Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Asymmetric Synthesis and Structure Revision of Guignardone H and I: Development of a Chiral 1,3-Diketone Possessing C2 Symmetry Toyoharu Kobayashi,† Iori Takizawa,† Ayumu Shinobe,† Yuichiro Kawamoto,† Hideki Abe,‡ and Hisanaka Ito*,† †
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan Department of Chemical and Biological Sciences, Faculty of Science, Japan Women’s University, 2-8-1 Mejirodai, Bunkyo-ku, Tokyo 112-8681, Japan
‡
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S Supporting Information *
ABSTRACT: A novel chiral 1,3-diketone possessing C2 symmetry was synthesized and utilized in the asymmetric synthesis of guignardone H and I by employing sequential condensation−6π-electrocyclization reactions with the novel 1,3-diketone followed by stereoselective hydrogenation as key steps. Although the synthetic compounds differed from natural guignardone H and I, we realized that the C4-epimers of the proposed structures for guignardone H and I were the actual structures.
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these compounds include three consecutive stereocenters on a cyclopentane ring and a trans-1,3-disubstituent on a cyclohexenone ring. When guignardone I (2) was discovered to possess antibacterial activity against MRSA, related compounds such as guignardone J (3), L (4), and S (5) were isolated and shown to have biological activities.1f,h Although members of the guignardone family show structural diversity and interesting bioactivity, no total synthesis or synthetic studies of these guignardones have been reported. The structural features and biological activities of these compounds prompted a synthetic study of guignardone H (1) and I (2) with a goal to develop an efficient synthetic procedure to access the guignardone family and other tricycloalternarene-type meroterpenoids, such as coibanols.2 Herein, we report the first asymmetric total synthesis and structure revision of guignardone H and I, involving the sequential condensation−6π-electrocyclization reaction3 between a novel chiral 1,3-diketone possessing C2 symmetry and an unsaturated aldehyde followed by highly stereoselective hydrogenation of the resulting tricyclic compound, and the determination of the absolute configuration of guignardone I and related natural products. The synthetic strategy for guignardone H (1) and I (2) is outlined in Scheme 1. Guignardone H (1) could be synthesized from tricyclic compound 6 via formation of an exo-olefin moiety and deprotection of the TBS group; guignardone I (2) would be obtained from 6 by deprotection of the TBS group. The common intermediate 6 would be derived from compound 7 via
he guignardones are a family of tricycloalternarene-type meroterpenoids, first isolated from cultures of Guignardia mangiferae IFB-GLP-4 associated with normal Ilex cornuta leaves by Tan and co-worker in 2010.1 More than 20 types of these compounds exist, some of which exhibit interesting bioactivity, such as antibacterial activity,1d,g TLR3-regulating activity,1e and cytotoxicity for MCF-7 cell lines.1h Guignardone H (1) and I (2) were isolated from the endophytic fungus of the mangrove plant Scyphiphora hydrophyllaceae in 2012 by Dai and coworkers (Figure 1).1d The structures of 1 and 2 were established through 2D NMR spectral analysis, including COSY, HMBC, and ROESY experiments, although the absolute configurations of compound 1 and 2 had not yet been determined. The structural features of
Figure 1. Structures of guignardone H (1) and I (2) and related natural products 3−5. © XXXX American Chemical Society
Received: February 5, 2019
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DOI: 10.1021/acs.orglett.9b00486 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
using Shi ketone 16, prepared from D-fructose and oxone as the oxidant, afforded diepoxide 10. After several attempts at acidcatalyzed epoxide opening of 10 with various acids, TBSOTf was selected as the Lewis acid. Thus, treatment of diepoxide 10 with a catalytic amount of TBSOTf (10 mol %) in THF at −78 °C provided the desired chiral diketone (+)-9 in 62% yield for two steps. 1,3-Diketone (+)-9 was determined to have 97% ee6 after transformation into the methyl enol ether (+)-14 using Zubaidha’s protocol.7 The absolute configuration of 1,3diketone (+)-9 was determined as 4R,6R using single-crystal X-ray crystallographic analysis after conversion to compound (+)-15.8 With the synthesis of 1,3-diketone (+)-9 in hand, we next focused on construction of the tricyclic skeleton of the guignardones via sequential condensation−6π-electrocyclization reaction and chemo- and stereoselective hydrogenation (Scheme 3). Ozonolysis of (−)-limonene (17) followed by intramolecular aldol condensation of the resulting keto aldehyde afforded
Scheme 1. Retrosynthetic Analysis of 1 and 2
Scheme 3a
chemo- and stereoselective hydrogenation and chemoselective methylation of the secondary alcohol. Compound 7 would be constructed by Knoevenagel condensation of the 1,3-diketone 9 possessing C2 symmetry and unsaturated aldehyde 8 and followed by 6π-electrocyclization. Chiral 1,3-diketone 9 could be obtained by acid-catalyzed epoxide-opening of known diepoxide 10,4 which was developed by Myers and co-workers from resorcinol (12) via Shi asymmetric epoxidation of compound 11. The synthetic study began with the development of the chiral 1,3-diketone 9, as shown in Scheme 2. According to Myers’ protocol,4 chiral diepoxide 10 was prepared from resorcinol (12). Thus, TBS protection of 12 and Birch reduction of resulting compound 13 afforded compound 11 in 98% yield for two steps. Shi asymmetric epoxidation5 of 11 Scheme 2a
a Reagents and conditions: (a) O3, CH2Cl2-MeOH, −78 °C, then Me2S, RT, 93%; (b) piperidinium acetate, benzene, reflux, quant.; (c) NCS, t-BuOH-H2O, RT; (d) LAH, THF, 0 °C, 50% (2 steps); (e) MnO2, CH2Cl2, RT, 90%; (f) piperidinium acetate, MS 4 Å, Et2O, RT, 53% 20 (dr 1:1), 24% 21 (dr 2:1); (g) p-TsOH, THF-H2O, 50 °C, 40% (brsm 96%); (h) H2, Crabtree’s catalyst, CH2Cl2, RT, 96%, single isomer; (i) MeI, Ag2O, MS 4 Å, Et2O, reflux, 98%; (j) 4 M HCl, THF, RT, quant.; (k) Burgess reagent, benzene, reflux; (l) 3 M HCl, THF, RT, 50% (2 steps).
a Reagents and conditions: (a) TBSCl, imidazole, DMF, 0 °C, 99%; (b) Li, t-BuOH, liq. NH3, reflux, 99%; (c) Shi ketone 16, oxone, K2CO3, MeCN-buffer, 0 °C; (d) TBSOTf (10 mol %), THF, − 78 °C, 62% (2 steps); (e) I2, MeOH, RT, 37%; (f) 4-bromobenzoyl chloride, Et3N, CH2Cl2, 0 °C, 85%.
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DOI: 10.1021/acs.orglett.9b00486 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters known compound (−)-18.9 The chlorohydrination of (−)-18 with NCS in t-BuOH-H2O, followed by reduction with LAH, provided diol (−)-19 in 50% yield for two steps. Treatment of compound (−)-19 with MnO2 gave unsaturated aldehyde (−)-8 in 90% yield. The sequential condensation−6π-electrocyclization reaction with 1,3-diketone (+)-9 was investigated in detail. Results showed that piperidinium acetate is essential for this reaction. Treatment of compounds (−)-8 and (+)-9 with piperidinium acetate in Et2O at room temperature afforded tricyclic compound 20 in 53% and 21 in 24% yield as an inseparable diastereomeric mixture. Selective TBS group deprotection of compound 20 using p-TsOH led to compound 21 in 40% yield (brsm 96% yield). Surprisingly, after many attempts at chemo- and stereoselective hydrogenation of diastereomeric mixture 21, the desired compound (−)-22 was obtained in excellent yield as a single isomer. Thus, treatment of diastereomeric mixture 21 with Crabtree’s catalyst10 in CH2Cl2 at room temperature afforded the desired (−)-22 in 96% yield as a single isomer. The stereochemistry of the two newly formed stereocenters of (−)-22 were confirmed by X-ray crystallographic analysis of (−)-1. Then, selective methylation of secondary alcohol (−)-22 provided compound (+)-6 in 98% yield. The TBS deprotection of (+)-6 gave (−)-2 (proposed structure of guignardone I) in quantitative yield. Furthermore, dehydration of compound (+)-6 with Burgess reagent,11 followed by TBS deprotection, afforded (−)-1 (proposed structure of guignardone H) in 50% yield over two steps. The structure of compound (−)-1 was confirmed unambiguously by X-ray crystallographic analysis. A proposed reaction mechanism for the chemo- and stereoselective hydrogenation (from 21 to (−)-22) is shown in Figure 2.
Thus, the asymmetric syntheses of the proposed structures of guignardone H (1) and I (2) were achieved. However, the 1H and 13C NMR spectra of synthetic 1 and 2 were not identical to those of naturally occurring guignardone H and I.1d Especially, in the spectra of 1 and 2, the chemical shift of the cyclohexenone moiety was different from the reported chemical shift of the guignardones.12 Therefore, the diastereomers of 1 and 2 with different stereochemistry of the cyclohexenone moiety are the real structures of guignardone H and I. Based on this assumption, a literature search was conducted to determine whether naturally occurring products with these spectra had been reported. Fortunately, the NMR spectra of two naturally occurring products, tricycloalternarene F (24)1b and guignarenone C (25),13 were identical with those of naturally occurring guignardone H. Tricycloalternarene F (24) has same planar structure as guignardone H; however, the stereochemistry of the cyclohexenone moiety was not determined.1b Guignarenone C (25) has cis-1,3-disubstituents on the cyclohexenone ring and an angular methyl group, isopropenyl group, and substituents on the cyclohexenone ring also in a cis-orientation. Therefore, the actual structures of guignardone H and I were predicted to be compounds 26 and 27, respectively, which are C4-epimers of (−)-1 and 2, respectively. The syntheses of 26 and 27 were conducted using compound (−)-2 as a starting material (Scheme 4). Thus, Mitsunobu reaction of (−)-2 with p-bromobenzoic acid led to compound (−)-28 in 83% yield. Solvolysis of (−)-28 provided desired compound (−)-27 in 58% yield. Dehydration of compound (−)-28 with Burgess reagent, followed by the solvolysis, afforded compound (−)-26 in 48% for two steps. The 1 H and 13C NMR spectra of both (−)-26 and (−)-27 were Scheme 4a
Figure 2. Proposed reaction mechanism for the chemo- and stereoselective hydrogenation of diastereomeric mixture 21.
It is proposed that Crabtree’s catalyst can coordinate to the secondary or tertiary alcohols to direct the hydrogenation of compound 21. For β-21, the hydroxyl groups would direct hydrogenation to the more sterically hindered concave face, which is disfavored and does not proceed. In contrast, hydroxyl groups would direct hydrogenation to the convex face of α-21, so hydrogenation can proceed to give (−)-22. It is hypothesized that an equilibrium exists between α-21 and β-21 via the 6πelectrocyclization of dienone A, which enables the hydrogenation reaction to converge the diastereomeric mixture exclusively to (−)-22.
a Reagents and conditions: (a) p-bromobenzoic acid, PPh3, DEAD, THF, RT, 83%; (b) 2 M NH3 in MeOH, RT, 58%; (c) Burgess reagent, benzene, reflux, 56%; (d) 2 M NH3 in MeOH, 60 °C, 85%.
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DOI: 10.1021/acs.orglett.9b00486 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(+)-31 in 36% yield as single isomer, respectively. Treatment of (+)-30 with Crabtree’s catalyst provided the desired (+)-32 in 91% yield as a single isomer. Selective TBS group deprotection of (+)-32 led to compound (+)-33. The stereochemistry of compound (+)-33 was confirmed using X-ray crystallographic analysis. Mitsunobu reaction of (+)-33 with formic acid, followed by solvolysis provided desired compound (+)-34 in 65% yield over two steps. The secondary alcohol selective methylation of (+)-34 afforded compound (+)-35 in 93% yield. Finally, dehydration of compound (+)-35 with Burgess reagent, followed by TBS deprotection, provided compound (+)-26 in 45% yield for two steps. The optical rotation absolute values of (+)- and (−)-26 were similar, suggesting that the isolated guignardone H is a racemic mixture or includes impurities. Additionally, the optical rotations of synthetic 26, (−)-tricycloalternarene F (24),1b and (+)-guignarenone C (25)13 were compared, and the absolute stereochemistries were determined as shown in Scheme 5. The result indicates that tricycloalternarene F and guignarenone C are enantiomers. In conclusion, a chiral diketone (+)-9 was developed and utilized in the first asymmetric synthesis of proposed guignardone H (1) and (2) in 11 and 10 linear steps from (−)-limonene (17). The syntheses featured the sequential condensation−cyclization reaction of unsaturated aldehyde (−)-8 and diketone (+)-9 to construct the tricyclic skeleton of guignardones, and chemo- and stereoselective hydrogenation with Crabtree’s catalyst utilized the equilibrium involving compound 21 via 6π-electrocyclization. Although synthetic 1 and 2 were different from naturally occurring guignardone H and I, compounds 26 and 27, which were C4-epimers of 1 and 2, were demonstrated to be the true structures of guignardone H and I. In addition, the absolute stereochemistry of guignardone I and guignarenone C and the relative and absolute stereochemistry of tricycloalternarene F were determined. This methodology can be extended to the synthesis of other guignardones and structurally related meroterpenoids. Further investigations are now in progress.
identical to those of naturally occurring guignardone H and I, respectively. These results suggest that the relative stereochemistry of some guignardones (guignardones J, K, L, R, and S1f,h) might be incorrect because it was determined based on the relative stereochemistry of guignardone H and I. The optical rotations of synthetic (−)-27 had the same rotation as that reported for natural guignardone I [synthetic 27: [α]D −35.7 (c 0.37, MeOH); guignardone I: [α]D −32 (c 0.24, MeOH),1d so the absolute stereochemistries were determined as depicted in Scheme 4. However, the optical rotation of synthetic (−)-26 had the reverse rotation with a very different absolute value than that reported for natural guignardone H.1d Therefore, to confirm the absolute value of compound 26, the synthesis of (+)-26 was conducted (Scheme 5). Sequential condensation−6π-electrocyclization reaction with unsaturated aldehyde (+)-8, prepared from (+)-limonene through an established procedure (Scheme 3), and diketone (+)-9 afforded tricyclic compound (+)-30 in 45% yield and Scheme 5a
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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.9b00486. General methods; detailed experimental studies; experimental procedures and spectral data; 1H and 13C NMR spectra (PDF) Accession Codes
CCDC 1884504−1884505 and 1884515 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.
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AUTHOR INFORMATION
Corresponding Author
a
Reagents and conditions: (a) piperidinium acetate, MS 4 Å, Et2O, RT, 45% (+)-30 (single isomer), 36% (+)-31 (single isomer); (b) (+)-33, H2, Crabtree’s catalyst, CH2Cl2, RT, 91%, single isomer; (c) 0.5 M HCl, THF, RT, 66%; (d) formic acid, PPh3, DEAD, RT; (e) 5% NH3 in H2O, RT, 65% (2 steps); (f) MeI, Ag2O, MS 4 Å, Et2O, reflux, 93%; (g) Burgess reagent, benzene, 50 °C; (h) 3 M HCl, THF, RT, 45% (2 steps).
*E-mail:
[email protected]. ORCID
Toyoharu Kobayashi: 0000-0002-7362-1129 Yuichiro Kawamoto: 0000-0003-1245-2090 Hideki Abe: 0000-0002-3608-7123 D
DOI: 10.1021/acs.orglett.9b00486 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science of the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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REFERENCES
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DOI: 10.1021/acs.orglett.9b00486 Org. Lett. XXXX, XXX, XXX−XXX
