Enantioselective Total Synthesis of (+)-Wortmannin - Journal of the

May 5, 2017 - A concise and enantioselective total synthesis of the potent PI3K inhibitor (+)-wortmannin is described. A Pd-catalyzed cascade reaction...
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Enantioselective Total Synthesis of (+)-Wortmannin Yinliang Guo,†,§ Tianfei Quan,‡,§ Yandong Lu,† and Tuoping Luo*,†,‡ †

Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and Beijing National Laboratory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China ‡ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China S Supporting Information *

ABSTRACT: A concise and enantioselective total synthesis of the potent PI3K inhibitor (+)-wortmannin is described. A Pd-catalyzed cascade reaction was first developed to connect a synthon derived from Hajos− Parrish ketone to a furan moiety. The subsequent Friedel− Crafts alkylation of the β-position of a furan ring to an epoxide was optimized to establish the C10 quaternary center. (+)-Wortmannin was eventually accomplished by transformations following a late-stage oxidation of the furan allylic position. Kinome profiling and in vitro enzymatic assays were performed on 17-β-hydroxywortmannin and an epoxide analogue.

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hosphoinositide 3-kinases (PI3Ks) play essential roles in a wide range of cellular processes and have consequently emerged as important targets for drug discovery.1 It is noteworthy, however, that one of the most potent PI3K inhibitors reported to date is the furanosteroid, natural product wortmannin (1, Figure 1).2 Compounds belonging to this structural class of natural products have a highly reactive [6,6,5]-furanocyclohexadienone lactone moiety with a calculated strain energy of 12.1 kcal/mol.3 Wortmannin can therefore inhibit the activity of PI3Ks via a unique mechanism-of-action involving the formation of a covalent bond to a lysine residue in the ATP-binding loop, as well as a hydrogen bond to the hinge domain (the C-17 carbonyl group).4 Given that this reactive lysine residue is conserved across all of the active kinases in the kinome,5 1 also inhibits several other kinases including PLK1 and DNA-PK.6 However, wortmannin (1) has been shown to exhibit a reasonable degree of selectivity for specific kinases and has been widely used as a chemical probe to investigate biological processes associated with PI3Ks.7 In addition to its potential in the area of oncology,3,4 wortmannin has recently found application in regenerative medicine,8 highlighting the need for further work toward the evaluation of this molecule and its analogues using the state-of-the-art technologies. In contrast to the large number of studies pertaining to the biological significance of wortmannin (1), only two strategies have been reported to date for the successful construction of this natural product, both of which were developed by Shibasaki group.9 One of the most challenging tasks in the synthesis of wortmannin (1) involves the construction of the quaternary stereogenic center at C10. Starting from hydrocortisone, the first reported synthesis circumvented the need to construct the C10 stereogenic center, as well as the B−C−D tricyclic ring system.9a The second strategy used an intramolecular Heck reaction to © 2017 American Chemical Society

Figure 1. Representative examples of natural products containing an electrophilic [6,6,5]-tricyclic furan moiety and our retrosynthetic analysis of wortmannin (1).

construct the C10 quaternary carbon as part of a de novo synthesis of racemic wortmannin over 35 steps.9b Based on this strategy, Shibasaki and co-workers further developed a formal synthesis of (+)-wortmannin using asymmetric catalysis.9c It is noteworthy that the research groups of Keay,10 Shibasaki,11 and Trauner have also used an intramolecular Heck reaction to achieve the asymmetric synthesis of several natural products closely related to wortmannin (2 and 3).12 During the review process of this Received: March 13, 2017 Published: May 5, 2017 6815

DOI: 10.1021/jacs.7b02515 J. Am. Chem. Soc. 2017, 139, 6815−6818

Communication

Journal of the American Chemical Society Scheme 1. Total Synthesis of (+)-Wortmannin (1)a

Reagents and conditions: (a) 14 (1.05 equiv), Pd2(dba)3 (0.02 equiv), dppf (0.08 equiv), DIPEA (2.4 equiv), PhCl, 130 °C, 1.5 h; 15, 42%; 16, 33%; (b) TBSCl (1.1 equiv), imidazole (1.3 equiv), DMF, 1.5 h, 0 °C to RT, 85%; (c) NiCl2·6H2O (5.0 equiv), NaBH4 (15.0 equiv), MeOH, −90 °C to −60 °C, 69%; (d) LHMDS (2.0 equiv), PhNTf2 (1.8 equiv), THF, −78 to 0 °C, 98%; (e) 10 (1.3 equiv), Pd2(dba)3 (0.04 equiv), AsPh3 (0.24 equiv), NMP, 70 °C, 6 h, 69%; (f) TBHP (2.0 equiv), (−)-DIPT (0.5 equiv), Ti(OiPr)4 (0.4 equiv), 4 Å MS, DCM, −40 °C, 5 h, 68%; (g) NaH (2.5 equiv), MeI (2.0 equiv), DMF, −10 °C to rt, 91%; (h) Ph4PBF4 (3 equiv), DCM:HFIP (4:1), −15 °C, 65 h; (i) TBAF·3H2O, rt, 1 h; 20, 47% (2 steps); (j) TEMPO (0.3 equiv), PhI(OAc)2 (1.5 equiv), DCM, rt, 20 h, 93%; (k) NaClO2 (5.0 equiv), NaH2PO4·2H2O (5.0 equiv), 2-methyl-2butene (30.0 equiv), tBuOH/THF/H2O (3:2:1), rt, 1.5 h; (l) CMPI (6.0 equiv), Et3N (8.0 equiv), DCM, rt, 12 h, 75% (2 steps); (m) urea hydrogen peroxide (4.0 equiv), TFAA (1.5 equiv), Na2CO3 (6.0 equiv), DCM, 0 °C, 1.5 h, 69% (brsm: 85%); (n) NBS (1.5 equiv), AIBN (0.3 equiv), CCl4, reflux, 1.5 h; then AgBF4 (1.2 equiv), Et3N (2.0 equiv), DMSO, rt, 65%; (o) Et2NH (2.0 equiv), DCM, rt, 20 min; then DBN (4.0 equiv), DCM, 35 °C, 6 h; then HCl, THF, 35 °C, 15 h, 25% (brsm: 40%); (p) Ac2O (15 equiv), pyridine, rt, 12 h; then 3HF·Et3N, THF, 45 °C, 76%; (q) DMP (1.5 equiv), DCM, 0 °C to rt, 2.5 h, 85%. a

fully, this strategy would also secure the C1 stereogenic center. The epoxide in 8 could be reliably introduced by a Sharpless asymmetric epoxidation, leading us back to ketone 9 given the fact that 10 is known.18 It was envisaged that ketone 9 could be prepared by the coupling of enolate 11 with furan 12 or suitable equivalents. In the forward direction (Scheme 1), we started from acid 13, which was synthesized in three steps from (+)-Hajos−Parrish ketone following reported procedures.19 The connection of Hajos−Parrish ketone and the furan moiety via direct Hajos− Parrish alkylation20 was deprioritized due to the two-fold alkylation in the model reaction and the multistep preparation of the halofuran electrophile (see Figure S1 in Supporting Information for details). We subsequently designed a cascade transformation based on the unique properties of π-propargylpalladium to achieve the first connection (Figure S2).21 Under the optimized reaction conditions (Table S1), acid 13 reacted with propargyl carbonate 14 to afford the coupling product 15 in 42% yield on a multigram scale, while the decarboxylated product 16 was isolated in 33% yield and reconverted to acid 13 in one step.19

manuscript, Guerrero and co-workers reported elegant asymmetric syntheses of furanosteroids (−)-viridin and (−)-viridiol, which featured an intramolecular Heck reaction as well.13 Based on our ongoing interest in chemotypes capable of reacting with proteinogenic amino acid residues,14 we envisaged that the electrophilic [6,6,5]-tricyclic furan moiety found in various natural products could hold great potential for this purpose, the chemical synthesis of which started from hibiscone C (4) by Smith group in 1982.15 We recently reported the first enantioselective synthesis of (−)-hibiscone C (4),16 but an innovative strategy would be needed to access wortmannin (1) in an efficient and modular manner. Careful consideration of the structural features of wortmannin (1) suggested that intermediate 5 could be prepared from the corresponding pentacycle 6 through olefin epoxidation and late-stage allylic oxidation. In turn, it was envisaged 6 could be traced back to furan 7 by opening the lactone ring. We planned to conduct an intramolecular Friedel−Crafts alkylation between the furan and epoxide moiety in 8 to install the critical C10 stereogenic center in which the SN2 mechanism framework would allow for specific stereocontrol.17 If success6816

DOI: 10.1021/jacs.7b02515 J. Am. Chem. Soc. 2017, 139, 6815−6818

Communication

Journal of the American Chemical Society As shown in Table S2, this Pd-catalyzed cascade reaction was discovered to be an efficient method for the preparation of substituted furans. Following the protection of the primary alcohol in 15 as the corresponding TBS ether, we performed the stereoselective 1,4-reduction of the enone moiety to furnish ketone 9 in 69% yield.22 This reaction also afforded 1,2-reduction product as a major side product (17% yield), which could be subjected to PCC oxidation to recycle the enone starting material 17 (see Supporting Information for details). Installation of the triflate under the kinetic-controlled enolization conditions, followed by a Stille coupling with 10 provided allylic alcohol 18 in 68% yield over two steps. The Sharpless epoxidation of 18, followed by methylation of the primary alcohol delivered the cyclization precursor 8 in 62% overall yield as a single diastereomer. A series of condition screening were conducted using substrate 8 to determine the optimal conditions for the cyclization (see Table S3 in Supporting Information for details). To the best of our knowledge, there have been very few reports describing the functionalization of furan β-position in the Friedel−Crafts alkylation involving an epoxide.23 While various Lewis acids only led to decomposition of the starting material 8, we were delighted to find 1,1,1,3,3,3-hexofluoroisopropol (HFIP) and Ph4PBF4 additive greatly facilitated the desired transformation,17 although the cyclization product 7 was contaminated with unidentified side products even after purification by flash chromatography. Therefore, the partially purified 7 was subsequently treated with TBAF at room temperature to afford diol 20 as a single diastereomer in 47% yield over two steps on a gram-scale.24 The stage was then set to investigate the elaboration of 20 to give wortmannin (1). The selective oxidation of the primary alcohol in 20 followed by lactonization of the resulting carboxylic acid with Mukaiyama’s reagent afforded 6, completing the pentacyclic skeleton of wortmannin. The epoxidation of 6 was found to be sluggish even in the presence of excess in situgenerated trifluoroacetyl peroxide,25 but the reaction cleanly produced the desired product as a single stereoisomer in 69% yield (85% based on recovered starting material), leaving only one allylic methylene in 21. The subsequent exposure of 21 to Nbromosuccinimide (NBS) in the presence of the radical initiator AIBN resulted in successful formation of the corresponding bromo intermediate, which underwent an immediate Kornblum oxidation to afford 5 in 65% isolated yield.26 It is noteworthy that a similar intermediate bearing a benzoyl protecting group on the C17 hydroxyl group instead of a TBS ether was reported in the semisynthesis of wortmannin.9a With this in mind, we applied the same sequence of operations as those developed by Shibasaki and co-workers to obtain 23 (via 22), albeit in low yield (25%, 40% based on recovered starting material).9a Nonetheless, subsequent acetylation and TBS deprotection of 23 delivered the previously reported 17-β-hydroxy-wortmannin (24),4b,c which was oxidized with DMP to give (+)-wortmannin (1) in 85% yield. The low yield of 23 was attributed in part to the lability of TBS protecting group under the acidic reaction conditions (see Supporting Information for details), which prompted us to develop an alternative and high yielding approach to 1 (Scheme 2). To this end, the removal of TBS protecting group in 5 afforded 25 in excellent yield, which was oxidized to give ketone 26. The structure of 26 was unambiguously confirmed by X-ray diffraction. Compound 26 was subjected to the same one-pot procedure involving the opening of the electrophilic furan ring with diethylamine, eliminative opening of the epoxide, and

Scheme 2. Alternative Approach to (+)-Wortmannin (1) from 5a

a Reagents and conditions: (a) 3HF·Et3N, THF, 45 °C, 17 h, 95%; (b) DMP (2.0 equiv), DCM, 0 °C to rt, 1.5 h, 89%; (c) Et2NH (2.0 equiv), DCM, rt, 20 min; then DBN (4.0 equiv), DCM, 35 °C, 4 h; then HCl, THF, 35 °C, 12 h, 54% (brsm: 62%); (d) Ac2O (12 equiv), pyridine, rt, 12 h, 84%.

reconstruction of the furan ring, to give 27 in 54% yield (62% based on recovered starting material), which was converted to (+)-wortmannin (1) upon acetylation. All of the analytic data for the synthesized samples of 1, 24, and 27 were consistent with those reported in the literature (Tables S4−S6).2,9,27 We next subjected wortamnnin and its analogues to characterization by biochemical assays. In order to determine the selectivity profiles using the KinomeScan approach (DiscoverX),28 the binding constants (Kds) of 1, 24, and 25 against several PI3Ks were first determined using the same platform, which also revealed that (−)-hibiscone C (4) was unable to bind the ATP binding site of p110α (Table S7). Consistent with previous reports,4b,29 17-β-hydroxy-wortmannin (24) was found to be more potent than 1, whereas the activities of 25 were at least an order of magnitude weaker than those of 1 except for its activities against VPS34 and p110β. The profiling of compounds 24 (1 μM) and 25 (5 μM) against a panel of 468 kinases showed they only interacted with class I PI3Ks, VPS34, and PI3K-C2β, while clinical p110α mutations did not have an adverse impact on the binding of these inhibitors (Figure S3 and Table S9).30 Compounds 24 and 25 were also evaluated using a series of enzymatic assays (Invitrogen), which confirmed that the introduction of an epoxide moiety to the C-ring led to a pronounced drop (>280fold) in the inhibitory activity, although this effect was less prominent for PI3Kβ (p110β/p85α) and VPS34 (Table S8). Given that several other changes to the C-ring substitution patterns in wortmannin were reasonably tolerated,4b,29 further investigation is needed to provide a rationale of our observation that the inclusion of an epoxide moiety resulted in significant decrease of activity. In summary, starting from the known acid 13 and triol 14, we have achieved the total synthesis of (+)-wortmannin (1) in 18 steps (21 steps from Hajos−Parrish ketone) (Scheme S1).31 The key features of our synthesis include the systematic optimization of a Pd-catalyzed cascade reaction and an intramolecular Friedel− Crafts alkylation, as well as the application of a late-stage allylic oxidation. Most notably, our approach allows for the synthesis of new wortmannin analogues to expand research territory of such an important irreversible kinase inhibitor, which is currently underway in our group and will be reported in due course. 6817

DOI: 10.1021/jacs.7b02515 J. Am. Chem. Soc. 2017, 139, 6815−6818

Communication

Journal of the American Chemical Society

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Rabien, A.; Makrantonaki, E.; Zouboulis, C. C. PLoS One 2016, 11, e0154770. (8) Zhang, D.; Jiang, W.; Liu, M.; Sui, X.; Yin, X.; Chen, S.; Shi, Y.; Deng, H. Cell Res. 2009, 19, 429. (9) (a) Sato, S.; Nakada, M.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 6141. (b) Mizutani, T.; Honzawa, S.; Tosaki, S.-y.; Shibasaki, M. Angew. Chem., Int. Ed. 2002, 41, 4680. (c) Shigehisa, H.; Mizutani, T.; Tosaki, S.y.; Ohshima, T.; Shibasaki, M. Tetrahedron 2005, 61, 5057. (10) Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A.; Keay, B. A. J. Am. Chem. Soc. 1996, 118, 10766. (11) Miyazaki, F.; Uotsu, K.; Shibasaki, M. Tetrahedron 1998, 54, 13073. (12) Kienzler, M. A.; Suseno, S.; Trauner, D. J. Am. Chem. Soc. 2008, 130, 8604. (13) Del Bel, M.; Abela, A. R.; Ng, J. D.; Guerrero, C. A. J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b02829. (14) Zhao, S.; Dai, J.; Hu, M.; Liu, C.; Meng, R.; Liu, X.; Wang, C.; Luo, T. Chem. Commun. 2016, 52, 4702. (15) Koft, E. R.; Smith, A. B. J. Am. Chem. Soc. 1982, 104, 5568. (16) Lu, Y.; Yuan, H.; Zhou, S.; Luo, T. Org. Lett. 2017, 19, 620. (17) (a) Li, G.-X.; Qu, J. Chem. Commun. 2010, 46, 2653. (b) Tian, Y.; Xu, X.; Zhang, L.; Qu, J. Org. Lett. 2016, 18, 268. (18) Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.; Prunet, J. J. Org. Chem. 1997, 62, 7768. (19) Frie, J. L.; Jeffrey, C. S.; Sorensen, E. J. Org. Lett. 2009, 11, 5394. (20) Hajos, Z. G.; Micheli, R. A.; Parrish, D. R.; Oliveto, E. P. J. Org. Chem. 1967, 32, 3008. (21) For reviews, see: (a) Guo, L.-N.; Duan, X.-H.; Liang, Y.-M. Acc. Chem. Res. 2011, 44, 111. (b) Yoshida, M. Chem. Pharm. Bull. 2012, 60, 285. (22) Yamashita, S.; Iso, K.; Hirama, M. Org. Lett. 2009, 10, 3413. (23) (a) Kantam, M. L.; Aziz, K.; Likhar, P. R. Catal. Lett. 2004, 98, 117. (b) Chung, W. K.; Lam, S. K.; Lo, B.; Liu, L. L.; Wong, W.-T.; Chiu, P. J. Am. Chem. Soc. 2009, 131, 4556. (24) The major side product in this key transformation was determined to be diene 19, resulting from the ring opening of epoxide (see Table S3 in Supporting Information for details).

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b02515. Detailed experimental procedures, compound characterization data, and complete ref 28 (PDF) KinomeScan profile of 24 and 25 (XLSX) Crystallographic data for 26 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Tuoping Luo: 0000-0003-2156-3198 Author Contributions §

These authors contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by generous start-up funds from the National “Young 1000 Talents Plan” Program, College of Chemistry and Molecular Engineering, Peking University and Peking-Tsinghua Center for Life Sciences, and the National Science Foundation of China (Grant Nos. 21472003, 31521004, and 21672011). We thank Dr. Nengdong Wang and Prof. Wenxiong Zhang (Peking University) for their help in analyzing the X-ray crystallography data.

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REFERENCES

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DOI: 10.1021/jacs.7b02515 J. Am. Chem. Soc. 2017, 139, 6815−6818