# Recent Advances in the Total Synthesis of Tetramic Acid-Containing Natural Products

Authors: Wen-Ju Bai; Chen Lu; Xiqing Wang
Journal: Journal of Chemistry
 (2016)

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## Abstract

With incredible bioactivities and fascinating structural complexities, tetramic acid- (TA-) containing natural products have attracted favorable attention among the organic chemistry community. Although the construction of the TA core is usually straightforward, the intricate C3-side chain sometimes asks for some deliberative strategy so as to fulfill an elegant total synthesis. This review mainly covers some exceptional synthetic examples for each type of natural product in recent years, showcasing the great achievements as well as unsettled obstacles in this area, in the hope of accelerating the synthetic and biological investigations for this unique type of natural product.


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## Body

## 1. Introduction

Natural products containing a tetramic acid motif (Figure1, red) are commonly seen in nature. These compounds, usually isolated from assorted terrestrial and marine organisms, exhibit important antibiotic, antitumor, or antiviral activities [1–4]. Their sophisticated structural complexities have attracted significant attention in organic chemistry community for total synthetic studies [5–8]. The TA core (2,4-pyrrolidinedione) originates from a variety of amino acids, typically displaying chirality at C5 position (Figure 1, inserted). Among their 4-O-alkyl ether variations, only theO-methylated form is seen in nature. Although there is not a standard way to categorize the TA-containing natural products, it is quite convenient to use different C3-side chains (Figure 1, blue) to classify their types. A TA bearing a C3-hydrido substitute can be frequently seen, for example, the dolastatin 15 [9]. In contrast, the C3-Me TA was not found until 2002 when palau’imide was isolated from the apratoxin producing marine cyanobacteriumLyngbya sp. in Palau [10]. Besides palau’imide, the C-3 Me TA only exists in the tetrapetalone family natural products that were isolated from soil bacteriaStreptomyces sp. USF-4727 in Japan [11–13]. The C3-acyl TAs are the most commonly found natural derivatives (Figures 1(c)–1(g)). They can be further categorized as the C3-multienoyl TA (polycephalin B [14]), C3-decalinoyl TA (paecilosetin [15]), macrocyclic TA (cylindramide A [16]), and C3-spiro TA (azaspirofuran B [17]). Some TA-containing natural products may be difficult to classify due to their structural complexities (Figure 1, phaeosphaeride B [18] and aspergilline A [1]). Several reviews have paid particular attention to the isolation and biological activity studies of TA-containing natural products together with short description of some laboratory syntheses [19–21]. Their total syntheses, especially the latest ones (2010−2016), are rarely covered. As a result, this review predominantly focuses on the synthetic efforts of TA-containing natural products in recent years. Examples for each type of TA can be seen below.Figure 1
Natural products bearing a tetramic acid motif.


## 2. Selected Preparative Methods

Among the various preparative ways to build the TA core, some notable asymmetric methods are listed here (Figure2). The chirality of the TAs generally arises from the amino acid building block. The acidity of the C5 position of the TA core (pK
a ≈ 12−17) should be particularly noticed during any asymmetric synthesis to avoid possible racemization, because it is known that exposure of a chiral TA with KOtBu leads to partial racemization even at −30°C in less than one minute [33]. For C3-acyl TA, the Lacey-Dieckmann procedure is most often adopted, whereby an amino acid derivative is converted into a 1,3-dione intermediate and then subjected to cyclization (Figure 2(a)) [34]. Jouin et al. has showed that coupling an amino acid with Meldrum’s acid can afford a cyclic intermediate that undergoes cyclization and decarboxylation resulting in the expected C3-H TA (Figure 2(b)) [35]. An answer to prepare the unusual C3-Me TA had proved to be more challenging due to the limitation of the two aforementioned methods. Bai et al. eventually answered this call via a mild SmI2-mediated radical cyclization, whereby the chirality of the emerging TA core is retained from the initial amino acid (Figure 2(c)) [36]. Its application to palau’imide synthesis was also disclosed. Interestingly, Yoshii and Moloney reported the transformation of the C3-H TA to the corresponding C3-acyl TA via anO-acylation followed by an acyl migration (Figure 2(d)) [20, 37, 38]. Albeit appealing, it is better to define the limitation and scope of this method before it can be widely applied for total synthesis. In addition, Schlenk et al. discovered a practical way to construct C3-enoyl TAs using a selective 3-acylation of C3-H TA with ylide Ph3PCCO followed by a Wittig olefination (Figure 2(e)) [39]. Overall, the Lacey-Dieckmann cyclization and Jouin’s method represent the most popularly employed strategies, as can be seen from the following synthetic examples.Figure 2
Notable asymmetric methods to build TA core.
(a)
(b)
(c)
(d)
(e)


## 3. C3-H TA (Sintokamide A)

Sintokamide A was isolated from the marine spongeDysidea sp. collected in Indonesia (Scheme 1) [40]. As the first small molecule known to selectively block transactivation of theN-terminus of the androgen receptor in prostate cancer cells, sintokamide A served as a promising drug leading us to evaluate and develop a new approach to treating castration-recurrent prostate cancer. Its chemical structure was unambiguously determined by X-ray crystallography. Sintokamide A contains both dichloromethyl and trichloromethyl groups, making it a challenging target for total synthesis because of the limited chemical methods for stereoselective di- or trichloromethylation. To solve this issue, Beaumont et al. first designed a method to achieve a highly diastereoselective haloalkylation of titanium enolates [41] and then successfully applied it to this total synthesis [22, 42]. The divergent route commenced with the preparation of the chlorinated amino acids6 and11. The known oxazolidinone1 underwent a direct ruthenium-catalyzed tri-/dichloromethylation to afford the chlorinated product2/7 that was further converted to nitrile3/8. These nitriles were then transformed into sulfinimine4/9 which proceeded with a diastereoselective scandium-catalyzed Strecker reaction to yield the advanced nitrile5/10. Upon hydrolysis followed by the corresponding amine or carboxylic acid protection, the desired precursors6 and11 were obtained. Subsequent peptide coupling was straightforward. And the obtained dipeptide12 underwent a methyl ester hydrolysis to release the free carboxylic acid that was ready to couple with Meldrum acid with Jouin’s procedure. Upon heating, the obtained crucial intermediate13 was converted to a free tetramic acid that underwent anO-methylation to produce sintokamide A (14). Notably, an epimerization occurred at C5 stereocenter of the TA core during this process, demonstrating the easy racemization nature of the tetramic acid. Overall, the synthesis features an asymmetric chloroalkylation, an asymmetric Strecker reaction, and Jouin’s method to construct the C3-H TA core.Scheme 1
Gu and Zakarian’s synthesis of sintokamide A [22].


## 4. C3-Me TA (Tetrapetalone A)

The tetrapetalone family, currently containing four derivatives, represents a rare type of C3-Me tetramic acid (Scheme2). They all share a highly decorated tetracyclic skeleton appended to a β-D-rhodinose. Because of these challenging structural motifs and the synthetic complexities, both alone and together, a variety of synthetic groups have pursued their syntheses for well over a decade. To date, no one has claimed to finish the total synthesis of any member of the tetrapetalone family. However, some notable approaches are worth of praise.Scheme 2
Marcus and Sarpong’s synthesis of tetrapetalone intermediate [23].In 2010, Marcus and Sarpong reported his synthetic approach leading to the tetracyclic core of tetrapetalones (Scheme2) [23]. A Nazarov cyclization of aryl dienone15 using AlCl3 in toluene at ambient temperature provided the aryl indanone16. Subsequent epimerization with base accomplished thetrans relationship of the Me and isopropenyl in 4 : 1 dr. This indanone was transformed to the primary alcohol17 that was then subjected to excess of Dess-Martin periodinane (DMP) to trigger the formation of the seven-membered ring. Likely, this process involves a three-step sequence, including a DMP oxidation of the primary alcohol17 to aldehydeA, an intramolecular aldol reaction to form a secondary alcoholB, and a succeeding DMP oxidation to generate the ketone18. After a reductive pyrrole ethylation and an oxidation, the α,β-unsaturated lactam19 was obtained. The following methylation of the ene-lactam moiety was reached with LDA and MeI to give intermediate20. The resulting conjugate addition with boron pinacolato ester and immediate oxidation afforded compound21. Finally, Swern oxidation finished the installment of the tetramic acid moiety to give the racemic tetrapetalone intermediate22. Further reformulation of the seven-membered cyclic ketone into the cyclic alkene likely proved arduous due to the known propensity of tetramate motifs to undergo retro-aldol reactions. Overall, the C3-Me TA core was constructed from a pyrrole ring in six steps, distinct from any aforementioned convenient TA preparative method.Carlsen et al. pronounced progress by accomplishing the first racemic synthesis of tetrapetalone A-Me aglycon, a known degradation product of tetrapetalone A (Scheme3) [24]. Similarly, the starting aniline23 was prepared via an AlCl3-catalyzed Nazarov cyclization. Like Sarpong’s observation, Carlsen et al. also realized that using a Buchwald-Hartwig cross-coupling to install the C-N bond was problematic. It proved that only the nonsterically congested NH3 could deliver the expected aryl amine24 that was further converted to a divinyl oxazolidinone25. The resulting diastereoselective RCM reaction was carefully examined to obtain an effective seven-membered ring formation so as to yield the oxazolidinone26. It was subsequently transformed to alcohol27 that underwent a Ley oxidation to give the aldehyde28. Its exposure to Stryker’s reagent followed by Swern oxidation smoothly furnished the chlorinated tetramate29. Further dechlorination andO-methylation afforded the advanced intermediate30 that proceeded with an atypical dearomatization [43] to complete the synthesis of tetrapetalone A-Me aglycon. A single-crystal X-ray diffraction experiment unambiguously secured the molecule’s structural assignment. Generally, the desiredO-methylated tetramate derivative30 was synthesized from the oxazolidinone26 in ten steps.Scheme 3
Carlsen et al.’s synthesis of tetrapetalone A-Me aglycon [24].Carlsen et al.’s synthetic effort represents a milestone for the tetrapetalone synthesis. But achieving the total synthesis of any member of the tetrapetalone family is still thought-provoking [44–46]. Conditions for cleaving the methyl ether on the tetramic acid core and the glycosylation should be mild enough to tolerate the complexity of the tetracyclic intermediate. More importantly, developing asymmetric method for tetrapetalone synthesis is not easy or trivial.


## 5. C3-Multienoyl TA (Tirandamycin and Streptolydigin)

The novel dienoyl TA tirandamycin C was isolated from the marine environmental isolateStreptomyces sp. 307-9, displaying interesting bioactivity against vancomycin-resistance (Scheme 4) [47]. Obviously, the racemic tetramic acid fragment33 could be easily accessed by subjecting phosphonate31 to glycine methyl ester to provide the amide32 that further proceeded with a typical Lacey-Dieckmann cyclization and a DMB protection (Schlessinger et al. had prepared similar tetramic acid core via the same method in his synthesis of tirandamycin A; see [48]) [49]. In contrast, the bicyclic ketal fragment36 asks for precautious design to achieve the desired stereochemistry presented in tirandamycin C [25, 48, 50–56]. The starting homoallylic alcohol34, prepared from the mismatched double asymmetric stannylcrotylboration of an aldehyde, was treated with excess MeLi at low temperature to trigger the formation of the lactol intermediateC. Subsequent ketalization occurred with catalytic amount ofpPTS, providing the bicyclic ketal35 that underwent a cross metathesis with methacrolein to deliver the aldehyde36 with excellentE/Z selectivity. Exposure of tetramic acid fragment33 to KOtBu followed by addition of aldehyde36 provided the N-DMB protected tirandamycin C. The resulting TFA deprotection released the desired natural product.Scheme 4
Chen and Roush’s synthesis of tirandamycin C [25].Another synthetic example can be seen in Pronin and Kozmin’s synthesis of streptolydigin (Scheme5) [26]. Isolated fromStreptomyces lydicus, streptolydigin was found to inhibit bacterial RNA polymerase but not eukaryotic RNA polymerase [57]. The starting chiral alcohol37 proceeded with a TEMPO-catalyzed oxidative cyclization followed by a Boc-deprotection to give the cyclic amine38. The followingN-glycosylation with the rhodinose and Ag-promotedN-acylation with the thioester provided the phosphonate fragment39. Meanwhile, a cross metathesis was deployed to obtain the lactone41. Similarly, conversion of lactone41 to the corresponding Weinreb amide followed by successive treatment with MeLi and TsOH triggered the intramolecular ketalization, providing the bicyclic ketal42. It was then transformed to the aldehyde43, which underwent a one-pot reaction with phosphonate39 to cleanly yield streptolydigin, resulting from a Horner-Wadsworth-Emmons olefination, a Lacey-Dieckmann cyclization, and a desilylation.Scheme 5
Pronin and Kozmin’s synthesis of streptolydigin [26].As seen from the aforementioned two synthetic examples, it is the construction of the intricate C3-side chains rather than the tetramic acid cores that plays a pivotal role in total synthesis of natural products containing a C3-multienoyl TA motif.


## 6. C3-Decalinoyl TA (JBIR-22)

JBIR-22, specifically inhibiting proteasome assembling chaperone homodimerizationin vitro, could be a useful primary compound for developing anticancer drugs [58, 59]. Due to its important bioactivity and unsolved stereochemical assignment, Healy et al. developed an elegant synthetic route (Scheme 6) [27]. One challenging problem is the lack of straightforward method to build the fragment 4,4-disubstituted glutamic acid derivative46. This goal was achieved by reacting compound44 with ethyl dimethylpyruvate to diastereoselectively give the lactone45 which underwent a subsequentN-methylation and cleavage of theN-sulfinyl group. In contrast, thetrans-fused decalin aldehyde48 was constructed from trienal47 via an organocatalytic intramolecular Diels-Alder (IMDA) reaction using MacMillan’s conditions. This aldehyde was then converted to the β-ketothioester49 via an aldol reaction followed by a DMP oxidation. Its following Ag-mediated coupling reaction with the fragment46 neatly delivered the intermediate50, which underwent a Lacey-Dieckmann cyclization and microwave-assisted ester hydrolysis to provide JBIR-22. The absolute stereochemistry was finalized through total synthesis of both possible diastereomers. Overall, this synthesis relies on a practical way to build the unnatural 4,4-disubstituted glutamic acid as well as an IMDA reaction to construct thetrans-fused decalin system.Scheme 6
Healy et al.’s synthesis of JBIR-22 [27].


## 7. Macrocyclic TA (Aburatubolactam A)

Aburatubolactam A was isolated from the culture broth ofStreptomyces sp., SCRC-A20 in Japan (Scheme 7) [60]. One synthetic challenge lies in the construction of the bicycle[3.3.0]octane ring. This issue was easily answered by Henderson and Phillips through a tandem ring-opening/ring-closing metathesis of functionalized bicyclo[2.2.1]heptane to obtain the starting cyclopentanone51 [28]. Subsequent enolate acylation with Mander’s reagent followed by a reduction of the ketone with NaBH4 gave an alcoholic intermediate, which underwent a mesylation with MsCl and an immediate elimination to safely yield the product52. It was then transformed to the bicycle53 by employing Majetich’s fluoride-mediated Sakurai allylation and subsequent epimerization to favor the desiredsyn-relationship. Further elaboration to compound54 was realized by ester reduction with LAH and cross metathesis with Piv-protected butene-1,4-diol. The carbon side chains of54 were further extended to deliver the dioxenone55, which upon heating with amine56 under reflux produced a sensitive β-ketoamide intermediate. This delicate intermediate then underwent Stille coupling withtert-butyl-β-iodoacrylate followed by the Lacey-Dieckmann cyclization that led to tetramic acid57. Subsequent removal of the Boc andtert-butyl ester groups with TFA, macrolactamization, and cleavage of the TBS group with HF effectively provided aburatubolactam A.Scheme 7
Henderson and Phillips’ synthesis of aburatubolactam A [28].


## 8. C3-Spiro TA (Fusarisetin A)

Fusarisetin A, isolated from a soil fungusFusarium sp. FN080326, displays potent inhibition of metastasis in MDA-MB-231 cells without any significant cytotoxicity [61]. Its intricate chemical structure possesses a 6,6,5,5,5-fused pentacyclic ring system and bears ten stereogenic centers. Due to the unprecedented complexity and remarkable bioactivity, fusarisetin A has attracted considerable attention in synthetic community (Schemes 8–11).Scheme 8
Deng et al.’s synthesis of (−)-fusarisetin A [29].Scheme 9
Xu et al.’s synthesis of (−)-fusarisetin A [30].Scheme 10
Yin et al.’s synthesis of (+)-fusarisetin A [31].Scheme 11
Liu et al.’s synthesis of (+)-fusarisetin A [32].Deng et al. concisely achieved the first asymmetric total synthesis of fusarisetin A and also established its absolute configuration as (+)-fusarisetin A by spectroscopic and optical rotation analysis (Scheme8) [29]. Thetrans-fused decalin derived β-ketothioester59 was accomplished by a Lewis acid catalyzed IMDA reaction from the ketothioester58 that originated from commercially available chiral building block (S)-(−)-citronellal. The cyclopentanone61 was formed by an Ag-catalyzed O-allylation to produce the kinetically stable intermediate60 followed by its Pd-catalyzedO toC rearrangement that ultimately gave the thermodynamically stable product. Subsequent peptide formation with amino acid62 and Wacker oxidation provided the methyl ketone63 that underwent a Luche reduction to deliver the alcoholic intermediate64 with acceptable diastereoselectivity. Finally, a typical Lacey-Dieckmann cyclization concurrently with a hemiketalization formation afforded the (−)-fusarisetin A, even though partial racemization of the tetramic acid was observed during this process.Unlike Deng et al.’s approach, Xu et al.’s synthesis featured an impressive one-pot radical cyclization/aminolysis, albeit employing a similar IMDA strategy to build the startingtrans-fused decalin66 (Scheme 9) [30]. The ensuing Reformatsky reaction produced a secondary alcohol that was further oxidized with IBX to β-ketoester67. Its deprotonation with LiHMDS followed by addition of TEMPO and ferrocenium hexafluorophosphate led to the key intermediate68 as inseparable diastereomers. Upon heating68 in the presence of the amino acid62, the radical cyclization smoothly occurred via the intermediacy of radical D to yield the tricyclic product69 that then proceeded with an aminolysis with amino acid62 to conveniently give the advanced intermediate70. Subsequent cleavage of the N-O bond with Zn/AcOH followed by the classic Lacey-Dieckmann cyclization afforded the (−)-fusarisetin A.Distinct from the two above-mentioned approaches, Yin et al.’s synthesis revealed a remarkable biomimetic oxidation process (Scheme10) [31]. AldehydeE, analogously produced through an IMDA reaction, proceeded with a Roskamp reaction to give the β-ketoester72. Succeeding aminolysis with TBS-protectedent-62 followed by a Lacey-Dieckmann cyclization generated a tetramic acid intermediate that underwent a TBS-cleavage to release the free alcoholic equisetin, another TA-containing natural product. Further oxidation with Mn(OAc)3 formed the radicalF, which was trapped by O2 to give a peroxy radicalG. This radical then underwent a cyclization to yield peroxy radicalH followed by intermolecular hydrogen abstraction to deliver the peroxyfusarisetin (73). The final Zn reduction in HOAc gave the naturally occurring (+)-fusarisetin A for the first time.Extra notable synthesis came from Liu et al., highlighting a one-pot-four-step cascade reaction (Scheme11) [32, 62]. Thetrans-fused decalin aldehydeI, prepared from the triene74 via an IMDA reaction, underwent an intramolecular Mukaiyama aldol reaction to give the tetracyclic intermediateK, which proceeded through a TMS-deprotection and a PCC oxidation to conveniently provide the tetracyclic compound75. Subsequent lactone opening followed by aminolysis with amino acid ent-62 produced the expected key intermediate77, though a significant racemization occurred during this process. The final Lacey-Dieckmann cyclization finished the total synthesis of (+)-fusarisetin A.


## 9. Conclusion and Outlook

As rich sources for remarkable bioactivity, tetramic acid-containing natural products also provide the organic chemistry community with a variety of fascinating synthetic targets with their complicated molecular architectures. Overall, the Lacey-Dieckmann cyclization and Jouin’s method represent two robust and prevalent methods to asymmetrically construct the C3-acyl and C3-H tetramic acid core, respectively. The challenges to synthesize these natural products sometimes lie in the intricate C3-side chains rather than the tetramic acid cores, and overcoming these issues depends on the deliberative design of novel strategies enabling the rapid construction of these C3-side chains. Occasionally, biomimetic synthesis can significantly expedite the process of their total synthesis. However, there are still unresolved complications, such as tetrapetalones, calling for innovative and efficient approaches. Meanwhile, the total synthesis of TA-containing natural products examines current synthetic methods for their atom- and step-economic assembly. Accordingly, the shortages and limitations of existing methods can be realized, and in doing so they stimulate new methodology developments. In thisreview, we have summarized some outstanding synthetic routes in the past five years, in the hope that we might accelerate the synthetic and biological studies for this exceptional type of natural product.



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