Letter Cite This: Org. Lett. 2017, 19, 6036-6039
pubs.acs.org/OrgLett
Synthesis of the ABC Substructure of Brevenal by Sequential exo‑Mode Oxacyclizations of Acyclic Polyene Precursors Jessica A. Hurtak and Frank E. McDonald* Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States S Supporting Information *
ABSTRACT: Exploratory studies on the sequential exo-mode oxacyclizations of acyclic polyene precursors have provided a substantial substructure of brevenal, including the fused tricyclic polyether with stereochemical patterns consistent with the AB and BC ring fusions. The synthesis of acyclic substrates featured two variations of Cr(II)/Ni(II) couplings for preparing 1,1-disubstituted allylic alcohols. A sequence of iodine-promoted cycloetherification, base-promoted intramolecular conjugate addition, and mercury-promoted cycloetherification produced the tricyclic substructure.
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this work, we describe sequential exo-mode oxacyclizations as a unique strategy for fused polycyclic ether synthesis. The origin of this idea involved a cascade of electrophilepromoted oxacyclizations from the proposed triene triol 2, aiming for diastereoselective formation of each new ring with stereoinduction from an allylic oxygen substituent to provide tricyclic polyether 3 (Figure 2).8 This synthetic scheme was
used polycyclic ether natural products are best known as potent marine neurotoxins, including brevetoxins, ciguatoxins, and maitotoxin. These toxins feature a regular framework of trans-fused cyclic ethers, mostly six- and seven-membered rings, with eight- and nine-membered rings in some of the larger and more toxic natural products.1 Brevenal, 1 (Figure 1), a
Figure 1. Structure of brevenal, highlighting the substructure described in this communication.
structurally simpler pentacyclic member of this family, is a naturally occurring nontoxic antagonist to the neurotoxic activity of the brevetoxins and ciguatoxins.1,2 As brevenal exhibits potential therapeutic activity for a variety of diseases associated with ion channel activation, including cystic fibrosis,3 an efficient and relatively short chemical synthesis of brevenal and various analogues is an exciting prospect. Sasaki reported the first synthesis of brevenal in 2006, which corrected the stereochemical assignment of the E ring tertiary alcohol. The synthesis was refined through three generations, ultimately providing gram-scale quantities of brevenal. 4 Yamamoto and Rainier subsequently described additional contributions by complementary approaches.5,6 However, these syntheses featured strategies involving sequential annulation of rings, requiring both carbon−carbon and carbon−oxygen bond-forming reactions. Our laboratory has a longstanding interest in strategies that form multiple cyclic ethers from polycyclization of an acyclic carbon chain. We previously focused on endo-regioselective polyepoxide cyclizations but uncovered consequential limitations with regard to substituent patterns at the ring fusions.7 In © 2017 American Chemical Society
Figure 2. Proposed sequence of exo-mode oxacyclizations of triene triol 2 to form the ABC substructure of brevenal.
conceived with the expectation that the six-membered A ring would form faster than the seven-membered B ring, and that the acetonide protective group might slow but not prevent oxacyclization to form the six-membered C ring.9 Model studies showed that stage a offered a stereoselective 6-exo-oxacyclization approach to the A ring.8 However, another model study directed at stage b was complicated by an unexpected 8-endo-mode pathway,10 suggesting that the proposed 7-exo electrophilepromoted oxacyclization of 4 to form the B ring could be Received: August 17, 2017 Published: October 30, 2017 6036
DOI: 10.1021/acs.orglett.7b02538 Org. Lett. 2017, 19, 6036−6039
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Organic Letters problematic. An alternative strategy to address stage b via intramolecular conjugate addition of dienone 5 to bicyclic product 6 was designed to electronically block the 8-endooxacyclization pathway.11,12 This approach would require stereoselective reduction of the ketone 6 to the allylic alcohol 7, prior to stage c to close the C ring of tricyclic product 3. We were confident that the residual “X” and “Y” groups could be replaced with “H” in a final step.13 Synthesis of the acyclic triene triol 2 began by linking the known aldehyde 814 and terminal alkyne 9,15 utilizing a Cr(II)/ Ni(II) reductive coupling developed by Takai (Scheme 1),16
Scheme 2. Sequential Stereoselective Oxacyclizations To Form the AB Rings from the Dienoate Diol 14
Scheme 1. Synthesis of Acyclic Triene Triol 2
substituted products 24 and 25.25 Notably, deiodination of the major diastereomer 22 required higher temperature and proceeded less cleanly than for the minor diastereomer 23. Structural assignments of the respective diastereomers 24 and 25 were made by comparing cross-ring NOE effects (Figure 3). In addition, the trans-ring fusion of the AB rings of the major diastereomer was unambiguously confirmed by an X-ray crystal structure of the primary alcohol derivative 26.26
Figure 3. Crystal structure of trans-fused polycyclic product 26; crossring NOE correlations of trans- and cis-fused polycyclic ethers 24 and 25.
A similar sequential oxacyclization process was applied to the triene triol substrate 2 (Scheme 3) to produce compounds 27
which gave superior results compared to Nozaki−Hiyama−Kishi (NHK) coupling with the corresponding vinylic halide.17 DessMartin periodinane oxidation of the diastereomeric mixture of allylic alcohols provided the enone 10, which underwent highly stereoselective ketone reduction promoted by chiral oxazaborolidine, favoring the (S)-alcohol 11.18 Attempts to selectively oxidize the primary alcohol of diol 12 resulted instead in the lactone 13, with PhI(OAc)2 and catalytic TEMPO providing the best yields.19 DIBAL-H reduction of lactone 13 concurrently unmasked the primary alcohol and converted the lactone to a cyclic hemiacetal, which underwent Wittig olefination to produce diene diol 14. This compound was more easily purified after silyl ether protection of both primary and secondary alcohols to isolate the (Z)-enoate 15. NHK coupling of the derived aldehyde 17 with vinylic iodide 1820 proceeded in modest yield and only worked on small scale, limiting the availability of triene triol 2.21 For this reason, formation of the A and B rings was explored with diene diol 14. Iodocyclization (stage a) proceeded with good diastereoselectivity (85:15 dr), favoring pyran 20 (Scheme 2).22 As diastereomers 20 and 21 arising from iodocyclization were inseparable at this stage, we carried the mixture forward through the conjugate addition step (stage b), with each diastereomer giving the corresponding polycyclic products 22 and 23, which were separated at this stage.23,24 Each individual diastereomer was deiodinated into the corresponding methyl-
Scheme 3. Sequential Oxacyclizations To Form the AB transFused Rings from Triene Triol 2
and 28 (corresponding to the generic structures 5 and 6; see Figure 2). Iodocyclization of 2 followed by chemoselective oxidation of the doubly allylic alcohol produced the iodomethylsubstituted dienone 27,27 which underwent intramolecular conjugate addition to form the trans-fused bicyclic enone 28 with high diastereoselectivity. Given the difficulties in the NHK reaction producing substrate 2, we augmented our supply of compound 28 from aldehyde 22 6037
DOI: 10.1021/acs.orglett.7b02538 Org. Lett. 2017, 19, 6036−6039
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Organic Letters
sterically blocked than in compound 22, which underwent deiodination to 24 (see Scheme 2). Perhaps the diminished reaction rate of trans-fused iodomethyl 22 relative to the cis-fused diastereomer 23 should have warned us that late-stage deiodination might be troublesome. Nonetheless, this route demonstrates viable methods for acyclic substrate synthesis, establishes conditions for diastereo- and regioselective construction of three of the five rings of brevenal, and will provide sufficient background for exploring and inventing catalytic methods for these oxacyclizations.
(Scheme 4). In this case, the NHK coupling with vinylic iodide 18 proceeded reproducibly and with better yield, providing Scheme 4. Alternative Synthesis of Enone 28 via Bicyclic Aldehyde 29 and Stereoselective Synthesis of Allylic Alcohol 30
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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.7b02538. Experimental details and characterization data (PDF) NMR spectra of selected compounds (PDF) X-ray data for 26 (CIF) X-ray data for 36 (CIF)
bicyclic enone 28 after oxidation. Upon exploring conditions for the stereoselective reduction of enone 28, we observed that the Luche reduction proceeded with high diastereoselectivity favoring the S-isomer 30 (97:3 dr at −78 °C; 83:17 dr at −40 °C).28 The acetonide-protected oxygen of 30 was not sufficiently nucleophilic to form the C ring by electrophilic cyclization methods.29 Fortunately, the acetonide protective group was rapidly and relatively cleanly hydrolyzed upon brief treatment with trifluoroacetic acid/water to afford the alkenyl triol substrate 31, for exploring stage c, namely, forming the C ring of brevenal (Scheme 5). Despite our earlier successes with the iodocycliza-
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Frank E. McDonald: 0000-0002-6612-7106 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This contribution is dedicated to Prof. Paul A. Wender on the occasion of his 70th birthday. This material is based upon work supported by the National Science Foundation under CHE1362249 and using NMR instrumentation supported by Grant CHE-1531620. Dr. John Bacsa provided crystallographic analysis of compounds 26 and 36 in the Emory X-ray Crystallography Center. Prof. Simon Blakey (Emory University) provided the use of a glovebox for the Cr(II)-promoted couplings. Dr. Kristen L. Stoltz and Mr. Xiang Liu (Emory University) assisted in early stages of this project.
Scheme 5. Preparation of Tricyclic Polyethers 32 and 33 from Alkenyl Triol 31
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REFERENCES
(1) (a) Bidard, J. N.; Vijverberg, H. P. M.; Frelin, C. J. Biol. Chem. 1984, 259, 8353. (b) Poli, M. Mol. Pharmacol. 1986, 30, 129. (c) Lombet, A.; Bidard, J. N.; Lazdunski, M. FEBS Lett. 1987, 219, 355. (d) Trainer, V. L.; Thomsen, W. J.; Catterall, W. A.; Baden, D. G. Mol. Pharmacol. 1991, 40, 988. (e) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897. (f) Trainer, V. L.; Baden, D. G.; Catterall, W. A. J. Biol. Chem. 1994, 269, 19904. (g) Gawley, R. E.; Rein, K. S.; Jeglitsch, G.; Adams, D. J.; Theodorakis, E. A.; Tiebes, J.; Nicolaou, K. C.; Baden, D. G. Chem. Biol. 1995, 2, 533. (h) Yasumoto, T. Chem. Rec. 2001, 1, 228. (i) Yamaoka, K.; Inoue, M.; Miyahara, H.; Miyazaki, K.; Hirama, M. Br. J. Pharmacol. 2004, 142, 879. (2) Bourdelais, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M.; Baden, D. G. J. Nat. Prod. 2005, 68, 2. (3) Abraham, W. M.; Bourdelais, A. J.; Sabater, J. R.; Ahmed, A.; Lee, T. A.; Serebriakov, I.; Baden, D. G. Am. J. Respir. Crit. Care Med. 2005, 171, 26. (4) (a) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 128, 16989. (b) Ebine, M.; Fuwa, H.; Sasaki, M. Org. Lett. 2008, 10, 2275. (c) Ebine, M.; Fuwa, H.; Sasaki, M. Chem. Eur. J. 2011, 17, 13754.
tions of diene diol 14 and triene triol 2, the iodocyclization of 31 failed, giving little reaction other than decomposition over extended reaction times. The 1H NMR coupling constants for 31 suggested that the conformation of the oxepane ring placed the C15-alcohol and C16-substituent in pseudoaxial orientations, inhibiting attempts at cyclization.30 Ultimately, we found that mercuric trifluoroacetate31 promoted the oxacyclization of 31 to the tricyclic product 32. Reductive demercuration32 provided tricyclic polyether 33 with the desired trans-syn-trans pattern, confirmed by NOE effects across the B and C rings. Although the reasons for success of the Hg(II)-promoted procedure in lieu of iodocyclization are unclear, an electrostatic interaction between the Lewis acidic mercuric ion and a hydroxyl group may bring the reactive groups into closer proximity. Unfortunately, we have not successfully deiodinated compound 33 under a variety of conditions.33 NOESY analysis of compound 33 indicates that the iodomethyl group may be more 6038
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(25) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188. (26) Another approach to diene diol substrate required basic methanolysis of the diacetate diene 34, which unexpectedly triggered intramolecular conjugate addition. The resulting oxepane 35 was inert to iodocyclization conditions with I2/NaHCO3 or IDCP. Diastereoselective epoxidation of 35 followed by acid-catalyzed regioselective oxacyclization provided cis-fused 36. Details on the preparations of 34− 36 and characterization of 36 are described in the Supporting Information.
(5) (a) Takamura, H.; Kikuchi, S.; Nakamura, Y.; Yamagami, Y.; Kishi, T.; Kadota, I.; Yamamoto, Y. Org. Lett. 2009, 11, 2531. (b) Takamura, H.; Yamagami, Y.; Kishi, T.; Kikuchi, S.; Nakamura, Y.; Kadota, I.; Yamamoto, Y. Tetrahedron 2010, 66, 5329. (6) Zhang, Y.; Rohanna, J.; Zhou, J.; Iyer, K.; Rainier, J. D. J. Am. Chem. Soc. 2011, 133, 3208. (7) McDonald, F. E.; Tong, R.; Valentine, J. C.; Bravo, F. Pure Appl. Chem. 2007, 79, 281. (8) McDonald, F. E.; Ishida, K.; Hurtak, J. A. Tetrahedron 2013, 69, 7746. (9) (a) Zhang, H.; Mootoo, D. R. J. Org. Chem. 1995, 60, 8134. (b) Dabideen, D.; Ruan, Z. M.; Mootoo, D. R. Tetrahedron 2002, 58, 2077. (10) Stoltz, K. L.; Roig Alba, A.-N.; McDonald, F. E.; Wieliczko, M. B.; Bacsa, J. Heterocycles 2014, 88, 1519. (11) Dr. Kristen L. Stoltz proposed the intramolecular conjugate addition approach to the B ring and conducted preliminary experiments supporting the viability of this approach. For further observations on intramolecular conjugate additions to form oxepanes, see: Stoltz, K. L. Ph.D. Dissertation, Emory University, 2014. (12) For examples of seven-membered ring ether formation by intramolecular conjugate addition, see: (a) Fall, Y.; Vidal, B.; Alonso, D.; Gómez, G. Tetrahedron Lett. 2003, 44, 4467. (b) Canoa, P.; Pérez, M.; Covelo, B.; Gómez, G.; Fall, Y. Tetrahedron Lett. 2007, 48, 3441. (c) Lanier, M. L.; Kasper, A. C.; Kim, H.; Hong, J. Org. Lett. 2014, 16, 2406. (13) (a) Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6656. (b) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 2000, 122, 6124. (14) Aldehyde 8 was prepared by acetylation and ozonolysis of 4penten-1-ol. The product matched the spectra of the same compound prepared by PCC oxidation in Holmes, A. B.; Smith, A. L.; Williams, S. F. J. Org. Chem. 1991, 56, 1393. (15) Alkyne 9 was prepared in three steps from 2-deoxy-D-ribose: Yuen, T. Y.; Brimble, M. A. Org. Lett. 2012, 14, 5154. (16) Takai, K.; Sakamoto, S.; Isshiki, T. Org. Lett. 2003, 5, 653. (17) (a) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. (b) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. (c) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Scola, P. M. Tetrahedron Lett. 1992, 33, 1549. (18) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986. (b) Smith, A. B.; Kim, D.-S.; Xian, M. Org. Lett. 2007, 9, 3307. (19) (a) Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57. (b) Ebine, M.; Suga, Y.; Fuwa, H.; Sasaki, M. Org. Biomol. Chem. 2010, 8, 39. (20) Vinylic iodide 18 was prepared by iodoboration of the pivalate ester of pent-4-yn-1-ol, followed by protonolysis of the vinylboron intermediate: Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett. 1983, 24, 731. (21) Triene triol 2 was produced as a 1:1 mixture of diastereomers of the doubly allylic alcohol. (22) Stereoselectivity of iodocyclizations was consistent with stereoinduction from the allylic alcohol, per a reactive conformation model: (a) Chamberlin, A. R.; Mulholland, R. L. Tetrahedron 1984, 40, 2297. (b) Chamberlin, A. R.; Mulholland, R. L.; Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 672. (23) Stereoselectivity of the intramolecular conjugate addition process was consistent with stereoinduction from the acetonide-protected allylic oxygen: (a) Paddon-Row, M. N.; Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc. 1982, 104, 7162. (b) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y.-D.; Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. J. Science 1986, 231, 1108. For examples of stereoselective conjugate additions to form six-membered rings from enoates with allylic oxygen substituents, see: (c) Nicolaou, K. C.; Hwang, C. K.; Duggan, M. E. J. Am. Chem. Soc. 1989, 111, 6682. (d) See ref 17c. (24) The (E)-enoate isomer does not undergo productive intramolecular conjugate addition and appears to simply decompose.
(27) Iodocyclization products consisted of the expected tetrahydropyran containing the doubly allylic alcohol (43% yield) along with a significant amount of the corresponding ketone 27 (25% yield). (28) (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226. (b) Nelson has observed similar 1,3-stereocontrol in a slightly different substrate: Crawford, C.; Nelson, A.; Patel, I. Org. Lett. 2006, 8, 4231. (c) These results are consistent with Evans’ electrostatic model for 1,3-stereocontrol, developed for the additions of carbon nucleophiles to aldehydes: Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. J. Am. Chem. Soc. 1996, 118, 4322. (29) Iodine- and mercury-promoted cyclizations of the acetonide 30 were explored. Compound 30 was recovered from all attempts, except with IDCP, which gave trace oxidation of the allylic alcohol. (30) (a) Iodocyclization of the C18 diastereomer 37 provided a tricyclic product 38; however, this product had the opposite stereochemistry from the natural product at both C18 and C19. (b) Diastereomer 37 was obtained from the NHK reaction of 18 + 29, followed by acetonide hydrolysis (TFA/H2O) and careful silica gel chromatographic separation from 31 (see Supporting Information).
(31) (a) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1985, 26, 1123. See also: (b) Pougny, J. R.; Nassr, M. A. M.; Sinay, P. J. Chem. Soc., Chem. Commun. 1981, 375. (c) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J. C.; Somfai, P.; Whritenour, D. C.; Masamune, S.; Kageyama, M.; Tamura, T. J. Org. Chem. 1989, 54, 2817. (d) Hori, K.; Hikage, N.; Inagaki, A.; Mori, S.; Nomura, K.; Yoshii, E. J. Org. Chem. 1992, 57, 2888. (e) De Koning, C. B.; Green, I. R.; Michael, J. P.; Oliveira, J. R. Tetrahedron 2001, 57, 9623. (32) Benhamou, M. C.; Etemad-Moghadam, G.; Speziale, V.; Lattes, A. Synthesis 1979, 1979, 891. (33) A variety of radical and hydrogenolysis deiodination methods were attempted with compound 33 (see Supporting Information).
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