those conditions, the esters were also partially reduced, so the reduction was completed with Dibal to deliver the crystalline triol 6. After protection of the alcohols, the remaining carbon atoms of 3 were added by sequential Claisen rearrangements. O-Alkylation with 7 delivered 8, which rearranged with 10:1 diastereoselectivity. After O-allylation, the second Claisen rearrangement led to 9 as the only isolable product. Selective hydroboration of 9 led to 10, which was deprotected, then dehydrated following the Grieco protocol. Functional group manipulation of 11 led to the aldehyde 12, which was condensed with nitromethane to give 13. Direct conjugate addition to 13 gave at best a 1:3 preference for the wrong diastereomer. With a chiral Cu catalyst, this was improved to 5:1 in favor of the desired diastereomer. Ozonolysis of 14 followed by selective reduction of the aldehyde gave the primary alcohol, which was carried onto the iodide. Elimination with DBU then delivered 15, setting the stage for the key intramolecular bond connection. After extensive exploration, it was found that irradiation of 15 in the presence of a catalytic amount of a cobaloxime catalyst and a stoichiometric amount of Hünig’s base gave clean cyclization to 16. The last carbocyclic ring of (+)-daphmanidin E 3 was closed by intramolecular aldol addition of the aldehyde of 17 to the ketone, followed by dehydration. The seemingly simple intramolecular imine formation to prepare the natural product, initially elusive, was effected by heating the ammonium salt in ethanol. The Co-catalyzed cyclization of 15 to 16 is particularly striking.

The Theodorakis Synthesis of (–)-Jiadifenolide

There has recently been a great deal of interest in the synthesis of natural products that promote neurite outgrowth. Emmanuel A. Theodorakis of the University of California, San Diego described (Angew. Chem. Int. Ed. 2011, 50, 3672) the preparation of one of the most potent (10 nM) of these, (–)-jiadifenolide 3. Fittingly, a key transformation en route to this highly oxygenated seco-prezizaane was the oxidative rearrangement of 1 to 2. The starting point for the synthesis was the commercially available diketone 4. Allylation followed by addition to 5 gave the prochiral triketone 6. Enantioselective aldol condensation following the Tu/Zhang protocol then delivered the bicyclic enone 7. Alkylation to give 8 proceeded with high diastereoselectivity, perhaps controlled by the steric bulk of the silyloxy group. Exposure of the protected ketone to the McMurry reagent PhNTf2 gave the enol triflate 9, which smoothly carbonylated to the lactone 10. Epoxidation with alkaline hydrogen peroxide followed by oxidation gave the carboxylic acid, which spontaneously opened the epoxide, leading to the bis lactone 1. With 1 in hand, the stage was set for the key oxidative rearrangement to 2. It was envisioned that epoxidation would generate the cis-fused 11, which on oxidation would undergo acid-catalyzed elimination to give 12. The newly freed OH would then be in position to engage the lactone carbonyl, leading to 2. In the event, oxidation of the epoxide with the Dess-Martin reagent required sonication for 2 h. The rearranged lactone, even though it was susceptible to further oxidation, was secured in 38% overall yield from 1. After hydrogenation and protection, preparation of the enol triflate 13 from the congested cyclopentanone necessitated the use of the more reactive Comins reagent. Hydrogenation of the trisubstituted alkene from coupling with Me3Al then required 90 atmospheres of H2 overpressure. Hydroxylation of the lactone 14 with the Davis oxaziridine followed by further oxidation to the ketone with the Jones reagent and deprotection then completed the synthesis of (–)-jiadifenolide 3.

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

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

Intramolecular Diels-Alder Cycloaddition: 7-Isocyanoamphilecta- 11(20),15-diene (Miyaoka), (–)-Scabronine G (Kanoh), Basiliolide B (Stoltz), Hirsutellone B (Uchiro), Echinopine A (Chen)

The amphilectane diterpenes, exemplified by 7-isocyanoamphilecta-11(20),15-diene 3, have been little investigated. In the course of a synthesis of 3, Hiroaki Miyaoka of the Tokyo University of Pharmacy and Life Sciences took advantage (Synlett 2011, 547) of the kinetic enolization and silylation of 1 to convert it into a trienone that spontaneously cyclized to 2. Scabronine G 6, isolated from the mushroom Sarcodon scabrosus, was found to enhance the secretion of neurotrophic factors from 1321N1 astrocytoma cells. To set the absolute configuration of the two quaternary centers that are 1, 4 on the cyclohexane ring of 6, Naoki Kanoh and Yoshiharu Iwabuchi of Tohoku University cyclized (Org. Lett. 2011, 13, 2864) 4 to 5. Although described by the authors as a double Michael addition, this transformation has the same connectivity as an intramolecular Diels-Alder cycloaddition. The diterpenes isolated from the genus Thapsia, represented by basiliolide B 9, induce rapid mobilization of intracellular Ca2+ stores. Brian M. Stoltz of Caltech effected (Angew. Chem. Int. Ed. 2011, 50, 3688) Claisen rearrangement of 7 to give an intermediate that cyclized to 8 as a mixture of diastereomers. A significant challenge in the synthesis was the assembly of the delicate enol ether/lactone of 9. Hirsutellone B 12, isolated from Hirsutella nivea, shows significant antituberculosis activity. Hiromi Uchiro of the Tokyo University of Science found it useful (Org. Lett. 2011, 13, 6268) to protect the intermediate unsaturated keto ester by intermolecular cycloaddition with pentamethylcyclopentadiene before constructing the triene of 10. Simple thermolysis reversed the intermolecular addition, opening the way to intramolecular cycloaddition to give 11. The tetracyclic ring system of the diterpene echinopine A 15 represents a substantial synthetic challenge. David Y.-K. Chen of Seoul National University approached this problem (Org. Lett. 2011, 13, 5724) by Pd-mediated cyclization of 13 to the diene, which then underwent intramolecular Diels-Alder cycloaddition to give 14, with control of the relative configuration of two of the three ternary centers of 15. Double bond migration followed by oxidative cleavage of the resulting cyclohexenone then set the stage for the intramolecular cyclopropanation that completed the synthesis of 15.

Metal-Mediated Carbocyclic Construction: The Chen Synthesis of Ageliferin

Djamaladdin G. Musaev and Huw M.L. Davies of Emory University designed (J. Am. Chem. Soc. 2011, 133, 19198) a Rh catalyst that added 2 to 1 to give 3 with high dr and ee. Shunichi Hashimoto of Hokkaido University reported (Angew. Chem. Int. Ed. 2011, 50, 6803) a Rh catalyst that would add the α-diazo ester 5 to a terminal alkyne 4 to give the cyclopropene 6 in high ee. Gaëlle Blond and Jean Suffert of the Université de Strasbourg cyclized (Adv. Synth. Catal. 2011, 353, 3151) the alkyne 7, then coupled the Pd intermediate with a terminal alkyne 8 to give the cyclobutane 9. Nuno Maulide of the Max-Planck-Institute Mülheim ionized (Angew. Chem. Int. Ed. 2011, 50, 12631) the lactone 10 to a prochiral intermediate, which could then be coupled with 11 to give either diastereomer of 12 in high ee. Martin Hiersemann of the Technische Universität Dortmund devised (Org. Lett. 2011, 13, 4438) a Pd catalyst for the selective cyclization of 13 to 14. Naoya Kumagai and Masakatsu Shibasaki of the Institute of Microbial Chemistry, Tokyo effected (Angew. Chem. Int. Ed. 2011, 50, 7616) the enantioselective Conia ene cyclization of 15 to 16. Barry M. Trost of Stanford University developed (J. Am. Chem. Soc. 2011, 133, 19483) an enantioselective variant of the trimethylenemethane cycloaddition of 18 to 17 to give 19. In the course of a synthesis of (–)-oseltamivir phosphate, Masahiko Hayashi of Kobe University found (J. Org. Chem. 2011, 76, 5477) conditions for the enantioselective oxidation of 20 to 21. Quanrui Wang of Fudan University and Andreas Goeke of Givaudan Fragrances (Shanghai) cyclized (J. Org. Chem. 2011, 76, 5825) the propargylic acetate 22 to the cyclohexenone 23. Chuang-chuang Li, Tuoping Luo, and Zhen Yang of Peking University cyclized (J. Am. Chem. Soc. 2011, 133, 14944) the diyne 24 to the lactone 25. Hiromitsu Takayama of Chiba University used (Angew. Chem. Int. Ed. 2011, 50, 8025) the silyl tether of 26 to constrain the diastereomeric outcome of the cyclization to 27.

Advances in Heterocyclic Aromatic Construction

Rubén Vicente and Luis A. López at the University of Oviedo in Spain reported (Angew. Chem. Int. Ed. 2012, 51, 8063) the synthesis of cyclopropyl furan 2 from alkylidene 1 and styrene by way of a zinc carbene intermediate. The same substrate 1 was also converted (Angew. Chem. Int. Ed. 2012, 51, 12128) to furan 3 via catalysis with tetrahydrothiophene in the presence of benzoic acid by J. Stephen Clark at the University of Glasgow. Xue-Long Hou at the Shanghai Institute of Organic Chemistry discovered (Org. Lett. 2012, 14, 5756) that palladacycle 6 catalyzes the conversion of bicyclic alkene 4 and alkynone 5 to furan 7. A silver-mediated C–H/C–H functionalization strategy for the synthesis of furan 9 from alkyne 8 and ethyl acetoacetate was developed (J. Am. Chem. Soc. 2012, 134, 5766) by Aiwen Lei at Wuhan University. Ning Jiao at Peking University and East China Normal University found (Org. Lett. 2012, 14, 4926) that azide 10 and aldehyde 11 could be converted to either pyrrole 12 or 13 with complete regiocontrol by judicious choice of a metal catalyst. Meanwhile, Michael A. Kerr at the University of Western Ontario developed (Angew. Chem. Int. Ed. 2012, 51, 11088) a multicomponent synthesis of pyrrole 16 involving the merger of nitrone 14 and the donor–acceptor cyclopropane 15. The pyrrole 16 was subsequently converted to an intermediate in the synthesis of the cholesterol-lowering drug compound Lipitor. A robust synthesis of the ynone trifluoroboronate 17 was developed (Org. Lett. 2012, 14, 5354) by James D. Kirkham and Joseph P.A. Harrity at the University of Sheffield, which thus allowed for the ready production of trifluoroboronate-substituted pyrazole 18. An alternative pyrazole synthesis via oxidative closure of unsaturated hydrazine 19 to produce 20 was reported (Org. Lett. 2012, 14, 5030) by Yu Rao at Tsinghua University. A unique fluoropyrazole construction was developed (Angew. Chem. Int. Ed. 2012, 51, 12059) by Junji Ichikawa at the University of Tsukuba that involved nucleophilic substitution of two of the fluorides in 21 to form pyrazole 22.

C–N Ring Construction: The Harrity Synthesis of Quinolizidine (–)-217A

David M. Jenkins of the University of Tennessee devised (J. Am. Chem. Soc. 2011, 133, 19342) an iron catalyst for the aziridination of an alkene 1 with an aryl azide 2. Yoshiji Takemoto of Kyoto University cyclized (Org. Lett. 2011, 13, 6374) the prochiral oxime derivative 4 to the azirine 5 in high ee. Organometallics added to 5 syn to the pendant ester. Hyeung-geun Park of Seoul National University used (Adv. Synth. Catal. 2011, 353, 3313) a chiral phase transfer catalyst to effect the enantioselective alkylation of 6 to 7. Yian Shi of Colorado State University showed (Org. Lett. 2011, 13, 6350) that a chiral Brønsted acid mediated the enantioselective cyclization of 8 to 9. Mattie S.M. Timmer of Victoria University of Wellington and Bridget L. Stocker of Malaghan Institute of Medical Research effected (J. Org. Chem. 2011, 76, 9611) the oxidative cyclization of 10 to 11. They also showed (Tetrahedron Lett. 2011, 52, 4803, not illustrated) that the same cyclization worked well to construct piperidine derivatives. Jose L. Vicario of the Universidad del País Vasco extended (Adv. Synth. Catal. 2011, 353, 3307) organocatalysis to the condensation of 12 with 13 to give the pyrrolidine 14. Jinxing Ye of the East China University of Science and Technology used (Adv. Synth. Catal. 2011, 353, 343) the same Hayashi catalyst to condense 15 with 16 to give 17. André B. Charette of the Université de Montreal expanded (Org. Lett. 2011, 13, 3830) 18, prepared by Petasis-Mannich coupling followed by ring-closing metathesis, to the piperidine 20. Marco Bella of the “Sapienza” University of Roma effected (Org. Lett. 2011, 13, 4546) enantioselective addition of 22 to the prochiral 21 to give 23. Ying-Chun Chen of Sichuan University and Chun-An Fan of Lanzhou University cyclized (Adv. Synth. Catal. 2011, 353, 2721) 24 to 25 in high ee. Andreas Schmid of TU Dortmund showed (Adv. Synth. Catal. 2011, 353, 2501) that ω-laurolactam hydrolases could be used to cyclize the ester 26, but not the free acid, to the macrolactam 27.

C–O Natural Products: (–)-Hybridalactone (Fürstner), (+)-Anthecotulide (Hodgson), (–)-Kumausallene (Tang), (±)-Communiol E (Kobayashi), (–)-Exiguolide (Scheidt), Cyanolide A (Rychnovsky)

Control of the absolute configuration of adjacent alkylated stereogenic centers is a classic challenge in organic synthesis. In the course of the synthesis of (–)-hybridalactone 4, Alois Fürstner of the Max-Planck-Institut Mülheim effected (J. Am. Chem. Soc. 2011, 133, 13471) catalytic enantioselective conjugate addition to the simple acceptor 1. The initial adduct, formed in 80% ee, could readily be recrystallized to high ee. In an alternative approach to high ee 2,3-dialkyl γ-lactones, David M. Hodgson of the University of Oxford cyclized (Org. Lett. 2011, 13, 5751) the alkyne 5 to an aldehyde, which was condensed with 6 to give 7. Coupling with 8 then delivered (+)-anthecotulide 9. The enantiomerically pure diol 10 is readily available from acetylacetone. Weiping Tang of the University of Wisconsin dissolved (Org. Lett. 2011, 13, 3664) the symmetry of 10 by Pd-mediated cyclocarbonylation. The conversion of the lactone 11 to (–)-kumausallene 12 was enabled by an elegant intramolecular bromoetherification. Shoji Kobayshi of the Osaka Institute of Technology developed (J. Org. Chem. 2011, 76, 7096) a powerful oxy-Favorskii rearrangement that enabled the preparation of both four-and five-membered rings with good diastereocontrol, as exemplified by the conversion of 13 to 14. With the electron-withdrawing ether oxygen adjacent to the ester carbonyl, Dibal reduction of 14 proceeded cleanly to the aldehyde. Addition of ethyl lithium followed by deprotection completed the synthesis of (±)-communiol E. En route to (–)-exiguolide 18, Karl A. Scheidt of Northwestern University showed (Angew. Chem. Int. Ed. 2011, 50, 9112) that 16 could be cyclized efficiently to 17. The cyclization may be assisted by a scaffolding effect from the dioxinone ring. Dimeric macrolides such as cyanolide A 21 are usually prepared by lactonization of the corresponding hydroxy acid. Scott D. Rychnovsky of the University of California Irvine devised (J. Am. Chem. Soc. 2011, 133, 9727) a complementary strategy, the double Sakurai dimerization of the silyl acetal 19 to 20.

C–O Ring Formation

A reductive radical cyclization of tetrahydropyran 1 to form bicycle 2 using iron(II) chloride in the presence of NaBH4 was reported (Angew. Chem. Int. Ed. 2012, 51, 6942) by Louis Fensterbank and Cyril Ollivier at the University of Paris and Anny Jutand at the Ecole Normale Supérieure. The enantioselective conversion of tetrahydrofuran 3 to spirocycle 5 via iminium ion-catalyzed hydride transfer/cyclization was developed (Angew. Chem. Int. Ed. 2012, 51, 8811) by Yong-Qiang Tu at Lanzhou University. Daniel Romo at Texas A&M University showed (J. Am. Chem. Soc. 2012, 134, 13348) that enantioenriched tricyclic β-lactone 8 could be readily prepared via dyotropic rearrangement of the diketoacid 6 under catalysis by chiral Lewis base 7. A dyotropic rearrangement was also utilized (Angew. Chem. Int. Ed. 2012, 51, 6984) by Zhen Yang at Peking University, Tuoping Luo at H3 Biomedicine in Cambridge, MA, and Yefeng Tang at Tsinghua University for the conversion of 9 to the bicyclic lactone 10. In terms of the enantioselective synthesis of β-lactones, Karl Scheidt at Northwestern University found that NHC catalyst 12 effects (Angew. Chem. Int. Ed. 2012, 51, 7309) the dynamic kinetic resolution of aldehyde 11 to furnish the lactone 13 with very high ee. Meanwhile, Xiaomeng Feng at Sichuan University has developed (J. Am Chem. Soc. 2012, 134, 17023) a rare example of an enantioselective Baeyer-Villiger oxidation of 4-alkyl cyclohexanones such as 14. The diastereoselective preparation of tetrahydropyran 18 by Lewis acid-promoted cyclization of cyclopropane 17 was accomplished (Org. Lett. 2012, 14, 6258) by Jin Kun Cha at Wayne State University. Stephen J. Connon at the University of Dublin reported (Chem. Commun. 2012, 48, 6502) the formal cycloaddition of aryl succinic anhydrides such as 18 with aldehydes to produce γ-butyrolactones, including 20, in high ee. The stereodivergent cyclization of 21 via desilylation-induced heteroconjugate addition to produce the complex tetrahydropyran 22 was discovered (Org. Lett. 2012, 14, 5550) by Paul A. Clarke at the University of York. Remarkably, while TFA produced a 13:1 diastereomeric ratio in favor of the cis diastereomer 22, the use of TBAF resulted in complete reversal of diastereoselectivity.