Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Total Synthesis of (−)-Xestosaprol N and O Yingbo Shi,† Yang Ji,† Kunyun Xin,† and Shuanhu Gao*,†,‡ †
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China ‡ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China S Supporting Information *
ABSTRACT: The first total synthesis of (−)-xestosaprol N and O is described. This synthetic work features a convergent strategy: (1) a Pd-catalyzed arylation followed by cyclization to build a naphthalene fragment (ring C, D); (2) utilization of (−)-quinic acid to construct the chiral hydroxyl group at C-2; (3) a substrate controlled intramolecular Heck reaction to construct a quaternary carbon center (ring B); (4) introduction of a hypotaurine moiety at a late stage to furnish the E ring.
taurine, respectively. Due to their wide array of biological activities and unique structures, halenaquinone-type natural products have attracted great interest from synthetic chemists.5a Total synthesis strategies have been developed using Diels− Alder reactions,5b−f Heck reactions,5g,h or metal promoted cyclization as key steps.5i,j The derivatives of halenaquinonetype natural products without a furan ring were also discovered in recent years. In 2012, xestosaprol N (5) was isolated from the Micronesian marine sponge by Lee and co-workers and exhibited weak inhibition activity against NCI-H23 and PC-3, with values of GI50 28.21 and 28.95 μg/mL.6 Two years later, Andersen and Mauk et al. isolated xestosaprol O (6) from Xestospongia vansoesti and synthesized its deoxy analogue via the Sato reaction as a key step.7 Further in vitro research indicated that xestosaprol O (6) exerts the enzyme indoleamine 2,3dioxygenase (IDO) inhibition (IC50 = 4 μM). Actually, the naphtha[1,8-bc]furan core is not unique to halenaquinone-type natural products. Beyond that, one class of steroidal furanoids8 isolated from fungus also presents this structure such as viridin (7)8c,d and viridiol (8).8e Our research group is devoted to developing new strategies for the collective synthesis of structurally and biogenetically related furanodecaline-containing natural products for medicinal chemistry and biological studies. We reported herein the total synthesis of (−)-xestosaprol N (5) and O (6) as the preliminary results for the whole synthetic project. Based on the retrosynthetic analysis outlined in Scheme 1, we envisioned that the taurine moiety (ring E) of xestosaprol N (5) and O (6) could be installed through a biogenetic condensation of quinone (ring D) with hypotaurine 9 at a late stage, which could be derived from tetracyclic framework 10. Compound 10, containing the core structure of halenaquinonetype natural products, could serve as a common precursor for
Xestospongia genus sponges are a veritable treasure chest of natural products and widely distributed in the Pacific Ocean, the Indian Ocean, and the Caribbean Sea. More than 40 quinones were found from these creatures, with halenaquinonetype compounds constituting an important subgroup of this family.1 Selected halenaquinone-type natural products are shown in Figure 1. Their structural diversity is mainly reflected in different oxidation states and substituents. Halenaquinone (1)2 features a highly oxidized pentacyclic structure, containing a naphtha[1,8-bc]furan core. Xestosaprol K (2)3 as well as 3ketoadociaquinone A (3) and B (4)4 may be generated from halenaquinone (1) via hydrogenation or condensation with
Figure 1. Structure of halenaquinone-type and structurally related natural products. © XXXX American Chemical Society
Received: December 11, 2017
A
DOI: 10.1021/acs.orglett.7b03865 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Retrosynthetic Analysis of Xestosaprol N and O
Scheme 3. Preparation of Naphthaldehyde Fragment 13
with triflic anhydride gave triflate 22 which was efficiently transformed to Weinreb amide 23 in 87% yield. We initially attempted to acquire the Heck reaction precursor ketone 11 by lithiation of 12 and addition with Weinreb amide 23, but only generated messy products. This may have resulted from instability of the triflate and low activity of the amide group on compound 23. Thereby, naphthaldehyde 13 with higher activity was prepared via reduction of amide 23 using DIBAL. Ketone 11 was smoothly obtained through the process of lithiation of 12, then coupling with naphthaldehyde 13, and Dess-Martin oxidation. Then we relied on a Pd-catalyzed intramolecular Heck reaction to construct the quaternary carbon center on C-5. Systematic screening of the reaction conditions for optimization was shown in Table 1. Among the screened ligands, we observed the formation of cyclized product 24 and hydrogenation byproduct 25 in poor yield with PPh3 and dppb as ligands (entries 1, 3, 6). When using toluene as solvent and potassium carbonate as base, the yield of 24 was slightly increased. On the other hand, with a dpppcontaining catalyst, the reaction completely gave byproduct 25 in 85% yield (entry 4). We suspected that the hydrogen source of 25 might come from the α-hydrogen of triethyl amine through a fast reductive elimination based on the similar observation by Cabri.11 Interestingly, we found that the yield of 24 was increased to 65% (entry 7) when 10 equiv of water were added to the reaction system (see Supporting Information for further discussion). Finally, replacement of the base with TMP further enhanced the yield of 24 to 74% nearly without observation of 25 (entry 8). With the basic tetracarbocyclic skeleton 24 (ring A−B-C−D) in hand, the next stage is an oxidation of C7 and construction of heterocyclic ring E. We tried to hydrogenate the redundant double bond of 24 via catalytic hydrogenation by using Pd/C and other similar conditions, but serious carbonyl hydrogenation products were always observed. Then we turned to employ hydrogen atom transfer (HAT) radical hydrogenation to achieve this transformation.12 Removing the TBS group of 24 was indispensable for this step. Under the conditions reported by Shenvi and co-workers (PhSiH3/TBHP/Mn(dpm)3),12b double bond hydrogenation of 26 successfully gave 10 in 73% yield. Meanwhile, the stereochemistry validity of hydroxyl and quaternary stereo center were confirmed through the X-ray single crystal diffraction of 10. Oxidation of 10 with SeO2 constructed oxidation state on C7 and gave 27 in
their chemical synthesis. The all-carbon quaternary carbon center on C-5 could be established from ketone 11 via an intramolecular Heck reaction, which contains the desired oxidation state on C-8. Ketone 11 can be afforded through a convergent approach by coupling with chiral iodide compound 12 and naphthaldehyde 13. Known chiral alcohol 149 was suitable starting material for transformation to fragment 12. Feasible synthesis of naphthaldehyde 13 from aryl bromide 15 and silyl enol ether 16 was inspired by the technology reported by Koert and co-workers.10 Our synthesis began with the preparation of chiral iodide fragment 12 (Scheme 2). The chiral alcohol 14 was prepared Scheme 2. Preparation of Chiral Iodide Fragment 12
from (−)-quinic acid according to a reported process9 and then underwent protection and hydrogenation to afford ketone 17 in favorable yield and diastereoselectivity (dr = 10:1). Compound 17 was converted to cyclohexene derivative 18 via triflate formation and methylation in 65% yield over two steps. Selective removal of the triethylsilyl with acetic acid gave alcohol 19 in 73% yield, which underwent Appel reaction to generate iodide fragment 12 in 61% yield. To prepare the naphthaldehyde fragment (Scheme 3), γ-arylβ-ketoesters 20 were first synthesized under the optimized conditions developed by Koert and co-workers.10 Building blocks 15 and 16 were converted to ketoesters 20 in 70% yield by using catalytic amounts of Pd(dba)2/t-Bu3P and stoichiometric amounts of Bu3SnF. Subsequently intramolecular condensation of ketoesters 20 in formic acid afforded substituted naphthalene 21 in 54% yield. Treatment of 21 B
DOI: 10.1021/acs.orglett.7b03865 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Attempts of Heck Reaction
entry a
1 2a 3b 4b 5b 6b 7b 8b
ligand
solvent
base
additivec
temp (°C)
time (h)
result
PPh3 t-Bu3P dppb dppp dppe dppb dppb dppb
MeCN MeCN toluene MeCN MeCN MeCN MeCN MeCN
Et3N Et3N K2CO3 Et3N Et3N Et3N Et3N TMPd
− − − − − − H2O H2O
80 80 100 80 80 80 80 80
12 8 12 12 12 12 22 18
24 (trace), 25 (39%) N.R. 24 (25%), 25(13%) 25 (85%) N.R. 24 (11%), 25 (69%) 24 (65%), 25 (22%) 24 (74%), 25 (trace)
a
Pd(OAc)2 (0.2 equiv), phosphine ligand (0.4 equiv). bPd(OAc)2 (0.2 equiv), phosphine ligand (0.2 equiv). cH2O (10.0 equiv). dTMP = 2,2,6,6tetramethylpiperidine.
Scheme 4. Preparation of Xestosaprol N and O
Although the poor solubility of xestosaprol N (5) led to an extremely low SNR (Signal to Noise Ratio) of NMR in Acetone-d6, we still believe that the structure of xestosaprol N (5), based on the NMR spectra and X-ray analysis, is confirmed. In summary, we have achieved the first total synthesis of (−)-xestosaprol N and O via a convergent strategy in 16 steps. In our synthesis, two coupling fragments of naphthalene and chiral six-membered ring were prepared first. Then, we used a substrate controlled intramolecular Heck reaction to set up the quaternary carbon center. Finally, xestosaprol N and O were concurrently obtained after enhancement of the oxidation state and installing the E ring. Our research affords further forceful proof for the structure determination of xestosaprol N and O, and also lays the foundation for the synthesis of structurally related natural products. Now, we are studying the total
61% yield. Due to the high oxidation state and enolization of 27, direct ring D oxidation failed by using ceric ammonium nitrate or chromium VI oxidants. Acetylation of 27 quantificationally afforded 28 which was able to stably undergo ring D oxidation to form quinone 29 in 90% yield. According to a literature procedure, the condensation of hypotaurine with quinone 29 generated a mixture of two isomers 30 and 31.13 Finally, removal of the acetyl group of 30 and 31 under hydrochloric acid gave xestosaprol N (5) and O (6) respectively (Scheme 4). As described by Andersen and Mauk et al, the 1H NMR and 13C NMR of these two compounds in DMSO-d6 are almost the same. After careful comparison of the NMR spectra of the synthetic sample with the natural product, we found that the spectra of xestosaprol O (6) were identical. Not only that, the structures of xestosaprol N (5) and O (6) were further confirmed by their X-ray analysis. C
DOI: 10.1021/acs.orglett.7b03865 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(6) Lee, Y. J.; Kim, C. K.; Park, S. K.; Kang, J. S.; Lee, J. S.; Shin, H. J.; Lee, H. S. Heterocycles 2012, 85, 895−901. (7) Centko, R. M.; Steinø, A.; Rosell, F. I.; Patrick, B. O.; de Voogd, N.; Mauk, A. G.; Andersen, R. J. Org. Lett. 2014, 16, 6480−6483. (8) For a review of naphtha[1,8-bc]furan containing natural products: (a) Wipf, P.; Halter, R. J. Org. Biomol. Chem. 2005, 3, 2053−2061. (b) Hanson, J. R. Nat. Prod. Rep. 1995, 12, 381−384. Isolation of viridin: (c) Brian, P. W.; McGowan, J. C. Nature 1945, 156, 144−145. (d) Grove, J. F.; McCloskey, P.; Moffatt, J. S. J. Chem. Soc. C 1966, 743, 743−747. Isolation and structure elucidation of viridiol: (e) Moffatt, J. S.; Bu’Lock, J. D.; Yuen, T. H. J. Chem. Soc. D 1969, 839a. Selected synthesis work: (f) Sato, S.; Nakada, M.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 6141−6144. (g) Mizutani, T.; Honzawa, S.; Tosaki, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2002, 41, 4680−4682. (h) Shigehisa, H.; Mizutani, T.; Tosaki, S.; Ohshima, T.; Shibasaki, M. Tetrahedron 2005, 61, 5057−5065. (i) Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew. Chem., Int. Ed. 2004, 43, 1998−2001. (j) Del Bel, M.; Abela, R. A.; Ng, J. D.; Guerrero, C. A. J. Am. Chem. Soc. 2017, 139, 6819−6822. (9) Arthurs, C. L.; Morris, G. A.; Piacenti, M.; Pritchard, R. G.; Stratford, I. J.; Tatic, T.; Whitehead, R. C.; Williams, K. F.; Wind, N. S. Tetrahedron 2010, 66, 9049−9060. (10) Wagner, F.; Harms, K.; Koert, U. Org. Lett. 2015, 17, 5670− 5673. (11) Cabri, W.; Candiani, I.; DeBernardinis, S.; Francalanci, F.; Penco, S.; Santo, R. J. Org. Chem. 1991, 56, 5796−5800. (12) (a) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693−11712. (b) Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W. M.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 1300−1303. (c) Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W. M.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 1300− 1303. (d) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 1304−1307. (e) Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C.; Baran, P. S. Nature 2014, 516, 343−348. (13) Chia, E. W.; Pearce, A. N.; Berridge, M. V.; Larsen, L.; Perry, N. B.; Sansom, C. E.; Godfrey, C. A.; Hanton, L. R.; Lu, G.; Walton, M.; Denny, W. A.; Webb, V. L.; Copp, B. R.; Harper, J. L. Bioorg. Med. Chem. 2008, 16, 9432−9442.
synthesis of the viridin family of molecules, which will be reported in due course.
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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.7b03865. Experimental procedures, characterization data, and NMR spectra (PDF) Accession Codes
CCDC 1590284−1590286 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shuanhu Gao: 0000-0001-6919-4577 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21772044), the “National Young Top-Notch Talent Support Program”, “the Fundamental Research Funds for the Central Universities”, and the China Postdoctoral Science Foundation (2017M611490) for generous financial support.
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REFERENCES
(1) For reviews of the secondary metabolites from Xestospongia sponges and their bioactivities, see: (a) Zhou, X.; Xu, T.; Yang, X.; Huang, R.; Yang, B.; Tang, L.; Liu, Y. Chem. Biodiversity 2010, 7, 2201−2227. (b) Liang, F.; Liu, H.; Li, Y.; Ma, W.; Guo, Y.; He, W. Yao Xue Xue Bao. 2014, 49, 1218−1237. (2) Roll, D. M.; Scheuer, P. J.; Matsumoto, G. K.; Clardy, J. J. Am. Chem. Soc. 1983, 105, 6177−6178. (3) Dai, J. Q.; Sorribas, A.; Yoshida, W. Y.; Kelly, M.; Williams, P. G. J. Nat. Prod. 2010, 73, 1188−1191. (4) Cao, S.; Foster, C.; Brisson, M.; Lazo, J. S.; Kingston, D. G. Bioorg. Med. Chem. 2005, 13, 999−1002. (5) For a review of synthesis toward halenaquinone-type natural products, see: (a) Schwarzwalder, G. M.; Vanderwal, C. D. Eur. J. Org. Chem. 2017, 2017, 1567−1577. For a selected total synthesis of halenaquinone-type natural products, see: (b) Harada, N.; Sugioka, T.; Ando, Y.; Uda, H.; Kuriki, T. J. Am. Chem. Soc. 1988, 110, 8483−8847. (c) Harada, N.; Sugioka, T.; Uda, H.; Kuriki, T. J. Org. Chem. 1990, 55, 3158−3163. (d) Harada, N.; Sugioka, T.; Uda, H.; Kuriki, T.; Kobayashi, M.; Kitagawa, I. J. Org. Chem. 1994, 59, 6606−6613. (e) Carlini, R.; Higgs, K.; Older, C.; Randhawa, S.; Rodrigo, R. G. A. J. Org. Chem. 1997, 62, 2330−2331. (f) Sutherland, H. S.; Souza, F. E. S.; Rodrigo, R. G. A. J. Org. Chem. 2001, 66, 3639−3641. (g) Wakefield, B.; Halter, R. J.; Wipf, P. Org. Lett. 2007, 9, 3121−3124. (h) Kienzler, M. A.; Suseno, S.; Trauner, D. J. Am. Chem. Soc. 2008, 130, 8604− 8605. (i) Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A.; Keay, B. A. J. Am. Chem. Soc. 1996, 118, 10766−10773. (j) Kojima, A.; Takemoto, T.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1996, 61, 4876−4877. D
DOI: 10.1021/acs.orglett.7b03865 Org. Lett. XXXX, XXX, XXX−XXX
