Grob-Fragmentation-Enabled Approach to Clavulactone Analogues

Letter Cite This: Org. Lett. 2019, 21, 5082−5085

pubs.acs.org/OrgLett

Grob-Fragmentation-Enabled Approach to Clavulactone Analogues Qi Gu,† Xuan Wang,† Bingfeng Sun,*,‡ and Guoqiang Lin† †

CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China ‡ Taizhou Synhigher Pharmaceutical Technology Co. Ltd., 1 Yaocheng Avenue, Taizhou, Jiangsu 225300, China

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S Supporting Information *

ABSTRACT: The novel synthetic strategy for dolabellane skeleton was realized, which allowed the synthesis of clavulactone analogues 26 and 27 in a concise and efficient manner. Salient transformations include a diastereoselective Mukaiyama aldol reaction, an intramolecular nucleophilic addition reaction, a Grob fragmentation reaction, and an efficient Mukaiyama−Michael addition reaction.

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nucleophilic addition of the vinyl carbanion, derived from the corresponding iodine−lithium exchange, to the carbonyl function, thus defining its precursor 5. Compound 5 was to be assembled from 6 and 7 by a Mukaiyama aldol reaction. The synthetic journey commenced with the asymmetric syntheses of 6 and 7. The synthesis of 6 entails the construction of the all-carbon quaternary stereocenter flanked by two reactive functions. The optimized synthetic route for 6 is depicted in Scheme 2. First, the D’Angelo reaction effectively

olabellanes are prominent diterpenoids that exhibit a wide array of biological activities.1 Dolabellanes are proposed to be biogenetic precursors of fusicoccane, dolastane, and neodolabellane skeletons.2 Their molecular architectures are characterized by an intriguing trans-bicyclo[9.3.0]tetradecane carbon skeleton decorated with an angular methyl group. From a synthetic perspective, the constrained 11membered carbocycle along with the C-1 all-carbon quaternary stereocenter poses a significant challenge.3 Herein we report our recent efforts toward the asymmetric total synthesis of clavulactone (1) by employing a novel synthetic strategy.4 As outlined in Scheme 1, enone 2 was envisioned to be the key synthetic precursor for clavulactone and related molecules.

Scheme 2. Synthesis of 6a

Scheme 1. Clavulactone (1) and Its Retrosynthetic Analysis

a

Reagents and conditions: (a) (R)-(+)-1-phenylethylamine, toluene, reflux, then 1-cyanovinyl acetate, 20% AcOH aq., 1 M HCl, THF, 96%; (b) K2CO3, 37% HCHO aq., THF/MeOH (10/1), 85%; (c) NH4Cl, MeOH, reflux, 80%; (d) (i) TEA, hydrazine hydrate, EtOH, reflux, then TEA, I2, THF, r.t., 58%; (ii) conc. HCl aq., acetone, r.t., 80%.

established the quaternary carbon in an enantioselective manner, furnishing 9 in 96% yield.5 Next, cyanohydrin acetate 9 was converted to dicarbonyl 10 and further transformed into dimethylacetal 11. This was necessary considering that 9 could not survive the following reaction sequence. Compound 11

The 11-membered carbocycle in 2 was envisaged to stem from the Grob fragmentation of 3, and the geometry of the trisubstituted double bond in 2 was to be governed by the relative stereochemistry of the anti diol 4. The allyl alcohol moiety in 4 was to be engendered by the intramolecular © 2019 American Chemical Society

Received: May 13, 2019 Published: June 14, 2019 5082

DOI: 10.1021/acs.orglett.9b01678 Org. Lett. 2019, 21, 5082−5085

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Organic Letters Scheme 4. Mukaiyama Aldol Reactiona

was exposed to hydrazine before being treated with iodine to afford 6 in a good overall yield.6 The asymmetric synthesis of 7 took advantage of (R)epichlorohydrin (12) (Scheme 3). First, compound 12 was Scheme 3. Synthesis of 7a

Reagents and conditions: (a) (i) nBuLi, 1,3-dithiane, THF, −78 °C to r.t., 92%; (ii) nBuLi, Me3SI, THF, −10 °C to r.t., 82%; (b) NaH, BnBr, THF, 60 °C; (ii) MeI, K2CO3, CH3CN/H2O (10:1), 45 °C, 74%; (iii) Ph3PCHCO2Me, DCM, r.t., 87%; (c) CuI, MeLi, TMSCl, THF, −78 °C, 90%; (d) (i) (MeO)MeNH·HCl, iPrMgCl, THF, r.t., then isopropenylmagnesium bromide, THF, 0 °C, 90%; (e) Grubbs second catalyst, toluene, reflux, 85%; (f) (i) 10% Pd/C, Na2CO3, EtOAC, r.t.; (ii) FeCl3, MeMgBr, TMSCl, triethylamine, HMPA, Et2O, r.t., 74%. a

Reagents and conditions: (a) BF3·Et2O, DCM, 0 °C to r.t., 69%; (b) BF3·Et2O, DCM, 0 °C to r.t., 61%; (c) BF3·Et2O, DCM, 0 °C to r.t., 38%. a

stereochemistry of the two newly formed stereocenters in 20 was deduced from the X-ray structure of 4 (vide infra). Grob fragmentation as a strategic tool to construct macrocycles has gained sustained attention from the synthetics community.16 The implementation of this strategy in our synthesis of 2 from 20 was successfully realized, as depicted in Scheme 5. First, the free hydroxyl group in 20 was masked as a

7

converted to 13 via the known procedure. The masked aldehyde was then released and subjected to a Horner− Wadsworth−Emmons (HWE) reaction to furnish unsaturated ester 14.8 The exposure of 14 to a Michael addition reaction with MeLi/CuI/TMSCl gave 15 as a 2.5/1 mixture in excellent yield favoring the desired diastereomer.9 Through the intermediacy of the Weinreb amide, 15 was transformed into enone 16.4d,10 Upon exposure to Grubbs-II catalyst, 16 underwent a smooth ring-closing metathesis (RCM) reaction to garner 17 in a satisfactory yield of 85%.11 The exposure of 17 to hydrogenation on Pd/C, followed by the employment of Holton’s procedure,12 afforded 7 in a good overall yield of 74% as a 2.5/1 diastereomeric mixture. With 6 and 7 in hand, we investigated the critical Mukaiyama aldol reaction (Scheme 4). Initially an extensive experimentation was carried out with 18 as the model substrate, which revealed BF3·Et2O to be the optimal promoter.13 Under the action of BF3·Et2O, the Mukaiyama aldol reaction of 6 and 18 proceeded smoothly to provide the aldol products 19a and 19b in a combined yield of 69% as a 2/ 1 diastereomeric mixture.14 The stereochemistry of the two newly formed stereocenters in both 19a and 19b could be accounted for by the putative transition states A and B, respectively.15 Delightfully, the reaction of 6 and 7 under the optimized conditions furnished 20 in 61% yield as a sole diastereomer whose stereochemistry was in agreement with transition state C. These intriguing results in terms of diastereoselectivity prompted us to further procure 7′ as a 1/ 1 diastereomeric mixture at the indicating stereocenter. Again, the reaction of 6 and 7′ furnished 20 as a sole diastereomer in 38% yield. It turned out that in both cases only trans-7 was productive. Probably because of stereoelectronic effects, trans7 was more reactive than cis-7 in this aldol reaction. The

Scheme 5. Synthesis of 2 by Grob Fragmentationa

a

Reagents and conditions: (a) TMSOTf, 2,6-lutidine, DCM, r.t., 95%; (b) (i) tBuLi, Et2O, 0 °C; (ii) TBAF, THF, r.t., 74%; (c) nBuLi, TsCl, THF, 0 °C, 39% for 3, 21% for 2, 95% brsm; (d) tBuOK, THF, r.t., 83%. 5083

DOI: 10.1021/acs.orglett.9b01678 Org. Lett. 2019, 21, 5082−5085

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Organic Letters

23 was realized with TEMPO/PIDA to provide 24 and 25 in 54 and 35% yield, respectively. Debenzylation, followed by oxidation, transformed 24 to 26. Through the same procedure, 25 was converted to 27. The stereochemistries of 26 and 27 were established by 2D-NMR techniques. Endeavors were also made to introduce an unsaturation to the lactone motif (Scheme 7). Selenylation of 24/25 with

trimethylsilyl (TMS) ether to furnish 5 in excellent yield, aiming to prevent the occurrence of the retro-aldol reaction under basic conditions. The exposure of 5 to t-BuLi at 0 °C effected the desired iodine−lithium exchange, engendering the vinyl carbanion intermediate, which attacked the internal ketone function, forming the carbinol. This intramolecular addition reaction and the following deprotection operation provided the 5/6/7 tricyclic product 4, whose structure, along with its stereochemistry, was established unambiguously through the X-ray crystallographic analysis. To our delight, the treatment of 4 with n-BuLi/TsCl afforded 3 and 2 in 39 and 21% yield, respectively, as well as recovered 4 (35%). Eventually, 3 could be converted to 2 in 83% yield under the action of t-BuOK. Enone 2 was further converted to two clavulactone analogues (Scheme 6). The conjugate addition of silylether

Scheme 7. Synthesis of 29a

Scheme 6. Synthesis of 25 and 26a

Reagents and conditions: (a) (i) LDA, (PhSe)2, THF, −78 °C; (ii) H2O2, pyridine, 75%; (b) RhCl3, EtOH, 84%. a

LDA/(PhSe)2, followed by oxidative elimination, furnished 28 in 75% yield. The isomerization of 28 to 29 was successfully realized with RhCl3. However, further efforts to either epimerize C11 or liberate the hydroxyl group from the benzyl ether in 29 proved abortive. In summary, the novel synthetic strategy for the dolabellane skeleton was realized, which allowed the synthesis of clavulactone analogues 26 and 27 in a concise and efficient manner. This strategy features the first application of Grob fragmentation in dolabellane skeleton synthesis. Other salient transformations include a diastereoselective Mukaiyama aldol reaction, an intramolecular nucleophilic addition reaction, and a highly efficient Mukaiyama−Michael addition reaction. This work, along with our previous research work,4k demonstrated enone 2 to be a versatile precursor to dolabellanes and related analogues. The newly validated synthetic strategy can readily lend itself to the total synthesis of relevant natural products.

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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.9b01678. Experimental procedures and spectroscopic data for new compounds (PDF)

a

Reagents and conditions: (a) LiClO4, DCM, r.t., then TBAF, THF, r.t., 98%; (b) LiBH4, Et2O, reflux, 77%; (c) TEMPO, PhI(OAc)2, DCM, r.t., 35% for 25, 54% for 24; (d) BCl3, DCM, −78 °C, then Dess−Martin periodinane, DCM, r.t., 74%; (e) BCl3, DCM, −78 °C, then Dess-Martin periodinane, DCM, r.t., 72%.

Accession Codes

CCDC 1899798 and 1900779 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.

21 (E/Z = 3/1) to 2 was realized under the action of LiClO4 and after desilylation with TBAF afforded 22 with a cis-fused 5/11 bicyclic framework in an excellent yield of 98%.17 The α face of the C12C11 double bond in 2 appeared to be more sterically hindered than the β face, rendering the conjugate addition to selectively take place from the β face. The formation of the C11 stereocenter via protonation of the intermediate enolate probably was dominated by the preformed stereochemistry at C12. Efforts aiming to invert the configuration of C11 were futile. The reduction of 22 with LiBH4 garnered diol 23 in 77% yield. The β face of the ketone group in 22 is probably sterically shielded by the 11-membered carbocycle and appears more sterically hindered than the α face. Accordingly, the hydride was selectively delivered from the α face of C10 in 22 to give 23. Oxidative lactonization of

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AUTHOR INFORMATION

Corresponding Author

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

Bingfeng Sun: 0000-0001-5804-0951 Notes

The authors declare no competing financial interest. 5084

DOI: 10.1021/acs.orglett.9b01678 Org. Lett. 2019, 21, 5082−5085

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Organic Letters

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(11) For a review on olefin metathesis and catalysts, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b) Grubbs, R. H.; Trnka, T. M. Acc. Chem. Res. 2001, 34, 18. (c) Grubbs, R. H.; Vougioukalakis, G. C. Chem. Rev. 2010, 110, 1746. (12) Holton, R. A.; Krafft, M.E. J. Org. Chem. 1984, 49, 3669. (13) See the Supporting Information for a detailed screening of reaction conditions. (14) For the diastereoselective Mukaiyama aldol reaction, see: (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322. (b) Mahrwald, R. Chem. Rev. 1999, 99, 1095. (15) Compound 19b was transformed to the crystalline 5/6/7 bicyclic diol whose X-ray structure was obtained, and thereby its stereochemistry was confirmed. The 1H NMR spectrum of 19a demonstrated a very similar pattern as that of 19b in the region of newly formed stereocenters. (16) (a) Molander, G. A.; Huerou, Y. L.; Brown, G. A. J. Org. Chem. 2001, 66, 4511. (b) Mulzer, J.; Prantz, K. Chem. Rev. 2010, 110, 3741. (c) Mulzer, J.; Prantz, K. Angew. Chem., Int. Ed. 2009, 48, 5030. (d) Li, Y.; Shi, J.-R.; Xu, H.; Qiu, D.-C.; He, J. J. Am. Chem. Soc. 2017, 139, 623. (e) Ding, H.-F.; Ma, B.-J.; Zhao, Y.-F.; He, C. Angew. Chem., Int. Ed. 2018, 57, 15567. (17) (a) Fukuzumi, S.; Otera, J.; Sato, T.; Wakahara, Y.; Nozaki, H. J. Am. Chem. Soc. 1991, 113, 4028. (b) Otera, J.; Fujita, Y.; Sakuta, N.; Fujita, M.; Fukuzumi, S. J. Org. Chem. 1996, 61, 2951. (c) Pihko, P. M.; Kemppainen, E. K.; Sahoo, G.; Valkonen, A. Org. Lett. 2012, 14, 1086. (d) MacMillan, D. W. C.; Brown, S. P.; Goodwin, N. C. J. Am. Chem. Soc. 2003, 125, 1192.

ACKNOWLEDGMENTS We acknowledge the financial support from the National Natural Science Foundation of China (21672243, 21472210) and the Youth Innovation Promotion Association CAS (2012202). Ming Wan (2009−2011, Northwest Normal University, Lanzhou, China) and Dr. Yifan Shan (2012− 2014, East China Normal University, Shanghai, China) contributed to this project in early stages.

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DOI: 10.1021/acs.orglett.9b01678 Org. Lett. 2019, 21, 5082−5085