Letter Cite This: Org. Lett. 2018, 20, 5177−5180
pubs.acs.org/OrgLett
Synthesis of Complex Stereoheptads en Route to Daphnane Diterpene Orthoesters Long V. Nguyen† and Aaron B. Beeler* Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
Org. Lett. 2018.20:5177-5180. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/08/18. For personal use only.
S Supporting Information *
ABSTRACT: Tricyclic cores of the daphnane diterpene orthoesters (DDOs) are synthesized in 10 steps from readily available materials. Key to their assembly is the development of a stereocontrolled p-quinol functionalization sequence which enables rapid access to DDO C-ring stereopolyads from simple precursors. Problems encountered in stereo- and regioselectivity are highlighted and solved by exact changes in choreography, although it is shown that the undesired stereochemical outcomes also proceed with high selectivity.
T
the tricyclic scaffold in the presence of equally complex, neighboring systems. As shown in Figure 2a, structures such as synaptolepis factor K7 (1) can be simplified by first excising the majority of oxygen
he daphnane diterpene orthoesters (DDOs) are a large group of plant secondary metabolites known to possess a broad spectrum of powerful biological activities.1 Chief among these complex phytochemicals are synaptolepis factor K7 (1), kirkinine B (2), and kirkinine (3) (Figure 1) which are, to the
Figure 1. Neurotrophic daphnane diterpene orthoesters. (a) EC50 = neuronal survival rate that is 50% of nerve growth factor (NGF, 10 ng/ mL).
best of our knowledge, the most potent nonpeptidic neurotrophic agents known.2,3 We have been engaged in the concise and practical chemical syntheses of DDOs in order to explore their neurotrophic properties and report herein a 10-step synthesis of a complex DDO tricycle possessing seven contiguous stereocenters (of which six are conserved in nearly all DDOs) from readily available starting materials. The route is scalable and fully stereocontrolled and necessitated the development of an exact p-quinol functionalization choreography to combat inherent issues of selectivity in establishing the DDO skeleton. Historically, DDOs represent a considerable challenge to de novo chemical synthesis, having succumbed to laboratory preparation by two academic groups with an average efficiency of 42 linear steps.4 In planning our approach toward these molecules, we identified three key challenges: (1) the concise assembly of the 5−7−6 all-carbon tricyclic core; (2) the introduction and management of overall increasing oxidation state; and (3) the selective functionalization of remote sectors of © 2018 American Chemical Society
Figure 2. (a) Simplification of 1 to stereoheptad 4 provides a tractable target. (b) Challenging C-ring stereopolyad can be derived from an achiral benzene nucleus.
appendages in the B-ring stereotetrad, all of which can be later reconstituted via iterative oxidation transforms.5 Following the precedent of previous synthetic efforts, the A-ring cyclopentenone should be elaborated last following orthoester formation.4 This leads to the tricyclic stereoheptad 4, of which the concise assembly serves as an ideal point of reconnaissance en route to natural DDOs. We reasoned the stereochemically rich cyclohexane ring of 4 could arise from an achiral benzene nucleus6 since alternating polarity analysis suggests a p-quinol is Received: July 6, 2018 Published: August 17, 2018 5177
DOI: 10.1021/acs.orglett.8b02124 Org. Lett. 2018, 20, 5177−5180
Letter
Organic Letters
tertiary alcohol 12 in 60% overall yield as a single diastereomer. This straightforward three-step sequence establishes key oxidation states at C3,4 and relative stereochemistry at C4,10 (Scheme 2). The seven-membered B-ring was quickly established by ringclosing metathesis which proceeded without incident when Grubbs second-generation catalyst (10 mol %) was added in several portions over the course of 2 h to a refluxing solution of diene 12 in toluene. Following a solvent switch to dimethylacetamide (DMA), addition of chlorotrimethylsilane (TMSCl) and imidazole effected C4 tert-alcohol protection uneventfully. Subsequently, direct addition of LiOH·H2O11 chemoselectively cleaves the tert-butyldimethylsilyl (TBS) protecting group and phenol 13 is isolated in essentially quantitative yield. This sequence could be executed in a single flask, although on larger scales (30−35 g batches) a two-pot procedure was found to be more practical. Following the precedent first established by Li and coworkers,6b oxidative dearomatization of phenol 13 was found to proceed with high stereoselectivity when singlet oxygen was employed. Here, the C4 trimethylsiloxy group serves as a critical stereocontrolling element in blocking the trajectory of singlet oxygen from the top face of 13. Irradiation of an aerated solution of 13 in the presence of catalytic rose bengal in chloroform− methanol (1:1) at −40 °C followed by in situ reduction with triphenylphosphine afforded quinol 14 in 59% yield (17 g scale). Interestingly, methanol was empirically found to be an essential cosolvent in this transformation; no reaction was observed in the absence of the alcohol. The stereochemical outcome of the dearomatization event as well as the relative configuration of the resulting stereotriad of 14 was confirmed by X-ray diffraction. The proposed quinol functionalization involves first stereocontrolled installation of the angular C11 methyl group. We planned to use the native C9 tertiary alcohol of 14 as a directing group for an alkoxide-directed 1,4-addition of methyl Grignard;12 however, despite convincing precedent for such a transformation in target-oriented synthesis,6b,13 compounds of type 14 as well as early model systems failed to deliver any trace of the anticipated product. This problem was solved after finding that the success of this transformation is predicated on the Schlenk equilibrium of the Grignard reagent in solution. We
an ideal synthetic equivalent for such a cyclohexane synthon (Figure 2b).7 Such p-quinols can be generated in a single step from p-alkyl phenols and simplifies the problem of rapidly accessing a requisite 5−7−6 tricycle. Our synthesis elaborates upon the union of two simple building blocks which are each accessed in three steps from commercial material. Epoxy ketal 7 (Scheme 1) is prepared in Scheme 1. Assembly of Building Blocks 7 and 10
three steps from cyclopentanone by halogenative ketalization, elimination, and epoxidation. Styrene 10 is prepared in three steps from commercially available 3-hydroxybenzaldehyde by nuclear bromination, aryl silyl ether formation, and Wittig olefination. Both 7 and 10 are known materials,8,9 though the preparations developed here proved optimal in terms of practicality and throughput (no chromatography, 150−500 mmol scale). The stereoselective arylation−methallylation of the nonsymmetric epoxycyclopentane 7 begins with treatment of styrene 10 with magnesium turnings at high concentrations at room temperature to afford Grignard reagent 11 which, following dilution with THF, is exposed to 7 in the presence of copper(I) iodide (5 mol %, 0 °C). The resulting secondary alcohol (isolated in 81% yield following flash chromatography) is oxidized employing 2-iodoxybenzoic acid (IBX, 2.0 equiv) in hot ethyl acetate10 to give an intermediate ketone which is reacted with freshly prepared β-methallylmagnesium chloride (3.0 equiv, THF, −78 °C), delivering decagram quantities of Scheme 2. Synthesis of Stereoheptad 17
5178
DOI: 10.1021/acs.orglett.8b02124 Org. Lett. 2018, 20, 5177−5180
Letter
Organic Letters found that inclusion of 1,4-dioxane (3.0−15.0 equiv)14 as a cosolvent effectively drives the Schlenk equilibrium of methyl Grignard (3.0 equiv) to the dialkylmagnesium reagent which is intercepted by a quinol alkoxide to generate an intermediate “ate” complex. Intramolecular delivery of the methyl nucleophile occurs from the same face of the alkoxide to afford γhydroxyenone 15 in 65% yield (>20:1 dr, 13.4 g scale). This simple procedure obviates generation of a lithium alkoxide prior to addition of the Grignard reagent and employs a commonplace solvent in place of less desirable additives like hexamethylphosphoramide (HMPA) or crown ethers. Furthermore, to the best of our knowledge, the use of 1,4-dioxane to modulate the solution reactivity of a Grignard reagent in a substrate-directed nucleophilic addition is without precedent. Lastly, the stereochemical outcome of this directed addition of MeMgCl was unambiguously confirmed by X-ray diffraction of 15. With ample quantities of 15 in hand, we initially identified a selective three-step protocol involving (1) 1,2-addition of isopropenylmagnesium bromide to the C13 ketone, (2) regioand stereocontrolled tert-hydroxyl directed epoxidation, and (3) titanocene-mediated radical epoxide opening15 to afford a complex stereoheptad 17 possessing a general constitution conserved in all DDOs. This result was initially satisfying as five contiguous stereocenters had been established from a benzene nucleus in five steps, providing good evidence for the utility of our proposed quinol functionalization in DDO synthesis. However, 2D-NMR studies intimated the three newly generated stereogenic centers at C8,13,14 were opposite the desired configuration. The relative configuration of the penultimate intermediate in this sequence, vinyl epoxide 16, was additionally established by X-ray diffraction, confirming our spectral assignment. Although considerable efforts were invested in correcting this observed outcome, it became evident intrinsic substrate control in the native DDO scaffold necessitated a change in terminal choreography if the correct C-ring stereochemistry was to be secured. The most obvious correction, since 1,2-addition and epoxidation proceeds with high contraselectivity, is carrying out an epoxidation prior to introduction of the C13 isopropenyl moiety. Although hydroxyl-directed nucleophilic epoxidations of γ-hydroxyenones and p-quinols is well precedented,16 an initial survey of conditions known to effect this transformation was discouraging since 1,6-addition of a range of nucleophilic oxidants was dominant. Eventually, it was discovered that an iminium-activation process17 was uniquely capable of enabling a directed 1,4-addition. In the event, treatment of 15 with pyrrolidine (1.0 equiv) followed by aqueous hydrogen peroxide (1.3 equiv) in methanol at room temperature afforded epoxy ketone 18 with high selectivity on gram scale (59% yield, > 10:1 rr, > 20:1 dr). Stereoselective addition of an isopropenyl nucleophile to 18, however, was not straightforward since it is prone to decomposition in the presence of Grignard reagents and early reconnaissance showed substrate-controlled addition from the convex β-face of 18 is exclusive (Figure 3). It was surmised that a reagent-based approach in establishing this challenging stereogenic center was unlikely to succeed in this context, though we reasoned if a transform equating the opposite polarity synthon could be identified, the facial approach of an external oxidant should proceed from the same trajectory observed with exogenous nucleophiles (Figure 3). Eventually, a simple solution was devised beginning with Wittig olefination of 18 using the phosphonium ylide generated
Figure 3. Our conceptual model to address the challenging C13 stereocenter of the DDO C-ring.
from isopropyltriphenylphosphonium bromide (5.0 equiv) and potassium hydride (5.0 equiv) in diethyl ether to deliver the tetrasubstituted alkene 19 in ∼80% yield. The success and efficiency of this olefination is notable since few nonstabilized Wittig reagents are capable of generating fully substituted alkenes from ketones.18 Additionally, the C9 tertiary alcohol and potentially labile epoxide functionality were left unscathed under these specific conditions. Irradiation of 19 with visible light in the presence of methylene blue and dioxygen (1 atm) at 0 °C followed by in situ reduction delivered vinyl epoxide 20 as a single diastereomer in 81−90% yield via a Schenck−ene reaction,19 the relative stereochemistry was confirmed to arise via addition of singlet oxygen favoring convex face, as we had hypothesized (Scheme 3). Notably, all three oxygen appendages of the C-ring of 20 were installed with high stereocontrol employing either neutral or reduced diatomic oxygen. Scheme 3. Synthesis of Stereoheptad 20
In summary, we have demonstrated a synthesis of the DDO tricyclic core possessing a complex stereoheptad throughout the 5−7−6 all-carbon skeleton. Notably, the pathway established thus far is short, fully stereocontrolled, and gives good support to a general solution of the challenging DDO C-ring via the intermediacy of an achiral benzene nucleus. Furthermore, six of the generated stereocenters in 20 are conserved in nearly all known DDOs. The overall oxidation state of compound 20 is well positioned for elaboration to the natural products themselves which, despite tremendous promise as effective tools for the study of biology and medicine, still remain elusive to the chemical science community. Efforts to execute these blueprints in the total synthesis of DDOs as well as unnatural analogues is ongoing in this laboratory and will be reported in due course. 5179
DOI: 10.1021/acs.orglett.8b02124 Org. Lett. 2018, 20, 5177−5180
Letter
Organic Letters
■
122, 1540. (g) Drew, M. G. B.; Harwood, L. M.; Macías-Sánchez, A. J.; Scott, R.; Thomas, R. M.; Uguen, D. Angew. Chem., Int. Ed. 2001, 40, 2311. (h) Chairgulprasert, V.; Drew, M. G.; Jahans, A.; Harwood, L. M. ARKIVOC 2002, 9, 37. (i) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. (j) Rigby, J. H.; Fleming, M. Tetrahedron Lett. 2002, 43, 8643. (k) Rigby, J. H.; Chouraqui, G. Synlett 2005, 16, 2501. (l) Winkler, J. D.; Lee, E. C. Y.; Nevels, L. I. Org. Lett. 2005, 7, 1489. (m) Page, P. C. B.; Hayman, C. M.; McFarland, H. L.; Willock, D. J.; Galea, N. M. Synlett 2002, 2002, 583. (n) Sekine, A.; Kumagai, N.; Uotsu, K.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2000, 41, 509. (o) Singh, V.; Samanta, B. ARKIVOC 2003, 3, 77. (p) Jackson, S. R.; Johnson, M. G.; Mikami, M.; Shiokawa, S.; Carreira, E. M. Angew. Chem., Int. Ed. 2001, 40, 2694. (q) Ritter, T.; Zarotti, P.; Carreira, E. M. Org. Lett. 2004, 6, 4371. (r) Murai, K.; Katoh, S.-I.; Urabe, D.; Inoue, M. Chem. Sci. 2013, 4, 2364. (s) Urabe, D. Chem. Pharm. Bull. 2015, 63, 565. (t) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563. (u) Marson, C. M.; Pink, J. H.; Hall, D.; Hursthouse, M. B.; Malik, A.; Smith, C. J. Org. Chem. 2003, 68, 792. (v) Stewart, C.; McDonald, R.; West, F. G. Org. Lett. 2011, 13, 720. (w) Catino, A. J.; Sherlock, A.; Shieh, P.; Wzorek, J. S.; Evans, D. A. Org. Lett. 2013, 15, 3330. (x) Hassan, A. H. E.; Lee, J. K.; Pae, A. N.; Min, S.J.; Cho, Y. S. Org. Lett. 2015, 17, 2672. (y) Li, Y.; Wei, M.; Dai, M. Tetrahedron 2017, 73, 4172. (5) B-ring oxidations have been employed in all successful DDO total syntheses, vide infra. For related examples, see also: (a) Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L. J. Am. Chem. Soc. 2004, 126, 16300. (b) Jørgensen, L.; McKerrall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. Science 2014, 341, 878. (c) Kawamura, S.; Chu, H.; Felding, J.; Baran, P. S. Nature 2016, 532, 90. (6) (a) Marson, C. M.; Pink, J. H.; Hall, D.; Hursthouse, M. B.; Malik, A.; Smith, C. J. Org. Chem. 2003, 68, 792. (b) Tong, G.; Liu, Z.; Li, P. Org. Lett. 2014, 16, 2288. (7) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104, 1383. (8) (a) Vankar, Y. D.; Chaudhuri, N. C.; Rao, C. T. Tetrahedron Lett. 1987, 28, 551. (b) Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 11551. (c) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435. (9) Lim, H. N.; Dong, G. Angew. Chem., Int. Ed. 2015, 54, 15294. (10) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001. (11) Ankala, S. V.; Fenteany, G. Tetrahedron Lett. 2002, 43, 4729. (12) (a) Solomon, M.; Jamison, W.; McCormick, M.; Liotta, D.; Cherry, D.; Mills, J.; Shah, R.; Rogers, J.; Maryanoff, C.; Paragamian, V. J. Am. Chem. Soc. 1989, 110, 3702. (b) Swiss, K.; Maryanoff, C.; Liotta, D. J. Am. Chem. Soc. 1990, 112, 9393. (c) Swiss, K.; Hinkley, W.; Maryanoff, C.; Liotta, D. Synthesis 1992, 1992, 127. (13) (13) White, J. D.; Shin, H.; Kim, T.-S.; Cutshall, N. S. J. Am. Chem. Soc. 1997, 119, 2404. (14) (a) Cope, A. C. J. Am. Chem. Soc. 1935, 57, 2238. (b) Langer, J.; Krieck, S.; Fischer, R.; Görls, H.; Walther, D.; Westerhausen, M. Organometallics 2009, 28, 5814. (15) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986. (16) For recent examples, see: (a) Carreño, M. C.; Merino, E.; Ribagorda, M.; Somoza, A.; Urbano, A. Chem. - Eur. J. 2007, 13, 1064. (b) Wenderski, T. A.; Huang, S.; Pettus, T. R. R. J. Org. Chem. 2009, 74, 4104. (c) Hammill, J. T.; Contreras-Garcia, J.; Virshup, A. M.; Beratan, D. N.; Yang, W.; Wipf, P. Tetrahedron 2010, 66, 5852. (17) (a) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964. (b) Lee, S.; MacMillan, D. W. C. Tetrahedron 2006, 62, 11413. (c) Wang, X.; List, B. Angew. Chem., Int. Ed. 2008, 47, 1119. (d) Wang, X.; Reisinger, C. R.; List, B. J. Am. Chem. Soc. 2008, 130, 6070. (18) (18) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698. (19) For a recent review on the use of singlet-oxygen in natural product and drug synthesis, see: Ghogare, A. A.; Greer, A. Chem. Rev. 2016, 116, 9994.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02124. Experimental procedures and characterization for all new compounds described herein (PDF) Accession Codes
CCDC 1851804−1851806 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.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Aaron B. Beeler: 0000-0002-2447-0651 Present Address †
(L.V.N.) Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Financial support from Boston University is gratefully acknowledged. We thank Dr. Norman Lee (Boston University) for obtaining high-resolution mass spectrometry data and Dr. Jeffrey Bacon (Boston University) for assistance in obtaining Xray crystallographic data and analyses. NMR (CHE-0619339) and MS (CHE-0443618) facilities at Boston University are supported by the NSF.
■
REFERENCES
(1) (a) Liao, S.-G.; Chen, H.-D.; Yue, J.-M. Chem. Rev. 2009, 109, 1092. (b) Evans, F. J.; Scoper, C. J. Lloydia 1978, 41, 193. (c) Borris, R. P.; Blasko, G.; Cordell, G. A. J. Ethnopharmacol. 1988, 24, 41. (d) He, W.; Cik, M.; Appendino, G.; van Puyvelde, L.; Leyson, J. E.; De Kimpe, N. Mini-Rev. Med. Chem. 2002, 2, 185. (e) Stanoeva, E.; He, W.; De Kimpe, N. Bioorg. Med. Chem. 2005, 13, 17. (2) (a) He, W.; Cik, M.; Lesage, A.; Van der Linden, I.; De Kimpe, N.; Appendino, G.; Bracke, J.; Mathenge, S. G.; Mudida, F. P.; Leysen, J. E.; Van Puyvelde, L. J. Nat. Prod. 2000, 63, 1185. (b) He, W.; Cik, M.; Van Puyvelde, L.; Van Dun, J.; Appendino, G.; Lesage, A.; Van der Lindin, I.; Leysen, J. E.; Wouters, W.; Mathenge, S. G.; Mudida, F. P.; De Kimpe, N. Bioorg. Med. Chem. 2002, 10, 3245. (c) Van Kolen, K.; Bruinzeel, W.; He, W.; De Kimpe, N.; Van Puyvelde, L.; Cik, M.; Pullan, S. Eur. J. Pharmacol. 2013, 701, 73. (3) For a review of neurotrophic natural products, see: Xu, J.; Lacoske, M. H.; Theodorakis, E. A. Angew. Chem., Int. Ed. 2014, 53, 956. (4) (a) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976. (b) Wender, P. A.; Buschmann, N.; Cardin, N. B.; Jones, L. R.; Kan, C.; Kee, J.-M.; Kowalski, J. A.; Longcore, K. E. Nat. Chem. 2011, 3, 615. (c) Hashimoto, S.; Katoh, S-i.; Kato, T.; Urabe, D.; Inoue, M. J. Am. Chem. Soc. 2017, 139, 16420. For select recent studies toward DDOs and related natural products, see: (d) Wender, P. A.; D’Angelo, N.; Elitzin, V. I.; Ernst, M.; Jackson-Ugueto, E. E.; Kowalski, J. A.; McKendry, S.; Rehfeuter, M.; Sun, R.; Voigtlaender, D. Org. Lett. 2007, 9, 1829. (e) Boudreault, P.-L.; Mattler, J. K.; Wender, P. A. Tetrahedron Lett. 2015, 56, 3423. (f) Paquette, L. A.; Zhao, Z.; Gallou, F.; Liu, J. J. Am. Chem. Soc. 2000, 5180
DOI: 10.1021/acs.orglett.8b02124 Org. Lett. 2018, 20, 5177−5180
