Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Studies toward the Synthesis of Iriomoteolide-2a: Construction of the C(6)−C(28) Fragment Lushun Wang, Fusong Wu, Xuelei Jia, Zhengshuang Xu, Yian Guo,* and Tao Ye* State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Xili, Nanshan District, Shenzhen 518055, China S Supporting Information *
ABSTRACT: The synthesis of an appropriately functionalized advanced C(6−28) fragment (3) of the marine macrolide iriomoteolide-2a (1) has been achieved in a highly efficient manner. The C(6)−C(18) fragment of 1 is prepared via a radical cyclization of a vinyl ether intermediate and palladium-promoted hydrostannylation/ iodination. Paterson aldol reaction and Peterson olefination are used to construct the C(19)−C(28) fragment. The union of the C(6)−C(18) and C(19)−C(28) fragments is accomplished via a Suzuki−Miyaura coupling reaction.
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stereochemistry assignments were based on extensive NMR studies, including modified Mosher ester7 and J-based configuration analysis.8 The unique biological profile and structural complexity of iriomoteolide-2a (1) render it an attractive target for synthesis and subsequent drug development research. As outlined in our retrosynthetic analysis, iriomoteolide-2a (1) should be readily available from the advanced precursor (2) by ruthenium-catalyzed ring-closing metathesis (RCM) and subsequent global deprotection. It was envisaged that precursor (2) would arise from the key intermediate 3 via a Yamaguchi esterification. In turn, 3 was planned to be synthesized by Suzuki−Miyaura coupling of vinyl iodide 4 with an alkyl boronate derived from alkene 5 (Scheme 1).
any of the natural products derived from marine dinoflagellates are challenging synthetic targets and could serve as lead compounds in drug development.1 A large number of macrolides with ring sizes from 12 to 29, as well as members of linear polyketides that possess unique molecular structures and impressive biological activities, were isolated from the dinoflagellate Amphidinium species.2 We have been engaged in a program devoted to the total synthesis of bioactive marine natural products and their synthetic derivatives/ analogues.3 In 2010, we disclosed our original approach that resulted in completion of the synthesis of the fully functionalized macrocyclic core of iriomoteolide-1a.4 We recently also achieved the convergent total synthesis of amphidinins E and F and epi-amphidinin F.5 Herein, we describe a concise and efficient route for the stereocontrolled synthesis of the fully elaborated C(6−28) fragment of iriomoteolide-2a (1) (Figure 1) as a prelude to ring-closure studies.
Scheme 1. Retrosynthetic Analysis
Figure 1. Structure of iriomoteolide-2a.
Iriomoteolide-2a (1), isolated from the cultured broth of the benthic dinoflagellate Amphidinium sp. (HYA024 strain) collected off the Iriomote Island, Okinawa, by the Tsuda group, is a new anticancer macrolide.6 It possesses potent cytotoxic activities against human B lymphoma DG75 cells and human cervix adenocarcinoma HeLa cells with IC50 values of 6 and 30 ng/mL, respectively.6 The structure, comprising an olefin-bearing three-stereogenic-center side chain, appended to the 23-membered macrocyclic lactone ring, was elucidated via a combination of NMR experiments. Relative and absolute © XXXX American Chemical Society
The synthesis of the key fragment 4 started from a displacement of the readily available iodide 69 with cesium trifluoroacetate, followed by cleavage of the trifluoroacetate ester with diethylamine to give rise to the corresponding alcohol 7 in 70% yield as a single diastereomer after flash chromatography (Scheme 2).10 Treatment of alcohol 7 with the Received: February 13, 2018
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DOI: 10.1021/acs.orglett.8b00542 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
18 was obtained in 60% yield. Vinyl iodide 18 was then transformed into the key intermediate 4 in a three-step sequence involving (1) oxidation of the primary alcohol with the Dess−Martin periodinane; (2) one-carbon homologation of the resulting aldehyde with (methoxymethyl)triphenylphosphonium ylide, followed by an acidic hydrolysis of the enol ether intermediately formed; and (3) Wittig olefination of the homologated aldehyde with triphenylphosphonium methylide. The synthesis of alkene 5 commenced with diazotization of (R)-2-aminobutyric acid to afford 19 in 60% yield (Scheme 3).
Scheme 2. Synthesis of Intermediate 4
Scheme 3. Synthesis of Intermediate 5
This acid was first converted into the corresponding methyl ester and then reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of i-PrMgBr to give the Weinreb amide 20 in 70% yield.18 Reaction of the Weinreb amide 20 with ethylmagnesium bromide cleanly provided the corresponding ethyl ketone, which underwent subsequent Obenzoylation to give rise to ketone 21 in 60% yield over two steps. A boron-mediated Paterson aldol reaction19 of ethyl ketone 21 with readily available aldehyde 2220 furnished antialdol product 23 as the sole detectable diastereomer, which was immediately protected as its TBS ether 24 in 81% yield over two steps. Mosher ester analysis7 confirmed that we had correctly assigned the stereochemistry at the newly formed hydroxyl position. Transesterification of the benzoate with potassium carbonate in methanol, followed by protection of the resulting alcohol, as its TBS ether 25 to set the stage for the upcoming olefination step. Attempted conversion of ketone 25 into its corresponding alkene 5 with various reagents/ conditions, including those developed by Wittig,21 Nysted,22 and Petasis23 afforded either very poor yield or none of the desired product. Eventually, we found that Peterson olefination protocol24 was effective in this capacity, and the desired product 5 was obtained in 60% yield. With both key intermediates 4 and 5 in hand, the stage was set for the crucial coupling reaction (see Scheme 4). Thus, hydroboration of olefin 5 with 9-borabicyclo[3.3.1] nonane (9BBN), followed by in situ β-alkyl Suzuki coupling25 with vinyl iodide 4 furnished fragment 3 in 90% yield. This key fragment
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Dess−Martin reagent provided aldehyde 8, which was subjected to an auxiliary-controlled Evans aldol reaction12 using the standard boron enolate to provide the desired synaldol adduct 10 in 60% yield. Reductive cleavage of the oxazolidinone moiety from 10 with lithium borohydride and subsequent selective tosylation of the primary alcohol, followed by treatment with ethyl propiolate in the presence of Nmethylmorpholine,13a afforded vinyl ether 11 in 85% yield over three steps. Displacement of the tosylate group of 11 with sodium iodide in tetrahydrofuran furnished iodide 12 in 96% yield. To our delight, treatment of 12 with tris(trimethylsilyl)silane in the presence of triethylborane gave rise to the cyclized product 13 in 99% yield as the sole diastereomer.13 To continue, 13 was converted into alcohol 14 in 89% yield by a four-step sequence that included reduction of the ethyl ester with DIBAL-H, cleavage of the PMB ether with DDQ, protection of the resulting diol as the corresponding bis-TBS ether, and reductive removal of the 2,5-dichlorobenzyl group by hydrogenolysis. Oxidation of the primary alcohol of 14 with Dess−Martin periodinane, followed by exposure of the resulting aldehyde to the Ohira−Bestmann14 modification of the Seyferth−Gilbert reagent,15 provided alkyne 16 in 72% yield. Alkylation with methyl iodide, followed by acid-catalyzed selective desilylation provided primary alcohol 17 in 78% yield. To directly access vinyl iodide 18 from alkyne 17, we explored Schwartz hydrozirconation/iodination.16 Unfortunately, under various conditions, the reaction resulted in either recovery of starting material or compound destruction. Fortunately, a twostep palladium-promoted hydrostannylation/iodination17 protocol completed construction of the desired vinyl iodide 18. Thus, slow addition of excess n-Bu3SnH to 17 in the presence of catalytic PdCl2(PPh3)2 afforded vinyl stannane as a mixture of geometrical isomers (E/Z = 4:1) which were readily separated. Upon treatment with iodine, the desired vinyl iodide
Scheme 4. Synthesis of Fragment 3
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DOI: 10.1021/acs.orglett.8b00542 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
(10) White, J. D.; Quaranta, L.; Wang, G. Q. Org. Lett. 2003, 5, 4109. (11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (12) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127. (b) Zhang, W.; Carter, R. G. Org. Lett. 2005, 7, 4209. (c) Fürstner, A.; Bouchez, L. C.; Funel, J. − A.; Liepins, V.; Porée, F. H.; Gilmour, R.; Beaufils, F.; Laurich, D.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46, 9265. (d) Sohn, T.; Kim, M. J.; Kim, D. J. Am. Chem. Soc. 2010, 132, 12226. (e) Sokolsky, A.; Cattoen, M.; Smith, A. B., III Org. Lett. 2015, 17, 1898. (13) (a) Lee, E.; Jin, S. T.; Lee, C.; Park, C. M. Tetrahedron Lett. 1993, 34, 4831. (b) Kwon, H. K.; Lee, Y. E.; Lee, E. Org. Lett. 2008, 10, 2995. (14) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Mueller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 1996, 521. (15) (a) Seyferth, D.; Hilbert, P.; Marmor, R. S. J. Am. Chem. Soc. 1967, 89, 4811. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997. (16) (a) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 679. (b) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912. (c) Huang, Z.; Negishi, E. Org. Lett. 2006, 8, 3675. (d) An, C.; Jurica, J. A.; Walsh, S. P.; Hoye, A. T.; Smith, A. B. J. Org. Chem. 2013, 78, 4278. (17) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857. (18) Williams, M. J.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461. (19) (a) Paterson, I.; Wallace, D. J.; Velázquez, S. M. Tetrahedron Lett. 1994, 35, 9083. (b) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 1998, 639. (c) Paterson, I.; Mackay, A. C. Tetrahedron Lett. 2001, 42, 9269. (d) Paterson, I.; Doughty, V. A. S.; McLeod, M. D.; Trieselmann, T. Tetrahedron 2011, 67, 10119. (e) Paterson, I.; Ng, K. K. H.; Williams, S.; Millican, D. C.; Dalby, S. M. Angew. Chem., Int. Ed. 2014, 53, 2692. (20) Chiral aldehyde 22 was prepared from PMB glycolate as reported by Crimmins. For detailed procedures, see the Supporting Information of: Crimmins, M. T.; McDougall, P. J.; Ellis, J. M. Org. Lett. 2006, 8, 4079. (21) (a) Wittig, G.; Schöllkopf, U. Chem. Ber. 1954, 87, 1318. (b) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654. (22) (a) Nysted, L. N. U.S. Patent 3,865,848, 1975; Chem. Abstr. 1975, 83, 10406q. (b) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 1998, 313. (c) Pasetto, P.; Franck, R. W. J. Org. Chem. 2003, 68, 8042. (23) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445. (c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798. (24) Peterson, D. J. J. Org. Chem. 1968, 33, 780. (25) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437. (b) Miyaura, N.; Suzuki. J. Chem. Soc., Chem. Commun. 1979, 866.
possesses 10 stereogenic centers of iriomoteolide-2a and was assembled using a highly effective synthetic strategy. In summary, we have developed a novel stereoselective approach to the key fragment of the marine macrolide iriomoteolide-2a (1). Key features of the synthesis of the building blocks include a radical cyclization of a vinylic ether intermediate, palladium-promoted hydrostannylation/iodination, Paterson aldol reaction, Peterson olefination, and Suzuki−Miyaura coupling reaction. Further work is currently underway to achieve the total synthesis of iriomoteolide-2a.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00542. Experimental details and data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Yian Guo: 0000-0002-0341-6816 Tao Ye: 0000-0002-2780-9761 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge financial support from Shenzhen Peacock Plan (KQTD2015071714043444), NSFC (21772009), SZSTIC (JCYJ20160527100424909, JCYJ20170818090017617, JCYJ20170818090238288), and GDNSF (2014B030301003).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00542 Org. Lett. XXXX, XXX, XXX−XXX
