Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Total Syntheses of Stoloniferol B and Penicitol A, and Structural Revision of Fusaraisochromanone Tatsuki Ohashi and Seijiro Hosokawa* Department of Applied Chemistry, Faculty of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan S Supporting Information *
ABSTRACT: The first total synthesis of stoloniferol B and penicitol A has been achieved. Stoloniferol B, which is the common structure of citrinin derivatives, has been constructed by a sequential elaboration that includes a stereoselective vinylogous Mukaiyama aldol reaction, a thermal esterification with methyl acetoacetate, an intramolecular Michael reaction, and a vinylogous Dieckmann cyclization. The enantiomer of the proposed structure of fusaraisochromanone and (S)-7-hydroxy-3-((R)-1hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (the enantiomer of a natural stoloniferol derivative) also have been synthesized. The synthesis revised the structure of fusaraisochromanone to (S)-7-hydroxy-3-((R)-1-hydroxyethyl)-5methoxy-3,4-dimethylisobenzofuran-1(3H)-one.
C
itrinin (1) and its derivatives have been isolated from a marine microorganism and found to have attractive bioactivities.1 Stoloniferol B (2, decarboxydihydrocitrinone), isolated from Penicillium stoloniferum QY2-10,2b is a common core structure of citrinin derivatives.3 The structure and activity of citrinin (1) has proven alluring to chemists, and several groups have reported the total synthesis of citrinin.4 However, the total synthesis of stoloniferol B (2) has never been reported.5 Although 2 is not a remarkably bioactive compound, derivatives of 2 have been found to have attractive bioactivities.3 Figure 1 shows some derivatives of 2. Penicitol A (3) has been isolated from mangrove-derived Penicillium chrysogenum HDN11-24 and found to possess antitumor activities.6 The structure and bioactivities of penicitol A (3) spurred us to establish a concise synthesis of 2 and 3. We were also interested in the structures of oxidized derivatives 47 and 5,8 which were reported to be isolated from the endophytic fungus Fusarium sp. PDB51F5 and from the cultured broth of Leptosphaeria sp. KTC 727, respectively. Herein, we present the synthesis of stoloniferol B (2) and its derivatives, including penicitol A (3), the enantiomer of the proposed structure of fusaraisochromanone (ent-4), and (S)-7-hydroxy-3-((R)-1-hydroxyethyl)-5methoxy-3,4-dimethylisobenzofuran-1(3H)-one (ent-5). Our synthetic plan is disclosed in Scheme 1. Penicitol A (3) would be synthesized by the conjugate addition of cyclohexanone (7) to orthoquinone methide 6 and acetalization. Vinylogous ester 6 might be derived from stoloniferol B (2), © XXXX American Chemical Society
Figure 1. Structures of citrinin (1), stoloniferol B (2), and stoloniferol derivatives (3, 4, 5).
while 2 could be constructed by the intramolecular conjugate addition of α,β-unsaturated imide 8, followed by the nucleophilic addition of the methyl ketone moiety to the imide carbonyl group. α,β-Unsaturated imide 8 would be prepared by the vinylogous Mukaiyama aldol reaction with acetaldehyde 9 and vinylketene silyl N,O-acetal 10.9 Our synthesis started with the vinylogous Mukaiyama aldol reaction between 10 and paraldehyde 11 (Scheme 2). The Received: April 3, 2018
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DOI: 10.1021/acs.orglett.8b01048 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
methanolysis to give methyl ester 15. Treatment of βketolactone 15 with potassium carbonate and dimethyl sulfate gave the corresponding enol ether 16, whose major isomer was determined to have 5S, 10R-configuration by X-ray crystallography. Deprotonation at the γ-position of the β-methoxy-α,βunsaturated carbonyl moiety of 16 with sodium hexamethyldisilazide (NaHMDS) led to C−C bond formation, i.e., the vinylogous Dieckmann cyclization,12 to give the cyclohexanone 17. The structures of the major isomer 17a and the minor isomer 17b were determined by X-ray crystallography. As shown in Scheme 3, oxidation of the major isomer 17a with
Scheme 1. Synthetic Plan of Stoloniferol B (2) and Penicitol A (3)
Scheme 3. Reactivity of Diastereomers 17a and 17b
Scheme 2. Total Synthesis of Stoloniferol B (2)
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) afforded 8-Omethyldecarboxyldihydrocitrinone 18 in moderate yield, while minor isomer 17b provided 18 in high yield. We also found that 17a was isomerized to 17b under acidic conditions. Therefore, as shown in Scheme 2, treatment of a mixture of 17a and 17b under acidic conditions, followed by oxidation with DDQ gave 18 in good yield. De-O-methylation of 18 with boron tribromide proceeded smoothly to give stoloniferol B (2) in excellent yield. Spectral data of synthetic 2 were identical with those of natural product.2c Therefore, the first total synthesis of stoloniferol B (2) was achieved. The total synthesis of penicitol A (3) was achieved by transformation of stoloniferol B (2) (Scheme 4). The carbonyl group of stoloniferol B (2) was unreactive to hydride reagents, including dibutylaluminum hydride (DIBAL) and LiAlH4 due to the electron-donating hydroxy groups. In order to increase the reactivity of the carbonyl group, the hydroxy groups were converted to the nosylates (electron-withdrawing groups). Lactone 19 smoothly underwent the reduction with DIBAL to afford the corresponding lactol, which was acetylated in situ to give acetal 20. Acetal 20 was submitted to the Mukaiyama aldol reaction with cyclohexanone derivative 2113 to give adducts 22a (the desired isomer) and 22b in 68% and 24% yields, respectively.14 Treatment of the major isomer 22a with thiophenol under the basic conditions at 0 °C promoted denosylation15 and acetalization to give acetal 23 in good yield. On the other hand, treatment of C14 epimer 22b under denosylation conditions at room temperature afforded a mixture of 23 (40%) and 14-epi-23 (45%). The structure of 23 was confirmed by H NMR including NOE between H1 and H3, as well as the coupling constant between H1 and H14 (11.0 Hz; cf. penicitol A:6 11.6 Hz). Tetracyclic 23 underwent acetalization in methanol under the acidic conditions to give penicitol A (3). The spectral data of synthetic 3 were identical
reaction proceeded in high yield with excellent stereoselectivity to give anti adduct 12.9 The alcohol in 12 was converted to acetoacetate 8 in excellent yield by a thermal reaction with methyl acetoacetate (13) via a ketene intermediate.10 Treatment of acetoacetate 8 with potassium carbonate in the presence of the crown ether at elevated temperature gave bislactone 14,11 of which the right lactone underwent the B
DOI: 10.1021/acs.orglett.8b01048 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Scheme 5. Synthesis of the proposed structure of entfusaraisochromanone (ent-4) and (S)-7-hydroxy-3-((R)-1hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)one (ent-5)
Scheme 4. Total Synthesis of Penicitol A (3)
with those of natural product. Therefore, the first total synthesis of penicitol A (3) was achieved. In addition, we accomplished a synthesis of the enantiomer of the proposed structure of fusaraisochromanone (ent-4) and (S)-7-hydroxy-3-((R)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (ent-5), the enantiomer of natural stoloniferol derivative (Scheme 5). 8-O-Methylstoloniferol B (18) was exposed to phenyliodinebis(trifluoroacetate) (PIFA) in a mixed solvent of 2,2,2-trifluoroethanol (TFE) and acetic acid (1:1) to afford α-acetoxyketone 24 and α-(2,2,2trifluoroethoxy)ketone 25. Treatment of 24 under acidic conditions promoted de-O-methylation and formation of the benzyl alcohol 27. The structure of 27 was determined by conversion to methyl ether ent-4 (vide infra). Trifluoroethyl ether 25 also underwent hydrolysis to give 27. The tertiary alcohol at C4 position of the major product 27 was constructed by approach of water to cation 26 from the opposite face of C3methyl group. The minor product 25 was also converted to 27 in the similar manner. Selective O-methylation of 27 under mild conditions provided ent-4, the enantiomer of the proposed structure of fusaraisochromanone. HMBC between H3 and C1 proved the δ-lactone, and stereochemistry of C4 position was determined by NOESY between two methyl groups of C3 and C4 positions. However, 1H and 13C NMR spectral data of synthetic ent-4 were not identical with those of the reported compound7 (Tables 1 and 2). Treatment of δ-lactone ent-4 with sodium methoxide in methanol produced γ-lactone ent-5, (S)-7-hydroxy-3-((R)-1hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)one.16 1H and 13C NMR spectral data of synthetic ent-5 were identical with those of the natural product8 (see Tables 1 and 2). To our surprise, 1H and 13C NMR spectral data of synthetic ent-5 were also identical with those of the reported 47 (fusaraisochromanone). Characterization of the natural product
Table 1. 400 MHz 1H NMR (CDCl3) Spectral Data of ent-4, Reported 4, ent-5, and Reported 5 synthetic ent-4
reported 4
synthetic ent-5
reported 5
11.62
11.28 7.87 6.43 4.22 3.88 2.11 1.80 0.93
7.85 6.43 4.21 3.88 2.11 1.80 0.93
7.88 6.43 4.22 3.88 2.11 1.80 0.93
6.44 4.38 3.86 2.34 1.50 1.49
Table 2. 100 MHz 13C NMR (CDCl3) Spectral Data of ent-4, Reported 4, ent-5, and Reported 5
C
synthetic ent-4
reported 4
synthetic ent-5
reported 5
170.1 165.2 163.3 145.0 115.8 99.3 98.4 80.1 72.2 55.9 19.3 13.7 12.1
171.5 165.4 156.5 149.9 112.2 103.0 98.2 91.9 71.0 56.3 21,2 17.8 11.2
171.5 165.3 156.4 149.8 112.2 102.9 98.2 91.9 70.9 56.3 21.3 17.8 11.2
171.5 165.4 156.5 149.9 112.2 103.0 98.2 91.3 70.9 56.3 21.3 17.8 11.2
DOI: 10.1021/acs.orglett.8b01048 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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from Fusarium sp. PDB51F58 indicated the γ-lactone 5, not δlactone 4. Isomerization of a γ-hydroxy-δ-lactone to the corresponding γ-lactone is well-established.16 These results indicate that fusaraisochromanone possesses a γ-lactone. However, the optical rotation of synthetic ent-5 ([α]D22 +23.6 (c 0.29, CHCl3)) indicated the absolute configuration of fusaraisochromanone ([α]D25 +23.2 (c 0.05, CHCl3)7) to be ent-5. Therefore, the structure of fusaraisochromanone was revised to (S)-7-hydroxy-3-((R)-1-hydroxyethyl)-5-methoxy3,4-dimethylisobenzofuran-1(3H)-one. In conclusion, the first total synthesis of stoloniferol B (2) and penicitol A (3) has been achieved. In the synthesis of stoloniferol B, the stereogenic centers were constructed by a vinylogous Mukaiyama aldol reaction using vinylketene silyl N,O-acetal 10, and sequential transformations, including the thermal esterification with methyl acetoacetate, an intramolecular Michael reaction, and a vinylogous Dieckmann cyclization. We also synthesized the enantiomer of the proposed structure of fusaraisochromanone (ent-4) and (S)-7hydroxy-3-((R)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (ent-5), the enantiomer of a natural stoloniferol derivative. The synthesis revised the structure of fusaraisochromanone to (S)-7-hydroxy-3-((R)-1-hydroxyethyl)5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one.
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REFERENCES
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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.8b01048. Experimental procedures, spectral data of compounds, and 1H and 13C NMR spectra (PDF) Accession Codes
CCDC 1835147−1835149 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, U.K.; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Seijiro Hosokawa: 0000-0002-8036-532X Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful for financial support from the Kurata Memorial Hitachi Science and Technology Foundation, the Naito Foundation, the Sumitomo Foundation, and the Tokyo Biochemical Research Foundation. D
DOI: 10.1021/acs.orglett.8b01048 Org. Lett. XXXX, XXX, XXX−XXX
