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Asymmetric Total Synthesis of Cerorubenic Acid-III Xin Liu, Junyang Liu, Jianlei Wu, Guocheng Huang, rong liang, Lung Wa Chung, and Chuang-Chuang Li J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 05 Feb 2019 Downloaded from http://pubs.acs.org on February 5, 2019

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Journal of the American Chemical Society

Asymmetric Total Synthesis of Cerorubenic Acid-III Xin Liu,†,§,# Junyang Liu,†,‡,# Jianlei Wu,† Guocheng Huang,† Rong Liang,† Lung Wa Chung,† and ChuangChuang Li*,† † ‡

Shenzhen Grubbs Institute, Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China SUSTech Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518055, China

§

Institute of Chinese Medical Sciences, University of Macau, Macau, China

Supporting Information Placeholder

ABSTRACT: The first asymmetric total synthesis of the highly strained compound cerorubenic acid-III is reported. A type II intramolecular [5+2] cycloaddition allowed efficient and diastereoselective construction of the synthetically-challenging bicyclo[4.4.1] ring system with a strained bridgehead (antiBredt) double bond in the final product. A unique transannular cyclization installed the vinylcyclopropane moiety with retention of the desired stereochemistry. Sesterterpenoids continue to play a significant role in synthetic organic chemistry and drug discovery, owing to their intriguing and broad range of biological activities and complicated, diverse structures.1,2 Cerorubenic acid-III (1, Fig. 1), a sesterterpenoid with a novel tetracyclo[8.4.1.0.0]pentadecane skeleton, was first isolated by Naya and coworkers in 1983 from secretions of the scale insect Ceroplastes rubens Maskell.3 This compound plays an important role in insect communication,4 although the relative scarcity of 1 from natural sources has impeded a more systematic evaluation of its biological activity. Therefore, the development of an efficient synthesis of 1 and its analogs is highly desirable. Structurally, 1 comprises a sterically compact 6/3/7/6 tetracyclic skeleton, with a unique bridged bicyclo[4.4.1]undecene ring system5 (highlighted in red in 1) and a vinylcyclopropane fragment (highlighted in blue in 2). In particular, 1 possesses a strained bridgehead (anti-Bredt) double bond at C6–C7,6a,6b as is also found in the well-known natural drug Taxol.6c This double bond is unstable in air, as it oxidizes to give the corresponding epoxide.3 These unique structural features of 1 make it highly strained.7 Moreover, 1 has seven contiguous stereocenters, including an allcarbon quaternary stereocenter on the cyclopropane moiety. Therefore, 1 presents a formidable synthetic challenge. Despite this difficulty, the promising pharmacological properties and unusual structural motifs of 1 have resulted in interest from the synthetic community.8-10 In particular, a campaign that crossed more than 10 years in the Paquette group has led to several reported approaches to 1.8 In 1998, Paquette and coworkers developed an elegant synthetic approach for cerorubenic acid-III methyl ester (2), in which an anionic oxy-Cope rearrangement and a 6-exo radical cyclization are key steps. The asymmetric synthesis of unnatural 2 based on the optical resolution8b of its precursor requires 30 steps in 0.3% overall yield.10 However, synthesis of 1 from 2 was unknown. According to previous studies,8 hydrolysis of the ester group in 2 under basic or acidic conditions would be potentially problematic, due to the instability of the bridgehead vinylcyclopropane double bond. To date, a total synthesis of 1 has

not yet been reported, and the catalytic asymmetric synthesis of 1 has not been achieved. In our continuing efforts towards the synthesis of biologically active natural products,11 we herein describe the first asymmetric total synthesis of 1, based on a type II intramolecular [5+2] cycloaddition.

Figure 1. Naturally-occurring cerorubenic acid-III (1) and the synthetic unnatural methyl ester (2). Using a retrosynthetic approach (Scheme 1), we expected that 1 could be obtained from 3 via chemoselective cross-metathesis (CM) with methacrylic acid.12 The tetracyclo[8.4.1.0.0]pentadecane core of 3 would be produced from 4 through transannular cyclization to install the cyclopropane moiety,13 followed by a series of functional group interconversion (FGI). Compound 4 would be synthesized from 5 by selective reductive cleavage of the C–O bond14 and additional functional group modifications. In turn, the bicyclo[4.4.1] ring system with the bridgehead double bond in 5 would be synthesized from 6 using type II intramolecular [5+2] cycloaddition,15,16 while 6 would be prepared from 7 using an Achmatowicz reaction.17 It was envisaged that 7, which would contain almost all the carbons of 1, would be assembled via a onestep process based on a cascade 1,4-addition-aldol reaction,18 starting with the readily available compounds vinylstannane (8), furan-aldehyde (9) and enone (10). Finally, 10 would be synthesized from the commercially-available starting material (S)citronellal (11) by organocatalytic enantioselective Michael addition19 with methyl vinyl ketone (MVK), followed by aldol condensation and dehydration. Our synthesis began with the asymmetric preparation of 10 (Scheme 2a) using a previously reported procedure with modifications.19b The organocatalytic Michael addition of 11 to MVK was promoted by employing the proline-derived catalyst 12

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(5 mol%) together with ethyl 3,4-dihydroxybenzoate (13) as a cocatalyst (20 mol%). Subsequent intramolecular aldol condensation and dehydration (using LiOH and i-PrOH) gave 10 in 72% overall yield with 93% de (on a 20 g scale). The Cu(I)catalyzed 1,4-addition of an organolithium reagent (generated from 820 via Sn-Li exchange) to 10 and quenching with TMSCl, gave the silyl enol ether. The silyl enol ether reacted with BuLi, followed by trapping the resulting enolate with the aldehyde 920 in the presence of ZnBr2, furnished 7 (see the structure in Scheme 1). This product was too unstable to be isolated, and so the ketone group in 7 was reduced in situ using DIBAL-H to give the more stable diol 14 in an overall yield of 50% from 10 (10 g scale). Treatment of 14 with TsOH in acetone followed by addition of TBAF afforded 15 in 85% yield. The oxidative rearrangement of 15 using VO(acac)2 and TBHP in DCM, followed by one-pot Ac-protection of the anomeric hydroxyl group, produced the key precursor 6 in 71% yield.

Charge neutralization of the dipolar precursor intermediate and the formation of the two strong C-C bonds in the [5+2] cycloaddition should provide a strong thermodynamically driving force. Scheme 2. a. Catalytic asymmetric synthesis of 5; and b. the

computed free energy profile of the two possible [5+2] cycloaddition pathways by the M06-2X/6-31G* method.

Scheme 1. Retrosynthetic analysis of cerorubenic acid-III (1).

Having obtained 6, we explored the possibility of performing a type II intramolecular [5+2] cycloaddition to prepare 5. Based on our previous synthetic study,15 a type II [5+2] cycloaddition reaction was expected to give a bicyclo[4.4.1]undecene ring system with endo selectivity, with the stereochemistry at the allylic position of the dienophile alkene group being critical in terms of controlling the diastereoselectivity. However, it was difficult to predict the diastereoselective outcome of the reaction using the complex precursor 6. That is, it was uncertain whether the product 5 or the undesired product 5a would be obtained. Density function theory (DFT) calculations showed that the reaction of 6 via the 1,3dipole intermediate TS5 to give 5 is both kinetically (by ~4.9 kcal/mol) and thermodynamically more favorable than the reaction to form 5a (see Scheme 2b and SI for computational details).

Consistent with the DFT results (Scheme 2a), the type II [5+2] cycloaddition of 6 was realized using TMP as a base in a sealed tube with heating, giving 5 as a single diastereomer in 72% yield (1.5 g scale). The structure of 5 was confirmed by the X-ray crystallographic analysis of its derivative (17, Fig. 2), obtained


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Journal of the American Chemical Society from 5 by reduction to give 16 followed by subsequent esterification. This synthetic route represented a facile means of obtaining a suitable quantity (20 g) of 5, highlighting the robust nature of this synthetic approach. Notably, this type II [5+2] cycloaddition enabled the efficient and diastereoselective construction of the desired core in 5, supplying the syntheticallychallenging bicyclo[4.4.1] ring system and bridgehead double bond.

Scheme 3. Asymmetric total synthesis of cerorubenic acid-III.

Having synthesized 16, we proceeded to the next stage of our proposed synthesis of 1 (Scheme 3). The initial efforts involved the double reductive cleavages of the C4-O and C5-O bonds, even though it was challenging to control the chemoselectivity during this process due to the presence of the additional allylic C24-O bond. To the best of our knowledge, there have been very few instances of the efficient reductive cleavage of double C-O bonds in the ring system of 8-oxabicyclo[3.2.1]oct-2-ene (highlighted in red in 16).21 After several unproductive methods were evaluated (see SI for more details), the following solution was identified. The C5-hydroxyl group in 16 was converted to the corresponding bromide using a nucleophilic substitution strategy to give 18 in 67% yield (3.7 g scale). Compound 18 was treated with sodium naphthalenide21e in THF and H2O at 25 °C to give the diol 20 in 78% (2.7 g scale), likely proceeding via the intermediate 19, which could be isolated in anhydrous condition. Notably, Nanaphthalenide played various roles in this reaction, including (i) selectively reductive eliminating the C4–O bond in 18, (ii) removing the Bn group, and (iii) unusually reducing the less sterically hindered C4-C5 double bond of the diene in 19.

Figure 2. ORTEP diagram of 17 and 23a We subsequently examined transannular cyclization as a means of installing the vinylcyclopropane moiety in 4 (Scheme 3). This was challenging, as there have been few reports concerning the complete retention of stereochemistry (such as R configuration at C24) during such cyclizations.13,22 The formation of an all-carbon quaternary stereocenter at C3 on the strained cyclopropane ring is especially difficult. Initially, we attempted to synthesize the aldehyde 21 with an activated sulfonate at C24 for cyclization, by regioselective oxidation followed by tosylation, although this approach was unsuccessful. In subsequent work, temporary TBSprotection of the primary hydroxyl group in 20, followed by tosylation of the C24-OH group and removal of the TBS group in a one pot sequence and DMP oxidation, gave 21 in 55% overall yield. Extensive trials found that the desired transannular cyclization of 21 using t-BuOK22b in t-BuOH afforded cyclopropyl-aldehyde 4 diastereoselectively in 78% yield (2.1 g scale). The reaction presumably proceeded through a cationic pathway via intermediate 22, with the enolate attacking the C24 cation stabilized by the adjacent vinyl group. The structure of 4 was confirmed by X-ray crystallographic analysis of its derivative 23a (Fig. 2, see SI for more details). Huang’s modification of the Wolff–Kishner reduction23 was used to convert the formyl group of 4 to a methyl moiety, followed by in situ deprotection using AcOH to generate the diol 23 (1.2 g scale). Chemoselective acetylation of the less sterically hindered hydroxyl group in 23, followed by DMP oxidation using a one-pot process and



subsequent base-mediated elimination, gave the enone 24 in an 80% overall yield. The final stage of the synthesis was accomplished via crossmetathesis to obtain the sole oxygenated side chain. The 1,4reduction of 24 using NaBH4 and NiCl224 and the Wittig olefination of the carbonyl group provided the triene 3. While the reaction of 3 with methacrylic acid gave none of the expected 1 when using a Grubbs II catalyst, reaction with methacrylaldehyde using this same catalyst in DCM was possible.12b This was followed by in situ Ag2O oxidation to give 125 in 27% overall yield from 24, completing the asymmetric total synthesis (see SI for more details). Cerorubenic acid-III methyl ester (2) was synthesized from 1 with TMS-diazomethane in 95% yield In summary, this work demonstrated the first asymmetric total synthesis of the highly strained compound cerorubenic acid-III. Notably, a type II intramolecular [5+2] cycloaddition enabled efficient and diastereoselective construction of the syntheticallychallenging bicyclo[4.4.1] ring system having a strained bridgehead anti-Bredt double bond in 1. A unique cascade reduction of 8-oxabicyclo[3.2.1]octene in 18 was achieved chemoselectively using sodium naphthalenide, and an unusual transannular cyclization installed the vinylcyclopropane moiety with retention of the desired stereochemistry. This approach could be extended to the asymmetric synthesis of other cerorubenic acids and their analogs to allow further biological studies. Such work is ongoing and the results will be reported in due course.

ASSOCIATED CONTENT Supporting Information. Detailed experimental and computational procedure, 1H NMR and 13C NMR spectra, DFT results as well as X-ray data information are available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author [email protected] # These authors contributed equally to this work.

ORCID Chuang-Chuang Li: 0000-0003-4344-0498

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This paper is dedicated to Professor Leo Paquette on the occasion of his 84th birthday. This work was supported by the Natural Science Foundation of China (Grant nos. 21602100, 21522204 and 21472081) and the Shenzhen Science and Technology Innovation Committee (Grant nos. JCYJ20170817110130636). We would also like to thank Prof. N. Burns at Stanford and Prof. T. Maimone at Berkeley for helpful discussions.

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(17) Achmatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.; Zamojski, A. Synthesis of Methyl 2, 3-Dideoxy-DL-Alk-2Enopyranosides from Furan Compounds: A General Approach to the Total Synthesis of Monosaccharides. Tetrahedron 1971, 27, 1973-1996. (18) Yang, Y.; Haskins, C. W.; Zhang, W.; Low, P. L.; Dai, M. J. Divergent Total Syntheses of Lyconadins A and C. Angew. Chem. Int. Ed. 2014, 53, 3922-3925. (19) (a) Chi, Y.; Gellman, S. H. Diphenylprolinol Methyl Ether: A Highly Enantioselective Catalyst for Michael Addition of Aldehydes to Simple Enones. Org. Lett. 2005, 7, 4253-4256. (b) Nicolaou, K. C.; Sarlah, D.; Shaw, D. M. Total Synthesis and Revised Structure of Biyouyanagin A. Angew. Chem., Int. Ed. 2007, 46, 4708-4711. (20) For synthesis of 8 and 9, see the Supporting Information for details. (21) For related reviews on the cleavage of C-O bond of [2.2.1] oxabicycles, see: (a) Chiu, P.; Lautens, M. Using Ring-Opening Reactions of Oxabicyclic Compounds as a Strategy in Organic Synthesis. Top. Curr. Chem. 1997, 190, 1-85. (b) Lautens, M.; Fagnou, K.; Hiebert, S. Transition Metal-Catalyzed Enantioselective Ring-Opening Reactions of Oxabicyclic Alkenes. Acc. Chem. Res. 2003, 36, 48-58. For selected references on the cleavage of C-O bond of [3.2.1] oxabicycles, see: (c) Lautens, M.; Fillion, E.; Sampat, M. Base-Induced Ring Opening of Aza- and Thiaoxa[3.2.1] and -[3.3.1]bicycles as an Enantioselective Approach to Azepines, Thiepines, and Thiocines. J. Org. Chem. 1997, 62, 7080-7081. (d) Rodríguez, J. R.; Castedo, L.; Mascareñas, J. L. Tandem Organolithium Addition/OxaBridge Opening of 8-Oxa[3.2.1]bicyclic Pyrone-Alkene Adducts. Synthesis 2000, 980-984. (e) Kreiselmeier, G.; Fölisch, B. Total Synthesis of Racemic Lasidiol via Intramolecular [4+3] Cycloaddition. Tetrahedron Lett. 2000, 41, 1375-1379. (f) Lee, J. C.; Cha, J. K. Total Synthesis of Tropoloisoquinolines: Imerubrine, Isoimerubrine, and Grandirubrine. J. Am. Chem. Soc. 2001, 123, 3243-3246. (g) Lautens, M.; Hiebert, S.; Renaud, J.L. Mechanistic Studies of the Palladium-Catalyzed Ring Opening of Oxabicyclic Alkenes with Dialkylzinc. J. Am. Chem. Soc. 2001, 123, 68346839. (h) Hodgson, D.; Maxwell, C. R.; Miles, T. J.; Paruch, E.; Stent, M. A. H.; Matthews, I. R.; Wilson, F. X.; Witherington, J. Enantioselective Alkylative Double Ring Opening of Epoxides: Synthesis of Enantioenriched Unsaturated Diols and Amino Alcohols. Angew. Chem., Int. Ed. 2002, 41, 4313-4316. (i) Williams, Y. D.; Meck, C.; Mohd, N.; Murelli, R. P. Triflic Acid-Mediated Rearrangements of 3-Methoxy-8oxabicyclo[3.2.1]octa-3,6-dien-2-ones: Synthesis of Methoxytropolones and Furans. J. Org. Chem. 2013, 78, 11707-11713. (j) Oblak, E. Z.; VanHeyst, M. D.; Li, J.; Wiemer, A. J.; Wright, D. L. Cyclopropene Cycloadditions with Annulated Furans: Total Synthesis of (+)- and (-)Frondosin B and (+)-Frondosin A. J. Am. Chem. Soc. 2014, 136, 4309-4315. (22) For selective examples, see: (a) Taylor, R. E.; Engelhardt, F. C.; Schmitt, M. J.; Yuan, H. Synthetic Methodology for the Construction of Structurally Diverse Cyclopropanes. J. Am. Chem. Soc. 2001, 123, 29642969. (b) Taber, D. F.; He, Y.; Xu, M. Enantioselective Construction of Carbobicyclic Scaffolds. J. Am. Chem. Soc. 2004, 126, 13900-13901. (c) Melancon, B. J.; Perl, N. R.; Taylor, R. E. Competitive Cationic Pathways and the Asymmetric Synthesis of Aryl-Substituted Cyclopropanes. Org. Lett. 2007, 9, 1425-1428. (23) Huang, M. Simple Modification of the Wolff-Kishner Reduction. J. Am. Chem. Soc. 1946, 68, 2487-2488. (24) Dhawan, D.; Grover,S. K. Facile Reduction of Chalcones to Dihydrochalcones with NaBH4/Ni2+ System. Synth. Commun. 1992, 22, 2405-2409. (25) Compounds 1, 2, 3, 4 and 24 were unstable in CDCl3, due to the instability of the bridgehead vinylcyclopropane double bond.




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Asymmetric Total Synthesis of Cerorubenic Acid-III - Journal of the

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