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Published in final edited form as: Chem Soc Rev. 2021 Sep 20;50(18):10044–10057. doi: 10.1039/d1cs00411e

Evolution Towards Green Radical Generation in Total Synthesis

Matthew S Galliher a,†, Bec J Roldan a,†, Corey R J Stephenson a
PMCID: PMC9074136  NIHMSID: NIHMS1802503  PMID: 34350919

Abstract

The use of radicals as intermediates in total synthesis has evolved since their initial use in the latter half of the twentieth century. Radical generation from metal hydride methodologies has shifted to “greener” techniques including catalytic metal-mediated systems, electrochemical and photoredox-mediated processes. This review will focus on these classical and contemporary methods for radical generation and their applications in recent total syntheses.

1. Introduction

The existence of carbon-centered radicals has been known for 120 years, but it was not until the latter half of the 20th century that their potential as intermediates in complex molecule synthesis was realized.1 In the last several decades, the use of radical methodologies has surged and radical intermediates are now an integral part of many synthetic pathways towards complex natural products, several of which are highlighted below (Figure 1).2 The analytical and synthetic methods used to characterize, generate, and utilize radicals in organic synthesis have evolved since the discovery of the triphenylmethyl radical by Moses Gomberg in 1900 at the University of Michigan.1 This discovery, which was made while attempting to prepare the compound hexaphenylethane by the Zn-mediated Wurtz coupling of triphenylmethyl chloride, paved the way for the new field of radical chemistry.

Figure 1.

Figure 1.

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Evolution of radical generation methods in organic synthesis

In the seminal report by Griller and Ingold, they provided a deeper understanding of radicals like the triphenylmethyl radical by defining radical “persistence” and “stability.”3 Persistent and transient radicals alike, have utility in complex molecule synthesis. Persistent radicals, owing to their longer lifetimes compared to transient radicals, facilitate slower inter- and intramolecular transformations as well as impart chemo-, regio-, and stereoselectivity before termination.4 Transient radicals can be useful as a result of their increased reactivity relative to persistent radicals, however can prove to be less selective than persistent radicals. Transient radicals can participate in intramolecular reactions as well as intermolecular reactions assuming they have the required stability. Radical cascades reactions in which a transient radical intermediate undergoes rapid termination can prevent the reverse cascade from occurring. This termination provides a kinetic driving force for the completion of the cascade. For a deeper discussion of the difference between persistent, stabilized, and transient radicals as well as the application of persistent and stabilized radicals in total synthesis, the following reviews are recommended.2, 4

Radical chain reactions, which include initiation, propagation, and termination steps, offer a way in which to utilize promiscuous radicals in complexity-building reactions in a selective manner (Figure 2).5, 6 The initiation stage often uses radical initiators (i.e. metals, one electron oxidants/reductants, photolabile initiators, etc). Dialkylazo compounds (11), dialkylhyponitrites (13), and peroxides (15, 17) are classes of molecules that are commonly used to thermally initiate radical processes via homolysis and loss of N2 or CO2 (Figure 3, top).7 Azobisisobutylnitrile (AIBN, 11) is one of the most common and well-studied aza-based radical initiators. Once the radical is generated, a variety of propagation steps can occur including: radical-radical couplings, β-eliminations, inter- and intramolecular C─C bond formations, and more. Radical chain reactions can be terminated in a number of ways including reduction, fragmentation, or a reaction of the final radical with the initial radical precursor.8

Figure 2.

Figure 2.

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A) Giese's synthesis of (−)-exo-brevicomin (5); B) Nagarajan’s synthesis of silphinene (10)

Figure 3.

Figure 3.

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Common "classical" techniques for the generation of radical intermediates.

The evolution of the use of radicals in the synthesis of complex molecules can be characterized into several phases. The first began in the late 1970’s with Bernd Giese’s development of the mercury hydride method to generate radicals for the coupling of organomercurials and olefins. This was the first form of the reaction we know today as the Giese reaction.9 The reductive demercuration conditions responsible for the generation of carbon-centered radicals have been known for some time, but this method was employed almost exclusively to reduce the radical to the alkane. The Giese reaction differs in that it forms C─C bonds intermolecularly.10 These conditions were greatly surpassed in popularity by the use of tin hydride in the presence of an initiator. This could be attributed to the benefits in reactivity that tin hydride offers (discussed in the next section) and perhaps due to these conditions being less toxic than organomercury salts. The use of tin hydride in current Giese reactions is still encountered in modern total synthesis. This reaction was utilized by Giese and co-workers in the total synthesis of (−)-exo-brevicomin (5, Figure 2A).5 Another early example of the use of radical chain reactions in total synthesis is Nagarajan’s synthesis of silphinene (10), which relies on the use of tin hydride and AIBN as the radical initiator, followed by an intermolecular cyclization as the propagation step (Figure 2B).6 Concurrently, metal hydrides as MH HAT (metal-hydride hydrogen atom transfer) reagents for the Markovnikov radical functionalization of olefins were being developed. Other developments included using samarium diiodide (SmI2) for the generation of radicals from carbonyl reduction were also being made at the time. Both of these methods remain steadfast in total synthesis.11, 12

Over time, synthetic chemistry has witnessed a shift in attitude regarding the means of radical initiation. Since the development of the principles of green chemistry, chemists have looked to incorporate these tenets into new and long-established methods. The principles of green chemistry advocate for limiting the use of toxic or hazardous reagents as well as minimize the generation of waste products due to bulk solvent use and poor atom economy.13 Although less toxic than mercury, organotin reagents have an associated toxicity to humans and aquatic life that has driven the field to find alternative techniques for radical genesis.14 Organotin byproducts are sometimes challenging to remove by chromatography as they coelute with desired products. This has necessitated the development of chromatography techniques that utilize alternative stationary phases.14 Generally, these “classical” means of radical genesis require either stoichiometric metal reagents or stoichiometric reductants and oxidants to regenerate reactive metal species at substoichiometric loadings.

The development of milder methods for radical generation over the last 15 years, taking the form of electrochemical and photoredox catalysis approaches, has fueled a resurgence of interest in radical chemistry. These new radical strategies have been applied to the total synthesis of complex molecules. Electrochemistry has historically been used for bulk chemical production.15 Improvements to chemoselectivity have permitted the use of electrochemistry in the synthesis of complex molecules, where chemoselectivity is often a challenge. Additionally, electrodes act as both a source and sink of electrons in an electrochemical reaction which circumvents the need for stoichiometric quantities of reagents. Similarly, developments and improvements to photoredox catalysis has allowed its use in total synthesis. When applied to net-redox neutral transformations, stoichiometric reductants and oxidants can be avoided. Both of these fields offer new ways to generate radicals in simpler, milder, and greener ways that differ from the classical methods mentioned above. To provide context for the development of these greener methods, this review highlights the application of “classical” radical methodologies in modern total synthesis. Then this review will highlight the use of greener electrochemical and photoredox-mediated catalytic strategies for generating radical intermediates in total synthesis.

2. Classical methods for radical synthesis

Some of the earliest examples of radical reactions have been performed with organomercurials, a class of stable compounds known since 1852.16 Organomercurials (R-HgX) can be decomposed to the alkyl radical in several ways (reductive demercuration, halogen cleavage, etc). Most common to organic synthesis is the treatment of the organomercurial salt with a reducing agent such as a borohydride. The hydride performs ligand substitutions yielding the mercuric hydride (R─HgH) intermediate. Mercuric hydrides contain an extremely labile Hg─H bond (BDE= 9.5 kcal/mol) and decompose readily to the carbon-centered radical forming mercury metal as a stoichiometric byproduct (Figure 3, middle).17 Though challenging, the resulting alkyl radical can undergo intermolecular chemistry. However, the rate of HAT termination via mercuric hydride is fast and often unavoidable making the mercury hydride method for radical generation less ideal for intermolecular chemistry. Due to this shortcoming of poor chemoselectivity coupled with the associated toxicities of these intermediates and the generated waste, mercury has been largely replaced by tin.

The use of tin hydrides (especially Bu3SnH) in radical transformations have been used for several decades and continues to persist despite the push to find greener alternatives.18 In addition to being “safer” than mercury, tin hydrides are especially advantageous due to the breadth of reactivity they offer in comparison to mercury (Figure 3, middle).19, 20 Due to the stability and longevity of the tin-centered radical generated following initiation via HAT (Sn─H BDE= 64 kcal/mol) from an initiator, they are used to propagate radical chain reactions.18 Propagation can occur when Bu3Sn performs HAT or XAT (halogen atom transfer) on labile C─H or C─X bonds, or when performing atom transfer radical additions (ATRA) that form carbon-centered radicals that can then undergo intra- or intermolecular reactions. Due to the affinity of tin towards sulfur and forming Sn─S bonds, thiocarbonyl-containing functional groups such as a xanthates have been employed with tin hydrides to serve as carbon-centered radical precursors (Figure 3, middle).21 In this process, the addition of tin radical to sulfur triggers a fragmentation event resulting in the carbon centered radical. This process is central for the mechanisms of the Barton-McCombie deoxygenation and Barton decarboxylation reactions.22, 23 Organosilanes (e.g. tris(trimethylsilyl)silane) have become an invaluable tool for mediating radical processes as they can act as H-atom sources.24

Organoboranes are a class of molecules used frequently as initiators upon reaction with oxygen (Figure 3, middle).25 Though this chemistry has been known for over 150 years, it was not until the late 1960’s that intensive mechanistic studies were performed and concluded the involvement of radical intermediates.26 Triethyl borane (20) is most commonly used. Initial reaction between triethyl borane and oxygen yields the autooxidation product, a peroxyboronate ester (21) which can decompose to the peroxy radical (22) and alkyl radical (23) species. This method of initiation is useful as it permits radical generation at low temperatures. However, as the presence of oxygen is required, chain processes become less efficient due to autooxidaiton of radical intermediates.

Techniques involving metal hydrides in radical processes have evolved such that transition metals (e.g., Fe, Co, and Mn) can be used in catalytic systems requiring substoichiometric quantities of metal and stoichiometric quantities of reductant (typically organosilanes).27 These developments have greatly reduced metal waste that is typically generated, although waste associated with the stoichiometric reductants and oxidants is challenging to avoid. In these systems, olefins (24) undergo MH HAT which results in a carbon-centered radical intermediate (25) that then undergoes reaction with a radical acceptor or termination by HAT or oxygen (Mukaiyama hydration) (Figure 3, middle).

Metals can generate radical intermediates simply by performing single-electron redox processes (Figure 3, bottom).28, 29 Ferrocenium, Mn(III), and Ce(IV) reagents have been useful as single electron oxidants.30-33 Samarium diiodide (SmI2) is frequently used as a stoichiometric reductant to generate carbon-centered radicals by single-electron reduction of ketone and aldehyde carbonyls (29, Figure 3, bottom).34 TiIII reagents are able to reductively open epoxides (31, via inner sphere SET) to give the more substituted carbon-centered radicals (32).35, 36

2.1. Kozikowski’s synthesis of malyngolide using the mercury hydride-mediated radical coupling

In 1982, Kozikowski and co-workers successfully synthesized malyngolide (36), a δ-lactone-containing antibiotic extracted from a marine blue-green alga (Figure 4).37 Key to the successful synthesis of 36 was the mercury-hydride-mediated Giese reaction which had only been developed 4 years prior.9 The synthetic route began from allylic alcohol 33 and provided access to organomercurial 34 in 6 steps. Treatment of 34 with trimethoxyborohydride in the presence of excess methyl acrylate furnished a 4:1 mixture of the desired nitrile 35 (as a 1:1 mixture of diastereomers) and reduction product. In this step, the organomercurial hydride (37) is formed from the reducing agent. 37 decomposes to form stoichiometric mercury metal and the alkyl radical 38 which can perform intermolecular coupling to methyl acrylate forming the α-nitrile radical 39. HAT from the mercurial hydride 37 ultimately delivers 35. The mixture of products highlights the challenge of using the mercury hydride method to generate radicals in C─C bond forming reactions. Organomercurial hydrides are excellent hydrogen atom donors and so the rate of HAT is fast compared to intermolecular C─C bond forming events. Therefore, it is essential to use a large excess of radical trapping agent. Even with 30 equivalents of methyl acrylate, 20% of the radical is terminated prematurely by HAT. From 35, the synthesis of malyngolide (36) was completed in one additional step.

Figure 4.

Figure 4.

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Kozikowski's 1982 total synthesis of malyngolide (36) leveraging the borohydride-induced carbon-centered radical generation from the organomercurial 34.

2.2. Inoue’s total synthesis of resiniferatoxin

In 2017, the Inoue group published a total synthesis of resiniferatoxin (47), a daphnane diterpenoid originally isolated from Euphorbia resinifera that was found to have strong analgesic properties (Figure 5).38 This synthesis leveraged two critical radical transformations with mechanisms proposed by the authors. First, a thermally-induced radical three-component coupling was used to construct intermediate 44, adding considerable complexity in single good-yielding (52% yield) transformation. In this step, the phenyl selenide (41) undergoes homolytic cleavage to form carbon-centered nucleophilic radical 49, which subsequently performs an intermolecular coupling with electrophilic enone 42, giving the α-keto radical intermediate 50. 50 then adds to the allylic triphenylstannane (43) resulting in the tri-coupled product 44. Radical 49 is able to participate in intermolecular coupling due to stabilization imparted by the alkoxy-substituent. This multicomponent coupling produces additional tin-centered radical which can further propagate the radical chain reaction as well as sequester phenylselenyl radical. This transformation incorporates the A-ring of the resinferatoxin core, introduces two new stereocenters, and incorporates the allylic chain that is critical in the formation of the 7-membered B-ring. Further in the sequence, a tin hydride-mediated radical cyclization constructs the 7-membered B-ring of the resiniferatoxin core. Upon heating, a sigmatropic rearrangement of the xanthate onto the neighboring olefin produces thioester 51. Bu3Sn, produced from the hydride and V-40 initiator, performs ATRA onto the xanthate forming the secondary radical 52 in a Barton-McCombie type fashion. 52 then performs a 7-exo-trig cyclization. Radical 53 subsequently forms exocyclic olefin 46 with the loss of the xanthyl group. The synthesis of resiniferatoxin (47) was successfully completed from 46 in 12 additional steps.

Figure 5.

Figure 5.

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Inoue's 2017 total synthesis of resiniferatoxin (47) that employs a themally induced three component radical coupling and Bu3SnH-mediated radical cyclization.

2.3. Xu’s tributyltin hydride-mediated cyclization approach to (+)-caldaphnidine J

The Xu group completed the asymmetric total synthesis of (+)-caldaphnidine J (57), a yuzurimine type alkaloid of the Daphniphyllum alkaloid family (Figure 6).39 Their synthetic approach demonstrates the utility of Bu3SnH and AIBN initiator to induce the intramolecular cyclization between tethered vinyl bromide and alkene moieties which constructed the tetrahydropyrrole motif. Initially, Xu and co-workers attempted this cyclization through a Ni0-mediated C─C coupling, but no appreciable quantity of 56 was formed. However, the tin-mediated strategy did successfully furnish 56. In this transformation, Bu3Sn is formed from Bu3SnH following initiation by AIBN. This radical then performs an atom transfer reaction to abstract bromide resulting in reactive vinyl radical 58. 58 then undergoes a 5-exo-trig cyclization onto the neighboring alkene to form cyclized secondary radical intermediate 59 and is ultimately terminated by Bu3SnH. Acidic workup gave the desired dehydrated, cyclized 56, which is then further elaborated to (+)-caldaphnidine J (57) following reduction of the exocyclic olefin.

Figure 6.

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Xu's 2020 total synthesis of (+)-caldaphnidine J (57) that employs a Bu3SnH-mediated radical cylclization.

2.4. Snyder’s Barton-McCombie deoxygenation strategy to spiroviolene

In 2020, the Snyder group completed the total synthesis of spiroviolene, a linear triquinane terpene (Figure 7) postulated to contain a misassigned steroecenter.40 Upon the completion of their synthesis of 62, the hotly debated stereocenter was correctly assigned by means of a number of synthetic, computational and analytical experiments. As part of their synthetic endeavor to synthesize 62, a Barton-McCombie deoxygenation was utilized as a last step in their synthetic route to furnish the sparsely functionalized natural product. The removal of functional groups in total synthesis is a challenge that is often circumvented by applying Barton-McCombie chemistry in this fashion. In this step, secondary alcohol 61 was thiocarbonylated with TCDI to give thiocarbamate 63. Bu3Sn generated from the hydride and AIBN forms the Sn─S bond to the thiocarbonyl which results in the generation of secondary alkyl radical 64. This reactive radical intermediate is then terminated by Bu3SnH affording the natural product spiroviolene (62) in good yield.

Figure 7.

Figure 7.

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Snyder's 2020 synthesis of spiroviolence (62) which leveraged a late stage Barton-McCombie deoxygenation.

2.5. Li’s total synthesis of xiamycin A via TiIII-mediated reductive epoxide opening and radical cyclization cascade

In 2015, the Li group published the total syntheses of xiamycin A (67) and several oridamycin natural products (Figure 8).41 67 is an indolosesquiterpenoid containing a central trans-fused decalin and a fused carbazole. Central to the successful synthesis of 67 was the construction of the trans-decalin which was achieved by a TiIII-mediated reductive epoxide opening and cyclization cascade of epoxide 65. The Li group leveraged conditions developed previously by the Gansäuer group in which substoichiometric loadings of Cp2TiIVCl2 could be used with stoichiometric reductant to generate the active Cp2TiIIICl reagent in situ.35 Epoxide-containing indole 65 was subjected to the reaction conditions to deliver the desired trans-fused decalin in 60% yield. In this step, the authors propose that Cp2TiIIICl is generated from Cp2TiIVCl2 by Mn-mediated reduction. Cp2TiIIICl performed inner-sphere SET reduction on epoxide to form the more stable tertiary radical 68. Two sequential 6-endo-trig cyclizations proceeded from radical 68 to give tertiary radical 70. Ti(III)-mediated loss of H ultimately delivers exocyclic olefin 71. The Lewis acid and base mixture in addition to excess reductant simultaneously generated the desired alcohol motif (66) and regenerated the Cp2TiIIICl reagent. Xiamycin A was synthesized from the indole-appended decalin in 3 additional steps.

Figure 8.

Figure 8.

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Li's 2015 total synthesis of xiamycin A (67) utilizing a TiIII-mediated reductive epoxide opening for an intramolecular radical cyclization cascade.

2.6. Inoue’s decarbonylative radical coupling strategy in the synthesis of 1-hydroxytaxinine

In 2019, Inoue and co-workers reported the total synthesis of a taxane diterpenoid, 1-hydroxytaxinine (76), isolated from the stems of the plant Taxus cuspidata.42 This natural product is linked to having cytotoxic properties in human epidermoid carcinoma cells. While this compound was first synthesized by the Kishi group in 1998, Inoue and co-workers cut down the 38-step synthetic pathway significantly by utilizing a combination of inter- and intramolecular radical coupling reactions. Starting from dione 72, radical precursor 73 was prepared in 9 steps (Figure 9). From there, they utilized previously developed chemistry from their group which involves an Et3B/O2-promoted radical coupling between an α-alkoxyacyl telluride and an electron-deficient olefin.43 The mechanism includes the generation of an ethyl radical from Et3B and O2 followed by an acyl radical 77 formation via C-Te homolysis. A subsequent decarbonylation produces the C9-α-alkoxy radical 78 which then adds to olefin 74 to form the new C8─C9 bond as a single isomer. The radical is the n trapped with Et3B to give the boron enolate 79 followed by a DDQ-oxidation to give intermediate 75. An additional twelve steps led to the total synthesis of 1-hydroxytaxinine (76).

Figure 9.

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Inoue’s synthesis of 1-hydroxytaxinine (76) via decarbonylative radical coupling

2.7. A comparison of Procter’s and Reisman’s synthetic strategies for the total synthesis of (+)-pleuromutilin

(+)-pleuromutilin (83) has been the target of several syntheses throughout recent years. (+)-pleuromutilin presents a challenging 5/6/8 fused ring system with 3 contiguous stereocenters (Figure 10). Procter and Reisman both utilized SmI2-mediated approaches to construct the 8-membered ring.44, 45 In Procter’s 2013 synthesis, dialdehyde 81 was subjected to SmI2 which resulted in the construction of both the 5 and 8 membered rings in a single step. It is proposed that the aldehyde that is to be part of the 5-membered ring first reacts with SmI2 to give radical 84 following single-electron reduction. This carbon centered radical cyclizes onto the neighboring olefin through a 5-exo-trig cyclization to give bicyclic radical 85. As the radical is positioned α to the ester, it is able to undergo reduction with an additional equivalent of SmI2 to give the corresponding Sm-coordinated enolate. It is thought that samarium coordination between the enolate and aldehyde allows for the diastereoselective aldol cyclization to occur thus constructing the 8-membered ring of 82 and completing the 5/6/8 tricyclic core. The Procter group successfully finished the synthesis of 83 in an additional 25 steps from 82.

Figure 10.

Figure 10.

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(Top) Procter's 2013 total synthesis of (+)-pleuromutilin (83) via Sml2-mediated tandem aldehyde-olefin coupling and aldol cyclization. (Bottom) Total synthesis of (+)-pleuromutilin by the Reisman group (2018) via Sml2-mediated radical aldehyde-enone coupling and coupled manganese hydride-mediated olefin reduction and alcohol oxidation through [1,5]-HAT.

In 2018, the total synthesis of (+)-pleuromutilin by the Reisman group leveraged a SmI2-mediated cyclization to integrate the 8-membered ring of the core structure onto the pre-existing 6/5 bicycle.45 Reduction of the aldehyde furnished radical intermediate 91 which then added intramolecularly to the enone to afford α-keto radical 92. Single-electron reduction by an additional equivalent of SmI2 formed enolate 93 which was quenched to ultimately form the ketone product 88, ultimately giving the 5/6/8 tricyclic core. Following silylation, a manganese hydride strategy was employed to reduce the exocyclic olefin moiety of 89 in the presence of a terminal olefin. This was accomplished by leveraging the thermodynamically favored formation of a tertiary radical. Unexpectedly, this reduction was accompanied by the oxidation of the alcohol to the ketone. In this reaction, the manganese hydride catalyst is generated from Mn(dpm)3 in the presence of Ph3SiH and TBHP. MHAT onto the olefin results in tertiary radical 94. This then performs a transannular [1,5]-HAT that ultimately oxidizes the alcohol. Although this oxidation state was undesired and necessitated a reduction of the ketone, it was found that the cleavage of the O─H bond during oxidation was critical for the success of this transformation.

3. Electrochemical generation of radicals

Although the field of electrochemistry has been well-established since the late 18th century, its synthetic use was largely grounded in the process-scale generation of bulk chemicals rather than the synthesis of fine chemicals and complex molecules.15 In recent decades, there has been a shift in interest toward the use of electrochemistry for total synthesis. Due to the number of parameters that can be adjusted (applied potential, electrode composite, electrolyte, divided vs. undivided cells, etc), desired chemoselectivity can be fine-tuned, making electrochemistry well-suited for complex molecule synthesis. Electrochemistry is particularly advantageous for single-electron processes that generate radical intermediates. Kärkäs and co-workers have published a recent review on advances in electrochemistry in organic synthesis.46

Electrochemical strategies for radical transformations can be performed under oxidizing or reducing conditions. Further control can be instilled by performing reactions with constant potential or a constant current. Performing an electrochemical reaction with a constant potential imparts greater chemoselectivity whereas doing so with a constant current imparts operational simplicity.47 Electron transfers are typically achieved at the double layer, the characterized stacking of charged molecules that forms around the electrode due to Coulombic interactions.48 These electron exchanges can occur between the electrode and substrate. In some instances, electrochemistry can be used to generate an active oxidant or reductant in situ that performs the electron transfer to or from the substrate. In these instances, regeneration of the active redox reagent is permitted without the need for exogenous, stoichiometric oxidants and reductants.47

3.1. Stephenson’s electrochemical phenol oxidation and bis-quinonemethide rearrangement for the synthesis of vitisins A & D

In 2020, the Stephenson group published the total syntheses of vitisins A and D (99 & 101, respectively), and the synthesis of the vitisin B core (98, Figure 11).49 97 was synthesized through a constant potential electrochemical phenolic oxidation method developed by the Stephenson group in 2018.50 In this transformation, substoichiometric quantities of the weak base 2,6-lutidine acts to weakly associate with the phenol proton. It is suspected that a proton-coupled electron transfer occurs at the anode to generate resonance stabilized radical 102 and protonated base. C8─C8’ dimerization occurs between two equivalents of 102 to give dimer bis-quinone methide 97 while the 2,6-lutidine is regenerated at the cathode following proton reduction. The persistent radical equilibrium of 97 was leveraged by means of a thermal rearrangement. When heated to 60 °C, the C8─C8’ bond undergoes thermolysis to the corresponding radicals. Radical localization at C─3 (103) and subsequent radical combination allows for the formation of C3─C8’ intermediate 104. Loss of the C–3 silyl group forms the phenol that cyclizes onto the quinone methide giving the rearranged dihydrobenzofuran 98 containing the vitisin B core. Subsequent treatment of 98 with methanolic HCl upon workup induces a rearrangement to afford vitisin A (99), whereas treatment of 98 with HF●Et3N removes the silyl protecting groups affording 100. Treatment of 100 with TMSCl and KI in water, conditions that generate HCl in situ, induces two sequential acid-promoted rearrangements yielding vitisin D (101).

Figure 11.

Figure 11.

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Stephenson's 2020 total synthesis of vitisins A & D (99 & 101) that utilized an electrochemical oxidation to form the key bis-quinonemethide intermediate 96. The persistent radical nature of 97 was then leveraged to thermally induce the C3─C8' reaarrangement to access the vitisin B core. Acid-mediated rearrangements furnished vitisins A & D.

3.2. Baran’s catalytic Snider-type cyclization for the synthesis of subglutinol A & B and higginsianin A

In 2018, Baran’s total synthesis of subglutinol A, B and higginsianin A showcases an electrochemically modified Snider-type polycyclization to access the key trans-fused decalin intermediate 106 as a single diastereomer (Figure 12).51 In a traditional Snider polycyclization, Mn(III) is used in stoichiometric quantities.52 Electrochemically, this can be performed with Mn(II) and with substoichiometric loading as the oxidizing current at the electrode provides the means to generate Mn(III) in situ. In this step, Mn(OAc)2 is oxidized under a constant current to the active Mn(OAc)3 catalyst. Following formation of the enolate, oxidation occurs to give the α-keto radical 111 which then cyclizes onto the olefin through a 6-endo-trig cyclization to give tertiary radical 112. This radical subsequently undergoes an additional 6-exo-trig cyclization onto the terminal olefin to give a highly reactive primary radical 113. The Cu(salen)2 catalyst then rapidly traps the primary radical which undergoes oxidative elimination to form exocyclic olefin 106. The resulting intermediate is then carried forward to successfully synthesize subglutinol A (107) and B (108) in 12 steps and higginsianin A (109) in 14 steps.

Figure 12.

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Baran's 2018 Total synthesis of subglutinol A (107) & B (108) and hippinsianin A (109) utilizing a catalytic Sinder polycyclization.

3.3. Chiba’s electrochemical total synthesis of pyrrolophenanthridone alkaloids

The 2020 total synthesis of pyrrolophenanthridone alkaloids by the Chiba group demonstrates the utility of electrochemistry to generate radical intermediates to accomplish an intramolecular C(sp2)–C(sp2) cross-coupling and indoline oxidations (Figure 13).53 In this method, the indoline 124 is first oxidized to the arene radical cation 125. Subsequent coupling of the neighboring arene to the radical cation forms tertiary radical 126. Subsequent re-aromatization and oxidation delivers coupled indole (127). The authors suggest that HFIP is critical to increase the electrophilicity of radical cation 125 in the presence of ClO4− electrolyte. Following the synthesis of cross-coupled indoline 127, constant current oxidation is utilized to oxidize the indoline to the indole (131). In this step, the indoline is oxidized to the radical cation 128. Deprotonation of 128 generates benzylic radical intermediate 129 whichthen undergoes a subsequent anodic oxidation to form benzylic cation 130. This is ultimately deprotonated by collidine to give the indole product 131. Several pyrrolophenanthridone natural products (121-123) were accessed from the coupled products following protecting group manipulation.

Figure 13.

Figure 13.

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Chiba's 2020 electrochemical total synthesis of pyrrolophenanthridone natural products via C(sp2)─C(sp2) cross coupling and indoline oxidation.

4. Generation of radicals by photoredox catalysis

Photoredox catalysis has had widespread use in the chemistry field over the last decade, it has only been recently applied to generating radical intermediates for natural product synthesis. Photoredox catalysts can take several forms including ligand-bound metal complexes or organic molecules which can permit redox chemistry using visible light. Using these catalysts provides a milder alternative to high energy UV light utilized in photochemistry of the previous century.54 Once excited with visible light, catalysts are able to perform single-electron transfer (SET) oxidation and/or reduction processes.55 There have been more comprehensive reviews on advances in photoredox-based methodology and applications in organic synthesis than what is covered in this review.54, 56 Photoredox catalysis has the ability to generate radicals for reductive couplings, photocycloadditions, intermolecular C─H functionalization reactions, and more. This provides multiple avenues to access natural product cores through complexity-building reactions. Net-neutral redox catalytic cycles offer a “green” means to generate reactive radical intermediates for total synthesis applications while reducing the generation of excess waste. Net-neutral redox cycles circumvent the need to handle toxic reagents as substoichiometric loadings of catalyst is achievable without relying on exogenous stoichiometric oxidants or reductants to regenerate the reactive oxidation state of the catalyst.

4.1. Smith’s total synthesis of danshenspiroketallactones

In 2019, Smith and co-workers reported the total synthesis of danshenspiroketallactone (136) and epi- danshenspiroketallactone (137) by utilizing [1,5]-radical relay chemistry (Figure 14).57 These natural products are isolated from the Salvia miltiorrhiza plant which is used in traditional Chinese medicine as a remedy for renal failure and heart disease. These lactones are intriguing targets due to their [5.5]- and [5.6]-spiroketal cores, which are normally accessed through an acid-catalyzed cyclization of 1,4,5- or 1,4,8-polyol precursors. Smith and co-workers directed their efforts to developing a catalytic method to access these precursors via direct C(sp3)–H functionalization. Starting from naphthoic acid 132, intermediate 133 was prepared in six steps to enable the [1,5]-radical relay reaction sequence. As proposed by the authors, the excited state of the photocatalyst was reduced by the Hantzsch ester (138). The Hantzsch ester radical cation then reduces 140 to the corresponding alkoxyl radical. 141 then undergoes [1,5]-HAT to form intermediate 142. This method is a thermodynamically favourable HAT as the electronically stabilized radical 142 is formed at the expense of the high energy oxyl radical 141. Radical addition of 142 to the Michael acceptor 134 give α-centered radical 143 which undergoes subsequent β-scission to furnish olefin product 135. An additional three steps led to the first synthesis of pure synthetic danshenspiroketallactones (136 and 137) in 10 steps.

Figure 14.

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Smith's approach to danshenspiroketallactones via [1,5]-radical relay chemistry

4.2. Luo’s total synthesis (−)-batrachotoxinin A

In 2020, Luo and co-workers reported an enantioselective total synthesis of (−)-batrachotoxinin A (148), a natural product related to (−)-batrachotoxin, an extremely toxic natural product that stabilizes voltage-gated sodium (NaV) channels (Figure 15).58 148 is less potent than (−)-batrachotoxin but can be converted to batrachotoxin analogs, thus serving as an interesting synthetic target for the purposes of further investigating NaV’s. Luo and co-workers sought to improve previous synthetic routes towards the synthesis of 148 by utilizing a local-desymmetrization approach. They also took advantage of recent developments in photoredox catalysis that allows access to highly oxygenated intermediates without relying solely on step-by-step increases of oxidation states. Starting from enantiopure 144, intermediate 145 was prepared in two steps enabling an open-shell radical substitution of 149 and diketone 146. The phenacyl radical 149 is formed from the reduction of the excited state photocatalyst. Then, in the presence of ethylene diamine triflic acid salt and diketone 146, enamine 150 is formed. The SOMO of the electrophilic phenacyl radical interacts with the HOMO of the enamine ketone affording radical intermediate 151. This α-amino radical is subsequently oxidized to the iminium which ultimately yields the final 1,3-diketone product 147 following workup in 70% yield on gram scale.59 An additional 12 steps led to the synthesis of (−)-batrachotoxinin A (148).

Figure 15.

Figure 15.

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Luo's total synthesis of (−)-batrachotoxinin A (148)

4.3. Overman total synthesis of (−)-macfarlandin C

In 2020, Overman and co-workers described the enantioselective total synthesis of (−)-macfarlandin C (157), a marine diterpenoids natural product (Figure 16).60 This class of natural products have been shown to induce irreversible fragmentation of the Golgi apparatus. While the Overman group has synthesized other marine diterpenoid natural products, (−)-macfarlandin C proved to be especially difficult given the steric congestion by the bulky hydrocarbon unit that resides on the concave face of the cyclooctenone fragment. Starting from 153, oxalate radical precursor 154 was synthesized in 10 steps. Irradiation of the Ir photocatalyst leads to the excited state oxidation of 154 via SET followed by a stepwise loss of two CO2 molecules forming the alkyl radical 158. Previous work in the Overman group showed that the incorporation of a radical-stabilizing group at the α-position of 5-alkoxybutenolide could increase efficiency of the fragment-coupling step.61 Through the coupling of 3-chloro-5-alkoxybutenolide 155 and a tertiary alcohol the conjugate addition product was achieved in an 80% yield as a single stereoisomer compared to the use of 5-methoxybutenolide and menthyloxybutenolide which gave 58% and 60% yields, respectively. Therefore, chlorobutenolide 155 was used to react with nucleophilic radical 158 to give the α-keto radical intermediate 159. Subsequent reduction of radical 159 leads to the halogenated intermediate 160. In the presence of excess tri-n-butylamine and under irradiation, the de-halogenated product 156 is obtained. An additional eight steps led to the first enantioselective total synthesis of the diterpenoid (−)-macfarlandin C (157). This synthesis is especially impressive due to the formation of new quaternary and tertiary stereocenters accessed through photoredox catalysis, allowing stereoselective entry into the structurally elaborate natural product target.

Figure 16.

Figure 16.

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Overman's total synthesis of diterpenoid, (−)-macfarlandin C (157)

4.4. Cordero-Vargas’ stereoselective total synthesis of aspergillide A

In 2019, Cordero-Vargas and co-workers reported the stereoselective total synthesis of aspergillide A (164, Figure 17), a natural product isolated from marine fungus Aspergillus ostianus found to have cytotoxic activity against leukemia cell lines.62 The main challenge of stereoselectively assembling the tri-substituted tetrahydropyran core was circumvented by using a photoredox-initiated free-radical approach, which relies on an atom transfer radical addition. Starting from the radical acceptor 161, the iodolactonization to access the intermediate 163 was tested. Initially, Cordero-Vargas and co-workers looked at a non-photoredox method involving initiation by lauroyl peroxide, and iodoacetic acid in 1,2-dichlorethane to give the lactone as a 1:1 mixture of diastereomers. Due to issues with purification and the scalability of this method, a new photoredox catalytic strategy was utilized. Based on initial results from Kokotos and co-workers, an atom transfer radical addition reaction occurs giving an iodoacid, followed by an SN2 cyclization with the carboxylate and the transferred iodine.63 In order to combat the formation of the carboxylate and the 5-exo-trig cyclization that follows, excess iodoacetic acid was used to ensure the hydroxyacid formation. Under acidic conditions the hydroxacid can form the desired δ-lactone. The photoredox method provided similar yields and selectivity as the aforementioned method, however was simpler to purify and was a more easily scalable method. In this step, the iodoacetic acid 162 undergoes reduction by the excited state photocatalyst giving α-carbon-centered radical 165 which then reacts with the olefin to give radical 166. This nucleophilic radical is able to perform an atom transfer radical addition with the transfer of the iodine from excess iodoacetic acid. Lactonization of 167 ultimately delivers product 163. An additional 14 steps led to the synthesis of aspergillide A (164).

Figure 17.

Figure 17.

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Cordero-Vargas' stereoselective synthesis of aspergillide A (164)

Conclusions

The frequency of radical-based strategies in natural product synthesis has grown as greener methods have been developed. These methods have not only paved the way for more sustainable radical chemistry, but have also provided organic chemists with novel restrosynthetic strategies that can be leveraged in the field of total synthesis. Electrosynthetic transformations utilize electricity as a cheap, versatile means to access radical species, while also allowing for high selectivity through the fine tuning of the electrode potential, among other things.46 For these reasons electrochemical methods for radical generation can be viewed as more sustainable options than their classical counterparts. As highlighted above, Stephenson and coworkers were able to use their previously developed electrochemical anodic oxidation in the synthesis of vitisins A and D, which allowed for an easily scalable, environmentally benign catalytic dimerization as opposed to their initial uses of stoichiometric oxidant to promote dimerization.31, 49 While we only highlight three examples of electrochemical radical generation in this review, there is indeed a wide array of electrochemical transformations that are applied to not only the total synthesis of complex molecules, but also in the development of new chemical methods and industrial applications.46 Due to all of the benefits of utilizing electrochemical methods in the synthetic endeavours mentioned above, scalable electrochemical methods have also found a place in the pharmaceutical industry, such as the academic-industrial collaboration between the Baran lab at Scripps Research Institute and chemists at Pfizer (Figure 18).64 This collaboration led to the development of a scalable electroreduction that was then applied in the synthesis of medicinally relevant compounds. More examples like this one are highlighted in this recent review by Lovato and coworkers at Merck.65

Figure 18.

Figure 18.

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Recent applications of photoredox catalysis and electrochemsitry in chemical industries

Through the generation of highly reactive intermediates in mild, controlled manners coupled with the ability of photoredox catalysts to act as both an oxidant and reductant simultaneously, photoredox catalysis gives access to previously inaccessible synthetic transformations and new forms of reactivity. Notably, as is highlighted in this review, photoredox catalysis can aid in the synthesis of highly congested quaternary centers (i.e. Smith’s synthesis 136 and 137, Luo’s synthesis of 148, and Overman’s synthesis of 157). In the syntheses of danshenspiroketallactones 136 and 137, Smith and coworkers’ expanded upon known transformations that rely on anion relay chemistry (ARC) to furnish 1,3,5-polyol by employing a Brook rearrangement. Brook rearrangements, which involve a [1,5]-negative charge migration to form reactive carbanions, rely on harsh conditions for silyl migration. Smith and coworkers instead utilize [1,5]-radical relay chemistry initiated by photoredox catalysis to generate carbon radicals via [1,5]-HAT of alkoxy radicals. This is only one of many examples in which photoredox catalysis can be leveraged to generate radicals that would be otherwise difficult or impossible to furnish using classical radical generation methods. When compared to the more traditional reaction methods used for radical generation that relied on harsh radical initiators highlighted at the beginning of this review, the utility of photoredox catalysis is now widely used in organic synthesis.

While classical methods for radical generation can still be leveraged in the field of total synthesis, their biggest limitations exist in their real-world applications in the chemical industries. Photoredox catalysis, like electrochemistry, provides pharmaceutical, agricultural and other chemical companies the opportunity to utilize radical chemistry in the synthesis of relevant compounds while also cutting down on toxic waste and impurities. Photoredox catalysis has seen a recent increase in applications in chemical industries, including academic-industrial collaborations between the Stephenson group at the University of Michigan and Eli Lilly and between Merck and the Knowles lab at Princeton in 2016 (Figure 18).66, 67 Abbvie has also taken advantage of photoredox catalysis in the synthesis of biologically interesting intermediates.68

As highlighted above, improvements and advances in electro- and photochemical methodologies to generate radicals under milder and greener conditions have made radicals more accessible. These methods have allowed radicals to be invoked in the presence of complex molecular architectures, have led to the formation of novel bond connections, and have been widely applied in the field of organic synthesis. Many of these applications of photoredox and electrochemistry-based methodologies would have been incompatible or unsustainable under the harsh conditions of past methodologies. The applications of these greener, more sustainable methods for radical generation are only just being realized, as they continue to find a role in the total synthesis of complex molecules, organic synthesis, process chemistry, and beyond.

Key learning points.

  1. This review will introduce the evolution of greener methods for radical generation in organic synthesis

  2. Traditional and modern photo- and electrochemical methods for radical generation will be covered

  3. This review will contexualize these methods by highlighting applications of these methods in natural product synthesis

Acknowledgements

The authors acknowledge the financial support from the NIH-NIGMS (GM121656), the Camille Dreyfus Teacher-Scholar Award Program, and the University of Michigan. We thank Cheng Yang, Dr. Sahil Arora, Efrey Noten, and Dr. Mike Supej for helpful discussions in the preparation of this manuscript.

Footnotes

Conflicts of interest

There are no conflicts to declare.

Notes and references

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