Synthesis of Four Illudalane Sesquiterpenes Utilizing a One-Pot Diels

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Synthesis of Four Illudalane Sesquiterpenes Utilizing a One-Pot Diels−Alder/Oxidative Aromatization Sequence Miao-Miao Xun,† Yunli Bai,† Yanhong Wang, Zhiyong Hu, Kai Fu, Wenbing Ma, and Changchun Yuan* National Demonstration Center for Experimental Chemical Engineering Comprehensive Education, School of Chemical Engineering and Technology, North University of China, Taiyuan 030000, P.R. China

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S Supporting Information *

ABSTRACT: The concise, divergent total syntheses of four illudalane sesquiterpenes using an indanone as the key intermediate are reported. The key elements in these total syntheses, which involve only four to six operational steps, consist of a Suzuki cross-coupling and a one-pot Diels−Alder/oxidative aromatization reaction.

T

used to synthesize another member of the illudalane class, coprinol.6 By use of the same strategy, alcyopterosin A was synthesized by Iglesias and co-workers in 14 steps using a bromoindanone as a key intermediate.7 Unfortunately, these approaches required multiple steps to achieve the requisite functionalization of the benzene core. The transition-metal-catalyzed [2 + 2 + 2] alkyne cycloaddition is a well-known, powerful reaction for the one-step construction of highly substituted benzenes,8 and such transformations in the synthesis of natural products have been widely used.9 Notably, several groups have reported efficient entry to a family of illudalane sesquiterpenoids, the alcyopterosins, enabled by Rh(I)-catalyzed inter- or intramolecular [2 + 2 + 2] alkyne cyclotrimerization reactions.10 Using a Ti-mediated formal [2 + 2 + 2] cycloaddition reaction, Sato and co-workers accomplished the synthesis of alcyopterosin A.11 Another interesting Pd-mediated cycloaddition reaction of conjugated enynes, developed by Nakao and coworkers,12 accomplished the synthesis of alcyopterosin N. Although such reactions have proven effective for this family of natural products, preparations of the functionalized triynes that serve as the cyclotrimerization precursors are often cumbersome. Most notably, in 2016, Dudley et al. reported a six-step synthesis of alcyopterosin A using a Rh-catalyzed oxidative cycloisomerization as a key step.13 More recently, Zhang et al. published the divergent total syntheses of five illudalane sesquiterpenes, including four of which are granulolactone (1), echinolactone A (2), radulactone (3), and riparol B (4) (Figure 1, B). Although their approach involved a Rh(I)-

he illudalane sesquiterpenes are a rare class of natural products typically isolated from fungi and ferns.1 Owing to their intriguing bioactivity profiles2 and unique structural features (Figure 1),2,3 total synthesis endeavors toward the

Figure 1. Selected illudalane natural products.

illudalane sesquiterpenoids have attracted extensive attention. Classic aromatic substitution chemistry, as the most direct and effective method, has been applied to synthesize these compounds. For example, as early as 1987, Rao and coworkers reported the total synthesis of onitin in 16 steps, starting from 2,4-dimethylphenol.4 In 2018, Singh et al. reported a nine-step synthesis of onitin characterized by Suzuki−Miyaura cross-coupling and Wacker oxidation reactions using their previously reported dimethylated indanone as a starting material5 and a key intermediate; the latter was also © XXXX American Chemical Society

Received: July 19, 2019

A

DOI: 10.1021/acs.orglett.9b02511 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters catalyzed intermolecular [2 + 2 + 2] cycloaddition as well as a lactone-directed aromatic C−H oxygenation (Figure 2),14 the

Scheme 2. Total Syntheses of 1−4

overall number of steps was unsatisfactory. Contemporaneously, we also completed the operationally simple total syntheses of 1−4 and herein describe these efforts (Figure 2). Our retrosynthetic analysis is shown in Scheme 1. Compound 1 could be accessed from echinolactone A (2)

reaction also performed very well for this transformation (Scheme 2, B). Next, we prepared intramolecular Diels− Alder/oxidative aromatization precursor 6 via an esterification reaction. Satisfactorily, the exposure of ketone 8 and acid 7 to DCC/DMAP/DCM at 0 °C easily generated 6 in 89% yield. With substrate 6 in hand, our next goal was the efficient preparation of indanone 5. Initially, we attempted to achieve the [4 + 2] Diels−Alder and oxidative aromatization reactions in one pot under thermodynamic conditions (Table 1). A

Scheme 1. Retrosynthetic Analysis

Table 1. Optimization of One-Pot Synthesis of 5 from 6

Figure 2. (Top) Total syntheses of granulolactone (1), echinolactone A (2), radulactone (3), and riparol B (4) reported by Zhang et al. (Bottom) Total syntheses of reported herein.

via Clemmensen reduction, and 2 could be obtained from indanone 5 after bismethylation. The strategic, de novo construction of arenes demonstrates the power at the late stage of total syntheses of arene-containing natural products.15 Thus, we speculated that the benzene ring of indanone 5 could be constructed by the intramolecular Diels−Alder reaction of propiolic acid ester 6, followed by oxidative aromatization. Disconnection of the ester bond of 6 would lead to dienone 8 and propiolic acid 7. Further disconnection of the C2−C3 bond of 8 gives rise to the two cross-coupling building blocks, which include commercially available 3-iodocyclopent-2-enone 10 and known compound 9.16 As outlined in Scheme 2, our synthesis commenced with known 3-iodocyclopent-2-enone 10, which could be prepared from commercially available 1,3-cyclopentanedione in one step17 or commercially acquired. To prepare conjugated dienone 8, a Suzuki or Stille cross-coupling reaction was employed using easily accessible organoboron 9a or organotin 9b, respectively, according to the literature.16 To our delight, the Pd-catalyzed Suzuki cross-coupling of 10 and 9a smoothly afforded 8 in quantitative yield (Scheme 2, A), while the Stille

entry

conditionsa

yield (%)

1 2 3 4 5 6 7

toluene, DDQ,b 80 °C toluene, DDQ, 160 °C DMSO, O2, 160 °C, 5 h toluene, O2, 160 °C, 5 h toluene, Ar, 160 °C, 5 h; then O2, 5 h toluene, Ar, 160 °C, 6 h; then air, 6 h toluene, Ar, 160 °C, 15 h; then air, 15 h

NRc complex 18 29 46 55, brsm,d 69 71

a All reactions were carried out in a sealed tube. bDDQ = 2,3-dichloro5,6-dicyano-1,4-benzoquinone. cNR = no reaction. dbrsm = based on recovered starting material.

DDQ-mediated oxidation protocol was first employed,18 but to our disappointment, desired product 5 was not detected regardless of temperature (80 or 160 °C, Table 1, entries 1 and 2). Subsequently, using an O2 oxidation protocol instead of DDQ improved the results, although the indanone 5 was generated in low yield (Table 1, entries 3 and 4). Toluene proved more favorable than DMSO as solvent for this reaction. Considering that the transformation involves two steps, we first effected the intramolecular [4 + 2] cyclization of 6 by heating under argon atmosphere before subjecting the resultant 1,4diene (11) to O2 oxidation to afford indanone 5 in 46% yield (Table 1, entry 5). Most interestingly, using air as the oxidant instead of O2 immensely improved the yield, and compound 5 was obtained in a yield of 69% brsm (Table 1, entry 6). Finally, prolonging the reaction times for both the [4 + 2] cyclization B

DOI: 10.1021/acs.orglett.9b02511 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

oxidative aromatization, and alkylation reactions and is amenable for the preparation of additional structural analogues of the illudalane sesquiterpenes.

and oxidative aromatization steps boosted the yield of 5 to 71% (Table 1, entry 7). From key intermediate 5, we completed the syntheses of the four target illudalanes through simple transformations (Scheme 2, A). Application of NaH/MeI-mediated dimethylation conditions produced echinolactone A (2),6 an illudalane sesquiterpenoid isolated from the culture broth of the fungus Echinodontium japonicum,2e in 84% yield. The molecular structure of 2 was confirmed by single-crystal X-ray crystallography. Subsequently, we subjected 2 to Clemmensen reduction conditions (Zn−Hg/H2SO4)6 to furnish granulolactone (1), which was originally isolated from an agar plate culture of Granulobasidium vellereum by Kokubun et al. in 2016.2h Exposure of 1 to DIBAL-H at −78 °C afforded riparol B (4),14 a potent pesticide against thrips,2f in 88% yield. Finally, NaBH4 reduction of the ketone in 2 provided (±)-radulactone (3), isolated from the fungus Radulomyces confluens (Fr.) M.P. Christ.,19 in 85% yield. Thus, with these manipulations, we achieved the concise total syntheses of the four illudalane sesquiterpenes. Furthermore, the practicality of this method was exemplified by gram-scale synthesis of echinolactone A.20 Finally, we turned our attention to investigating the asymmetric synthesis of radulactone (3). Through total synthesis, the absolute configuration of natural 3 was assigned as 1S by Zhang et al. (Scheme 3).14 Initial asymmetric

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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.9b02511. Full experimental procedures, characterization data, copies of the NMR spectra for all new compounds (PDF) Accession Codes

CCDC 1940530 contains 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

*E-mail: [email protected]. ORCID

Changchun Yuan: 0000-0002-2889-4566

Scheme 3. Asymmetric Synthesis of Radulactone

Author Contributions †

M.X. and Y.B. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Grant No. 21702192), Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi (STIP), Applied Basic Research Programs of Shanxi Province (Grant No. 201801D221087), and Program for Young Leaders of Disciplines in North University of China (Grant No. QX201806). Prof. Dr. Kuiling Ding and Dr. Zhaobin Han (State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences) are highly appreciated for their assistance in the asymmetric hydrogenation of echinolactone A (2).

reduction testing for the chiral reagent (−)-DIP chloride was disappointing,21 which resulted only in recovery of ketone 2 because of the high steric hindrance around the ketone group. We then attempted to accomplish the enantioselective synthesis of (+)-radulactone (3) by utilizing a known procedure,14 and the venerable CBS reduction can afford (+)-radulactone (3) in 47% yield with only 67% ee (Scheme 3). Asymmetric hydrogenation of carbonyl compounds is one of the most important catalytic reactions against synthesis of optically active secondary alcohols.22 Ultimately, a strategy of asymmetric hydrogenation of 2 was proved to be successful (Scheme 3), and chiral alcohol (−)-radulactone (3) was obtained in nearly quantitative yield with excellent enantioselectivity (98% ee) catalyzed by Mn complex (R, R)-12, which developed by Ding and co-workers.23 So far, the asymmetric synthesis of (−)-radulactone is well solved. In summary, the total syntheses of illudalanes 1−4 were accomplished in four to six steps from a readily available material, 3-iodocyclopent-2-enone (10). Our divergent synthetic strategy features Suzuki cross-coupling, Diels−Alder/

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REFERENCES

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