Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Asymmetric Total Synthesis of Laurallene Fumihiko Yoshimura,*,†,§ Taku Okada,‡ and Keiji Tanino*,† †
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0810, Japan
‡
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S Supporting Information *
ABSTRACT: The asymmetric total synthesis of laurallene was achieved in 13 steps for the longest linear sequence with 3.3% overall yield from commercially available trans-2-pentenal. This synthesis features the highly efficient construction of a branched ether system with five oxygenated asymmetric stereocenters by the combination of a palladium-catalyzed alkoxy substitution reaction and a cobalt-catalyzed Mukaiyama oxidative cyclization.
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suffers from a competitive E2 reaction, other approaches such as asymmetric glycolate aldol addition−bromoetherification,4 derivatization of D-ribonic γ-lactone−intramolecular epoxide opening,5 and substrate-controlled amide enolate or nitrile anion alkylation6 have been utilized in the previous total syntheses of 1. It is noteworthy that, in these total syntheses, nearly half of the overall synthetic steps were spent constructing the ether moiety. In this context, our group reported an efficient palladiumcatalyzed stereoselective substitution reaction of γ,δ-epoxy α,βunsaturated esters 3 with primary alcohols that proceeds with double inversion of configuration at the γ-position (Scheme 1).9 We envisaged that if chiral secondary alcohols 5 were to
aurallene (1), which was isolated from the red algae Laurencia nipponica Yamada by Fukuzawa and Kurosawa in 1979,1 belongs to the lauroxane family of C15 acetogenins. Compounds of this family, including prelaureatin (2a), isolaurallene (2b), and laurencin, bear a medium-ring ether of various sizes (Figure 1).2 Structurally, laurallene (1)
Figure 1. Structures of laurallene (1) and related natural products.
Scheme 1. Palladium-Catalyzed Alkoxy Substitution of Epoxy Unsaturated Esters
possesses a unique 2,9-dioxabicyclo[6.3.0]undecene skeleton (8,5-fused bicyclic ether) containing an exocyclic chiral bromoallene unit. This complex chemical structure has made laurallene an attractive target for chemical synthesis. However, in contrast to monocyclic lauroxane natural products such as prelaureatin and laurencin,3 synthetic studies of bicyclic laurallene have not been explored as much due to its complexity, and only three total syntheses by Crimmins,4 Suzuki,5 and Kim6 and one formal synthesis by Takeda7 have been reported. These previous total syntheses required 21−42 steps from commercially available materials in the longest linear sequence (LLS). From a synthetic perspective, the challenges posed by laurallene (1) are as follows: (1) construction of the entropically and enthalpically disfavored eight-membered ether, (2) stereoselective construction of four oxygenated stereocenters (i.e., the branched ether system), and (3) installation of the chiral bromoallene unit. While reliable methods for medium-ring ether formation such as ring-closing metathesis (RCM) and free-radical cyclization have been established in the last two decades,8 the stereocontrolled construction of a branched ether system is still the greatest challenge for achieving an efficient total synthesis of 1. Since the Williamson ether synthesis between a secondary alkyl halide and an alkoxide generated from a secondary alcohol © XXXX American Chemical Society
be used in the above substitution reaction, a branched ether system bearing three oxygenated stereocenters (cf. compound 6) would be directly constructed. Because a variety of epoxy unsaturated esters 3 and secondary alcohols 5 could be easily prepared with high enantiopurity through an asymmetric epoxidation and an asymmetric reduction, respectively, or from Received: December 6, 2018
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DOI: 10.1021/acs.orglett.8b03889 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
catalyst 15.13 Because the resulting epoxy aldehyde 14 was highly volatile, this compound was subjected to a one-pot Horner−Wadsworth−Emmons olefination under Masamune− Roush conditions14 to afford γ,δ-epoxy (E)-α,β-unsaturated ester 10 in 64% yield with high enantiopurity (97% ee). Meanwhile, C2-symmetric chiral diol 11 was synthesized from (S,S)-diepoxide 1312 via a copper-catalyzed regioselective epoxide-opening reaction with vinylmagnesium chloride (91% yield).11 With these two chiral fragments in hand, we next investigated their coupling using our palladium-catalyzed alkoxy substitution reaction (Scheme 4). After extensive investigation, we found that when a mixture of trans-epoxide 10 (1 equiv), diol 11 (1.1 equiv), boric anhydride (B2O3, 0.5 equiv), and pinacol (0.5 equiv) was treated with Pd(PPh3)4 (0.1 equiv) in the presence of molecular sieves 4A,15 the substitution reaction proceeded smoothly to give the desired syn-γ-alkoxy-δ-hydroxy-α,β-unsaturated ester 9. Because the remaining diol 11 could not be separated from 9, the crude mixture was treated with an aqueous solution of NaIO4 in a one-pot reaction, which effected oxidative cleavage of 11, furnishing pure 9 in 75% yield after purification by silica gel column chromatography. The product 9 was then subjected to a cobalt-catalyzed Mukaiyama oxidative cyclization under modified Pagenkopf conditions using Co(nmp)2 catalyst16 to produce trans-THF 16 as a single diastereomer,17 and subsequent silylation with TBSCl afforded bis-TBS ether 17 (53% yield, two steps). Thus, we could construct the branched ether system of laurallene (i.e., compound 17) with five oxygenated asymmetric stereocenters in only four steps (LLS) from the commercially available material 12, which clearly demonstrates the significant synthetic utility of the palladiumcatalyzed alkoxy substitution reaction. The formation of the oxocene core was then examined (Scheme 4). Reduction of α,β-unsaturated ester 17 with DIBAL-H gave allyl alcohol 18 (93% yield), which was then converted to terminal diene 8 in 82% yield by Movassaghi’s reductive rearrangement.18 Deprotection of the primary TBS group occurred during the in situ hydrolysis with aqueous trifluoroethanol. Diene 8 was treated with ruthenium catalyst 1919 in refluxing CH2Cl2 (5 mM), resulting in its smooth conversion to oxocene 20 in 96% yield with no detectable dimerization or oligomerization. The remaining tasks in the synthesis were the installation of the chiral bromoallene unit and introduction of the C13bromide (Scheme 4). The former was achieved by the application of Overman’s procedure.20,21 Thus, Swern oxidation of alcohol 20 gave a highly hygroscopic aldehyde which readily formed the corresponding hydrate. Because isolation of the aldehyde by silica gel chromatography was difficult, the crude product, which was obtained through anhydrous workup conditions,22 was immediately used in the next step. In the presence of Ti(O-i-Pr)3Cl, addition of ethynyl Grignard reagent to the resulting aldehyde proceeded with Felkin−Anh selectivity (dr = 74:26) to give propargyl alcohols 21 as an inseparable mixture at the C3 position. It is important to note that the use of CH2Cl2 as a cosolvent in this addition was indispensable for achieving this level of selectivity and full conversion. The mixture of isomers was then converted to trisylate 22 (42% yield, three steps) and its C3-epimer 23 (15% yield, three steps), which were separable at this stage. Upon treatment with bromocuprate reagent (LiCuBr2) in Et2O,23 trisylate 22 underwent an anti-SN2′ bromination
a chiral pool, as well as because the reaction proceeds under mild neutral conditions, such alkoxy substitution reactions would provide an efficient approach for the construction of a branched ether system. Herein, we report a novel and concise approach that enables the asymmetric total synthesis of laurallene (1) in 13 steps (LLS) based on the palladiumcatalyzed alkoxy substitution reaction as the key step. Our retrosynthetic analysis for laurallene (1) is shown in Scheme 2. The sensitive bromide at the C13 position and the Scheme 2. Retrosynthetic Analysis
chiral bromoallene unit were to be installed at the final stage of the synthesis from bicyclic aldehyde 7. The eight-membered ring in 7 was to be constructed through an RCM reaction of diene 8. The trans-THF ring of 8 would be constructed by a cobalt-catalyzed Mukaiyama oxidative cyclization.10 The requisite branched ether 9 could be synthesized through our palladium-catalyzed alkoxy substitution reaction9 of chiral γ,δepoxy (E)-α,β-unsaturated ester 10 with C2-symmetric chiral diol 11 as described above. Epoxy ester 10 was to be derived from the commercially available trans-2-pentenal (12) via an asymmetric epoxidation, and diol 1111 could be prepared from the commercially available (S,S)-diepoxide 13.12 The synthesis commenced with the preparation of the two fragments 10 and 11 (Scheme 3). Asymmetric epoxidation of trans-2-pentenal (12) was achieved with hydrogen peroxide (30% w/w in water) in the presence of chiral pyrrolidine Scheme 3. Synthesis of the Optically Active Fragments 10 and 11
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DOI: 10.1021/acs.orglett.8b03889 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 4. Asymmetric Total Synthesis of Laurallene (1)a
a
Tris = 2,4,6-triisopropylbenzenesulfonyl.
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reaction in a highly stereoselective manner, giving rise to bromoallene 24. Finally, the TBS group of 24 was removed with camphorsulfonic acid in methanol, and the resulting secondary alcohol was subjected to a bromination reaction with inversion of configuration. Thus, the combined use of CBr4, trioctylphosphine, and 1-methyl-1-cyclohexene24 furnished laurallene (1) in 42% yield over three steps. The synthetic laurallene was identical in all respects to natural laurallene, including the optical rotation, 1H and 13C NMR spectra, IR spectrum, and mass spectrum. In conclusion, we have developed an efficient and enantiocontrolled synthetic route to laurallene having 13 steps (LLS) from the commercially available trans-2-pentenal with 3.3% overall yield (14 total steps). The synthesis features concise and stereoselective construction of a branched ether system through a palladium-catalyzed alkoxy substitution reaction of a chiral epoxy unsaturated ester with a chiral secondary alcohol and a cobalt-catalyzed Mukaiyama oxidative cyclic ether formation. In addition, the strategic use of a protecting group (i.e., minimal use of protecting groups) and a one-pot reaction sequence25 (cf., 12 → 10 and 10 → 9) contributed to minimizing the overall synthetic steps. Considering the wide availability of chiral epoxy unsaturated esters and chiral secondary alcohols, our approach should allow rapid access to lauroxane natural products and the related C15 acetogenins bearing a variety of branched ether systems.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Fumihiko Yoshimura: 0000-0002-1187-6062 Keiji Tanino: 0000-0002-0580-0125 Present Address §
(F.Y.) School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge Dr. Eri Fukushi and Mr. Yusuke Takata (GCMS & NMR Laboratory, Faculty of Agriculture, Hokkaido University) for their mass spectral measurements. This work was supported by JSPS KAKENHI Grant Numbers JP18K05339, JP18H01970, and JP15H05842 in Middle Molecular Strategy. T.O. was supported by The Ministry of Education, Culture, Sports, Science and Technology through the Program for Leading Graduate Schools (Hokkaido University “Ambitious Leader’s Program”). We thank Umicore AG & Co. KG for providing the ruthenium catalyst (Umicore Grubbs Catalyst® M2).
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ASSOCIATED CONTENT
S Supporting Information *
REFERENCES
(1) Fukuzawa, A.; Kurosawa, E. Tetrahedron Lett. 1979, 2797−2800. (2) For a review, see: Zhou, Z.; Menna, M.; Cai, Y.; Guo, Y. Chem. Rev. 2015, 115, 1543−1596. (3) For a review, see: (a) Fujiwara, K. In Topics in Heterocyclic Chemistry; Kiyota, H., Ed.; Springer: Berlin, 2006; Vol. 5, pp 97−148. For recent examples, see: (b) Lin, R.; Cao, L.; West, F. G. Org. Lett. 2017, 19, 552−555. (c) Kim, H. S.; Kim, T.; Ahn, J.; Yun, H.; Lim,
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03889. Experimental procedures, characterization data, and copies of 1H and 13C NMR spectra (PDF) C
DOI: 10.1021/acs.orglett.8b03889 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters C.; Jang, J.; Sim, J.; An, H.; Surh, Y.; Lee, J.; Suh, Y. J. Org. Chem. 2018, 83, 1997−2005. (4) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473−5476. (5) Saitoh, T.; Suzuki, T.; Sugimoto, M.; Hagiwara, H.; Hoshi, T. Tetrahedron Lett. 2003, 44, 3175−3178. (6) Kim, M. J.; Sohn, T.; Kim, D.; Paton, R. S. J. Am. Chem. Soc. 2012, 134, 20178−20188. (7) Sasaki, M.; Hashimoto, A.; Tanaka, K.; Kawahata, M.; Yamaguchi, K.; Takeda, K. Org. Lett. 2008, 10, 1803−1806. (8) For reviews, see: (a) Kleinke, A. S.; Webb, D.; Jamison, T. F. Tetrahedron 2012, 68, 6999−7018. (b) Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919−3952. (c) Yet, L. Tetrahedron 1999, 55, 9349−9403. For representative examples, see: (d) Fujiwaraa, K.; Souma, S.; Mishima, H.; Murai, A. Synlett 2002, 1493−1495. (e) Ortega, N.; Martín, V. S.; Martín, T. J. Org. Chem. 2010, 75, 6660−6672. (9) Yu, X.; Yoshimura, F.; Ito, F.; Sasaki, M.; Hirai, A.; Tanino, K.; Miyashita, M. Angew. Chem., Int. Ed. 2008, 47, 750−754. (10) Inoki, S.; Mukaiyama, T. Chem. Lett. 1990, 19, 67−70. (11) Koert, U.; Stein, M.; Wagner, H. Chem. - Eur. J. 1997, 3, 1170− 1180. (12) Chiral diepoxide 13 is commercially available and can also be prepared by the following methods. For preparation of 13 from tartaric acid, see: (a) Robbins, M. A.; Devine, P. N.; Oh, T. Org. Synth. 1999, 76, 101. For preparation from (E)-1,4-dichloro-2-butene through asymmetric dihydroxylation, see: (b) Vanhessche, K. P. M.; Wang, Z.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 3469−3472. (13) (a) Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964−6965. (b) Bondzic, B. P.; Urushima, T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12, 5434−5437. (14) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183−2186. (15) In the absence of pinacol, 2 equiv of diol 11 was required for completion of the reaction. Molecular sieves 4A worked as a dehydrating agent for avoiding the side reaction in which a hydroxy group was introduced at the γ-position of substrate 10. The details of the optimization of alkoxy substitution will be reported in a full paper. (16) Palmer, C.; Morra, N. A.; Stevens, A. C.; Bajtos, B.; Machin, B. P.; Pagenkopf, B. L. Org. Lett. 2009, 11, 5614−5617. (17) Stereochemistry at the C4 position was determined by NOE measurements. For details, see Figure S1 in the Supporting Information. (18) (a) Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838−1841. (b) Fujiwara, K.; Kawamura, N.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2009, 50, 1236−1239. (19) Clavier, H.; Nolan, S. P. Chem. - Eur. J. 2007, 13, 8029−8036. (20) Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J. Org. Chem. 1993, 58, 2468−2477. (21) The reported procedure for the installation of the bromoallene unit on a THF−aldehyde required a four-step sequence including addition of TMS-acetylene.20 However, establishment of the stereoselective addition of ethynyl Grignard reagent shortened this conversion to a three-step sequence because desilylation of the TMS group on the alkyne was unnecessary. (22) Paquette, L. A.; Oplinger, J. A. J. Org. Chem. 1988, 53, 2953− 2959. (23) Jian, Y.; Wu, Y. Synlett 2009, 3303−3306. (24) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345− 4348. (25) Hayashi, Y. Chem. Sci. 2016, 7, 866−880.
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DOI: 10.1021/acs.orglett.8b03889 Org. Lett. XXXX, XXX, XXX−XXX
