Shaping Molecular Landscapes: Recent Advances, Opportunities, and Challenges in Dearomatization

Abstract

Dearomatization is a fundamental chemical transformation, and it underlies some of the most efficient tactics for generating three-dimensional complexity from basic two-dimensional precursors. The dearomative toolbox, once restricted to only a handful of reactions, has begun to grow more sophisticated as novel methods are added, introducing more functionality under milder conditions and with more control over chemo-, regio-, and stereoselectivity than ever before. Over the past two decades, major developments in dearomative processes have bolstered significant total-synthesis endeavors and greatly expanded the scope and complexity of chemical building blocks accessible from feedstock arenes. In this Perspective, we highlight some of the recent advances and key challenges that remain in this vibrant area of organic chemistry.

INTRODUCTION

Approximately 100 million tons of aromatic compounds are produced annually by the petrochemical and coal industries. Although consumed mainly in the manufacture of polymeric materials, solvents, and fuels, arenes remain some of the most abundant and inexpensive carbogenic raw materials available to chemists. High electronic stabilization renders the aromatic ring inert to many common chemical transformations, yet also endows it with reactive properties orthogonal to those of other molecular entities.¹ Seminal accounts of arene hydrogenation were followed by reports that aromatic functionalization and substitution processes would proceed readily only as long as they restored aromaticity. Reactions that could indelibly disrupt aromatic resonance stabilization with concomitant introduction of functionality (dearomative functionalizations) proved to be challenging, and they became the subject of intense study.

Transformations of benzene derivatives that result in permanent loss of aromaticity have since become a cornerstone of synthetic methodology; over the last century, dearomative reactions such as hydrogenation,² the Birch reduction,³ and dearomatizations of phenols⁴ have revolutionized the way chemists make molecules (Figure 1).⁵ More sophisticated methods employing biocatalysis,⁶ transition metals,^7,8 and arenophiles⁹ have increased the complexity of building blocks accessible from simple benzene derivatives. Heteroaromatic compounds, which possess lower resonance stabilization than carbogenic arenes, have an equally rich canon of robust dearomative transforms.¹⁰ Dearomatization can be regarded as a bridge between the disparate worlds of arene feedstocks and the alicyclic structures pervasive among natural products, pharmaceuticals, perfumes, and other fine chemicals. The purpose of this Perspective is to review the state of the art, demonstrate the capacity of dearomative transformations in organic synthesis, discuss their limitations, and enumerate some of the challenges that lie ahead in the future of dearomative methodology.

Figure 1.

Representative Examples of Dearomatizations—Past, Present, and Future

DEAROMATIZATIONS IN THE TOTAL SYNTHESIS OF NATURAL PRODUCTS

The total synthesis of natural products provides rigorous conditions to evalúate and demarcate synthetic methods as they are pushed to their limits, demanding high chemo-, regio-, and stereoselectivity as well as functional-group tolerance—all on complex and delicate substrates.⁵ Countless applications of dissolving metal reduction³ and oxidative phenol dearomatization⁴ in this context are a testament to their value and longevity. Such classical dearomatization tactics have been employed in total synthesis for decades, but in recent years a number of underutilized and novel dearomative methods that have greatly streamlined the synthesis of ornate natural products have emerged. What follows are selected outstanding examples of modern dearomative methods applied within total synthesis during the past two decades, chosen both for their diversity and for their ability to rapidly generate complexity. Although in no way comprehensive, we hope that this collection is illustrative of the powerfully simplifying disconnections made possible through dearomative transformations.

Tetracyclines

First reported in 1971 by Reiner and Hegemon,¹¹ the ipso,ortho-cis-dihydroxylation of benzoic acid (1) derivatives by Alcaligenes eutrophus B9 (Ralstonia eu.) stands as a powerful tool for the generation of molecular complexity. This enantioselective, dearomative difunctionalization remains one of the only methods capable of generating a stereodefined tertiary alcohol from nonactivated carbogenic arenes, and it has proven invaluable in the preparation of intricate, chiral starting materials for total synthesis. In a 2001 report, Myers and co-workers showed that the biocatalytic process could be readily adapted to the laboratory on >90 gram scale and with >95% ee (Figure 2).¹² Optically pure cis-dihydrodiol (2) was subjected to a number of highly chemo- and diastereoselective reactions, including an interesting epoxidation and vinylogous Payne rearrangement sequence to furnish cyclitol (3). This intermediate could be elaborated to the complex isoxazole (4), which was used to prepare a plethora of tetracyclines, including (−)-tetracycline (5)¹³ and (−)-doxycycline (6).¹⁴ Myers and co-workers also synthesized numerous unnatural analogs such as 7 and 8, work that would later serve as the foundation for the Tetraphase pharmaceutical company.

Figure 2.

Selected Highlights of Dearomative Chemistry in Total Synthesis (Part 1)

Indoline Alkaloids

Many indoline alkaloids exhibit potent and desirable biological activities, and the catalytic, asymmetric dearomatization of indoles has attracted considerable attention over the past two decades, including in notable work from You, MacMillan, and others.¹⁵ Although these transformations are typically promoted by a transition-metal catalyst, MacMillan’s work stands out as a pioneering application of organocatalysis in the construction of these synthetically challenging alkaloids (Figure 2). First reported in 2004, the imidazolidinone 9-catalyzed cyclization of tryptamines via enantioselective addition into α,β-unsaturated iminium ions was used by MacMillan and co-workers in the total synthesis of the pyrroloindoline alkaloid (−)-flustramene B (data not shown). The scope of this organocatalytic method was later expanded to include the asymmetric [4 + 2] cycloaddition of enals and ynals with vinyltryptamine derivatives 10, the cascade process effectively forging two vicinal chiraI centers embedded within [4.3.3]-diazapropellane core 11 in a single operation.¹⁶ Notably, the use of vinyl selenides instead of sulfides triggered an alternative sequence that furnished tetracyclic spiroindoline scaffold 12.¹⁷ Complex intermediates generated through this process were rapidly advanced to numerous alkaloid natural products, including (−)-minfiensine (13), (−)-vincorine (14), (−)-kopsinine (15), (−)-kopsanone (16), (−)-akuammicine (17), (+)-vincadifformine (18), and (−)-strychnine (19).^15–17

Nominine

Dearomatization is a particularly rewarding tactic for the construction of topologically complex, caged polycyclic frameworks. Although flat, the high degree of unsaturation in aromatic systems provides them with substantially greater bond- and ring-forming potential than in saturated systems, where one must contend with a large number of C–H bonds and functional-group manipulations. A clear demonstration of this faculty can be found in Gin and Peese’s total synthesis of the hetisine-type C₂o diterpenoid alkaloid (+)-nominine (20).^18,19 Their remarkable retrosynthetic strategy tears the molecule in half via two dearomatizations and cycloadditions onto an oxidoisoquinolium betaine (Figure 2). Although the tandem cycloaddition was untenable for chemoselectivity reasons, a stepwise process was used to great effect. Intramolecular 1,3-dipolar cycloaddition of the cyanoalkene and oxidopyridinium betaine moieties of 22 assembled two heterocyclic rings and the western half of the molecule. Conversion of nitrile 23 to alkene 24 was followed by Birch reduction of the methyl phenyl ether to deconjugated enone 25. Intramolecular Diels-Alder cycloaddition of this alkene, with the dienamine formed from pyrrolidine, closed three additional rings and completed the dauntingly complex hetisine ring system 26, from which Gin and Peese were able to synthesize (+)-nominine (20) in only a few additional steps.^18,19 This work represents a distinctive example in which the authors constructed an arene de novo specifically to harness its reactive properties, only to destroy it in subsequent operations.

Kainoid Acids

The power of dearomatization in stereoselective synthesis need not be restricted to cyclic systems, as was aptly demonstrated by Clayden and co-workers in creative syntheses of the kainoid amino acids (−)-kainic acid (27)²⁰ and (−)-isodomoic acid C (28, Figure 3).²¹ Central to their strategy was an unusual dearomative, anionic cyclization of lithiated N-benzylbenzamide 29, furnishing a dienol ether that could be hydrolyzed to enone 30 under acidic conditions. This reaction was rendered enantioselective through the use of chiral lithium amide 31, generating enone 30 in 86% ee. Bearing the correct configuration of the three contiguous stereocenters of the kainoids, 30 could be advanced to (−)-kainic acid (27) and (−)-isodomoic acid C (28) after several oxidative manipulations, including cleavage of the phenyl group with ruthenium tetraoxide and a Baeyer-Villiger reaction to sever the remains of the aromatic ring into the two acyclic side chains.^20,21

Figure 3.

Selected Highlights of Dearomative Chemistry in Total Synthesis (Part 2)

Azaphilones

Enantioselective, non-enzymatic oxidative dearomatization of phenols has been a longstanding challenge in organic synthesis. One elegant solution to this problem was reported by Porco and co-workers in 2005, during a second-generation synthesis of the azaphilone family of natural products.²² Bis-μ-oxodicopper-sparteine complex 32 (formed in situ from a copper salt, the alkaloid, and molecular oxygen) was shown to be a competent tyrosinase mimic, capable of promoting the asymmetric oxidative dearomatization of 2-methylresorcinols such as 33 (Figure 3). Given that the (+)-sparteine enantiomer is not readily available, Porco and co-workers extended their asymmetric method by using the accessible (+)-sparteine surrogates reported by O’Brian,²³ rendering the asymmetric oxidative dearomatization stereodivergent.²⁴ The group has also reported several protocols for constructing the pyranoquinone nucleus of the azaphilone core 34—through cycloisomerization of the o-alkynylbenzaldehyde moiety—under carefully buffered conditions²⁴ via gold(III) or copper(I) catalysis.²² With access to both configurations of the chiral center and a number of cycloisomerization conditions, Porco and co-workers were able to complete the syntheses of multiple azaphilone natural products, including (−)-mitorubrin (35),⁵ (−)-S-15183a (data not shown),²² and (+)-sclerotiorin (data not shown).²⁴

Merrilactone A

Despite their low degree of aromaticity and high reactivity in a number of different transformations, furans are recalcitrant substrates in Nazarov-type 4π-electrocyclizations. Nonetheless, this reaction would be desirable as a method for constructing fused dihydrofuran and butenolide rings that could be elaborated to common structuresfound in natural products. An exciting approach that achievesthistype of furan dearomatization was shown by Frontier and co-workers during a 2007 total synthesis of (G)-merrilactone A (36, Figure 3).²⁵ Catalytic amounts of iridium complex 37 are proposed to activate the enone 38, triggering the dearomative Nazarov cyclization of its 2-silyloxyfuran motif. The remaining unsaturation in the resultant butenolide 39 was then used in a radical cyclization initiated from the pendent alkyne, assembling the [3.3.3]-oxapropellane system 40 of merrilactone A (36) in a three-step sequence. From this intermediate, Frontier and co-workers were able to close the final two rings and complete the synthesis of the natural product.²⁵

Dalesconol B, Totaradiol, Aspidospermidine, and Orinine

Whereas the oxidative dearomatization of phenols in the presence of heteroatom nucleophiles has proven to be a fundamental synthetic tactic in both inter- and intramolecular fashion, the corresponding C-C bond-forming transformations are underdeveloped and typically restricted to Diels-Alder cycloadditions with the cyclohexadienones that result from solvent addition during the dearomative event. Examples of direct dearomatization with carbon nucleophiles are scarce and mainly used to produce spirocyclic compounds. The electrophilic variant of this reaction has found much more widespread application in organicsynthesis but is limited to highly reactive electrophiles such as allylic halides. In 2015, Tang and co-workers developed a powerful addition to the arsenal of electrophilic dearomatization methods by using enantioselective transition-metal catalysis.²⁶ Substrates such as 41, containing a para-substituted phenol and an aryl or vinyl (pseudo)halide, were found to undergo an intramolecular dearomative arylation in the presence of a suitable palladium catalyst, generating tricyclic systems like 42 with a bridgehead quaternary carbon with high enantioselectivity (Figure 4). Although one might expect either ortho- or para-attack of the phenol onto the electrophilic palladium(II) species 43 after oxidative insertion, Tang posits para-substitution as being more kinetically accessible, generating product 42 rather than the thermodynamically preferred 44.²⁶ The utility and robustness of this method are manifest in the myriad streamlined synthesis of terpenoids,²⁶ alkaloids,²⁷ and aromatic polyketides²⁸ reported by Tang and co-workers. A few of the many natural products they have completed by using this method are (+)-dalesconol B (45), (−)-totaradiol (46), (−)-aspidospermidine (47), and (−)-crinine (48).^26–28

Figure 4.

Selected Highlights of Dearomative Chemistry in Total Synthesis (Part 3)

Isocarbostyril Alkaloids

The development of arenophile-mediated dearomative methodology has increased the scope and complexity of dearomative functionalizations that can be performed on simple, nonactivated arenes such as benzene (49, Figure 4).^1,9 Sarlah and co-workers reported an expansion of this prior work in 2017 by merging arenophile-mediated dearomatization with chiral transition-metal catalysis to achieve an unprecedented catalytic desymmetrization of benzene (49).²⁹ After visible-light-promoted para-cycloaddition of MTAD (50) onto benzene (49) and treatment of the resultant cycloadduct 51 with a nickel(0) source and an aryl Grignard reagent initiates a catalytic, enantioselective substitution reaction that delivers the products of a formal trans-1,2-carboamination. Norbornadiene-like π-complexation and oxidative addition of the metal into the bisallylic C-N bond is proposed to generate a symmetric, η⁵-nickel(II)cyclohexadienyl complex with strong cationic character localized at the termini. Transmetalation with the arylmagnesium bromide 52 and reductive elimination furnishes trans-1,2-carboaminated product 53. The use of chiral, bidentate ligands on nickel enables profound catalyst discrimination between the two enantiotopic termini of the η⁵-complex, generating diene 53 in 98:2 er. Notably, as with other arenophile-mediated dearomatizations, this transformation effectively functionalizes one formal double bond in the aromatic system, leaving the other two available for further manipulation. By treating benzene as a surrogate for the fictitious cyclohexa-1,3,5-triene, this approach enables the synthesis of hexafunctionalized cyclohexane derivatives in only two or three steps; this stratagem is used nicely in rapid, enantioselective syntheses of the potent antineoplastic isocarbostyril alkaloids (+)-7-deoxypancratistatin (54), (+)-lycoricidine (55), (+)-pancratistatin (56), and (+)-narciclasine (57).^29,30

ent-Kaurenoids

The Diels-Alder reaction of cyclohexa-1,3-dienes has proven to be one of the most effective and general methods to build the carbogenic bicyclo[2.2.2]octane motifs found in a wide range of diterpenoids and other natural products. Such dienes are often highly reactive and are difficult to carry through multistep organic synthesis. The use of phenols as masked 1,3-dienes—which can be liberated under mild oxidative conditions—is an attractive and oft-used strategy for the assembly of bicyclo [2.2.2]octane scaffolds. Construction of the isomeric bicyclo[3.2.1]octane framework also common to many terpenoid architectures is less straightforward and has left room for many creative, target-specific approaches. A novel, robust dearomative approach to the [3.2.1] bicyclic skeleton was reported by Ding and co-workers in 2017.³¹ Treatment of monoprotected catechols bearing olefin side chains (e.g., 58) with hypervalent iodine oxidants initiates an oxidative dearomatization-induced [5 + 2] cycloaddition whose cationic intermediate 59 readily undergoes 1,2-acyl migration to assemble the complete bicyclo[3.2.1]octene system 60 in a single step (Figure 4). The efficacy of this unique method was showcased through the synthesis of four ent-kaurene diterpenoids by the Ding group, including (−)-pharicin A (61).³¹ Ding and co-workers also used this strategy in a recent synthesis of (−)-rhodomollanol A (data not shown).³²

Jorumycin

Although one of the earliest known dearomative methods, the hydrogenation of arenes and heteroarenes remains a vibrant and active field of research to this day. Advances in enantioselective catalysis as well as functional-group and heterocyclic tolerance have established dearomative hydrogenation as one of the premier methods for generating complex, saturated cyclic structures.² A demonstrative example of the powerfully simplifying disconnections made possible through enantioselective hydrogenation of arenes is found in the 2019 synthesis of (−)-jorumycin (62) from the Stoltz group (Figure 4).³³ Many successful syntheses of the bis-tetrahydroisoquinoline (bis-THIQ) alkaloid natural products have been disclosed before, but almost all rely upon stepwise construction of individual THIQ rings through Pictet-Spengler and other electrophilic aromatic substitution-based cyclization methods. The elegant approach reported from the Stoltz group leverages the power of modern cross-coupling to quickly assemble 63 from two simple, flat isoquinoline motifs. This is followed by a newly developed, enantioselective dearomative isoquinoline hydrogenation that sets four stereocenters and triggers cyclization to the bis-THIQ core 64 through lactamization. From this complex intermediate, Stoltz and co-workers were able to complete the syntheses of (−)-jorunnamycin (not shown) and (−)-jorumycin (62)—as well as a series of unnatural analogs—in a rapid and efficient manner.³³

STATE OF THE FIELD AND FUTURE DIRECTIONS

As illustrated with the selected examples above, dearomatization chemistry offers unique molecular disconnections, providing one of the most rapid complexity-generating strategies in organic synthesis. Although these transformations have steadily gained momentum during the last decades, there remain numerous opportunities and unsolved challenges still to be addressed. This section covers some of the most notable recent achievements and draws attention to elusive transformations that are likely to find widespread adoption within the synthetic community.

Dearomative Reductions

Reductions of aromatic nuclei are among the oldest known dearomatizations, and although homogeneous catalytic dearomative hydrogenation processes were first reported more than 50 years ago,³⁴ only recently has this area seen some of its most significant breakthroughs (Figure 5A).² Major efforts in this realm have been invested in asymmetric reductions, resulting in numerous highly enantioselective methods that provide solutions for many heteroaromatic substrates.³⁵ However, the enantioselective reduction of aromatic hydrocarbons is virtually nonexistent, such that only one report involves the highly enantioselective hydrogenation of substituted naphthalenes (e.g., 66 → 67) based on a Ru catalyst.³⁶ Nevertheless, this indicatesthat perhapssoon wewill see more of these transformations, especially with elusive benzene derivatives that could unlock complementary access to enantioenriched cyclohexane derivatives. In addition to enantioselective reductions, the field has recently seen a surge of dearomative hydrogenations with unprecedented chemoselectivities. Among the outliers are several methods based on the use of cyclic (amino)(alkyl)carbene rhodium complex CAAC-Rh (69), which has significanti advanced the field of reductive dearomatizations by tolerating a range of functionalities that were traditionally incompatible with previous catalytic systems. For example, no reduction of ketones is observed (e.g., 70 → 71),³⁷ and just as impressively, this catalytic manifold can reduce benzene derivatives containing fluorine and boron functionalities (e.g., 72 → 73).^38,39 Without question, these methods will see extensive use and further developments as they provide products of high synthetic utility and complexity by practical means.

Figure 5. Selected Dearomative Methods.

(A) Dearomative reductions.

(B) dearomative functionalizations.

In addition to hydrogenation methods, Birch-type reductions have recently seen major developments as new, ammonia-free protocols drastically simplified the preparation of partially reduced compounds. For example, inspired by the design of Li-ion batteries, electrochemical reduction using TPPA and DMU as additives for over-charge protection and potential stabilization of electrogenerated lithium species was successfully applied in the dearomatization of numerous arenes (e.g., 74 → 75), and the yields and functional-group tolerance often exceeded those of dissolving metal-based methods.⁴⁰ Furthermore, recent advances in photoredox chemistry resulted in photoreduction of arenes through a combination of Ir-photocatalyst-mediated energy transfer and electron transfer (e.g., 76 → 77),⁴¹ intercepting similar radical anion intermediates operative in classical Birch reductions. And although photoredox dearomatizations have a steep path ahead to provide reduction of nonactivated monocyclic arenes, their mildness and practicality would translate well into the field of total synthesis. Finally, these two examples represent just a portion of many new concepts that were recently disclosed in the rapidly developing areas or dearomative photochemistry⁴² and electrochemistry.⁴³

Not surprisingly, the main challenges that remain in the field of dearomative reductions are associated with selectivity. Overreduction in the case of hydrogenations and substrate-specific selectivity of single-electron-transfer reductions precludes the ultimate site-selective reductions (e.g., 79 → 80 or 81 or 82). These are often major limitations, dissuading chemists from choosing these methods for the preparation of cyclohexane-based intermediates. Going a step further, perhaps the “holy grail” of dearomative reductions would be the establishment of trans-selective processes (e.g., 83 → 85 or 84 → 86), which would drastically change the landscape of small-molecule synthesis. Not long ago, such transformations were considered a distant science fiction, yet recent investigations involving Mo-catalyzed homogeneous hydrogenations of different xylenes provided 1,2-, 1,3-, and 1,4-dimethyl-substituted cyclohexanes as 4:1 to 1:1 mixtures of cis:trans diastereoisomers,⁴⁴ hinting that trans-selective reductions might become reality soon.

Dearomative Functionalizations

As seen in many of the earlier synthetic examples, reactions that install functionality concurrently with dearomatization are highly sought after in organic synthesis. Ultimately, dearomative functionalization offers a powerful synthetic stratagem for the construction of a multitude of highly decorated carbo- and heterocycles. However, the chief hindrance in this area is the dearth of suitably general methods, as most of this research has been conducted on a small number of activated substrates; the most significant developments have been in asymmetric dearomatizations of phenols and specific heterocycles (Figure 5B).⁸ For example, aryl iodide-based catalyst 87 enabled dearomative spirocyclizations (e.g., 88 → 89) in a highly enantioselective fashion via the intermediacy of a chiral hypervalent iodine species.⁴⁵ Moreover, an organocatalytic approach with chiral phosphoric acid 90 as a catalyst was used for dearomative amination of naphthols (e.g., 91 → 92),⁴⁶ providing enantioenriched tertiary amines that are amenable to further derivatizations. Furthermore, dearomative functionalization of heterocycles has seen a wave of development over the last decade. Among many notable achievements are new chemoselective, dearomative functionalizations of pyridines—traditionally dearomatized as pyridinium salts at positions 2 or 4—which can now be altered at position 3. Through a two-step protocol, involving dearomative reduction of in-situ-generated pyridinium and subsequent Cu-catalyzed enantioselective borylation (e.g., 93 → 94), a range of pyridines could be transformed to functionalized piperidine derivatives with high optical purity.⁴⁷ In a similar yet distinct fashion, piperidinium salts could undergo a series of Ir-catalyzed interrupted hydrogen transfer reductions, ultimately delivering 3-hydroxymethylated tetrahydropyridine products (e.g., 96 → 97),⁴⁸ which could not be readily prepared by established chemistry. Finally, the most underdeveloped dearomative functionalizations involve nonactivated arenes. These have been mainly achieved with transition-metal-arene complexes that can drastically alter aromatic character of bound arenes.^7,49 Although synthetically quite useful, the stoichiometric use of expensive and toxic metals has been a significant impediment to their widespread application. Alternatively, cycloaddition could be used as a mechanism forthe introduction of functionality, as recently demonstrated with the use of arenophile-based dearomatizations.⁹ For example, naphthalene underwent cycloaddition with MTAD (50) followed by in situ dihydroxylation of the cycloadduct (e.g., 98 → 99). The corresponding arenophile motif—a urazole heterocycle—was hydrolyzed and reduced to a diamine, ultimately delivering a dearomatized product with four newly installed functional groups.⁵⁰ As seen above in the synthesis of pancratistatin (56) (Figure 4),²⁹ arenophile-arene cycloadducts could also be exposed to transition-metal catalysis, specifically the Ni-catalyzed dearomative trans-1,2-carboamination. Application of other metals can result in a complete change of selectivity; the combination of Pd catalysis and either enolates⁵¹ or Grignard reagents⁵² as nucleophiles affords a complementary syn-1,4-carboamination. Heteroatom nucleophiles are compatible as well, as showcased with Pd-catalyzed syn-1,4-diamination of benzene (e.g., 49 → 100).⁵³ Although effective for introducing a variety of functionalities, the arenophile-based dearomatizations are currently restricted to aminofunctionalizations.

Compared with reductions, dearomative functionalizations have so far been limited to only a few subtypes of aromatic compounds, and many opportunities and subsequent developments are incumbent. For instance, there are no general chemical approaches to dearomative functionalization of nonactivated arenes (e.g., 101 → 104). Established methods using arenophiles or stoichiometric complexation with transition metals have begun to move the field in this direction; however, these methods are limited to specific aromatic substrates and have a narrow functionalization scope. Moreover, regarding heterocycles, dearomative methodsthat can install heteroatom functionality (e.g., 102 → 105 or 103 → 106) are heavily underdeveloped despite the fact that they could easily outcompete most of the established strategies to such synthetic intermediates. Finally, the site-selective dearomatization of polycyclic arenes (e.g., 107 → 108), which can avoid inherent substrate-driven reactivity, is virtually nonexistent.

Dearomative Molecular Editing

An alternative to the dearomative processes described above are transformations that result in skeletal changes. Although transformations of this type provide a more narrow and specific scope of products—often not structurally related to natural products—such “molecular editing” is becoming increasingly applicable in medicinal chemistry because it enables rapid transition of simple arenes into uncharted chemical space. Most of these dearomatizations are based on cycloaddition chemistry, providing complex polycyclic architectures. For example, intramolecular thermal Diels-Alder reaction between arenes and allenes (e.g., 109 → 110)⁵⁴ can deliver elaborate polycyclic structures amenable to further chemistry that would be very difficult to prepare by any other means (Figure 6). In addition, one-electron-based cyclizations are equally capable of dearomative structural elaborations, as was recently demonstrated with a photocatalytic reductive reaction between aldimines and quinolines that yielded bridged 1,3-diazepanes (e.g., 111 → 112).⁵⁵ Moreover, photocatalytic para-cycloaddition between pyridines and tethered olefins, proceeding through a triplet excited-state of the alkene moiety, gave unique isoquinuclidine-based polycycles (e.g., 114 → 115).⁵⁶ Dearomative cycloadditions based on the arenophile MTAD (50) were also used for expansion of arenes to oxepines (e.g., 116 → 117).⁵⁷ Such heteroatom insertions and shapeshifting reactions are rare; however, their development will continue to enrich the dearomative molecular editing toolbox. Similarly, arenes could undergo asymmetric Rh-catalyzed cyclopropanation, providing enantioenriched bicyclic norcaradienes (e.g., 118 + 119 → 120)⁵⁸ that offer myriad functionalization possibilities. This type of dearomative editing, based on heteroatom insertions (e.g., 123 → 122) and expansions (e.g., 125 → 124), would be highly desirable, and major developments are still forth-coming. Likewise, dearomatizations accompanied by atom mutations (e.g., 123 → 124) are among the missing transformations that the field is likely to see in the future.

Figure 6.

Dearomative Molecular Editing

SUMMARY AND OUTLOOK

Dearomatization is a fundamental chemical transformation, and it remains one of the most efficient tactics for generating three-dimensional complexity from basic two-dimensional precursors. From simple Birch reductions and oxidative dearomatization of phenols, to more modern, transition-metal-catalyzed dearomative functionalization, the application of dearomatization in organic synthesis has been pivotal in addressing the ever-greater challenges faced by synthetic chemists in the search for practicality. This Perspective outlines a number of modern dearomative strategies, many of which were incorporated into the broader framework of natural product total synthesis and illustrates what we perceive to be a renaissance in dearomative strategy and method development that has occurred during the past two decades. In particular, we would like to draw attention to the increasing use of photochemistry, a powerful tool that has enabled numerous advances in dearomative reduction, functionalization, and molecular editing. As more sophisticated transformations emerge, we anticipate that dearomatization will continue to serve as a premier strategy for sculpting complex, three-dimensional molecular landscapes. Nonetheless, several challenging limitations remain in this field, and numerous opportunities lay unaddressed. Perhaps most notably, applications of dearomative chemistry within industrial settings are scarce and largely restricted to hydrogenations. The extension of dearomative functionalization reactions to process scale could open new avenues within the pharmaceutical, perfume, and fine chemical industries; however much anticipated, such developments have yet to be realized. We hope that these hindrances will serve as inspiration to stimulate new growth and advancement, such that the field of dearomative organic synthesis can continue to thrive for years to come.

The Bigger Picture.

Challenges and opportunities:

• Developing new strategies for chemo- and stereoselective dearomative hydrogenations that avoid the problem of overreduction.

• Expanding the scope of functionality that can be introduced through dearomative functionalization and increasing the level of complexity that can be achieved through such transformations.

• Developing tactics for “molecular editing”—transformations that radically alter the carbon skeleton of (hetero)arenes through dearomatization.