Methods Utilizing First-Row Transition Metals in Natural Product Total

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Methods Utilizing First-Row Transition Metals in Natural Product Total Synthesis Joshua E. Zweig, Daria E. Kim, and Timothy R. Newhouse* Department of Chemistry, Yale University, 275 Prospect Street, New Haven, Connecticut 06520-8107, United States ABSTRACT: First-row transition-metal-mediated reactions constitute an important and growing area of research due to the low cost, low toxicity, and exceptional synthetic versatility of these metals. Currently, there is considerable effort to replace existing precious-metal-catalyzed reactions with first-row analogs. More importantly, there are a plethora of unique transformations mediated by first-row metals, which have no classical second- or third-row counterpart. Herein, the application of first-row metal-mediated methods to the total synthesis of natural products is discussed. This Review is intended to highlight strategic uses of these metals to realize efficient syntheses and highlight the future potential of these reagents and catalysts in organic synthesis.

CONTENTS 1. Introduction 1.1. History and Background of First-Row Transition Metals 1.2. Scope of This Review 2. Reductive Halide Coupling 2.1. Nickel-Mediated Couplings 2.2. Cobalt- and Titanium-Mediated Coupling 3. The Nozaki−Hiyama−Kishi Reaction 3.1. Initial Development 3.2. NHK Coupling in Total Synthesis 4. Cross-Coupling 4.1. Early History 4.2. Examples in Total Synthesis 5. The Pauson−Khand Reaction 5.1. Discovery and Mechanism 5.2. Pauson-Khand Reactions in Total Synthesis 5.3. Noncobalt Pauson−Khand Reactions 6. The Nicholas Reaction 6.1. Discovery and Mechanism 6.2. Nicholas Reaction in Total Synthesis 7. [2+2+2] Cycloaddition 7.1. Discovery 7.2. Cobalt-Mediated [2+2+2] in Total Synthesis 8. First-Row Metal Carbenoids 8.1. Copper Carbenoids 8.2. Chromium Carbenoids 8.3. Schrock Carbenes 9. The Kharasch Reaction and C−H Functionalization 9.1. Allylic Functionalization 9.2. Unactivated C−H Bond Oxidation 9.3. Biomimetic C−H Oxidation 10. The Mukaiyama Hydration 10.1. Discovery and Mechanism 10.2. Examples in Total Synthesis 10.3. Related Alkene Hydrofunctionalizations © 2017 American Chemical Society

11. Oxidative Coupling 11.1. Enolate−Alkene Coupling 11.2. Enolate−Enolate Coupling 11.3. Enolate−Arene Coupling 11.4. Arene−Arene Coupling 12. Oxidative Ring Fragmentation 13. Reductive Ring Fragmentation 13.1. Discovery and Simple Epoxide-Opening Reactions 13.2. Radical Cascade Reactions 14. The Jacobsen Hydrolytic Kinetic Resolution 15. Conclusion Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Abbreviations References

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1. INTRODUCTION 1.1. History and Background of First-Row Transition Metals

The prevalence of first-row transition metals in the biosynthesis of natural products may simply derive from their abundance relative to second- and third-row transition metals, but the remarkable ability of nature to construct varied molecular structures using these metals suggests underutilized potential for first-row transition metal chemistry.1−3 The unique properties of first-row transition metals, especially their generally reduced electronegativity and tendency to participate

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Special Issue: Natural Product Synthesis Received: December 21, 2016 Published: May 19, 2017 11680

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these 18 metals by name. While a dramatic rise of precious metals can be seen throughout the 1990s and early 2000s, the overall use of first-row transition metals remains fairly constant. While some of this apparent lack of utilization may be the result of the replacement of older methods that used first-row transition metals, such as Jones oxidation, with metal-free methods, this trend may also point to an imminent precipice of application of methods that employ first-row transition metals to problems in complex molecule synthesis. Forecasting this development, we review the current state of the art for the application of first-row transition metals to methodologies in total synthesis.

in one-electron processes, offer orthogonal opportunities for reaction development relative to their second- and third-row counterparts. In addition to orthogonal reactivity, first-row transition metals offer higher levels of sustainability due to their greater abundance and can also lead to more economic solutions, provided that the cost associated with other reaction parameters, including ligands, does not outweigh that of the metal. We attempted to quantify the use of the most commonly encountered transition metals in natural product synthesis as compared to their occurrence in other published work through analysis of Google Scholar data.4 Figure 1 compares the

1.2. Scope of This Review

With the goal of broadly analyzing the impact of first-row transition metal catalysis and stoichiometric reactions on total synthesis, the classes of reactions discussed herein were limited categorically. Although first-row transition metals have been exploited for their varied and unique properties as Lewis acids,34 notably as oxophilic promoters of carbonyl activation35−40 and cycloadditions,41−46 effectors of alkene47−51 and alcohol oxidation52−54 reactions, stoichiometric reductants,55 and their abilities to serve in a supporting role to precious metals,56−60 these topics have been excluded from this Review as they have been discussed comprehensively elsewhere. Of the reaction classes discussed in this Review, we have chosen to highlight only select representative examples for the sake of brevity.

2. REDUCTIVE HALIDE COUPLING 2.1. Nickel-Mediated Couplings

Realizing the general retrosynthetic disconnection of C−C bonds to unactivated precursors remains a core pursuit of synthetic organic chemistry. One powerful methodology along these lines is the reductive coupling of alkyl, allylic, and benzylic halides. Beginning in the 1940s, first-row transition metals including nickel tetracarbonyl were first used to form Csp3−Csp3 bonds by the homocoupling of allylic halides.61,62 The general propensity of first-row transition metals to engage in single electron chemistry has led to the discovery of variants of this reaction using not only Ni, but Ti,63−65 V,66 Cr,67 Fe,68−70 Mn,71 Co,72−74 and Cu.75,76 The first example of reductive Csp3−Csp3 halide coupling using first-row transition metals is found in a 1943 Belgian patent from I. G. Farben in which the reductive coupling of methallyl chloride (1-1) to form 2,5-dimethylhexa-1,5-diene (12) is described (Scheme 1).1 This transformation required stoichiometric quantities of the highly toxic nickel tetracarbonyl, and despite the utility of this transformation, to the best of our knowledge no further investigation of this chemistry was published for nearly a decade. In 1951, Borcherdt and Webb disclosed the coupling of crotyl and isoprenyl chlorides.2 The authors noted the regioselectivity of the reaction: in the case of crotyl chloride (1-3), a 3.5:1 ratio of C1−C1 dimer 1-4 and C1−C3 1-5 dimer was obtained in 74% yield overall, with no C3−C3 dimer observed. Subsequently, Bauld expanded on this work by demonstrating the dimerization of allyl and cinnamyl acetate with Ni(CO)4.77 In addition to homodimerization, the reaction of Ni(CO)4 with allylic halides was also employed independently by Chiusoli and Fisher to perform carboxymethylations with and without the incorporation of acetylene into the products (Scheme 2).78−81 Chiusoli also performed isotopic labeling

Figure 1. Google Scholar citation analysis of first-row and noble metals in total synthesis.

number of citations (in millions) for a given metal to the number of citations (in thousands) for a given metal and the phrase “total synthesis” from 1960 to 2014. The abundance of the metal is shown by the size of the circle on a log scale. While some artifacts may be present in this comparison, it is interesting to note the outliers. The metals that deviate positively from the linear correlation are suspected to be overutilized in total synthesis relative to other fields, while those that deviate from linearity in a negative fashion are thought to be underutilized. It is unsurprising that Ru,5−13 Os,14 Rh,15−20 Ir,21−23 and Pd24−31 have a disproportionate occurrence with “total synthesis” given the dramatic impact that these metals have had on organic synthesis.32,33 The remarkable occurrence of Pd in articles on total synthesis contrasts sharply with the abundance and deviation from linearity seen with Fe, and to a lesser extent the other first-row transition metals, with Cu being an exception. The graphical abstract for this Review contains a similar analysis tracking the use of transition metals over the last several decades. Some interesting trends can be seen by comparing the occurrence of first-row transition metals (Sc through Zn) and some precious metals (Ru, Os, Pd, Pt, Rh, Ir, Ag, and Au) in articles mentioning total synthesis to articles that mention total synthesis but contain no reference to any of 11681

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macrocycle 3-3, which was then isomerized to the natural product 3-4 with diphenyl disulfide under irradiation. Corey and co-workers have also synthesized non-natural carbon macrocycles up to 18 members in size by both single C−C bond formation and oligomerization.86,87 Macrocyclic lactones are also accessible through this strategy.88 Humulene has been synthesized a number of times since Corey’s first report, including several alternative approaches by Corey himself.89−95 For the synthesis of other natural products, intramolecular allylic halide coupling has also been employed as a key step in Corey’s total synthesis of d,l-elemol,96 Dauben’s total synthesis of cembrene,97,98 Pattenden’s total synthesis of casbene,99,100 and (with benzylic halides) Iyoda’s total synthesis of rioccardin B.101 The synthetic utility of reductive halide coupling is clearly demonstrated in Corey’s synthesis of α-santalene (4-2), where a prenyl group is introduced as a late-stage modification (Scheme 4).102 In the final step of the synthesis, neopentyl

Scheme 1. Early Examples of Nickel-Mediated Homocoupling

Scheme 2. Chiusoli’s Nickel Carbonylation Chemistry Scheme 4. Corey’s Synthesis of α-Santalene and epi-βSantalene

iodide 4-1 was reacted with preformed α,α-dimethylallylnickel bromide 4-5 to provide the natural product 4-2 in 88% yield. Similarly, the reaction of neopentyl iodide 4-3 provides epi-βsantalene (4-4) in 90% yield. Corey and co-workers also note that more elaborated allylic halide fragments, such as geranyl bromide, can also be employed. The coupling of such an elaborated fragment (bearing a protected alcohol) was employed in Takagi’s 1976 total synthesis of α-santalol.103 In addition to terpene natural products, Gut and co-workers have utilized this prenylation in their total synthesis of the steroid desmosterol.104 Because of the ubiquity of prenyl groups in natural products, Corey’s nickel prenylation has found use in many total syntheses and has been the subject of much mechanistic interest, including studies by Corey and Hegedus.105−107 Mechanistically, an SN2 pathway can be ruled out (in some cases) due to the observation of allylnickel species coupling with aryl halides. Additionally, inhibition of the reaction by radical scavengers such as m-dinitrobenzene suggests radical intermediates.

studies to elucidate the nature of the allyl-nickel intermediate in which he determined the presence of an intermediate where the allyl C1 and C3 carbons were equivalent.82 Heck has also investigated the mechanism of the carbonylation reaction.83 Allylic halide coupling was first employed in total synthesis by E. J. Corey in a 1964 model system toward the synthesis of the sesquiterpene humulene,84 which was later completed in 1967 (Scheme 3).85 In the completed synthesis, diallyl bromide 3-2 was treated with Ni(CO)4 to afford 11-membered Scheme 3. Corey’s Synthesis of Humulene

2.2. Cobalt- and Titanium-Mediated Coupling

The first published report of cobalt-mediated allylic halide coupling was in 1979 by Rieke and co-workers, who stated that “Cobalt metal reacts with allyl bromide to yield 1,5-hexadiene without any evidence of an organocobalt compound.”72 In the 11682

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products is consistent with the observations of Borcherdt and Webb discussed above. CoCl(PPh3)3 was also employed by Nicolaou and co-workers toward the natural product rugulin (Scheme 7).114,115 Benzylic

early 1980s, Momose and co-workers subsequently discovered that chlorotris(triphenylphosphine)cobalt(I) was an effective reagent for coupling benzylic halides to form Csp3−Csp3 bonds, including the synthesis of vicinal quaternary centers (Scheme 5).73 Further exploration of the reactivity of this complex

Scheme 7. Nicolaou’s Synthesis of Rugulin Model System Scheme 5. Early Cobalt-Mediated Reductive Homocoupling by Momose

resulted in the reductive coupling of allyl halides and the transformation of bromohydrins to ketones.74,108,109 Since Momose’s discovery of these cobalt-mediated transformations, the solid, air-stable CoCl(PPh3)3 has essentially supplanted the volatile and toxic Ni(CO)4 as the reagent of choice for the reductive coupling of tertiary halides. In 2003, Baldwin and co-workers employed Momose’s conditions to complete their synthesis of biatractylolide and biepiasterolide (Scheme 6), which recognized the symmetry

chloride 7-1 was successfully dimerized to afford the desired d,lisomer in 55% yield, with an additional 25% yield of the undesired meso-isomer. Ultimately, the Nicolaou group was able to access 7-2 in a more direct fashion using an enolization dimerization strategy. While that chemistry was applied in their total syntheses of 2,2′-epi-cytoskyrin A, rugulosin, and the proposed structure of rugulin, the utility of CoCl(PPh3)3 allowed for a rapid means to obtain the dimerized compound 7-2. Barrero and co-workers have demonstrated that Ti(III) reagents are capable of catalyzing reductive halide coupling in the presence of stoichiometric reductants (Scheme 8).65,116 This methodology was used in their 2007 synthesis of cymbodiacetal (8-4). Using 20 mol % of Cp2TiCl2 with Mn dust as a stoichiometric reductant, perrilyl bromide 8-1 was

Scheme 6. Baldwin’s Synthesis of Biatractylolide and Biepiasterolide

Scheme 8. Barrero’s Synthesis of Cymbodiacetal

inherent to these targets.110−112 From lactol 6-1, which was accessed by oxidation of the corresponding siloxyfuran (not shown), chlorination with SOCl2 afforded chloride 6-2, which was then dimerized with CoCl(PPh3)3 to provide a mixture of biatractylolide (6-3), biepiasterolide (6-4), and the two other possible diastereomers (not shown), which proved inseparable. In a following study investigating the regioselectivity of the dimerization reaction, Baldwin and co-workers noted that when analogues of 6-2, which lacked an enone α-substituent, were subjected to the reaction conditions, dimerization occurred selectively at the enone α-position to form α-linked butenolides.113 This preference for the formation of linear 11683

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dimerization allows for convergent synthesis, increasing yields and reducing step counts. In addition to dimerization, the nickel-mediated prenylation methodology developed by Corey, Semmelhack, and Hegedus has enabled the synthesis of a number of natural products, and continues to be advanced under the banner of cross-electrophile coupling to this day.

reductively dimerized to provide 8-2 in 42% yield. Barrero and co-workers also described a procedure using catalytic Cp2ZrCl2 and Mn dust, which provided 8-2 in 48% yield. Dihydroxylation then afforded tetraol 8-3, which could be oxidized to form the natural product 8-4 albeit only in approximately 5% yield. The Movassaghi group has applied CoCl(PPh3)3 to the syntheses of a number of dimeric indole alkaloids (Scheme 9).

3. THE NOZAKI−HIYAMA−KISHI REACTION Scheme 9. Movassaghi’s Synthesis of Chimonanthine

3.1. Initial Development

The Nozaki−Hiyama−Kishi reaction is the nickel-catalyzed reductive coupling of aldehydes to vinyl- and allyl-halidederived organochromium species. In 1977, Hiyama and Nozaki reported what they described as a “Grignard-type carbonyl addition of allyl halides”, which used the lithium aluminum hydride (LAH) reduction product of CrCl3 to generate the organometallic intermediate.125 They continued to explore the scope of this Barbier−Grignard-type reaction, eventually finding CrCl2 to be the optimal reagent for this transformation.126,127 After the publication of this report in 1983, Nozaki and coworkers noticed that the success of the organochromium formation was highly dependent on the source of the CrCl2. They had initially purchased a container of anhydrous CrCl2 from ROC/RIC Corp. in New Jersey, which consistently produced the desired addition products in appreciable yields. However, subsequent batches obtained from Aldrich Co. and Rare Metal Co. gave completely irreproducible results. This stark difference in reactivity suggested that the initial source contained a contaminant, perhaps a second metal species, which was effectively catalyzing the reaction. Fluorescent X-ray analysis revealed that there was, in fact, 0.5 mol % of nickel present relative to chromium. The Nozaki group confirmed the involvement of nickel by adding a catalytic amount of NiCl2 to the uncontaminated CrCl2, thereby restoring the catalytic competency of the system.128 In this seminal communication, they demonstrated that the NiCl2−CrCl2 system could catalyze the reductive coupling of enol triflates and aldehydes. Up until this point, enol triflates had been largely underutilized, but had been used to generate unsaturated carbenes through α-elimination.129 In fact, there were only two prior reported examples of these pseudohalides being utilized in cross-coupling processes, both in the context of palladium-catalyzed Heck-type coupling.130,131 The ability to easily create bonds between carbonyl-derived fragments made this methodology very attractive from the perspective of total synthesis. It is fitting then that aldehyde− vinyl halide coupling was simultaneously reported by Kishi and co-workers during their synthetic studies on the dauntingly complex marine polyether palytoxin (Scheme 10).132 They had been trying to make the C7−C8 bond (10-5) using conventional strategies like the Wittig olefination and aldol condensation without success. After coming across Nozaki’s 1983 report, they were able to produce the desired coupling product (10-5) using the CrCl2-mediated process described therein. Unsurprisingly, the Kishi group quickly encountered reproducibility issues, which they then resolved with the inclusion of NiCl2 or Pd(OAc)2 as an additive. As the independent reports of the reaction by the Nozaki and Kishi groups were published near simultaneously, the transformation came to be known as the Nozaki−Hiyama−Kishi reaction. The first step of the nickel-catalyzed process is the reduction of Ni(II) to the active Ni(0) species by 2 equiv of Cr(II), a

They first utilized cobalt-mediated benzylic dimerizations in their 2007 total syntheses of chimonanthine (9-3) and folicanthine (9-4).117 The key dimerization reaction was achieved via the treatment of bromopyrroloindoline 9-1 with CoCl(PPh3)3 in acetone to obtain hexacycle 9-2 in 60% yield. The authors noted that acetone and 2-butanone were optimal solvents for the reaction, while solvents such as benzene provided lower yields of 9-2 and more byproducts. Therefore, it was proposed that a solvent cage plays an important role in effecting the desired dimerization selectively. In subsequent reports, the Movassaghi group has demonstrated the generality of their pyrroloindoline dimerization strategy by completing the total syntheses of WIN-64821,118 11,11′-dideoxyverticillin A,119 and chaetocin A, and others.120 This approach was also used by Baran and co-workers in their synthesis of (+)-psychotetramine.121 Bisindole alkaloids have become an important proving ground for reductive dimerization methodologies. In 2013, Peng and co-workers employed NiCl2, 2,2′-bipyridine, and stoichiometric Zn en route to chimonanthine and folicanthine.122 Oguri and co-workers developed a reductive coupling with catalytic NiCl2, DPPBz, and stoichiometric Mn for their 2014 total synthesis of chimonanthine and folicanthine.123 Several oxidative dimerization strategies toward the chimonanthine skeleton have been reported as well. One recent example is Xia’s synthesis of chimonanthine using Cu-mediated oxidative indole coupling (section 10.3, Scheme 104).124 Since its discovery in the 1940s, the reductive coupling of allylic and benzylic halides has been developed from a method to produce simple hydrocarbons to a robust and versatile technique for intermediate and late-stage functionalization in natural product synthesis. Particularly after Momose’s report of CoCl(PPh3)3, this methodology has had a significant impact on the synthesis of dimeric natural products. Mild, late-stage 11684

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Scheme 10. Mechanism of the Nozaki−Hiyama−Kishi Reaction Depicted in Kishi’s Synthesis of Palytoxin

Scheme 11. Danishefsky’s Synthesis of Eleutherobin

C2 position to the terminal carbon of the pendant chain. While functionalization of the furan at the desired position was easily accomplished, Danishefsky and co-workers were unable to install an appropriate vinylic coupling partner through olefination. Turning their attention to intermediate 11-1, they attempted to enact the addition of furan C-2 into the aldehyde through radical cyclization, lithiation-addition, and samarium(II) iodide cyclization. While these strategies could not overcome the highly strained character of the resulting macrocycle (11-2), treatment of bromoaldehyde 11-1 with CrCl2−NiCl2 gave the desired product in 74% yield. In a more recent instance, Hatakeyama and co-workers use an intermolecular NHK reaction to reductively couple vinyl iodide 12-2 with aldehyde 12-1 to synthesize oxazolomycin A (12-4) (Scheme 12). The addition product (12-3) was

single electron donor. The newly formed Ni(0) oxidatively adds into the organohalide (10-1) to yield the Ni(II) complex (10-2).133 The alkyl ligand then transmetallates to the Cr(III) generated in the initial reduction. The Cr(III) complex (10-3) chelates to the aldehyde oxygen, bringing it into close proximity for the nucleophilic addition. Finally, the organochromium species adds into the aldehyde (10-4) to generate the alcohol (10-5), driven by the formation of the strong O−Cr bond. Although the organochromium reagent can add into ketones as well as aldehydes, the rate of ketone addition is markedly reduced, allowing for selective addition into aldehydes in multifunctional substrates.134,135 The most significant drawback of the NHK reaction is the toxicity of the stoichiometric chromium reagents used. This is particularly problematic in the case of chromium, which is typically used in a large excess for intermolecular reactions and macrocyclizations. Even in the most favorable intramolecular bond-forming scenario, a minimum of 2 equiv is required per turnover of the nickel catalyst. In 1996 Fürstner and co-workers published the first report of an NHK reaction catalytic in chromium.136 They were able to achieve catalyst turnover by adding a chlorosilane and manganese metal to the reaction. The oxophilicity of the silane additive facilitates the release of CrX3 by forming the silyl ether of the addition product, while the manganese reduces Cr(III) to the desired Cr(II). In this initial report, Fürstner and co-workers observed yields as high as 80% at a CrCl2 catalyst loading of 15 mol %.

Scheme 12. Hatakeyama’s Synthesis of Oxazolomycin A

3.2. NHK Coupling in Total Synthesis

Danishefsky and co-workers’ 1999 synthesis of the marine diterpene eleutherobin (11-3) illustrates the complementarity of the NHK reaction to existing C−C bond-forming methods (Scheme 11).137 Compound 11-1 was accessed by functionalizing commercially available chiral cyclohexadiene α-phellandrene (not shown). It was envisioned that the furan bridged macrocycle 11-2 could be formed via the coupling of the furan 11685

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obtained in 81% yield, with a diastereomeric ratio of 4:1, favoring the undesired compound.138 The stereochemistry at the position in question was corrected by oxidation with DMP followed by a diastereoselective reduction with L-Selectride. This synthesis showcases the comparable efficiency of the NHK in the intermolecular context, and demonstrates complementary stereocontrol that can be obtained if necessary. The earliest successful attempt at creating an enantioselective Nozaki−Hiyama−Kishi reaction used superstoichiometric amounts of chiral bipyridines or bisphosphines to yield highly variable ee’s of 28−74%.139 One of the primary challenges in the implementation of a viable catalytic system for this purpose was the aggregation of chromium(II) species in the presence of bidentate ligands.140 The first catalytic enantioselective method was reported by Cozzi and co-workers in 2000, using salen-type ligands.141,142 They were able to observe catalyst turnover by reducing CrCl3 in situ, thereby minimizing the concentration of CrCl2 in the reaction. The salen ligand allowed for asymmetric reactions to occur with up to 79% ee. Consistently high enantioinduction has been observed with the oxazoline-based ligands described by Nakada in 2003,143 and recently by Kishi.144 An illustrative example of oxazoline ligands used to effect stereoselective Nozaki−Hiyama−Kishi coupling is found in Micalizio’s studies toward pectenotoxin 2 (13-5) (Scheme 13).145 In this work, an oxazoline/sulfonamide ligand (13-3) was used to promote the diastereoselective addition of vinyl iodide 13-1 into tricyclic aldehyde 13-2 to generate the allylic alcohol (13-4) with a diastereoselectivity of 20:1. The resulting product was then subjected to NIS-mediated iodoetherification, resulting in cyclization of the pendant alcohol.

The broad functional group tolerance, intra- and intermolecular capabilities, and opportunities for enantioselective catalysis have made the Nozaki−Hiyama−Kishi reaction a mainstay in total synthesis. In the synthesis of the diterpenoid chromodorolide B (14-5), Overman and co-workers use the NHK to realize a strategic retrosynthetic disconnection between the two hemispheres of the natural product (Scheme 14).146 The exceptionally mild conditions of the NHK coupling Scheme 14. Overman’s Synthesis of Chromodorolide

allow for the convergent coupling of two highly functionalized fragments, bicyclic vinyl iodide 14-1 and aldehyde 14-2. They were able to obtain the product (14-4) diastereoselectively by using Kishi’s oxazole/sulfonamide ligand,147 which also elevated the yield to 66% from ∼20% observed with all other conditions. The selectivity and functional group tolerance of the NHK coupling are dramatically demonstrated in Kishi’s 2014 synthesis of the complex marine polyether halichondrin A (Scheme 15).148 Although Kishi and co-workers had previously exploited the reaction capabilities of the NHK to synthesize large polyethers, the halichondrin A synthesis brings together two highly oxidized fragments, 15-1 and 15-2, with potentially sensitive functionalities with an overall reaction yield of 91% (15-4). The NHK reaction is a convenient strategy for constructing C−C bonds that complements and provides an alternative to other carbonyl-addition processes. The resulting allylic alcohol allows for subsequent dehydration, making it an analogue for cross-coupling reactions like the Heck, among other derivatization reactions. As one of the first examples of oxidative addition into vinyl triflates, the Nozaki−Hiyama−Kishi helped to shape first-row transition metal-catalyzed cross-coupling applied to total synthesis.

Scheme 13. Micalizio’s Synthesis of Pectenotoxin 2 C1−C26 Subunit

4. CROSS-COUPLING 4.1. Early History

One of the first known examples of a transition metal-catalyzed cross-coupling reaction was reported by Carl Andreas Glaser in 1869.149,150 He found that under basic conditions phenylacetylene could form an acetylenic organocuprate, with an unknown ligand environment, which underwent homocoupling in the presence of molecular oxygen. This Glaser coupling was utilized by Adolf von Baeyer in an early synthetic route to 11686

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incarnation of this process had limited application to complex systems due to high reaction temperatures (>200 °C) and competitive homocoupling, subsequent modifications have made the Ullman coupling a convenient procedure for forming C−C, C−O, and C−N bonds between aromatic rings.155−157 It was found that rings containing electron-donating substituents underwent coupling more readily, which allowed for heterocoupling to occur in systems wherein one of the coupling partners is more reactive than the other.158 Using activated copper or Ni(0) catalysis allowed the reaction to proceed at significantly lower temperatures, and the Ziegler modification, in which aryl-copper species are used to generate the organocuprate and the subsequent aryl radical, facilitated the coupling of sterically congested substrates.159−161

Scheme 15. Kishi’s Synthesis of Halichondrin A

4.2. Examples in Total Synthesis

The standard high temperature conditions were utilized by Sarli and co-workers in their total synthesis of the alkaloid marinopyrrole A (Scheme 17).162 The bis-pyrrole core (17-3) Scheme 17. Sarli’s Synthesis of Marinopyrrole A

indigo dye in 1882 (Scheme 16).151 Indigo was one of the most complex molecules to be synthesized at the time and would subsequently contribute to Baeyer’s 1905 Nobel Prize in Chemistry.152 One of the next major developments in the field of crosscoupling was Fritz Ullman’s copper-catalyzed biaryl synthesis from aryl halides, reported in 1901.153,154 Although the initial

was constructed from fragments 17-1 and 17-2 by subjecting the monomers to Cu(OAc)2 and DBU at 200 °C. One of the byproducts was protodemetalation, as is commonly observed in cross-coupling reactions. The synthesis is completed with deprotection of the two phenols and a remarkably efficient tetra-chlorination of the bis-pyrrole moiety to provide the natural product 17-4. Flippin and co-workers’ synthesis of the Amaryllidaceae alkaloids tortuosine, criasbetaine (18-5), and ungeremine utilized the Ziegler modification to perform the coupling under very mild conditions (Scheme 18).163 The N-Bocindoline 18-1 was used to direct lithiation to the indoline C7 position, after which the aryl-copper complex generated the organocuprate 18-2 at this relatively hindered position. This species then underwent Ziegler−Ullman coupling with iodoarene 18-3 at −45 °C to give the coupled product 18-4. The electron-donating substituents of 18-3, the increased reactivity of aryl iodides, and steric promotion of the Ziegler modification all increased the reactivity of the system and afforded the product 18-4 at low temperature.164 Deprotection of the Boc group followed by the condensation of the free amine onto the aldehyde gives the desired natural product 18-5. The application of a nickel-based system to the Ullman reaction has allowed for an atroposelective coupling.165 In Lin

Scheme 16. Baeyer’s Synthesis of Indigo

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Scheme 18. Flippin’s Synthesis of Criasbetaine

Scheme 20. Beaudry’s Synthesis of Myricatomentogenin

tion allowing for an improved of ratio of 87:13. Exposure of the ether product 20-2 to BCl3 resulted in protecting group cleavage and gave myricatomentogenin (20-3) in 44% yield. These atroposelective syntheses, taken together, are impressive examples of both early- and late-stage introduction of axial chirality. The utilization of both nickel and copper as viable catalyst manifolds for this type of transformation provides an excellent basis for future syntheses of axially chiral molecules.169 Moving approximately 70 years forward from the introduction of the Ullman coupling, we see the advent of modern transition metal-catalyzed cross-coupling chemistry with the discovery of the Kumada coupling. The reaction was reported independently by the Corriu and Kumada groups in 1972.170,171 Corriu demonstrated the coupling of aryl Grignard reagents with olefinic halides using Ni(acac)2, while Kumada published a more extensive study of substrate tolerance and suggested a possible mechanism for the transformation. Kumada proposed that the reaction proceeds via the oxidative addition of the vinyl or aryl halide onto the Ni(I) species to generate the Ni(III) intermediate. The Grignard undergoes a transmetalation reaction with the nickel complex, which subsequently reverts back to its Ni(I) form with the reductive elimination of the coupling product. Although this remains the formal mechanistic description of the nickel-catalyzed Kumada coupling, a detailed mechanistic pathway for the process has not yet been elucidated. The isolation of alternative oxidation states of the nickel species, such as Ni(II), Ni(III), and Ni(IV), has been observed with certain polydentate ligands such as terpyridines and butadienes, suggesting that the mechanism may be influenced by the identity of the ligands bound to the metal center.172−177 In 1975, Murahashi and co-workers reported an early example of a palladium-catalyzed Kumada coupling.178 In this publication, the researchers explored the oxidative addition of alkyl halides into Pd(0) complexes and the C−C bond-forming potential of those intermediates. Initially, they attempted to introduce the alkyl coupling partner through the corresponding organolithium reagents, but found that the reaction was only viable in the presence of stoichiometric Pd catalyst due to the fast process of lithium halogen exchange between the alkyl and vinyl components. The less activated Grignard reagents, on the other hand, allowed the coupling to proceed in a catalytic fashion. The Pd-catalyzed Kumada coupling and the contemporaneous discovery of the Pd-catalyzed Heck reaction jump started decades of innovation, which would give rise to the Sonogashira, Negishi, Stille, and Suzuki couplings and

and co-workers’ formal synthesis of isoschizandrin (19-5), the electron-rich bromoarene 19-1 was dimerized using NiCl2(PPh3)2 and chiral phosphine ligand 19-2 to give an ee of 68% (Scheme 19).166 The resulting biaryl structure (19-3) Scheme 19. Lin’s Synthesis of Isoschizandrin

was elaborated through ketalization and Wittig reaction of the free aldehyde to generate intermediate 19-4, which can then be used to obtain the natural product (19-5) over two steps using an existing protocol.167 The increased reactivity of the nickel catalyst allowed the reaction to proceed to completion with gentle heating (45 °C). Atroposelective coupling has also been demonstrated in copper-catalyzed systems in Beaudry and co-workers’ 2013 synthesis of diarylether heptanoids myricatomentogenin (203), jugcathanin, galeon, and pterocarine.168 Beginning from the precursor biaryl (20-1), they found proline to be the most effective ligand to provide atropisomer 20-2 (Scheme 20). Upon treatment with CuI, K3PO4, and proline ligand, ether formation was effected with an er of 67:33, with recrystalliza11688

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mechanistic hypothesis, Fürstner proposed that the critical metal intermediates in the cycle are Fe(−II)/Fe(0). The active [Fe(MgX)2] catalyst is generated in situ from an Fe(II) source and 4 equiv of the Grignard.191 This alternative catalytic system is quite attractive from the perspective of total synthesis, as iron catalysis can use less reactive electrophiles. The iron catalysts developed by Fürstner and co-workers readily catalyze Grignard coupling to aryl and vinyl chlorides, tosylates, and triflates, in addition to the standard bromide and iodide substrates. Furthermore, orthogonal modes of selectivity have been demonstrated relative to more typical palladium-catalyzed processes.192 Yu’s total synthesis of the terpene (+)-asteriscanolide (22-4) (Scheme 22) demonstrates one of the most commonly used

culminated in the recognition of the impact of those achievements with the 2010 Nobel Prize in Chemistry, awarded “for palladium-catalyzed cross-couplings in organic synthesis”.179 Although Murahashi’s introduction of the palladium catalyst as a viable facilitator of the Kumada coupling conferred certain synthetic advantages such as comparatively mild reaction conditions and an expanded substrate scope, the nickel-based system offered alternative advantages. The rate-limiting step in the palladium catalytic cycle is typically oxidative addition of the metal into the carbon−halogen bond, a process that is significantly faster and available to a greater diversity of leaving groups for the nickel catalyst.180,181 Additionally, the relative abundance and low cost of nickel, $1.20 per mole, in comparison to $1500 per mole of palladium, has made nickel-catalyzed cross-coupling increasingly more attractive from an economic standpoint.182 The greater abundance of nickel relative to palladium also suggests more sustainable solutions could be developed with nickel.4 In their 1995 total synthesis of the marine natural product arenarol (21-4), Wender and co-workers installed the pendant arene (21-2) onto the decalin structure (21-1) by executing an sp3−sp2 cross-coupling at a neopentyl center (Scheme 21).183

Scheme 22. Yu’s Synthesis of Asteriscanolide

Scheme 21. Wender’s Synthesis of Arenarol

applications of this chemistry, which is the conversion of a ketone to a vinyl methyl group.193,194 The 5-8 ring system in intermediate 22-1 was the product of a [(5+2)+1] cyclization followed by the conversion of the resulting ketone to the vinyl triflate (22-2) via treatment with Tf2O. The ketone that was generated in the carbonylative cyclization provided a convenient handle for accessing their desired cross-coupling partner. Yu and co-workers’ application of the Fe(acac)3 catalyst for the coupling ensures that the oxidative addition into the vinyl triflate was robust enough to afford the desired vinyl methyl compound (22-3) in 58% yield. Furthermore, the substrate tolerance afforded by Fürstner’s iron-catalyzed conditions was showcased in Isobe’s total synthesis of the right-hand fragment of the marine polyether ciguatoxin (23-4) (Scheme 23).195 The ketone coupling precursor 23-1 is the nearly completed eastern hemisphere of the natural product, containing ketals, a complex ring system, and all of the requisite oxidation states. First, this ketone was converted to the vinyl triflate 23-2 using KHMDS and PhNTf2. The vinyl pseudohalide was then treated with Fe(acac)3 and methyl Grignard to yield the vinyl methyl intermediate 23-3. Subsequent hydrogenation and deprotection of the crosscoupling product give the desired natural product fragment. The use of a vinyl triflate as a coupling partner is particularly appealing, as carbonyl compounds are common retrons and their conversion to vinyl triflates occurs readily. In this particular work, the ketone in question (23-1) functions as a convenient handle for functionalization, being derived from an

They were able to achieve this transformation with yields up to 50% upon treatment with Ni(dppf)Cl2 and ZnCl2. Exposure of 21-3 to CAN resulted in the formation of the related quinonecontaining natural product arenarone, which was reduced to afford the target natural product arenarol (21-4). The synthetic utility of the key transformation was demonstrated in the joining of the aryl nucleophile with the hindered primary electrophile, a challenging transformation in the absence of catalysis.184,185 Early in the development of Kumada-type coupling reactions, the Kochi group reported the cross-coupling of Grignard reagents with alkenyl halides using iron salts.186,187 They proposed an Fe(I)/Fe(III) catalytic cycle for the process, wherein the Fe(III) precatalyst would enter the cycle upon reduction by the Grignard reagent. Fe(I) was thought to undergo oxidative addition to the Fe(III) intermediate followed by transmetalation with the Grignard. The reductive elimination to form the coupling product would then regenerate the active catalyst to continue the cycle.188 This work remained largely underappreciated until Fü rstner and co-workers expanded this area in the early 2000s, leading to its widespread adoption in total synthesis.189,190 In contrast to the Kochi 11689

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Scheme 23. Isobe’s Synthesis of Ciguatoxin Right-Hand Fragment

Scheme 24. Hu’s Synthesis of Recifeiolide

Scheme 25. Carreira’s Synthesis of Daphmanidin E

enone, which undergoes an oxy-Michael addition to install the neighboring tetrahydropyran ring. Broadly speaking, first-row transition metal analogues of classical Pd-catalyzed reactions have been less frequently employed in natural product synthesis.24−31,196 In Hu and coworkers’ total synthesis of the fungal macrolide recifeiolide (246), a nickel-catalyzed Suzuki−Miyaura coupling was used to synthesize esterification precursor 24-5 (Scheme 24).197 The researchers began by performing a hydroboration of alkyne 241. Subsequent treatment with alkyl bromide 24-3 in the presence of 5 mol % of the Nickamine catalyst (24-2) yielded the sp2−sp3 cross-coupling product 24-4.198−200 As is generally the case for first-row transition metal catalysis, the nickel catalyst was particularly well suited for alkyl−alkenyl coupling because of its increased propensity to effect oxidative addition and decreased tendency toward β-elimination. Last, Suzuki product 24-4 was deprotected using TBAF and KOH and subjected to Yamaguchi esterification conditions201 to generate racemic recifeiolide (24-6). In Carreira and co-workers’ 2011 synthesis of daphmanidin E (25-4), a cobalt-catalyzed sp2−sp3 Heck reaction was used to close the molecule’s largest ring late in the synthetic route (Scheme 25).202 The cyclization product (25-3) was obtained through treatment of compound 25-1 with cobaloxime 252.203,204 After successfully executing the transformation with 1.1 equiv of cobaloxime under sunlamp irradiation, Carreira and

co-workers found that they could achieve the same result with 25 mol % catalyst loading with Hünig’s base and a blue LED light in comparable yield. The authors noted that the successful cobaloxime-catalyzed Heck was discovered after a wide variety of free-radical and Pd-catalyzed transformations failed to generate the desired product. This methodology is an excellent example of the alternative modes of reactivity available using first-row transition metal catalysis.

5. THE PAUSON−KHAND REACTION 5.1. Discovery and Mechanism

The Pauson−Khand reaction is a transition metal-catalyzed [2+2+1] annulation between an alkyne, alkene, and carbon monoxide, which results in the formation of a cyclopentenone ring, in an inter- or intramolecular fashion.205 The transformation was first reported by Pauson and Khand in 1973. Prior to the discovery of their eponymous reaction, Pauson and Khand had been attempting to demonstrate the insertion of a norbornyl alkene into the hexacarbonyl dicobalt complex of acetylene.206 They observed the formation of the corresponding enone through the exo-mode of addition, exclusively. The endo-byproduct, which was formed over an extended reaction 11690

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period, was attributed to a catalytic isomerization process that was found to attenuate with increased substitution of the acetylene moiety. Although their initial research objective was never realized, they discovered that heating the two reaction components in ethereal solvent resulted in the formation of a cyclopentenone product of the exo-derived stereochemical orientation. Further investigation of this methodology by Pauson and co-workers showed that the formal [2+2+1] cycloaddition has both a broad substrate scope and a welldefined regioselectivity with respect to the alkyne component.207 The overall trends governing the stereo- and regioselectivity of this process are as follows: (1) The orientation of the acetylene-derived fragment is largely determined by steric factors, with the larger substituent occupying the α-position in the enone product. This selectivity may be formally reversed by utilizing a trimethylsilyl acetylene derivative, which places most alkyl substituents at the β-position and can be subsequently desilylated.208−210 (2) The regioselectivity of the alkene in the intermolecular reaction is much harder to predict, with some reactions resulting in equal mixtures of both regioisomers. Some studies suggest that in the absence of strong electronic factors, there is a preference for placing the larger substituent adjacent to the carbonyl to minimize the steric clash between the resulting β-carbons during bond formation.211,212 In intramolecular reactions, the reaction typically proceeds under kinetic control and results in a single product.213 (3) In accordance with the Mayr nucleophilicity scale, strained cyclic alkenes react with the fastest rate, followed by terminal alkenes and disubstituted alkenes. Trisubstituted alkenes react very slowly, while tetrasubstituted alkenes do not participate in the reaction at all.214,215 (4) Alkenes adjacent to electronwithdrawing groups or electron-rich conjugated systems are not viable substrates as they undergo dimerization under the reaction conditions to yield conjugated dienes.216 In 1985, Phillip Magnus suggested a general mechanistic sequence for the reaction in a manuscript aimed at rationalizing the diastereoselectivity of an intramolecular Pauson−Khand that Magnus and co-workers applied to the total synthesis of the antitumor sesquiterpene coriolin (Scheme 26).217−219 This proposed mechanism rationalized experimental observations of the transformation, and the plausibility of the proposal was later verified through theoretical calculations.220−223 The reaction is initiated by the formation of a hexacarbonyl dicobalt complex (26-2) upon heating of dicobalt octacarbonyl with the alkyne fragment (26-1). Subsequently, the alkene component coordinates to a cobalt center upon the dissociation of a CO ligand (26-3). The incorporation of the alkene into the complex is often the rate-determining step for the overall reaction because it is highly dependent upon the relative affinities for complexation of CO and the alkene. The dissociation of CO can be impeded by overpressure of carbon monoxide gas above the reaction, which biases the equilibrium toward the fully CO-saturated hexacarbonyl dicobalt complex. Beyond simply adjusting the reaction atmosphere, CO dissociation can be promoted by treating the hexacarbonyl dicobalt complex with amine oxides such as N-methylmorpholin e oxide (NMO) and t rimethy lamine N-o xide (TMAO).224,225 The amine N-oxide initiates a nucleophilic attack onto a cobalt-bound CO ligand, which causes disproportionates to the amine and carbon dioxide, vacating a coordination site on the metal center. Upon coordination, the olefin inserts into the complex to form the cobaltacycle (26-

Scheme 26. Magnus’ Mechanism of the Pauson−Khand Reaction

4).226,227 The relative orientations of the alkyne and alkene components during the insertion determine the regiochemistry of the resulting product. The newly formed cobaltacycle reveals a site of coordinative unsaturation, which is quickly trapped by excess CO or Lewis base in a very energetically favorable process, effectively rendering the step irreversible. Following the formation of the cobaltacycle, a cobalt bound CO ligand inserts into the carbon−cobalt bond. Although, to date all efforts to observe the post-insertion intermediate (265) to differentiate between the possibility of insertion at the sp3 carbon or the formally sp2 hybridized carbon have proven unsuccessful, theoretical calculations suggest that the sp3 insertion proceeds via a slightly lower energy transition state.228 Finally, the acylcobaltacycle undergoes reductive elimination to reveal a weakly bound cyclopentenone-dicobalt complex, which quickly decomposes to reveal the product cyclopentenone (26-6). The formation of substituted cyclopentenones from simple, acyclic precursors is a desirable transformation from the perspective of total synthesis; consequently, the Pauson− Khand reaction has been utilized in the synthesis of natural products with regularity. Magnus’ 1983 synthesis of coriolin, with its accompanying studies on reaction stereochemistry, was the first application of the methodology in this context and served to establish the Pauson−Khand as a complexity building construction reaction with reliable stereochemical outcomes. The subsequent discovery of amine N-oxide promotion in 1990 by Stuart Schreiber and co-workers further improved the ability of the transformation to be applied to problems in multistep synthesis by allowing the reaction to proceed at room temperature, eliminating many problems associated with functional group tolerance.229 11691

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5.2. Pauson-Khand Reactions in Total Synthesis

phosphine sulfides, thioureas, 1,2-dimethoxyethane, and water. These catalytic reactions typically require a temperature range of 50−70 °C and perform efficiently at catalyst loadings of as low as 3 mol %.238−244 In an example from Baran and co-workers, an NMO promoted Pauson−Khand reaction was used to synthesize the central stereochemically complex ring of axinellamine A (28-5) and B (not shown) in the first step (Scheme 28).245 The

In the aforementioned total synthesis of epoxydictymene (Scheme 27), Schreiber and co-workers construct the Scheme 27. Schreiber’s Synthesis of Epoxydictymene

Scheme 28. Baran’s Synthesis of Axinellamine A

tetracyclic ring system of the natural product using an acidcatalyzed Nicholas reaction followed by a thermally induced Pauson−Khand cycloaddition.230 The key sequence is initiated with the formation of the hexacarbonyl dicobalt complex of alkyne 27-1. This complex is then treated with trimethylsilyl triflate to ionize the acetal and trigger the attack of the Sakuraitype nucleophile to generate the eight-membered ring (272).231−233 In subsequent studies on this system, it was found that the tetrahydropyran and cyclopentenone moieties (27-3) can be produced in a single step by treating the complex with NMO at ambient temperature. Thermal, ultrasound, and amine N-oxide initiation of the cycloaddition were attempted.234 Ultrasound activation resulted in a modest yield of 45% and a dr of 3:1, while heating at reflux produced compound 27-3 in 85% yield with a dr of 5:1. The NMO promoter allowed for improvement of the diastereoselectivity to 11:1.235 The synthesis of (+)-epoxydictymene (27-4) from intermediate 27-3 was completed after installation of the challenging quaternary center at the ring fusion positon. Another advancement that served to further popularize the application of this methodology was the introduction of a practical catalytic variant of the Pauson−Khand by Jeong in 1994.236 Prior to this, it was known that dicobalt octacarbonyl, on its own, was capable of producing anywhere from a 1.5 to 3 times excess of cyclopentenone at highly elevated temperatures and 1 atm of CO.237 Promoter-enhanced cycloadditions, conversely, proceeded much more readily but produced a substoichiometric quantity of product, quickly forming dark precipitates comprised of inactive metal species such as Co4(CO)12. By introducing triphenyl phosphite as a ligand, Jeong and coworkers were able to generate a catalytic species active enough to be synthetically useful, but stable upon release of the cyclopentenone product. In this initial report, temperatures of 100 °C, with 5 mol % Co2(CO)8 and 20 mol % of triphenyl phosphite, were shown to successfully catalyze intermolecular Pauson−Khand reactions, attaining yields as high as 94%. Since then, there have been a number of viable ligands introduced including cyclohexylamine, bulky phosphites, phosphines,

researchers used N-Boc propargylamine (28-2) and the relatively unactivated bis-allylic trimethylsilyl ether (28-1) to perform an intermolecular Pauson−Khand yielding cyclopentenone 28-3.246 N-Oxides, unlike the other tested additives, were found to promote the reaction, generating the cyclopentenone in yields ranging from 15% to 25%. After extensive screening, it was found that NMO, in the presence of ethylene glycol, afforded the product in a 46−58% range. Although the specific role of the ethylene glycol additive has not been established, it is possible that it acts as a stabilizing ligand for cobalt. The stereochemical relationships established in the resultant cyclopentenone are used to elaborate the molecule in a stereocontrolled fashion with the installation of the guanidinium rings (28-4) and the pendant 2-acyl pyrroles (28-5). In a recent application of the catalytic Pauson−Khand reaction, Mukai and co-workers use 20 mol % of dicobalt octacarbonyl and tetramethylthiourea (TMTU) ligand to produce the bicyclic intermediate 29-2 in a catalytic fashion (Scheme 29).247 The TMTU binds to the coordination site vacated by the cobaltacycle formation and stabilizes the dicobalt complex that is released from the cyclopentenone at the end of the cycle, thereby allowing for continued catalyst turnover. This early intermediate 29-2 was then used to access a selection of structurally related Lycopodium alkaloids: (±)-fawcettimine (29-4), (±)-fawcettidine, (±)-lycoflexine, and (±)-lycoposerramine-Q. Yang and co-workers’ synthesis of the Schisandracea-derived nortriterpenoids propindilactone G (Scheme 30) and schindilactone A (Scheme 31) illustrated the applications of the Pauson−Khand reaction as a late-stage functionalization 11692

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Grignard addition into the carbonyl. The authors noted that the −TMS substitution of the alkyne proved critical to the success of the annulation.250 Attempts to perform the reaction on the terminal alkyne derivative did not yield any of the desired product, possibly as a result of reversed regioselectivity with respect to the alkyne. In the case of schindilactone A, the Pauson−Khand reaction was performed with a catalyst loading of 50 mol % and TMTU as a ligand. Despite the complexity and the sensitive functionality in the cyclization precursor (311), schindilactone A (31-3) was produced in an appreciable 74% yield.

Scheme 29. Mukai’s Synthesis of Fawcettimine

5.3. Noncobalt Pauson−Khand Reactions

In Baran’s 2014 synthesis of ingenol (32-4), the researchers attempted to form the 5-7-6 ring system by performing a Pauson−Khand cyclization on vicinally functionalized cyclohexane model system 32-1 (Scheme 32).251 Under cobaltcatalyzed conditions, they only observed the formation of the product 32-3. While the trans-eight-membered ring (32-3) was hardly expected, the regioselectivity of the reaction with reference to the alkyne proceeded according to the established trend of placing the more substituted alkyne carbon at the αposition of the enone (32-2). Baran and co-workers resolved

Scheme 30. Yang’s Synthesis of Propindilactone G

Scheme 32. Baran’s Synthesis of Ingenol

Scheme 31. Yang’s Synthesis of Schindilactone A

strategy.248,249 In the case of propindilactone G (30-3), the precyclization intermediate was (30-1) derived from the α-halo cycloheptenone via Sonogashira coupling followed by a 11693

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trend toward greater enantioselectivity and chemoselectivity under increasingly mild reaction conditions. This tendency, taken together with the structural complexity, which can be introduced with the [2+2+1] annulation, suggests that the Pauson−Khand reaction will continue to be widely utilized in total synthesis.

the issue using a rhodium-catalyzed allyne-yne Pauson−Khand with 32-5 to access the desired 5-7-6 ring system (32-7).252−255 The additional unsaturation, which arises from the use of the allene starting material, provides a ready handle for incorporation of the vicinal diol. Although the catalytic species here is rhodium, this serves as an illustrative example of the expansion of the Pauson−Khand methodology beyond cobalt as well as the complementarity unique reactivity of Co- and Rhbased systems. An allene-yne Pauson−Khand was carried out by Williams and Shah in their total synthesis of ileabethoxazole (33-3) (Scheme 33).256 Beginning from precursor 33-1, they

6. THE NICHOLAS REACTION 6.1. Discovery and Mechanism

In the early 1970s, K. M. Nicholas and co-workers were looking to devise a way of selectively functionalizing the alkene portion of ene-ynes.260 With these substrates, complexation with dicobalt octacarbonyl occurs selectively at the alkyne to form the bridged alkyne-dicobalt hexacarbonyl intermediate, effectively precluding it from participating in any further reactivity. The remaining alkene moiety can engage many of the typical transformations associated with the functionality outside of metal-catalyzed hydrogenation reactions, which are seemingly poisoned by the alkyne-dicobalt hexacarbonyl complex.261,262 When propargylic alcohols were treated with Co2(CO)8, however, it was observed that a new mode of reactivity was activated. Nicholas and co-workers observed that these compounds formed very stable α-(alkynyl)dicobalt hexacarbonyl carbocations (Scheme 34). These putative carbocations

Scheme 33. Shah’s Synthesis of Ileabethoxazole

Scheme 34. Mechanism of the Nicholas Reaction

attempted to enact the cyclization using the classic Co2(CO)8 precatalyst as well as Mo(CO)6, neither of which resulted in product formation. While W(CO)6 afforded the desired compound (33-2) in very modest yields, it was Fe2(CO)9 that proves to be the catalyst of choice, generating 33-2 at low temperature in 61% yield.257,258 Investigating this transformation further, the researcher found that it proceeds in a fashion that is mechanistically distinct from the typical “Magnus” reaction pathway. The primary intermediate they were able to isolate was three-membered iron metallacycle complex of the allene, implying that the subsequent steps would be complexation of the alkyne followed by alkyne insertion into the metallacycle.259 Since Magnus’ initial application of the [2+2+1] annulation in total synthesis, variations of this transformation proliferated. The aforementioned rhodium catalysis is often used to desymmetrize ene-ynes using chiral bis-phosphine ligands and is tolerant of styrenyl alkenes. Iridium catalysts are also frequently utilized for enantioselective annulations, with enantioselectivities typically exceeding those observed with rhodium. Additionally, rhodium and iridium catalysts display a useful complementarity in alkyne/allene cyclizations because rhodium tends to selectively complex to the terminal portion of the allene, while iridium favors the internal portion. Shifting focus back to first-row transition metal-catalyzed transformations, chiral titanocenes have been used to perform intramolecular Pauson−Khand cyclizations with high enantioselectivity. All of these emerging methodologies demonstrate a

could be used to regenerate the alkene, as was done in the preliminary studies, or undergo substitution with the addition of a nucleophile. In Lockwood and Nicholas’ seminal 1977 report, they are able to synthesize propargyl arene (34-4) with the addition of anisole as a weak nucleophile in a Friedel− Crafts-type process.263 6.2. Nicholas Reaction in Total Synthesis

Upon further exploration of this cobalt-mediated nucleophilic substitution, it was found that a wide variety of C-, N-, O-, and S-nucleophiles were amenable to addition into the α-(alkynyl)dicobalt hexacarbonyl carbocation.264,265 In this early synthesis of the diterpene (+)-epoxydictymene (35-5) (Scheme 35) by Schreiber and co-workers, the carbocation was quenched with a Sakurai-type nucleophile.266,267 Acetal 35-1 was constructed via the alkylation of the lithium acetylide with the alkyl triflate. This intermediate was then treated with dicobalt octacarbonyl to form the requisite transition metal complex. Exposure to TMSOTf resulted in facile cyclization to the eight-membered ring (35-2), which was obtained as a single diastereomer, and 11694

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Scheme 35. Schreiber’s Synthesis of Epoxydictymene

Scheme 36. Hanaoka’s Synthesis of Syributin 1

an 8.5:1 mixture of ethers favoring the desired compound. This convenient selectivity can be rationalized by predicting that the Lewis acid coordination would be more facile at the smaller, less sterically encumbered substituent of the acetal.268−270 The additional oxocarbenium-type stabilization available to the α(alkynyl)dicobalt hexacarbonyl complex likely contributes to the ease and stereoselectivity of this transformation, allowing the intermediate to adopt the conformation 35-3 prior to bond formation. It is worth noting that a variety of oxygen-based leaving groups have been found to be viable precursors to the α-(alkynyl)dicobalt hexacarbonyl carbocation, from free alcohols to ethers, esters, or even acetals, as seen in this case. A convenient feature of the Nicholas reaction is that the resulting product (35-2) can be used in subsequent transformations like the Pauson−Khand due to the retention of the cobalt cluster. Schreiber and co-workers exploit this functional handle in their synthesis, taking the cluster 35-2, which is generally quite stable and amenable to storage, and subjecting it to heating at 82 °C in air to obtain the tetracyclic enone intermediate 35-3.271,272 The resulting compound represents the nearly completed carbon skeleton of (+)-epoxydictymene (35-4), which could be used to obtain the natural product. In Hanaoka and co-workers’ total synthesis of the syributin 1 (36-4), the Nicholas reaction was utilized to synthesize the spirocyclic center of the molecule (Scheme 36).273 Hanaoka and co-workers chose a strategy in which the tetrahydrofuran and critical spirocyclic center would be constructed early in the synthesis. They derived the precursor alcohol from the addition of a thioester enolate to a propargyl ketone. The requisite starting material for a Nicholas reaction, a propargylic alcohol, is readily prepared by nucleophilic addition of an organometallic reagent to an aldehyde of ketone. Treatment of the intermediate 36-1 with p-toluenesulfonyl chloride (p-TsCl), triethylamine, and DMAP results in the formation of a tetrahydrofuran with the undesired stereochemical configuration at the tertiary ether, a position that would be challenging to invert. In contrast, the exploitation of the Nicholas effect (36-2) gives the correct tetrahydrofuran 363 in a yield of 74%. Compound 36-1 undergoes complexation with the dicobalt hexacarbonyl and treatment with BF3·Et2O to initiate the cyclization. The resulting tetrahydropyran was exposed to CAN, which performs an oxidative decomplexation,

regenerating the alkyne (36-3). Alternatively, a reductive decomplexation with Li/NH3 or H2 and Wilkinson’s can provide an alkene.274 All of the reagents typically utilized in reductive decomplexation could result in deprotection of the benzyl ethers or reduction of the thioester. This synthesis demonstrates the complementarity of the Nicholas reaction with existing transformations such as the Michael reaction and other nucleophilic displacements. The stabilization provided to the carbocation by the proximal cobalt cluster can allow for the formation of hindered quaternary centers with a defined stereochemical outcome. Echoing the origins of the Nicholas reaction, Green used an electron-rich arene nucleophile to add into an α-(alkynyl)dicobalt hexacarbonyl carbocation in a Friedel−Crafts reaction twice in the synthesis of velloziolide (37-7) (Scheme 37).275 Complex 37-2 was synthesized from methyl 4-methoxybut-2ynoate (37-1), providing a potential precursor to the desired γcarbonyl cation. Because of the foreseeable instability of such a cation, it was anticipated that there would be some difficulty associated with the substrate, and a variety of Lewis acids were screened on a model system. While treatment with BF3·Et2O resulted in incomplete and sluggish reactivity, Bu2BOTf gave appreciable yields in the presence of 1.5 equiv of the arene reaction component. When applied to the velloziolide, treatment of 37-2 with Bu2BOTf in the presence of 1.5 equiv of 37-1 gave and 85% yield of the Nicholas adduct, which was oxidized by treatment with I2 to give 37-3.276 The alkynoate moiety was elaborated into the six-membered ring by hydrogenation of the alkyne, double addition of MeLi to the ester, and Lewis acid-mediated Friedel−Crafts cyclization to yield gem-dimethyl-tetrahydronaphthalene 37-4. This intermediate (37-4), primed for another Friedel−Crafts addition, was exposed to 1.2 equiv of the same dicobalt hexacarbonyl complex 37-2 in the presence of Bu2BOTf to give the Nicholas adduct 37-5 in 92% yield after decomplexation with I2. The pendant alkynoate was used to construct the sevenmembered ester through conjugate addition of methyl cuprate, reduction to the allylic alcohol, and a Johnson−Claisen rearrangement. Ester 37-6 then contained all of the carbons necessary to undergo lactonization after deprotection of the phenol moieties with BCl3. This synthesis highlights the complementarity of the Nicholas reaction to other available nucleophilic substitution methodologies by demonstrating the 11695

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Scheme 37. Green’s Synthesis of Velloziolide

Scheme 38. Isobe’s Synthesis of the ABC Fragment of Ciguatoxin

synthetic potential of primary carbocation stabilization by dicobalt hexacarbonyl complexes on relatively electron-deficient substrates. In Isobe and co-workers’ total synthesis of ciguatoxin, a formidable challenge for any synthetic chemist, the Nicholas reaction was utilized as the keystone of the central synthetic strategy, forming many of the molecule’s 13 rings.277 Their Nicholas reaction-based approach proved quite versatile, resulting in the stereoselective synthesis of seven-, eight-, and nine-membered rings with the desired syn,trans relationship, while also providing convenient reactive handles as a result of the variable decomplexation strategies employed at each site.278 In the synthesis of the A/B/C fragment (38-6) (Scheme 38), intermediate 38-2 was coupled with the dihydropyran 38-1 using SnCl4.279 The pendant dihydropyran was opened and the resultant primary alcohol trapped with pivalic anhydride while the methanol solvent quenches the carbocation. With this intermediate (38-3) in hand, Isobe and co-workers synthesized the dicobalt hexacarbonyl complex (38-4), deacetylated the nucleophile, and exposed the compound to BF3·Et2O, triggering the formation of the seven-membered ether (38-5). Treatment of this penultimate intermediate with Wilkinson’s catalyst in the presence of H 2 resulted in reductive decomplexation to reveal the alkene and deprotection of the compound to the vicinal diol (38-6). For ciguatoxin’s B/C/D ring synthesis (39-6) (Scheme 39), alkyne 39-3 was prepared by the Corey−Fuchs-type coupling of 1,1-dibromoalkene 39-1 with aldehyde 39-2, followed by deprotection of the secondary alcohol. After generation of the cobalt complex, treatment with BF3·Et2O led to the formation of cyclic ether 39-4.280 In this case, silylative decomplexation

was achieved through treatment with Et3SiH at elevated temperatures, which results in the formation of vinyl silane 39-5.281 This functionality facilitates subsequent transformations in which Isobe and co-workers install an allylic alcohol, which serves as the nucleophile in yet another Nicholas reaction later in the route. In the final synthesis of the entire ciguatoxin structure (Scheme 40), polycyclic fragments 40-1 and 40-2 were coupled through the addition of the Li-acetylide of 40-1 into aldehyde 40-2 to give the Nicholas precursor 40-3.282 This complex intermediate was then subjected to global acetylation followed by the removal of the ethoxyethyl group with the Amberlyst-15 resin to reveal the nucleophilic alcohol (40-3). Synthesis of the cobalt complex and treatment with p-toluenesulfonic acid gave the nine-membered ring (40-4) in 72% yield over the two steps. With the nine-membered ring in hand, Isobe and coworkers were able to obtain ketone 40-5 in a regioselective fashion by heating cobalt complex 40-4 with a large excess of bis(diphenylphosphino)methane (dppm) ligand to displace CO at two coordination sites on the dicobalt complex. This modified complex was quickly oxidized to the ketone upon exposure to air at 100 °C.283−285 In prior efforts toward installing this ketone, the researchers discovered that simply heating the acetylene-dicobalthexacarbonyl complex in a highly pressurized H2 atmosphere would result in the formation of the desired ketone, although typically in irreproducible yields between 10% and 40%. A screen of a 11696

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Scheme 39. Isobe’s Synthesis of the BCD Fragment of Ciguatoxin

Scheme 40. Isobe’s Coupling of Ciguatoxin Fragments

variety of mono- and bidentate phosphines revealed dppm as particularly suited to inducing oxidative decomposition of the complex. This late-stage intermediate (40-5) represents the nearly completed skeleton of the ladder polyether. The central ring was synthesized using the functional handle afforded by the newly installed oxidation state, and the terminal sevenmembered A ring was constructed using the Nicholas cyclization strategy formulated in one of Isobe’s earliest ciguatoxin reports described in Scheme 38. This total synthesis of ciguatoxin demonstrated the reliability of the Nicholas reaction for the stereocontrolled construction of repeating structural motifs. While ladder polyethers like ciguatoxin are excellent substrates for the Nicholas reaction, the related ionophore polyethers can also be constructed efficiently by a Nicholasbased synthetic strategy. In Martin and co-workers’ 2013 total synthesis of the ionophore teurilene (41-3), a Nicholas reaction served as the initiating event for an epoxide-opening cascade, resulting in the formation of all three cyclic ethers in the course of a single step (Scheme 41).286 Cyclization precursor 41-1 was prepared from a linear diol accessed from 2,5-dimethoxytetrahydrofuran. The right-most epoxide was then synthesized using the Katsuki−Sharpless epoxidation, and the remaining epoxides were installed stereoselectively using the Shi epoxidation. The substrate was then primed for the key step

with the addition of TMS-acetylide into the terminal aldehyde, generating the propargyl alcohol (41-1). The alkyne-cobalt complex was formed and treated with silica gel, resulting in the formation of the tricyclic teurilene core (41-2). One of the most significant difficulties associated with performing multiepoxide-opening cascades is the generation of the initiating cation in a regioselective fashion.287 The extremely facile ionization of the α-(alkynyl)dicobalt hexacarbonyl alcohol allowed Martin and co-workers to use the weakly acidic silica gel as their Lewis acid initiator, leaving the relatively stable epoxides untouched. Once the stabilized cation is 11697

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7.2. Cobalt-Mediated [2+2+2] in Total Synthesis

Scheme 41. Martin’s Synthesis of Teurilene

The pioneering early work in the application of the metalcatalyzed [2+2+2] to total synthesis was performed by Vollhardt and co-workers (Scheme 42).296−299 They found Scheme 42. Vollhardt’s First Synthesis of Estrone

formed, the proximal epoxide opens to engage the carbocation, a process that is repeated three times over the course of the cascade. In employing the epoxide as a nucleophile, the researchers acknowledged that the endo/exo regiochemical outcome could result in the formation of fused tetrahydropyrans instead of their desired tethered tetrahydrofurans. From McDonald’s and Jamison’s work on polyepoxide cyclizations, it was known that in the case of the formation of a discrete carbocation, the exo mode is favored as epoxide opening precedes the attack of the electrophile by the alkoxide.288−290 Conversely, in instances, typically under weakly acidic conditions, where an electron-deficient position is generated inductively, the epoxide attacks the site directly, forming an epoxonium ion. The opening of this intermediate occurs at the internal position, generating the endo product. The α(alkynyl)dicobalt hexacarbonyl carbocation is provided with a greater degree of stabilization than the relatively stabilized allylic or propargylic cations. The reaction proceeds cleanly to the desired exo product, affording tricycle 41-2 in 75% yield after oxidative decomplexation.

that CpCo(CO)2 was an effective catalyst for synthesizing functionalized benzene rings and began applying the transformation to the synthesis of steroidal structures. In 1977, the group published a total synthesis of an estrone derivative (424) via a [2+2+2] cyclization from functionalized cyclopentanone 42-1.300,301 The starting material (42-1) was accessed from the conjugate addition of vinyl cuprate into 2methyl cyclopentenone followed by trapping of the enolate with 3-(iodoethyl)-1,5-hexadiyne. The cycloannulation precursor (42-1) was syringed into bis(trimethylsilyl)acetylene (as solvent) containing a catalytic amount of CpCo(CO)2 over 35 h. The extended reaction time was necessary to ensure that all of the benzocyclobutene intermediate (42-2) had participated in the second cyclization event (42-3). The [2+2+2] reaction converted 42-1 to the benzocyclobutene intermediate (42-2), which performs a retro-[2+2] followed by a [4+2] with the pendant alkene.302,303 Over the two transformations, Vollhardt and co-workers were able to synthesize three new rings in a sterically defined trans-anti-trans arrangement in a single operation. The diastereoselectivity of this reaction was attributed to the preferred exo-transition state as a result of steric interference. In a complementary approach, Vollhardt and co-workers began the synthesis of estrone from a functionalized arene (Scheme 43).304,305 Compound 43-1 was treated with a stoichiometric amount of CpCo(CO)2 to catalyze formation of cyclohexadiene 43-2. Subsequent treatment with FeCl3 released the η-4 substrate from the cobalt catalyst. Removal of the ketal, reduction of the diene to the trans-anti-trans ring system (43-3), and cleavage of the methyl ether revealed the steroid estrone (43-4).306 Overall, this second-generation synthesis can be viewed as an improvement upon the prior work in that the BCD ring synthesis is accomplished in a single step. In a 1991 study toward the stemodane-type terpenes, Vollhardt and co-workers demonstrated the application of the [2+2+2] to a bridged bicycle (Scheme 44).307 Cyclization

7. [2+2+2] CYCLOADDITION 7.1. Discovery

One of the first known reports of a [2+2+2] cyclization was published by Marcellin Berthelot in 1866. Berthelot, a chemist made famous for his work on pressurized gas explosions, induced this cyclotrimerization by heating acetylene to 400 °C.291 In 1949, nearly a century later, Reppe and co-workers reported on alkene cyclotrimerizations catalyzed by Ni(PPh3)2(CO)2 at temperatures in a more synthetically useful range of 25−80 °C.292 From the perspective of total synthesis, a mild [2+2+2] reaction is a very attractive disconnection strategy, in one step bringing together three disparate pieces and synthesizing a new ring. In practice, this methodology has been most successfully applied to tethered π systems with an innate steric bias toward the desired regioselectivity. Controlling the regioselectivity of multicomponent reactions has been one of the primary challenges in this area.293,294 In industrial applications, various first-row transition metal catalysts have been employed to induce the cyclotrimerization of butadiene to C12 products.295 11698

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In the same year, Vollhardt and co-workers disclosed the synthesis of an additional natural product, the sesquiterpene illudol (45-3), using the [2+2+2] reaction (Scheme 45).309

Scheme 43. Vollhardt’s Second Synthesis of Estrone

Scheme 45. Vollhardt’s Synthesis of Illudol

Scheme 44. Vollhardt’s Synthesis of Stemodin Here, the acyclic ene-diyne 45-1 was cyclized using CpCo(CO)2. Treatment with CuCl2 released the diene from cobalt coordination and gave the product 45-2 in a yield of 92%. The tricycle (45-2) was formed stereoselectively and in very good yield despite the strained nature of the resulting ring system. During the course of this synthesis, the researchers were pleasantly surprised to find that the desired cyclization occurred readily with two terminal alkynes as comparable substrates had been known to result in post-cyclization hydride shifts. Although the stabilization afforded by the TMS-substituted alkyne is often necessary, here the authors were able to access their desired intermediate (45-2) directly, without further deprotection steps. The complexity building potential of the [2+2+2], illustrated by Vollhardt’s foundational work in this area, has inspired a number of creative applications of the transformation in total synthesis. In a recent example, Ramana and More synthesized a series of cyclopropylallocolchicinoids using this methodology (Scheme 46).310 The cyclization precursor (46-3) was derived from the pentasubstituted arene 46-1, which was functionalized via Simmons−Smith cyclopropanation and Sonogashira coupling. Diyne 46-3 was then treated with 20 mol % CpCo(CO)2 in the presence of methyl propiolate to give product 46-4 as a single regioisomer. Despite the long reaction time, high temperature, and potential sensitivity of the cyclopropane substrates, the [2+2+2] reaction provided product 46-4 in a remarkable 79% yield. The complete regioselectivity with respect to propiolate component is surprising given the mixtures of isomers typically obtained in multicomponent [2+2+2] reactions with unsymmetric acetylene derivatives311 and underscores the challenge in predicting the regiochemical outcome of [2+2+2] cycloadditions.312 In Schmalz’s allocolchicinoid synthesis, diyne 47-3 was treated with 20 mol % CpCo(CO)2 in the presence of a nitrile to form pyridine-fused ring systems (Scheme 47). The regiochemistry of the nitrile incorporation in the [2+2+2] is thought to be dictated by steric factors. The authors propose that the increased steric repulsion of the alkynyl substituent and the R-group of the nitrile biases the system toward orienting the nitrile substituent toward the smaller terminal alkyne.313

precursor (44-5) was synthesized from 1,4-cyclohexadione (441).308 Treatment with CpCo(CO)2 resulted in the formation of the tetracyclic structure 44-6 as a pair of epimers at the peripheral hydroxyl group as well as the Co(I)-bound diene for a combined yield of 59%. A deprotection and several oxidation state manipulations give compound 44-7. The three stereogenic centers generated in the cyclotrimerization event result from the preferred endo-orientation for the reaction between the Co(III)-bound diene and the metal coordinated olefin. 11699

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Scheme 46. Ramana’s Synthesis of Cyclopropylallocolchicinoid

Scheme 48. Siegel’s Synthesis of Complanadine A

Scheme 47. Schmalz’s Synthesis of Allocolchicinoid

(48-6) either. Removal of both TMS-groups with TBAF prior to dimerization resulted in only decomposition upon exposure to the metal catalyst, likely as a result of the reactive terminal alkyne. Reprotection of the alkyne position with TMS was found to generate a viable substrate (48-4) for the [2+2+2] with fragment 48-5. Unfortunately, the product distribution acquired with CpCo(CO)2 was 1:3.3, favoring the undesired regioisomer. Remarkably, an addition of an excess quantity of PPh3 was found to reverse this selectivity to 3:1 toward the desired product 48-4 when paired with a formyl-protected nitrile monomer (48-5). Deiters and co-workers’ total synthesis of illudinine showcases a rare example of a nickel-catalyzed [2+2+2] reaction in the construction of the molecule’s core (Scheme 49).315 Using an electron-deficient diynoate ester fragment (492) and protected homopropargylic amine 49-3, they induce the cycloaddition using Ni(PPh3)2(CO)2 under microwave irradiation.316−318 The disubstituted alkynes of fragment 49-2 are unusual substrates for the reaction; previous reports found that internal alkynes are typically not suitable. Looking back at the origins of this methodology, it becomes apparent that the original Ni(PPh3)2(CO)2 catalyst has not enjoyed the same popularity in total synthesis as the later developed CpCo(CO)2 catalyst.319 The nickel-based system is

Given the structure of Ramana’s cyclization precursor and propiolate fragment, it seems more likely that the regioselectivity observed in that case is a result of electronic, rather than steric factors. These two examples demonstrate that steric and electronic factors, although not completely understood in the context of the [2+2+2], can be used to achieve selective results. In Siegel and co-workers’ 2010 synthesis of complanadine A (Scheme 48), a [2+2+2] pyridine synthesis strategy was applied twice.314 The nitrile 48-2 was treated with CpCo(CO)2, which caused it to undergo a [2+2+2] reaction with bis(trimethylsilyl)butadiyne, yielding the desired regioisomer in a ratio of 25:1. Initially, it seemed plausible this cyclization product (48-3) could go on to perform the “dimerization” with 48-5, but it was found that the reaction did not proceed in situ. Alternative transition metal catalysts such as Ru(COD)Cl2 and Cp2Zr/NiCl2 did not yield the complanadine dimer precursor 11700

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Scheme 49. Deiters’ Synthesis of Illudinine

Scheme 50. Corey’s Synthesis of Antheridic Acid

typically associated with long reaction times, higher levels of polymerization, and is limited to the synthesis of aromatic carbocycles from terminal alkynes.320,321 The order of reactivity observed in these cyclotrimerizations is that acetylenic carbonyl compounds react with greatest readiness, followed by arylalkynes and then alkylalkynes. Disubstituted alkynes are usually inert to the reaction conditions.322 Despite the obvious limitations of the nickel-catalyzed [2+2+2], there have been successful efforts to perform cyclotrimerizations in an enantioselective fashion using Ni(cod)2 and chiral ligands.323 Enantioselective [2+2+2] reactions have only been explored to a limited extent with nickel and with Ti-η6-arene complexes.324 Additionally, the demonstrated ability of (DME)NiBr2 to catalyze [2+2+2+2] alkyne tetramerization positions the metal as an interesting potential mediator of cyclooctatetraene formation in total synthesis.325

acid, Et2AlCl, induced rearrangement to cyclopentene 50-4, which possess the three carbocyclic rings of the natural product 50-5. Corey has also successfully employed the Cu(TBS)2 catalyst in the total synthesis of cafestol in 1987.337 A testament to its versatility, the Corey−Myers catalyst has seen frequent use in total synthesis, including Johnson’s synthesis of polyanthellin A,338 Danishefsky’s syntheses of aplykurodinone-1 and spirotenuipesines A and B,339,340 Fukuyama’s synthesis of Lycopalhine A,341 and many others.342,343 Asymmetric copper carbene chemistry has become a reliable method for enantiodetermining steps in total synthesis. One example of this is found early in Overman’s total synthesis of scopadulcic acid A (Scheme 51).344−347 In the enantiodetermining step, diazoacetate 51-1 was treated with 0.6 mol % of copper complex 51-2 to afford lactone 51-3 with >99% ee. This compound was then elaborated to ketone 51-4, which upon derivatization to the corresponding enoxysilane underwent [3,3]-sigmatropic rearrangement to provide cycloheptanone 51-6 (after desilylation). Subsequently, this cycloheptane was leveraged to form the bicyclo[3.2.1]octane of 51-7 after methylenation of the ketone and a Pd-catalyzed Heck cascade. Nakada’s total synthesis of digitoxigenin cleverly employed asymmetric copper carbene chemistry to access key intermediate 52-4 in an enantioselective fashion (Scheme 52).348−350 Treatment of the prochiral 52-1 with Cu(OTf)2 and ligand 52-2 provided the chiral sulfonylcyclopropane 52-3 in high yield and ee. The cyclopropane ring was then fragmented with lithium thiophenolate, and then both the thiophenyl and the phenylsulfonyl groups were removed with lithium naphthalenide. This desymmetrization sequence allowed Nakada and co-workers to efficiently set the challenging quaternary stereocenter of 52-4. Salvileucalin B, a diterpenoid natural product isolated from Salvia leucantha, possesses an unusual norcaradiene structure at its core. The propensity of norcaradiene moieties to undergo retro-6π-electrocyclizations to form cycloheptatrienes made the isolation of such a structure from nature truly remarkable. In the late 19th century, Buchner had published reports of the reaction of diazocarbonyls with benzene,351,352 although they had only scarcely been employed in total synthesis.353,354 In

8. FIRST-ROW METAL CARBENOIDS 8.1. Copper Carbenoids

The reaction of organic diazo-compounds with metal salts dates back to the late 19th century, with seminal contributions from Sandmeyer326,327 and Gatterman.328 The discovery of the Sandmeyer functionalization of aryl diazonium species with copper(I) salts opened many new avenues of organic synthesis and remains a cost-efficient alternative to many Pd-catalyzed cross-couplings. Gatterman’s discovery of the copper-catalyzed cyclopropanation has been transformative in the field of natural product synthesis. While other reactions, including the Simmons−Smith cyclopropanation,329,330 are perhaps more commonly employed for the construction of simple cyclopropanes, the convenient synthesis of α-diazocarbonyls331 (with sulfonyl azides, for example) has made copper carbenoids a particularly attractive strategy for intramolecular cyclopropanation. In Corey’s 1985 total synthesis of antheridic acid (Scheme 50), bis(N-tert-butylsalicylaldiminato)copper(II) (Cu(TBS)2, 50-2) was found to be a highly active catalyst for intramolecular cyclopropanation.332 The principle advantage of Cu(TBS)2 over inorganic salts or Cu powder is its solubility in organic solvents.333 Enantioselective variants of these catalysts have also been reported by Nozaki and others.334−336 When treated with this copper complex in refluxing toluene, diazoketone 50-1 was efficiently converted to tetracycle 50-3. After 50-3 was obtained, treatment of the vinyl cyclopropane with a Lewis 11701

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Scheme 51. Overman’s Synthesis of Scopadulcic Acid A

Scheme 53. Reisman’s Synthesis of Salvileucalin B

transition metals.356 In the final step of their synthesis, Reisman and co-workers employ another first-row metal-mediated reaction, a C−H oxidation to furnish lactone 53-4 from ether 53-3. In their 2008 synthesis of vigulariol (Scheme 54), Clark and co-workers employed copper carbenes to access a key Scheme 54. Clark’s Synthesis of Vigulariol

Scheme 52. Nakada’s Synthesis of Digitoxigenin

oxocarbenium ion intermediate.357 Diazoketone 54-1, upon treatment with Cu(hfacac)2, reacts to form oxocarbenium 54-2. This reactive intermediate undergoes a [2,3]-Wittig rearrangement to provide the 2-allyl-tetrahydrofuranone core of 54-3, which is then elaborated to the natural product. Clark has demonstrated the generality of this carbene-[2,3] cascade, applying this methodology to the synthesis of numerous members of the cladiellin family,358 macrolides,359 and bicyclic amine scaffolds via ammonium ylides.360

their 2011 total synthesis of salvileucalin B (Scheme 53), Reisman and co-workers successfully developed conditions to access the norcaradiene core.355 Ultimately, it was found that treatment of diazonitrile 53-1 with Cu(hfacac)2 at 120 °C under microwave irradiation provided the hexacyclic core (532) in 65% yield. In their efforts to determine the optimal conditions, it was noted the steric profile of the electronwithdrawing groups stabilizing the diazo- functionality (e.g., a β-ketoester or β-ketonitrile) strongly affected the yield of the desired norcaradiene versus dimerization byproducts. It was also found that Rh catalysts generally favored C−H insertion pathways over the desired cyclopropanation, highlighting the alternative modes of reactivity between first- and second-row

8.2. Chromium Carbenoids

While copper carbenoids are the most common first-row transition metal carbene in organic chemistry, several other first-row transition metals form carbenoids that have been employed in total synthesis. The Wulff−Dötz reaction is a reaction of stoichiometrically formed allylic or benzylic 11702

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chromium carbenoids, which allows access to substituted benzene and napthalene derivatives through a formal [3+2+1] reaction that cyclizes the carbene, an alkene/alkyne, and a CO ligand.361 The immediate product of the reaction is a chromium tricarbonyl arene complex, which can be treated with an oxidant to liberate the arene from the chromium. Often, improved yields are obtained by treatment with CAN, which results in not only oxidation of the chromium species, but also oxidation of the product to the corresponding napthoquinone. In addition to the synthesis of all-carbon aromatic species, group(VI) carbenes can be employed in the synthesis of various O- and N-heterocycles with an appropriate choice of substrates and reagents.362 Semmelhack and co-workers used the Wulff−Dötz reaction to construct a 2,6-disubstituted naphthoquinone as an intermediate en route to nanaomycin A (Scheme 55).363

Scheme 56. Boger’s Synthesis of Fredericamycin A

Scheme 55. Semmelhack’s Synthesis of Nanaomycin A

reagents. Broadly, these reagents are most useful for the olefination of carbonyls and can react even with esters and amides in contrast to Wittig and Horner−Wadsworth− Emmons reagents.371 Because of the general familiarity of the synthetic community with these reactions, we direct readers to existing reviews on these topics.372,373 One intriguing example of the Tebbe reagent in total synthesis can be found in Grubbs’ total synthesis of the sesquiterpenoid Δ(9,12)-capnellene (Scheme 57).374 The formidable cis-anti-cis framework of 57-6 was summited starting from tricycle 57-1, which is the product of a transannular Diels− Alder cycloaddition of a substituted cyclopentadiene. This alkene was treated with the Tebbe reagent, which underwent a [2+2] cycloaddition to afford metallocyclobutane 57-2. Upon heating, carbenoid 57-3 was formed by a retro-[2+2]cycloaddition, and then an intramolecular olefination reaction provided cyclobutene 57-4. After protection of the masked cyclobutanone, acetal 57-5 was obtained in 81% yield. The synthesis of the natural product was completed by oxidative cleavage of the pendant vinyl group, reduction to the corresponding alcohol, a two-step ring expansion sequence, and finally the Tebbe reagent was employed again to install the exocyclic methylene of the natural product, 57-6.

Initially, efforts to employ a disubstituted alkyne were stymied by the preference of chromium carbene 55-1 to add to the least substituted position of the alkyne. Therefore, attempts to introduce a PMB protected 1-hydroxyethyl substituent at this point in the synthesis produced only undesired regioisomers. This roadblock was circumvented using terminal alkyne 55-2, which provided napthoquinone 55-3 as a single regioisomer after oxidation with CAN. The 1-hydroxyethyl functionality required at C3 to form the dihydropyran ring was introduced by bromination, lithium−halogen exchange, and trapping with acetaldehyde. To address the challenging pattern of functionalization found on fredericamycin A’s hexacyclic scaffold, Boger and co-workers also turned to the Wulff−Dötz reaction (Scheme 56).364 After constructing the pyridine-containing DEF fragment and installing an alkyne handle, treatment of alkyne 56-1 with chromium carbene 56-2 resulted in the formation of benzannulated product 56-3 in 35% yield. The difference in steric bulk between the secondary and primary TBS ethers of 56-1 was sufficient to provide 56-3 as only a single regioisomer. With 56-3 in hand, an oxidation-aldol-oxidation sequence completes the construction of the natural product skeleton.

9. THE KHARASCH REACTION AND C−H FUNCTIONALIZATION 9.1. Allylic Functionalization

The selective oxidation of C−H bonds to C−O, C−N, and C− C bonds is an active area of research whose impacts on chemical synthesis cannot be understated.375−382 To date, investigations of metal catalysts from all three rows have proved exceptionally fruitful.383−404 In addition to being profoundly impactful in natural product synthesis, the development of catalysts for the selective oxidation of feedstock chemicals would have a profound impact. The general propensity of firstrow transition metals to undergo single-electron trans-

8.3. Schrock Carbenes

Schrock carbenes, or triplet carbenes, are found with poorly stabilized carbenes and early transition metals of high oxidations states.365−368 In the field of natural product synthesis, perhaps the most common examples of first-row metal Schrock carbenes are observed with Ti(IV) reagents. Common examples include the Tebbe369 and Petasis370 11703

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Scheme 57. Grubbs’ Synthesis of Δ(9,12)-Capnellene

Scheme 58. Mukaiyama’s Synthesis of Taxol

In addition to copper(I) catalysts, low-valent chromium reagents have also proven to be useful for Kharasch-type functionalizations. In Shing’s 2000 total synthesis of the terpene quassin (Scheme 59), the discovery of optimal allylic oxidation Scheme 59. Shing’s Synthesis of Quassin formations has led to the discovery of C−H functionalization reactions using V,405−410 Cr,411,412 Mn,413−417 Fe,418−429 Co,430,431 Ni,432−440 and Cu.441−446 The oxidation of allylic C−H bonds with quinones, SeO2, Nhalo compounds, and molecular oxygen (terpene autoxidation) has been known since the early 20th century.447 This reactivity is due to weakening of allylic and benzylic C−H bonds by 16.4−16.7 kcal/mol,448 which is generally interpreted as arising from either the stereoelectronic effect of weakening the C−H bond by the neighboring double bond or through the stabilization of the intermediate radical or cation in the allyl system. In the late 1950s, Kharasch and Sosnovsky observed that in the presence of Cu(II) or Co(II) salts, olefins would react with t-butyl perbenzoate to provide allylic benzoates.441,442 The authors noted a marked selectivity in favor of the terminal alkene product (when applicable), while a comparable reaction with benzoyl peroxide and cyclohexene provided mixtures of olefin addition and allylic oxidation products. This discovery, now known as the Kharasch− Sosnovsky reaction, was the first of many synthetically valuable allylic functionalizations that employed first-row transition metals. Mukaiyama’s 1999 total synthesis of Taxol made use of the Kharasch reaction to install an oxidation on the Taxol C-ring (Scheme 58).449 Treatment of 58-1 with an excess of both CuBr and PhCO3tBu (in a 1:1 molar ratio of the two reagents) afforded a mixture of 58-2 and 58-3. After separation of the two bromides, Mukaiyama and co-workers were then able to isomerize 58-2 to 58-3 with CuBr in MeCN at 50 °C. Efficient installation of the reactive allylic bromide 58-3 from the relatively inert alkene 58-1 was crucial to the success of Mukaiyama’s synthesis as the allylic bromide provided the handle necessary to construct the oxetane D ring of 58-4.

conditions was crucial to the completion of the highly oxidized tetracyclic core. Attempts to oxidize the A-ring in the presence of the D-ring lactone with various Cr reagents or SeO2 were unsuccessful. Ultimately, a successful route to quassin required late-stage installation of the D-ring lactone, which was masked as silyl ether 59-1 during the allylic oxidation. Shing and coworkers found that Pearson’s Cr(CO)6/t-BuOOH conditions were able to provide 59-2 in 78% yield from alkene 59-1.450,451 The authors then employed another first-row transition metalmediated reaction to provide 59-3 by α-oxidation of the newly installed ketone with Mn(OAc)3. In their 1993 synthesis of oleanolic acid (Scheme 60), Corey and co-workers employed the Kharasch reaction in a unique way to access 60-3. Treatment of vinylcyclopropane 60-1 with 11704

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Allylic oxidation can also be effected with common Cr(VI) reagents such as PCC. Nicolaou and co-workers employed the Kharasch reaction to functionalize the taxol A-ring in their 1994 total synthesis (Scheme 62).453 After opening carbonate 62-1

Scheme 60. Corey’s Synthesis of Oleanolic Acid

Scheme 62. Nicolaou’s Synthesis of Taxol

CuBr and tert-butyl perbenzoate resulted in abstraction of a hydrogen atom from C11 to form allylic radical 60-2. The allylic radical then was transformed to 60-3 by homolytic cleavage of the cyclopropane ring and recombination of the resultant primary and benzyloxy radicals. This unique combination of the Kharasch reaction and the Simmons− Smith cyclopropanation to install the cyclopropyl group in 60-1 allowed the installation of an oxidized methyl group in an efficient and stereoselective fashion. The site-selective oxidation of the steroidal scaffold is a significant challenge in the total synthesis of steroids and related terpenes. Yamashita, Hayashi, Hirama, and co-workers employed the Kharasch reaction to install the C-7 oxidation in limonin (Scheme 61).452 Treatment of 61-1 with CuBr and tBuOOH afforded the C-7 ketone in 77% yield after two cycles. This ketone was then converted to the protected α-alcohol 613, before reoxidation to complete the natural product 61-4.

to the corresponding monoprotected diol 62-2, a Kharasch allylic oxidation provides enone 62-3. Notably, this reaction proceeds in high yield despite the many other sites at which an oxidation could be envisioned, including the oxetane D ring. In 2016, Siegel and co-workers masterfully utilized Cr(VI) allylic oxidations to install two oxidations simultaneously in their total synthesis of eupalinilide E (Scheme 63).454,455 While Scheme 63. Siegel’s Synthesis of Eupalinilide E

Scheme 61. Yamashita, Hayashi, and Hirama’s Synthesis of Limonin

63-2 has seven allylic sites at which a C−H oxidation could occur, Siegel and co-workers could successfully obtain the enone/enoate 63-3 in 36% yield on gram scale. This reagent can also be employed in the context of alkaloid synthesis, for example, in Martin’s synthesis of macrocyclic marine alkaloid manzamine A.456 11705

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Reddy and co-workers utilized allylic oxidation with Mn(OAc)3·2H2O to install two oxidations simultaneously en route to nardoaristolone B (Scheme 64).457 Bicyclic hydro-

Scheme 65. Movassaghi’s Synthesis of 11,11′Dideoxyverticillin A

Scheme 64. Reddy’s Synthesis of Nardoaristolone B

carbon 64-1 was obtained following the Diels−Alder reaction of tiglic aldehyde with a diene partner (not shown) and installation of both terminal alkene moieties. Ring-closing metathesis then provided 1,5-diene 64-2. Treatment of diene 64-2 with Mn(OAc)3·2H2O afforded a mixture of 64-3 and mono-oxidized products, which were isolated and resubjected to the reaction conditions to provide 64-3 in a total yield of 61%. Finally, selective cyclopropanation of the cyclopentenone under Corey−Chaykovsky conditions provides the natural product 64-4. One key feature of this reaction is the transposition of the alkene from cyclohexene 64-2 to cyclohexenone 64-3. This step-efficient isomerization/oxidation enables the use of a cycloaddition strategy to assemble cyclohexene 64-1 as a precursor to 64-4, even though it possesses a different unsaturation, which at first glance is less amenable to a direct Diels−Alder disconnection. Movassaghi and co-workers have employed Mn-initiated hydroxylation to install four alcohols in a single step in their landmark 2009 total synthesis of (+)-11,11-dideoxyverticillin A (Scheme 65).119 After cobalt-mediated reductive dimerization of benzylic bromide 65-1, installation of the four hydroxyl groups of 65-3 was desired. On the basis of a monomeric indole model system (not shown), n-Bu4MnO4 was initially selected as the reagent of choice. Despite success in model studies, treatment of 65-2 with n-Bu4MnO4 provided only 40% of the desired 65-3 as a mixture of hemiaminal diastereomers. This problem was solved with the application of bis(pyridine)silver(I) permanganate, which afforded tetraol 65-3 as a single diastereomer in 63% yield. The selectivity of this transformation is ascribed to a fast-abstraction rebound mechanism.458,459 The installation of these four hydroxyl groups provided handles for the installation of the disulfide bridges of the natural product 65-4. Baran and co-worker’s synthesis of taxuyunnanine D employed a number of exquisitely selective C−H oxidations and serves as a showcase of their cyclase phase/oxidase phase approach to terpene synthesis (Scheme 66).460 Attempts to install the C13 enone via traditional Cr(VI) reagents provided low yields of 66-5 along with byproducts deriving from epoxidation and cleavage of the D-ring alkene. However, Baran

Scheme 66. Baran’s Synthesis of Taxuyunnanine D

and co-workers discovered that Cr(V) compounds such as 662, which had shown reduced propensity for diol cleavage,461 were effective in selectively installing the D-ring enone. Baran and co-workers propose that this reaction proceeds via a single electron transfer mechanism. Nicolaou and co-workers have used allylic oxidation in the final steps of the total synthesis of marine ladder polyether brevetoxin B (Scheme 67).462−464 After completing the entirety of the ladder polyether framework, Nicolaou and co-workers needed to install the A-ring enoate of 67-2. Remarkably, installation of the A-ring enone proceeded in 85% yield with PCC despite the presence of potentially competitive allylic sites 11706

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and subsequent nucleophilic addition of the carboxylate provided lactone 68-3 in 92% yield. Nicolaou and co-workers have also employed this simplifying strategy in their syntheses of aspidophytine and haplophytine.466,467

Scheme 67. Nicolaou’s Synthesis of Brevetoxin B

9.2. Unactivated C−H Bond Oxidation

In contrast to the oxidation of allylic C−H bonds, the oxidation of unactivated C−H bonds is considerably less common in total synthesis. Because of the ubiquity of C−H bonds in complex molecules, highly chemoselective methods are required to obtain synthetically useful yields when many nonequivalent C− H bonds are available for reaction. Brown and co-workers envisioned a C−H oxidation to construct the final lactone of gracilioether F (Scheme 69).468 Powerful oxidants such as Scheme 69. Brown’s Synthesis of Gracilioether F

in the eight-membered H-ring of 67-1, presumably due to the presence of the additional activation afforded by the ethereal oxygen atom. To complete the polycyclic scaffold of aspidophytine, Corey and co-workers utilized an intramolecular lactonization reaction with K3Fe(CN)6 to install the lactone functionality (Scheme 68).465 After saponification of 68-1 to provide free acid 68-2, oxidation of the tertiary amine to the corresponding iminium

RuO4 and TFDO failed to provide significant yields of 69-4. Additionally, simple first-row transition metal acetates such as Fe(OAc)2 and Mn(OAc)2 with H2O2 also failed to produce 694. Instead, utilizing Cu(OAc)2 in MeCN provided up to 15% of the desired natural product 69-4. Decreasing the reaction temperature to 0 °C afforded 10% of 69-4 and 88% of recovered 69-3. In their total synthesis of cyclopamine (Scheme 70),469 Giannis and co-workers used the directed C−H oxidation reaction developed by Schönecker to install a C12 hydroxyl group on dehydroepiandrosterone 70-1.470 This transformation was enabled by the formation of picolinyl imine 70-3 after benzyl protection of the C3 alcohol. Treatment of the imine with Cu(I) and O2 followed by removal of the directing group provides the C12 alcohol in 48% yield. This alcohol functionality was then employed to rearrange the androsterone 6-6-6-5 skeleton to the cyclopamine 6-6-5-6 ring system. The Schönecker oxidation has also been employed in the total syntheses of cephalostatin 1 by Shair,471 and in the synthesis of several polyoxypregnanes by Baran, who has also extensively investigated and improved this methodology.472 Recently, Burns and co-workers have disclosed a synthesis of [5]-ladderanoic acid and several related ladderane lipids and phospholipids, which employs a number of remarkable first-row metal-catalyzed reactions (Scheme 71).473−475 These lipids present a formidable synthetic challenge due to their strained architectures and lack of obvious handles for retrosynthetic

Scheme 68. Corey’s Synthesis of Aspidophytine

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Maimone and co-workers have recently employed iron catalysis to effect a key C−H oxidation in their synthesis of pseudoanisatin (Scheme 72).478 Presented with bicyclic acid

Scheme 70. Giannis’ Synthesis of Cyclopamine

Scheme 72. Maimone’s Synthesis of Pseudoanisatin

72-1, Maimone and co-workers were faced with the daunting challenge of functionalizing a doubly neopentyl tertiary C−H bond in the presence of numerous other C−H bonds activated by α-heteroatoms. To realize this simplifying disconnection, the presence of directing functionality was leveraged. When treated with Costas’ catalyst (72-2),479 a putative directed C−H oxidation product (72-3) was obtained in addition to methyl and silyl ether cleavage products (not shown). The authors note that, while thallium(I) triflate was not required for C−H cleavage, significant improvement to the yield were observed with this additive. In addition to iron catalysis, Maimone and co-workers also employ a Cu-mediated lactone formation (not shown) in the preparation of 72-1.

Scheme 71. Burns’ Synthesis of [5]-Ladderanoic Acid

9.3. Biomimetic C−H Oxidation

The cytochrome P450 family is found in all forms of life, and plays a pivotal role in the metabolism of drugs and other molecules, commonly through C−H hydroxylation.480,481 These enzymes contain at their active sites a single iron atom surrounded by a heme with an axial cysteine ligand. Recently, much progress has been made in the field of directed evolution of P450s and other enzymes to control their activity for synthetically useful transformations.482−485 In the mid 20th century, however, this chemistry inspired a great deal of interest in biomimetic C−H hydroxylation reactions with nonenzymatic metal catalysts. Pre-eminent in this field is Nobel Laureate Derek Barton’s work, which has become known as Gif and GoAgg chemistry (named after their sites of discovery: Gif-surYvette, France and Texas A&M, respectively). The first generation of Gif chemistry, initially disclosed in 1983,486 used iron powder, sodium sulfide, acetic acid, and oxygen to oxidize adamantane with pyridine as solvent. The mechanism of Gif oxidation of adamantane has been the subject of much study.487,488 To the best of our knowledge, Barton’s exact Gif and GoAgg methodology has not directly been employed in the synthesis of natural products. Regardless, the derivatization of natural products with metal-catalyzed C−H activation has become an active area of research. While P450s are the among most ubiquitous, there are many other biosynthetically important first-row-metalloenzymes, including nonheme irondependent oxygenases and copper-dependent tyrosinases.489

disconnection. Pentacycle 71-1 was accessed via Kochi’s Cucatalyzed photo-[2+2] cycloaddition of bicyclohexene (not shown) conducted in frozen benzene.476 At this point, functionalization of the hydrocarbon skeleton was required to proceed with the synthesis. Burns and co-workers found that Groves’ Mn(TMP)Cl catalyst was optimal for inducing C−H chlorination to provide alkyl chloride 71-2.417 Elimination of this chloride smoothly afforded meso-alkene 71-3 in 90% yield. Desymmetrization of this alkene was accomplished with yet another first-row transition metal-catalyzed reaction, a coppercatalyzed enantioselective hydroboration.477 This organoboron species was then employed in a Zweifel olefination to install the pendant fatty acid chain. In the same report, Burns and coworkers also synthesize [3]-ladderanol (not shown) using a remarkable Cu-mediated hydrazone oxidation. 11708

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Work into elucidating their structures and mechanisms is ongoing.

kopsijasminilam (Scheme 74).498 In their synthesis, hemiaminal 74-1 was accessed by a sequence involving a Tf2O-induced

10. THE MUKAIYAMA HYDRATION

Scheme 74. Magnus’ Synthesis of Kopsijasminilam

10.1. Discovery and Mechanism

In 1989, Isayama and Mukaiyama first disclosed the cobaltmediated radical hydration of alkenes, which would come to be known as the Mukaiyama hydration.490 Using 5 mol % of Co(acac)2 and an excess of phenylsilane, Markovnikov hydration products could be obtained via a net redox-neutral oxidation−reduction process. It was postulated that the reaction pathway involved a Co(II)/Co(III) cycle and the intermediacy of a cobalt peroxide formed by the reaction of cobalt, molecular oxygen, and the silane reductant. In contrast to other cobalt-catalyzed hydrations disclosed by Mukaiyama and co-workers,491−493 employing silane reductants (as opposed to secondary alcohols) allowed the reaction to be performed without heating. In the decades following its discovery, the Mukaiyama hydration has become a mainstay in natural product synthesis due to its mild conditions, the accessibility of olefin starting materials, and its redox neutral nature.494 Simultaneously, this work has inspired the development of several metal-catalyzed olefin hydrofunctionalizations; we direct readers interested in a focused discussion of these transformations to a recent review written by Shenvi and coworkers.495 Early investigations by Mukaiyama and co-workers suggested the intermediacy of a cobalt peroxide species such as 73-5 in the mechanism of the Mukaiyama hydration. 496 Later investigations by Nojima and co-workers supported this hypothesis and were unable to demonstrate C−O bond formation by direct alkene insertion into the Co−O bond.497 Rather, the presence of a discrete radical mechanism (Scheme 73) was supported by the observation of ring-opening when vinylcyclopropane radical clocks (not shown) were employed.

cyclization of a macrocyclic N-carboxyphenyl tryptamine (not shown) and Diels−Alder cycloaddition to form the bicyclo[2.2.2]octane core. The hemiaminal functionality was then converted to amide 74-2 after oxidation of the tertiary amine, activation of the N-oxide with TFAA, and Grob fragmentation. Magnus and co-workers then were able to access kopsijasminilam (74-3) with a Mukaiyama hydration of the resultant diene. Notably, resubjection of 74-3 to Mn(dpm)3, PhSiH3, and O2 at 25 °C led to 1,4-reduction of the enoate followed by fragmentation of the putative manganese enolate. In the first reported synthesis of cortistatin A, Baran and coworkers employed two different cobalt-mediated reactions to elaborate the highly oxidized A-ring of the natural product (Scheme 75).499,500 Protected steroid 75-1, available in two steps from prednisone, was subjected to nucleophilic epoxidation, reductive amination, and cobalt-assisted epoxide opening (for Jacobsen’s enantioselective variant, see section 14) to provide allylic carbamate 75-2. Mukaiyama hydration of 75-2 with triethylorthoformate resulted in single-pot formation of orthoamide 75-3. The stereoselectivity of this key C5 oxidation was strongly influenced by the A-ring substituents. The stereochemical course of this reaction has been rationalized by the proposal that the most stable trans-decalin radical leads to the observed product. When the A-ring epoxide intermediate (not shown) was subjected to identical Mukaiyama hydration conditions, the undesired β-alcohol was preferred by a 5:1 ratio. In contrast to this approach, the subsequent total syntheses of cortistatin A by Myers, Nicolaou/Chen, Funk, and Hirama install the A-ring oxidations in final steps of their syntheses; Shair and co-workers cyclize the A-ring with the oxygenations already installed.501−507 Ryanodol (76-3), first described in 1951,508 is a hydrolysis product of ryanodine (not shown), which was first isolated in 1948 from Ryania speciose.509 Since their isolation, ryanoids have been attractive targets not only due to their potent binding to calcium receptors in skeletal muscles,510 but also due to their densely functionalized structure. The complexity of this structure has engendered numerous studies toward including three completed total syntheses by Deslongchamps,511

10.2. Examples in Total Synthesis

An early example of the Mukaiyama hydration in natural product synthesis is found in Magnus’ 2002 synthesis of Scheme 73. Proposed Mechanism of the Mukaiyama Hydration

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Maimone’s highly efficient four-step synthesis of cardamom peroxide employs a Mn-mediated hydroperoxidation cascade to install both the endoperoxide and the tertiary alcohol oxidations in a single step (Scheme 77).514 Enedione 77-1

Scheme 75. Baran’s Synthesis of Cortistatin A

Scheme 77. Maimone’s Total Synthesis of Cardamom Peroxide

was prepared by McMurry coupling of (−)-myrtenal followed by a singlet oxygen [4+2]/Kornblum−DeLaMare rearrangement and DMP oxidation. Treatment of this ene-dione with Mn(dpm)3, tert-butyl hydroperoxide, and phenylsilane under an atmosphere of oxygen provided diperoxide 77-2, which could be selectively reduced to the natural product 77-3 with triphenylphosphine in the same pot. Maimone and co-workers noted that cobalt- and iron-based catalysts were incapable of inducing the desired transformation. Additionally, it was observed that slow addition of phenylsilane and the incorporation of tert-butyl hydroperoxide to the reaction mixture resulted in enhanced and reproducible yields of 77-3. In the course of synthesizing a number of atisane monoterpene indole alkaloids (Scheme 78), Zhu and coworkers found that Mn(dpm)3 was capable of effecting the

Inoue,512 and Reisman.513 The numerous sites of oxygenation underscore the need for regio- and stereoselective methods of C−O bond formation. To this end, Inoue employed the Mukaiyama hydration to install the C15 oxygenation from olefin 76-1 (Scheme 76). Treatment of the olefin with Scheme 76. Inoue’s Total Synthesis of Ryanodol

Scheme 78. Zhu’s Synthesis of Scholarisine G

Co(acac)2, tert-butyl hydroperoxide, and triethylsilane under oxygen atmosphere provided silyl peroxide 76-2, which was then taken directly to the corresponding perfluorobutylsulfonyl peroxide. Conveniently, elimination of the sulfonate was observed under the reaction conditions, which led to the formation of the C15 ketone and thus bis-hemiacetal 76-3 during silica gel chromatography. 11710

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transformation of melodinine E (78-1) to scholarisine G (784).515 The reverse transformation, that of 78-4 to 78-1, could be accomplished in a straightforward fashion with MsCl and NEt3. However, initial attempts to synthesize leuconodine A (78-5) from 78-1 by reduction and α-oxidation were stymied by the facile enolization of the C2 amide. In an attempt to access 78-5 from 78-1 by Mn-mediated 1,4-reduction and enolate oxidation, 78-4 was unexpectedly obtained. Reduction of the enamide and elimination of the aniline provided enamine 78-2. This intermediate underwent oxidation and trapping to provide scholarisine G (78-4) in 90% yield. Ultimately, Zhu and co-workers were able to obtain leuconodine A (78-5) via a copper-promoted elimination-addition sequence with TFA, which proceeds through an α-trifluoroacetoxy amide. In their synthesis of the previously assigned structure of banyaside B, Carreira and co-workers apply a highly regioselective Mukaiyama hydration516−521 to decorate the azabicyclononane core (Scheme 79).522,523 After obtaining

Scheme 80. Qin’s Total Synthesis of Crotobarin

The bisindole alkaloids vinblastine (81-4) and vincristine (not shown) are potent inhibitors of microtubule formation.525 For this reason, they are widely used to treat various cancers. Biosynthetically, they arise from the oxidative coupling of two monomeric alkaloids, vindoline (81-2) and catharanthine (811), with a further alkene hydration affording vinblastine (Scheme 81).526 Their potent bioactivity has inspired

Scheme 79. Carreira’s Synthesis of the Nominal Structure of Banyaside B

Scheme 81. Boger’s Total Synthesis of Vinblastine

tricycle 79-1, hydration of the cyclic alkene was envisioned to lead to diol 79-2. Remarkably, Carreira and co-workers found Mn(dpm)3 to be an efficient catalyst of this transformation. The unprotected axial hydroxyl group was also found to be necessary for this reaction, as acylated analogues failed to participate in the desired hydration. Other strategies, such as epoxidation−reduction and hydroboration−oxidation were also unsuccessful despite the investigation of a plethora of reagents and conditions. After completing the synthesis of 79-3, Carreira and co-workers have proposed that the true structure of banyaside B consists of the C9 glycosylation product as opposed to the C7 glycosylated 79-3. In Qin’s 2015 synthesis of crotobarin, a double Mukaiyama hydration was used to install two alcohol functionalities in a single step (Scheme 80).524 When 80-2 was treated with Mn(dpm)3, phenylsilane, and oxygen at 0 °C, the selective monohydration of the trisubstituted alkene (not shown) could be obtained. Warming the reaction to room temperature promoted the subsequent hydration of the disubstituted alkene and formation of diol 80-3 in 43% yield. Alternative catalysts such as Co(acac)2 and Fe(acac)3 provided inferior yields or no detectable 80-3, respectively.

numerous synthetic investigations by Boger and others.527−531 Among Boger’s remarkable contributions to this area was the development of the iron-catalyzed alkene hydration modeled on that of anhydrovinblastine to vinblastine (81-4) and leurosidine (81-5).532−536 Despite the success of this challenging coupling, routes to the fully oxidized vinblastine skeleton required five or more synthetic steps starting from the monomeric indoles.537,538 To address this problem, Boger and co-workers developed the first one-pot dimerization-oxidation procedure to access vinblastine from its monomeric precursors. In their novel procedure, reduction of iminium 81-3 along with olefin hydration of the alkene afforded a 5:2 mixture of vinblastine 11711

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tions to other reagents (Scheme 84).547 In their efforts to obtain the natural product 84-4, Carreira and co-workers

(81-4) and leurosidine (81-5) in a single step from 81-1 and 81-2. 10.3. Related Alkene Hydrofunctionalizations

Scheme 84. Carreira’s Total Synthesis of Hippolachnin A

To synthesize the natural stereochemical configuration of (+)-7,20-diisocyanoadociane, Shenvi and co-workers utilized a Mn(dpm)3-mediated radical alkene reduction (Scheme 82).539 Scheme 82. Shenvi’s Synthesis of 7,20-Diisocyanoadociane

needed to install the exo-oriented ethyl group at C10. When bicycle 84-1 was treated with Fe(acac)3 and phenylsilane, reductive coupling afforded C10 endo product 84-2. While this was not the desired orientation, it is worth noting the exquisite selectivity of first-row metal reductants with this system. When 84-3 was obtained via Lewis acid-mediated cyclization, 84-3 could be converted to the fully reduced compound, 84-2, using Mn(dpm)3, phenylsilane, and t-BuO2H in isopropanol. Other first-row catalysts such as Co(acac)2 and Fe(acac)3 provided similar diastereoselectivity, albeit at lower yield. Heterogeneous precious metal catalysts provided mixtures of diastereomers in all reported cases. Pronin and co-workers have employed a related ironmediated olefin hydroalkylation in the synthesis of emindole SB (Scheme 85).548 After obtaining hemiaminal 85-2 by Parikh−Doering oxidation from diol 85-1, a reductive cascade was initiated by Fe(acac)3 and PhSiH2(O-i-Pr). The reaction commenced with HAT to the 1,1-disubstituted alkene followed by 1,4-addition into the pendant enone. On related structures, which lacked an indole (not shown) and thus possessed a second aldehyde instead of a hemiaminal, a subsequent 1,2-

This hydrogen atom transfer chemistry, developed by Shenvi and Herzon,540−544 presents an attractive alternative to dissolving metal reductions, which also obtain thermodynamically favored reduction products, but suffer from poor chemoselectivity and require hazardous reagents. In the specific case of the transformation of 82-2 to 82-3, Shenvi and coworkers found that noble metal catalysts induced isomerization of the alkene, and subsequent reduction formed the undesired diastereomer. When Mn(dpm)3 was employed in concert with t-BuO2H and PhSiH3, the desired thermodynamic transreduction product was obtained as the major diastereomer. In contrast to Birch-type conditions, ketone and ester functionalities were well tolerated during this reaction. Krische has employed Shenvi’s conditions to complete the synthesis of isoiresin (Scheme 83).545 Diol 83-1 was subjected

Scheme 85. Pronin’s Synthesis of Emindole SB

Scheme 83. Krische’s Synthesis of Isoiresin

to Fétizon oxidative lactonization546 and then Shenvi’s reduction conditions to afford the natural product 83-2. Notably, the reduction occurs with excellent chemoselectivity for the less substituted olefin as opposed to reduction of the more electron-poor butenolide. The observed trans-decalin product is consistent with the expected formation of the thermodynamic reduction product. Carreira’s synthesis of hippolachnin A is an exemplary case of the complementarity of first-row metal-mediated transforma11712

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synthesize substituted lactones.556 It was noted that use of reactive acids like cyanoacetic acid allowed for lower temperatures (50 °C) and obviated the need for a buffering carboxylate. Kurosawa later discovered the double cyclization reaction of malonic acid with olefins to form [4.4] spirocyclic systems.557 Corey and co-workers demonstrated the potential applicability of this transformation to natural product synthesis by developing a lactonization using β-ketoacids, which enabled the rapid synthesis of complex polycyclic structures such as 86-10 under very mild conditions.558,559 One of the first examples of this lactonization strategy in total synthesis is described in Paquette and co-worker’s 1987 synthesis of 14-epi-upial (Scheme 87).560 Using a Mn(III)-

addition into this aldehyde was observed. Other Fe(III) reagents as well as Co(III) and Mn(III) reagents generally favored the formation of 1,4-reduction byproducts. The hydration and hydrofunctionalization of olefins comprise one of the oldest classes of organic reactions. Traditional methods have generally required strong acids, harsh reductants, or toxic heavy metals. The work of Mukaiyama and others has enabled these textbook transformations to be conducted under mild and neutral conditions, broadly expanding the functional group tolerance of this reaction class. Additionally, metal-mediated H atom addition into olefins has become a starting point for numerous new and useful synthetic methods including not only olefin hydration, but also reduction,540−544 hydroamination,549 hydroazidation,516,498 hydrocyanation,520 hydromethylation,550 hydroarylation,544,551,552 and many others. The scope of this methodology shows great promise for its use by the synthetic community.

Scheme 87. Paquette’s Synthesis of 14-epi-Upial

11. OXIDATIVE COUPLING 11.1. Enolate−Alkene Coupling

Carbon−carbon double bonds are a ubiquitous handle in synthetic organic chemistry. In the late 1960s, Bush and Finkbeiner553 and Heiba and Dessau554,555 independently discovered the formal [3+2] reactions of manganese acetate with acetic acid and alkenes to synthesize γ-lactones (Scheme 86). Heiba and Dessau continued to investigate this reactivity, and later discovered the related reaction of α-substituted or disubstituted acids (and their carboxylate salts) with alkenes to Scheme 86. Early Oxidative Enolate−Alkene Coupling

initiated oxidative cyclization of potassium salt 87-1, they were able to synthesize not only the strained bicyclic carbon framework of the target (87-2), but also the requisite lactone in a single step. However, efforts to complete the synthesis of natural diastereomer (87-5), which has a β-oriented methyl group at C-14, were hampered by the steric interaction of the C-14 methyl group with the one carbon bridge (87-4). While Paquette and co-workers were able to isolate 14-β-Me epimer in 9% yield, the significant degree of polymerization precluded synthesis of the natural diastereomer. Corey and co-workers have employed this powerful transformation to great success in their 1993 synthesis of paeoniflorin (Scheme 88).561 In this reaction, cyanoacetic acid (88-2) was added regioselectively across enoxysilane 88-1, with the lactone formed after oxidation of the α-silyloxy radical to the corresponding oxonium ion. Oxidation of 88-1 to mcresol was observed as a byproduct in this transformation. The cyclohexene-fused γ-lactone formed in this reaction contains all of the carbon atoms in the right-hand terpenoid fragment of the target structure. Notably, Corey uses the nitrile group in 88-2 not only out of necessity for the cyclization, but also elaborates this group into the pendant benzyloxymethylene group in 88-5. In 1989, White and co-workers employed a Mn/Cumediated β-ketoester cyclization in their construction of the [4.3.1] bicyclic core of dihydropallescensin D (Scheme 89).562 After a 7-endo-trig cyclization, the resultant tertiary radical was 11713

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Scheme 88. Corey’s Synthesis of Paeoniflorin

Scheme 90. Prunet’s Studies toward Hexacyclinic Acid

Scheme 89. White’s Synthesis of Dihydropallescensin D

Scheme 91. George’s Synthesis of Yezo’otogirin A

oxidized by Cu(OAc)2, and a proton was eliminated to form the exocyclic alkene of the bicyclic motif. This mode of reactivity complements the use of a carboxylate salt or acid to produce a lactone as in the two previous examples. After obtaining bicycle 89-2, White and co-workers advanced the βketoester to a propargylic alcohol and employed the Miller furan synthesis to complete the natural product 89-4.563 This retrosynthetic disconnection of the electron-rich furan to a βketoester was key in enabling the radical synthesis of the [4.3.1] bicycle. In their 2008 studies toward the synthesis of complex polyketide hexacyclinic acid (Scheme 90), Prunet and coworkers applied a similar oxidative radical ring closure.564 In the course of developing this cyclization, it was noted that while starting material 90-1 underwent cyclization to 90-2 nicely, its epimer 90-4 resulted only in decomposition. In George’s 2014 synthesis of yezo’otogirin A (91-5), the importance of the copper oxidant’s counterion was demonstrated (Scheme 91).565 Following the precedent of Kochi566 and Burton567−570 who had elucidated some of the effects of the copper species on product distributions, it was concluded that copper(II) sources bearing noncoordinating counterions were more likely to provide net oxidative substitution rather than alkene formation via syn-elimination of a hydrogen atom. Ultimately it was found that Mn(OAc)3/Cu(OTf)2 in DMF was “essential” to the success of the reaction, while other oxidants and solvents failed to provide the desired product. George and co-workers found that avoiding secondary steric

interactions in the cyclization transition state was critical, as the C-6 epimer of 91-1 (not shown) failed to undergo the analogous cyclization to 91-5. The biomimetic cyclization of polyenes to rapidly form multiple rings and stereocenters is a cornerstone in the synthesis of terpene natural products. In nature, these transformations are initiated by Brønsted acid catalysis provided by enzymes. Ex vivo, among other methods, these reactions can be initiated by first-row transition metals and can proceed through a one-electron pathway in addition to the aforementioned “cationic” pathways. In the mid-1960s, pioneering work by Breslow and co-workers571 resulted in the cyclization of farnesyl acetate, constructing two C−C bonds and five stereocenters in one step. Over the next several decades, Mn(III) salts, particularly Mn(OAc)3 (in the anhydrous or hydrated form), became mainstays in the toolbox 11714

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of synthetic chemists for radical additions and functionalization of olefins. In 1985, Snider and co-workers employed a β-ketoester cyclization in their formal synthesis of podocarpic acid (92-3) (Scheme 92).572 After the first 6-endo-trig cyclization, the

Scheme 93. Yamashita, Hayashi, and Hirama’s Synthesis of Limonin

Scheme 92. Snider’s Synthesis of Podocarpic Acid

Scheme 94. Snider’s Synthesis of Isosteviol

resultant tertiary radical adds into the arene to form a second C−C bond before undergoing oxidation and deprotonation to restore aromaticity (92-2). Welch and co-workers have reported the synthesis of 92-3 from tricycle 92-2 in a further six steps.573 Snider and co-workers noted that the C4 stereochemistry of 92-2 was set by equilibration of the product rather than during the reaction. To better understand the reaction mechanism, Snider and co-workers synthesized 92-4, which cannot undergo such equilibration. Observing the axial ester substituent, the authors propose that “the cyclization proceeds via an extended enol radical to form ring A in the chair form or via an enol radical in the U form to form ring A as a boat.” Tricycle (92-4) has also been reported as an intermediate in the synthesis of podocarpic acid (92-3).574 Later, Snider revisited this synthesis and was able to obtain the natural product in enantioenriched form by means of a (+)-phenylmenthyl ester, which provided the desired diastereomer in 10:1 dr.575 As radical formation of 2-substituted-1,3-dicarbonyls is more facile than corresponding unsubstituted 1,3-dicarbonyls, overoxidation of cyclization products can be problematic. Carbonyls with a single α-chloro substituents are often employed in oxidative cyclizations to circumvent this problem. Conveniently, for reactions in acetic acid, the chloride group may be removed in the same pot by addition of Zn dust.576 Such an αchloro-β-ketoester was a crucial intermediate in the 2015 synthesis of limonin (Scheme 93), the elusive flagship member of the limonoid family.452 From linear precursor 93-1, Yamashita, Hayashi, Hirama, and co-workers were able to efficiently construct the B, C, and D rings in a single operation using Mn(OAc)3. The masking chloride was then cleanly reduced with zinc dust in the next step. First-row transition metals also played a key role in Snider’s 1998 synthesis of isosteviol (Scheme 94).577 Using Mn(OAc)3, a tertiary carbon-centered radical was generated from β-

ketoester 94-1. This radical then undergoes four sequential additions into unactivated olefins and was finally oxidized by Cu(OAc)2 to provide tetracycle 94-3, which contains all of the carbon−carbon bonds of 94-4. In one step, four carbon− carbon bonds and six stereocenters, including four all-carbon quaternary centers, are formed. The ketone functionality was retrosynthetically removed to enable the cyclization reaction. The total synthesis of garcibracteatone by George and coworkers in 2012 is one of the most stereochemically dense polycycles synthesized to date by a first-row TM initiated reaction (Scheme 95).578,579 In one pot, the complex ring system was constructed through four sequential cyclizations, which formed five stereocenters, including three all-carbon quaternary centers, and four new rings. The cascade reaction begins with oxidation of the more electron-rich enol of 95-1 to form a tertiary carbon-centered radical, which undergoes a 7endo-trig cyclization. The new tertiary radical created as a result of this cyclization then undergoes a 5-exo-trig cyclization into the remaining enol. Diketo radical 95-2 reacts with a pendant prenyl group to form tertiary radical 95-3. Following one more olefin addition to provide 95-5, this radical undergoes radical 11715

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Scheme 95. George’s Synthesis of Garcibracteatone

Scheme 96. Gao’s Synthesis of Fusarisetin A

Scheme 97. Lee’s Synthesis of Yezo’otogirin C aromatic substitution with the nearby arene to form garcibracteatone (95-6) after rearomatization. In addition to the rapid construction of complex carbocyclic systems, oxidative radical cascades can also incorporate molecular oxygen into their final products. In the early 1990s, work done by Isoe, Kurosawa, and others demonstrated the utility of radical incorporation of molecular oxygen as an alternative to [4+2] cycloadditions of activated singlet O2.580−583 In the final step of their synthesis of pentacyclic fungal metabolite (+)-fusarisetin A (Scheme 96), Gao and coworkers utilized this chemistry to synthesize the carbocyclic C ring and heterocyclic B ring in a single step. Commencing with generation of a tertiary radical (96-2) from oxidation of enol 96-1, the reaction proceeds though a 5-exo-trig cyclization to provide secondary radical 96-3. This radical then reacts with molecular oxygen to form alkylperoxy radical 96-4, which cyclizes to form endoperoxide 96-5. After hydrogen atom abstraction to form the corresponding alcohol, the endoperoxide was reduced in the same pot with zinc metal to form the natural product 96-6. Another instructive example of the inclusion of molecular oxygen in radical cascades is the Lee group’s 2013 synthesis of yezo’otogirin C (Scheme 97).584 From substituted cyclohexanone 97-1, it was envisioned that oxidation to a diketo radical, a cyclization cascade, and subsequent H atom transfer would yield tricyclic endoperoxide 97-2. After screening a variety of metals and conditions, Lee and co-workers found that

the combination of Mn(II)/Mn(III), which had been employed by Kurosawa,582,583 provided the highest yield of endoperoxide 97-2. Li’s synthesis of oridamycin A clearly demonstrates the complementarity of oxidative and reductive radical cyclizations (Scheme 98).585 When Li and co-workers attempted to employ a reductive epoxide-initiated radical cyclization using an α,βepoxyester analogue of 98-1 to construct the core of 11716

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Scheme 98. Li’s Synthesis of Oridamycin A

Scheme 99. Cohen’s Synthesis of Hirsutene

oridamycin A, they found that the undesired equatorial carboxylic substituent was obtained. Conversely, when the oxidative cyclization of 98-1 was explored, the axial carboxylic 98-2 was obtained as a single diastereomer. The analogous reductive cyclization product then was employed to access xiamycin A (section 13.2, Scheme 145).

Scheme 100. Paquette’s Synthesis of Cerorubenic Acid Methyl Ester

11.2. Enolate−Enolate Coupling

The oxidative coupling of enolates to form 1,4-dicarbonyls is a useful reaction for organic synthesis.586−589 Classic reactions such as the Claisen condensation and Michael addition provide access to 1,3-dicarbonyls and 1,5-dicarbonyls through the union of nucleophilic α-carbon and an electrophilic carbonyl or enone. In contrast, 1,4-dicarbonyls require the dissonant coupling of two otherwise nucleophilic α-carbons. While twostep solutions (such as carbonyl α-halogenation and nucleophilic substitution with a second enolate) to this problem are well established, one-step oxidative coupling reactions are more step economic. The first report of oxidative enolate coupling with Br2 was disclosed by Ivanoff and Spassoff in 1935, yet very little followup work appears in the literature.590 Pioneering work in the late 1970s by Rathke,591 Heiba,592 Kobayashi,593 Saegusa,594,595 Mislow,596 and others597−600 demonstrated the utility of the reaction in both inter- and intramolecular coupling using various V, Cu, and Fe salts. One of the first examples601 of direct oxidative enolate coupling in total synthesis is Cohen’s 1992 synthesis of the tricyclic sesquiterpene hirsutene (Scheme 99).602 Cohen’s approach was to synthesize the central ring of hirsutene by coupling two cyclopentenones and a one-carbon synthon, which would be derived from tris(phenylthio)methane (99-1). After deprotonation of the orthothioester with n-BuLi, a sequence of conjugate addition, sulfur−lithium exchange, and conjugate addition afforded dienolate 99-4. While efforts to isolate the corresponding diketone of 99-4 were unsuccessful, treatment of the dienolate in situ with a solution of FeCl3 in DMF yielded tricyclic diketone 99-5 in 64% yield. In 1993, Paquette demonstrated the utility of oxidative enolate coupling to construct the highly strained tricyclo[3.2.1.0]octane 100-2 in their total synthesis of cerorubenic acid methyl ester (Scheme 100).603−607 As with Cohen’s method, the dienolate of 100-1 was prepared in THF with LDA and then treated with a solution of FeCl3 in DMF to

form 100-2. The highly strained tricycle was then employed in a strain-relieving anionic oxy-Cope reaction to form the tricyclo[5.4.0.0]undecane 100-4, which was then elaborated to the natural product 100-5. In 1995, Paquette and co-workers also applied similar conditions toward the dimerization of verbenone, a bicyclic monoterpene (not shown).608 In 2005, Baran and co-workers applied oxidative coupling to construct the bicyclodiaza[2.2.2]octane core of stephacidin A (Scheme 101).609 In contrast to previous methods, which utilized FeCl3 in DMF, the more soluble Fe(acac)3 was used, which allows the conversion of 101-1 to 101-2 to be conducted entirely in less polar solvents such as THF. It was also observed that addition of the Fe(III) solution after only 5 min of enolization was essential to the success of the reaction. In later work, Baran and co-workers postulated that the intermediate oxidation potential of Fe(acac)3 (−1.14 V vs ferrocene/ ferrocenium standard) may play an important role in the efficiency of the reaction, as both stronger and weaker oxidants, such as Cu(2-EH)2 (−1.65 V) and I2 (−0.39 V), gave inferior yields of the bicyclic product.610 Baran and co-workers continued to explore the applications of intermolecular enolate coupling with their 2006 total 11717

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Scheme 101. Baran’s Synthesis of Stephacidin A

Scheme 103. Overman’s Synthesis of Actinophyllic Acid

an oxidative enolate coupling (Scheme 104).616 Bromoanilide 104-1 was treated with LiHMDS to generate the corresponding Scheme 104. Zhang’s Synthesis of Chimonanthine synthesis of (−)-bursehernin (Scheme 102).611,612 One key advance of this work was the use of copper(II) 2-ethylScheme 102. Baran’s Synthesis of Bursehernin

hexanoate to obtain synthetically useful yields of heterocoupled products without the need for a stoichiometric (previously, up to 3-fold) excess of one enolate. This advance enabled the synthesis of the asymmetric lignan 102-3 efficiently in three steps from chiral oxazolidinone 102-1 and ester 102-2. In their synthesis of actinophyllic acid, Overman and coworkers employed the oxidative coupling of a malonate and an α-aminoketone to form bicyclo[3.3.1]nonane (Scheme 103).613,614 Notably, compound 103-1 possesses an unprotected indole N−H functionality and thus forms a trianion upon treatment with LDA. The soluble complex [Fe(DMF)3Cl2][FeCl4] is easily prepared by the reaction of DMF and FeCl3 in ether.615 This reagent effectively generated tetracycle 103-2, establishing some of the key connectivity required for the completion of the natural product 103-4. After installation of a vinyl coupling and the reduction of one methyl ester, the synthesis concludes with an aza-Cope−Mannich cascade to provide 103-4. Zhang’s 2015 synthesis of chimonanthine employed copper catalysis for both an enolate−arene cross-coupling reaction and

enolate, which underwent intramolecular cross-coupling in the presence of CuI to generate an oxindole (not shown). After cooling, addition of t-BuO2H to the reaction mixture induced oxidative dimerization of the oxindoles to provide dimer 104-2 in 78% yield as an 84:16 mixture of diastereomers. When the oxindole was prepared and treated with t-BuO2H in the absence of CuI, only the C3-hydroxylation product was isolated, suggesting the peroxide is a stoichiometric oxidant and that a Cu(II)/Cu(I) cycle is responsible for the production of 104-3. In addition to this work, others have developed oxidative dimerizations to access this class of natural products using iodine-based oxidants, 617−625 first-row transition metals,601,626−628 and other metal oxidants.629−631 During Harran and co-worker’s studies toward the synthesis of axinellamine A, oxidative enolate coupling of a titanium α,βunsaturated γ-enolate was used to synthesize the dimeric 105-2, allowing effective exploitation of the hidden symmetry of axinellamine A (Scheme 105).632 The authors note that the only oxidant other than Cu(OTf)2 that afforded comparable 11718

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structures such as 107-1 and 107-2, these transformations can be sensitive to steric effects. During their studies toward lomaiviticin A aglycon, Shair and co-workers were unable to effect the dimerization of bisallylated hydroquinone 107-1 (Scheme 107). Suspecting that

yields of the desired dimer was Livinghouse’s reagent, (CF3CH2O)VOCl2.633 Scheme 105. Harran’s Studies toward Axinellamine A

Scheme 107. Shair’s Studies toward Lomaiviticin A Aglycon

steric interaction of the allyl groups prevented dimerization, they synthesized monoallylated phenol 107-2, which could be successfully dimerized in good yield to 107-4. Additionally, the propensity of the C3 oxygenation to undergo β-elimination necessitated the synthesis of the 7-oxanorbornane scaffold to suppress this side reactivity while maintaining the C3 oxidation. In their landmark total synthesis of lomaiviticin A aglycon (108-3), Herzon and co-workers used quinone 108-1 as a dimerization precursor (Scheme 108). Notably, the mesityl acetals prevent the notorious β-elimination problem in this

The oxidative homocoupling of enolates has proven to be an exceptionally useful strategy for the construction of C2 symmetric-based natural products. The Thomson group’s total synthesis of bismurrayquinone A in 2011 is an example of an early stage dimerization using first-row transition metals (Scheme 106).634 Notably, the use of the enolate derived from chiral cyclohexenone 106-1 enabled the bidirectional synthesis of the natural product 106-4 in an atroposelective fashion.635

Scheme 108. Herzon’s Synthesis of Lomaiviticin A Aglycon

Scheme 106. Thomson’s Synthesis of Bismurrayquinone A

Oxidative enolate coupling has also been employed for convergent late-stage couplings. Shair636 and Herzon637 both employed late-stage oxidative homocouplings in pursuit of the complex dimeric diazofluorene lomaiviticin A aglycon. While first-row transition metal-mediated couplings provide the mild conditions necessary for dealing with densely functionalized 11719

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context. Through exhaustive screening of oxidants, Herzon and co-workers successfully developed a procedure to solve this long-standing challenge whereby the TMS enoxysilanes of 1081 could be dimerized using Mn(hfacac)3 to provide 108-2. The unique success of Mn(hfacac)3 in this reaction is attributed to its coordinative saturation. Furthermore, the high solubility and stability of the manganese complex allows the oxidation to be conducted in nonpolar solvents. After achieving the desired coupling product, one-step global deprotection then afforded lomaiviticin aglycon (108-3) in 39% yield. The oxidative homo- and heterocoupling of enolates is an important synthetic challenge that is addressed uniquely well by first-row transition metal chemistry. In the last two decades, oxidative enolate coupling has been transformed from a niche reaction to a truly robust synthetic method and has enabled the synthesis of exquisitely complex molecular architectures such as stephacidin A and lomaiviticin A.

Scheme 110. Baran’s Synthesis of 12-epi-Fischerindole U Isothiocyanate

11.3. Enolate−Arene Coupling

In addition to the oxidative homo- and heterocoupling of enolates, the oxidative coupling of enolate to arenes and heteroarenes has become a powerful tool for the construction of natural products. This methodology complements the αarylation of carbonyl enolates discovered in the late 1990s by the Buchwald and Hartwig groups.638,639 In contrast to these palladium-catalyzed methodologies, which require an aryl halide or pseudohalide as an electrophile, and thereby are also highly regiospecific with respect to the arene partner, an electrophilic handle is not required on the arene for oxidative coupling. As a result, the arene regioselectivity is dictated by the inherent nucleophilicity of the heteroarene, blocking groups, or by the length and position of intramolecular tethers. Oxidation-prone pyrroles are viable substrates for enolate− arene coupling (Scheme 109). In this reaction, Baran and co-

regioselectivity in this case is in line with the conventional C-3 nucleophilicity of indole, and the reaction proceeds in good yield without the need for N-protection or preparation of an enoxysilane. The broad utility of this reaction laid the groundwork for completion of the total synthesis of a number of marine alkaloids, including 12-epi-fischerindole U (110-3), hapalindole Q (110-4),12-epi-hapalindole D, 12-epi-fischerindole G, 12-epi-fischerindole I, welwitindolinone A, and ambiguine H.643−645 The welwitindolinones are a family of marine alkaloid natural products that have attracted a great deal of attention due to their unusual bicyclic indolinone scaffold.646 These natural products comprise an interesting case study in first-row transition metal-catalyzed oxidative arene−enolate coupling. In 2005, Baran and co-workers employed a Cu(II)-mediated intermolecular coupling of indole and ketone 111-1 in their total synthesis of welwitindolinone A (Scheme 111).647 Here, coupling in the presence of alkyl chlorides and alkenes was demonstrated, allowing access to the challenging stereogenic secondary alkyl chloride of 111-4. In addition to good functional group tolerance, this methodology is particularly attractive as it can be applied on gram scale and can obviate the need for prefunctionalization of the coupling partners. In subsequent work, Baran and co-workers employed their enolate−indole coupling reaction in the total synthesis of acremoauxin A (111-5) and oxazinin 3 (111-6) as well.648 Rawal and co-workers took another approach in their synthesis of the welwitindolinone framework in 2011 (Scheme 112).649 Rawal circumvented the propensity of carbon−carbon bond formation at C2 by the introduction of a chlorine blocking group at this position. This blocking group enabled the cyclization of a tethered β-ketoester onto the less reactive indole C-5 position instead. The success of these reactions notwithstanding, Rawal and co-workers also employed a Pdcatalyzed enolate arylation in their syntheses of several members of the welwitindolinone family.650−652 Much progress has been made in developing the oxidative coupling of indoles and 1,3-dicarbonyls. Kerr and co-workers demonstrated the cyclization of β-ketoesters with the indole C2 position in cases where no blocking group was present

Scheme 109. Baran’s Synthesis of (S)-Ketorolac

workers demonstrated the intramolecular coupling of chiral Oppolzer sultam 109-1 with a tethered pyrrole to give fused bicycle 109-2 in 4.5:1 dr.640 This bicycle was then elaborated in a further two-step one-pot operation to provide (S)-ketorolac (109-4) in 38% yield from 109-2. Muchowski and co-workers have also demonstrated the application of Mn(III) reagents to the racemic synthesis of ketorolac.641 In 2004, the Baran laboratory employed the intermolecular coupling of indole and carvone to provide access to the fischerindole and hapalindole scaffolds (Scheme 110).642 The 11720

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Scheme 111. Baran’s Synthesis of Welwitindolinone A

Scheme 113. Indole C2−Enolate Coupling

Mn(acac)3 with O2 as the stoichiometric oxidant, although not in the context of total synthesis.656 A similar intramolecular malonate−indole C3 coupling was achieved by Ma and coworkers during their synthesis of vincorine using I2 without any metal oxidants.657 In 2015, the Ding group published a one-pot dehydrogenation−oxidative coupling cascade reaction to form fused indoles from acyl indolines en route to alsmaphorazine D (Scheme 114).658 While the authors found that employing 10 mol %

Scheme 112. Rawal’s Synthesis of the Welwitindolinone Scaffold

Scheme 114. Ding’s Synthesis of Alsmaphorazine D

(Scheme 113). In their studies toward tronocarpine, Kerr and co-workers synthesized the indole-fused tricycle 113-2 by coupling a pendant malonate with the indole at C-2.653 Later, in their total synthesis of indole alkaloid mersicarpine, Kerr and co-workers successfully coupled a pendant 1,3-diketone to the indole C-2 position as well (113-4).654 In their complementary 2010 synthesis of subincanadine F, Li and co-workers coupled a C3-linked malonate to the indole C2 position to provide 113-6 with ferrocenium hexafluorophosphate as the oxidant.655 In 2013, Kanai and co-workers demonstrated the C-2 coupling of both C3- and N1-linked malonates using catalytic

(NH4)2Ce(NO3)6 with O2 as a terminal oxidant provided higher yields than the manganese/hypervalent iodine-based conditions to convert 114-1 to 114-2, the 54% yield afforded by the first-row transition metal catalyst is also a viable application of early transition metal catalysis. Carbocyclic arenes have also been employed as coupling partners, one example being present in Hatakeyama’s 2014 synthesis of (−)-ophiodilactone B (Scheme 115).659 In this 11721

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Scheme 115. Hatakeyama’s Synthesis of Ophiodilactone B

Scheme 116. Kutney’s Synthesis of Anhydrovinblastine

example, molecular oxygen was employed as a terminal oxidant with Cu(OAc)2 as a catalyst to induce the oxidative coupling of an ester and pendant benzyl group. Hatakeyama and coworkers employed neutral conditions developed by Taylor due to the base sensitivity of 115-3.660 Kutney’s oxidative coupling of catharanthine (116-1) and vindoline (116-2) to form anhydrovinblastine (116-7) is one of the most complex examples of a late-stage oxidative arylation reaction (Scheme 116).526,537 When treated with FeCl3, catharanthine (116-1) is oxidized at the tertiary amine to form radical cation 116-3. Fragmentation of the strained bicycle then generates benzylic radical 116-4, which is in turn oxidized to dication 116-5. This dication reacts with the electron-rich arene of vindoline (116-2) through a typical electrophilic aromatic substitution pathway to provide 116-6, which is finally reduced by borohydride to yield anhydrovinblastine (116-7). Boger and co-workers have subsequently developed and optimized an iron-mediated one-pot coupling/hydration of vindoline and catharanthine to directly synthesize vinblastine, which is described in greater detail in section 10.2. Ce(IV) salts have been reported to induce oxidative coupling of β-ketoesters and furans.661 Nicolaou and co-workers have used such salts to effect oxidative coupling to form macrocyclic furans in their efforts to synthesize bielschowskysin.662 However, to the best of our knowledge, there are no example of first-row transition metal coupling of enolates to furans in the context of total synthesis. However, the coupling of enolates and enoxysilanes to furans via electrochemical oxidation is well established by work done in the Wright group.663−668 Moeller and co-workers applied such a coupling in their 2003 total synthesis of alliacol A,669,670 and in 2006, the Trauner group reported a remarkable oxidative coupling in their synthesis of guanacastepene E.671 Other examples of oxidative enolate coupling of furans,672−674 pyrroles,649,675 oxindoles,676−678 and carbocyclic arenes679 are reported in the literature, but have not yet been applied in the context of total synthesis.

11.4. Arene−Arene Coupling

The coupling of arenes to form biaryls is one of the most widely performed reactions in medicinal chemistry, and generally Pdcatalyzed cross-coupling or SNAr reactions are employed.680,681 While these powerful reactions have been developed to have broad substrate scopes, they require the installation of functional handles on one or both coupling partners. On the other hand, oxidative arene−arene coupling through first-row transition metal catalysis can synthesize biaryl moieties from two sp2 C−H bonds, particularly for electron-rich aromatics. Additionally, C−C bond formation can be accompanied by oxidative dearomatization with appropriate reagents and conditions. This enables the synthesis of complex 3D structures from arenes where regiochemistry can be easier to control. One early example of oxidative arene coupling was Barton’s 1952 total synthesis of usnic acid (Scheme 117).682 Treatment of methylphloracetophenone 117-1 with potassium ferricyanide affords 4-arylcyclohexadienone 117-2, which undergoes intramolecular oxy-Michael addition to provide tricycle 117-3 in 15% yield. Treatment of 117-3 with sulfuric acid then provides the natural product 117-4. The Trauner group made efficient use of ferricyanidemediated dimerization in their phenomenal total synthesis of dibefurin (Scheme 118).683 In one step, epicoccine, 118-1, was oxidized with ferricyanide to form hydroxyquinone 118-2. Subsequently, two aldol reactions then constitute a formal 11722

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Scheme 117. Barton’s Synthesis of Usnic Acid

Scheme 119. Trauner’s Synthesis of Epicolactone

Scheme 118. Trauner’s Synthesis of Dibefurin

Scheme 120. Jordis’ Synthesis of Galanthamine

[3+3] cycloaddition, which affords dibefurin 118-4 in 49% yield. In 2015, Trauner and co-workers expanded this approach further in their extraordinary synthesis of epicolactone (Scheme 119).684 In their route, the heterocoupling of epicoccine 119-1 and vanillyl alcohol derivative 119-2 was effected with potassium ferricyanide in aqueous acetonitrile. After oxidation to the corresponding quinones, a formal [5+2] cycloaddition provides tetracycle 119-5. The cascade continues with a retroDieckmann condensation and aldol reaction to afford pentacycle 119-7 in a single step from two simple precursors. Deprotection of the enol ether then provided natural product 119-8 in only eight linear steps. The use of potassium ferricyanide to couple arenes has proved to be a scalable alternative to conventional crosscoupling chemistries. In 1999, Jordis employed this procedure on kilogram scale to synthesize galanthamine, a drug approved by the FDA for the treatment of Alzheimer’s disease (Scheme 120).685 Formamide 120-1 was oxidized with potassium ferricyanide to first form spirocycle 120-2, which then underwent oxy-Michael addition to form 120-3. After several steps including reduction of the formamide to a methylamino

group and removal of the bromine blocking group, galanthamine (120-4) was obtained as its hydrobromide salt. In addition to iron(III)-based reagents, vanadium(V) reagents also are capable of effecting a wide variety of oxidative aryl−aryl couplings. One of the first such examples is demonstrated in Kende’s 1975 total synthesis of steganacin (Scheme 121).686 In this work, biaryl compound 121-1 was treated with 3.5 mol equiv of VOF3 in a mixture of methylene chloride and trifluoroacetic anhydride, which provided biaryl 121-2 in 45% yield.687 This compound was then taken on to 11723

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Scheme 121. Kende’s Synthesis of Steganacin

Scheme 123. Comins’ and Georg’s Syntheses of Tylophorine

the natural product 121-3 after installation of the benzylic ketone and decarboxylation. Shortly afterward, Schlessigner applied similar conditions to the total synthesis of isostegane in 1976 (Scheme 122).688

Scheme 124. Yang’s Synthesis of Decinine

Scheme 122. Schlessinger’s Synthesis of Isostegane

Interestingly, Schlessinger and co-workers noted that due to the presence of the lactone in 122-2, the biaryl moiety formed during the oxidative cyclization was exclusively the non-natural isomer, albeit in somewhat higher yield. In 1997, Comins and co-workers applied VOF3-induced oxidative coupling to complete the total synthesis of the phenanthroizidine alkaloid (−)-tylophorine (Scheme 123).689 Notably, other oxidation prone functionality such as a tertiary amine (123-1) was tolerated. Additionally, in 2011, Georg employed a similar transformation in the synthesis of boehmeriasin A.690 One other useful advance in this field was made by Georg and co-workers in their 2011 syntheses of tylophorine and several other related natural products via oxidative arene−alkene coupling.691 In this reaction, an orthoarylstyrene derivative 123-3 was cyclized to form anthracene derivative 123-2. In their 2012 synthesis of decinine (124-3), Yang and coworkers used the biaryl construction as their penultimate step (Scheme 124).692 This disconnection is particularly advantageous in the case of decinine, as it allows the stereochemistry of the piperidine moiety in 124-1 to control the axial chirality of the biaryl contained within the macrocycle of 124-3. The choice of PNB as a phenolic protecting group was necessary to obtain 124-2 in synthetically useful yields; other protecting groups such as OMe, OMOM, OBn, and OAc provided only 0−7% of the corresponding biaryl product.

Because of their potent antibiotic properties,693 considerable effort has been dedicated to determining effective approaches for the construction of the biaryl groups in the vancomycin family of natural products.694−696 In particular, the C−C linked biaryl moiety in the M(5−7) region of the natural product introduces a synthetically challenging element of axial chirality that is formed biosynthetically through oxidative coupling.697 In their initial construction of the M(5−7) subunit of vancomycin in 1993 (Scheme 125),698 Evans and co-workers were plagued by the homodimerization of the M7 peptide. For this reason, a temporary electron-donating benzyloxy substituent was added on the M5 peptide to alleviate the electronic bias for M7 oxidative dimerization. However, when a substituent was in this position on the M5 residue, the unnatural atropisomer was thermodynamically favored upon equilibration at 160 °C in DMSO. This necessitated the removal of the M5 benzyloxy group after the oxidative coupling via hydrogenolysis, triflation, and Pd-catalyzed reduction.699−702 The scope of the oxidative coupling is limited to electron-rich arenes, and, as can be seen in Evans’ synthesis of vancomycin, this strong bias can lead to undesired intermolecular homocoupling. However, when 11724

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form a pyrroloindoline-C3 radical, which then undergoes dimerization. This radical can also be trapped with TEMPO or O2 to generate 3-hydroxypyrroloindolines, which Xia has used to synthesize protubonine A.703 Xia has also demonstrated the dimerization of tryptamine derivatives with chiral auxiliaries to synthesize chimonanthine.704 Oxidative aryl−aryl coupling can be an ideal synthetic transformation. The coupling of two arenes via two instances of C−H oxidation obviates the need for handles such as aryl halides and boronic acids, which can require several steps to install. From classic examples using noble metals, such as Chapman’s carpanone synthesis705 to the modern syntheses of vancomycin and epicolactone, which use abundant first-row metals, the need for step-efficient methods for arene−arene coupling remains an important synthetic challenge. Principally, matching some of the exquisite selectivities exhibited by biosynthetic first-row transition metal metalloenzymes remains challenging.

Scheme 125. Evans’ Synthesis of Vancomycin Aglycon

12. OXIDATIVE RING FRAGMENTATION In addition to C−H bond oxidation, first-row transition metals are capable of creating radicals by the oxidative fragmentation of weak C−C bonds. In the mid-1970s, Saegusa and co-workers demonstrated the use of FeCl3 in tandem ring expansionoxidation reactions of cyclopropanols.706,707 This allows for the expedient transformation of easily prepared six-membered cyclic ketones to more challenging seven-membered rings. Simultaneously, the generation of a β-keto radical opened the door to a number of other synthetically valuable transformations such as oxidation or C−C bond formation at the ketone β-position. In the 1980s, Murai and others developed this approach to allow for the dimerization of β-keto radicals and the synthesis of numerous halogenated ring expanded cyclohexanone derivatives.708 In 1991, Narasaka and coworkers first employed Mn(pic)3 to fragment cyclopropanols to β-keto radicals and then induce an oxidative coupling of silyl enol ethers to synthesize 1,5-dicarbonyls.709 Vanderwal and co-workers made use of this chemistry to effect a net oxidative ring expansion of 127-1 in their noteworthy total synthesis of echinopine B (Scheme 127).710 Ketone 127-1 was converted to the corresponding trimethylsilyl enol ether (not shown) and subjected to a Simmons− Smith cyclopropanation329 to afford a mixture of diastereomeric protected cyclopropanols (127-2). Oxidative cleavage of the

intramolecular selectivity can be realized, oxidative arene coupling allows even macrocyclic biaryl linkages to be rapidly installed with transfer of stereochemical information from distal regions of the substrate. The biomimetic oxidative coupling of tryptophan derivatives has been a commonly employed tactic in the synthesis of Clinked dimeric indole alkaloids.617 Xia and co-workers developed a Cu-mediated indole dimerization to access the bisindole alkaloid (+)-WIN 64821 (Scheme 126).626 Treatment of tryptophan derivative 126-1 with DBU and CuCl2 is thought to result first in oxidative C−N bond formation to Scheme 126. Xia’s Synthesis of WIN 64821

Scheme 127. Vanderwal’s Synthesis of Echinopine B

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resulting ketone was used to install the cyclopentene portion of 129-3 by an intramolecular aldol condensation, and the pendant hydroxymethyl was installed via vinylcuprate addition and oxidation. The authors also strategically employ the THP protected alcohol as a handle to install the aldehyde through vinyl Grignard addition into the corresponding ketone. The tertiary allylic alcohol obtained through this transformation was activated with ethyl chloroformate, which allows a Tsuji−Trost allylation to complete the construction of the bicyclo[2.2.1]heptane present in the natural product 129-4. In their synthesis of tricyclic hydrocarbon (−)-silphiperfol-6ene (Scheme 130), Snider and co-workers employed Mn(pic)3

cyclopropane by the Saegusa−Ito ring expansion afforded enone 127-3. This strategy to form enones is likely to be used to solve other problems in multistep synthesis in addition to the synthesis of echinopine B (127-4). In 1994, Narasaka and co-workers employed such a radical cyclopropanol fragmentation in the synthesis of (−)-10isothiocyanatoguaia-6-ene (Scheme 128).711 The key cycloScheme 128. Narasaka’s Synthesis of (−)-10Isothiocyanatoguaia-6-ene

Scheme 130. Snider’s Synthesis of Silphiperfol-6-ene

propanol intermediate 128-2 was synthesized efficiently from enone 128-1 in a high-yielding three-step sequence of conjugate addition/protection, Simmons−Smith cyclopropanation, and deprotection. With cyclopropanol 128-2 in hand, treatment with Mn(pic)3 resulted in the fragmentation of the cyclopropanol moiety to form a β-keto radical, which underwent 5-exo-dig cyclization with the pendant alkene chain to form the fused bicyclo[5.3.0]decane 128-3 in 76% yield. In 2004, Narasaka and co-workers disclosed a synthesis of sordaricin, a potent inhibitor of fungal protein synthesis (Scheme 129).712,713 Notably, both the ketone and the alcohol functionality of 129-2 are critical to the construction of the ring system of 129-4. After obtaining the bicyclo[5.3.0]decane, the

to fragment cyclobutanol 130-1.714 After fragmentation, the tertiary radical 130-2 undergoes 5-exo-dig cyclization with the pendant ynone and forms 130-3 following hydrogen atom abstraction or reduction/protonation. As propargylic cyclobutanols such as 130-1 are accessible by acetylide addition into the cyclobutanone product of a Paterno−Büchi [2+2] photocycloaddition, this three-step sequence is a powerful method for construction of exocyclic cyclopentenones such as 130-3. In 2005, Chiba and co-workers utilized the generation of βketo radicals to generate an iminyl radical from a vinyl azide in their total synthesis of melinonine E (Scheme 131).715 After fragmentation to form the β-keto radical, addition into the vinyl azide and loss of nitrogen affords iminyl radical 131-4. This radical was then reduced by Mn(II) to form an iminyl anion, which adds back into the cyclohexanone to form bridgehead alcohol 131-6. Phillips and co-workers employed the iron-initiated fragmentation of a cyclopropanol as part of a reductive coupling of 132-1 and 132-2 en route to routiennocin methyl ester 132-4 (Scheme 132).716 Initially, cyclopropanol 132-3 was constructed using Cha’s terminal olefin modification717 of the Kulinkovich cyclopropanation.718 When the reductant was cyclohexylmagnesium bromide, 132-3 was obtained in 37% yield. Fragmentation of this ring with ferric nitrate and tributyltin hydride to reduce the β-keto radical provided 1324. Intriguingly, by changing the reductant to n-butyllithium, 132-4 was obtained as the product in a single step. Ollivier and co-workers have used this Cha−Kulinkovich/ fragmentation to synthesize 2-phenylpiperidin-3-one from N-

Scheme 129. Narasaka’s Synthesis of Sordaricin

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of the Ti(III) species) were disclosed.723−725 The groups of Weiler726 and Merlic727,728 also employed radicals generated by reductive epoxide opening for addition into β-stannylenones and group VI carbenes, respectively. The utility of this reaction attracted a great deal of interest, and over the next decades, a number of improvements and stereochemical studies were conducted. In 1998, Gansäuer and co-workers disclosed a catalytic variant of the Nugent− Rajanbabu reaction.729,730 Freeing the highly oxophilic titanium species from the alkoxide product was accomplished using sterically hindered and weakly acidic pyridinium salts such as 2,6-dimethyl- and 2,4,6-trimethylpyridinium hydrochloride, with subsequent electron transfer from a stoichiometric reductant regenerating the active Ti(III) catalyst. This work culminated in Gansäuer’s development of a chiral titanocene for catalytic enantioselective reductive epoxide opening both with and without tandem C−C bond formation.731 Reductive opening of epoxides with Cp2TiCl has become a frequently employed methodology, due to its complementarity to the nucleophilic opening of epoxides. Generally, reductive opening of epoxides gives the less substituted alcohol (due to formation of the more substituted radical), while hydridic opening gives the more substituted alcohol following attack of hydride on the less hindered carbon of the epoxide. Epoxides derived from allylic alcohols are particularly attractive due to the ease of enantioselective and diastereospecific epoxide synthesis,14 and the value of 1,3-diols as intermediates in polyketide synthesis.732 Yadav and workers have developed this chemistry to enable the isomerization of allylic alcohols in an efficient two-step procedure.733 Chakraborty and co-workers have studied the regio- and diastereoselectivity of these reactions, including the opening of trisubstituted epoxides.734,735 This selective reductive epoxide opening was instrumental in their 2001 synthesis of polyketide prelactone C (Scheme 133).736 In this route, the ring of

Scheme 131. Chiba’s Synthesis of Melinonine E

Scheme 132. Phillip’s Synthesis of Routiennocin Methyl Ester

Scheme 133. Chakraborty’s Synthesis of Prelactone C

allyl-2-phenylglycine methyl ester.719 The fragmentation of strained rings with MnO2 and with Minisci-type coupling has also been reported by Lectka.720

13. REDUCTIVE RING FRAGMENTATION 13.1. Discovery and Simple Epoxide-Opening Reactions

In 1988, Nugent and Rajanbabu disclosed the reductive opening of epoxides using Cp2TiCl, a single-electron reducing agent accessible by the reduction of commercially available Cp2TiCl2.721,722 In their seminal publication, Rajanbabu and coworkers demonstrated that the alkyl radicals generated from the epoxide opening rapidly underwent intramolecular addition to unactivated alkenes. In subsequent years, intermolecular C−C bond-forming reactions as well as the reductive deoxygenation of epoxides (favored by addition of the substrate to a solution

opening of epoxy alcohol 133-2, which had been installed via Sharpless asymmetric epoxidation,47 was opened to give antisyn diol 133-4. This two-step sequence constitutes a formal anti-Markovnikov alkene hydration. Other syntheses enabled by this diastereoselective transformation include prelactone B by Chakraborty,737 two Cryptocarya latifolia isolates by Nakata,738 and Rama Rao’s studies toward Rhizoxin.739 In Mander’s 1996 synthesis of GA32, this radical epoxide opening was employed to access bromoaldehyde 134-4 from 11727

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spirocyclic epoxide 134-1 (Scheme 134).740 After ring opening of the epoxide, the tertiary radical was reduced by a second

to synthesize this ring involving addition of tributylstannyl radical to the alkyne or by fragmentation of a thionocarbonate resulted in undesired rearrangements. The natural product ceratopicanol (135-4) was obtained after oxidative cleavage of the alkene and deoxygenation of the B-ring alcohol. Roy and co-workers utilized the Nugent−Rajanbabu reaction to expediently access the fused 3,7-dioxobicyclo[3.3.0]octane core of the lignan kobusin (Scheme 136).745−747 Following

Scheme 134. Mander’s Synthesis of GA32

Scheme 136. Roy’s Synthesis of Kobusin

The first example of tandem reductive epoxide opening and C− C bond formation in total synthesis is found in Clive’s 1995 total synthesis of ceratopicanol (Scheme 135).743,744 To synthesize the third ring of the triquinane core, Clive and coworkers employed the radical opening of δ,ε-alkynyl epoxide 135-1 to access 135-2 through a 5-exo-dig cyclization. Attempts

opening of the epoxide, C−C bond formation occurs to form the first tetrahydrofuran ring, and the radical was again reduced to the alkyltitanium species. This species was treated with iodine, and the second ring was subsequently formed in the same pot. Roy and co-workers had previously synthesized these lignan natural products through tin-based radical chemistry,748,749 but the advent of the Nugent−Rajanbabu reaction enabled more rapid synthesis of these natural products due to the availability of the epoxide and alkene electrophiles necessary for the cyclization.750−752 Reisman’s synthesis of maoecrystal Z uses radical epoxide opening as a highly effective means to effect a formal epoxide to δ-lactone ring expansion (Scheme 137).753 Epoxide 137-1 was treated with Cp2TiCl and zinc dust to form a tertiary radical (137-2), which was trapped with trifluoroethyl acrylate to form 137-3 after condensation of the titanium alkoxide and activated

Scheme 135. Clive’s Synthesis of Ceratopicanol

Scheme 137. Reisman’s Synthesis of Maoecrystal Z

equivalent of Ti(III) to form alkyltitanium species 134-2. βHydride elimination then provides titanium enolate 134-3, which gives 134-4 upon treatment with an electrophilic bromine source. The introduction of the bromine orients the formyl group of 134-4 syn to the three-carbon bridge such that reduction to the alcohol and Suárez C−H functionalization can install the requisite oxidation state.741,742 13.2. Radical Cascade Reactions

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ester. The authors found that the use of the trifluoroethyl ester provided significantly higher yields than the corresponding methyl ester. Additionally, it was reported that the reaction provided 137-3 as a single diastereomer regardless of whether the α or β epoxide was used, corroborating the intermediacy of radical 137-2. The Nugent−Rajanbabu reaction was critical to the success of Trost’s total synthesis of sicannin (Scheme 138).754

Scheme 139. Barrero’s Formal Synthesis of Stypoldione

Scheme 138. Trost’s Synthesis of Sicannin

Scheme 140. Barrero’s Syntheses of Hydroxydrimanes

Attempts to induce cyclization of 138-1 to 138-2 via Lewis acid catalysis led only to hydride shifts and aldehyde formation. Highlighting the contrast between cationic and radical intermediates, reductive epoxide opening afforded the desired tetracycle 138-2 and pentacyclic side product 138-4 as a 3:1 ratio in 81% combined yield. Pentacycle 138-4 was thought to arise from recombination of the titanium alkoxide and benzylic radical, which is favorable when the alkoxide is formed on the concave side of the natural product. Reductive epoxide opening is a powerful complementary methodology to cationic epoxide-initiated polyene cyclization. As such, it has become a mainstay in terpene and meroterpenoid synthesis. Epoxide opening with a single subsequent C−C bond formation has used by Barrero and colleagues in the syntheses of achilleol A,755 achilleol B,756 and α-ambrinol,757 among other targets. One exemplary use can be found in Barrero’s syntheses of eudesmanolides758,759 in which reductive epoxide opening was followed by a transannular cyclization to form the natural products bicyclo[4.4.0]decane core. In 2001, Barrero and co-workers reported the first example of a reductive epoxide opening followed by multiple C−C bondforming events (Scheme 139),760 which represents an attractive alternative to analogous cationic reactions.761 Subsequently, the Barrero group demonstrated the first use of a cascade reductive epoxide ring opening followed by three C−C bond-forming events on epoxygeranylgeranyl acetate in the formal synthesis of stypoldione (139-4).762,763 This polycyclization has enabled access to a number of meroterpenoid-related structures via convergent Stille coupling of an epoxyfarnesyl carbonate and an aryl stannane.764 The reductive cyclization of epoxyfarnesylacetate was employed in Barrero’s total synthesis of several 3-hydroxydrimane natural products including 140-6 (Scheme 140).765

Reductive epoxide opening plays a dual role in this synthesis; in addition to initiating the radical polyene cyclization of 140-1, the solvent-dependent nature of the simple epoxide opening was used to diverge from common intermediate 140-3. Exploiting the effects of proton and hydrogen atom sources on the epoxide-opening reaction,766−768 Barrero and coworkers were able to access both reduced compound 140-4 and cyclohexene 140-5, which are key intermediates in the syntheses of 140-6 and several other drimanes, respectively. In addition to epoxyfarnesylacetate, Ti(III)-induced cyclization has been reported on the dioxolane protected epoxyfarnesylacetone in a formal synthesis of rostratone by Barrero.769 Other examples of reductive cyclizations of epoxyfarnesyl derivatives 11729

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can be found in the syntheses of puupehedione770 and sclareol oxide.771,772 The Nugent−Rajanbabu cyclization can also provide entry to the fused 6-6-7 structures of laukarlaol (141-3) and barekoxide (141-4) (Scheme 141).773 As the required 7-endo-trig reaction

reagents (in particular, their byproducts) could not be used to synthesize 142-3 and 142-6. However, catalytic conditions using only 10 mol % of the titanocene catalysts were amenable to automation on multigram scale. Optimal conversion and yields were obtained in the presence of stoichiometric Et3B.778 It was postulated that the borane reagent serves as a soluble reducing agent to regenerate the active Ti(III) species analogously to known pathways with Zr(IV) reagents.779 In their 2009 total synthesis of paeonisuffrone (Scheme 143), Bermejo and co-workers applied the Nugent−Rajanbabu

Scheme 141. Barrero’s Synthesis of Laukarlaol and Barekoxide

Scheme 143. Bermejo’s Synthesis of Paeonisuffrone

is slow, several measures may be necessary to suppress side reactions. First, dilution of the reaction mixture by 1 or 2 orders of magnitude to suppress homocoupling can be beneficial. Second, the use of a tertiary allylic acetate retards the 6-exo-trig pathway by creating a syn-pentane interaction in the chairlike transition state, which thus allows the 7-endo-trig product to predominate.774 Gansäuer’s development of catalytic Nugent−Rajanbabu conditions was critical in the success of Takahashi’s automated total synthesis of baccatin III (Scheme 142) and formal synthesis of taxol.775−777 Because of engineering constraints of their autosynthesizer, stoichiometric amounts of titanium

conditions to the synthesis of strained bicycle 143-2.780 Interestingly, the authors reported that while higher yields were obtained with stoichiometric titanium conditions, the catalytic variant published by Gansäuer (not shown) provided higher diastereoselectivities. In their total synthesis of seco-C-oleanane (Scheme 144), Barrero and co-workers undertook a thorough computational study to investigate the plausibility of selectively terminating a Nugent−Rajanbabu cascade after two cyclization events. The

Scheme 142. Takahashi’s Partially Automated Synthesis of Taxol

Scheme 144. Barrero’s Synthesis of Seco-C-oleanane

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opening with oxygen and nitrogen nucleophiles.792,793 Jacobsen has also employed a combination of the HKR and catalyzed epoxide opening to synthesize enantioenriched terminal aziridines from the corresponding racemic epoxides by a fourstep sequence.794 Additionally, Jacobsen has demonstrated the use of (salen)Cr(III) complexes for the desymmetrization of meso-epoxides.795 Jacobsen’s synthesis of peloruside A employs both the asymmetric hydrolytic kinetic resolution and the Jacobsen− Katsuki asymmetric epoxidation (Scheme 146).796,797 Asym-

authors found that the activation energy for oleanane C ring closure is ∼29 kcal/mol due to the severe steric interactions involved in forming the two vicinal quaternary centers of pentacyclic oleanane structure.781 Again, the authors noted different product distributions under catalytic and stoichiometric titanium conditions. Under catalytic conditions, 44% of 144−3 and 8% of the endocyclic trisubstituted alkene isomer (not shown) were obtained. Under stoichiometric conditions, 39% of the desired 144-3 was obtained along with another 10% combined of two B,C-seco isomers. In 2014, Cuerva and coworkers noted that introduction of a ketone functionality can be used to control the number of cyclizations in Nugent− Rajanbabu reactions also.782 In 2015 the Li group employed the reductive radical opening of an α,β-epoxyenoate to induce a key polyene cyclization in their route to xiamycin A (Scheme 145).585 This method was

Scheme 146. Jacobsen’s Synthesis of Peloruside A

Scheme 145. Li’s Synthesis of Xiamycin

metric epoxidation of pent-1-en-3-yne using Mn catalyst 146-5 provides 146-2 in only 50% ee. However, resolution with Co catalyst 146-6 provides the compound in 99% ee. Alkyne 146-3 is used to access the pendant alkenyl group in the natural product 146-4. The α,β-dioxygenated ester functionality within the macrocycle is also derived from a HKR reaction catalyzed by an oligomeric Co(salen) catalyst.798 Another example of the HKR in the early stages of a natural product synthesis is Fürstner’s synthesis of zearalenone (Scheme 147).799 Selective hydrolysis of epoxide 147-1 affords

but had not been first described by Hardouin in 2001, applied toward the total synthesis of natural products. The key advantage of this methodology is the installation of an oxidation state at the equatorial methyl group of 145-2. This nicely complements the oxidative β-ketoester cyclization, which was reported to provide an oxidized axial methyl group for the synthesis of oridamycin A (section 11.1, Scheme 98). Efficient routes to access epoxyfarnesol and epoxygeraniol derivatives in both racemic and enantiopure forms have been developed by Corey and others.784−788 Additionally, the Nobel Prize winning work of Sharpless47,48 has made enantioselective synthesis of epoxides directly from allylic alcohols a routine operation. Leveraging the ease of epoxide synthesis has allowed the Nugent−Rajanbabu reaction to make significant contributions in many fields of natural product synthesis, from polyketides to terpenoids and meroterpenoids. 783

Scheme 147. Fürstner’s Synthesis of Zearalenone

14. THE JACOBSEN HYDROLYTIC KINETIC RESOLUTION Since the hydrolytic kinetic resolution (HKR) of epoxides was first disclosed in 1997, it has been widely embraced by the synthetic community.789,790 Although Jacobsen’s initial publication only addressed the resolution of terminal epoxides, subsequent publications have expanded the scope of the HKR to include resolution of 2,2-disubstituted epoxides791 and the enantiospecific derivatization of epoxides by nucleophilic 11731

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chiral epoxide 147-2 in 41% yield and greater than 99% ee. This epoxide can be reductively opened with LiEt3BH to provide the secondary alcohol, efficiently setting the only stereocenter of the natural product 147-3. Nelson’s formal synthesis of hemibrevetoxin B (148-5) exhibits a rare late-stage use of the HKR (Scheme 148).800 To

Scheme 149. Selected Enantiopure Compounds Accessed by HKR

Scheme 148. Nelson’s Formal Synthesis of Hemibrevetoxin B

C−O, C−N, C−H, and C−C bonds). More frequent application of these emerging methodologies is an inevitability that will follow the identification of more practical procedures that proceed under more mild conditions in the face of the functional group-rich and reactive synthetic intermediates encountered in total synthesis.

AUTHOR INFORMATION

access intermediate 148-3, a method to differentiate the enantiotopic epoxides of 148-1 was required. When treated with Jacobsen catalyst 148-4, diepoxide 148-1 was selectively transformed to diol 148-2 in 98% yield. This diol was efficiently protected to form 148-3, intercepting a late-stage intermediate in Nakata’s total synthesis of hemibrevetoxin (148-5).801 The hydrolytic kinetic resolution of epoxides has been widely employed in the early steps of many total syntheses to generate enantiopure epoxide or epoxide-derived starting materials. The generality of this resolution has led to its widespread adoption; Jacobsen has written that “virtually every terminal epoxide examined to date [undergoes] clean and highly selective resolution.”789 Scheme 149 shows a small selection of chiral epoxide starting materials that have been employed in the total synthesis of natural products.802−812

Corresponding Author

*E-mail: [email protected]. ORCID

Timothy R. Newhouse: 0000-0001-8741-7236 Notes

The authors declare no competing financial interest. Biographies Joshua Zweig was born in New Jersey and grew up in Pennsylvania. He received his B.S. in Chemistry from the College of Chemistry at UC Berkeley (2014). During his time at Berkeley, he worked in the laboratory of Prof. Matthew B. Francis on the synthesis of artificial light-harvesting systems. He is currently an NSF fellow at Yale University in the laboratory of Prof. Timothy R. Newhouse, where he is working on the synthesis of new functional organic chromophores.

15. CONCLUSION First-row transition metal-mediated reactions have played an important role in multistep synthesis since the early stages of the field, and the recent surge of development of methodologies is already having a major impact on the execution of otherwise challenging retrosynthetic analyses. The unique properties of first-row transition metals, in particular, their propensity to participate in one-electron processes, greater electronegativities, and favored ligand spheres, allow for exciting opportunities in natural product synthesis. Of particular interest are the alternative modes of reactivity, and orthogonal reaction design possible using first-row transition metals allows for the functionalization of otherwise inert groups (e.g., formation of organometallic intermediates by breaking

Daria Kim was born in Moscow and grew up in Southern California. She received her B.S. in Chemistry with a concentration in Biochemistry from the University of California-San Diego (2014). While at UCSD, she worked in the laboratory of Prof. Chambers C. Hughes on the total synthesis of marine natural products. She is currently a doctoral student at Yale University in the laboratory of Prof. Timothy R. Newhouse, where she is working on natural products total synthesis. Tim Newhouse was born in New Hampshire and grew up in northern New England. He received his B.A. in Chemistry from Colby College (2005) in Waterville, ME, where he was mentored by Prof. Dasan M. Thamattoor. After moving to La Jolla, CA, he completed his Ph.D. at 11732

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Piv PMB PPTS py TBAF TBDPS TBS TES Tf TFA TFAA TFE THF TIPS TMEDA TMP TMS TMTU Ts

The Scripps Research Institute with Prof. Phil S. Baran (2010). During his time at Scripps, he also worked in the laboratories of Prof. Donna G. Blackmond. He then returned to the east coast for postdoctoral studies with Prof. E. J. Corey at Harvard University. He began his current position as an Assistant Professor at Yale University in the Department of Chemistry in 2013, and became a member of the Interdepartmental Neuroscience Program in 2014.

ACKNOWLEDGMENTS Financial support for this work was provided by Yale University, the Sloan Foundation, and the NSF (CAREER Award #1653793, GRF to J.E.Z.). ABBREVIATIONS 2-EH 2-ethylhexanoate 9-BBN 9-borabicyclo[3.3.1]nonane Ac acetyl acac acetylacetonate Bn benzyl Boc tert-butoxycarbonyl BOM benzyloxymethyl brsm based on recovered starting material Bu butyl Bz benzoyl CAN ceric ammonium nitrate Cbz carboxybenzoyl Cp cyclopentadienyl Cy cyclohexyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DEP diethylpyrazole DET diethyl tartrate DMA N,N′-dimethylacetamide DMAP 4-(dimethylamino)pyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMP Dess−Martin periodinane DMSO dimethyl sulfoxide dpm dipivaloylmethane dppf 1,1′-bis(diphenylphosphino)ferrocene EE 1-ethoxyethyl Et ethyl ETMS 2-(trimethylsilyl)ethyl hfacac hexafluoroacetylacetonate HMDS hexamethyldisilazide HMPA hexamethylphosphoramide imid imidazole Me methyl MPM 4-methoxybenzyl Ms methanesulfonyl MVK methylvinylketone NAP 2-naphthylmethyl NCS N-chlorosuccinimide Nf nonafluorobutanesulfonyl NIS N-iodosuccinimide NMO N-methylmorpholine N-oxide NMP N-methylpyrrolidine ox oxalate PCC pyridinium chlorochromate Ph phenyl pic 2-picolinate pin pinacolato

pivalate 4-methoxybenzyl pyridinium p-toluenesulfonate pyridine tetrabutylammonium fluoride tert-butyldiphenylsilyl tert-butyldimethylsilyl triethylsilyl trifluoromethanesulfonyl trifluoroacetic acid trifluoroacetic anhydride 2,2,2-trifluoroethyl tetrahydrofuran triisopropylsilyl N,N,N′,N′-tetramethylethane-1,2-diamine 2,2,6,6-tetramethylpyridinyl trimethylsilyl tetramethylthiourea tosyl

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