Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Stereocontrolled Synthesis of 19′-Deoxyperidinin Naoto Kinashi, Shigeo Katsumura,* Tetsuro Shinada, and Kazuhiko Sakaguchi* Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan S Supporting Information *
ABSTRACT: The stereocontrolled convergent synthesis of 19′-deoxyperidinin, 2, which might be a useful peridinin analog to understand the ICT characteristics, was efficiently achieved by sequential Pd-catalyzed cross-coupling reactions using bidirectionally extensible conjugated C5 olefin segments. The crucial 5(2H)-ylidenedihydrofuran function of 2 was successfully constructed by the Au-catalyzed regio- and stereoselective 5-exo-dig etherification.
T
charge transfer (ICT) state, which is a unique excited energy level coupling with the close S1 state due to a conjugated carbonyl group,9 and have also predicted that the unique ICT characteristics would enable the carbonyl carotenoids to carry out the superefficient energy transfer. In order to confirm the obtained prediction, it is necessary to directly compare the energy transfer efficiencies of the light-harvesting complex, such as PCP, incorporating a carotenoid possessing the remarkable ICT characteristics with those of the complex corresponding to PCP (quasi-PCP) incorporating a carotenoid having poor ICT characteristics. We then designed 19′-deoxyperidinin, 2, as the molecule that has poor ICT characteristics in addition to the possibility of forming the quasi-PCP complex. The structure of this molecule 2 is different only from that of peridinin lacking the butenolide-carbonyl group. In this paper, we describe the stereocontrolled efficient synthesis of 19′-deoxyperidinin, 2. We planned the highly convergent synthesis of 2 (Scheme 1). Since there is no natural carotenoid containing a polyeneconjugated 5(2H)-ylidenedihydrofuran, information on the chemical property and stability of the compound 2 was not available. We anticipated that the late-stage construction of the 5(2H)-ylidenedihydrofuran function would be preferable for the synthesis of 2. Based on the retrosynthetic perspective, we envisioned that the synthesis of 2 with the requisite stereochemistry would be achieved by the metal-catalyzed cyclization of the ene-yne alcohol 3, which would be constructed by the sequential Suzuki−Miyaura and Sonogashira couplings of the boron- and iodine-attached diene 510 with vinyl iodide 411 and epoxy acetylene 6, respectively. The diene 5 has already been developed as a bidirectionally extensible C5 diene unit for the stereocontrolled construction of a versatile conjugated polyene system.10 The vinyl iodide 4 could be obtained from aldehyde 74a,12 by the Wittig olefination. The epoxy acetylene 6 would be synthesized by the Stille coupling
he highly oxidized marine C37 nor-carotenoid, peridinin, 1 (Figure 1), isolated from the planktonic algae
Figure 1. Peridinin and 19′-deoxyperidinin.
dinoflagellates,1 is a representative light-harvesting pigment for photosynthesis in the sea. Peridinin exhibits an exceptionally high-energy transfer efficiency to chlorophyll a (>95%) in the peridinin−chlorophyll a−protein (PCP) complex during the initial process of photosynthesis.2 This super function would be due to the unique chemical structure of 1 possessing an allene and ylidenebutenolide functional groups in the main conjugated polyene chain along with functionalized cyclohexane rings at both ends of the molecule, and this molecule is regarded as one of the most architecturally complex molecules among carotenoids. During the course of our studies toward understanding the mechanism of the highly efficient energy transfer shown in marine photosynthesis, we have reported the syntheses of peridinin,3b,c fucoxanthin,4b which is also a representative lightharvesting marine carotenoid exhibiting a high energy transfer efficiency (>80%),5 and a series of their analogs6 along with the results of their ultrafast time-resolved absorption7 and the Stark spectroscopy analyses.8 These studies have revealed that peridinin and fucoxanthin possess a remarkable intramolecular © XXXX American Chemical Society
Received: November 29, 2017
A
DOI: 10.1021/acs.orglett.7b03695 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 1. Synthetic Plan
Scheme 3. Synthesis of 3
of the ene-yne 811 with vinyl iodide 913 followed by the reduction of an ester group. The E-α-stannyl-β-trimethylsilylethynyl acrylate 8 is a recently developed building block for the efficient construction of the ylidenebutenolide moiety along with the extension of the conjugated system at both terminals of 8 toward the peridinin synthesis.11 It should be noted that no protecting groups are utilized in the above-planned synthesis. We began the synthesis starting with the preparation of the epoxy acetylene 6 (Scheme 2). The Stille reaction of stannyl
the instability of 5 against CsF. The Suzuki−Miyaura reaction of the obtained 11 with vinyl iodide 4 (E/Z = 7.4:1)16 in the presence of Pd(OAc)2, SPhos, and Cs2CO3 produced the desired 3, a precursor of 19′-deoxyperidinin, 2, in 46% yield as a single isomer.17 Toward the complete synthesis of 2, we investigated the construction of a 5(2H)-ylidenedihydrofuran (Scheme 4). Scheme 4. Synthesis of 19′-Deoxyperodinin, 2
Scheme 2. Synthesis of 6
Although we examined the cyclization of the ene-yne alcohol 3 using AgOTf as a catalyst (10 mol %), the reaction was quite slow at 0 °C, and elevating the reaction temperature (ambient temperature) resulted in a gradual decomposition. Several investigations of the cyclization reaction conditions revealed that a gold catalyst was effective for the construction of 5(2H)ylidenedihydrofuran. The reaction of 3 in the presence of [Au(JohnPhos)(MeCN)]SbF618 (10 mol %) smoothly proceeded (CH2Cl2, −10 °C, 30 min) in a complete regio- and stereoselective 5-exo-dig manner to give 19′-deoxyperidinin, 2, in 74% yield as a single diastereomer. This cyclization reaction conditions utilizing the gold catalyst was found to be extremely mild without affecting the conjugated polyene structure including allene.19 To the best of our knowledge, this is the first example of the construction of a polyene-conjugated 5(2H)-ylidenedihydrofuran function by the Au-catalyzed intra-
acrylate 8 (E/Z = 8.9:1), prepared by the ethynyl stannylation of propiolate in a single step,11 with the vinyl iodide 9 (Pd(PPh3)4, CuI, DMF, rt, 1 h) produced the coupling product 10 (Z/E = 8.9:1), from which the desired Z-isomer was isolated by SiO2 chromatography in 78% yield.11 Reduction of the resulting 10 with DIBAL-H successfully proceeded to give the desired 6 in 84% yield as the sole product.14,15 We next examined the introduction of the epoxy acetylene 6 and vinyl iodide 4 into both ends of the diene 5 (Scheme 3). After removal of the TMS group on the alkyne terminus of 6 with CsF, the resulting mixture was allowed to react with the diene 5 in the presence of Pd(OAc)2, CuI, and Et3N to give the coupling product 11 in 70% yield. When an excess amount of CsF (>1 equiv) was employed, the yield of 11 decreased due to B
DOI: 10.1021/acs.orglett.7b03695 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
S.; Blankenship, R. E.; Sharples, F. P.; Hiller, R. G.; Birge, R. R.; Frank, H. A. Biochemistry 2004, 43, 1478. (j) Schulte, T.; Niedzwiedzki, D. M.; Birge, R. R.; Hiller, R. G.; Polívka, T.; Hofmann, E.; Frank, H. A. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 20764. (3) Total synthesis of peridinin: (a) Yamano, Y.; Ito, M. J. Chem. Soc., Perkin Trans. 1 1993, 1599. (b) Furuichi, N.; Hara, H.; Osaki, T.; Mori, H.; Katsumura, S. Angew. Chem., Int. Ed. 2002, 41, 1023. (c) Furuichi, N.; Hara, H.; Osaki, T.; Nakano, M.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 7949. (d) Olpp, T.; Brückner, R. Angew. Chem., Int. Ed. 2006, 45, 4023. (e) Vaz, B.; Domınguez, M.; Alvarez, R.; de Lera, A. R. Chem. - Eur. J. 2007, 13, 1273. (f) Woerly, E. M.; Cherney, A. H.; Davis, E. K.; Burke, M. D. J. Am. Chem. Soc. 2010, 132, 6941. (4) Total synthesis of fucoxanthin: (a) Yamano, Y.; Tode, C.; Ito, M. J. Chem. Soc., Perkin Trans. 1 1995, 1895. (b) Kajikawa, T.; Okumura, S.; Iwashita, T.; Kosumi, D.; Hashimoto, H.; Katsumura, S. Org. Lett. 2012, 14, 808. (5) Papagiannakis, E.; van Stokkum, I. H. M.; Fey, H.; Buchel, C.; van Grondelle, R. Photosynth. Res. 2005, 86, 241. (6) Ylidenebutenolide−modified analogs: (a) Kajikawa, T.; Aoki, K.; Iwashita, T.; Niedzwiedzki, D. M.; Frank, H. A.; Katsumura, S. Org. Biomol. Chem. 2010, 8, 2513. Allene−modified analogs: (b) Kajikawa, T.; Aoki, K.; Singh, R. S.; Iwashita, T.; Kusumoto, T.; Frank, H. A.; Hashimoto, H.; Katsumura, S. Org. Biomol. Chem. 2009, 7, 3723. Different π-electron-chain length analogs: (c) Kajikawa, T.; Hasegawa, S.; Iwashita, T.; Kusumoto, T.; Hashimoto, H.; Niedzwiedzki, D. M.; Frank, H. A.; Katsumura, S. Org. Lett. 2009, 11, 5006. (d) Kajikawa, T.; Okumura, S.; Iwashita, T.; Kosumi, D.; Hashimoto, H.; Katsumura, S. Org. Lett. 2012, 14, 808. (e) Okumura, S.; Kajikawa, T.; Yano, K.; Sakaguchi, K.; Kosumi, D.; Hashimoto, H.; Katsumura, S. Tetrahedron Lett. 2014, 55, 407. (7) (a) Chatterjee, N.; Niedzwiedzki, D. M.; Kajikawa, T.; Hasegawa, S.; Katsumura, S.; Frank, H. A. Chem. Phys. Lett. 2008, 463, 219. (b) Niedzwiedzki, D. M.; Chatterjee, N.; Enriquez, M. M.; Kajikawa, T.; Hasegawa, S.; Katsumura, S.; Frank, H. A. J. Phys. Chem. B 2009, 113, 13604. (c) Kaligotla, S.; Doyle, S.; Niedzwiedzki, D. M.; Hasegawa, S.; Kajikawa, T.; Katsumura, S.; Frank, H. A. Photosynth. Res. 2010, 103, 167. (d) Fuciman, M.; Enriquez, M. M.; Kaligotla, S.; Niedzwiedzki, D. M.; Kajikawa, T.; Aoki, K.; Katsumura, S.; Frank, H. A. J. Phys. Chem. B 2011, 115, 4436. (e) Enriquez, M. M.; Hananoki, S.; Hasegawa, S.; Kajikawa, T.; Katsumura, S.; Wagner, N. L.; Birge, R. R.; Frank, H. A. J. Phys. Chem. B 2012, 116, 10748. (f) Niedzwiedzki, D. M.; Kajikawa, T.; Aoki, K.; Katsumura, S.; Frank, H. A. J. Phys. Chem. B 2013, 117, 6874. (g) Magdaong, N. M.; Niedzwiedzki, D. M.; Greco, J. A.; Liu, H.; Yano, K.; Kajikawa, T.; Sakaguchi, K.; Katsumura, S.; Birge, R. R.; Frank, H. A. Chem. Phys. Lett. 2014, 593, 132. (h) Kosumi, D.; Kajikawa, T.; Okumura, S.; Sugisaki, M.; Sakaguchi, K.; Katsumura, S.; Hashimoto, H. J. Phys. Chem. Lett. 2014, 5, 792. (i) Kosumi, D.; Kajikawa, T.; Yano, K.; Okumura, S.; Sugisaki, M.; Sakaguchi, K.; Katsumura, S.; Hashimoto, H. Chem. Phys. Lett. 2014, 602, 75. (8) Kusumoto, T.; Horibe, T.; Kajikawa, T.; Hasegawa, S.; Iwashita, T.; Cogdell, R. J.; Birge, R. R.; Frank, H. A.; Katsumura, S.; Hashimoto, H. Chem. Phys. 2010, 373, 71. (9) (a) Bautista, J. A.; Connors, R. E.; Raju, B. B.; Hiller, R. G.; Sharples, F. P.; Gosztola, D.; Wasielewski, M. R.; Frank, H. A. J. Phys. Chem. B 1999, 103, 8751. (b) Frank, H. A.; Bautista, J. A.; Josue, J.; Pendon, Z.; Hiller, R. G.; Sharples, F. P.; Gosztola, D.; Wasielewski, M. R. J. Phys. Chem. B 2000, 104, 4569. (10) Nishioka, Y.; Yano, Y.; Kinashi, N.; Oku, N.; Toriyama, Y.; Katsumura, S.; Shinada, T.; Sakaguchi, K. Synlett 2017, 28, 327. (11) Kinashi, N.; Sakaguchi, K.; Katsumura, S.; Shinada, T. Tetrahedron Lett. 2016, 57, 129. (12) Yamano, Y.; Sumiya, S.; Ito, M. J. Chem. Soc., Perkin Trans. 1 1995, 167. (13) Kajikawa, T.; Iguchi, N.; Katsumura, S. Org. Biomol. Chem. 2009, 7, 4586. (14) Using LAH and LiBH4 instead of DIBAL-H resulted in producing complex mixtures.
molecular etherification. Although the novel compound 2 easily decomposed under an oxygen atmosphere, it could be safely stored as a frozen solution in benzene (−15 °C) under argon for several months. We thus successfully achieved the stereocontrolled convergent synthesis of 19′-deoxyperidinin, 2. The key features of the present synthesis are as follows: (1) highly efficient construction of the carbon framework of 2 by sequential Pdcatalyzed cross-coupling reactions using conjugate olefin segments including our developed building blocks 5 and 8; (2) the first construction of the polyene-conjugated 5(2H)ylidenedihydrofuran function by the Au-catalyzed regio- and stereoselective 5-exo-trig etherification; and (3) complete protecting-group-free synthesis. This highly convergent synthetic method is expected to be applied to the synthesis of peridinin and its analogs. Spectroscopic investigation of the obtained 2 revealed that this molecule has no ICT characteristics as we expected.20 Reconstitution of the light-harvesting complex using 2 is now under investigation.
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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.7b03695. Full experimental details and characterization data of all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Tetsuro Shinada: 0000-0001-9145-1533 Kazuhiko Sakaguchi: 0000-0002-2364-0970 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Numbers JP25410183, JP26410183, and JPK17K05935. REFERENCES
(1) (a) Strain, H. H.; Svec, W. A.; Aitzetmuller, K.; Grandolfo, M. C.; Katz, J. J.; Kjosen, H.; Norgard, S.; Lieean-Jensen, S.; Haxo, F. T.; Wegfahrt, P.; Rapoport, H. J. Am. Chem. Soc. 1971, 93, 1823. (b) Johansen, J. E.; Borch, G.; Lieean-Jensen, S. Phytochemistry 1980, 19, 441. (2) (a) Song, P. S.; Koka, P.; Prezelin, B. B.; Haxo, F. T. Biochemistry 1976, 15, 4422. (b) Koka, P.; Song, P. S. Biochim. Biophys. Acta, Protein Struct. 1977, 495, 220. (c) Hofmann, E.; Wrench, P. M.; Sharples, F. P.; Hiller, R. G.; Welte, W.; Diederichs, K. Science 1996, 272, 1788. (d) Bautista, J. A.; Hiller, R. G.; Sharples, F. P.; Gosztola, D.; Wasielewski, M. R.; Frank, H. A. J. Phys. Chem. A 1999, 103, 2267. (e) Bautista, J. A.; Connors, R. E.; Raju, B. B.; Hiller, R. G.; Sharples, F. P.; Gosztola, D.; Wasielewski, M. R.; Frank, H. A. J. Phys. Chem. B 1999, 103, 8751. (f) Zigmantas, D.; Hiller, R. G.; Sundstroem, V.; Polívka, T. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 16760. (g) Vaswani, H. M.; Hsu, C.-P.; Head-Gordon, M.; Fleming, G. R. J. Phys. Chem. B 2003, 107, 7940. (h) Shima, S.; Ilagan, R. P.; Gillespie, N.; Sommer, B. J.; Hiller, R. G.; Sharples, F. P.; Frank, H. A.; Birge, R. R. J. Phys. Chem. A 2003, 107, 8052. (i) Ilagan, R. P.; Shima, S.; Melkozernov, A.; Lin, C
DOI: 10.1021/acs.orglett.7b03695 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters (15) The reduction of 8 (E/Z = 8.9:1) with DIBAL-H gave the corresponding allyl alcohol in 96% yield as a mixture of E/Z isomers (ca. 1:1).
(16) According to our previous study, the E-vinyl iodide 4 was easy to isomerize into its Z-isomer by SiO2 chromatography.11 The purification of 4 (E/Z = 1.4:1), prepared by the Wittig reaction of aldehyde 7 with (iodomethyl)triphenylphosphonium iodide and LHMDS, by SiO2 chromatography using n-hexane and AcOEt (6:1) with 5% Et3N as the eluent afforded the E-enriched 4 (E/Z = 7.4:1).
(17) In this reaction, several compounds whose structure was undetermined were generated in addition to 3, but no geometric isomer of 3 (derived from Z-4 in particular) was detected. Selection of a base is important in this reaction. When K3PO4 was used instead of Cs2CO3, the reaction did not proceed at room temperature, and when heated (50 °C), a complicated mixture was formed. (18) Carreras, J.; Livendahl, M.; McGonigal, P. R.; Echavarren, A. Angew. Chem., Int. Ed. 2014, 53, 4896. (19) When Ph3PAuOTf, prepared in situ from Ph3PAuCl and AgOTf, was used as a catalyst, the formation of 2 was confirmed by 1H NMR, but many compounds whose structure was undetermined were by-produced. (20) Greco, D. M.; LaFountain, A. M.; Kinashi, N.; Shinada, T.; Sakaguchi, K.; Katsumura, S.; Magdaong, N. C. M.; Niedzwiedzki, D. M.; Birge, R. R.; Frank, H. A. J. Phys. Chem. B 2016, 120, 2731. A steady-state absorption spectroscopic experiment on the obtained 2 fortunately observed the clear S0 → S1 absorption transition which was not evident in the natural peridinin, and this absorption transition is generally said to be a forbidden transition in polyene-chain systems such as carotenoids.
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DOI: 10.1021/acs.orglett.7b03695 Org. Lett. XXXX, XXX, XXX−XXX
