Asymmetric Total Syntheses of Insulicolide A, 14-O-Acetylinsulicolide

Jul 2, 2018 - State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, ...
0 downloads 0 Views 1MB Size
Download PDF
Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Asymmetric Total Syntheses of Insulicolide A, 14‑O‑Acetylinsulicolide A, 6β,9α-Dihydroxy14‑p‑nitrobenzoylcinnamolide, and 7α,14-Dihydroxy6β‑p‑nitrobenzoylconfertifolin Yang Lai,† Nan Zhang,† Yi Zhang,† Jia-Hua Chen,*,† and Zhen Yang*,†,‡,§

Downloaded via UNIV OF TOLEDO on June 29, 2018 at 22:03:52 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China ‡ State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China § Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China S Supporting Information *

ABSTRACT: Asymmetric total syntheses of insulicolide A, 14-O-acetylinsulicolide A, 6β,9α-dihydroxy-14-p-nitrobenzoyl cinnamolide, and 7α,14-dihydroxy-6β-p-nitrobenzoylconfertifolin have been achieved for the first time. The key steps in the synthesis include: (1) an iridium-catalyzed enantioselective polyene cyclization to construct the drimane core bearing two allcarbon quaternary chiral centers at C4 and C10 and (2) a cascade ozonolysis of the phenol ring to form the lactone fragment of the target molecules. nsulicolide A1 (1), an important family member of rare naturally occurring nitrobenzoyloxy-substituted sesquiterpenoids2 (2−6, Figure 1), was isolated from the marine Fungus Aspergillus insulicola in 1997.1

I

It has a unique drimane-type skeleton, which bears five contiguous stereogenic centers, two of which are all-carbon quaternary carbons (C-4 and C-10). The structure of insulicolide A (1) was confirmed by X-ray crystallographic analysis.1 Biologically, insulicolide A (1) shows significant cytotoxicity against 10 human cancer cell lines (H1975, U937, K562, BGC823, Molt-4, MCF-7, A549, Hela, HL60, and Huh-7), with IC50 values that range from 2.11 to 6.35 μM.2b Under mildly basic conditions, 1 was converted to lactone 7 in 65% yield2a by treatment with K2CO3 in MeOH. This result indicates that 1 is susceptible to nucleophilic addition at C-7, which leads to elimination of the hydroxyl at C-9 to afford methyl ether 7, presumably through a sequential Michael reaction and enolatedriven dehydration (see b in Scheme 1). The proposed C-9 tertiary hydroxyl group dependent fragmentation in 1 could help to clarify whether compounds 4−6 lack cytotoxicity because of the absence of the C-9 hydroxyl group. The unique mode of action shown by 1 makes it an attractive irreversible probe3 in the fields of drug discovery and chemical biology.

Figure 1. Naturally occurring drimane-type sesquiterpenoids.

Received: June 4, 2018

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b01733 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Scheme 4 shows our retrosynthetic analysis. We reasoned that insulicolide A (1) could be synthesized by sequential

Scheme 1. Scaffold Fragmentation of Insulicolide A (1)

Scheme 4. Retrosynthetic Analysis

Drimane-type sesquiterpenoids are a large group of natural products that have a variety of biological activities.4 The conventional method for their synthesis focuses on use of a cascade polyene cyclization reaction5 and an intramolecular Diels−Alder reaction6 to construct the tricyclic core structure. However, despite its unique mode of action as a potent cytotoxic agent, the total synthesis of insulicolide A (1) has not been reported. Herein, we present the asymmetric total syntheses of 1 and three other family members 2, 3, and 4 (Figure 1). Biosynthetically, the drimane scaffold can be constructed from farnesyl pyrophosphate (FPP, 8) via a cation-initiated cascade polyene cyclization7 through intermediate IV (Scheme 2).

benzoylation of the C-6 hydroxyl group and desilylation of diol 12 which, in turn, could be derived from lactone 13 via either epoxidation of its unsaturated double bond with H2O2/NaOH, followed by base-mediated epoxide opening,12 or dihydroxylation13 of its double bond, followed by dehydration of the newly generated C-8 hydroxyl group. Oishi14 reported that lactone 13 could be generated from phenol 14 via regioselective oxidative cleavage of its C−C bonds at C-11/ C-11′ and C-12/C-12′. We expected that phenol 14 could be synthesized from the branched racemic allylic alcohol 15 via an iridium-catalyzed enantioselective polyene cyclization cascade as first developed by Carreira and co-workers.15 Our retrosynthetic analysis therefore was traced back to the formation of diene 15, which can be obtained by Suzuki coupling16 of vinyl iodide 17 and substituted styrene 16. Scheme 5 shows the preparation of polyene 15 for the proposed asymmetric synthesis of the drimane core 19 via an

Scheme 2. Cation-Initiated Cascade Polyene Cyclization of FPP

Scheme 5. Iridium-Catalyzed Enantioselective Polyene Cyclization In 2015,8 we developed a concise and scalable approach to the asymmetric synthesis of the anticancer agent (−)-antrocin9 (11) via ozonolysis of the electron-rich phenol10 in the abietane (+)-carnosic acid (9) through intermediate 10 (Scheme 3). We have synthesized 20 g of antrocin (11) to enable investigation of its biological activities.11 Scheme 3. Ozonolysis of Aromatic Abietane (+)-Carnosic Acid As a Key Step for Asymmetric Synthesis of Antrocin (11)

iridium-catalyzed enantioselective polyene cyclization. Styrene 16 was first reacted with 9-BBN, and the resultant derivative then underwent Pd-catalyzed Suzuki coupling with vinyl iodide 17 in the presence of Pd(dppf)Cl2·CH2Cl2 under basic conditions.15 Further treatment of the resultant silyl ether 18 with TBAF afforded polyene 15 in 74% yield in two steps. With 15 in hand, we next explored its enantioselective Lewis acid promoted polycyclization17 under the reaction conditions reported by Carreira and co-workers15a and found that in the presence of 20 mol % of Zn(OTf)2 the desired product 19 could be generated in 73% yield with 99.6% ee.

On the basis of this chemistry, we explored an asymmetric approach to the total synthesis of insulicolide A (1) with a cascade polyene cyclization and phenol ozonolysis as the key steps, and we hoped that our developed method could be applied to the total syntheses of other family members. B

DOI: 10.1021/acs.orglett.8b01733 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters We next turned our attention to the synthesis of phenol 14 from 19. The initial step was installation of the C-4 quaternary carbon center in acetate 21. The terminal olefin can undergo selectively ozonolysis in the presence of an anisole scaffold;18 therefore, we conducted chemoselective ozonolysis of 19 under the typical conditions. The resulting ozonide was reduced with Ph3P to afford aldehyde 20 in 91% yield. The C-4 quaternary chiral center was installed by treating aldehyde 20 with tBuOK in tBuOH, and the resultant enolate was reacted with MeI followed by reduction with LiAlH4 and acetylation with Ac2O in the presence of Et3N and DMAP to give acetate 21 in 81% yield in three steps. The diastereoselective formation of the C-4 quaternary chiral center was achieved presumably because the enolate derived from aldehyde 20 adopts a conformation that favors approach of the MeI to the enolate from its less-hindered bottom face (see the three-dimensional structure of enolate 20 in Scheme 6).

Scheme 7. Sequential Ozonolysis and Reduction of Phenol 14

Scheme 8. Synthesis of Natural Products

Scheme 6. Synthesis of Phenol 14

For the preparation of olefin 23, 21 was first subjected to an oxidation with CrO3,19 followed by demethylation by treatment with BBr3 to afford ketone 22. Further treatment of the keto group in 22 with LiAlH4 in THF at reflux19 initiated a cascade reduction20 (see SI for details). The C-6 hydroxyl group in phenol 14 was installed by treatment of 23 with BH3· SMe2 and oxidation of the resultant alkyl borane with H2O2 to generate phenol 14 regio- and diastereoselectively in 78% yield (Scheme 6). We then began to evaluate the proposed phenolic ozonolysis fragmentation for the formation of lactone 24 from phenol 14, and the details are listed in Table 2 in the SI. When phenol 14 was subjected to ozonolysis at −78 °C in a mixed solvent consisting of CH2Cl2/MeOH (2:1), it underwent double ozonolysis through two ozonides (see SI for details) to generate the oxocarbenium ion 14′, which was then subjected to NaBH4 reduction (Scheme 7) to give product 24 in 73% yield in a one-pot operation. With lactone 24 in hand, we began to complete the total synthesis. To achieve this, we had to stereoselectively install the two hydroxyl groups at C-6 and C-9, respectively (Scheme 8). The primary alcohol in 24 was selectively protected as its silyl ether, and its secondary alcohol was converted to the corresponding ketone 13 by DMP oxidation in 85% yield in

two steps. Initially, we attempted to install the C-9 hydroxyl group in 25 via a sequential dihydroxylation (OsO4 in pyridine or RuCl3/NaIO4) and dehydration. However, unlike the results in our model studies (see the SI for details), the dihydroxylation of 13 did not proceed. We then explored a selenium-oxide-based [2,3]-sigmatropic rearrangement21 for the formation of 25. In the event, ketone 13 was treated with KHMDS in THF followed by reaction with PhSeBr, and the resultant selenenyl ketone was then reacted with H2O2 to generate a selenoxide, which then underwent a [2,3]sigmatropic rearrangement to afford 25 in 80% yield. Further treatment of 25 with DIBAL-H reduced the ketone and lactone moieties to the corresponding alcohol and hemiacetal, which were then subjected to Fétizon oxidation22 to afford a mixture of 12 (major isomer) and its diastereisomer which, without separation, underwent benzoylation with 4NO2−PhCOCl in the presence of Et3N and DMAP to afford 26 in 53% yield, together with its diastereoisomer in 13% yield. To complete the total synthesis of insulicolide A (1), 26 was treated with HF·py, to give 1 in 92% yield. Further treatment of 1 with the acetylation agent Ac2O/Et3N/DMAP gave 14-Oacetylinsulicolide A (2). When substrate 12 (as a pair of C-6 diastereoisomers) was subjected to desilylation with HF·py, C

DOI: 10.1021/acs.orglett.8b01733 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters the resultant triols were reacted with 4-NO2−PhCOCl in the presence of Et3N and DMAP; as a result, 6β,9α-dihydroxy-14p-nitrobenzoyl-cinnamolide (3) was obtained in 25% yield. In the presence of PDC,23 substrate 26 underwent a 1,3-hydroxyl group shift, and the resultant product was desilylated to give 7α,14-dihydroxy-6β-p-nitrobenzoylconfertifolin (4) in 89% yield. In conclusion, asymmetric and divergent syntheses24 of insulicolide A (1), 14-O-acetylinsulicolide A (2), 6β,9αdihydroxy-14-p-nitrobenzoyl-cinnamolide (3), and 7a,14-dihydroxy-6β-p-nitrobenzoylconfertifolin (4) have been achieved for the first time. The key elements in our synthesis are (1) an iridium-catalyzed enantioselective polyene cyclization to construct the drimane core bearing two all-carbon quaternary chiral centers at C-4 and C-10 and (2) a cascade ozonolysis of the phenol ring to form the lactone fragment of the target molecules.

■

Takao, K.-i.; Tadano, K.-i. Tetrahedron 2001, 57, 7291. (d) Jauch, J. Eur. J. Org. Chem. 2001, 2001, 473. (e) Jauch, J. Synlett 2001, 2001, 87. (f) Jauch, J.; Wallner, C.; Herdtweck, E. Eur. J. Org. Chem. 2003, 2003, 3060. (g) Ishihara, J.; Yamamoto, Y.; Kanoh, N.; Murai, A. Tetrahedron Lett. 1999, 40, 4387. (7) Jansen, B. J. M.; de Groot, A. Nat. Prod. Rep. 2004, 21, 449. (8) Li, F.-Z.; Li, S.; Zhang, P.-P.; Huang, Z.-H.; Zhang, W.-B.; Gong, J.-X.; Yang, Z. Chem. Commun. 2016, 52, 12426. (9) (a) Chiang, H.-C.; Wu, D.-P.; Cherng, I.-W.; Ueng, C.-H. Phytochemistry 1995, 39, 613. (b) Geethangili, M.; Tzeng, Y.-M. J. Evidence-Based Complementary Altern. Med. 2011, 2011, 212641. (10) (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749. (b) Bell, R. A.; Gravestock, M. B. Can. J. Chem. 1970, 48, 1105. (11) (a) Chiu, K.-Y.; Wu, C.-C.; Chia, C.-H.; Hsu, S.-L.; Tzeng, Y.M. Cancer Lett. 2016, 373, 174. (b) Yeh, C.-T.; Huang, W.-C.; Rao, Y. K.; Ye, M.; Lee, W.-H.; Wang, L.-S.; Tzeng, D. T. W.; Wu, C.-H.; Shieh, Y.-S.; Huang, C.-Y. F.; Chen, Y.-J.; Hsiao, M.; Wu, A. T. H.; Yang, Z.; Tzeng, Y.-M. Carcinogenesis 2013, 34, 2918. (12) (a) Collado, I. G.; Madero, J. G.; Massanet, G. M.; Luis, F. R.; Fronczek, F. R. Tetrahedron Lett. 1990, 31, 5795. (b) Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1992, 114, 8333. (13) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973. (b) Schroeder, M. Chem. Rev. 1980, 80, 187. (c) Shing, T. K. M.; Tai, V. W.-F.; Tam, E. K. W. Angew. Chem., Int. Ed. Engl. 1994, 33, 2312. (14) (a) Akita, H.; Oishi, T. Chem. Pharm. Bull. 1981, 29, 1580. For other early work associated with ozonolysis of phenols, see: (b) Bell, R. A.; Gravestock, M. B. Can. J. Chem. 1970, 48, 1105. (c) Akita, H.; Oishi, T. Tetrahedron Lett. 1978, 19, 3733. (15) (a) Schafroth, M. A.; Sarlah, D.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2012, 134, 20276. (b) Jeker, O. F.; Kravina, A. G.; Carreira, E. M. Angew. Chem., Int. Ed. 2013, 52, 12166. (c) Deng, J.; Zhou, S.; Zhang, W.; Li, J.; Li, R.; Li, A. J. Am. Chem. Soc. 2014, 136, 8185. (d) Ungarean, C. N.; Southgate, E. H.; Sarlah, D. Org. Biomol. Chem. 2016, 14, 5454. (16) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Sato, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314. (17) (a) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2007, 46, 409. (b) Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7508. (c) Ishihara, Y.; Baran, P. S. Synlett 2010, 2010, 1733. (d) Tao, Z.; Robb, K. A.; Zhao, K.; Denmark, S. E. J. Am. Chem. Soc. 2018, 140, 3569. (18) (a) Jones, S. B.; He, L.; Castle, S. L. Org. Lett. 2006, 8, 3757. (b) Martinez-Solorio, D.; Jennings, M. P. Org. Lett. 2009, 11, 189. (c) Fujii, H.; Imaide, S.; Watanabe, A.; Yoza, K.; Nakajima, M.; Nakao, K.; Mochizuki, H.; Sato, N.; Nemoto, T.; Nagase, H. J. Org. Chem. 2010, 75, 995. (19) Alvarez-Manzaneda, E.; Chahboun, R.; Alvarez, E.; Ramos, J. M.; Guardia, J. J.; Messouri, I.; Chayboun, I.; Mansour, A. I.; Dahdouh, A. Synthesis 2010, 2010, 3493. (20) Hoarau, C.; Pettus, T. R. R. Org. Lett. 2006, 8, 2843. (21) Enomoto, M.; Morita, A.; Kuwahara, S. Angew. Chem., Int. Ed. 2012, 51, 12833. (22) (a) Fétizon, M.; Golfier, M. Compt. Rend. 1968, 900. (b) Burke, S. D.; Shankaran, K.; Helber, M. J. Tetrahedron Lett. 1991, 32, 4655. (23) Li, J.; Huang, W.; Zhang, H.; Wang, X.; Zhou, H. Bioorg. Med. Chem. Lett. 2007, 17, 6891. (24) Serba, C.; Winssinger, N. Eur. J. Org. Chem. 2013, 2013, 4195.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01733. Experimental procedures and characterization for new compounds, including 1H and 13C NMR spectra (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Zhen Yang: 0000-0001-8036-934X Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS We thank the financial support from the National Science Foundation of China (Grant No. 21472006). REFERENCES

(1) Rahbæk, L.; Christophersen, C.; Frisvad, J.; Bengaard, H. S.; Larsen, S.; Rassing, B. R. J. Nat. Prod. 1997, 60, 811. (2) (a) Belofsky, G. N.; Jensen, P. R.; Renner, M. K.; Fenical, W. Tetrahedron 1998, 54, 1715. (b) Fang, W.; Lin, X.; Zhou, X.; Wan, J.; Lu, X.; Yang, B.; Ai, W.; Lin, J.; Zhang, T.; Tu, Z.; Liu, Y. MedChemComm 2014, 5, 701. (c) Tan, Y.; Yang, B.; Lin, X.; Luo, X.; Pang, X.; Tang, L.; Liu, Y.; Li, X.; Zhou, X. J. Nat. Prod. 2018, 81, 92. (3) (a) Drahl, C.; Cravatt, B. F.; Sorensen, E. J. Angew. Chem., Int. Ed. 2005, 44, 5788. (b) Gersch, M.; Kreuzer, J.; Sieber, S. A. Nat. Prod. Rep. 2012, 29, 659. (c) Lagoutte, R.; Patouret, R.; Winssinger, N. Curr. Opin. Chem. Biol. 2017, 39, 54. (4) Jansen, B. J. M.; de Groot, A. Nat. Prod. Rep. 1991, 8, 309. (5) (a) Armstrong, R. J.; Harris, F. L.; Weiler, L. Can. J. Chem. 1986, 64, 1002. (b) Sanchez, A. J.; Konopelski, J. P. J. Org. Chem. 1994, 59, 5445. (c) Vlad, P. F. Pure Appl. Chem. 1993, 65, 1329. (d) Polovinka, M. P.; Korchagina, D. V.; Gatilov, Y. V.; Bagrianskaya, I. Y.; Barkhash, V. A.; Perutskii, V. B.; Ungur, N. D.; Vlad, P. F.; Shcherbukhin, V. V.; Zefirov, N. S. J. Org. Chem. 1994, 59, 1509. (e) Vlad, P. F.; Ungur, N. D.; Hung, N. V.; Perutsky, V. B. Russ. Chem. Bull. 1995, 44, 2390. (6) (a) Jauch, J. Angew. Chem., Int. Ed. 2000, 39, 2764. (b) Suzuki, Y.; Nishimaki, R.; Ishikawa, M.; Murata, T.; Takao, K.-i.; Tadano, K.-i. J. Org. Chem. 2000, 65, 8595. (c) Suzuki, Y.; Ohara, A.; Sugaya, K.; D

DOI: 10.1021/acs.orglett.8b01733 Org. Lett. XXXX, XXX, XXX−XXX