Appreciation of symmetry in natural product synthesis

Wen-Ju Bai *a and Xiqing Wang *b
aDepartment of Chemistry, Stanford University, Stanford, California 94305-5080, USA. E-mail:
bCollege of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu 225009, China. E-mail:

Received 11th September 2017

First published on 23rd November 2017

Covering: 2012 to June 2017

This review aims to show that complex natural product synthesis can be streamlined by taking advantage of molecular symmetry. Various strategies to construct molecules with either evident or hidden symmetry are illustrated. Insights regarding the origins and adjustments of these strategies as well as inspiring new methodological developments are deliberated. When a symmetric strategy fails, the corresponding reason is analysed and an alternative approach is briefly provided. Finally, the importance of exploiting molecular symmetry and future research directions are discussed.

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Wen-Ju Bai

Dr Wen-Ju Bai initially studied chemistry with Professor Qi-Lin Zhou at Nankai University. He then went to Santa Barbara to pursue his doctoral degree with Professor Pettus at the University of California, working on the synthesis of tetrapetalones. He subsequently moved to Palo Alto in early 2015 and has been working with Professor Barry Trost on the synthesis of amphidinolides as a postdoctoral fellow at Stanford University. His research interests focus on natural product synthesis and related enzymatic transformations.

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Xiqing Wang

Dr Xiqing Wang is currently an Associate Professor at the College of Bioscience and Biotechnology at Yangzhou University. Dr Wang obtained his Bachelor of Science in Biology at the University of Science and Technology of China and his Doctor of Philosophy in Chemistry with Professor Frederick W. Dahlquist at the University of California Santa Barbara. His research interests include natural product related biocatalysis and protein engineering as well as exploring the mechanism of bacterial chemotaxis.

1 Introduction

Natural products, which are produced by living organisms, have evolved over millions of years. Due to their fascinating bioactivities, natural products have provided the source or inspiration for approximately half of the US FDA-approved drugs, thus playing a dominant role in the discovery of lead compounds for drug development.1 Moreover, their structural complexities and diversities have inspired innovations among the chemistry community by exposing current method limitations and calling for superior tactics to prepare these molecules. Building on its rich history, modern natural product synthesis has shifted its focus from feasibility to efficiency, featuring atom-,2 step-,3 redox-economy4 and scalability.5 Besides, the intensifying environmental concerns require the investigation of green and sustainable approaches.6 The persistent desire to create molecules in a sequence of only construction reactions with no intermediary refunctionalizations7 has encouraged chemists to produce complex natural products in a concise fashion. In this review, we show the various ways to realize short synthesis by the appreciation of symmetry.

Symmetry, especially bilateral symmetry, is ubiquitous in nature, architecture, and natural products (Fig. 1a–c). More than 99% of animals are bilaterally symmetric, including humans. Architecture makes extensive use of symmetry for internal stability and balance as well as external harmony and beauty. Although all natural products exhibit stunning structural complexity, >7% of them possess bilateral symmetry,8 and 17% of them possibly involve a dimerization process in their biogenesis and thus display a certain form of symmetry.9 Accordingly, taking advantage of these symmetric elements can drastically accelerate their total syntheses.

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Fig. 1 Symmetry is universal in nature, architecture, and natural products.

Strictly speaking, molecular bilateral symmetry is defined as including C2,10Cs, and C2v point groups in a molecule. However, herein, we broadly define symmetric molecules from a synthetic perspective (Fig. 1d). Both bilaterally symmetric and non-symmetric dimers are comprised of two identical monomers, which display evident symmetry. We also treat non-symmetric pseudo-dimers as molecules with evident symmetry since the two monomers, albeit non-identical, are usually prepared in a similar manner. Consequently, exploring appropriate methods to connect these (pseudo-) identical halves can significantly simplify their construction. Molecules with hidden symmetry do not globally exhibit obvious symmetry but may retrosynthetically include limited symmetric elements. Therefore, strategies such as desymmetrization or sharing a common fragment can be employed to shorten their syntheses. Since the exploitation of desymmetrization in natural product synthesis has been recently reviewed,11 it will not be covered in this article.

Typical examples of symmetric molecules can be seen in Fig. 2. SCH 351448,12 methylenebismehranine,13 chloranthalactone F,14 and HMP-Y1[thin space (1/6-em)]15 possess C2 symmetry, whereas teurilene16 and polyozellic acid17 present Cs and C2v symmetry, respectively; however, they are all bilaterally symmetric dimers. Molecules with evident symmetry such as paracaseolide A,18 thionuphlutine,19 and pungiolide A20 are non-symmetric dimers. Sometimes, it is difficult to observe the symmetry in non-symmetric dimers because further transformations occur after the connection of two identical monomers. For example, pungiolide A arises from the [4 + 2] cycloaddition of the monomer 8-epi-xanthatin followed by additional functionality elaborations involving epoxidation and subsequent epoxide ring opening.21 Unlike evident symmetry, molecules with hidden symmetry are recognized from a synthetic perspective. For example, pactamycin22 is accessible from the symmetric α-ureido-2,4-pentanedione via desymmetric reduction.23 Additionally, shizukaol D can be synthesized via the [4 + 2] cycloaddition of two monomers that are non-identical but share the same 3/5/6-tricyclic skeleton.24

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Fig. 2 Typical examples of natural products bearing evident or hidden symmetry.

In this review, symmetry refers not only to symmetric molecules (see our definition in Fig. 1d), but also to symmetric strategies to construct these molecules. As demonstrated below, symmetric strategies are particularly beneficial for building molecules with hidden symmetry in a concise fashion. Herein, we highlight the most incredible and cutting-edge natural product syntheses that take advantage of symmetry to accelerate their constructions. A wide range of molecules with either evident or hidden symmetry is succinctly discussed below. In each section, a guideline of the symmetric designs is given, followed by examples to help readers understand the principle of these synthetic strategies. New methodological developments inspired from the synthetic processes are also emphasized. Biosynthesis sometimes inspire chemists to propose possible symmetric designs. However, when a biomimetic synthesis25 proves to be unproductive, symmetric designs are usually adopted. For symmetric macrodiolides or hidden symmetric molecules that share a common fragment for synthetic convenience, their constructions often largely consider potential molecular symmetry for efficiency. When a symmetric strategy fails, the synthetic experience obtained from the initial symmetric design is still well appreciated for the alternative strategy. All selected synthetic examples, which are mostly from 2012 to 2017, have not been covered in other reviews on this topic before.26

2 Molecules with evident symmetry

Synthetic strategies to build molecules with evident symmetry rely on the deployment of appropriate reactions to rapidly join two (pseudo-) identical fragments. Commonly seen reactions include esterifications, coupling reactions, conjugate additions, and cycloaddtions/oxidative cyclizations.

2.1 Esterifications

In symmetric macrodiolides, two identical halves are connected through ester bonds. Accordingly, various known macrolactonization methods27 may provide straightforward strategies for these molecules. However, the pursuit of better synthetic efficiency always motivates chemists to design novel methods for the corresponding fragment assembly or preparation. For example, rather than using any known macrolactonization methods, Breit developed his own fragment assembly method to build ester bonds in his synthesis28k of clavosolide A.28 This new method, which features the rhodium-catalyzed atom-economical addition of carboxylic acids to allenes,29 enabled him to conveniently access the key intermediate 2 (eqn (1)).
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For symmetric macrodiolides, it seems apparent that coupling two identical halves can realize their total syntheses. However, where to break the bonds within these macrodiolides, concisely preparing these proposed halves, and successfully stitching them together are not trivial or easily achieved. Without efficient novel methods, the concise synthesis of a symmetric macrodiolide is not guaranteed. The use of new methods for fragment preparation can be seen in Aggarwal's synthesis of clavosolide A,28l which highlights his lithiation-boration method,30 as well as Krische's synthesis of swinholide A 31 which features his enantioselective alcohol-mediated carbonyl allylations.32 Taking advantage of Ir-catalyzed enantioselective C–C coupling methods to rapidly address the fragment preparations, Krische was able to accomplish the short synthesis of swinholide A [LLS (longest linear sequence): 15 steps; TS (total steps): 30]. Compared to previous work with a 27 LLS & 50 TS31f–j or 35 LLS & 59 TS,31k,l Krische's approach is almost half of both the longest-linear-sequence and total-step counts.

2.2 C–C/N–N coupling reactions

The cross-coupling reaction has been frequently used for symmetric natural product synthesis, among which palladium-catalyzed reactions play an important role in C–C/C–N bond formation and act as a site-controlling tool to fuse two coupling partners together.33 Sometimes, uncontrolled oxidative coupling reactions may serve as a faster approach to build molecules with evident symmetry. When known strategies fail to efficiently access symmetric molecules, new methods or techniques stand out.

Pd-catalyzed Suzuki coupling was harnessed as a central fragment-assembly method in Brückner's synthesis of γ-actinorhodin (Fig. 3).34 Starting from the tetramethoxynaphthalene 3, directed ortho-lithiation/iodination followed by NBS bromination introduced dihaildes onto the aromatic core at desired positions, during which the steric effect of the bromo substitute guided the instalment of the iodo moiety via a remote but relayed effect. The Heck reaction of dihailde 4 with ethyl 2-vinylacetate chemoselectively produced the β,γ-unsaturated ester, which upon exposure to Sharpless asymmetric dihydroxylation conditions formed the β-hydroxyl-γ-lactone 5. Its subsequent oxa-Pictet–Spengler cyclization with acetaldehyde diastereoselectively offered the naphthohydroquinonopyrano-γ-lactone 6, thus allowing the key aryl–aryl coupling process. Treatment of bromonaphthalene 6 with (Bpin)2, CsF, and Pd0 generated the boronate intermediate that was used directly for the Suzuki coupling in a one-pot fashion. Subjecting the afforded bisnaphthalene 7 to (NH4)2[Ce(NO3)6] (CAN) gave the quinone mixture that was used as crude for the following methyl ether cleavage to ultimately give the γ-actinorhodin.

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Fig. 3 Brückner's synthesis of γ-actinorhodin.

Complanadines A and B are non-symmetric (pseudo-) dimers, but both Tsukano and Sarpong recognized the evident molecular symmetry for their expeditious constructions by means of a Pd-catalyzed cross-coupling reaction to site-selectively connect two hetroaryl partners together (Fig. 4 and 5).35 The N-Cbz-lycodine 9, which was prepared via chiral resolution, proceeded with mCPBA oxidation to give the N-Cbz-lycodine N′-oxide 10 (Fig. 4).35f Meanwhile, subjecting compound 9 to Hartwig–Miyaura borylation36 conditions followed by bromination with CuBr2 regioselectively provided the other coupling partner 11. The subsequent direct C2 arylation of N-oxide 10 with bromopyridine 11 delivered the anticipated common intermediate 12 for both complanadines A and B. Treatment of this intermediate with Pd(OH)2/C and HCO2NH4 led to the global reduction of the N-oxide and Cbz moieties to successfully yield the complanadine A. In addition, exposure of compound 12 to hot acetic anhydride triggered regioselective benzylic oxidation through tautomerization and resulted in the Claisen-type rearrangement of O-acetylated pyridine N-oxide, which provided the acetate 13 as mixed diastereomers. Successive methanolysis, Dess–Martin oxidation, and Cbz cleavage furnished complanadine B.

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Fig. 4 Tsukano's syntheses of complanadines A and B.

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Fig. 5 Sarpong's synthesis of complanadines B.

Building on the successful synthesis of complanadine A,35c Sarpong first examined a biomimetic approach to obtain complanadine B via the regioselective benzylic oxidation of N-Boc complanadine A (Fig. 5, top).35e Unfortunately, the benzylic oxidation occurred at the unwanted pyridine core A, and strategies to directly differentiate the two pyridine cores proved unproductive. Accordingly, an indirect approach by introducing a traceless methoxy substituent onto pyridine core A was proposed (Fig. 5, bottom). As an inductively electron-withdrawing group, the methoxy moiety may sterically shield the nitrogen atom of pyridine core A and therefore alleviate its reactivity toward oxidants. To fulfil this goal, Ir-catalyzed direct C–H borylation36 was employed to prepare the coupling partner boronic ester 15. The observed site selectivity was supposedly guided by steric factors. Its subsequent Suzuki cross-coupling with tosylate 14 provided the designed intermediate 16. The used coupling conditions were previously proven successful in Sarpong's synthesis of complanadine A.35c As expected, the following oxidation of compound 16 exclusively occurred at the benzylic position of pyridine core B. The obtained product 17 underwent consecutive methyl ether cleavage with NaH/EtSH, triflation, and Pd-catalyzed reduction to eventually afford the desired complanadine B.

Instead of relying on site-controlled transitional-metal-catalyzed cross-coupling reactions, Ishikawa demonstrated that bravely employing uncontrolled oxidative couplings sometimes may lead to magnificent outcomes, as demonstrated in his two-pot synthesis of WIN 64821,37 ditryptophenaline38, and naseseazine B39 (Fig. 6).40 The idea is to oxidize the tryptophan species 18 to form a radical intermediate with its radical dispersed on the C3, C7, or N1 positions, and this radical intermediate may undergo spontaneous homo- or hetero-dimerizations with different coupling possibilities. The oxidation was carried out in acidic conditions which led to the formation of the water-soluble tryptophan salt 18 and thus possibly prevented side reactions arising from the nucleophilicity of the unprotected primary amine. A variety of common oxidants, including MoCl5, [Cu(acac)2], CuBr2, FeCl3, Mn(OAc)3, VOF3, and V2O5 were examined. It was found that Mn(OAc)3 favoured the Csp3–Csp2 coupling type, delivering 19c–d as the major products, whereas V2O5 preferred the Csp3–Csp3 coupling type, providing 19a–b as the major products. Subsequent peptide preparations and Boc cleavage of 19a–c were carried out under vacuum in a one-pot fashion, effectively affording WIN 64821, ditryptophenaline, and naseseazine B, respectively. As seen, the key oxidative coupling of tryptophan species 18 barely dictates the product distribution, which contradicts the general pursuit of chemo-, regio-, and stereoselective-transformation, but the two-pot syntheses that provide three dimeric diketopiperazine alkaloids in 13–20% overall yield, is almost unbeatable by other synthetic approaches.

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Fig. 6 Ishikawa's syntheses of WIN 64821, ditryptophenaline and naseseazine B.

Unlike Ishikawa's uncontrolled strategy, Movassaghi continually searched for a controlled way to prepare diketopiperazine alkaloids.41 After encountering the problematic extension of his previously developed Co(I)-promoted homo-dimerization of cyclotryptamine derivatives to hetero-dimerization, Movassaghi designed a new method to tame the latter process. His new general approach may even link two dissimilar fragments through a sulfamide bridge, which upon oxidation forms a diazene.42 Subjecting this diazene to photochemical conditions expulses N2 and achieves the desired C–C coupling (eqn (2)).43

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This new method has been successfully applied for the total synthesis of calycanthidine,44 a non-symmetric pseudo-dimer (Fig. 7).45 The Rh-catalyzed selective tertiary C–H amination of cyclotryptamine 20a afforded a sulfamate ester which underwent basic hydrolysis to give product 21a. Similar C–H amination of compound 20b formed the sulfamate ester 21b, which smoothly reacted with compound 21a to deliver the key sulfamate 22. Its resultant oxidation to diazene 23 was nearly quantitatively achieved with the use of DBU and 1,3-dichloro-5,5-dimethylhydantoin. Photolysis of the obtained diazene 23 in a solid state afforded the product 24 in satisfying yield. Finally, subsequent protecting group manipulation provided the calycanthidine.

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Fig. 7 Movassaghi's synthesis of calycanthidine.

Dissimilar to the above coupling reactions to build C–C bonds, Baran accomplished direct oxidative N–N bond formation to rapidly construct dixiamycin B (Fig. 8).46 The preparation of the coupling monomer commenced with the hydroboration of the diene 25 with 9-BBN followed by Suzuki coupling with 2-bromocarbazole, affording the cyclization precursor 26. After N-Boc protection, the obtained carbazole intermediate was subjected to Lewis acidic conditions to give the pentacycle 27. The succeeding benzyl cleavage released a free alcohol which underwent stepwise oxidation to produce a carboxylic acid, which upon treatment with hot aqueous ethanol smoothly delivered the anticipated xiamycin A. However, the following N–N coupling proved extremely challenging. Using carbazole as a model study, Baran tried to realize the desired oxidative dimerization via traditional approaches employing KMnO4, PIFA, or LDA/[Cu]. Unfortunately, they all failed to give any promising results. Eventually, he turned his attention to electrochemistry.47 Mild electrochemical conditions allowed him to solve this key N–N coupling problem and successfully provided the dixiamycin B, albeit in low yield.

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Fig. 8 Baran's synthesis of dixiamycin B.

2.3 Conjugate additions

Conjugate addition, including the Mannich reaction, Michael addition, and Morita–Baylis–Hillman reaction, represents another favourable tool to quickly access molecules with evident symmetry, which are typically non-symmetric dimers.

A Mannich reaction48 was performed to join two identical halves via a sulphur bridge during Shenvi's synthesis19b of neothiobinupharidine (Fig. 9).49 The Beckmann rearrangement of the starting cyclopentanone 28 resulted in the formation of the lactam 29, which underwent successive N-alkylation, intramolecular RCM, and in situ protodesilylation to deliver the bicycle 31. Its treatment with 3-furyl-lithium followed by reduction with NaBH(OAc)3 afforded quinolizidine 32 which upon exposure to mCPBA gave the N-oxide 33. Subjecting compound 33 to TFAA generated the α,β-unsaturated iminium ion A. It was found that the following key dimerization process occurred best in presence of DMSO with excess Na2S4·H2O. Trapping the iminium ion A with Na2S4 formed the enamine B, which initiated the proposed Mannich-type process. This reaction took place on the convex-face of enamine B to afford the intermediate C. The subsequent enamine sulfenylation proceeded in a concave-face fashion to deliver the dimerized product D. The final NaBH4 reduction of the intermediate D smoothly provided the natural product neothiobinupharidine.

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Fig. 9 Shenvi's synthesis of neothiobinupharidine.

Kuramochi executed a successive intermolecular–intramolecular Michael addition50 sequence as a chief stitching strategy to fasten two identical pieces together for the synthesis of juglorescein (Fig. 10).51 The copper reagent 35, in situ prepared from its Grignard reagent in the presence of a catalytic amount of CuCN, opened the chiral epoxide 34 to give an alcohol which was additionally elaborated to 1,4-naphthoquinone 36. Subjecting compound 36 to DBU triggered the double Michael addition sequence in a highly regio- and stereoselective fashion. The initially formed enolate A underwent intermolecular Michael addition with compound 36 to give the intermediate B. The immediate intramolecular Michael addition of B led to the formation of the hydroquinone C, which underwent air oxidation to afford the dimer 37. Removal of its TBS protecting groups with TBAF released a free alcohol and the subsequent stepwise Dess–Martin/Pinnic oxidation delivered the dicarboxylic acid D. Its acid-promoted intermolecular lactonization generated compound 38. Eventually, global MOM-cleavage and lactone hydrolysis with the aid of Amberlyst 15 in hot aqueous conditions provided juglorescein.

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Fig. 10 Kuramochi's synthesis of juglorescein.

The biosynthesis of flueggenine C encouraged Han to study the Rauhut–Currier reaction (vinylogous Morita–Baylis–Hillman reaction) to directly couple two molecules of norsecurinine together (Fig. 11, top).52 Unluckily, this biomimetic plan did not work. As a result, Han turned his attention to the Rauhut–Currier reaction of a simple fragment 40, prepared from enone 39 by silyl enol ether formation with TMSOTf and subsequent DMDO oxidation. Treatment of the newly obtained product 40 with TBAF knocked off the TMS moiety and initiated the key Rauhut–Currier reaction. This dimerization process proceeded through an intermolecular–intramolecular Michael addition sequence to give the tetrahydrofuran intermediate A, which further underwent β-alkoxy elimination to produce diketone B which was immediately trapped with Ac2O. Subjecting the afforded acetylated dimer 41 to diethyl phosphonoacetic acid formed diphosphonate 42. The resulting HWE reaction and methanolysis generated the expected butenolide derivative 43. Mesylation of the free secondary alcohols followed by Boc cleavages in TFA resulted in N-alkylation, delivering the corresponding amine salt which upon treatment with K2CO3 released the free flueggenine C.

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Fig. 11 Han's synthesis of flueggenine C.

2.4 Cycloadditions/oxidative cyclizations

Combining two identical fragments via cycloaddition or oxidative cyclization reaction leads to multiple bond formations in one reaction, usually giving a cyclic adduct with considerable structural complexity. Consequently, this has been broadly exploited to construct natural products with evident symmetry.

A [4 + 2] cycloaddition was carried out to bind two molecules of dihydrovalparicine together during Andrade's synthesis of leucoridine A (Fig. 12).53 The preparation of the monomer started with Boc cleavage and site-selective N-alkylation of tetracycle 44. An intramolecular Heck reaction set up the fifth ring, giving product 46 which underwent stepwise reduction of the trisubstituted olefin with Adam's catalyst and the α,β-unsaturated ester with NaBH3CN and LAH. The obtained alcohol 47 was protected as its TES ether and then chemoselectively oxidized to indolenine 48. Its subjection to HF·Pyr released the free alcohol 49. Treatment of this compound with TFA triggered a dehydration process to form the monomer dihydrovalparicine, which spontaneously participated in a [4 + 2] cycloaddition to yield leucoridine A.

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Fig. 12 Andrade's synthesis of leucoridine A.

Likewise, Lawrence also employed a [4 + 2] cycloaddition54 as the crucial strategy to synthesize thymarnicol (Fig. 13).55 The monomer 50, existing as a mixture of lactol and enal, sluggishly underwent the hetero-Diels–Alder reaction, yielding the cyclic adduct 51. However, this hypothetical biosynthesis was not selective and efficient enough, producing a trace amount product 51 which was only identifiable by crude 1H NMR. Accordingly, this free phenol was protected as an acetate before subjecting it to [4 + 2] cycloaddition. Heating enal 52 almost quantitatively led to the cyclic product A, which upon aqueous basic treatment provided lactol 51. The subsequent aerial oxidation/cyclization smoothly occurred under visible light, affording the expected thymarnicol. Interestingly, this stereo-dynamic natural product stays as a mixture with 78[thin space (1/6-em)]:[thin space (1/6-em)]22 dr in CDCl3, but exists as a single diastereomer in the solid state.

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Fig. 13 Lawrence's synthesis of thymarnicol.

Evanno and Poupon showed that [2 + 2] cycloaddition could offer an expeditious approach to access dictazole B, a non-symmetric pseudo-dimeric cyclobutane (Fig. 14).56 The monomers 54 and 55 were straightforwardly prepared from creatinine 53 and 3-formylindole derivative. However, the following [2 + 2] photocycloaddition proved to be quite challenging. Luckily, a fortuitous observation that the dimerization only occurred in a highly concentrated solution or the solid state eventually solved the reactivity problem. Placing the DMF solution of aplysinopsins 54 and 55 in a crystallizing dish as a thin film in the presence of Bi(OTf)3 followed by irradiation with artificial sunlight initiated the desired cycloaddition, delivering the desired dictazole B, albeit in low yield.

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Fig. 14 Evanno and Poupon's synthesis of dictazole B.

Unlike the above pericyclic reactions, oxidative cyclization57 was implemented by Trauner to connect two molecules of epicoccine together to construct the symmetric dibefurin (Fig. 15).58 Treatment of eudesmic acid with hot acidic formalin resulted in the formation of isobenzofuranone 56. The subsequent dechlorination with Zn, stepwise lactone reductions with DIBAL and Et3SiH, and global demethylation with BBr3, delivered the expected epicoccine. Subjecting this monomer to basic K3[Fe(CN)6] afforded an ortho-quinone intermediate which spontaneously underwent homodimerization to provide dibefurin in moderate yield.

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Fig. 15 Trauner's synthesis of dibefurin.

3 Molecules with hidden symmetry

Defining molecules with hidden symmetry makes more sense from a synthetic perspective since these natural products may not display evident symmetry and only include partial symmetric elements. The idea to take advantage of limited molecular symmetry can be inspired by the biosynthetic pathway or more commonly, just driven by synthetic expediency. Desymmetrization11 and sharing a common fragment are the two most frequently employed approaches.

3.1 Strategies motivated by biosynthesis

The strategy of exploiting partial molecular symmetry motivated by biosynthesis can be quite obvious. For instance, Liu's construction of sarcandrolide J largely considered the proposed bio-pathway involving [4 + 2] cycloaddition (Fig. 16).24b,59 The required diene and dienophile share the same 3/5/6-tricyclic skeleton, and thus could be both accessed from the common fragment 57. The afforded cyclic adduct 58 underwent MOM cleavage and ethyl ester reduction to give the triol 59. Irradiation of compound 59 in the presence of oxygen and tetraphenylporphyrin (TPP) followed by Kornblum–DeLaMare-type rearrangement of the afforded peroxide A with Hünig's base resulted in the formation of a carboxylic acid, which was further trapped with TMSCHN2 to ultimately deliver the desired methyl ester sarcandrolide J.
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Fig. 16 Liu's synthesis of sarcandrolide J.

Trauner's epicolactone synthesis does not share a common intermediate but apparently also makes use of partial molecular symmetry (Fig. 17).60 The established purpurogallin biosynthetic pathway contains [5 + 2] homodimerization of an ortho-quinone, nucleophilic attack with water, oxidation, decarboxylation, and tautomerizations (Fig. 17, top). Enlightened by this, Trauner proposed that epicolactone could be obtained from epicocine and epicocone B via a comparable reaction cascade (Fig. 17, bottom). Since epicocine is perhaps biosynthetically derived from epicocine B, epicolactone can be treated as a non-symmetric pseudo-dimer and thus bears evident symmetry. However, it was experimentally proven that epicocone B cannot participate in this anticipated dimerization, making it inappropriate to attribute epicolactone to a pseudo-dimer. Nevertheless, exposure of epicocine and catechol 60 to aqueous basic K3[Fe(CN)6] generated the corresponding ortho-quinones and triggered the expected [5 + 2] cycloaddition to give the cyclic adduct A, which underwent intramolecular nucleophilic addition with the primary alcohol to afford lactone B. The immediate vinylogous aldol addition delivered product 61 which upon removal of the methyl moiety with MgI2 furnished epicolactone. Considering the structural similarity between catechol 60 and epicocone B, it seems reasonable to conclude herein that epicolactone displays partial symmetric elements from a synthetic perspective and thus bears hidden symmetry.

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Fig. 17 Trauner's synthesis of epicolactone.

3.2 Strategies motivated by synthetic convenience

Rather than getting inspiration from biosynthetic pathways, organic chemists may rely on their own synthetic knowledge and experience to devise strategies that use partial molecular symmetry. These designs often solely consider the synthetic convenience by maximally sharing an identical fragment.

By revealing the hidden symmetry of cardamom peroxide, Maimone achieved its total synthesis in a highly efficient way by appropriately choosing a common starting material to rapidly access the overall carbon skeleton (Fig. 18).61 The synthetic route superficially resembles a biosynthetic pathway, but previous studies have demonstrated that similar peroxy radicals prefer 6-exo-cycliaztion rather than the desired 7-endo-cycliaztion, which questions this biosynthetic postulate.62 Nonetheless, the McMurray coupling of the commercial myrtenal smoothly provided the triene 62, which participated in [4 + 2] cycloaddition with O2 to give the endo-peroxide A. The resulting Kornblum–DeLaMare rearrangement with DBU followed by Dess–Martin oxidation furnished the diketone 63. After extensive experimentation, it was revealed that the Mn-catalyzed hydration-hydroperoxidation could be realized with Mn(dpm)3, PhSiH3, and O2, affording the peroxy radical B. Its instantaneous 7-endo-cyclization delivered the diperoxide 64 which was further reduced with PPh3 to provide the desired cardamom peroxide.

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Fig. 18 Maimone's synthesis of cardamom peroxide.

Similarly, the benzaldehyde 65 was selected as the starting material for synthetic expediency in Pettus' kushecarpin A construction (Fig. 19).63 The designed strategy took advantage of the well-established ortho-quinone methide (o-QM) chemistry to enantioselectively build the chromane core via [4 + 2] cycloaddition of the o-QM A and enol ether 66, both accessed from the starting 65. The obtained cyclic adduct 67 was further converted to chromane acetal 68 by removal of the chiral auxiliary. The subsequent regioselective benzylic oxidation with Pb3O4 followed by benzyl cleavage with Pd/C and H2 released the free phenol 69. Basic treatment of this crude product resulted in the formation of the para-QM C, which spontaneously proceeded in an intramolecular cyclization to give the sophoracarpan A. The final dearomatization and peroxide reduction furnished kushecarpin A.

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Fig. 19 Pettus' synthesis of kushecarpin A.

Another brilliant example of maximally sharing a common fragment regardless of the biosynthetic pathway can be seen in Carter's synthesis of amphidinolide F (Fig. 20).64 Carter observed partial symmetry hidden among the tetrahydrofuran residues of fragments 71 and 72, revealing that the C1–C8 and C15–C25 portions share almost identical functionalization, oxidation states, and stereochemistry. As a result, both fragments were prepared from the common fragment 70. Joining the two obtained fragments was realized via sulfone alkylation under basic conditions to give the coupling product 73, which was further elaborated to macrolide 74. The subsequent removal of the EEE protecting group released the free secondary alcohol, which underwent Dess–Martin oxidation and TBS cleavage to eventually deliver the natural product amphidinolide F.

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Fig. 20 Carter's synthesis of amphidinolide F.

4 When a symmetric strategy fails

As demonstrated above, exploring and harnessing either evident or hidden symmetry often dramatically advance the brevity of natural product synthesis. Occasionally, designed symmetric strategies may not work as expected. For example, the attempted photo-dimerization of hymenidin and its various derivatives to access sceptrin65 was in vain (Fig. 21). However, this observation seems reasonable, considering the fact that sceptrin was isolated from the deep ocean where there is inadequate light to initiate such transformation. Alternatively, Baran constructed the cyclobutane core via the rearrangement66 of 3-oxaquadricyclane 76 under acidic conditions to give the key intermediate 75. Also, compound 76 in turn could be quickly prepared from the furan 78 and dimethyl acetylenedicarboxylate via successive intermolecular [4 + 2] and intramolecular [2 + 2] cycloaddition.
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Fig. 21 Baran's alternative synthetic strategy for sceptrin.

Another example can be seen in Snyder's recent synthesis of psylloborine A, a non-symmetric pseudo-dimer (Fig. 22).67 The planned symmetric strategy of converting propyleine/isopropyleine to psylloborine A via intermolecular Mannich reactions was futile, leading to the unwanted psylloborine B. The steric hindrance arising from the methyl group of the enamine propyleine (highlighted in red) blocked its neighbouring nucleophilic addition to the iminium ion 79, and thus disfavoured the anticipated reactions. To avoid this issue, a controlled approach was deployed by combining C3 and C5′ (highlighted in yellow) in the beginning to ensure the required regio-control and then stereoselectively building the other rings. This alternative intramolecular cyclization of compound 81, involving condensations, Michael, and Mannich reactions, successfully delivered the dimerized product 80, which upon reduction of its aryl sulfone moiety with Na/Hg amalgam smoothly provided psylloborine A.

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Fig. 22 Snyder's alternative synthetic strategy for psylloborine A.

Therefore, failed symmetric strategies still offer chemists some meaningful information. They may shed some light on the mysterious biosynthetic origins by excluding some previously proposed bio-pathways. In addition, the synthetic knowledge accumulated from the initial monomer preparation and assembly can be beneficial to the alternative synthetic plan. For instance, building upon the synthetic experience in preparation of the monomer propyleine, the key compound 81 was conveniently accessed for the second-generation approach.

5 Conclusion and outlook

In summary, the aforementioned synthetic designs profess their loyalty to molecular symmetry, especially when designing strategies to build a symmetric macrodiolide or hidden symmetric molecule with a common intermediate for synthetic convenience, or when a biomimetic synthesis fails. A brief natural product synthesis depends on many factors such as convergency, redox-economy, free of protecting groups, and availability of commercial materials, alone or combined. In this review, appreciation of either evident or hidden molecular symmetry favourably contributed to the concise construction of these molecules. For example, both Liu's synthesis of sarcandrolide J24b and Cater's synthesis of amphidinolide F64b,c employed some common intermediates to benefit the total-step count. Sometimes, developing symmetry-based novel methods to proficiently join monomers is rewarding. For instance, relying on a new metal-catalyzed oxidative coupling reaction, the total syntheses of WIN 64821, ditryptophenaline, and naseseazine B are realized in only two pots, demonstrating extraordinary synthetic brevity.40

Most of the aforementioned natural products exhibit remarkable bioactivities. It is worth mentioning that pactamycin22a displays antitumor, antimicrobial, antiviral, and antiprotozoal properties, whereas sceptrin65a is a potent antibacterial, antiviral, antihistaminic, and antimuscarinic agent. Likewise, epicolactone60a–b and cardamom peroxide61a present antifungal and antimalarial activities, respectively. Additionally, swinholide A31a–e shows extraordinary cytotoxicity against diverse tumor cell lines at nanomolar concentrations, and complanadines A and B35a,b may serve as lead compounds to treat Alzheimer's disease or spinal cord injury. In contrast to molecules with attractive bioactivities, clavosolide A28a and sarcandrolide J59 possess no significant biological activity. Additionally, the biological activities of some natural products such as γ-actinorhodin,34a calycanthidine,44 flueggenine C,52a and psylloborine A67a have not been fully studied due to either a lack of sufficient material or their long isolation time.

Exploiting symmetry to achieve succinct natural product synthesis is of significance in multiple aspects. From the biological or pharmaceutical perspective, a short synthesis allows for the convenient supply of ample natural products for further biological studies. This is particularly appreciated for molecules such as flueggenine C, whose biological activity has not been well recognized. Also, for molecules with promising bioactivities but high cytotoxicity such as pactamycin, a brief synthesis is often able to address related natural product analogues in a reasonable timeframe so as to accelerate the investigation of structure–activity relationships, which may eventually result in the discovery of precious lead compounds. From the chemical perspective, besides the accomplishment of total synthesis itself, the pursuit of succinct synthesis usually inspires chemists to develop novel methods for the effective assembly of fragments in a symmetric fashion. For example, a variety of new methods with broad applications have been discovered during the total syntheses of clavosolide A, swinholide A, and calycanthidine. Moreover, a concise synthesis offers a way to verify the previously unsettled absolute configuration of natural products, such as γ-actinorhodin, juglorescein, and amphidinolide F.

17% of natural products display a certain form of symmetry since their biogenesis possibly involves a dimerization process,9 in addition to those bearing hidden symmetry. Thus, designing strategies for short natural product syntheses will be continually appreciated, during which new methods are expected to appear for efficiently joining (pseudo-) identical monomers together. The conciseness of the total synthesis realized by symmetric designs will constantly allow for the expedient access of not only natural products but also their analogues for subsequent biological or pharmaceutical studies. As a result, interdisciplinary collaborations among both academic and industrial communities will be fostered and strengthened.68

6 Conflicts of interest

There are no conflicts to declare.

7 Acknowledgements

X. W. acknowledges the financial support from National Natural Science Foundation of China (Grants 31400649 and 31670792), Natural Science Foundation of Jiangsu Province (Grant BK20140477), Natural Science Research Grant from Department of Education of Jiangsu Province (Grant 14KJB180026), and Talent Support Program of Yangzhou University.

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