Total synthesis of sesterterpenoids

Yuye Chen ab, Jing Zhao *a, Shaoping Li a and Jing Xu *b
aState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, China. E-mail:;
bDepartment of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, Guangdong, China. E-mail:

Received 5th June 2018

First published on 14th September 2018

Covering: January 2012 to January 2018

Sesterterpenoids are a small family of terpenes that often possess intriguing biological profiles and complicated chemical structures. Their total syntheses are usually remarkably challenging, requiring methodological and strategic innovation. In this review, we summarize and discuss the total syntheses of sesterterpenoids published during the coverage period, and the key chemical transformations are highlighted.

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Yuye Chen

Yuye Chen received his BS and MS degrees in Chemistry from Nanjing University of Science & Technology in 2010 and 2013, under the supervision of Prof. Aiqun Jia. During his masters period, he was co-supervised by Prof. Xingwei Li at Dalian Institute of Chemical Physics, CAS. He joined Prof. Jian Xiao’s group as a research assistant at Qingdao Agricultural University from 2013 to 2014. He is now pursuing his PhD study at the University of Macau under the supervision of Prof. Shaoping Li and Prof. Jing Zhao. As a jointly supervised PhD student, he is currently focusing on the total synthesis of complex natural products under the supervision of Prof. Jing Xu at Southern University of Science and Technology.

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Jing Zhao

Jing Zhao received her Ph.D. in 2009 from the Department of Pharmacognosy at China Pharmaceutical University under the direction of Professor Ping Li. Then she moved to Institute of Chinese Materia Medica in China Academy of Chinese Medical Sciences as a postdoctoral researcher (2009–2011) and worked under the supervision of Professor Lu-Qi Huang who also is the Academician of the Chinese Academy of Engineering. Then she worked as an Assistant Professor/Associate professor (2011–now) in the State Key Laboratory for Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau. Prof. Zhao focuses her research interest on the standardization of Traditional Chinese Medicine, including natural product biosynthesis.

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Shaoping Li

Shaoping Li received his Ph.D. in Pharmacognosy in 2000 from the Chinese Pharmaceutical University under the direction of Professor Ping Li. After two years of postdoctoral research with Prof. Quan Zhu at Nanjing University of Chinese Medicine and Prof. Karl W. K. Tsim at Hong Kong University of Science and Technology (2000–2002), he moved to the Institute of Chinese Medical Sciences, University of Macau, as an Assistant Professor (2003–2005) and Associate Professor (2006–2008). In 2009, he was appointed as Professor. His research interests mostly focus on quality control and active components in Chinese medicines, as well as herbal glycoscience.

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Jing Xu

Jing Xu received his BSc from Nanchang University (2000); and MSc from Tongji University (2004) working under the direction of Professor Ronghua Zhang. He received his PhD from Leipzig University with Prof. Athanassios Giannis (2009). Afterwards, he joined the lab of Prof. Emmanuel A. Theodorakis at UC San Diego from 2009 to 2013 for postdoctoral research. After a short period of collaboration with Prof. Carlos A. Guerrero at UC San Diego, he began his independent career at SUSTech where he is currently an Associate Professor. In 2015, he was selected into the China national “1000 Talents Program” for Young Professionals. His research interests include natural product total synthesis and small-molecule drug discovery.

1 Introduction

Nature provides a seemingly limitless range of diverse secondary metabolites, such as terpenes, alkaloids, and polyketides.1 Among the fascinating terpene family, sesterterpenoids, which contain 25 carbon atoms within their highly diversified and often complicated chemical skeletons, regularly show interesting biological activities, such as anti-inflammatory, anticarcinogenic, and antimicrobial activities.2

Since Friedrich Wöhler’s historical synthesis of urea in 1828, natural product synthesis has been a long-term pursuit that has attracted the attention of numerous great chemists.3 These endeavors not only recreate complex and often useful natural chemicals in the laboratory, but also inspire and advance organic chemistry theory, synthetic methodology, pharmaceutical research, and applications.

A vast amount of research effort has been directed toward the synthesis of natural sesterterpenoids, motivated by the intrinsic chemical complexity and intriguing biological profiles of these small molecules. Trauner et al. have well documented such efforts published before 2012.4 Since that time, more than 40 natural sesterterpenoids, with various levels of complexity, have been synthesized. Therefore, this review focuses on the syntheses of sesterterpenoids completed in the period from January 2012 to January 2018. Following the logic of Trauner’s seminal review, the targets discussed here are ordered according to the number of carbocyclic rings. The key chemical transformations are highlighted and discussed, and the longest linear steps (LLSs) and overall yields are also noted.

2 Linear sesterterpenoids

Since 2012, only two linear sesterterpenoids, namely (18S)-variabilin (1) and astakolactin (2), have been synthesized. These syntheses were rather straightforward because of their relatively simple chemical structures. Marine furanosesterterpene 1 was isolated from the sponge Ircinia variabilis5 and later Sarcotragus sp.6 It possesses antiviral and cytotoxic activities,5 while its congeners have shown anticancer,7 antiviral,7a antibacterial,8 anti-inflammatory,9 and antifeedant activities.10 Recently, Xu, Ji and colleagues reported their synthesis of 1 (13 LLS, 7.2% overall yield, Scheme 1),11 following the first synthesis by Takabe et al. in 2004.12 The key step was a Julia–Lythgoe alkylation13 between the chiral fragment 3 and the allyl bromide derivative 4.
image file: c8np00050f-s1.tif
Scheme 1 Brief description of Xu and Ji’s synthesis of (−)-(18S)-variabilin. TBS = tert-butyldimethylsilyl.

Astakolactin (2) was isolated from marine sponge Cacospongia scalaris by Roussis et al.14 Interestingly, its chemical structure was originally misassigned as 5.14 In 2014, Tonoi, Shiina and co-workers finished the synthesis of the original proposed structure 5.15 However, discrepancies were observed in the spectroscopic data between the natural and synthetic compounds, resulting from the incorrectly proposed eight-membered ring motif. Three years later, the same group reported the asymmetric synthesis of 2, revised its chemical structure and confirmed its absolute configuration (Scheme 2).16 This synthesis began with the (E,E)-farnesol-derived aldehyde 6. Reduction of the ester motif followed by an asymmetric Mukaiyama aldol reaction in the presence of (S)-diamine–Sn(II) complex 7 as the catalyst17 yielded 9. A silver trifluoroacetate-mediated transesterification then produced the corresponding ethyl ester. A Mitsunobu-type cyclodehydration assisted by phospholane-type reagent (cyanomethylene)tributylphosphorane (CMBP)18 afforded the desired pyran moiety, and the final compound 2 was produced after hydrolysis of the carboxylic ester (<4.2% overall yield, 25 LLS from (E,E)-farnesol). Although final structure confirmation might be expected to be simple, it was necessary to synthesize both the syn- and anti-isomers and carefully compare their spectroscopic and optical rotation data with the natural compound to unambiguously confirm the structure and the absolute configuration of astakolactin (2).

image file: c8np00050f-s2.tif
Scheme 2 Tonoi and Shiina’s total synthesis of (−)-astakolactin. TBDPS = tert-butyldiphenylsilyl, DIBAL-H = diisobutylaluminum hydride, OTf = triflate, TMS = trimethylsilyl, DIPEA = diisopropylethylamine, py = pyridine, CMBP = (cyanomethylene)tributylphosphorane.

3 Monocarbocyclic sesterterpenoids

3.1 Alotaketals and phorbaketal A

(−)-Alotaketals A–D were isolated by Andersen et al. from marine sponge Hamigera sp. (Fig. 1).19 Their biosynthetically related congener, phorbaketal A, was isolated from Phorbas sp.20 These sesterterpenoids have shown interesting biological activities with moderate to strong potency. For example, (−)-alotaketals A–C (10–12) are cAMP cell signaling pathway activators (EC50 = 18 nM to 6.5 μM),21 whereas (−)-alotaketal C is a PKC agonist and can activate latent HIV-1 reservoirs.19c Furthermore, phorbaketal A (14) has shown moderate cytotoxicity (IC50 ≥ 4.9 μM) against human colorectal, hepatoma, and lung cancer cell lines.20 In addition, 14 was found to stimulate osteoblast differentiation through TAZ-mediated Runx2 activation22a to inhibit adipogenic differentiation via the suppression of PPARγ-mediated gene transcription,22b and to show anti-inflammatory effects by inhibiting NF-κb.22c These intriguing biological profiles, together with the unique tricyclic spiroketal architectures of alotaketals and phorbaketals, have attracted considerable synthetic efforts.23
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Fig. 1 Molecular structures of successfully synthesized alotaketals and (−)-phorbaketal A. Ac = acetyl.

In 2012, Yang and Zhang presented an efficient synthesis of (−)-alotaketal A that featured a SmI2-mediated reductive allylation reaction (Scheme 3).23a,b The synthesis of bicyclic lactone 16 was achieved from the readily available asymmetric building block 5β-hydroxycarvone 15 over 11 steps. The other coupling fragmentation, allyl iodide 18, was prepared from β-keto ester 17. The assembly of 16 and 18 proceeded smoothly via a SmI2-mediated reductive allylation under Barbier conditions, followed by desilylation and spiroketalization, to give compound 19. During the pivotal spiroketalization step, a key point to suppress the undesired exo-alkene isomerization was the usage of the less acidic pyridinium p-toluenesulfonate (PPTS) (Δ11,23 isomer[thin space (1/6-em)]:[thin space (1/6-em)]Δ10,11 isomer = 1[thin space (1/6-em)]:[thin space (1/6-em)]1) instead of p-toluenesulfonic acid (Δ11,23 isomer[thin space (1/6-em)]:[thin space (1/6-em)]Δ10,11 isomer = 1[thin space (1/6-em)]:[thin space (1/6-em)]3–6). After oxidation and removal of the p-methoxybenzyl (PMB) group, the first total synthesis of (−)-alotaketal A (10) was achieved (2.1% overall yield, 18 LLS from (R)-(−)-carvone). Further biological studies have shown that both 10 and the de-PMB analogue of 19 (not depicted) are able to increase PKA activity by increasing cellular levels of cAMP in a subcellular specific manner.23a,b It is also noteworthy that although more than 10 steps were needed to produce fragments 16 and 18 from commercially available materials, Yang and Zhang’s impressive convergent strategy greatly compensated this issue. Only four more steps were needed to accomplish the complex target molecule after the combination of these two fragments.

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Scheme 3 Yang and Zhang’s total synthesis of (−)-alotaketal A. PMB = p-methoxybenzyl, TBS = tert-butyldimethylsilyl, TBAF = tetrabutylammonium fluoride, PPTS = pyidinium p-toluenesulfonate, IBX = 2-iodoxybenzoic acid, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

A few months after Yang and Zhang’s seminal report, Dalby et al. also finished a stereocontrolled total synthesis of 10 (Scheme 4).23c Similar to Yang and Zhang’s work, the efficiency of this synthesis originated from the convergent strategy that involved coupling a bicyclic lactone building block and an allylic halide fragment. Starting from (R)-carvone (20), bicyclic lactone 21 was furnished in 12 steps (Scheme 4). Meanwhile, geraniol 22 was carried through a nine-step synthetic sequence to afford the allyl bromide 23. After condition screening for the pivotal coupling of 21 and 23, target hemiacetal 24 was obtained in moderate yield after the addition of excess lithium 4,4′-di-t-butylbiphenylide (LDBB) and isolated as a single (presumably stabilized) anomer. Treatment with pyridine-buffered HF (HF·Py) promoted removal of the triethylsilyl (TES) group along with contemporary spiroketalization to give the corresponding spiroketal in a diastereoselective manner. Compared with Yang and Zhang’s work, the advantage of this spiroketalization method is that the undesired exo-alkene isomerization was better suppressed (isomeric ratio = 3.7[thin space (1/6-em)]:[thin space (1/6-em)]1, favoring the desired isomer). Finally, double desilylation, double oxidation, and selective aldehyde reduction afforded (−)-alotaketal A (10, 17 LLS from (R)-carvone, 0.5% overall yield). The authors mentioned that although the one-pot global desilylation of 24 and concurrent spiroketalization could provide a shorter route, the unbuffered HF·Py conditions led to increased amounts (ca. 30%) of the undesired endo-alkene isomer. The similarity between the first two syntheses of 10 is probably not merely coincidence, but demonstrates well the power of the Barbier-type coupling method (using SmI2 or LDBB) as well as the power of the convergent strategy in complex molecule synthesis.

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Scheme 4 Dalby’s total synthesis of (−)-alotaketal A. TBS = tert-butyldimethylsilyl, TIPS = triisopropylsilyl, TES = triethylsilyl, LDBB = lithium 4,4′-tert-butylbiphenylide, py = pyridine, DMP = Dess–Martin periodinane, Ac = acetyl.

In 2017, Tong et al. accomplished collective, asymmetric total syntheses of (−)-alotaketals A–D (10–13) and (−)-phorbaketal A (14) using a novel cascade cyclization of vinyl epoxy δ-keto-alcohols (VEKAs, Schemes 5 and 6).23d Starting from known β-keto ester 25 (four steps from (−)-malic acid), six steps were required to furnish epoxy aldehyde 26 (Scheme 5). Subsequently, NHC-catalyzed redox esterification,24 TMS protection, Weinreb amidation, and addition of the Grignard reagent freshly-prepared from allylic chloride 28 afforded intermediate 29. After desilylation with HF·Py, the key cascade cyclization was performed by sequential treatment with dimethyldioxirane (DMDO) to stereoselectively achieve 30, and TfOH to initiate the unprecedented VEKA cascade reaction (56% for 3 steps). While two previously reported syntheses of 10 both somehow suffered the isomerisation of the exo-alkene, Tong’s use of strong acidic conditions, interestingly, did not trigger the undesired exo-methylene isomerization, and was also different from the author’s model study. This afforded the desired tricyclic spiroketal 31 on an impressive 4.5 g scale, with nine additional steps needed to obtain the advanced common intermediate 32. The installation of the mono-substituted terminal alkene allowed the late-stage introduction of various side chains via cross-metathesis reaction, whereas the corresponding aldehyde olefination strategy was unsuccessful.

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Scheme 5 Tong’s synthesis of common intermediate of (−)-alotaketals A–D and (−)-phorbaketal A. TBDPS = tert-butyldiphenylsilyl, TES = triethylsilyl, TMS = trimethylsilyl, py = pyridine, DMDO = 3,3′-dimethyldioxirane, TfOH = triflic acid, Ac = acetyl.

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Scheme 6 Tong’s unified asymmetric total synthesis of (−)-alotaketals A–D and (−)-phorbaketal A. TBDPS = tert-butyldiphenylsilyl, Ac = acetyl, DIBAL-H = diisobutylaluminum hydride, DMP = Dess–Martin periodinane, G-II = Grubbs’ 2nd generation catalyst, TBAF = tetrabutylammonium fluoride, Ac2O = acetic anhydride.

With key intermediate 32 in hand, (−)-alotaketal A (10) and (−)-phorbaketal A (14) were then targeted (Scheme 6). Cleavage of the acetyl group and the subsequent oxidation generated enone 33. Dehydration of 33 with Burgess reagent gave a 1[thin space (1/6-em)]:[thin space (1/6-em)]2 mixture of 34a/34b. The Martin sulfurane was also tested, but only 34a was produced. The Grubbs-II-catalyzed olefin cross-metathesis of 34a and 34b with 1,6-diene 35a and 1,5-diene 35b, respectively, followed by desilylation afforded (−)-alotaketal A (10, 0.20% overall yield, 31 LLS from (−)-malic acid) and (−)-phorbaketal A (14, 0.09% overall yield, 31 LLS from (−)-malic acid). The synthesis of (−)-alotaketal B (11) was also accomplished by acylation with isovaleric anhydride 36, olefin cross-metathesis with 1,6-diene 35a, and desilylation (0.08% overall yield, 31 LLS from (−)-malic acid). Oxidation of 32 with Dess–Martin periodinane followed by cross-metathesis with 1,5-diene 35b provided crude 37, which was then treated with either tetra-n-butylammonium fluoride (TBAF) to complete the total synthesis of (−)-alotaketal C (12, 0.30% overall yield, 29 LLS from (−)-malic acid) or sequentially with NaBH4/CeCl3, acetic anhydride, and TBAF to furnish (−)-alotaketal D (13, 0.21% overall yield, 31 LLS from (−)-malic acid).

Tong’s highly diversified strategy allowed access to five structurally different and biologically promising tricyclic spiroketal alotane-type sesterterpenoids, whereas four of them (11–14) were synthesized for the first time. Although this linear synthetic strategy led to generally longer routes (29–31 steps) than the previously reported alotaketal A synthesis (17 or 18 steps),23a–c this work is a beautiful application of the unique VEKA cascade reaction, and allowed the structural variations at both the C ring and the side chains, which are important to further address the biological potential of these intriguing sesterterpenoids.

Almost contemporaneous with Tong’s work, Lee and co-workers also reported a concise synthesis of (−)-phorbaketal A (14) in only ten linear steps with an overall yield of 1.04% (Scheme 7).23e Cu(I)-catalyzed coupling between two enantiomerically rich fragments,25 namely allylic chloride 38 and alkyne 40, followed by a hydroxyl-group-induced homoallylic epoxidation with VO(acac)2 (ref. 23f and 26) and removal of the acetyl group yielded the key intermediate 41. Although the stereochemistry of this epoxide was ambiguous, this issue was clearly trivial because the stereocenter of this epoxide would be diminished in the last-step rearrangement. The intermediate 41 was then subjected to an elegant Au(I)-catalyzed spiroketalization cascade27 concomitant with the isomerization of the exo-olefin to give compound 45. The detailed mechanism is also depicted in Scheme 7. The very last step of Lee’s synthesis was to rearrange the epoxide moiety to the corresponding allylic alcohol. Interestingly, epoxide 45 is a known compound from a previously reported synthetic study toward 14, but failed to rearrange to the final target under various acidic conditions.23f Fortunately, Lee et al. found that treatment of 45 with borontrifluoride etherate28 successfully produced (−)-phorbaketal A (14) in moderate yield (54%, based on recovered starting material) even though this specific condition is commonly known to give the corresponding aldehyde.29 Like Yang/Zhang and Dalby’s synthesis, Lee’s work also used a convergent synthetic strategy, but with fewer synthetic steps (10 steps versus 17 or 18 steps). This fine example shows that natural products, even if structurally sophisticated, can be very efficiently accessed through properly selected and developed synthetic methods and rational strategic design.

image file: c8np00050f-s7.tif
Scheme 7 Lee’s total synthesis of (−)-phorbaketal A. PPTS = pyridinium p-toluenesulfonate, acac = acetylacetone.

3.2 Aplysinoplide B

Aplysinoplide B (46, Fig. 2) and its natural congeners were isolated from marine sponge Aplysinopsis digitata in 2008.30 It has exhibited cytotoxic activity against P388 mouse leukemia cells (IC50 = 0.45 μg mL−1).30 Interestingly, although the natural analogue of 46, manoalide (47, Fig. 2) is a well-known phospholipase A2 (PLA2) inhibitor with potent anti-inflammatory activity,3146 was incapable of inhibiting bovine pancreas PLA2 even at a concentration of 100 μM.30
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Fig. 2 Aplysinoplide B (46) and manoalide (47).

In 2015, Kutsumura and Saito reported the first total synthesis of 46 (Scheme 8).32 Triene 50 (ref. 31b) was converted into the corresponding alkyl-9-BBN derivative and then coupled with vinyl bromide 49 (ref. 33) under Suzuki–Miyaura conditions34 followed by desilylation to afford compound 51. Introduction of the furan moiety followed by a Corey–Bakshi–Shibata (CBS) reduction35 afforded enantiomers 53a and 53b. After deprotection and photochemical oxidation of the furan moiety,36 both enantiomers of 46 were obtained and the absolute configuration of C-4 was assigned as R by comparing the spectroscopic and optical rotation data of synthetic (+)-46 and natural aplysinoplide B (17 LLS, 3.0% overall yield).

image file: c8np00050f-s8.tif
Scheme 8 Kutsumura and Saito’s total synthesis of aplysinoplide B. PMB = p-methoxybenzyl, Bz = benzoyl, TBS = tert-butyldimethylsilyl, 9-BBN = 9-borabicyclo[3.3.1]nonane, TBDPS = tert-butyldiphenylsilyl, CBS = Corey–Bakshi–Shibata catalyst, TBAF = tetrabutylammonium fluoride.

3.3 Phorbin A

Phorbin A (54) was isolated from marine sponge Monanchora sp. Along with many other phorbaketal family members, it has shown cytotoxic activity against various cancer cell lines.37 In 2015, Brimble et al. reported a synthesis of 54 using their unique cis-γ-hydroxycarvone construction strategy (Scheme 9).38 The vinyl cuprate derivative of vinyl bromide (56) was added to the α,β-unsaturated carboxylic ester 55 to afford compound 57. To this end, 57 was transferred to the benzoyl enol ether-masked β-ketophosphonate 58. Selective oxidation of the primary alcohol under Swern conditions afforded the corresponding aldehyde, which was then subjected to the NaH-triggered intramolecular benzoyl transfer, from the ketophosphonate to the free secondary hydroxyl group, concurrently generating the phosphonate anion which underwent the Horner–Wadsworth–Emmons (HWE) reaction to accomplish the crucial annulation. Treating the intermediate with N-bromosuccinimide converted the allyl-TMS moiety to the desired allyl-bromide moiety to yield compound 59, which was subjected to Barbier conditions to react with farnesal and then benzoyl ester hydrolysis to finally produce phorbin A (54, 10 steps, 6.4% overall yield). While it is quite common to synthesize γ-hydroxycarvone derivatives directly from naturally abundant carvone in the literature,23a–c,39 this work contributed a useful addition to this issue.
image file: c8np00050f-s9.tif
Scheme 9 Brimble’s total synthesis of (−)-phorbin A. TMS = trimethylsilyl, Bz = benzoyl, Swern = Me2SO, (COCl)2, then Et3N.

4 Bicarbocyclic sesterterpenoids

4.1 Leucosceptroids

Leucosceptroids (with some norleucosceptroids) have been isolated from Leucosceptrum canum (Fig. 3).40 Members of this intriguing family of compounds contain a densely functionalized and congested ring system, most of which possess eight contiguous stereocenters. Notably, many leucosceptroids possess a thermodynamically less stable trans-hydrindane motif (compare with corresponding cis-isomer), thus further increasing the synthetic challenge. These sesterterpenoids also exhibit fascinating bioactivities, including potent antifungal and antifeedant effects, strong antiangiogenic activity, and inhibition of prolyl endopeptidase.40 As a result of their great biological potential and challenging chemical skeletons, these leucosceptroids have attracted considerable synthetic efforts.41
image file: c8np00050f-f3.tif
Fig. 3 Molecular structures of successfully synthesized leucosceptroids and norleucosceptroids.

The first synthesis of a leucosceptroid family member, leucosceptroid B, was reported in 2012 by Liu et al. (Scheme 10).41a Because of the above-mentioned trans-hydrindane issue, the authors decided to carry the cis-hydrindane motif throughout their synthesis and take advantage of the adjacent carbonyl group to execute a late-stage epimerization to achieve the trans-hydrindane moiety. This work began with lactone 76, which was converted into bicyclic cis-intermediate 78via conjugate addition, ozonolysis, aldol condensation, and hydrogenation steps. Introduction of the alkyne moiety simultaneously opened the lactone motif. The resultant alcohol was oxidized to the corresponding aldehyde and then subjected to a Brown asymmetric allylation.42 A subsequent Dess–Martin oxidation yielded compound 81. A Michael addition/aldol reaction cascade was used for facile construction of cis-hydrindane 82. This step is especially challenging because only few precedents in natural product synthesis have been documented43 and the controlling of the Z/E selectivity is a daunting task.44 Treatment of ynone 81 with methyl magnesium bromide and copper(I) iodide achieved favorable Z/E selectivity (3.6[thin space (1/6-em)]:[thin space (1/6-em)]1) with excellent yield (88%), while the Ni(0) or Cu(I) catalysts were completely inactive in the presence of the organozinc reagent.44a,44b Subjecting 82 to boron trifluoride conditions activated the tertiary hydroxyl group, which allowed attack from the methoxymethyl (MOM) ether through an SN2′ process. This was followed by simultaneous cleavage of MOM and t-butyldimethylsilyl (TBS) groups, affording tricyclic compound 83. Mechanistically, the authors ruled out the MOM-deprotection/oxa-Michael addition/elimination pathway, by observing rapid transformation of 82 into the TBS-protected analogue of 83 on silica gel, while typical MOM-deprotection conditions did not work for substrate 82. Ketone reduction, epoxidation, ozonolysis, and Wittig reaction steps smoothly transformed 83 into 84. After global oxidation, side-chain introduction, and epoxide opening, the furan motif was formed via a one-pot oxidation–cyclization–dehydration sequence under Dess–Martin oxidation conditions. Concurrent oxidation of the secondary hydroxyl group was also achieved. Liu’s asymmetric synthesis of leucosceptroid B was finally completed by epimerization of the cis-hydrindane moiety to the trans-hydrindane moiety (7.8% overall yield, 19 LLS from 76).

image file: c8np00050f-s10.tif
Scheme 10 Liu’s asymmetric total synthesis of (+)-leucosceptroid B. pTsOH = p-toluenesulfonic acid, TBS = tert-butyldimethylsilyl, TEMPO = (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, DAIB = (diacetoxyiodo)benzene, MOM = methoxymethyl, Ipc = isopinocampheyl, DMP = Dess–Martin periodinane, DIBAL-H = diisobutylaluminum hydride, acac = acetylacetone.

In 2014, Magauer and Hugelshofer reported the enantioselective syntheses of norleucosceptroid A/B and leucosceptroid K, starting from building blocks 87 and 89,41b which were synthesized from homoallylic alcohol 86 and (R)-pulegone (88), respectively (Scheme 11). A Hauser–Kraus-type annulation reaction followed by hydrogenation furnished dilactone 90,45 which was then converted into 91 in three steps, with an unprecedented intramolecular dilactol aldol-type condensation46 and an elimination triggered by lithium diisopropylamide to form the α,β-unsaturated lactone moiety. In turn, treatment of 91 with dimethyl cuprate underwent a Michael addition, followed by dihydrofuran formation conditions to give 92. Epoxidation of 92 with DMDO47 yielded an unstable epoxide, which was then directly treated with tris-(2-methyl-1-propenyl) aluminum to introduce the propenyl group, in an epoxide-directed manner. The stereoselectivity of this transformation was critical and could be reasoned by the coordination of the organoaluminum reagent to the epoxide to give the alanate and simultaneous internal delivery of the propenyl nucleophile. Subsequent oxidation with pyridinium chlorochromate (PCC) of the secondary hydroxyl group delivered 93. After removal of the p-methoxyphenyl (PMP) group and ketone α-oxygenation, oxidation with 2-iodoxybenzoic acid (IBX) successfully afforded (+)-norleucosceptroid A (71, 0.65% overall yield, 18 LLS from (R)-pulegone) as the major product and (−)-norleucosceptroid B (72, 18 LLS, 0.16% overall yield) as the minor product, which was reacted with phosphonate 94 to yield (−)-leucosceptroid K (66, 19 LLS, 0.11% overall yield).

image file: c8np00050f-s11.tif
Scheme 11 Magauer and Hugelshofer’s total synthesis of (+)-norleucosceptroid A, (−)-norleucosceptroid B and (−)-leucosceptroid K, PMP = p-methoxyphenyl, LHMDS = lithium bis(trimethylsilyl)amide, DIBAL-H = diisobutylaluminum hydride, TFA = trifluoroacetic acid, PDC = pyridinium dichromate, LDA = lithium diisopropylamide, Ms = methanesulfonyl, DMDO = 3,3′-dimethyldioxirane, PCC = pyridinium chlorochromate, CAN = calcium ammonium nitrate, IBX = 2-iodoxybenzoic acid.

Concurrent with Magauer’s work, Ma et al. reported an elegant and scalable synthesis of leucosceptroid B and the first total synthesis of leucosceptroid A, both in an asymmetric manner (Scheme 12).41c A gold-catalyzed cyclization was used to prepare furan derivative 96 from compound 95.48 The addition of 96 to aldehyde 97 followed by an iron-catalyzed carbometallation of the corresponding propargylic alcohol afforded 98.49 After ketal hydrolysis and protection of the primary alcohol, dihydrofuranone 99 was obtained via a PhSeCl-mediated cyclization and subsequent oxidation/elimination. Fragment 102 was produced from (S)-citronellal in three steps, including a key diastereoselective allylation using MacMillan’s SOMO organocatalysis.50 Although other regular aldol conditions were unsuccessful, a boron-mediated aldol reaction between 99 and 102 proceeded smoothly to give 103.51 The authors noted that the following six synthetic steps from 103 to 104 were necessary because an axially orientated β-OH or β-OTMS group severely interfered with the desired SmI2-mediated intramolecular ketyl–olefin radical cyclization.52 In contrast, the α-OTMS moiety of 104 provided much less steric hindrance in this pivotal reductive cyclisation, making 104 an ideal substrate for producing cyclized product 105. Finally, IBX oxidation, Wittig olefination and Swern oxidation steps produced (+)-leucosceptroid B (61a, 18 LLS, 5.6% overall yield), which was further converted to (+)-leucosceptroid A (60a, 19 LLS, 3.3% overall yield) under ketone α-oxygenation conditions.

image file: c8np00050f-s12.tif
Scheme 12 Ma’s total synthesis of (+)-leucosceptroid B and (+)-leucosceptroid A. OTf = triflate, acac = acetylacetone, TBDPS = tert-butyldiphenylsilyl, Ac = acetyl, IBX = 2-iodoxybenzoic acid, TMS = trimethylsilyl, py = pyridine, Swern = Me2SO, (COCl)2, then N,N-diisopropylethylamine, LDA = lithium diisopropylamide, DMP = Dess–Martin periodinane, CAN = calcium ammonium nitrate, Bn = benzyl, TFA = trifluoroacetic acid.

A few months later, Magauer and Hugelshofer reported a collective synthesis of leucosceptroids via a diversified strategy that impressively produced 15 leucosceptroid family members (Scheme 13).41d From common intermediate 93, ketone α-oxygenation followed by oxidative removal of the PMP group yielded (+)-norleucosceptroid F (74, 0.53% overall yield, 17 LLS from (R)-pulegone) and compound 106. Treatment of 74 with IBX produced (+)-norleucosceptroid G (75, 18 LLS, 0.36% overall yield), which was further reacted with phosphonate 94 to give (−)-leucosceptroids L (67, 19 LLS, 0.23% overall yield) and M (68, 19 LLS, 0.11% overall yield). Furthermore, 106 could be α-deoxygenated, oxidized, hemiacetalized, and epimerized to afford (−)-norleucosceptroid C (73, 20 LLS, 0.20% overall yield). Oxidation of 106 gave (−)-norleucosceptroid B (72, 18, LLS, 0.27% overall yield), which was converted to (−)-leucosceptroid K (66, 19 LLS, 0.21% overall yield) under the same HWE conditions. Treating 66 with the rarely reported conditions of NaBH4/CuCl2 furnished the β,γ-unsaturated butenolide,53 which was further isomerized to (−)-leucosceptroid G (63, 21, LLS, 0.15% overall yield) via asymmetric proton transfer catalysis.54 The α-deoxygenation of 63 afforded two epimeric natural leucosceptroids, namely (−)-leucosceptroids I (64, 22 LLS, 0.079% overall yield) and J (65, 22 LLS, 0.011% overall yield). The butenolide motif of 63 was also reduced to give (−)-leucosceptroid A (60b, 22 LLS, 0.11% overall yield). Further deoxygenation of 60b and the subsequent α-epimerization afforded (−)-leucosceptroid B (61b, 24 LLS, 0.020% overall yield). Furthermore, 60b was photochemically oxidized to yield four other leucosceptroids, namely (−)-leucosceptroid C (62, 23 LLS, 0.045% overall yield), P (70, 23 LLS, 0.097% overall yield), O (69, 23 LLS, 0.030% overall yield) and K (66, 23 LLS, 0.039% overall yield), providing an even broader expansion of leucosceptroid synthesis.

image file: c8np00050f-s13.tif
Scheme 13 Magauer and Hugelshofer’s total synthesis of the leucosceptroid family of natural products. PMP = p-methoxyphenyl, LHMDS = lithium bis(trimethylsilyl)amide, CAN = calcium ammonium nitrate, py = pyridine, IBX = 2-iodoxybenzoic acid, DIBAL-H = diisobutylaluminum hydride, DIPEA = diisopropylethylamine, TPP = tetraphenylporphyrin, Ac2O = acetic anhydride.

The above syntheses of leucosceptroids were culminated through markedly different strategies and methods, but nevertheless are equally impressive. Liu’s seminal synthesis of (+)-leucosceptroid B offers a critical gateway for the research of these natural products. Comparing with Liu’s straightforward linear synthetic route, Magauer’s convergent/divergent synthesis and Ma’s convergent strategy further expanded the accessibility towards these chemically and biologically intriguing sesterterpenoids.

4.2 Luffarins

The luffarins (Fig. 4) were isolated from marine sponge Luffariella geometrica in 1992.55 Structurally, luffarins share the same decalin motif with a butenolide-group-containing side chain. Moreover, several luffarins and their synthetic analogues have shown moderate antiproliferative activities against several human solid tumor cell lines.56–58 The relatively simple structures and promising biological profiles of luffarins make them appropriate synthetic and biological research targets.
image file: c8np00050f-f4.tif
Fig. 4 Molecular structures of (+)-luffarin A (108), (+)-luffarin I (109) and (+)-luffarin L (110).

Basabe et al. have achieved a series of successful syntheses.56–58 Their synthesis of (+)-luffarin I, reported in 2015, began from (−)-sclareol,56 which was converted into aldehyde 113 in eight steps (Scheme 14). Further addition of 3-bromofurane lithium derivative and oxidation-state manipulations furnished 114. A diastereoselective CBS reduction followed by treatment with DIBAL-H, photochemical oxidation of the furan moiety, and finally hemiacetal reduction yielded (+)-luffarin I (109, 4.1% overall yield, 20 LLS from (−)-sclareol).

image file: c8np00050f-s14.tif
Scheme 14 Basabe’s total synthesis of (+)-luffarin I. THP = 2-tetrahydropyranyl, Ac2O = acetic anhydride, pTsOH = p-toluenesulfonic acid, DMP = Dess–Martin periodinane, Pinnick = NaClO2, NaH2PO4, t-BuOH, TMS = trimethylsilyl, CBS = Corey–Bakshi–Shibata catalyst, DIBAL-H = diisobutylaluminum hydride, DIPEA = diisopropylethylamine.

Also in 2015, Basabe et al. developed a convergent and more efficient synthesis of luffarin natural products (Scheme 15).57 Two simple building blocks, 115 and 117, were linked together as silyl bis-enol ether 118, which allowed the following pivotal silicon-tethered ring-closing-metathesis (RCM) reaction. Subsequent removal of the silyl group produced luffarin L (110, 0.65% overall yield, 11 LLS from 2-deoxy-D-ribose) and (+)-16-epi-luffarin L (110′, 5.2% overall yield, 9 LLS from (−)-sclareol). Moreover, this work successfully established the stereochemistry and absolute configuration of luffarin L.

image file: c8np00050f-s15.tif
Scheme 15 Basabe’s synthesis of (+)-luffarin L and (+)-16-epi-luffarin L, G-II = Grubbs’ 2nd generation catalyst, py = pyridine.

In 2016, Basabe et al. reported their syntheses of (+)-luffarin I (109), (−)-16-epi-luffarin I (109′), and (+)-luffarin A (108) (Scheme 16).58 Compound 119 was synthesized from (−)-sclareol in eight steps. Meanwhile, asymmetric allylation of the 3-furaldehyde motif formed both enantiomers of 122. The two synthons, 119 and 122, were connected via a simple esterification reaction. The subsequent RCM reaction furnished lactone 125. Reduction of the formed lactone and formation of the butenolide moiety afforded (+)-luffarin I (109, 5.4% overall yield, 13 LLS from (−)-sclareol) and (−)-16-epi-luffarin I (109′, 13 LLS, 2.9% overall yield). Furthermore, 125R was converted to (+)-luffarin A (108, 14 LLS, 1.6% overall yield) via lactone reduction and furan oxidation.

image file: c8np00050f-s16.tif
Scheme 16 Basabe’s total synthesis of (+)-luffarin I, (−)-16-epi-luffarin I and (+)-luffarin A. BINOL = 1,1′-bi-2-naphthol, DMAP = 4-dimethylaminopyridine, G-II = Grubbs’ 2nd generation catalyst, DIBAL-H = diisobutylaluminum hydride, DIPEA = diisopropylethylamine, TBSOTf = tert-butyldimethylsilyl trifluoromethanesulfonate, TBAF = tetrabutylammonium fluoride.

4.3 Terpestacin

Terpestacin (126) was first isolated in 1993 from Arthrinium59 and then from Ulocladium in 2001.60 Terpestacin has shown promising anti-HIV59,60 and antiangiogenesis59e activities that, in combination with its complex chemical architecture that features a unique 15-membered ring system, has resulted in vast efforts from synthetic chemists, including total syntheses61 and synthetic studies.62 In 2012, Qiu and Jin reported a convergent total synthesis of 126 (Scheme 17).63 Two major synthetic fragments, namely the tri-substituted cyclopentanone 128 and the allyl bromide derivative 129, were synthesized from a known chiral building block 127 (ref. 64) and (E,E)-farnesol,61a,b,h respectively. The slow addition of sodium bis(trimethylsilyl)amide (0.95 equiv.) to 128 was critical for the regioselective alkylation with 129, which successfully produced 130. Subsequently, an intramolecular HWE reaction effectively yielded macrocycle 131, which was then converted into target molecule 126 in seven more steps. Qiu’s synthesis of terpestacin (126) took 22 steps in 3% overall yield from intermediate 127.
image file: c8np00050f-s17.tif
Scheme 17 Qiu’s total synthesis of (−)-terpestacin. THP = 2-tetrahydropyranyl, MEM = (2-methoxyethoxy)methyl, TBS = tert-butyldimethylsilyl, NaHMDS = sodium bis(trimethylsilyl)amide, TBAF = tetrabutylammonium fluoride, IBX = 2-iodoxybenzoic acid, DIPEA = diisopropylethylamine.

5 Tricarbocyclic sesterterpenoids

5.1 Ansellones A and B, and phorbadione

Ansellones and phorbadione (Fig. 5) belong to the family of ansellane-type sesterterpenoids.19b,c,65 These structurally novel marine natural products have exhibited interesting anticancer and anti-HIV activities.65 (−)-Ansellone A (132) is able to activate the cAMP signaling pathway and latent HIV-1 reservoirs,65 whereas ansellone B (134) has shown cytotoxicity against HEK293 cells.19b However, the biological profile of phorbadione (133) remains unknown because of the very limited amount of sample available.
image file: c8np00050f-f5.tif
Fig. 5 Molecular structures of successfully synthesized ansellanes. Ac = acetyl.

Recently, Tong et al. reported their total syntheses of ansellones A/B and phorbadione (132–134).66 The synthesis of (−)-ansellone A (132) started with the zinc-mediated Barbier-type reaction of allyl iodide (−)-136, which was derived from (S)-carvone, and the decalin aldehyde 138, which was synthesized from (+)-sclareolide 137 (Scheme 18). The diastereo- and regio-selective epoxidation mediated by DMDO was crucial, as was the 6-exo-trig cyclization/epoxide opening cascade triggered by BiBr3, which also represented the first example of a 6-exo-trig cyclization (1,4-addition, SN2′ substitution) of vinyl epoxides with internal alcohols. This reaction can be also triggered by weak protic acids, such as PPTS and silica gel, although the reaction yields were significantly lower. Because reaction of the vinyl epoxide with alcohols usually proceeds with a 1,2-addition,67 Tong’s novel finding made an important addition to vinyl epoxide chemistry.68 Moreover, this method development also inspired Tong’s collective syntheses of alotaketals and phorbaketal.23d The subsequent IBX oxidation of 140 produced ketone 141. Because of difficulties encountered in direct allylic functionalization, (−)-ansellone A (132, 0.77% overall yield, 16 LLS from (+)-sclareolide) was obtained via bromoacetoxylation followed by elimination.

image file: c8np00050f-s18.tif
Scheme 18 Tong’s total synthesis of (−)-ansellone A. DMDO = 3,3′-dimethyldioxirane, IBX = 2-iodoxybenzoic acid, NBS = N-bromosuccinimide, Ac = acetyl.

In turn, Tong’s synthesis of (+)-phorbadione (133) started from 142, a synthetic analogue of compound 138 (Scheme 19). The zinc-mediated Barbier reaction of 142 and (−)-136 afforded a mixture of two separable diastereomers with moderate diastereoselectivity. After a DMDO-mediated regio- and diastereo-selective epoxidation of the desired diastereomer 143, the desired 6-exo-trig cyclization occurred in the presence of silica gel to furnish 144 in 57% yield (two steps). (+)-Phorbadione (133) was then obtained after a sequence of transformations, including IBX oxidation, allylic oxidation, chlorination, and acetoxylation (18 LLS, 1.5% overall yield).

image file: c8np00050f-s19.tif
Scheme 19 Tong’s total synthesis of (+)-phorbadione. DMDO = 3,3′-dimethyldioxirane, IBX = 2-iodoxybenzoic acid, Ac = acetyl.

Subsequently, an even more challenging 8-exo-trig cyclization was performed to synthesize (−)-ansellone B (134) (Scheme 20). The decalin aldehyde 146 was converted into compound 147 using an indium-mediated Barbier-type reaction. In contrast, the zinc-mediated conditions gave the completely opposite diastereoselectivity (1[thin space (1/6-em)]:[thin space (1/6-em)]3). After acylation of the secondary hydroxyl group, the DMDO-mediated epoxidation and subsequent treatment with PPTS triggered the desired cyclization of the alcohol-tethered vinyl epoxides to give the eight-membered ring moiety. Eventually, IBX oxidation and removal of the TBS group completed the synthesis of (−)-ansellone B (134, 23 LLS, 0.24% overall yield).

image file: c8np00050f-s20.tif
Scheme 20 Tong’s total synthesis of (−)-ansellone B. TBS = tert-butyldimethylsilyl, Ac2O = acetic anhydride, Ac = acetyl, DMDO = 3,3′-dimethyldioxirane, PPTS = pyidinium p-toluenesulfonate, IBX = 2-iodoxybenzoic acid, TBAF = tetrabutylammonium fluoride.

5.2 6-epi-Ophiobolin N

6-epi-Ophiobolin N (148) belongs to the ophiobolin sesterterpene family, which possess a 5–8–5 fused ring system with multiple stereogenic centers. These sesterterpenes have shown intriguing bioactivities,69 including cytotoxicity against various cancer cell lines.70 Their promising biological potential and synthetically challenging chemical skeleton have attracted considerable synthetic attention.71 In 2016, Maimone et al. reported a nine-step, asymmetric synthesis of 148, featuring an impressive radical cascade reaction (Scheme 21).72
image file: c8np00050f-s21.tif
Scheme 21 Maimone’s enantioselective synthesis of (−)-6-epi-ophiobolin N. HG-II = Hoveyda–Grubbs’ 2nd generation catalyst, TBS = tert-butyldimethylsilyl, DIBAL-H = diisobutylaluminum hydride, Ac2O = acetic anhydride, Ac = acetyl, TMS = trimethylsilyl, Swern = Me2SO, (COCl)2, then Et3N, pTsOH = p-toluenesulfonic acid.

Building block 150 was synthesized in two steps from (−)-linalool (149). Notably, the critical chiral center present in 149 offered fine diastereoselectivity control for constructing several other stereogenic centers of 6-epi-ophiobolin N. On the other hand, farnesol (151) was subjected to asymmetric cyclopropanation followed by Appel reaction conditions to yield the alkyl iodide, which was then treated with t-BuLi to trigger lithium–halogen exchange and subsequent anionic cyclopropane fragmentation. This alkyllithium intermediate was converted into the corresponding organocopper species, coupled with 150via conjugate addition, and trapped by trichloroacetyl chloride. Diastereoselective reduction of the ketone motif afforded 153. Triethylborane/(TMS)3SiH triggered the elegantly-designed radical cascade, via the intermediate 155, and was terminated by the chiral thiol 154. The author stated that, although several other thiols were also suitable for this reaction, 154 provided the best diastereoselectivity, which was critical in the radical termination, to afford 156. A Corey–Chaykovsky epoxidation followed by reductive ring opening of the epoxide with concomitant dehalogenation produced allylic alcohol 158.73 An oxidation–elimination reaction sequence finally afforded (−)-6-epi-ophiobolin N (148).

Maimone’s milestone work presents as one of the shortest syntheses of complex sesterterpenoids to date (nine steps, 2% overall yield), whereas two pioneering syntheses, namely Kishi’s (+)-ophiobolin C synthesis (38 steps, <1.1% overall yield)71d and Nakada’s (+)-ophiobolin A synthesis (47 steps, 1.0% overall yield),71h,j demonstrate the challenge of ophiobolin synthesis. The most remarkable feature of the presented synthesis is a very ambitious but successful radical cascade reaction, which formed two carbocycles (including a challenging eight-membered ring) and three stereogenic centers in one pot with excellent chemo-, regio-, and stereo-selectivities.

6 Tetracarbocyclic sesterterpenoids

6.1 Nitidasin

In 1997, Nitidasin (159) was isolated from the Peruvian folk medicine “Hercampuri”,74 which has been used, since ancient times, to treat diseases such as hepatitis, hypertension, and diabetes. Nitidasin belongs to the so-called isopropyl trans-hydrindane subfamily.75 Other well-known natural congeners of nitidasin include retigeranic acids76 and astellatol.77,78 Although the biological profile of nitidasin remains mysterious, this pentacyclic sesterterpenoid contains a rare 5–8–6–5 carbon skeleton with ten stereogenic centers and a highly substituted trans-hydrindane moiety, which makes it a formidable challenge for chemical synthesis.

In 2014, Trauner and co-workers accomplished a landmark synthesis of nitidasin (34 LLS and 1.9% overall yield) (Scheme 22),79 which is the second synthesized member of the isopropyl trans-hydrindane sesterterpenoid subfamily, following Corey et al.,76b Paquette et al.,76c,d Hudlicky et al.76e,f and Wender’s76g pioneering synthesis of retigeranic acid A. This synthesis of 159 began with the readily available compound trans-hydrindane building block 160.75 A 12-step sequence was needed to transform 160 into 164, owing to the difficult chemo-, regio- and diastereo-selective chemistry involved. Critical to the success of this seemingly simple transformation sequence was a regio- and diastereo-selective Pd-catalyzed allylation80 to afford 161. Subsequent steps were also necessary to diastereoselectively introduce the methyl group. Reduction of the ketone moiety, olefin oxidative cleavage, and PCC oxidation of the resultant hemiacetal produced the lactone 162. α-Methylation of this lactone followed by oxidation state modifications allowed the synthesis of aldehyde 163. Three more steps, including a Wittig olefination, removal of the TES group and Dess–Martin oxidation were required to access the building block 164. On the other hand, alkyne 166 was obtained from citronellene (165) via oxidative cleavage, Corey–Fuchs homologation and methylation. Zr-mediated cyclometallation81 followed by N-iodosuccinimide quenching,82 elimination of the primary iodide with DBU and hydroboration with 9-BBN afforded alcohol 167, which was then converted to key intermediate 168 in two more steps. This vinyl iodide was treated with t-BuLi to afford the vinyl lithium species in situ, which then attacked previously prepared ketone 164 to yield the corresponding tertiary alcohol. In turn, the alcohol was then converted into 169via stereoselective epoxidation. A further four steps, including an RCM reaction, removal of the [(trimethylsilyl)ethoxy]methyl group, hydrogenation of the double bond and a Ley oxidation, eventually afforded (−)-nitidasin (159). Notably, because of the close biosynthetic relationship between nitidasin and astellatol, a biomimetic synthetic study towards astellatol was also undertaken using an advanced intermediate from the nitidasin synthesis.79b

image file: c8np00050f-s22.tif
Scheme 22 Trauner’s total synthesis of (−)-nitidasin. SEM = 2-(tri-methylsilyl)ethoxymethyl, KHMDS = potassium bis-(trimethylsilyl) amide, K-selectride = potassium tri-sec-butylborohydride, PCC = pyridinium chlorochromate, LHMDS = lithium bis-(trimethylsilyl) amide, TES = triethylsilyl, Swern = Me2SO, (COCl)2, then Et3N, CSA = camphor-10-sulfonic acid, DMP = Dess–Martin periodinane, mCPBA = meta-chloroperbenzoic acid, Cp = cyclopentadienyl, NIS = N-iodosuccinimide, DBU = 1,8-diazabicyclo[5.4.0]-undec-7-ene, 9-BBN = 9-borabicyclo[3.3.1]nonane, G-II = Grubbs’ 2nd generation catalyst, TASF = tris-(dimethylamino)sulfonium difluorotrimethylsilicate, TPAP = tetrapropylammonium perruthenate, NMO = 4-methylmorpholine N-oxide.

The long-standing, notorious problem of the trans-hydrindane synthesis75,76b makes Trauner’s compound 160 an important achievement because it could serve as a general chiral synthon for the syntheses of many other isopropyl trans-hydrindane subfamily members. Moreover, owing to the highly challenging chemical architecture of nitidasin, Trauner’s team needed 36 linear steps from commercially available starting materials to conquer this remarkable target, but nevertheless leaving some room for improvement.

6.2 Salmahyrtisol A and hippospongide A

(−)-Salmahyrtisol A (170) and (−)-hippospongide A (171) belong to the salmahyrtisane sesterterpenoid family and were isolated from the Red Sea sponge Hyrtios erecta83a and sponge Hippospongia sp.,83b respectively (Fig. 6). Whereas 171 is yet to show any noteworthy biological activity, 170 has exhibited significant cytotoxicity in several cancer cell lines, including murine leukemia (P-388), human lung carcinoma (A549), and human colon carcinoma (HT-29).83a In 2015, Basabe et al. accomplished the first synthesis of these two furanosesterterpenoids (Scheme 23).84 On the basis of their established chemistry,85 (−)-sclareol (111) was converted into intermediate 172. Based on the biosynthetic proposal of Scheuer et al.,83a Basabe and co-workers attempted the Prins-type cyclization under various acid-promoted conditions using compound 172, but failed to produce any desired product. Therefore, Pinnick oxidation of the aldehyde moiety followed by a biomimetic Friedel–Crafts acylation reaction afforded pentacyclic compound 173/173′. A series of oxidation-state, stereochemical, and functional group manipulations successfully furnished (−)-salmahyrtisol A (170, 9 LLS from 172, 2.2% overall yield) and (−)-hippospongide A (171, 7 LLS from 172, 2.6% overall yield). A series of synthetic intermediates, along with 170, were tested for antiproliferative activity against various human cancer cell lines, such as A549, HBL-100, HeLa, SW-1573, T-47D and WiDr using the NCI protocol.86 (−)-Salmahyrtisol A (170) was recognized as the most active (GI50 = 0.6–77 μM) compound during this test, whereas all the other tested compounds also showed significant activities. Because of the relatively easy access to the salmahyrtisane’s pentacyclic ring skeletons from Basabe’s semi-synthetic and biomimetic route, further biological investigation of these sesterterpenoids to address their anti-cancer potential is certainly worthy.
image file: c8np00050f-f6.tif
Fig. 6 Molecular structures of (−)-salmahyrtisol A (170) and (−)-hippospongide A (171). Ac = acetyl.

image file: c8np00050f-s23.tif
Scheme 23 Basabe’s total synthesis of (−)-salmahyrtisol A and (−)-hippospongide A. Ac = acetyl, Pinnick = NaClO2, NaH2PO4, t-BuOH, TFAA = trifluoroacetic anhydride, Ms = methanesulfonyl, Ac2O = acetic anhydride.

6.3 Sesterstatin 1

Sesterstatin 1 (175) is a polyhydroxylated scalarane which was isolated from the sponge Hyrtios erecta two decades ago, and has shown interesting activity against P-388 lymphocytic leukemia.87 In 2012, Justicia and Cuerva’s group used the unique titanocene(III)-mediated Barbier-type addition of prenyl chlorides to α-substituted α,β-unsaturated aldehydes and a titanocene(III)-promoted biomimetic radical cyclization cascade to efficiently finish the first total synthesis of 175 in 11 steps and 0.94% overall yield (Scheme 24).88 Under the treatment of [TiCl(tBuC5H4)2] and Mn dust,89 the aldehyde 176 and prenyl chloride derivative 177 underwent the Barbier-type reaction smoothly to give compound 178 in 45% yield. Although no detailed mechanistic explanation was given for the usage of this unique condition, the authors suggested that the reduced Lewis acidity might be the key for the success of this coupling reaction. After acylation and epoxide formation, linear intermediate 179 was then subjected to a titanocene(III)-promoted biomimetic radical cyclization cascade,90 which rapidly formed the tetracyclic ring system of sesterstatin 1, albeit with moderate yield (35%). Only seven more steps were required, including the late-stage lactone formation, to achieve the final target 175. This synthesis showcases the supremacy of titanocene(III) chemistry in the context of complex natural product synthesis. Specifically, several hydroxylated substrates that are incompatible with classic biomimetic cationic cyclization reactions,91 such as compound 176, can be well cyclized under the mild titanocene(III)-mediated radical conditions, which provide an important addition to the polyene cyclization methods.
image file: c8np00050f-s24.tif
Scheme 24 Justicia and Cuerva’s total synthesis of sesterstatin 1. Ac = acetyl, DMAP = 4-dimethylaminopyridine, NBS = N-bromosuccinimide, Cp = cyclopentadienyl, TMS = trimethylsilyl.

7 Pentacarbocyclic sesterterpenoids

7.1 Bolivianine

In 2007, bolivianine (188) was isolated from Hedyosmum angustifolium (Chloranthaceae) by Jullian et al., with a highly complex chemical structure.92 Although no biological activity was reported for this sesterterpenoid, the intriguing and challenging architecture, with an impressive heptacyclic skeleton and nine stereogenic centers, attracted Liu and co-workers to initiate a total synthesis program toward this natural product.93 In 2013, Liu et al. reported their impressive 14-step synthesis of bolivianine with an overall yield of 3.0%, featuring a Diels–Alder/intramolecular hetero-Diels–Alder (DA/IMHDA) cascade reaction (Scheme 25). Starting from (+)-verbenone (181), five steps of transformations were required to produce the tosylhydrazone 182. This set the stage for the key cyclopropanation, while the other attempts to install this pivotal cyclopropane were much less fruitful.93b To this end, tosylhydrazone 182 was subjected to a palladium-catalyzed intramolecular cyclopropanation,94 followed by ketal hydrolysis to afford tricyclic compound 183. Treatment of 183 with the functionalized pyruvate 184 followed by acid-catalyzed furan formation, reduction, and silyl protection, produced compound 185. Decorating the furan moiety and removal of the silyl group yielded the naturally occurring lindenane-type sesquiterpenoid, onoseriolide (186).95 Although the attempted intermolecular Diels–Alder reaction between 186 and β-E-ocimene (187) was not successful, changing the primary hydroxyl group of 186 to the corresponding aldehyde motif dramatically improved the reactivity of the dienophile. Heating the aldehyde and diene 187 triggered a remarkable intermolecular Diels–Alder/intramolecular hetero-Diels–Alder cascade, based on the biosynthetic proposal by Liu and co-workers, to furnish the final target (−)-bolivianine (188). Although the reaction yield was only moderate (52%), this cascade reaction generated three rings, four C–C bonds, and five stereogenic centers in a one-pot process and achieved perfect selectivities (no other isomers were detected).
image file: c8np00050f-s25.tif
Scheme 25 Liu’s total synthesis of (−)-bolivianine. Ts = toluenesulfonyl, dba = dibenzylideneacetone, pTsOH = p-toluenesulfonic acid, LDA = lithium diisopropylamide, TES = triethylsilyl, DIBAL-H = diisobutylaluminum hydride, TBS = tert-butyldimethylsilyl, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TBAF = tetrabutylammonium fluoride, IBX = 2-iodoxybenzoic acid, LTMP = lithium tetramethylpiperidide, PPTS = pyidinium p-toluenesulfonate, DBU = 1,8-diazabicyclo[5.4.0]-undec-7-ene, DMAP = 4-dimethylaminopyridine, Ac = acetyl.

This beautiful work from Liu et al. highlights a rare allylic metal carbene-involved cyclopropanation that allows rapid synthesis of onoseriolide and a biomimetic, unprecedented DA/IMHDA cascade. It revised the original biosynthetic proposal,92 confirmed the absolute configuration of bolivianine, and its biogenetic relationship with onoseriolide. Moreover, the mechanistic study supported the proposed DA/IMHDA reaction pathway rather than an IMHDA/DA reaction pathway.93a

One year later, Liu and Qin’s team published a full account of their bolivianine synthesis,93b and revealed that the previously communicated work was actually their second-generation synthesis. Their first-generation route started from the cyclohexanone derivative 190, which was synthesized in three steps from compound 189. Resolution of racemic 190 and five more steps of transformations yielded the epoxide 194, which was then subjected to Hodgson’s cyclopropanation conditions96 to produce compound 195 in 92% yield. A further five steps of elaboration furnished butenolide 197, which was reacted with diene 187 to achieve the desired DA product 198. After reducing the carboxylic ester moiety to the corresponding aldehyde motif, the IMHDA reaction proceeded smoothly under heating to afford compound 199. Finally, acetonide cleavage and Corey–Winter olefination successfully gave (−)-bolivianine (188, 21 LLS from (+)-verbenone, 0.51% overall yield). Moreover, another slightly modified synthesis of 188, by using compound 183 from their second-generation synthesis and a modified butenolide synthetic strategy, was also reported by the same group with an even shorter route (12 steps, 1.9% overall yield).93c These three syntheses of bolivianine not only reveal the author’s admirable efforts towards such a complicated molecule, but also the efficiency and elegance of biomimetic natural product synthesis.

7.2 Astellatol

Astellatol (202) also belongs to the isopropyl trans-hydrindane sesterterpenoids subfamily75 and was isolated from Aspergillus stellatus (syn. A. variecolor) and structurally characterized in 1989.77 Other well-known natural congeners of astellatol are retigeranic acid76 and nitidasin.79 Although its biological activity remains unknown, astellatol is among the most challenging targets for sesterterpenoid synthesis, owing to its rare and highly congested pentacyclic ring system that contains ten stereocenters, a unique bicyclo[4.1.1]octane motif, a cyclobutane that possesses two quaternary centers, an exo-methylene group, and a sterically encumbered isopropyl trans-hydrindane motif. Recently, we accomplished the first and enantiospecific synthesis of 202 (Scheme 26).78
image file: c8np00050f-s26.tif
Scheme 26 Xu’s total synthesis of (+)-astellatol. TMSOTf = trimethylsilyl trifluoromethanesulfonate, TMS = trimethylsilyl, G-II = Grubbs’ 2nd generation catalyst, DBU = 1,8-diazabicyclo[5.4.0]-undec-7-ene, HMPA = hexamethylphosphoramide, DIBAL-H = diisobutylaluminum hydride, TPAP = tetrapropylammonium perruthenate, NMO = N-methylmorpholine N-oxide, NaHMDS = sodium bis(trimethylsilyl)amide, Im = imidazole, py = pyridine.

Our synthesis of 202 began from readily available chiral synthon 203. After alkylation, methoxyallene addition, and TMS protection steps, 205 was obtained and subjected to the RCM reaction. Subsequent hydrogenation produced bicyclic compound 206. The TMS group was crucial for a good yield in the RCM reaction and facial selectivity in the hydrogenation. Specifically, the hydrogenation step provided the desired stereochemistry at C-10, which also provided the crucial stereoselectivity in the subsequent introduction of the methallyl side chain. Another five synthetic steps afforded intermediate 207. The isopropenyl group on the alkyne motif was probably not necessary for the success of the following intramolecular Pauson–Khand reaction (PKR); however, other attempts to introduce the isopropyl-substituted alkyne side chain were not successful. To this end, 207 was subjected to the Pauson–Khand reaction97 to rapidly give the pentacyclic skeleton (compound 208, 68% for desired epimer, dr = 4[thin space (1/6-em)]:[thin space (1/6-em)]1). This PKR strategy was inspired by the recent synthetic study of Yang et al. towards retigeranic acid.97r However, to our team, this was also a quite risky decision because there is no known solution to stereoselectively reduce such a highly substituted and hindered double bond to produce the desired trans-hydrindane moiety. After elimination, lactone-opening, esterification, and oxidation-state manipulation, a pivotal and unprecedented Sm(II)-mediated reductive radical 1,6-addition98 afforded a mixture of two cyclobutanol compounds (209 and 210), which were both successfully converted into 211. This reductive radical addition was proven to be very reliable in our previous synthetic study.78a Finally, to access the extremely challenging trans-hydrindane motif, an extra hydroxyl group at C-6 was introduced to the skeleton to yield 212 as our last hope in the deep desperation after all of the other attempts failed miserably,78b,c especially when the mono-hydroxyl group-directed homogeneous catalytic hydrogenation only led to undesired elimination of the hydroxyl group.78c While our team had already started to design other completely new synthetic routes, this extra C-6 hydroxyl group and Professor Crabtree’s powerful catalyst99 saved the whole project in the very last second: it provided the critical solution to this extremely difficult late-stage, facially selective hydrogenation and yielded the desired trans-hydrindane 213. Eventually, a subsequent five steps afforded astellatol (202) for the first time, three decades after its initial isolation and structural characterization.

Although the overall synthetic efficiency (0.5% yield, 27 steps from (R)-(+)-pulegone) could be further improved, this work accomplished the third-synthesized isopropyl trans-hydrindane sesterterpenoid, following the seminal achievements of retigeranic acid A76 and nitidasin.79 It is not only a triumph of well-designed synthetic strategy, but it also demonstrated the elegance and power of various classic synthetic methods, reagents, and catalysts. Moreover, it should be noted that, because there is no reported solid evidence, such as optical rotation data, to unambiguously assign the absolute stereochemistry of natural astellatol, it is possible that we have prepared the natural product enantiomer.100

8 Conclusions

We have summarized recently accomplished total syntheses of sesterterpenoids. A combination of properly selected and/or novel synthetic methods and often elegant synthetic strategies were key to these impressive endeavors. Meanwhile, some of the above-mentioned targets, along with some other unsynthesized and challenging targets within this family, such as variecolin71i,101 and aspterpenacids,102 should inspire even better blends of method innovation with well-planned strategic design. Opportunities will be provided by unprecedented transformations allowed by advancements in synthetic methods. Moreover, applying the ideas of redox-economic,103 atom-economic,104 step-economic,105 and protecting-group-free synthesis,106 perhaps even with the assistance of artificial intelligence107 in the near future, will bring us closer to the “ideal synthesis”105b,108 of the fascinating sesterterpenoid family members.

9 Conflicts of interest

There are no conflicts to declare.

10 Acknowledgements

Financial support from the National Natural Science Foundation of China (No. 21772082), SZDRC (Discipline Construction Program), SZSTI (JCYJ20170817110515599 and KQJSCX2017072815423320), and the Shenzhen Nobel Prize Scientists Laboratory Project (C17213101) are greatly appreciated. This research was also partially supported by grants from the National Natural Science Foundation of China (No. 81603069), and the Science and Technology Development Fund of Macau (034/2017/A1 and 040/2016/A).

11 References

  1. (a) K. C. Nicolaou and T. Montagnon, Molecules that changed the world, Wiley-VCH, 2008 Search PubMed; (b) K. Chen and P. S. Baran, Nature, 2009, 459, 824–828 CrossRef CAS; (c) D. J. Newman and G. M. Cragg, J. Nat. Prod., 2016, 79, 629–661 CrossRef CAS PubMed.
  2. (a) J. R. Hanson, Nat. Prod. Rep., 1986, 3, 123–132 RSC; (b) J. R. Hanson, Nat. Prod. Rep., 1992, 9, 481–489 RSC; (c) J. R. Hanson, Nat. Prod. Rep., 1996, 13, 529–535 RSC; (d) Y. Liu, L. Wang, J. H. Jung and S. Zhang, Nat. Prod. Rep., 2007, 24, 1401–1429 RSC; (e) L. Wang, B. Yang, X. P. Lin, X. F. Zhou and Y. Liu, Nat. Prod. Rep., 2013, 30, 455–473 RSC.
  3. (a) K. C. Nicolaou, D. Vourloumis, N. Winssinger and P. S. Baran, Angew. Chem., Int. Ed., 2000, 39, 44–122 CrossRef CAS; (b) P. S. Baran, J. Am. Chem. Soc., 2018, 140, 4751–4755 CrossRef CAS.
  4. D. T. Hog, R. Webster and D. Trauner, Nat. Prod. Rep., 2012, 29, 752–779 RSC.
  5. D. J. Faulkner, Tetrahedron Lett., 1973, 14, 3821–3822 CrossRef.
  6. C. J. Barrow, J. W. Blunt, M. H. G. Munro and N. B. Perry, J. Nat. Prod., 1988, 51, 275–281 CrossRef CAS.
  7. (a) C. J. Barrow, J. W. Blunt and M. G. Munro, J. Nat. Prod., 1989, 52, 346–359 CrossRef CAS; (b) K. Choi, J. Hong, C. O. Lee, D. Kim, C. J. Sim, K. S. Im and J. H. Jung, J. Nat. Prod., 2004, 67, 1186–1189 CrossRef CAS.
  8. M. R. Kernan, R. C. Cambie and P. R. Bergquist, J. Nat. Prod., 1991, 54, 265–268 CrossRef CAS.
  9. (a) L. Gomez-Paloma, M. C. Monti, S. Terracciano, A. Casapullo and R. Riccio, Curr. Org. Chem., 2005, 9, 1419–1427 CrossRef CAS; (b) V. Escrig, A. Ubeda and M. L. Ferrandiz, J. Pharmacol. Exp. Ther., 1997, 282, 123–131 CAS.
  10. (a) U. Holler, G. M. Konig and A. D. Wright, J. Nat. Prod., 1997, 60, 832–835 CrossRef; (b) R. D. Epifanio, R. Gabriel, D. L. Martins and G. Muricy, J. Chem. Ecol., 1999, 25, 2247–2254 CrossRef CAS; (c) J. R. Pawlik, G. McFall and S. Zea, J. Chem. Ecol., 2002, 28, 1103–1115 CrossRef CAS.
  11. W. Xiong, Y. Zhao, L. Xu and H. Ji, Chin. J. Org. Chem., 2017, 37, 2101–2108 CrossRef CAS.
  12. K. Takabe, H. Hashimoto, H. Sugimoto, M. Nomoto and H. Yoda, Tetrahedron: Asymmetry, 2004, 15, 909–912 CrossRef CAS.
  13. F. W. Sum and L. Weiler, J. Am. Chem. Soc., 1979, 101, 4401–4403 CrossRef CAS.
  14. M. Tsoukatou, H. Siapi, C. Vagias and V. Roussis, J. Nat. Prod., 2003, 66, 444–446 CrossRef CAS.
  15. T. Tonoi, K. Mameda, M. Fujishiro, Y. Yoshinaga and I. Shiina, Beilstein J. Org. Chem., 2014, 10, 2421–2427 CrossRef.
  16. T. Tonoi, Y. Yoshinaga, M. Fujishiro, K. Mameda, T. Kato, K. Shibamoto and I. Shiina, J. Nat. Prod., 2017, 80, 2335–2344 CrossRef CAS.
  17. (a) T. Mukaiyama, S. Kobayashi, H. Uchiro and I. Shiina, Chem. Lett., 1990, 19, 129–132 CrossRef; (b) S. Kobayashi, H. Uchiro, Y. Fujishita, I. Shiina and T. Mukaiyama, J. Am. Chem. Soc., 1991, 113, 4247–4252 CrossRef CAS; (c) I. Shiina, Chem. Rec., 2014, 14, 144–183 CrossRef CAS.
  18. (a) T. Tsunoda, F. Ozaki and S. Ito, Tetrahedron Lett., 1994, 35, 5081–5082 CrossRef CAS; (b) T. Tsunoda, M. Nagaku, C. Nagino, Y. Kawamura, F. Ozaki, H. Hioki and S. Ito, Tetrahedron Lett., 1995, 36, 2531–2534 CrossRef CAS; (c) T. Tsunoda, C. Nagino, M. Oguri and S. Ito, Tetrahedron Lett., 1996, 37, 2459–2462 CrossRef CAS; (d) I. Sakamoto, H. Kaku and T. Tsunoda, Chem. Pharm. Bull., 2003, 51, 474–476 CrossRef CAS.
  19. (a) R. Forestieri, C. E. Merchant, N. J. de Voogd, T. Matainaho, T. J. Kieffer and R. J. Andersen, Org. Lett., 2009, 11, 5166–5169 CrossRef CAS PubMed; (b) J. Daoust, M. Chen, M. Wang, D. Williams, M. Garcia Chavez, Y. Wang, C. Merchant, A. Fontana, T. Kieffer and R. Andersen, J. Org. Chem., 2013, 78, 8267–8273 CrossRef CAS; (c) M. Wang, I. Tietjen, M. Chen, D. E. Williams, J. Daoust, M. A. Brockman and R. J. Andersen, J. Org. Chem., 2016, 81, 11324–11334 CrossRef CAS.
  20. J.-R. Rho, B. S. Hwang, C. J. Sim, S. Joung, H. Y. Lee and H.-J. Kim, Org. Lett., 2009, 11, 5590–5593 CrossRef CAS.
  21. J. A. Beavo and L. L. Brunton, Nat. Rev. Mol. Cell Biol., 2002, 3, 710–718 CrossRef CAS.
  22. (a) M. R. Byun, A. R. Kim, J.-H. Hwang, M. K. Sung, Y. K. Lee, B. S. Hwang, J.-R. Rho, E. S. Hwang and J.-H. Hong, FEBS Lett., 2012, 586, 1086–1092 CrossRef CAS; (b) M. R. Byun, C. H. Lee, J.-H. Hwang, A. R. Kim, S. A. Moon, M. K. Sung, J.-R. Roh, E. S. Hwang and J.-H. Hong, Eur. J. Pharmacol., 2013, 718, 181–187 CrossRef CAS; (c) Y.-J. Seo, K.-T. Lee, J.-R. Rho and J.-H. Choi, Mar. Drugs, 2015, 13, 7005–7019 CrossRef CAS.
  23. (a) J. Huang, J. R. Yang, J. Zhang and J. Yang, J. Am. Chem. Soc., 2012, 134, 8806–8809 CrossRef CAS; (b) J. Huang, J. R. Yang, J. Zhang and J. Yang, Org. Biomol. Chem., 2013, 11, 3212–3222 RSC; (c) M. Yuan, I. Paterson and S. M. Dalby, Org. Lett., 2012, 14, 5491–5495 Search PubMed; (d) H. Cheng, Z. Zhang, H. Yao, W. Zhang, J. Yu and R. Tong, Angew. Chem., Int. Ed., 2017, 56, 9096–9100 CrossRef CAS; (e) S. Joung, R. Kim and H.-Y. Lee, Org. Lett., 2017, 19, 3903–3906 CrossRef CAS; (f) J. G. Hubert, D. P. Furkert and M. A. Brimble, J. Org. Chem., 2015, 80, 2715–2723 CrossRef CAS; (g) H. J. Shirley and C. D. Bray, Eur. J. Org. Chem., 2016, 2016, 1504–1507 CrossRef CAS.
  24. K. Y.-K. Chow and J. W. Bode, J. Am. Chem. Soc., 2004, 126, 8126–8127 CrossRef CAS PubMed.
  25. (a) T. Jeffery, Tetrahedron Lett., 1989, 30, 2225–2228 CrossRef CAS; (b) J. M. Betancort, T. Martin, J. M. Palazon and V. S. Martin, J. Org. Chem., 2003, 68, 3216–3224 CrossRef CAS; (c) A. Buzas and F. Gagosz, J. Am. Chem. Soc., 2006, 128, 12614–12615 CrossRef CAS.
  26. (a) D. W. C. MacMillan, L. E. Overman and L. D. Pennington, J. Am. Chem. Soc., 2001, 123, 9033–9044 CrossRef CAS; (b) F. Camara, J. Angarita and D. R. Mootoo, J. Org. Chem., 2005, 70, 6870–6875 CrossRef CAS PubMed; (c) D. C. Braddock, D. S. Millan, Y. Perez-Fuertes, R. H. Pouwer, R. N. Sheppard, S. Solanki and A. J. P. White, J. Org. Chem., 2009, 74, 1835–1841 CrossRef CAS; (d) M. G. Rigamonti and F. Gatti, Beilstein J. Org. Chem., 2015, 11, 2117–2124 CrossRef CAS.
  27. (a) S. Antoniotti, E. Genin, V. Michelet and H.-P. Genet, J. Am. Chem. Soc., 2005, 127, 9976–9977 CrossRef CAS PubMed; (b) B. Liu and J. K. De Brabander, Org. Lett., 2006, 8, 4907–4910 CrossRef CAS; (c) B. M. Trost, B. M. O’Boyle and D. Hund, J. Am. Chem. Soc., 2009, 131, 15061–15074 CrossRef CAS; (d) J. A. Palmes and A. Aponick, Synthesis, 2012, 44, 3699–3721 CrossRef CAS; (e) X. Wang, T. J. Paxton, N. Li and A. B. Smith III, Org. Lett., 2012, 14, 3998–4001 CrossRef CAS PubMed; (f) B. B. Butler Jr, N. J. Manda and A. Aponick, Org. Lett., 2015, 17, 1902–1905 CrossRef; (g) R. Quach, D. P. Furkert and M. A. Brimble, Org. Biomol. Chem., 2017, 15, 3098–3104 RSC.
  28. (a) A. Yasuda, S. Tanaka, K. Oshima, H. Yamamoto and H. Nozaki, J. Am. Chem. Soc., 1974, 96, 6513–6514 CrossRef CAS; (b) S. Murata, M. Suzuki and R. Noyori, J. Am. Chem. Soc., 1979, 101, 2738–2739 CrossRef CAS; (c) G. A. Kraus and K. Frazier, J. Org. Chem., 1980, 45, 2579–2581 CrossRef CAS.
  29. (a) H. O. House, J. Am. Chem. Soc., 1955, 77, 3070–3075 CrossRef CAS; (b) B. Rickborn and R. M. Gerkin, J. Am. Chem. Soc., 1971, 93, 1693–1700 CrossRef CAS; (c) R. Sudha, K. Malola Narasimhan, V. Geetha Saraswathy and S. Sankararaman, J. Org. Chem., 1996, 61, 1877–1879 CrossRef CAS; (d) Y. Kita, S. Kitagaki, Y. Yoshida, S. Mihara, D. F. Fang, M. Kondo, S. Okamoto, R. Imai, S. Akai and H. Fujioka, J. Org. Chem., 1997, 62, 4991–4997 CrossRef CAS; (e) B. C. Ranu and U. Jana, J. Org. Chem., 1998, 63, 8212–8216 CrossRef CAS; (f) I. Karame, M. L. Tommasino and M. Lemaire, Tetrahedron Lett., 2003, 44, 7687–7689 CrossRef CAS.
  30. R. Ueoka, Y. Nakao, S. Fujii, R. W. M. van Soest and S. Matsunaga, J. Nat. Prod., 2008, 71, 1089–1091 CrossRef CAS.
  31. (a) E. D. De Silva and P. J. Scheuer, Tetrahedron Lett., 1980, 21, 1611–1614 CrossRef CAS; (b) V. E. Amoo, S. De Bernardo and M. Weigele, Tetrahedron Lett., 1988, 29, 2401–2404 CrossRef CAS; (c) A. Soriente, M. De Rosa, A. Apicella, A. Scettri and G. Sodano, Tetrahedron: Asymmetry, 1999, 10, 4481–4484 CrossRef CAS; (d) B. C. M. Potts, D. J. Faulkner and R. S. Jacobs, J. Nat. Prod., 1992, 55, 1701–1717 CrossRef CAS; (e) A. Pommier, V. Stepanenko, K. Jarowicki and P. J. Kocieński, J. Org. Chem., 2003, 68, 4008–4013 CrossRef CAS PubMed; (f) M. C. Monti, A. Casapullo, R. Riccio and L. Gomez-Paloma, Bioorg. Med. Chem., 2004, 12, 1467–1474 CrossRef CAS; (g) R. A. Keyzers and M. T. Davies-Coleman, Chem. Soc. Rev., 2005, 34, 355–365 RSC; (h) F. Folmer, M. Jaspars, M. Schumacher, M. Dicato and M. Diederich, Biochem. Pharmacol., 2010, 80, 1793–1800 CrossRef CAS.
  32. N. Kutsumura, K. Matsuo and T. Saito, Tetrahedron Lett., 2015, 56, 2602–2604 CrossRef CAS.
  33. (a) N. Kutsumura, K. Niwa and T. Saito, Org. Lett., 2010, 12, 3316–3319 CrossRef CAS PubMed; (b) N. Kutsumura, Y. Matsubara, K. Niwa, A. Ito and T. Saito, Eur. J. Org. Chem., 2013, 2013, 3337–3346 CrossRef CAS.
  34. S. Raghavan and V. S. Babu, Chem.–Eur. J., 2011, 17, 8487–8494 CrossRef CAS.
  35. (a) E. J. Corey, R. K. Bakshi and S. Shibata, J. Am. Chem. Soc., 1987, 109, 5551–5553 CrossRef CAS; (b) E. J. Corey, R. K. Bakshi, S. Shibata, C.-P. Chen and V. K. Singh, J. Am. Chem. Soc., 1987, 109, 7925–7926 CrossRef CAS; (c) E. J. Corey and C. J. Helal, Angew. Chem., Int. Ed., 1998, 37, 1986–2012 CrossRef CAS; (d) D. R. Williams, P. K. Mondal, S. A. Bawel and P. P. Nag, Org. Lett., 2014, 16, 1956–1959 CrossRef CAS.
  36. (a) M. R. Kernan and D. J. Faulkner, J. Org. Chem., 1988, 53, 2773–2776 CrossRef CAS; (b) D. Demeke and C. J. Forsyth, Tetrahedron, 2002, 58, 6531–6544 CrossRef CAS; (c) S. N. Patil and F. Liu, J. Org. Chem., 2008, 73, 4476–4483 CrossRef CAS.
  37. W. Wang, B. Mun, Y. Lee, M. V. Reddy, Y. Park, J. Lee, H. Kim, D. Hahn, J. Chin, M. Ekins, S.-J. Nam and H. Kang, J. Nat. Prod., 2013, 76, 170–177 CrossRef CAS.
  38. J. G. Hubert, D. P. Furkert and M. A. Brimble, J. Org. Chem., 2015, 80, 2231–2239 CrossRef CAS.
  39. G.-Q. Tian, J. Yang and K. Rosa-Perez, Org. Lett., 2010, 12, 5072–5074 CrossRef CAS.
  40. (a) S. H. Luo, Q. Luo, X. M. Niu, M. J. Xie, X. Zhao, B. Schneider, J. Gershenzon and S. H. Li, Angew. Chem., Int. Ed., 2010, 49, 4471–4475 CrossRef CAS; (b) S. H. Luo, L. H. Weng, M. J. Xie, X. N. Li, J. Hua, X. Zhao and S. H. Li, Org. Lett., 2011, 13, 1864–1867 CrossRef CAS; (c) S. H. Luo, J. Hua, C. H. Li, S. X. Jing, Y. Liu, X. N. Li, X. Zhao and S. H. Li, Org. Lett., 2012, 14, 5768–5771 CrossRef CAS; (d) S. H. Luo, J. Hua, X. M. Niu, Y. Liu, C. H. Li, Y. Y. Zhou, S. X. Jing, X. Zhao and S. H. Li, Phytochemistry, 2013, 86, 29–35 CrossRef CAS; (e) S. H. Luo, J. Hua, C. H. Li, Y. Liu, X. N. Li, X. Zhao and S. H. Li, Tetrahedron Lett., 2013, 54, 235–237 CrossRef CAS; (f) S.-H. Luo, C. L. Hugelshofer, J. Hua, S.-X. Jing, C.-H. Li, Y. Liu, X.-N. Li, X. Zhao, T. Magauer and S.-H. Li, Org. Lett., 2014, 16, 6416–6419 CrossRef CAS.
  41. (a) X. Huang, L. Song, J. Xu, G. Zhu and B. Liu, Angew. Chem., Int. Ed., 2013, 52, 952–955 CrossRef CAS PubMed; (b) C. L. Hugelshofer and T. Magauer, Angew. Chem., Int. Ed., 2014, 53, 11351–11355 CrossRef CAS; (c) S. Guo, J. Liu and D. Ma, Angew. Chem., Int. Ed., 2015, 54, 1298–1301 CrossRef CAS; (d) C. L. Hugelshofer and T. Magauer, J. Am. Chem. Soc., 2015, 137, 3807–3810 CrossRef CAS; (e) J. Xie, Y. L. Ma and D. A. Horne, J. Org. Chem., 2011, 76, 6169–6176 CrossRef CAS; (f) C. L. Hugelshofer and T. Magauer, Synlett, 2015, 26, 572–579 CrossRef CAS.
  42. H. C. Brown, P. K. Jadhav and K. S. Bhat, J. Am. Chem. Soc., 1988, 110, 1535–1538 CrossRef CAS.
  43. (a) A. B. Dounay, R. A. Urbanek, V. A. Frydrychowski and C. J. Forsyth, J. Org. Chem., 2001, 66, 925–938 CrossRef CAS; (b) R. Tello-Aburto and H. F. Olivo, Org. Lett., 2008, 10, 2191–2194 CrossRef CAS.
  44. (a) S. Xue, L. He, Y.-K. Liu, K.-Z. Han and Q.-X. Guo, Synthesis, 2006, 666–674 CrossRef CAS; (b) T. Arai, Y. Ikematsu and Y. Suemitsu, Pure Appl. Chem., 2010, 82, 1485–1490 CAS; (c) M. Xie, C. Feng, J. Zhang, C. Liu, K. Fang, G. Shu and W. Zuo, J. Organomet. Chem., 2011, 696, 3397–3401 CrossRef CAS.
  45. D. Mal and P. Pahari, Chem. Rev., 2007, 107, 1892–1918 CrossRef CAS.
  46. (a) E. J. Corey, R. L. Danheiser, S. Chandrasekaran, P. Siret, G. E. Keck and J. L. Gras, J. Am. Chem. Soc., 1978, 100, 8031–8034 CrossRef CAS; (b) G. Coulthard, W. Erb and V. K. Aggarwal, Nature, 2012, 489, 278–281 CrossRef CAS.
  47. D. F. Taber, P. W. Dematteo and R. A. Hassan, Org. Synth., 2013, 90, 350–357 CrossRef CAS.
  48. (a) Y. Liu, F. Song, Z. Song, M. Liu and B. Yan, Org. Lett., 2005, 7, 5409–5412 CrossRef CAS; (b) X. Du, F. Song, Y. Lu, H. Chen and Y. Liu, Tetrahedron, 2009, 65, 1839–1845 CrossRef CAS; (c) C. H. Oh, H. J. Yi and K. H. Lee, Bull. Korean Chem. Soc., 2010, 31, 683–688 CrossRef CAS.
  49. D. Zhang and J. M. Ready, J. Am. Chem. Soc., 2006, 128, 15050–15051 CrossRef CAS.
  50. (a) P. V. Pham, K. Ashton and D. W. C. MacMillan, Chem. Sci., 2011, 2, 1470–1473 RSC; (b) R. J. Comito, F. G. Finelli and D. W. C. MacMillan, J. Am. Chem. Soc., 2013, 135, 9358–9361 CrossRef CAS.
  51. (a) D. A. Evans, J. V. Nelson, E. Vogel and T. R. Taber, J. Am. Chem. Soc., 1981, 103, 3099–3111 CrossRef CAS; (b) D. A. Evans, B. Cote, P. J. Coleman and B. T. Connell, J. Am. Chem. Soc., 2003, 125, 10893–10898 CrossRef CAS.
  52. (a) G. A. Molander and J. A. McKie, J. Org. Chem., 1992, 57, 3132–3139 CrossRef CAS; (b) G. A. Molander and J. A. McKie, J. Org. Chem., 1995, 60, 872–882 CrossRef CAS; (c) G. A. Molander, J. C. McWilliams and B. C. Noll, J. Am. Chem. Soc., 1997, 119, 1265–1276 CrossRef CAS.
  53. T. Satoh, K. Nanba and S. Suzuki, Chem. Pharm. Bull., 1971, 19, 817–820 CrossRef CAS.
  54. Y. Wu, R. P. Singh and L. Deng, J. Am. Chem. Soc., 2011, 133, 12458–12461 CrossRef CAS.
  55. M. S. Butler and R. J. Capon, Aust. J. Chem., 1992, 45, 1705–1743 CrossRef CAS.
  56. A. Urosa, I. S. Marcos, D. Díez, A. Lithgow, G. B. Plata, J. M. Padrón and P. Basabe, Mar. Drugs, 2015, 13, 2407–2423 CrossRef CAS.
  57. A. Urosa, I. S. Marcos, D. Díez, J. M. Padrón and P. Basabe, J. Org. Chem., 2015, 80, 6447–6455 CrossRef CAS.
  58. A. Urosa, I. S. Marcos, D. Díez, G. B. Plata, J. M. Padrón and P. Basabe, Mol. Diversity, 2016, 20, 369–377 CrossRef CAS.
  59. (a) M. Oka, S. Iimura, O. Tenmyo, Y. Sawada, M. Sugawara, N. Ohkusa, H. Yamamoto, K. Kawano, S.-L. Hu, Y. Fukagawa and T. Oki, J. Antibiot., 1993, 46, 367–373 CrossRef CAS; (b) S. Iimura, M. Oka, Y. Narita, M. Konishi, H. Kakisawa, Q. Gao and T. Oki, Tetrahedron Lett., 1993, 34, 493–496 CrossRef CAS; (c) M. Oka, S. Iimura, Y. Narita, T. Furumai, M. Konishdfi, T. Oki, Q. Gao and H. Kakisawa, J. Org. Chem., 1993, 58, 1875–1881 CrossRef CAS; (d) A. Ritieni, S. M. Monti, G. Randazzo, A. Logrieco, A. Moretti, G. Peluso, R. Ferracane and V. Fogliano, J. Agric. Food Chem., 1997, 45, 3039–3043 CrossRef CAS; (e) H. J. Jung, H. B. Lee, C. J. Kim, J. R. Rho, J. Shin and H. J. Kwon, J. Antibiot., 2003, 56, 492–496 CrossRef CAS.
  60. B. Schlegel, M. Schmidtke, H. Dorfelt, P. Kleinwachter and U. Gräfe, J. Basic Microbiol., 2001, 41, 179–183 CrossRef CAS.
  61. (a) K. Tatsuta and N. Masuda, J. Antibiot., 1998, 51, 602–606 CrossRef CAS; (b) K. Tatsuta, N. Masuda and H. Nishida, Tetrahedron Lett., 1998, 39, 83–86 CrossRef CAS; (c) A. G. Myers, M. Siu and F. Ren, J. Am. Chem. Soc., 2002, 124, 4230–4232 CrossRef CAS; (d) A. G. Myers and M. Siu, Tetrahedron, 2002, 58, 6397–6404 CrossRef CAS; (e) J. Chan and T. F. Jamison, J. Am. Chem. Soc., 2003, 125, 11514–11515 CrossRef CAS PubMed; (f) J. Chan and T. F. Jamison, J. Am. Chem. Soc., 2004, 126, 10682–10691 CrossRef CAS; (g) B. M. Trost, G. Dong and J. A. Vance, J. Am. Chem. Soc., 2007, 129, 4540–4541 CrossRef CAS; (h) G. O. Berger and M. A. Tius, J. Org. Chem., 2007, 72, 6473–6480 CrossRef CAS; (i) B. M. Trost, G. Dong and J. A. Vance, Chem.–Eur. J., 2010, 16, 6265–6277 CrossRef CAS.
  62. (a) K. Takeda, A. Nakajima and E. Yoshii, Synlett, 1995, 249–250 CrossRef CAS; (b) M.-P. Mermet-Mouttet, K. Gabriel and D. Heissler, Tetrahedron Lett., 1999, 40, 843–846 CrossRef CAS; (c) G. O. Berger and M. A. Tius, Org. Lett., 2005, 7, 5011–5013 CrossRef CAS.
  63. Y. Jin and F. G. Qiu, Org. Biomol. Chem., 2012, 10, 5452–5455 RSC.
  64. S. P. Andrews, M. Ball, F. Wierschem, E. Cleator, S. Oliver, K. Hegenauer, O. Simic, A. Antonello, U. Hinger, M. D. Smith and S. V. Ley, Chem.–Eur. J., 2007, 13, 5688–5712 CrossRef CAS.
  65. J. Daoust, A. Fontana, C. E. Merchant, N. J. D. Voogd, B. O. Patrick, T. J. Kieffer and R. J. Andersen, Org. Lett., 2010, 12, 3208–3211 CrossRef CAS.
  66. W. Zhang, H. Yao, J. Yu, Z. Zhang and R. Tong, Angew. Chem., Int. Ed., 2017, 56, 4787–4791 CrossRef CAS.
  67. (a) G. H. Posner and D. Z. Rogers, J. Am. Chem. Soc., 1977, 99, 8214–8218 CrossRef CAS; (b) K. C. Nicolaou, M. E. Duggan, C.-K. Hwang and P. K. Somers, J. Chem. Soc., Chem. Commun., 1985, 1359–1362 RSC; (c) B. M. Trost and A. Tenaglia, Tetrahedron Lett., 1988, 29, 2931–2934 CrossRef CAS; (d) K. C. Nicolaou, C. V. C. Prasad, P. K. Somers and C.-K. Hwang, J. Am. Chem. Soc., 1989, 111, 5330–5334 CrossRef CAS; (e) K. C. Nicolaou, M. E. Duggan and C.-K. Hwang, J. Am. Chem. Soc., 1989, 111, 6676–6682 CrossRef CAS; (f) G. Prestat, C. Baylon, M.-P. Heck and C. Mioskowski, Tetrahedron Lett., 2000, 41, 3829–3831 CrossRef CAS.
  68. J. He, J. Ling and P. Chiu, Chem. Rev., 2014, 114, 8037–8128 CrossRef CAS.
  69. (a) T. K. Au, W. S. H. Chick and P. C. Leung, Life Sci., 2000, 67, 733–742 CrossRef CAS; (b) A. Evidente, A. Andolfi, A. Cimmino, M. Vurro, M. Fracchiolla, R. Charudattan and A. Motta, Phytochemistry, 2006, 67, 2281–2287 CrossRef CAS; (c) M. Fernández-Aparicio, A. Andolfi, A. Cimmino, D. Rubiales and A. Evidente, J. Agric. Food Chem., 2008, 56, 8343–8347 CrossRef PubMed; (d) D. Xue, Q. Wang, Z. Chen, L. Cai, L. Bao, Q. Qi, L. Liu, X. Wang, H. Jin, J. Wang, H. Wu, H. Liu and Q. Chen, Bioorg. Med. Chem. Lett., 2015, 25, 1464–1470 CrossRef CAS PubMed; (e) V. Locato, E. N. Uzal, S. Cimini, M. C. Zonno, A. Evidente, A. Micera, C. H. Foyer and L. De Gara, J. Exp. Bot., 2015, 66, 2991–3000 CrossRef CAS PubMed; (f) A. Pósa, R. Szabó, Z. Szalai, K. Kupai, Z. Deim, Z. Murlasits, O. Bencsik, A. Szekeres, C. Vágvölgyi, L. Balogh, B. Juhász, Z. Szilvássy and C. Varga, Hum. Exp. Toxicol., 2017, 36, 594–602 CrossRef PubMed.
  70. (a) H. Wei, T. Itoh, M. Kinoshita, Y. Nakai, M. Kurotaki and M. Kobayashi, Tetrahedron, 2004, 60, 6015–6019 CrossRef CAS; (b) T. Yang, Z. Lu, L. Meng, S. Wei, K. Hong, W. Zhu and C. Huang, Bioorg. Med. Chem. Lett., 2012, 22, 579–585 CrossRef CAS; (c) D. Zhang, S. Fukuzawa, M. Satake, X. Li, T. Kuranaga, A. Niitsu, K. Yoshizawa and K. Tachibana, Nat. Prod. Commun., 2012, 7, 1411–1414 CAS; (d) W. Sun, C. Lv, T. Zhu, X. Yang, S. Wei, J. Sun, K. Hong, W. Zhu and C. Huang, Mar. Drugs, 2013, 11, 4570–4584 CrossRef CAS PubMed; (e) M. Bury, A. Girault, V. Mégalizzi, S. Spiegl-Kreinecker, V. Mathieu, W. Berger, A. Evidente, A. Kornienko, P. Gailly, C. Vandier and R. Kiss, Cell Death Dis., 2013, 4, e561 CrossRef CAS; (f) M. Bury, E. Novo-Uzal, A. Andolfi, S. Cimini, N. Wauthoz, P. Heffeter, B. Lallemand, F. Avolio, C. Delporte, A. Cimmino, J. Dubois, P. Van Antwerpen, M. C. Zonno, M. Vurro, Y. Poumay, W. Berger, A. Evidente, L. De Gara, R. Kiss and V. Locato, Int. J. Oncol., 2013, 43, 575–585 CrossRef CAS; (g) R. Morrison, C. Gardiner, A. Evidente, R. Kiss and H. Townley, Pharm. Res., 2014, 31, 2904–2917 CrossRef CAS; (h) R. Dasari, M. Masi, R. Lisy, M. Ferdérin, L. R. English, A. Cimmino, V. Mathieu, A. J. Brenner, J. G. Kuhn, S. T. Whitten, A. Evidente, R. Kiss and A. Kornienko, Bioorg. Med. Chem. Lett., 2015, 25, 4544–4548 CrossRef CAS; (i) C. Lv, W. Qin, T. Zhu, S. Wei, K. Hong, W. Zhu, R. Chen and C. Huang, Mar. Drugs, 2015, 13, 431–443 CrossRef; (j) C. R. De Carvalho, M. De L. A. Vieira, C. L. Cantrell, D. E. Wedge, T. M. A. Alves, C. L. Zani, R. S. Pimenta, P. A. Sales Jr, S. M. F. Murta, A. J. Romanha, C. A. Rosa and L. H. Rosa, Nat. Prod. Res., 2016, 30, 478–481 CrossRef; (k) D. R. Bhatia, P. Dhar, V. Mutalik, S. K. Deshmukh, S. A. Verekar, D. C. Desai, R. Kshirsagar, P. Thiagarajan and V. Agarwal, Nat. Prod. Res., 2016, 30, 1455–1458 CrossRef CAS PubMed; (l) C. Chidley, S. A. Trauger, K. Birsoy and E. K. O’Shea, eLife, 2016, 5, e14601 CrossRef PubMed; (m) R. Morrison, T. Lodge, A. Evidente, R. Kiss and H. Townley, Int. J. Oncol., 2017, 50, 773–786 CrossRef CAS.
  71. (a) W. G. Dauben and D. J. Hart, J. Org. Chem., 1977, 42, 922–923 CrossRef; (b) L. A. Paquette, J. A. Colapret and D. R. Andrews, J. Org. Chem., 1985, 50, 201–205 CrossRef CAS; (c) J. H. Rigby and C. Senanayake, J. Org. Chem., 1987, 52, 4634–4635 CrossRef CAS; (d) M. Rowley, M. Tsukamoto and Y. Kishi, J. Am. Chem. Soc., 1989, 111, 2735–2737 CrossRef CAS; (e) P. A. Wender, J. M. Nuss, D. B. Smith, A. Suárez-Sobrino, J. Vágberg, D. Decosta and J. Bordner, J. Org. Chem., 1997, 62, 4908–4909 CrossRef CAS; (f) G. Mehta and V. Singh, Chem. Rev., 1999, 99, 881–930 CrossRef CAS; (g) M. Michalak, K. Michalak, Z. Urbanczyk-Lipkowska and J. Wicha, J. Org. Chem., 2011, 76, 7497–7509 CrossRef CAS; (h) K. Tsuna, N. Noguchi and M. Nakada, Angew. Chem., Int. Ed., 2011, 50, 9452–9455 CrossRef CAS PubMed; (i) K. Li, C. Wang, G. Yin and S. Gao, Org. Biomol. Chem., 2013, 11, 7550–7558 RSC; (j) K. Tsuna, N. Noguchi and M. Nakada, Chem.–Eur. J., 2013, 19, 5476–5486 CrossRef CAS.
  72. Z. G. Brill, H. K. Grover and T. J. Maimone, Science, 2016, 352, 1078–1082 CrossRef CAS PubMed.
  73. J. M. Concellón, L. Llavona and P. L. Bernad Jr, Tetrahedron, 1995, 51, 5573–5584 CrossRef.
  74. N. Kawahara, M. Nozawa, D. Flores, P. Bonilla, S. Sekita, M. Satake and K. Kawai, Chem. Pharm. Bull., 1997, 45, 1717–1719 CrossRef CAS.
  75. D. T. Hog, P. Mayer and D. Trauner, J. Org. Chem., 2012, 77, 5838–5843 CrossRef CAS.
  76. (a) M. Kaneda, R. Takahashi, Y. Iitaka and S. Shibata, Tetrahedron Lett., 1972, 13, 4609–4611 CrossRef; (b) E. J. Corey, M. C. Desai and T. A. Engler, J. Am. Chem. Soc., 1985, 107, 4339–4341 CrossRef CAS; (c) L. A. Paquette, J. Wright, G. J. Drtina and R. A. Roberts, J. Org. Chem., 1987, 52, 2960–2962 CrossRef; (d) J. Wright, G. J. Drtina, R. A. Roberts and L. A. Paquette, J. Am. Chem. Soc., 1988, 110, 5806–5817 CrossRef CAS; (e) T. Hudlicky, L. Radesca-Kwart, L. Q. Li and T. Bryant, Tetrahedron Lett., 1988, 29, 3283–3286 CrossRef CAS; (f) T. Hudlicky, A. Fleming and L. Radesca, J. Am. Chem. Soc., 1989, 111, 6691–6707 CrossRef CAS; (g) P. A. Wender and S. K. Singh, Tetrahedron Lett., 1990, 31, 2517–2520 CrossRef CAS.
  77. (a) I. H. Sadler and T. J. Simpson, J. Chem. Soc., Chem. Commun., 1989, 1602–1604 RSC; (b) I. H. Sadler and T. J. Simpson, Magn. Reson. Chem., 1992, 30, 18–23 CrossRef.
  78. (a) N. Zhao, S. Xie, G. Chen and J. Xu, Chem.–Eur. J., 2016, 22, 12634–12636 CrossRef CAS; (b) N. Zhao, S. Yin, S. Xie, H. Yan, P. Ren, G. Chen, F. Chen and J. Xu, Angew. Chem., Int. Ed., 2018, 57, 3386–3390 CrossRef CAS; (c) N. Zhao, S. Xie, H. Huang and J. Xu, Synlett, 2018, 29, 1933–1936 CrossRef CAS.
  79. (a) D. T. Hog, F. M. E. Huber, P. Mayer and D. Trauner, Angew. Chem., Int. Ed., 2014, 53, 8513–8517 CrossRef CAS; (b) D. T. Hog, F. M. E. Huber, G. Jiménez-Osés, P. Mayer, K. N. Houk and D. Trauner, Chem.–Eur. J., 2015, 21, 13646–13665 CrossRef CAS.
  80. (a) E.-I. Negishi, H. Matsushita, S. Chatterjee and R. A. John, J. Org. Chem., 1982, 47, 3188–3190 CrossRef CAS; (b) E.-I. Negishi, F.-T. Luo, A. J. Pecora and A. Silveira Jr, J. Org. Chem., 1983, 48, 2427–2430 CrossRef CAS.
  81. G. Agnel, Z. Owczarczyk and E.-I. Negishi, Tetrahedron Lett., 1992, 33, 1543–1546 CrossRef CAS.
  82. A. M. Garcia, J. L. Mascarenas, L. Castedo and A. Mourino, J. Org. Chem., 1997, 62, 6353–6358 CrossRef CAS.
  83. (a) D. T. A. Youssef, R. K. Yamaki and P. J. Scheuer, J. Nat. Prod., 2002, 65, 2–6 CrossRef CAS; (b) Y.-C. Chang, S.-W. Tseng, L.-L. Liu, Y. Chou, Y.-S. Ho, M.-C. Lu and J.-H. Su, Mar. Drugs, 2012, 10, 987–997 CrossRef CAS.
  84. M. Martín, A. Urosa, I. S. Marcos, D. Díez, J. Padrón and P. Basabe, J. Org. Chem., 2015, 80, 4566–4572 CrossRef PubMed.
  85. (a) P. Basabe, A. Diego, D. Díez, I. S. Marcos and J. G. Urones, Synlett, 2000, 1807–1809 CAS; (b) P. Basabe, A. Diego, D. Díez, I. S. Marcos, F. Mollinedo and J. G. Urones, Synthesis, 2002, 1523–1529 CrossRef CAS.
  86. A. Monks, D. Scudiero, P. Skehan, R. Shoemaker, K. Paull, D. Vistica, C. Hose, J. Langley, P. Cronise, A. Vaigro-Wolff, M. Gray-Goodrich, H. Campbell, J. Mayo and M. Boyd, J. Natl. Cancer Inst., 1991, 83, 757–766 CrossRef CAS.
  87. G. R. Pettit, Z. A. Cichacz, R. Tan, M. S. Hoard, N. Melody and R. K. Pettit, J. Nat. Prod., 1998, 61, 13–16 CrossRef CAS.
  88. T. Jiménez, S. P. Morcillo, A. Martín-Lasanta, D. Collado-Sanz, D. J. Cárdenas, A. Gansäuer, J. Justicia and J. M. Cuerva, Chem.–Eur. J., 2012, 18, 12825–12833 CrossRef.
  89. (a) A. Gansäuer, D. Franke, T. Lauterbach and M. Nieger, J. Am. Chem. Soc., 2005, 127, 11622–11623 CrossRef PubMed; (b) T. Klawonn, A. Gansäuer, I. Winkler, T. Lauterbach, D. Franke, R. J. M. Nolte, M. C. Feiters, H. Bçrner, J. Hentschel and K. H. Dçtz, Chem. Commun., 2007, 1894–1895 RSC; (c) A. Gansäuer, I. Winkler, D. Worgull, T. Lauterbach, D. Franke, A. Selig, L. Wagner and A. Prokop, Chem.–Eur. J., 2008, 14, 4160–4163 CrossRef PubMed; (d) A. Gansäuer, I. Winkler, D. Worgull, D. Franke, T. Lauterbach, A. Okkel and M. Nieger, Organometallics, 2008, 27, 5699–5707 CrossRef; (e) R. E. Estévez, J. Justicia, B. Bazdi, N. Fuentes, M. Paradas, D. Choquesillo-Lazarte, J. M. García-Ruiz, R. Robles, A. Gansäuer, J. M. Cuerva and J. E. Oltra, Chem.–Eur. J., 2009, 15, 2774–2791 CrossRef; (f) A. Gansäuer, I. Winkler, T. Klawonn, R. J. M. Nolte, M. C. Feiters, H. Börner, J. Hentschel and K. H. Dötz, Organometallics, 2009, 28, 1377–1382 CrossRef.
  90. (a) R. Breslow, S. S. Olin and J. T. Groves, Tetrahedron Lett., 1968, 9, 1837–1840 CrossRef; (b) J. Y. Lallemand, M. Julia and D. Mansuy, Tetrahedron Lett., 1973, 14, 4461–4464 CrossRef; (c) J. Justicia, A. Rosales, E. Buñuel, J. L. Oller-López, M. Valdivia, A. Haidour, J. E. Oltra, A. F. Barrero, D. J. Cárdenas and J. M. Cuerva, Chem.–Eur. J., 2004, 10, 1778–1788 CrossRef CAS; (d) J. Justicia, J. E. Oltra and J. M. Cuerva, Tetrahedron Lett., 2004, 45, 4293–4296 CrossRef CAS; (e) J. Justicia, J. E. Oltra and J. M. Cuerva, J. Org. Chem., 2004, 69, 5803–5806 CrossRef CAS PubMed; (f) J. Justicia, J. L. Oller-López, A. G. Campaña, J. E. Oltra, J. M. Cuerva, E. Buñuel and D. J. Cárdenas, J. Am. Chem. Soc., 2005, 127, 14911–14921 CrossRef CAS PubMed; (g) J. Justicia, J. E. Oltra, A. F. Barrero, A. Guadaño, A. González- Coloma and J. M. Cuerva, Eur. J. Org. Chem., 2005, 2005, 712–718 CrossRef; (h) A. Gansäuer, D. Worgull and J. Justicia, Synthesis, 2006, 2151–2154 CrossRef; (i) A. Gansäuer, A. Rosales and J. Justicia, Synlett, 2006, 927–929 CrossRef; (j) A. Gansäuer, J. Justicia, A. Rosales, D. Worgull, B. Rinker, J. M. Cuerva and J. E. Oltra, Eur. J. Org. Chem., 2006, 2006, 4115–4127 CrossRef; (k) J. Justicia, A. G. Campaña, B. Bazdi, R. Robles, J. M. Cuerva and J. E. Oltra, Adv. Synth. Catal., 2008, 350, 571–576 CrossRef CAS; (l) J. Justicia, L. Á. de Cienfuegos, A. G. Campaña, D. Miguel, V. Jakoby, A. Gansäuer and J. M. Cuerva, Chem. Soc. Rev., 2011, 40, 3525–3537 RSC.
  91. (a) K. U. Wendt, G. E. Schulz, E. J. Corey and D. R. Liu, Angew. Chem., Int. Ed., 2000, 39, 2812–2833 CrossRef CAS; (b) R. A. Yoder and J. N. Johnston, Chem. Rev., 2005, 105, 4730–4756 CrossRef CAS PubMed.
  92. L. Acebey, M. Sauvain, S. Beck, C. Moulis, A. Gimenez and V. Jullian, Org. Lett., 2007, 9, 4693–4696 CrossRef CAS PubMed.
  93. (a) C. Yuan, B. Du, L. Yang and B. Liu, J. Am. Chem. Soc., 2013, 135, 9291–9294 CrossRef CAS PubMed; (b) B. Du, C. Yuan, T. Yu, L. Yang, Y. Yang, B. Liu and S. Qin, Chem.–Eur. J., 2014, 20, 2613–2622 CrossRef CAS PubMed; (c) J.-P. Li, C.-C. Yuan, B. Du and B. Liu, Chin. Chem. Lett., 2017, 28, 113–116 CrossRef CAS.
  94. (a) A. De Meijere, T.-J. Schulz, R. R. Kostikov, F. Graupner, T. Murr and T. Bielfeldt, Synthesis, 1991, 547–560 CrossRef CAS; (b) J.-L. Zhang, P. W. H. Chan and C.-M. Che, Tetrahedron Lett., 2003, 44, 8733–8737 CrossRef CAS; (c) J. R. Fulton, V. K. Aggarwal and J. Vicente, Eur. J. Org. Chem., 2005, 2005, 1479–1492 CrossRef; (d) J. Barluenga, N. Quiñones, M. Tomás-Gamasa and M.-P. Cabal, Eur. J. Org. Chem., 2012, 2012, 2312–2317 CrossRef CAS; (e) Y. Yang, J. Li, B. Du, C. Yuan, B. Liu and S. Qin, Chem. Commun., 2015, 51, 6179–6182 RSC.
  95. (a) F. Bohlmann, C. Zdero, R. M. King and H. Robinson, Phytochemistry, 1980, 19, 689–691 CrossRef CAS; (b) A. P. Trentin, A. Santos, A. Guedes, M. G. Pizzolatti, R. A. Yunes and J. B. Calixto, Planta Med., 1999, 65, 517–521 CrossRef CAS PubMed; (c) L. Acebey, V. Jullian, D. Sereno, S. Chevalley, Y. Estevez, C. Moulis, S. Beck, A. Valentin, A. Gimenez and M. Sauvain, Planta Med., 2010, 76, 365–368 CrossRef CAS PubMed.
  96. (a) D. M. Hodgson, Y. K. Chung and J.-M. Paris, J. Am. Chem. Soc., 2004, 126, 8664–8665 CrossRef CAS PubMed; (b) D. M. Hodgson, Y. K. Chung and J. M. Paris, Synthesis, 2005, 2264–2266 CrossRef CAS.
  97. (a) Y. Tang, L. Deng, Y. Zhang, G. Dong, J. Chen and Z. Yang, Org. Lett., 2005, 7, 593–595 CrossRef CAS; (b) Y. Tang, Y. Zhang, M. Dai, T. Luo, L. Deng, J. Chen and Z. Yang, Org. Lett., 2005, 7, 885–888 CrossRef CAS PubMed; (c) Y. F. Tang, L. J. Deng, Y. D. Zhang, G. B. Dong, J. H. Chen and Z. Yang, Org. Lett., 2005, 7, 1657–1659 CrossRef CAS; (d) Y. Lan, L. J. Deng, J. Liu, C. Wang, O. Wiest, Z. Yang and Y. D. Wu, J. Org. Chem., 2009, 74, 5049–5058 CrossRef CAS PubMed; (e) Q. Xiao, W. Ren, Z. Chen, T. Sun, Y. Li, Q. Ye, J. Gong, F. Meng, L. You, Y. Liu, M. Zhao, L. Xu, Z. Shan, Y. Shi, Y. Tang, J. Chen and Z. Yang, Angew. Chem., Int. Ed., 2011, 50, 7373–7377 CrossRef CAS PubMed; (f) T. Sun, W. Ren, Q. Xiao, Y. Tang, Y. Zhang, Y. Li, F. Meng, Y. Liu, M. Zhao, L. Xu, J. Chen and Z. Yang, Chem.–Asian J., 2012, 7, 2321–2333 CrossRef CAS PubMed; (g) Y. Li, Z. Chen, Q. Xiao, Q. Ye, T. Sun, F. Meng, W. Ren, L. You, L. Xu, Y. Wang, J. Chen and Z. Yang, Chem.–Asian J., 2012, 7, 2334–2340 CrossRef CAS PubMed; (h) W. Ren, Z. Chen, Q. Xiao, Y. Li, T. Sun, Z. Zhang, Q. Ye, F. Meng, L. You, M. Zhao, L. Xu, Y. Tang, J. Chen and Z. Yang, Chem.–Asian J., 2012, 7, 2341–2350 CrossRef CAS PubMed; (i) Y. Yang, X. Fu, J. Chen and H. Zhai, Angew. Chem., Int. Ed., 2012, 51, 9825–9828 CrossRef CAS PubMed; (j) Q. Liu, G. Yue, N. Wu, G. Lin, Y. Li, J. Quan, C. Li, G. Wang and Z. Yang, Angew. Chem., Int. Ed., 2012, 51, 12072–12076 CrossRef CAS PubMed; (k) Y. Wang, L. Xu, R. Yu, J. Chen and Z. Yang, Chem. Commun., 2012, 48, 8183–8185 RSC; (l) J. Huang, L. Fang, R. Long, L. Shi, H. Shen, C. Li and Z. Yang, Org. Lett., 2013, 15, 4018–4021 CrossRef CAS; (m) L. Shi, H. Shen, L. Fang, J. Huang, C. Li and Z. Yang, Chem. Commun., 2013, 49, 8806–8808 RSC; (n) L. Jørgensen, S. J. McKerrall, C. A. Kuttruff, F. Ungeheuer, J. Felding and P. S. Baran, Science, 2013, 341, 878–882 CrossRef; (o) S. Liu, H. Shen, Z. Yu, L. Shi, Z. Yang and Y. Lan, Organometallics, 2014, 33, 6282–6285 CrossRef CAS; (p) D. R. Williams and A. A. Shah, J. Am. Chem. Soc., 2014, 136, 8829–8836 CrossRef CAS PubMed; (q) L. You, X. Liang, L. Xu, Y. Wang, J. Zhang, Q. Su, Y. Li, B. Zhang, S. Yang, J. Chen and Z. Yang, J. Am. Chem. Soc., 2015, 137, 10120–10123 CrossRef CAS PubMed; (r) J. Zhang, X. Wang, S. Li, D. Li, S. Liu, Y. Lan, J. Gong and Z. Yang, Chem.–Eur. J., 2015, 21, 12596–12600 CrossRef CAS PubMed; (s) J. Huang, L. Fang, J. Gong, C. Li and Z. Yang, Tetrahedron, 2015, 71, 3720–3733 CrossRef CAS; (t) J. S. Clark and C. Xu, Angew. Chem., Int. Ed., 2016, 55, 4332–4335 CrossRef CAS PubMed; (u) K. V. Chuang, C. Xu and S. E. Reisman, Science, 2016, 353, 912–915 CrossRef CAS PubMed; (v) L. Shi and Z. Yang, Eur. J. Org. Chem., 2016, 2356–2368 CrossRef CAS; (w) C. Lv, X. Yan, Q. Tu, Y. Di, C. Yuan, X. Fang, Y. Ben-David, L. Xia, J. Gong, Y. Shen, Z. Yang and X. Hao, Angew. Chem., Int. Ed., 2016, 55, 7539–7543 CrossRef CAS; (x) D. Liu, T. Sun, K. Wang, Y. Lu, S. Zhang, Y. Li, Y. Jiang, J. Chen and Z. Yang, J. Am. Chem. Soc., 2017, 139, 5732–5735 CrossRef CAS PubMed; (y) G. Volpin, N. A. Vepřek, A. B. Bellan and D. Trauner, Angew. Chem., Int. Ed., 2017, 56, 897–901 CrossRef CAS PubMed; (z) C. Lv, Q. Tu, J. Gong, X. Hao and Z. Yang, Tetrahedron, 2017, 73, 3612–3621 CrossRef CAS; (a a) W. Zhang, M. Ding, J. Li, Z. Guo, M. Lu, Y. Chen, L. Liu, Y.-H. Shen and A. Li, J. Am. Chem. Soc., 2018, 140, 4227–4231 CrossRef CAS PubMed; (a b) Y. Chang, L. Shi, J. Huang, L. Shi, Z. Zhang, H.-D. Hao, J. Gong and Z. Yang, Org. Lett., 2018, 20, 2876–2879 CrossRef CAS PubMed; (a c) Z. Huang, J. Huang, Y. Qu, W. Zhang, J. Gong and Z. Yang, Angew. Chem., Int. Ed., 2018, 57, 8744–8748 CrossRef CAS PubMed; (a d) T.-W. Sun, D.-D. Liu, K.-Y. Wang, B.-Q. Tong, J.-X. Xie, Y.-L. Jiang, Y. Li, B. Zhang, Y.-F. Liu, Y.-X. Wang, J.-J. Zhang, J.-H. Chen and Z. Yang, J. Org. Chem., 2018, 83, 6893–6906 CrossRef CAS PubMed; (a e) K.-Y. Wang, D.-D. Liu, T.-W. Sun, Y. Lu, S.-L. Zhang, Y.-H. Li, Y.-X. Han, H.-Y. Liu, C. Peng, Q.-Y. Wang, J.-H. Chen and Z. Yang, J. Org. Chem., 2018, 83, 6907–6923 CrossRef CAS PubMed.
  98. (a) K. Weinges, S. B. Schmidbauer and H. Schick, Chem. Ber., 1994, 127, 1305–1309 CrossRef CAS; (b) D. Johnston, C. M. McCusker and D. J. Procter, Tetrahedron Lett., 1999, 40, 4913–4916 CrossRef CAS; (c) D. Johnston, C. M. McCusker, K. Muir and D. J. Procter, J. Chem. Soc., Perkin Trans. 1, 2000, 681–695 RSC; (d) D. Johnston, N. Francon, D. J. Edmonds and D. J. Procter, Org. Lett., 2001, 3, 2001–2004 CrossRef CAS; (e) D. Johnston, E. Couche’, D. J. Edmonds, K. W. Muir and D. J. Procter, Org. Biomol. Chem., 2003, 1, 328–337 RSC; (f) T. K. Hutton, K. W. Muir and D. J. Procter, Org. Lett., 2003, 5, 4811–4814 CrossRef CAS; (g) D. J. Edmonds, K. W. Muir and D. J. Procter, J. Org. Chem., 2003, 68, 3190–3198 CrossRef CAS; (h) H. Y. Harb, K. D. Collins, J. V. G. Altur, S. Bowker, L. Campbell and D. J. Procter, Org. Lett., 2010, 12, 5446–5449 CrossRef CAS; (i) H. Y. Harb and D. J. Procter, Synlett, 2012, 6–20 CAS; (j) K. Takema, A. Masaatsu and N. Toshio, Chem. Lett., 2012, 41, 287–289 CrossRef; (k) P.-A. Nocquet, D. Hazelard, G. Gruntz and P. Compain, J. Org. Chem., 2013, 78, 6751–6757 CrossRef CAS PubMed; (l) H.-Y. Chuang and M. Isobe, Org. Lett., 2014, 16, 4166–4169 CrossRef CAS PubMed; (m) J.-P. Chen, W. He, Z.-Y. Yang and Z.-J. Yao, Org. Lett., 2015, 17, 3379–3381 CrossRef CAS PubMed; (n) H.-Y. Chuang and M. Isobe, J. Org. Chem., 2017, 82, 2045–2058 CrossRef CAS PubMed; (o) H.-Y. Chuang and M. Isobe, Tetrahedron, 2017, 73, 2705–2714 CrossRef CAS.
  99. R. H. Crabtree, Acc. Chem. Res., 1979, 12, 331–337 CrossRef CAS.
  100. A. C. Huang, S. A. Kautsar, Y. J. Hong, M. H. Medema, A. D. Bond, D. J. Tantillo and A. Osbourn, Proc. Natl. Acad. Sci. U. S. A., 2017, 114, E6005–E6014 CrossRef CAS.
  101. (a) O. D. Hensens, D. Zink, J. M. Williamson, V. J. Lotti, R. S. L. Chang and M. A. Goetz, J. Org. Chem., 1991, 56, 3399–3403 CrossRef CAS; (b) K. Yoganathan, C. Rossant, R. P. Glover, S. Cao, J. J. Vittal, S. Ng, Y. Huang, A. D. Buss and M. S. Butler, J. Nat. Prod., 2004, 67, 1681–1684 CrossRef CAS; (c) H. Fujimoto, E. Nakamura, E. Okuyama and M. Ishibashi, Chem. Pharm. Bull., 2000, 48, 1436–1441 CrossRef CAS; (d) E. Piers and S. L. Boulet, Tetrahedron Lett., 1997, 38, 8815–8818 CrossRef CAS; (e) G. A. Molander, M. S. Quirmbach, L. F. Silva Jr, K. C. Spencer and J. Balsells, Org. Lett., 2001, 3, 2257–2260 CrossRef CAS; (f) M. R. Krout, C. E. Henry, T. Jensen, K.-L. Wu, S. C. Virgil and B. M. Stoltz, J. Org. Chem., 2018, 83, 6995–7009 CrossRef CAS PubMed.
  102. Z. Liu, Y. Chen, S. Chen, Y. Liu, Y. Lu, D. Chen, Y. Lin, X. Huang and Z. She, Org. Lett., 2016, 18, 1406–1409 CrossRef CAS PubMed.
  103. (a) T. Newhouse, P. S. Baran and R. W. Hoffmann, Chem. Soc. Rev., 2009, 38, 3010–3021 RSC; (b) N. Z. Burns, P. S. Baran and R. W. Hoffmann, Angew. Chem., Int. Ed., 2009, 48, 2854–2867 CrossRef CAS.
  104. B. M. Trost, Science, 1991, 254, 1471–1477 CrossRef CAS.
  105. (a) P. A. Wender, V. A. Verma, T. J. Paxton and T. H. Pillow, Acc. Chem. Res., 2008, 41, 40–49 CrossRef CAS PubMed; (b) P. A. Wender, Nat. Prod. Rep., 2014, 31, 433–440 RSC; (c) P. A. Wender, R. V. Quiroz and M. C. Stevens, Acc. Chem. Res., 2015, 48, 752–760 CrossRef CAS PubMed.
  106. (a) R. W. Hoffmann, Synthesis, 2006, 3531–3541 CrossRef CAS; (b) I. S. Young and P. S. Baran, Nat. Chem., 2009, 1, 193–205 CrossRef CAS; (c) R. N. Saicio, Tetrahedron, 2014, 70, 8183–8218 CrossRef.
  107. (a) S. Szymkuć, E. P. Gajewska, T. Klucznik, K. Molga, P. Dittwald, M. Startek, M. Bajczyk and B. A. Grzybowski, Angew. Chem., Int. Ed., 2016, 55, 5904–5937 CrossRef PubMed; (b) M. H. S. Segler, M. Preuss and M. P. Waller, Nature, 2018, 555, 604–610 CrossRef CAS PubMed; (c) T. Klucznik, B. Mikulak-Klucznik, M. P. McCormack, H. L. S. Szymkuć, M. Bhowmick, K. Molga, Y. Zhou, L. Rickershauser, E. P. Gajewska, A. Toutchkine, P. Dittwald, M. P. Startek, G. J. Kirkovits, R. Roszak, A. Adamski, B. Sieredzińska, M. Mrksich, S. L. J. Trice and B. A. Grzybowski, Chem, 2018, 4, 522–532 CrossRef CAS.
  108. T. Gaich and P. S. Baran, J. Org. Chem., 2010, 75, 4657–4673 CrossRef CAS.

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