Letter Cite This: Org. Lett. 2017, 19, 5713-5716
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Total Synthesis of Biselide E, a Marine Polyketide Ichiro Hayakawa,*,† Kazuaki Suzuki,‡ Masami Okamura,‡ Shota Funakubo,‡ Yuto Onozaki,‡ Dai Kawamura,‡ Takayuki Ohyoshi,‡ and Hideo Kigoshi*,‡ †
Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan ‡ Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan S Supporting Information *
ABSTRACT: The total synthesis of biselide E, a marine polyketide isolated from the Okinawan ascidian, has been accomplished. The highlight of this approach is the use of the β-elimination reaction of the chloroacetoxy group for the construction of an unstable six-membered α,β,γ,δ-unsaturated lactone portion at the late stage of the total synthesis. membered α,β,γ,δ-unsaturated lactone,1b and is unstable to decompose under concentrated conditions.3 Therefore, the biological activity of biselide E (1) has not been studied so far due to a lack of samples for biological evaluations. We have been interested in the unique biological activities of biselides and haterumalides and have studied the total synthesis and structure−activity relationships of these natural products.4 As part of our structure−activity relationship studies of these natural products, we planned the synthesis of biselide E (1), whose structure differs from those of the other biselides, based on our synthetic route for biselide A (2)4a and haterumalides NA (6) and B (8).4b,c In this paper, we describe the total synthesis of biselide E (1) by using the β-elimination reaction for the construction of a six-membered α,β,γ,δ-unsaturated lactone portion as a key step. The total synthesis of biselide E (1) has never been reported.5 Whereas the synthesis of the C1−C8 segment of biselide E was reported by Cossy’s group,6 we reported the construction of the C1−C15 segment of biselide E (10) (Scheme 1).7a We then prepared aldehyde 11 from segment 10 and attempted the Ni/Cr-mediated coupling (Nozaki− Hiyama−Takai−Kishi coupling)8 between aldehyde 11 and vinyl iodide 124 to afford coupling compound 13. However, this reaction gave the desired compound 13 unreproducibly (0−42%) along with decomposed compounds at C5. This result is similar to that of the decomposition of natural biselide E (1).3 Also, removal of the DMPM group at C13 in 13 did not afford the desired compound 14 under several reaction conditions, resulting in the decomposition of compound 13. Our investigations revealed that the DMPM group at C13 could not be removed at the late stage of synthesis. Therefore, biselide E (1) could not be synthesized by simple application of
B
iselides A−D (2−5),1 oxygenated analogues of haterumalides2 [except for biselide D (5)], are macrolides isolated from the Okinawan ascidian Didemnidae sp. by our group (Figure 1). Biselides A (2) and B (3) and haterumalide
Figure 1. Structures of biselides and haterumalides.
NA methyl ester (7) show stronger cytotoxicity than cisplatin, a commercially available anticancer drug, against various human cancer cells. In contrast, these natural products are not toxic to brine shrimp.1b These results suggested that biselides and haterumalides could become a scaffold for the lead compounds of novel-type anticancer drugs without severe side effects. Among biselides, biselide E (1) has a unique structure, a six© 2017 American Chemical Society
Received: September 26, 2017 Published: October 11, 2017 5713
DOI: 10.1021/acs.orglett.7b03009 Org. Lett. 2017, 19, 5713−5716
Letter
Organic Letters
aldehyde 16, where the protecting group at C13 was changed from a DMPM group to a TBS group. The β-hydroxy-δ-lactone portion of aldehyde 16 was prepared using lactonization of dihydroxycarboxylic acid 17. Dihydroxycarboxylic acid 17 can be synthesized from our synthetic intermediate for biselide A (18) through a regioselective enzymatic hydrolysis.4a Our synthesis of biselide E (1) started from the allylic alcohol 18, which was employed in our total synthesis of biselide A (2) (Scheme 3).4a Oxidation of allylic alcohol 18
Scheme 1. Our Previous Synthetic Study of Biselide E (1)
Scheme 3. Synthesis of Compound 22 with All of the Carbon Framework of Biselide E (1)
our previous synthetic strategy for macrolactone-type biselides and haterumalides. From the above-mentioned results, we planned an improved new synthetic route for biselide E (1). The new retrosynthetic pathway of biselide E (1) is shown in Scheme 2. The sixScheme 2. Retrosynthetic Pathway of Biselide E (1)
gave an aldehyde, the aldol reaction of which with isopropyl acetate afforded β-hydroxy ester 19.7 β-Hydroxy ester 19 was transformed into dihydroxycarboxylic acid 17 by the removal of the TBDPS group and hydrolysis of the isopropyl ester. Lactonization of dihydroxycarboxylic acid 17 with EDC and DMAP gave β-hydroxy-δ-lactone 20. For the smooth removal of the protecting group at C13 after the introduction of the side chain portion, the DMPM group at C13 in 20 was replaced by a TBS group to give di-TBS ether 21. Removal of the acetonide group in 219 and oxidative cleavage of the resultant diol group afforded aldehyde 16. Ni/Cr-mediated coupling between aldehyde 16 and vinyl iodide 12 and removal of the TBS groups gave triol 22 as a precursor of the β-elimination reaction.10 We next investigated the β-elimination reaction of βhydroxy-δ-lactone derivative 23 as a model compound (Scheme 4). Treatment of 23 with DBU did not give the desired sixmembered α,β,γ,δ-unsaturated lactone 24 but instead gave the
membered α,β,γ,δ-unsaturated lactone portion in biselide E (1), which was unstable, would be constructed by the β-elimination reaction of a C3 oxygen functional group in β-hydroxy-δlactone derivative 15 at the late stage of total synthesis. The side chain portion might be introduced by using the Ni/Crmediated coupling reaction between vinyl iodide 124 and 5714
DOI: 10.1021/acs.orglett.7b03009 Org. Lett. 2017, 19, 5713−5716
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Organic Letters Scheme 4. Model Study of β-Elimination for Preparation of the α,β,γ,δ-Unsaturated Lactone Part
preparative ODS-TLC (50% MeCN) to give biselide E (1) (quant in two steps).12 Thus, we achieved the total synthesis of biselide E (1). The spectral data (1H NMR and 13C NMR,13 HRMS, and CD spectra) of synthetic biselide E (1) were in full agreement with those of the natural product. Because of the low stability of the preparative HPLC conditions, the yield of biselide E (1) after HPLC purification was quite low.14 In conclusion, we have achieved the total synthesis of biselide E (1). The highlight of this approach is the use of the βelimination reaction of the chloroacetoxy group at C3 for the construction of an unstable six-membered α,β,γ,δ-unsaturated lactone portion at the late stage of total synthesis.
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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.7b03009. Full experimental details and spectral data (PDF)
undesired conjugated carboxylic acid 25. We can interpret the mechanism underlying the undesired reaction in the following way: (1) the β-elimination reaction of the acetoxy group at C3 in 23 proceeded to give the desired α,β,γ,δ-unsaturated lactone 24, and (2) deprotonation at C6 in 24 by DBU and subsequent electrocyclic reaction afforded conjugated carboxylic acid 25. Thus, we decided to use a chloroacetyl group instead of an acetyl group as the protecting group at the C3 hydroxy group. The chloroacetoxy group’s greater eliminating ability compared to the acetoxy group would make possible the β-elimination reaction at the C3 position under mild conditions without the deprotonation at C6. Introduction of the chloroacetyl groups at all hydroxy groups in triol 22 and removal of the 2,4-DMPM esters gave carboxylic acid 26 (Scheme 5). Treatment of
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Ichiro Hayakawa: 0000-0003-2749-9078 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas “Chemical Biology of Natural Products” (Grant No. JP23102014) and for Scientific Research (Grant Nos. JP26242073, JP23310148, and JP21510221) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS). I.H. thanks The Society of Synthetic Organic Chemistry, Japan (Meiji Seika Award in Synthetic Organic Chemistry, Japan), and the Okayama Foundation for Science and Technology for their financial support.
Scheme 5. Total Synthesis of Biselide E (1)
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REFERENCES
(1) (a) Teruya, T.; Shimogawa, H.; Suenaga, K.; Kigoshi, H. Chem. Lett. 2004, 33, 1184. (b) Teruya, T.; Suenaga, K.; Maruyama, S.; Kurotaki, M.; Kigoshi, H. Tetrahedron 2005, 61, 6561. (2) (a) Ueda, K.; Hu, Y. Tetrahedron Lett. 1999, 40, 6305. (b) Takada, N.; Sato, H.; Suenaga, K.; Arimoto, H.; Yamada, K.; Ueda, K.; Uemura, D. Tetrahedron Lett. 1999, 40, 6309. (3) 1H NMR spectra of decomposed compounds of biselide E (1) revealed that the six-membered α,β,γ,δ-unsaturated lactone portion in 1 was decomposed. (4) (a) Hayakawa, I.; Okamura, M.; Suzuki, K.; Shimanuki, M.; Kimura, K.; Yamada, T.; Ohyoshi, T.; Kigoshi, H. Synthesis 2017, 49, 2958. (b) Ueda, M.; Yamaura, M.; Ikeda, Y.; Suzuki, Y.; Yoshizato, K.; Hayakawa, I.; Kigoshi, H. J. Org. Chem. 2009, 74, 3370. (c) Hayakawa, I.; Ueda, M.; Yamaura, M.; Ikeda, Y.; Suzuki, Y.; Yoshizato, K.; Kigoshi, H. Org. Lett. 2008, 10, 1859. (d) Kigoshi, H.; Kita, M.; Ogawa, S.; Itoh, M.; Uemura, D. Org. Lett. 2003, 5, 957. (e) Hayakawa, I.; Kigoshi, H. Yuki Gosei Kagaku Kyokaishi 2010, 68, 814. (5) Total synthesis of haterumalide by other groups: (a) Kigoshi, H.; Hayakawa, I. Chem. Rec. 2007, 7, 254. (b) Hoye, T. R.; Wang, J. J. Am. Chem. Soc. 2005, 127, 6950. (c) Roulland, E. Angew. Chem., Int. Ed.
carboxylic acid 26 with iPr2NEt caused the β-elimination of the chloroacetoxy group at C3 to afford the desired six-membered α,β,γ,δ-unsaturated lactone 27. In this case, undesired deprotonation at C6 did not occur under these conditions. Because the six-membered α,β,γ,δ-unsaturated lactone 27 was unstable, the chloroacetyl groups in 27 were removed without purification. To avoid deprotonation at C6 in 27, we attempted to remove the two chloroacetyl groups by using Zn(OAc)2 in MeOH.11 The resultant reaction mixture was purified by 5715
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Organic Letters 2008, 47, 3762. (d) Schomaker, J. M.; Borhan, B. J. Am. Chem. Soc. 2008, 130, 12228. (e) Synthesis of ent-haterumaralide NA methyl ester (6): Gu, Y.; Snider, B. B. Org. Lett. 2003, 5, 4385. (f) Synthetic study of haterumalides and biselides: Halperin, S. D.; Kang, B.; Britton, R. Synthesis 2011, 2011, 1946. (6) Salit, A.-F.; Barbazanges, M.; Miege, F.; Larraufie, M.-H.; Meyer, C.; Cossy, J. Synlett 2008, 2008, 2583. (7) (a) Satoh, Y.; Kawamura, D.; Yamaura, M.; Ikeda, Y.; Ochiai, Y.; Hayakawa, I.; Kigoshi, H. Tetrahedron Lett. 2012, 53, 1390. (b) Satoh, Y.; Yamada, T.; Onozaki, Y.; Kawamura, D.; Hayakawa, I.; Kigoshi, H. Tetrahedron Lett. 2012, 53, 1393. (8) (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. (9) Yuan, C.; Du, B.; Yang, L.; Liu, B. J. Am. Chem. Soc. 2013, 135, 9291. (10) (a) The newly generated stereochemistry of the secondary hydroxy group at C15 has been determined by a modified Mosher’s method. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092. (11) Lan, P.; White, L. E.; Taher, E. S.; Guest, P. E.; Banwell, M. G.; Willis, A. C. J. Nat. Prod. 2015, 78, 1963. (12) Synthetic biselide E (1) was mostly decomposed by preparative HPLC under the purification conditions of natural biselide E (1) (column: Develosil ODS-HG-5 (ϕ250 × 20 mm); flow rate = 5 mL/ min; detection = UV 215 and 254 nm; solvent 40 or 50% MeCN/0.1% TFA).1b Thus, we purified synthetic biselide E (1) by preparative ODS-TLC (50% MeCN) without TFA. (13) See the Supporting Information. (14) Because the synthetic biselide E (1) was almost decomposed under HPLC purification conditions, we could not evaluate the cytotoxicity against HeLa S3 cells.
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DOI: 10.1021/acs.orglett.7b03009 Org. Lett. 2017, 19, 5713−5716
