Communication Cite This: J. Am. Chem. Soc. 2018, 140, 5365−5369
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Asymmetric Total Synthesis of Cyclocitrinol Junyang Liu, Jianlei Wu, Jian-Hong Fan, Xin Yan, Guangjian Mei, and Chuang-Chuang Li* Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China S Supporting Information *
μM,5b while compound 1 has shown antibacterial activity against Staphylococcus epidermidis and Enterococcus durans.3 However, the relative scarcity of these compounds from natural sources has impeded a more systematic evaluation of their biological activity. Structurally, cyclocitrinol (3) comprises a sterically compact 7/7/6/5 tetracyclic skeleton with a unique bicyclo[4.4.1]undecene A/B ring system (highlighted in red), rather than the common decalin system. In particular, cyclocitrinol possesses a strained bridgehead (anti-Bredt) double bond at C1−C10,6a,b as also observed in the wellknown natural drug taxol,6c and eight stereocenters, including two quaternary centers. Therefore, cyclocitrinol presents a formidable synthetic challenge. The fascinating and synthetically challenging structure combined with potential pharmacological properties has prompted much interest in cyclocitrinols from the synthetic community (several publications7 and eight dissertations8 on studies toward 1 or 3). In 2007, Schmalz and co-workers reported an elegant synthesis of the core structure of cyclocitrinol from dehydroepiandrosterone using a SmI2mediated fragmentation of a cyclopropane precursor.7a In 2014, Leighton and co-workers reported an elegant approach to the (iso)cyclocitrinol core structure using a tandem Ireland− Claisen/Cope rearrangement sequence.7c However, the total synthesis of any member of the cyclocitrinol family has yet to be reported. In our continuing efforts toward the synthesis of biologically active natural products,9 we herein describe the first and asymmetric total synthesis of cyclocitrinol (3), based on a type II intramolecular [5 + 2] cycloaddition. Scheme 1 shows the retrosynthetic analysis of cyclocitrinol (3) used to develop the concise strategy employed in our synthesis. We anticipated that 3 could be generated from compound 5 by the chemoselective and diastereoselective 1,2addition of lithium reagent 4. Tetracyclic core 5 would be synthesized from 6 through a series of functional group transformations, including selective reductive cleavage of the C18−O bond,10 installation of an enone group at C6−C8 and oxidative deformylation at C22.11a In turn, the bicyclo[4.4.1] A/B ring system in 6 could be synthesized from 7 using the type II intramolecular [5 + 2] cycloaddition developed by our group in 2014,12 although it would be difficult to control the diastereoselectivity of the reaction of compound 7. Compound 7 can be prepared from 8 using an Achmatowicz reaction.13 Finally, compound 8 could be prepared from readily available furan 9, bromide 10, and commercially available 1114 as the chiral pool compound15 using a Stille coupling and 1,2-addition reaction. Synthetically, isocyclocitrinol (1) and some other
ABSTRACT: The first and asymmetric total synthesis of cyclocitrinol, an unusual C25 steroid, has been accomplished in a linear sequence of 18 steps from commercially available compound 11. The synthetically challenging bicyclo[4.4.1] A/B ring system with a strained bridgehead (anti-Bredt) double bond of cyclocitrinol was constructed efficiently and diastereoselectively via a type II intramolecular [5 + 2] cycloaddition.
O
wing to their biological importance and structural diversity, steroids continue to play a significant role in synthetic organic chemistry and drug discovery.1,2 Isocyclocitrinol (1) (Figure 1), an unusual C25 steroid with a novel
Figure 1. Isocyclocitrinol (1) and cyclocitrinol (3).
structure, was isolated by Crews and Clardy et al. in 2003 from sponge-derived Penicillium citrinum.3 The structure of cyclocitrinol (3) has been revised from the original incorrectly assigned structure (2).4 To date, more than 25 diverse cyclocitrinols have been isolated,5 some of which have exhibited interesting biological activities.3−5 Cyclocitrinol (3) can induce the production of cAMP in GPR12-transfected CHO cells at 10 © 2018 American Chemical Society
Received: March 8, 2018 Published: April 4, 2018 5365
DOI: 10.1021/jacs.8b02629 J. Am. Chem. Soc. 2018, 140, 5365−5369
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Journal of the American Chemical Society Scheme 1. Retrosynthetic Analysis of Cyclocitrinol (3)
Scheme 2. Asymmetric Synthesis of Tetracyclic Core 6
cyclocitrinols5 could be collectively synthesized from 5 using simple functional group transformations. The synthesis began with the asymmetric preparation of compound 8 (Scheme 2). Commercially available starting material 11 was treated with LDA and TMSCl in THF, followed by oxidation of the resultant silyl enol ether with 2iodoxybenzoic acid (IBX) to give enone 12 in an overall yield of 80% (20 g scale). Treatment of 12 with I2 in the presence of TMSN3 and pyridine (Py) in DCM16 afforded iodide 13 in 70% yield (15 g scale). Pleasingly, the Stille coupling of 13 and 917 catalyzed by Pd(PPh3)4, copper(I) thiophene carboxylate (CuTc), and LiOAc in N-methyl-2-pyrrolidone (NMP) afforded 14 in 83% yield (8.4 g scale). The 1,4-reduction of the enone in 14 using NaBH4 and NiCl218 in MeOH provided ketone 15 as a single diastereomer in 67% yield (8.5 g scale). Treatment of 15 with the lithium reagent generated from bromide 1019 in Et2O gave compound 8 as a single product in 83% yield (2.3 g scale). Removal of the TBS and TIPS protecting groups using TBAF in THF, followed by oxidative rearrangement in situ by NBS in the presence of NaOAc and NaHCO3, generated compound 16 in excellent yield. After extensive experimentation, treatment of the anomeric and primary hydroxyl groups in 16 with acetyl anhydride (Ac2O), 2,2,6,6-tetramethylpiperidine (TMP), and 4-dimethylaminopyridine (DMAP) gave the key precursor 7, as shown in Scheme 1. According to our previous synthetic study,17 an alkyl group at the allylic position of the dienophile alkene group would control the diastereoselectivity of the type II intramolecular [5 + 2] cycloaddition to give bicyclo[4.4.1]undecene ring system with endo selectivity. As expected, the subsequent type II intramolecular [5 + 2] cycloaddition of 7 was achieved using TMP as a base in a sealed tube with heating, to afford
tetracyclic core 6 as a single diastereomer in an overall yield of 68% (1.9 g scale from 8, one column chromatography step), as shown in Scheme 2. Furthermore, type II [5 + 2] cycloaddition of compound 7a without substituted groups at C6 was also studied, surprisingly to give 6a as the major product with undesired stereochemistry12a at C3 and C5 (see Supporting Information for further details). The structures of 6 and 6a were confirmed by the X-ray crystallographic analysis of 6 and 6a’s derivative, respectively. Based on these results, we conclude that the stereochemistry of the CH2OAc group at C6 in 7 (cyclocitrinol numbering) is critical for this desired highly diastereoselective outcome. This route provided facile access to 3.5 g of 6, highlighting the robust nature of this chemistry. Notably, our type II intramolecular [5 + 2] cycloaddition 5366
DOI: 10.1021/jacs.8b02629 J. Am. Chem. Soc. 2018, 140, 5365−5369
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Accordingly, the ketone in compound 6 was reduced to an alcohol using NaBH4, followed by a standard Barton deoxygenation to give 17 in a 41% yield overall. Subsequent treatment of 17 with SOCl2, pyridine, and 2,4,6-trimethylpyridine in DCM at 0 °C gave 18, containing the desired C7−C8 double bond, as the major product in good yield, see Supporting Information for the structures of the minor products. After extensive trials, we identified a mild protocol as the optimal conditions for cleaving the desired C−O bond, where 18 was treated with lithium metal in EtNH221 at 25 °C for 1 h to give triol 19 in an overall yield of 51% (from 17, one column chromatography step). Notably, Li−EtNH2 had various roles in this reaction, including (i) selectively cleaving the allylic C18−O bond, (ii) removing the Ac group, and (iii) reducing the C22-ketal group to an alcohol. Next, the chemoselective oxidation of two primary hydroxyl groups in 19 using TEMPO and NCS in the presence of tetrabutylammonium chloride (TBACl)22 in DCM afforded the desired dialdehyde, followed by TES protection to give compound 20 in an overall yield of 60% (Scheme 3). With 20 in hand, we proceeded to study the double oxidative deformylation of the two aldehyde groups in 20, although there have been few reports in the literature concerning the use of a β,γ-unsaturated aldehyde such as 20 in the direct oxidative deformylation reaction to give a α,β-unsaturated ketone.11 Particularly, the high strain of the bridged A/B ring system makes this reaction more challenging. Pleasingly, following a period of optimization, the desired oxidative deformylation of the dialdehyde group in 20 using t-BuOK and O2 in t-BuOH23 afforded diketone 21 in 56% yield. Moving forward, we continued toward the final stage of the synthesis via the chemoselective and diastereoselective installation of the side-chain. Thus, treatment of 21 with lithium reagent 4 (generated from 4a24 via Sn−Li exchange) in THF and a subsequent TBAF workup gave 3 as a single diastereomer in 84% yield, completing the first and asymmetric total synthesis of cyclocitrinol. The 1H and 13C NMR spectra of synthetic cyclocitrinol (3) and its optical rotation (synthetic, [α]D20 = +124.0 (c = 0.45, MeOH); natural, [α]D20 = +130.3 (c = 0.3, MeOH)) were in agreement with those of the natural product.5b Therefore, the structure and absolute configuration of naturally occurring 3 were unambiguously confirmed by our total synthesis. In summary, we have achieved the first and asymmetric total synthesis of cyclocitrinol (3) in a linear sequence of 18 steps and 1.0% overall yield from commercially available compound 11. Notably, the synthetically challenging bicyclo[4.4.1] A/B ring system with a strained bridgehead double bond found in cyclocitrinols was synthesized efficiently and diastereoselectively using a type II intramolecular [5 + 2] cycloaddition. A unique chemoselective reductive cleavage of the C−O bond of 8-oxabicyclo[3.2.1]octene in 18 was successfully realized using Li−EtNH2. Furthermore, the eight stereocenters of cyclocitrinol were constructed in a facile and diastereoselective fashion. This work will serve as a basis for the asymmetric synthesis of other diverse cyclocitrinols3,5 and their analogs to facilitate further biological research, which is underway and will be reported in due course.
allowed the efficient and diastereoselective construction of the tetracyclic core in 6, including the synthetically challenging bicyclo[4.4.1] A/B ring system with bridgehead double bond, which was synthesized in a linear sequence of only nine steps from 11. With compound 6 in hand, we proceeded to the next stage of our proposed synthesis of cyclocitrinol (Scheme 3). Our initial Scheme 3. Asymmetric Total Synthesis of Cyclocitrinol
efforts involved the selective reductive cleavage of the allylic C18−O bond.10 Although a lot of approaches are reported for the cleavage of the C−O bond of [2.2.1] oxabicycles, the cleavage of the C−O bond of [3.2.1] oxabicycles is more challenging.20 To the best of our knowledge, there have been scarce reports for the selective reductive cleavage of the C−O bond in the ring system of 8-oxabicyclo[3.2.1]oct-2-ene in one step (in the blue box). A wide variety of conditions were screened (i.e., SmI2 , Pd(OAc)/HCO 2 H, Na/NH 3 , Li/ MeNH2,10b Li/NH2CH2CH2NH2,10d Sc(OTf)3/Et3SiH,10e TiCl4/Et3SiH,10f and (C6F5)3B/Et3SiH10g), but none afforded the desired products. After testing numerous different substrates, it was found that the C2-carbonyl and C8-hydroxyl groups had played a deleterious effect on the desired selective cleavage. Therefore, we envisaged that compound 18 would be a good precursor for selective cleavage of the C18−O bond.
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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/jacs.8b02629. 5367
DOI: 10.1021/jacs.8b02629 J. Am. Chem. Soc. 2018, 140, 5365−5369
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Journal of the American Chemical Society
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Detailed experimental procedure and 1H NMR and 13C NMR spectra (PDF) Crystallographic information for 6 (CIF) and 6b (CIF)
Thesis, Columbia University, 2008. (c) Plummer, C. W. Ph.D. Thesis, Columbia University, 2012. (d) Meier zu Greffen, A. Ph.D. Thesis, Universität zu Köln, 2012. (e) De, S. Ph.D. Thesis, Wayne State University, 2013. (f) Liu, T. Ph.D. Thesis, East China University of Science and Technology, 2014. (g) Wei, C. S. Ph.D. Thesis, Columbia University, 2015. (h) Mei, G. J. Ph.D. Thesis, Peking University, 2016. (9) (a) Cheng, M.-J.; Cao, J.-Q.; Yang, X.-Y.; Zhong, L.-P.; Hu, L.-J.; Lu, X.; Hou, B.-L.; Hu, Y.-J.; Wang, Y.; You, X.-F.; Wang, L.; Ye, W.C.; Li, C.-C. Chem. Sci. 2018, 9, 1488. (b) Chen, B.; Liu, X.; Hu, Y.; Zhang, D.; Deng, L.; Lu, J.; Min, L.; Ye, W.-C.; Li, C.-C. Chem. Sci. 2017, 8, 4961. (c) Qiao, C.; Zhang, W.; Han, J.; Li, C.-C. Org. Lett. 2016, 18, 4932. (d) Han, J. C.; Li, F.; Li, C.-C. J. Am. Chem. Soc. 2014, 136, 13610. (e) Wei, H.; Qiao, C.; Liu, G.; Yang, Z.; Li, C.-C. Angew. Chem., Int. Ed. 2013, 52, 620. (10) For selected examples of reductive cleavage of the cyclic allylic C−O bond, see: (a) Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1979, 44, 3678. (b) Rigby, J. H.; Wilson, J. Z. J. Am. Chem. Soc. 1984, 106, 8217. (c) Zhou, J.; Lu, G.; Huang, X.; Wu, S. Synth. Commun. 1991, 21, 435. (d) Molander, G. A.; Eastwood, P. R. J. Org. Chem. 1995, 60, 4559. (e) Qin, H.-L.; Lowe, J. T.; Panek, J. S. J. Am. Chem. Soc. 2007, 129, 38. (f) Reddy, C. R.; Reddy, G. B.; Rao, C. L. Tetrahedron Lett. 2008, 49, 863. (g) Mack, D. J.; Guo, B.; Njardarson, J. T. Chem. Commun. 2012, 48, 7844. For reviews on the cleavage of the C−O bond, see: (h) Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 1983, 249. (i) Maercker, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 972. (11) For selected examples about the direct oxidative deformylation of aldehydes, see: (a) Van Rheenen, V. Tetrahedron Lett. 1969, 10, 985. (b) Havare, N.; Plattner, D. A. Org. Lett. 2012, 14, 5078. (c) Tiwari, B.; Zhang, J.; Chi, Y. R. Angew. Chem., Int. Ed. 2012, 51, 1911. (d) Sun, H.; Yang, C.; Gao, F.; Li, Z.; Xia, W. Org. Lett. 2013, 15, 624. (e) Watanabe, E.; Kaiho, A.; Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2013, 135, 11744. (f) Kipke, A.; Schöning, K.-U.; Yusubov, M.; Kirschning, A. Eur. J. Org. Chem. 2017, 2017, 6906. (g) Shipilovskikh, S. A.; Rubtsov, A. E.; Malkov, A. V. Org. Lett. 2017, 19, 6760 and references therein.. (12) (a) Mei, G.; Liu, X.; Qiao, C.; Chen, W.; Li, C.-C. Angew. Chem., Int. Ed. 2015, 54, 1754. (b) Mei, G.; Yuan, H.; Gu, Y.; Chen, W.; Chung, L. W.; Li, C.-C. Angew. Chem., Int. Ed. 2014, 53, 11051. We were also stimulated by Wender’s seminal synthetic studies of [5 + 2] cycloaddition, see: (c) Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8954. (d) Wender, P. A.; Kogen, H.; Lee, H. Y.; Munger, J. D.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8957. (e) Wender, P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997, 119, 7897. (f) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976. For review and selected recent application of [5 + 2] cycloaddition reaction in natural product synthesis, see: (g) Ylijoki, K. E. O.; Stryker, J. M. Chem. Rev. 2013, 113, 2244. (h) Roethle, P. A.; Hernandez, P. T.; Trauner, D. Org. Lett. 2006, 8, 5901. (i) Zhang, M.; Liu, N.; Tang, W. J. Am. Chem. Soc. 2013, 135, 12434. (j) Kruger, S.; Gaich, T. Angew. Chem., Int. Ed. 2015, 54, 315. (k) He, C.; Hu, J.; Wu, Y.; Ding, H. J. Am. Chem. Soc. 2017, 139, 6098. (13) Achmatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.; Zamojski, A. Tetrahedron 1971, 27, 1973. (14) Compound 11: (1R,3aR,7aR)-1-[(1S)-2,2-dimethoxy-1-methylethyl]octahydro-7a-methyl-4H-inden-4-one, CAS#: 957214-01-6, was purchased in 500 g for $4700 from Shanghai Huqi Pharmaceutical Science & Technology Co. Ltd. in 2016. Compound 11 also could be synthesized from vitamin D2 in one step, see, Tavera-Mendoza, L. E.; Quach, T. D.; Dabbas, B.; Hudon, J.; Liao, X.; Palijan, A.; Gleason, J. L.; White, J. H. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 8250. (15) For a review about the chiral pool in the total synthesis, see: Brill, Z. G.; Condakes, M. L.; Ting, C. P.; Maimone, T. J. Chem. Rev. 2017, 117, 11753. (16) Angeles, A. R.; Waters, S. P.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 13765. (17) Liu, X.; Liu, J.; Zhao, J.; Li, S.; Li, C.-C. Org. Lett. 2017, 19, 2742.
AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Chuang-Chuang Li: 0000-0003-4344-0498 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This paper is dedicated to Professor E. J. Corey on the occasion of his 90th 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, JCYJ20170412152454807, and JSGG20160301103446375). We would also like to thank Prof. N. Burns at Stanford and Prof. T. Maimone at Berkeley for helpful discussions.
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