Asymmetric Total Synthesis of (+)-Intricenyne via an Endocyclization

Letter Cite This: Org. Lett. 2017, 19, 6642−6645

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Asymmetric Total Synthesis of (+)-Intricenyne via an Endocyclization Route to Oxocane Skeleton Jungmin Ahn,† Changjin Lim,†,‡ Hwayoung Yun,§ Hyun Su Kim,† Soonbum Kwon,† Jeeyeon Lee,† Seungbeom Lee,† Hongchan An,† Hyeong-geun Park,† and Young-Ger Suh*,†,‡ †

Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea College of Pharmacy, CHA University, 120 Haeryong-ro, Pocheon, Gyeonggi-do 11160, Republic of Korea § College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea ‡

S Supporting Information *

ABSTRACT: The first total synthesis of (+)-intricenyne consisting of an oxocane skeleton was achieved via an extremely selective endocyclization strategy. The key features of the synthesis include a regio- and diastereoselective epoxide opening reaction, concise elaboration of oxocane cores via abnormally selective endocyclization ether ring formation, and versatile incorporation of the labile functional groups. has not been synthesized. Herein, we report the first total synthesis of (+)-intricenyne. Our synthetic approach, shown in Scheme 1, envisions easy access to the key eight-membered cyclic ether intermediate 5 with versatile substituent functionalization, which is suitable for facile introduction of halogen atoms and side chain. The labile enyne moiety was introduced

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auroxanes, a class of acetogenins consisting of a mediumsized cyclic ether produced by the marine genus Laurencia, have attracted considerable attention owing to their unique structural features.1 Recent reports regarding the identification of new lauroxanes and their interesting biological properties inspired synthetic and medicinal interest.1c (+)-Intricenyne2 (1, Figure 1) has characteristic features of eight-membered

Scheme 1. Strategy for the Asymmetric Total Synthesis of (+)-Intricenyne

Figure 1. Structures of (+)-intricenyne (1), (+)-laurencin (2), and (+)-cis-lauthisan (3).

lauroxanes (oxocanes), which typically possess an enyne side chain and one or more halogen atoms. Since the first identification of (+)-laurencin (2) of the oxocane family by Irie in 1965,3 numerous synthetic approaches for oxocane skeleton formation and incorporation of appropriate substituents to the core ring skeleton and side chains have been continually studied.4 (+)-Intricenyne (1) was isolated from the lipid extract of the red alga Laurencia intricata by White2a in 1978 and by Blunt2b in 1984. This marine natural product, which consists of an α,α′cis-disubstituted oxocane skeleton, four stereogenic centers including two halogen atoms, and a Z-olefinic enyne side chain, © 2017 American Chemical Society

Received: October 29, 2017 Published: December 1, 2017 6642

DOI: 10.1021/acs.orglett.7b03370 Org. Lett. 2017, 19, 6642−6645

Letter

Organic Letters at the final stage of synthesis by the Julia olefination5 of aldehyde 4. We envisaged the bromine substituent in the ether ring and the chlorine substituent in the side chain of 4 could be diastereoselectively elaborated from the ether ring carbonyl and the secondary alcohol in the side chain from the key intermediate 5. The oxocane 6 would be effectively constructed by the substrate-controlled Pd(0)-catalyzed endocyclization of allylic acetate 7, which should be certainly established for our reliable strategy. In particular, the α,α′-cis-stereochemistry of the oxocane system could be effectively controlled by our synthetic route.4l,6 The cyclization precursor 7 possessing three stereogenic centers can be convergently prepared by the coupling of epoxide 8 with alkoxybutanol 9 via an acidcatalyzed regio- and diastereoselective epoxide ring opening reaction.7 As outlined in Scheme 2, the synthesis was commenced by preparation of the cyclization precursor 7 from the known

As shown in the table in Scheme 3, the bulky TBDPS protecting group (7d) of the side chain at the α-position of the Scheme 3. Endocyclization of Allylic Acetate 7

Scheme 2. Preparation of the Cyclization Precursor 7

ether ring oxygen dramatically enhanced the regioselectivity for exclusive production of the desired endoocyclization product (6d), although formation of the six-membered cyclic ether is kinetically preferred.11,13 The excellent regioselectivity enhanced by the bulky substituent of the side chain is likely due to the cyclization through the favorable 7-anti transition state rather than the 7-syn transition state, which possesses the thermodynamically preferred π-allyl palladium complex.11,14 The 7-syn transition state suffers severe 1,2-steric interaction. More importantly, the allylic acetate 7 provided significantly improved regioselectivity (30:1) for endocyclization, which is not clearly explained. However, the relatively low leaving group ability of acetate results in the decreased rate of catalytic turnover15 and lower basicity of the acetate anion liberated by Pd-complexation of allylic acetate 7, compared to the ethoxide anion liberated from carbonate 7d, which results in slower deprotonation of the benzenesulfonylmethyl moiety, seems to retard the overall cyclization rate. Thus, prolonged interconversion between the 7-anti transition state and the 7-syn transition state11,14 may induce the cyclization preferentially through the energetically favorable 7-anti transition state. Subsequently, the selective endo cyclization of allylic acetate 7 in DMSO produced a mixture of the 8-membered cyclic ether 6 and 6-membered cyclic ether 15 in 92% isolated yield in a 30:1 ratio. The endocyclization product 6 was subjected to desulfonylation with 5% sodium−mercury amalgam and then hydrogenation to afford the oxocane 16 possessing adequate substituents and stereochemistry as shown in Scheme 4. Saegusa oxidation16 of 16 and DBU-induced deconjugation17 of the resulting enone 17 followed by desilylation with TBAF afforded alcohol 5 in 84% yield for four steps. Facile Mitsunobu reaction18 of alcohol 5 and Appel type chlorination4f,19 of the resulting alcohol produced chloride 18 in 89% yield for three steps. To complete the synthesis, highly diastereoselective carbonyl reduction of ketone 18 with LS-Selectride20 and Appel-type bromination 4a,19 of the resulting alcohol followed by debenzylation4h of 19 produced bromo alcohol 20 in 99% yield for three steps. Nearly perfect diastereoselective carbonyl

epoxide 11,8 which is readily accessible from the commercially available homopropargyl alcohol 10. DIBAL-H reduction of ester 11 and acylation of the resulting alcohol with tetrafluorobenzoyl chloride afforded benzoate 8. The tetrafluorobenzoyl moiety proved to be important for the next acidcatalyzed regio- and stereoselective epoxide opening reaction.9 The reaction of epoxide 8 with the optically active alcohol 9,10 which was prepared from (−)-glycidol via a two-step sequence, produced ether 12 as a single regioisomer with good diasteroselectivity (12:1) in 72% isolated yield. TBDPS protection of 12 and selective PMB-deprotection produced alcohol 13 in 73% yield for two steps. DMP oxidation of alcohol 13, condensation of the resulting aldehyde with methylphenyl sulfonyl anion, and concomitant debenzoylation provided hydroxyl sulfone 14, which was subjected to selective acetylation of the resulting allylic alcohol and then to oxidation of the secondary alcohol to provide the cyclization precursor 7. Because previous studies,4l,11 including our early work,12 on Pd(0)-catalyzed endocyclization of allylic precursors have shown only limited synthetic utility due to poor or moderate regioselectivity and functional diversity, we initially confirmed feasibility of the key endocyclization reaction through intensive cyclization studies for the efficient construction of oxocane skeletons, which has functional groups for further synthesis of natural oxocane. Finally, the extremely selective endocyclization of the allylic precursor could be achieved by the substratecontrolled Pd(0)-catalyzed cyclization. 6643

DOI: 10.1021/acs.orglett.7b03370 Org. Lett. 2017, 19, 6642−6645

Letter

Organic Letters

Experimental details and procedures, compound characterization data, and 1H and 13C NMR spectra for all new compounds (PDF)

Scheme 4. Preparation of Oxocane 18

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AUTHOR INFORMATION

Corresponding Author

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

Hwayoung Yun: 0000-0003-1414-6169 Jeeyeon Lee: 0000-0003-3995-5747 Hongchan An: 0000-0001-6689-9571 Hyeong-geun Park: 0000-0002-9645-8221 Young-Ger Suh: 0000-0003-1799-8607

reduction of 18 can be explained by the approach of the bulky reducing agent from the less hindered side due to the ethyl side chain as shown in Scheme 5. Alcohol 20 was transformed into

Notes

The authors declare no competing financial interest.

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Scheme 5. Completion of (+)-Intricenyne Synthesis

ACKNOWLEDGMENTS This work was supported by the Global Frontier Project grant of the National Research Foundation funded by the Ministry of Science and ICT of Korea (NRF-2015M3A6A4065798) and by the National Research Foundation of Korea grant funded by the Ministry of Science and ICT of Korea (2009-0083533).

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(1) (a) Faulkner, D. J. Nat. Prod. Rep. 1991, 8, 97. (b) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141. (c) Zhou, Z. F.; Menna, M.; Cai, Y. S.; Guo, Y. W. Chem. Rev. 2015, 115, 1543. (2) (a) White, R. H.; Hager, L. P. Phytochemistry 1978, 17, 939. (b) Blunt, J. W.; Lake, R. J.; Munro, M. H. G. Aust. J. Chem. 1984, 37, 1545. (3) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965, 6, 1091. (4) (a) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345. (b) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall, J. G.; Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483. (c) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029. (d) Kim, G.; Sohn, T. I.; Kim, D.; Paton, R. S. Angew. Chem., Int. Ed. 2014, 53, 272. (e) Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988, 110, 2248. (f) Kim, H.; Choi, W. J.; Jung, J.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2003, 125, 10238. (g) Snyder, S. A.; Brucks, A. P.; Treitler, D. S.; Moga, I. J. Am. Chem. Soc. 2012, 134, 17714. (h) Baek, S.; Jo, H.; Kim, H.; Kim, H.; Kim, S.; Kim, D. Org. Lett. 2005, 7, 75. (i) Kleinke, A. S.; Webb, D.; Jamison, T. F. Tetrahedron 2012, 68, 6999. (j) Martin, T.; Padron, J. I.; Martin, V. S. Synlett 2014, 25, 12. (k) Braddock, D. C.; Sbircea, D. T. Chem. Commun. 2014, 50, 12691. (l) Hoffmann, H. M. R.; Brandes, A. Tetrahedron 1995, 51, 155. (5) (a) Lei, X. G.; Danishefsky, S. J. Adv. Synth. Catal. 2008, 350, 1677. (b) Bonini, C.; Chiummiento, L.; Videtta, V. Synlett 2006, 2006, 2079. (6) Pohlmann, J.; Sabater, C.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 1998, 37, 633. (7) (a) Prestat, G.; Baylon, C.; Heck, M. P.; Mioskowski, C. Tetrahedron Lett. 2000, 41, 3829. (b) Heck, M. P.; Baylon, C.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2001, 3, 1989. (c) Couladouros, E. A.; Vidali, V. P. Chem. - Eur. J. 2004, 10, 3822. (d) Prestat, G.; Baylon, C.; Heck, M. P.; Grasa, G. A.; Nolan, S. P.; Mioskowski, C. J. Org. Chem. 2004, 69, 5770. (e) Wen, S. G.; Liu, W. M.; Liang, Y. M. Synthesis 2007, 2007, 3295. (f) Gholap, S. L.; Woo, C. M.; Ravikumar, P. C.; Herzon, S. B. Org. Lett. 2009, 11, 4322. (8) (a) Iwata, Y.; Maekawara, N.; Tanino, K.; Miyashita, M. Angew. Chem., Int. Ed. 2005, 44, 1532. (b) Schomaker, J. M.; Pulgam, V. R.; Borhan, B. J. Am. Chem. Soc. 2004, 126, 13600. (c) Schmidt, J.; Eschgfaller, B.; Benner, S. A. Helv. Chim. Acta 2003, 86, 2937.

enyne 22 by sequential alcohol oxidation with DMP and Julia 5,15a,21 olefination of the resulting aldehyde with bezothizolyl sulfone anion (21) to produce selective Z-olefinic product 22 in 54% yield for two steps. The moderate yield was due to consistent chlorine elimination during the olefination. Finally, desilylation of 22 afforded (+)-intricenyne in 99% yield, and the synthetic (+)-intricenyne was identical in all respects to natural (+)-intricenyne.2 In summary, the first total synthesis of (+)-intricenyne consisting of an oxocane skeleton was achieved via a unique endocyclization strategy in 29 steps from the commercially available starting materials (25 steps from the known epoxide 11). The key features of the syntheses include an efficient and stereocontrolled approach to the precursor of cyclization synthesis via a regio- and diastereoselective epoxide opening reaction, extremely selective endocyclic ether ring formation by Pd(0)-catalyzed alkylation of allylic acetate, and versatile functional group transformations for the corresponding natural product.

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REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03370. 6644

DOI: 10.1021/acs.orglett.7b03370 Org. Lett. 2017, 19, 6642−6645

Letter

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DOI: 10.1021/acs.orglett.7b03370 Org. Lett. 2017, 19, 6642−6645