Letter Cite This: Org. Lett. 2017, 19, 5549-5552
pubs.acs.org/OrgLett
Total Synthesis of the Proposed Structure of (±)-Nidemone Day-Shin Hsu,* Jen-Yu Yeh, and Chiao-Yun Cheng Department of Chemistry and Biochemistry, National Chung Cheng University, Minhsiung 621, Taiwan S Supporting Information *
ABSTRACT: Total synthesis of the proposed structure of (±)-nidemone has been accomplished either from 2-hydroxy-6methoxybenzaldehyde (7) or 2-bromo-6-methoxybenzaldehyde (8) in 10 and 13 synthetic steps, respectively. Sonogashira coupling, regioselective hydrogenation, and an intramolecular Stetter reaction were the key steps in the synthesis.
N
idemone (1),1 which possesses a novel benzo-fused spiro[4.5]decane framework and a β-methoxy-α,β-unsaturated enone moiety, was isolated from an orchid, Nidema boothii, in 2004 (Figure 1). Nidemone (1) exhibits some
Scheme 1. Retrosynthetic Analysis
Figure 1. Structure of nidemone.
interesting biological activities.1 The carbocyclic skeleton of nidemone (1) is novel for any known naturally occurring product. The absolute configuration of natural (−)-1 was deduced on the basis of the circular dichroism data. In this paper, we report the first total synthesis of the proposed structure of (±)-nidemone. Retrosynthetically, we envisioned spirocyclic 1,4-dione 2 to be a potentially well-suited structure to access nidemone (1) (Scheme 1). Spirocyclic 1,4-dione 2 would be obtained from key intermediate 3 via an intramolecular Stetter reaction. Spirane precursor, enone−benzaldehyde 3, would be generated from enynone 4 through the regioselective reduction of the triple bond. Enynone 4 would be obtained from triflate 5 and 6 via Sonogashira coupling. Triflate 5 was prepared from 2-hydroxy-6-methoxybenzaldehyde (7) in 98% yield using phenylbis(trifluoromethanesulfonimide) as a triflating reagent (Scheme 2). Coupling of 5 and 6 was carried out with triethylamine in the presence of bis(triphenylphosphine)palladium(II) dichloride and copper(I) iodide in DMF at 120 °C, and coupling product 4, which bears all the necessary carbon atoms present in the nidemone, was obtained in 50% yield. Attempts to improve the yield by changing the palladium catalyst, solvent, and temperature were unsuccessful. Selective reduction of the alkyne moiety took place with hydrogen in the presence of Pd/ C in isopropyl alcohol and EtOAc to furnish enone− benzaldehyde 3. © 2017 American Chemical Society
Because the yield of the coupling reaction between 5 and 6 was only 50%, we designed an alternative procedure to synthesize enone−benzaldehyde 3, as outlined in Scheme 3. This synthesis started from known 2-bromo-6-methoxybenzaldehyde (8).2 The protection of the aldehyde with 2,2-dimethyl1,3-propanediol afforded 9,3 which was followed by a lithium− halogen exchange and subsequent treatment with DMF to give benzaldehyde 10. The aldehyde was then transformed into acetylene using Bestmann−Ohira reagent 114 in the presence of potassium carbonate in methanol. Coupling 12 with 13 under Sonogashira conditions5 gave 14 in 91% yield. It is Received: August 25, 2017 Published: September 29, 2017 5549
DOI: 10.1021/acs.orglett.7b02645 Org. Lett. 2017, 19, 5549−5552
Letter
Organic Letters
the recovery of the starting material. The reason for the failure of the coupling reaction is probably due to the steric hindrance between the o-acetal group in 9 and enynone 6. Selective reduction of the triple bond was carried out with a hydrogen balloon in the presence of Lindlar’s catalyst in MeOH/THF (1:2).6 The reaction was completed in 1 h and gave desired product 15 in 81% yield. It should be mentioned that when this reaction was carried out in a more polar solvent system, e.g., MeOH or MeOH/THF (1:1), the double bond was also reduced. With a less polar solvent system, e.g., MeOH/THF (1:3), 15 was also obtained in a similar yield (80%); however, the reaction took 2 h to reach completion. Hydrolysis of the acetal moiety with bis(acetonitrile)dichloropalladium(II) in acetone7 gave the desired enone−benzaldehyde 3 in 95% yield. At this stage, we have developed two different procedures for the preparation of enone−benzaldehyde 3 from 7 and 8 in three and six synthetic steps, respectively. Although the threestep sequence yields a lower overall yield (34%) than the sixstep sequence (55%), this procedure shows that the desired 3 is more efficiently prepared than the latter. With compound 3 in hand, we then turned our attention to the construction of the spiro core of nidemone. Compound 3 was first treated with thiazolium salt A (1 equiv)8 and triethylamine (2 equiv) in refluxing ethanol, and the intramolecular Stetter reaction proceeded smoothly to give desired product 2 in 62% yield (Table 1, entry 1). Decreasing the amount of thiazolium salt A from 1.0 equiv to 0.2 equiv under the same conditions led to the formation of spiro compound 2 in 67% yield (entry 2). Attempts to improve the yield by using other thiazolium salts (B and C) were not successful (entries 3 and 4). When the reaction was carried out with triazolium salts instead of thiazolium salts and potassium bis(trimethylsilyl)-
Scheme 2. Preparation of Spirane Precursor 3
Scheme 3. Alternative Procedure for the Preparation of Enone−Benzaldehyde 3
Table 1. Intramolecular Stetter Reaction of 3
noteworthy that the coupling of bromoacetal 9 with enynone 6 under Sonogashira conditions was unsuccessful and led only to
entry
cat. (equiv)
1 2 3 4 5
A (1.0) A (0.2) B (0.2) C (0.2) D (0.2)
6
E (0.2)
a
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base (equiv) Et3N (2.0) Et3N (2.0) Et3N (2.0) Et3N (2.0) KHMDS (0.2) KHMDS (0.2)
solvent
temp (°C)
time (h)
yield (%)
EtOH EtOH EtOH EtOH PhMe
reflux reflux reflux reflux rt
8 8 8 8 24
62 67 54 40 a
PhMe
rt
24
a
Recovery of the starting material. DOI: 10.1021/acs.orglett.7b02645 Org. Lett. 2017, 19, 5549−5552
Letter
Organic Letters amide (KHMDS) in toluene at room temperature,9 only the starting material was recovered (entries 5 and 6). Having achieved the construction of the required benzofused spiro[4.5]decane core 2 from 3 in good yield, we then proceeded to install the remaining methyl enol ether on the cyclopentanone. Oxidation of 2 with o-iodoxybenzoic acid (IBX) and N-methylmorpholine N-oxide (NMO)10 afforded cyclopentenone 17 (Scheme 4). Deprotection of the methyl Scheme 4. Completion of the Total Synthesis of 1
Figure 2. ORTEP plot of the crystal structure of 1 (numbering is arbitrary). Ellipsoid contour percent probability level is 50%.
Figure 3. Suggested structure of nidemone.
Sonogashira coupling, regioselective hydrogenation, and an intramolecular Stetter reaction were the key steps in our strategy. It is noteworthy that the intramolecular Stetter reactions used to prepare spirocyclic structures are known;14 however, this is the first example using intramolecular Stetter reaction to construct an all-carbon spirocyclic skeleton in natural product synthesis. Further investigation to synthesize our suggested structure of nidemone is currently underway.
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ether with boron tribromide followed by conversion of the resulting hydroxyl group to acetate gave 18. Michael addition of thiophenol to cyclopentenone under basic conditions11 generated phenyl sulfide 19, which was then treated with Nchlorosuccinimide (NCS)12 to afford phenyl vinyl sulfide intermediate 20. It should be noted that without modification of the phenol-protecting group from methyl to acetyl, a complex mixture was observed when the corresponding phenyl sulfide derived from 16 was treated with NCS. Finally, removal of the acetyl group and replacement of the phenyl sulfide moiety were achieved simultaneously by the reaction with sodium methoxide13 to give 1. However, the 1H and 13C NMR spectra of 1 were different from those reported for the natural product. The structure of (±)-1 was further confirmed by single-crystal X-ray diffraction analysis (Figure 2). By comparison of 13C NMR data between natural and synthetic 1, we found that there are three quite different signals in the β-methoxycyclopentenone moiety as indicated by asterisks in Figure 3. Therefore, we suggested that the methyl enol ether and ketone should be transposed in the cyclopentane ring for natural nidemone (Figure 3). In conclusion, total synthesis of the proposed structure of (±)-nidemone (1) has been accomplished from either 2hydroxy-6-methoxybenzaldehyde (7) or 2-bromo-6-methoxybenzaldehyde (8) in 10 and 13 synthetic steps, respectively.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02645. Comparison tables of the 1H and 13C NMR data between natural and synthetic 1; experimental procedures and spectra data of all new compounds (PDF) X-ray crystallographic data and CIF file for 1 (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Day-Shin Hsu: 0000-0002-2196-7451 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to Dr. Gene-Hsiang Lee, Department of Chemistry, National Taiwan University, for the X-ray crystallographic measurement. We thank the Ministry of Science and 5551
DOI: 10.1021/acs.orglett.7b02645 Org. Lett. 2017, 19, 5549−5552
Letter
Organic Letters Technology (MOST) of the Republic of China for financial support (MOST 102-2113-M-194-001-MY3).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02645 Org. Lett. 2017, 19, 5549−5552
