Aldrichimica ACTA 17 VOL. 50, NO. 1 • 2017

Recent Advances in Metathesis for Natural Product Synthesis—Striking Achievements Resulting from Increased Sophistication in Catalyst Design and Synthesis Strategy

Christopher D. Vanderwal* and Brian R. Atwood 1102 Natural Sciences II Department of Chemistry University of California, Irvine Irvine, CA 92697-2025, USA Email: [email protected]

Prof. C. D. Vanderwal

Mr. B. R. Atwood

Keywords. metathesis; natural product synthesis; strategy; 7. Cross-Metathesis catalysts; stereocontrol. 8. Conclusion 9. References Abstract. Every year, advances in the design of metathesis catalysts and insightful strategic applications of alkene metathesis work in concert 1. Introduction to drive the feld into new and exciting directions. From ring-closing The importance of alkene metathesis to synthetic chemistry cannot be to enyne and cross-metathesis, and from late-stage steps that directly overstated. The pioneering work by Chauvin, Grubbs, and Schrock furnish natural products to early transformations that supply starting on improving our mechanistic understanding of metathesis, on materials, metathesis can play a role at every stage of a synthesis. This developing novel metathesis catalysts, and on developing metathesis review will highlight some of the particularly innovative or surprising applications garnered them the 2005 Nobel Prize in Chemistry.1 ways in which alkene metathesis has been implemented in natural For over two decades, organic chemists have harnessed the power product synthesis. of alkene metathesis in academic and industrial settings, and new applications continue to be reported on a regular basis. In the decade Outline following Nicolaou’s extensive review of the use of alkene metathesis 1. Introduction in natural product synthesis,2 the number of examples of such uses 2. Ring-Closing Metathesis has grown at a dizzying rate. Books3–7 and reviews8–11 have been 3. Tethered Ring-Closing Metathesis written to chronicle the breadth of applications of alkene metathesis. 4. Macrocycles Herein, we aim to provide a structured look at a select group of alkene 4.1. Macrocyclic Ring Closure by Metathesis metathesis reactions that are employed in natural product synthesis. 4.1.1. The Alkylpiperidine Alkaloids We discuss accomplishments from the past ten years that exemplify 4.1.2. The Ansatrienins groundbreaking strategic applications of alkene metathesis and/ 4.1.3. Other Natural Products or a particularly impressive reactivity or selectivity in metathesis 4.1.4. Tiacumicin B Aglycon processes. We have organized the discussion by transformation type: 4.2. Macrocyclic Ring Closure by Other Means (i) ring-closing metathesis for normal- and medium-size rings, (ii) 5. Tandem Metatheses metathesis in the synthesis of macrocycles, (iii) tandem metatheses, 5.1. Enyne Metatheses (iv) ring-opening metathesis, and (v) cross-metathesis. 5.2. Ene-yne-ene Metatheses We note here that our purpose is only to demonstrate the power 6. Ring-Opening Cross-Metathesis of metathesis for complex-molecule synthesis using select examples. Recent Advances in Alkene Metathesis for Natural Product Synthesis—Striking Achievements Resulting from Increased Sophistication in Catalyst Design and Synthesis Strategy 18 Christopher D. Vanderwal* and Brian R. Atwood

Furthermore, although closely related, metathesis12 is not a synthesis of elatol.15 The authors built on Weinreb's earlier work which prime focus of this article, and select examples are provided only had demonstrated the general feasibility and utility of this type of RCM.16 to provide context. In this short review, only a small number of the To access the salient chlorinated cyclohexene of elatol, the researchers myriad and incredibly versatile metathesis catalysts developed to date utilized an RCM between two 1,1-disubstituted alkene groups in 18 are showcased (Figure 1). (Scheme 2), one with two carbon substituents and one bearing an alkyl substituent and a chlorine atom. Substrate 18 underwent RCM in the 2. Ring-Closing Metathesis presence of 3 to provide intermediate 19 containing a tetrasubstituted By the mid-2000s, ring-closing metathesis (RCM) to form unstrained, alkene. Following its introduction, catalyst 3 has become an important normal-size rings was a well-established, reliable tool for synthesis. addition to the arsenal of available metathesis catalysts.3,17 The examples below were selected because they have pushed forward In one of a few reported examples of stereochemical equilibration– the frontiers of what was thought possible in terms of reactivity and/ RCM, Tang, Chen, Yang and co-workers reported the synthesis or selectivity. Reiser’s group reported the frst enantioselective synthesis of the 13 Me complex sesquiterpenoid arglabin (Scheme 1). A challenging RCM AcO AcO 4 H H Me of two 1,1-disubstituted to forge a tetrasubstituted alkene 2 4 H (3 x 5 mol %) + C-4 epimer within a 7-membered ring serves as a key step. A particularly direct, O o O PhMe, 95 C, 6 h O O 17 stereoselective synthesis of the RCM precursor, 16, set the stage for H H H epi- , 16% this challenging ring closure. This metathesis required three separate Me OPMB Me OPMB 16 17 charges (5 mol %) of the Grubbs second-generation catalyst14 (2) and , 70% inert-gas sparging at 95 oC to successfully provide the tetrasubstituted alkene in 17. Epoxidation of the tetrasubstituted alkene and installation H Me O of the requisite functional groups completed the synthesis of arglabin. At O O the time, and to this day, this RCM is striking for its effcient generation H H of a ring size that can often be slow to form, while simultaneously Me arglabin forging a tetrasubstituted alkene. Stoltz’s group was among the frst to employ the RCM of alkenyl Scheme 1. Efficient Formation by RCM of a Cycloheptene with a Tetrasubstituted Double Bond in Reiser's Enantioselective Synthesis of chlorides in natural product synthesis in the course of their innovative Arglabin. (Ref. 13)

N N N N N N P(Cy)3 N N Ar Ar Ar Ar Ar Ar Me Me Cl Cl Cl Cl Cl Ru Ru Ru Ru Ph Ru O Cl Cl Cl Cl P(Cy)3 Cl Ph O O O S NMe2 P(Cy)3 i-Pr i-Pr i-Pr O

Grubbs Grubbs Hoveyda-Grubbs first-generation second-generation Stewart-Grubbs second-generation (GI, 1) (GII, 2) (SG, 3) (HGII, 4) Zhan-1B (5)

F 1-Ad Et SiO P(Cy)3 3 C6F5 N N N N N Ar N Ar Ar Cl O N Mo R' Ru Mo R' Br O H S Ru F R Br Ru Cl O O O F N O F O S i-Pr – O O Et SiO i-Pr Ph i-Pr 3

6 7 8 9 10

OMe 1-Ad N CF 3 Me Me N Cl Cl Mo R' N N N N N O Mo R' Mo R' N Br W t-Bu Br Ph3SiO OSiPh3 O O Mo Br Br O R N Br Br Ph3SiO Ar' Ar' R R N

11 12 13 14 15

R = TBSO; R' = CMe2Ph; Ar = 2,4,6-Me3C6H2; Ar' = 2,4,6-(i-Pr)3C6H2

Figure 1. Structures of Metathesis Catalysts Featured in This Review. Aldrichimica ACTA 19 VOL. 50, NO. 1 • 2017 of schindilactone A, in which that process provided the central 3. Tethered Ring-Closing Metathesis oxabicyclo[4.2.1]nonane ring system of the target (Scheme 3).18 In the Temporary tethers are enormously useful for increasing the rates of presence of GII (2), the desired RCM gave 21, with in situ epimerization slow bimolecular reactions, and are advantageous with respect to producing a single diastereomer at the hemiketal carbon.19 The resulting both chemo- and stereoselectivity. In Kobayashi’s total synthesis cyclooctene later participated in a Pauson–Khand reaction to annulate of (+)-TMC-151C, a silicon-tethered RCM reaction convergently another one of the rings of the natural product. Other examples of assembled the polyketide natural product from two fragments of similar stereochemical equilibration during RCM mostly involve epimerization complexity in a reaction that would have been virtually impossible of stereogenic centers adjacent to ketones.20 to achieve in a bimolecular setting (Scheme 5).22 Further, the tether In their synthesis of sculponeatin N, a bioactive diterpene, served to reinforce the selectivity of the alkene geometry in forming Thomson and co-workers accomplished the equivalent of a the trisubstituted alkene. The RCM reaction of 25 was effected with –cyclopentenone Diels–Alder cycloaddition by a sequence the Hoveyda–Grubbs second-generation catalyst (4),23 and global featuring an unusual equilibrating diastereoselective RCM reaction desilylation of 26 afforded (+)-TMC-151C directly. (Scheme 4).21 When 24 could not be made by the more straightforward Diels–Alder approach, sequential alkene installation converted the spiro-cyclopentenone precursor to the triene-containing RCM substrate 22. Subjecting triene 22 to metathesis conditions with GII (2) Me 2 (5 mol %) Me afforded the desired cis-fused cyclohexene-containing 24. The authors Me DCM, rt, 15 h Me commented that spirocyclopentene 23 could be isolated by stopping t-BuPh2SiO O t-BuPh2SiO O the reaction early; however, the trans-fused cyclohexene was never 22 24, 91% observed. This particularly creative workaround to the unsuccessful cycloaddition also sets a key quaternary stereogenic center of the target.

Me Me t-BuPh SiO Me 2 O O O Me 23 O 3 (5 mol %) Cl Cl Me PhH, 60 oC i-BuO Me i-BuO Me Me Me Me HO O (–) (+) O 18 19, 97% sculponeatin N

Scheme 4. Diastereoselective RCM as a Butadiene–Cyclopentenone 3 steps Me Diels–Alder Equivalent in Thomson's Total Synthesis of Sculponeatin N. (Ref. 21)

Cl HO Me Me Br Me Me Me Me Me Me Me Me Me OR OR (+)-elatol O 28% (from 19) Et OR RO OR O O O OR OR O Si RO O Scheme 2. First Application of the RCM of Alkenyl Chlorides in Natural RO Ph Ph Product Synthesis as Demonstrated in Stoltz's Asymmetric Total 25 Synthesis of (+)-Elatol. (Ref. 15) R = TES 4 (20 mol %) p-benzoquinone xylene, reflux, 24 h

O OTES 2 (10 mol %) O OTES Me Me Me Me Me Me Me Me Me OR OR O MgBr (0.2 equiv) O O 2 Et OR O o O OH DCM, 30 C, 6 h OH RO OR O O O OR OR O Me H OBn Me H OBn RO O Si Me Me RO Ph Ph 20 21, 65% 26; 87%, E/Z > 20:1

1. HF–Pyr, Pyr O 2. HF(aq), THF–MeCN O o Me Me 0 C to rt H O H HO O Me Me Me Me Me Me Me Me Me OH OH H O O O O Et OH O Me H O H HO OH OH OH O OH OH Me O Me HO O HO (±)-schindilactone A (+)-TMC-151C, 54%

Scheme 3. Yang's Diastereoselective Synthesis of the Fully Functionalized Scheme 5. Silicon-Tethered RCM in Kobayashi’s Convergent Total CDE Ring System in (±)-Schindilactone A by RCM. (Ref. 18) Synthesis of (+)-TMC-151C. (Ref. 22) Recent Advances in Alkene Metathesis for Natural Product Synthesis—Striking Achievements Resulting from Increased Sophistication in Catalyst Design and Synthesis Strategy 20 Christopher D. Vanderwal* and Brian R. Atwood

4. Macrocycles Overman’s group reported the frst total synthesis of the incredibly 4.1. Macrocyclic Ring Closure by Metathesis complex alkaloid sarain A, which exhibits antibacterial, insecticidal, 4.1.1. The Alkylpiperidine Alkaloids and antitumor activities. In this work, the saturated 13-membered- A number of structurally related alkaloids, including the ring of the natural product was formed via RCM and subsequent manzamines,24a sarains,24b haliclonacyclamines,24c and haliclonins,24d hydrogenation (Scheme 7),26 while the second, 14-membered ring belong to the family of alkylpiperidine natural products. In addition of sarain A containing the skipped-triene was ultimately constructed to an alkylpiperidine subunit, these secondary metabolites usually by a Stille cross-coupling, and not by metathesis. In the RCM step to contain one or more macrocycles. The synthesis of the macrocycle(s) generate the saturated macrocycle, the use of catalyst 2 with 29 led of the various alkylpiperidines has been accomplished by ring-closing to signifcant quantities of dimeric byproducts, in addition to some of alkene or alkyne metathesis numerous times, by employing various the desired macrocyclization product, 30. Switching to the less active, strategies aimed at accomplishing the transformation selectively for frst-generation (1)27 diminished the amount of dimer the challenging Z-confgured alkene present in many of the natural formed and, after optimization, a 75–85% yield of the macrocyclization products. In 1999, Martin and co-workers were the frst to utilize a product, 30, was obtained. It was postulated that the use of the more macrocyclizing RCM reaction in the synthesis of an alkylpiperidine active catalyst 2 gave a thermodynamic ratio of products, as supported natural product (Scheme 6).25 Since then, few have achieved the same by subjection of either the isolated macrocycle or dimer to the same level of substrate-controlled Z-selectivity Martin’s group observed reaction conditions, which yielded in each case a similar mixture of for the conversion of 27 to 28, without the use of modern Z-selective macrocycle and dimer. The less active 1, however, may have been metathesis catalysts. In the past decade, a number of syntheses unable to initiate metathesis on the resultant internal alkene, making of alkylpiperidine natural products relying on RCM reactions for the RCM step effectively irreversible, and providing only the desired macrocyclic ring-closure have been reported. RCM product. Nishida’s frst-generation synthesis of nakadomarin A28 was published in 2003, and, since then, many other groups have contributed CH(OMe) CH(OMe)2 H 2 H impressive syntheses of their own. The Z-alkene-containing, 15-membered ring of nakadomarin A has been constructed by ring- H 1 (10 mol % + 3 mol %) H N N closing alkene metathesis,28–32 ring-closing alkyne (RCAM) metathesis O DCM, reflux, 7 h 33–34 35 N H N O and semi-reduction, and by macrolactamization. In their H O pioneering work, Nishida and co-workers achieved a Z:E ratio of 1:1.8 O 27 28, 67% (Z) by using catalyst 1 to close the 15-membered ring from 32a (Scheme 8). Subsequent syntheses by the groups of Kerr,29 Dixon,30 and Zhai,31 using either substrate 32a, 32b, or 31 resulted in only slightly improved N N H H Z:E ratios (up to 2:1). Nilson and Funk33 were the frst to employ a two- H OH step RCAM–semi-reduction to afford the Z alkene as the sole product. N Dixon’s group embraced this approach as well,34 but later reported a H N collaborative effort with the Schrock and Hoveyda labs, making use of the recently developed Z-selective, tungsten-based metathesis catalyst

manzamine A

Scheme 6. Macrocycle Ring Closure by Metathesis, as Illustrated in Martin’s Total Synthesis of Manzamine A, an Alkylpiperidine Alkaloid. (Ref. 25) H H O O 15 (5 mol %) N N PhMe, 22 oC, 8 h N N OTIPS OTIPS

N N O 1 (5 mol %) N N O 31 (–)-nakadomarin A DCM, reflux O O 63% (94% Z )

OTBS OTBS 29 30, 75–85%* H O (*) With 2 (15 mol %), AcOH (2 equiv), X DCM, reflux: N O 30 (17%), dimer (61%) N Y 32 H a: X = CH2, Y = O N N b: X = O, Y = CH OH 2 alternate RCM substrates used in HO other syntheses of nakadomarin A Stille cross- (Ref. 29,31) coupling (–)-sarain A

Scheme 7. Macrocycle Ring Closure by Metathesis in Overman’s Total Scheme 8. Final Step in the Synthesis of (–)-Nakadomarin A by Synthesis of (–)-Sarain A. (Ref. 26) Catalyst-Controlled Z-Selective RCM. (Ref. 36) Aldrichimica ACTA 21 VOL. 50, NO. 1 • 2017

15. 36 Use of this catalyst with 31 produced (–)-nakadomarin A in 63% yield and 94% Z-selectivity, the highest Z-selectivity observed in a RCM with 1 synthesis of nakadomarin A by RCM. RO RO 12 Huang and co-workers reported the frst asymmetric total synthesis NR' (6 mol %) NR' H MnCl H of the alkaloid (–)-haliclonin A using catalyst 1 for RCM, followed by 2 Me 5 Å & 4 Å MS 37 hydrogenation, to form the saturated macrocycle of the molecule. At PhMe, rt, 33 h O O a later point in the synthesis, an RCAM with molybdenum benzylidyne N N Me O O catalyst 1238 closed the second, unsaturated, 15-membered ring of 33 34, 70% compound 33, affording intermediate 34. Partial hydrogenation R = TBS; R' = SO Ph 37 2 installed the desired Z-alkene geometry (Scheme 9). It is worth noting H that the alkyne metathesis and partial hydrogenation steps were both O NCHO tolerant of the unconjugated alkene, and no isomerization was noted. H

O 4.1.2. The Ansatrienins N The ansatrienins,39a-c a subclass of the ansamycins,39 bear an all-trans O (–)-haliclonin A conjugated triene subunit in their macrocyclic core. Cross-coupling40 41 and alkenylation approaches to this triene fragment have been Scheme 9. Ring-Closing Alkyne Metathesis (RCAM) Step in Huang’s successfully employed in syntheses of some of the members of this Asymmetric Total Synthesis of (–)-Haliclonin A. (Ref. 37) class of natural products. The application of an RCM between two units to furnish an all-trans triene—an approach that certainly would appear to harbor risk—was central to two successful syntheses.42–43 OTES Hayashi and co-workers reported an asymmetric total synthesis of the Me anticancer drug (+)-cytotrienin A, where RCM successfully provided NH 42 Me TESO the macrocyclic ring containing the all-trans triene (eq 1). Krische’s TESO O group rapidly assembled a related tetraene-containing RCM substrate O OMe H using their C–H functionalization methodology, and completed the N synthesis of trienomycins A and F (not shown).43 O O

1. 1 (40 mol %) 4.1.3. Other Natural Products DCM, 23 oC, 71 h Krische’s group utilized a ring-closing enyne metathesis (RCEYM) to 2. Amberlyst® 15 form the macrocyclic ring in their total synthesis of 6-deoxyerythro- THF–H2O(10:1) OH o nolide B (Scheme 10).44 Some of the challenges that were overcome 23 C, 47 h in this synthesis include: (i) Terminal alkene isomerization from 35 Me NH was the only observed product in the absence of ethylene. (ii) Enyne Me HO metathesis proceeded at 80 oC, converting the alkyne into a terminal HO O O OMe diene but not into the macrocycle. To overcome this second challenge, H N the ethylene atmosphere was replaced with after the enyne O metathesis was complete, and the reaction mixture was then heated to O (+)-cytotrienin A 110 oC, accomplishing the desired ring closure. The macrocyclic diene 37% (two steps) eq 1 (Ref. 42) 36 was then converted in a few steps into 6-deoxyerythronolide B. Together with Krische’s effcient methods for assembling the precursor, this RCEYM process was strategically advantageous. 4 In their synthesis of (+)-neopeltolide, Fuwa and co-workers utilized Me 1. (30 mol %) Me C2H4 (1 atm) Me Me Me Me a chemoselective cross-metathesis (CM) to form an α,β-unsaturated OBn PhMe, 80 oC OBn Me Me ester from a terminal alkene and methyl acrylate, ultimately facilitating o Et O O 2. N2, 110 C Et O O pyran formation by an oxa–Michael cyclization (Scheme 11).45 O O PMP O O PMP Since the pendant styrenyl group in substrate 37 was also poised to Me Me competitively undergo an undesired RCM, the ability of the proximal 35 36, 89% hydroxyl group to form an intramolecular H….Cl interaction 3 steps between the OH and the Cl in the substrate-bound catalyst was key to O 71% accomplishing the selective CM leading to 38. When the proximal OH Me Me was protected with a BOM group, a signifcant amount (46–71%) of the Me Me OH ring-closed product was formed. Finally, RCM of intermediate 39 with Me catalyst 2 afforded the macrocyclic, trisubstituted alkene 40, which was Et O OH then hydrogenated to the saturated macrolactone, constituting a formal O OH synthesis of (+)-neopeltolide. Hoveyda, Schrock, and Yu also reported Me the synthesis of (+)-neopeltolide, making extensive use of alkene 6-deoxyerythronolide B metathesis to construct the natural product (not shown).46 Scheme 10. Ring-Closing Enyne Metathesis (RCEYM) in Krische's Total Kita and Kigoshi reported an asymmetric total synthesis of the Synthesis of the Polyketide 6-Deoxyerythronolide B. (Ref. 44) marine macrolides mycalolides A and B, and evaluated both an RCM Recent Advances in Alkene Metathesis for Natural Product Synthesis—Striking Achievements Resulting from Increased Sophistication in Catalyst Design and Synthesis Strategy 22 Christopher D. Vanderwal* and Brian R. Atwood

and a CM approach (Scheme 12).47 In their work, the RCM strategy form of the tiacumicin B aglycon,50 whereby ester-linked ring-closing suffered from low selectivity for the desired alkene geometry; even metathesis precursor 52a underwent the desired RCM macrocyclization after extensive optimization, it proceeded in only a 63% yield and an in the presence of 2, with only deprotection required to complete E:Z ratio of 2.7:1. The CM approach was more successful; the reaction the synthesis. Gademann’s group targeted the protected tiacumicin of 41 with 42 proceeded to give 43 in 77% yield and an E:Z ratio of 5:1. B aglycon and utilized a macrocyclic RCM similar to that used in Although adhering to the rules48 for best-case CM substrates (Type 1 Zhu’s synthesis, closing the diene fragment of 52b.51 Gademann’s and Type 2 alkenes), this CM is remarkable for the extreme complexity substrate underwent a more effcient ring closure, reminding us of the of both reaction partners used in close to equimolar amounts. signifcant effect that different protecting group strategies can have on Krische and co-workers synthesized swinholide A using their macrocyclization by RCM (and indeed by any method). The authors asymmetric, hydrogen-mediated C–C bond-forming methodology also reported a procedure to isomerize the undesired Z alkene to the E and alkene metathesis each at multiple stages (Scheme 13).49 An alkene allowing material to be recycled. Altmann’s group reported a enantioselective, iridium-catalyzed allylation provided product synthesis of the tiacumicin B aglycon, in which they employed a CM 46, which underwent CM with acrolein catalyzed by 2 to afford to assemble the linear precursor to the natural product.52 Complex 4 dihydropyran hemiacetal 47; this product was elaborated into a key catalyzed the synthesis of tetraene fragment 53, attaining the highest fragment for convergent coupling. Construction of a second fragment E/Z ratio of the three syntheses (6.7:1). Yamaguchi esterifcation with began with a diastereo- and site-selective iridium-catalyzed allylation to a vinyl boronate containing fragment and Suzuki macrocyclization supply 48, which was subjected to CM with cis-1,4-diacetoxy-2-butene. completed the synthesis. The resulting allylic acetate 49 underwent palladium-catalyzed Tsuji– Trost cyclization to give a cis-2,4-disubstituted vinyl tetrahydropyran 4.2. Macrocyclic Ring Closure by Other Means 50. The two fragments were elaborated and coupled, yielding the fnal Hoye and co-workers synthesized (+)-peloruside A—a cytotoxic marine metathesis substrate, 51. In the presence of 4, intermediate 51 was macrolide that is being evaluated for use against paclitaxel-resistant converted, via sequential CM–RCM, into the dimeric macrodiolide cancers—by utilizing a relay RCM between the tethered alkenes to swinholide A in 25% yield, as well as via an RCM of the monomer, into the macrolide hemiswinholide in 43% yield. This fnal step that directly affords two natural products is striking for its effciency in the MeO O presence of two other alkenes, a host of unprotected hydroxyl groups, O and numerous other Lewis basic sites. N Me Et3Si OMe MeO O OMe RO O + TBDPSO O N 4.1.4. Tiacumicin B Aglycon Me Me Me Me O OTCE In 2015, three research groups concurrently reported syntheses of N tiacumicin B, with each group utilizing alkene metathesis in their O 50–52 synthesis (Scheme 14). Zhu and co-workers targeted a protected 41 (1 equiv) 42 (1.2 equiv) 4 (20 mol %) DCM, reflux MeO O

Ph 2 (5 mol %) Ph H C=CHCO Me MeO2C O 2 2 TBSO N Me TBSO (30 equiv) O DCM, rt N TBDPSO OTCE O

OH OH Et3Si OMe N 37 38, 77% MeO O OMe RO O O 4 steps Me Me Me Me 43; 77%, E:Z = 5:1 n-Pr OMe n-Pr MeO O O O Me 2 (30 mol %) O O OMe Me -benzoquinone H H p H H O O O Ph N Me PhMe, 100 oC

N HO OBOM OBOM O O 40, 85% 39, 62% N MeO O OMe OAc Me n-Pr OMe X N O CHO O O Me Me Me Me Me H H O O mycalolide A (44): X = C OMe OMe O 45 MeO O HN mycalolide B ( ): X = CH O O O O

N R = (3,4-dimethoxyphenyl)methoxymethyl (DMPMOM) TBDPS = tert -butyldiphenylsilyl; TCE = 2,2,2-trichloroethyl (+)-neopeltolide

Scheme 11. CM and RCM Key Steps in Fuwa's Concise Total Synthesis Scheme 12. CM between Two Advanced Intermediates in Kita and of (+)-Neopeltolide. (Ref. 45) Kigoshi's Total Synthesis of Mycalolides A and B. (Ref. 47) Aldrichimica ACTA 23 VOL. 50, NO. 1 • 2017 construct the trisubstituted alkene group present in the natural product (Scheme 15).53 Two tethering approaches, one via a silaketal (54) 4 4 and the other via an ester linkage (55), were investigated. Each tether Me OR Zhu's Synthesis Me OR Et Et contained an (R)-citronellene derived tail, initially incorporated to 52a : R1 = MOM, R2 = Bn, R3 = TES, R4 = H 2 o enable effcient enzymatic resolution of the diastereomeric mixtures of R3O (20 mol %), PhMe, 100 C R3O Me 43%, E:Z = 2:1 Me alcohols. This tail was cleaved during the metathesis step and the two OR1 OR1 Me Me routes converged to a substrate with differentially protected alcohol Gademann's Synthesis O O 52b: R1 = R2 = R4 = TBS, R3 = TES groups. This fragment was coupled to a polyol fragment via an aldol O O 2 o Me (i) (15 mol %), PhMe, 40 C (mW), Me addition, after which a macrolactonization–deprotection sequence R2O 10 min , E:Z = 2:3 R2O (ii) 100 oC, 18 h completed the synthesis of peloruside A. 52 R1 = R2 = R3 = R4 = H 90%, = 2:1 Volchkov and Lee completed the asymmetric total synthesis of E:Z tiacumicin B aglycon (–)-amphidinolide V by employing metatheses at multiple stages in the synthesis (Scheme 16).54 RCEYM of silyl-tethered enyne 56 Altmann's Synthesis Me OTBS Me OTBS Et formed the desired silacycle 57, which was ring-opened and coupled to Et provide polyene 58. RCM of the latter compound led to an 8-membered OTBS 4 (15 mol %) TESO TESO + Me silacycle (59). Subsequent elaboration, including allylic transposition, Me EtOAc, rt, 3.5 h OTBS MeO 56%, E:Z = 6.7:1 gave a fragment corresponding to roughly half of the target. Acetylenic O I I MeO intermediate 60 was subjected to enyne metathesis with ethylene, 53 O catalyzed by 2 to afford the salient 1,3-diene, 61. Ultimately, fragments 59 and 61 were combined to complete the synthesis of (–)-amphidinolide V. Another member of the amphidinolide family, (–)-amphidinolide K, Scheme 14. RCM and CM in the Synthesis of Tiacumicin B Aglycon. was synthesized by Lee and co-workers, whose work featured strategic (Ref. 50–52) use of enyne metathesis (not shown).55 Et In their total synthesis of disorazole C1, an antifungal and Et 2 anticancer macrocyclic natural product, Hoveyda and co-workers O (5 mol % Me + 3 x 7 mol %) O employed a number of metathesis steps to tackle the construction of O SiPh2 PhMe, 65 oC O SiPh2 56 Me the C2-symmetric dimeric macrocycle (Scheme 17). The disorazole Me NC Et NC C1 ring contains two conjugated triene units, within which are found 54 92% OTBS four Z-confgured carbon–carbon double bonds. The convergent, OPMB stereoselective route employed required the RCM of a Z-vinyl iodide Et Me O 2 Et tethered to a Z-vinylborane in the precursor 68, which was assembled (23 mol % NC Me in 3 portions) O O with the help of a number of Z-selective cross-metathesis steps. A o O DCM, 45 C, 37 h Me Me NC NC 55 70% (+)-peloruside A OPMB OPMB (i) OH O Fragment A Scheme 15. Relayed, Tethered RCMs in Hoye's Total Synthesis of OH Peloruside A. (Ref. 53)

46 47, 85%

Me2 OH OH OMe Si Me2 O 1 (15 mol %), C2H4 Si O Me (ii) Me Fragment B Ph DCM, 55 oC, 12 h Ph HO Me HO Me O Me 56 57, 88% OAc 48 49;83%, E:Z = 5:1 50 OMe

Ph Ph SiMe Ph SiMe3 Me Ph 3 2 (5 mol %) O Me Si O Si O BQ (20 mol %) Me swinholide A HO HO OH Me o Me 25% 4 (10 mol %) Fragment A DCM, 40 C, 12 h Me O + o OPMP PMPO Ph hemiswinholide PhMe, 25 C Fragment B Me 59, 96% 58 43% OMe O 2 O OH (10 mol %), C2H4 HO O BQ (20 mol %) O o 51 DCM, 50 C, 12 h OMe Me OMe HO 60 61, 76% (i) acrolein (3 equiv), 2 (2 mol %), DCM, 25 oC. 2 o (ii) cis-(AcOCH2CH)2 (4 equiv), (3 mol %), DCM, 50 C. 59 + 61 (–)-amphidinolide V (62)

Scheme 13. CMs and CM–RCM Sequences Employed in Krische's Total Scheme 16. Enyne Metatheses and RCM in Lee's Asymmetric Total Synthesis of the Actin-Binding Marine Polyketide Swinholide A. (Ref. 49) Synthesis of (–)-Amphidinolide V. (Ref. 54) Recent Advances in Alkene Metathesis for Natural Product Synthesis—Striking Achievements Resulting from Increased Sophistication in Catalyst Design and Synthesis Strategy 24 Christopher D. Vanderwal* and Brian R. Atwood

double Suzuki cross-coupling strategy served to dimerize compound 68, frst total synthesis of these lignan natural products, Sherburn's group. affording less than 2% of the unimolecular cross-coupling product. A targeted a dimethylene tetrahydrofuran intermediate that could be 58 careful deprotection led to completion of the synthesis of disorazole C1. dimerized to a mixture of the different ramonanins (eq 3). Starting from vanillin, the authors arrived at 72, the alkyne-bridged diacetate 5. Tandem Metatheses substrate for enyne metathesis, after four steps. Enyne metathesis with In their synthesis of (+)-cylindramide A, Hart and Phillips developed ethylene, catalyzed by 4, furnished the diene diacetate 73. Hydrolysis a tandem ROM–RCM–CM sequence to rearrange a bicyclo[2.2.1]- of the diacetate, tetrahydrofuran ring formation from the resultant diol, heptene into the bicyclo[3.3.0]octene core of (+)-cylindramide A (eq 2).57 and cleavage of the benzenesulfonate protecting groups afforded the In the presence of GI (1) and the butenyl-substituted dioxinone 70, desired dimerization precursor, which was taken to generate the natural the metathesis cascade substrate 69 was transformed into the desired product targets by intermolecular Diels–Alder cycloadditions. bicyclo[3.3.0]octene 71 with incorporation of the butenyl-substituted dioxinone. This work showcases how the reliably predictable 5.2. Ene-yne-ene Metatheses stereochemical relationships generated in the course of Diels–Alder Tandem, ring-closing ene-yne-ene metathesis (RCEYEM) sequences reactions can be transferred to very different ring topologies via tandem are powerful for the construction of bicyclic ring systems and have metathesis chemistry. been applied in a number of different natural product syntheses in the past decade. 5.1. Enyne Metatheses Movassaghi’s group reported particularly non-obvious metathesis- Ramonanins A–D are spirocyclic phenylpropanoid tetramers that show based approaches to the semisynthetic illudin derivatives (–)-acylfulvene cytotoxic activity against lines of human breast cancer cells. In the and (–)-irofulven, the latter being an especially active antitumor agent against a variety of solid tumors (Scheme 18).59 Silyl-tethered RCEYEM substrate 74 underwent the desired metathesis cascade catalyzed by GII 1. 13 (3 mol %) (2) providing 75, which was then converted into 76 via a reductive TBSO OTMS H2C=CHB(pin) TBSO OTMS allylic transposition. The resulting intermediate 76 underwent RCM (3 equiv) (a) Me Me in the presence of 2 to form the cyclopentane ring of the illudins. PhH, 100 torr, Me Me Me Me I 22 oC, 20 h Oxidation with DDQ or chloranil and IBX (ortho-iodoxybenzoic acid) 63 64; 57%, > 98:2 2. I2 (2 equiv) Z:E furnished (–)-acylfulvene (not shown), and reaction of (–)-acylfulvene dr = 91:9 NaOH(aq),TH F with aqueous formaldehyde provided (–)-irofulven. 22 oC, 10 h

1. 4 (5 mol %) OMe OMe H2C=CH(CH2)2Br OSO2Ph O (5 equiv) O (b) OMe N OMe N OMe OSO Ph PhMe, 70 oC, 18 h 2 O 2. DBU (3 equiv) O AcO o OMe 4 (5 mol %) 65 EtOAc, 22 C, 7 h 66; 74%, = 93:7 E:Z H2C=CH2 AcO ramonanins A–D PhMe, 110 oC AcO O OMe OMe OMe 14 (10 mol %) AcO (5 g scale) N H2C=CH B(pin) 64 OSO2Ph (7 equiv) OMe (c) + TBSO O O B(pin) 72 66 PhH, 100 torr, OSO2Ph o 68, 91% Me 22 C, 4 h 73; 74%, dr = 1:1 Z:E > 98:2 eq 3 (Ref. 58) Me Me I 67

disorazole C1 Et Et Et Et Scheme 17. Z-Selective CM and RCM in Hoveyda's Convergent, Si Si O O O O Diastereoselective, and Enantioselective Total Synthesis of Disorazole TMSO Ph 2 (15 mol %) TMSO Ph C1. (Ref. 56) Me Me PhMe, 90 oC, 0.5 h Me Me Me Me OTIPS 74 75, 74–79% O H O 1 (4 mol %) Me + O Me O Me DCM, 40 oC O H O 2 O Me O HO 1. (15 mol %) H O tandem o O Ph TIPSO Me PhMe, 78 C Me O ROM–RCM–CM O Me 69 70 71, 59% 2. NaOMe, AcOH Me (3 equiv) dr = 2:1 chloranil Me OH 3. IBX, DMSO Me (–)-irofulven 4. H2CO(aq), H2SO4 76 36% (from 76)

(+)-cylindramide A Scheme 18. RCEYEM and RCM in Movassaghi's Enantioselective Total eq 2 (Ref. 57) Synthesis of (–)-Irofulven. (Ref. 59) Aldrichimica ACTA 25 VOL. 50, NO. 1 • 2017

Spectacular use of RCEYEM was demonstrated in the bis-alkenyl bicycle served to introduce two two-carbon groups that enantioselective total synthesis of three tetracyclic kempene diterpenes would give rise to two of the four ethyl groups present in the natural (Scheme 19).60 Tandem RCEYEM substrate 77, when heated in product. This method of ethyl group introduction is distinct from other the presence of GII (2), gave rise to intermediate 78, possessing approaches to hippolachnin A. the tetracyclic core of the kempenes. The key to the success of this complexity-building transformation was the substitution pattern of each 7. Cross-Metathesis of the unsaturated reaction partners, which was carefully considered so Kim and co-workers developed a procedure for the installation of a that the order of reaction was the proper one to yield the desired product Z-enyne fragment, which they applied to the synthesis of (+)-3-(Z)- outcome. Following the synthesis of 78, protecting group exchange, laureatin and ent-elatenyne (Scheme 22).64 In the key CM step in the ketone reduction, and acylation afforded the kempene natural products. synthesis of ent-elatenyne, a protected enyne bearing a tethered allyl Yang, Li, and co-workers reported the stereoselective total syntheses ether reacted with the terminal alkene of 87 to provide the enyne CM of the alkaloids (–)-fueggine A and (+)-virosaine B, derived in a product 88 with high Z-selectivity. biomimetic fashion from (–)-norsecurinine and (+)-allonorsecurinine, The frst applications of Grubbs Z-selective ruthenium metathesis which were each constructed via relay RCEYEM.61 An N-Boc- catalysts65 to natural product synthesis were reported by the Grubbs protected, commercially available, d-proline-derived Weinreb amide group, when they prepared, in stereochemically pure form, nine served as the starting material to construct the RCEYEM substrate lepidopteran female sex pheromones that had been approved by possessing a heptadienoate chain. This tethering strategy successfully the EPA as insecticide alternatives (Scheme 23).66 Starting from controlled the direction of ring closure in the cascade process. Both two different seed-oil derivatives, CM with a variety of terminal diastereomers of the RCEYEM substrate could be successfully carried alkenes provided, either directly or after one step, seven different through the reaction sequence to furnish both (–)-norsecurinine and (+)-allonorsecurinine, which were ultimately converted into their more complex relatives. Me Me In 2016, Smith’s group reported a total synthesis of (±)-morphine NBoc NBoc that makes use of an RCEYEM sequence (Scheme 20).62 In the 4 (5 mol %) MeO MeO presence of catalyst HGII (4), the desired RCEYEM proceeded to DCM, 20 oC O O give the intermediate tetracycle 81, which, after amine deprotection, H H O O underwent an intramolecular 1,6-addition forming 82, a fnal reduction 80 81 away from morphine. 1. TFA (40 equiv), 20 oC o 2. Na2CO3(aq) (60 equiv), 20 C 6. Ring-Opening Cross-Metathesis A collaborative synthesis of the potent antifungal agent (±)-hippolachnin Me Me N N A has been disclosed by the groups of Wood and Brown. This complex 1. NaBH4 (10 equiv) H 20 oC H natural product has an unusual structure that features six contiguous HO MeO 2. BBr3 (6.0 equiv) O O stereocenters, a quaternary center, and a congested compact core. The DCM –CHCl H 3 H two groups had arrived at similar and “complementary” approaches OH 20 oC O and sought to design a collaborative synthesis playing to the strengths (±)-morphine (83) 82 of each of their separate syntheses. In their combined strategy, the 56% (from 80) [2 + 2] photocycloaddition of quadricyclane and an α,β-unsaturated acid chloride ultimately forged the tricyclic ROCM precursor 84, Scheme 20. Smith's Use of RCEYEM for a Key Strategic Cyclization which underwent ethylenolysis catalyzed by 1 to give 85 (Scheme That Forms the Tetracyclic Morphine Core. (Ref. 62) 21).63 Strategically, the use of ring-opening metathesis to afford the

CO H CO H Me Me Me 2 2 Me H 1 (2 mol %) H

Me H2C=CH 2, THF Me Me H 2 (5 mol %) Me H H H Me Me H Me H Me Me H DCM, reflux Me H 84 85, 92% O O H H OTBS OTBS OMe 77 78, 92% Me O

O Me Me H Me H Me Me H X Me H H OAc 79 Me 86 kempene-2, X = CO (±)-hippolachnin A ( ) 85 kempene-1, X = HC OAc 11% (4 steps from ) 3-epi-kempene-1, X = HC OAc

Scheme 19. Spectacular Use of RCEYEM by Schubert and Metz in the Scheme 21. ROCM in a Collaborative Total Synthesis by Wood and Enantioselective Total Synthesis of the Kempene Diterpenes. (Ref. 60) Brown of the Potent Antifungal Agent (±)-Hippolachnin A. (Ref. 63) Recent Advances in Alkene Metathesis for Natural Product Synthesis—Striking Achievements Resulting from Increased Sophistication in Catalyst Design and Synthesis Strategy 26 Christopher D. Vanderwal* and Brian R. Atwood

pheromones. The fnal two pheromones synthesized each required proceeded with very high Z-selectivity to give 95, setting the stage for a total of four steps to complete. Though not structurally complex, alkene chlorinolysis, a second dichlorination, and fnally sulfation to these pheromones are otherwise challenging to synthesize because of complete a short synthesis of the chlorosulfolipid mytilipin A. The key the remoteness of the functional groups and necessity for control of aspect of selectivity in reaction partner 94 can be explained in part alkene geometrical isomers. The metatheses employed each required by the reduced reactivity of alkenyl chlorides and the low rates of catalyst loadings of 2 mol % or less, with Z-selectivities all greater cyclooctene formation; however, almost certainly, the key determinant than 75%. One CM partner, trans-1,4-hexadiene (91), underwent of selectivity involves the recalcitrance of catalyst 8 to engage any selective CM at the terminal position to afford 92, not engaging the kind of E alkene, thus sparing the chlorinated alkene moiety of 94 and (E)-alkene moiety, owing to the catalyst’s selectivity for Z alkenes. product 95. Our group’s chlorosulfolipid syntheses took advantage of catalyst 8 for a highly Z-selective convergent cross-metathesis of two chlorinated 8. Conclusion partners (Scheme 24).67 The stereoselective CM between the chlorine- Over the past two decades, alkene metathesis has become an essential containing vinyl epoxide 93 and the dienyl chloride partner 94 component of the synthetic chemist’s toolbox. The syntheses presented in this review, and the many more which could not be discussed, are evidence of both the objective utility of alkene metathesis as well as TIPS the widespread adoption of metathesis as a go-to, reliable reaction

O TIPS in synthetic planning. The featured syntheses also serve to highlight Br H Br H some of the advances made in the feld; catalyst and reaction design O 4 (3 x 20 mol %) O have overcome supposed limitations of reactivity or selectivity, O PhH, 70 oC, 6 h O H Br H Br and implementation in complex settings has illuminated new, non- 87 88; 78%, Z:E = 4.6:1 obvious, and increasingly clever strategies to make use of alkene metathesis. We anticipate continued developments along both of these

TBAF, THF lines in the coming years. 0 oC, 0.5 h Br H O 9. References O H Br (1) The Nobel Prize in Chemistry 2005: Yves Chauvin, Robert H. Grubbs, ent-elatenyne (89), 98% and Richard R. Schrock; Nobelprize.org; Nobel Media AB 2014; http:// www.nobelprize.org/nobel_prizes/chemistry/laureates/2005/index.html Scheme 22. Relay RCM-CM in Burton and Kim's Total Synthesis of ent- (accessed Jan 16, 2017). Elatenyne. (Ref. 64) (2) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490. (3) Metathesis in Natural Product Synthesis: Strategies, Substrates and 8 (1 mol %) Catalysts; Cossy, J., Arseniyadis, S., Meyer, C., Eds.; Wiley-VCH: Me OH + OH 78 8 Me THF, rt, 5 h Me Weinheim, Germany, 2010. oleyl alcohol (4) Green Metathesis Chemistry; Dragutan, V., Demonceau, A., Dragutan, I., 90 91 92; 68%, 88% Z Finkelshtein, E. S., Eds.; NATO Science for Peace and Security Series A:

Ac2O, Pyr Chemistry and Biology; Springer: Netherlands, 2010. (5) Olefn Metathesis: Theory and Practice; Grela, K., Ed.; Wiley: Hoboken, 8 OAc Me NJ, 2014. (Z,E)-9,12-TDDA pheromone (6) Handbook of Metathesis, 2nd ed.; Grubbs, R. H., O’Leary, D. J., Eds.; 89% Wiley-VCH: Weinheim, Germany, 2015; 3 vols.

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Chem. 1997, 62, 8290. In 2005, he began his independent academic career at the University of (41) Smith, A. B., III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem. Soc. California, Irvine, where he is currently Professor of Chemistry. 1995, 117, 10777. Brian R. Atwood received a B.S. degree in chemistry (2012) (42) Hayashi, Y.; Shoji, M.; Ishikawa, H.; Yamaguchi, J.; Tamura, T.; Imai, from the University of California, Davis. He then moved to the H.; Nishigaya, Y.; Takabe, K.; Kakeya, H.; Osada, H. Angew. Chem., Int. University of California, Irvine, for doctoral studies in the group of Ed. 2008, 47, 6657. Professor Chris Vanderwal, where he has worked on the synthesis of (43) Del Valle, D. J.; Krische, M. J. J. Am. Chem. Soc. 2013, 135, 10986. alkaloid and polychlorinated natural products. His graduate research (44) Gao, X.; Woo, S. K.; Krische, M. J. J. Am. Chem. Soc. 2013, 135, 4223. has been supported by a GAANN fellowship and an NSF graduate (45) Fuwa, H.; Saito, A.; Sasaki, M. Angew. Chem., Int. Ed. 2010, 49, 3041. research fellowship. m