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Asymmetric Total Synthesis of (−)-Spirochensilide A Xin-Ting Liang, Jia-Hua Chen,* and Zhen Yang*

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ABSTRACT: An asymmetric total synthesis of (−)-spirochensilide A has been achieved for the first time. The synthesis features a semipinacol rearrangement reaction to stereoselectively construct the two-vicinal quaternary chiral centers at C8 and C10, a tungsten-mediated cyclopropene-based Pauson−Khand reaction to install the C13 quaternary chiral center, and a furan-based oxidative cyclization to stereoselectively form the spiroketal motif.

Spirochensilide A (1, Figure 1) 1 is a member of an

emerging and biologically important class of natural

products with a unique spirocyclic core2,3 and has been isolated by Gao and co-workers from Abies chensiensis, which is an endemic Chinese plant.4 The crude extracts and metabolites of the Abies species have been found to possess various bioactivities, including antitumor, antimicrobial, antiulcero- genic, anti-inflammatory, antihypertensive, antitussive, and central nervous system activities.5 Biologically, 1 showed a moderate inhibitory effect on the NO production with 30% inhibition at the concentration of 12.5 μg/mL, indicating 1 could be a useful probe for study of inflammatory diseases.6

The structure of 1 was determined on the basis of NMR spectroscopic data and single-crystal X-ray diffraction analysis. The structure contains two pairs of vicinal all-carbon quaternary chiral centers7 (C8/C10 and C13/17), an unusual spiro[4.5]ring system (BC ring), and an anomeric spiroketal

(EF ring).8 Natural products bearing both quaternary chiral centers and spirocycles can impose conformational constraints to reduce the conformational entropy penalty upon binding to a protein target in a favorable geometry.9

Herein, we report our effort on the development of an approach for the asymmetric total synthesis of spirochensilide A (1). The synthesis features a semipinacol rearrangement and a tungsten-mediated cyclopropene-based Pauson−Khand (PK) reaction as key steps. Figure 1 illustrates our retrosynthetic analysis. We

envisioned that the anomeric spiroketal of 1 could be derived from furyl alcohol A via an intramolecular oxidative cyclization.10 A was expected to be constructed from ketones B and C via a furyl acetaldehyde aldol condensation11 as a key step. To construct the cyclopentenone bearing an all-carbon quaternary chiral center in intermediate B, we intended to employ the PK reaction12 of enyne D because this reaction has been successfully applied in our total synthesis of the nontriterpenoid propindilactone G.13 Enyne D was expected to be derived from aldehyde E with a pair of vicinal quaternary chiral centers at C8 and C10, which was envisioned to be derived from epoxide F through a semipinacol rearrange- ment.14 F could be prepared via a sequential Pd-catalyzed Sonogashira reaction and epoxidation from vinyl halide G, which in turn could be prepared via a biomimetic cyclization of the functionalized isoprenoid polyene H.15

Our synthesis began by exploring the chemistry for an enantioselective preparation of enyne 8 (Scheme 1). We rationalized that a Lewis acid induced cyclization16 of polyenoid 2 could enantioselectively afford halogenated decalin18 3 bearing three stereogenic centers at C3, C5, and C10 via a concerted cyclization process.17 The selectivity results from the chair-like transition state were achieved via a

Received: March 4, 2020 Published: April 14, 2020

Figure 1. Retrosynthetic analysis of spirochensilide A (1).

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sequence of biomimetic epoxide-initiated cationic cyclization and nucleophilic bromination reaction. Experimentally, we found that vinyl bromide 3 could be

obtained in 90% yield when acetylenic epoxide 219 of 97% ee was treated with TiCl4 (0.4 equiv) in CH2Br2 at −35 °C for 1 h (Scheme 1),20 and unlike the previously reported protocols,21 the current reaction could be carried out on 50 g scale. We next turned our attention to map out an effective

stereoselective synthesis of aldehyde 6, which bears two vicinal quaternary chiral centers at C8 and C10. To this end, 3 was converted into alkyne 4 in an 88% overall yield by a sequence of conventional Sonogashira and silylation reactions. After epoxidation of 4 with m-CPBA, the resultant epoxide could undergo the proposed semipinacol rearrangement via treat- ment with BF3·Et2O (0.05 equiv)

22 to afford 6 as a single diastereoisomer in 65% yield. The reaction of 6 with Grignard reagent 7 in the presence of CeCl3

23 followed by a silylation afforded 8 in 76% overall yield. We then turned our attention to the synthesis of the

cyclopentenone motif in 9 by the proposed PK reaction (Scheme 2). Initially, we attempted various Co-mediated PK reactions of 8; however, desired product 9 was not observed (see Supporting Information (SI) for details). We attributed this failure to the low reactivity of enyne 8 and its steric rigidity. Since enynes bearing a chloride as a σ-electron- withdrawing group could promote polarization and thereby reduce the activation barrier of the Rh-catalyzed PK reaction,24

we prepared chloroenyne 10. However, under different optimized conditions, 11 or 12 was obtained in 33% or 67% yield, respectively. The formation of 11 indicated the expected carbonylative annulation reaction had indeed proceeded and provided the desired C13 quaternary center, but the resultant product underwent a further Rh-catalyzed carbonylative C−H insertion25 to afford 11. While the formation of 12 could be a result of a double bond isomerization followed by a PK

reaction. The structures of 11 and 12 were confirmed by X-ray crystallographic analysis (see SI for details). In 2005, Fox and co-workers reported a cyclopropene-based,

Co-mediated PK reaction26 for the stereoselective synthesis of structurally diverse cyclopropane-based cyclopentenones. We also considered the fact that the inherent strain of cyclo- propene27 can increase its reactivity in PK reactions, and their defined chiral environment can influence the diastereoselective outcome of the PK reaction.28 Since the three-membered ring can be cleaved under mild conditions, we identified an alternative pathway to install the CD ring system into the target molecule 1. With these chemistries in mind, we then applied this strategy

for the synthesis of 15a. To this end, we have developed a diastereoselective approach for the synthesis of enyne 14 via the reaction of aldehyde 6 with lithium reagent 1329 (see SI for details) in the presence of CeCl3 at −98 °C. The resultant secondary alcohol was protected as its TES ether followed by removal of TMS to afford 14 in 73% overall yield in two steps (Scheme 3). However, the annulation of enyne 14, under both the conventional PK reaction (Co2(CO)8) and PK-type reactions (with other metal complexes derived from Rh, Pd, Ir, or Ru), failed to afford 15a. To further explore the PK reactions with other types of metal catalysts, such as W(CO)3(MeCN)3,

30 Ni(COD)2/bipy, 31 and Mo-

(CO)3(DMF)3, 32 we fortunately found out that when

W(CO)3(MeCN)3 was used as the catalyst, 15a was isolated in ca. 30% yield, together with its diastereoisomer 15b in 30% yield. Other catalysts, such as Ni(COD)2/bipy or Mo- (CO)3(DMF)3, could also provide 15a and 15b, but in favor of 15b, although the overall yields were higher (Scheme 3). We also attempted to improve the yield by systematic investigation of the W(CO)3(MeCN)3-catalyzed PK reaction for the formation of 15a; no better results were obtained (see SI for details). To complete the total synthesis of 1 (Scheme 4), initially, we

attempted to carry out the reductive cyclopropane ring- opening reaction by treatment of 15a with SmI2 or

nBu3SnH. However, under such reaction conditions, 15a was converted to 16 through 16a, presumably because the orbitals of the double bond in 15a overlapped better with its carbonyl group than orbitals of its cyclopropane motif. To achieve the regioselective cyclopropane opening, 15a underwent a selective

Scheme 1. Diastereoselective Synthesis of Enyne 8a

aReagents and conditions: (a) TiCl4 (0.4 equiv), CH2Br2 (epoxide 2 was 0.2 M in CH2Br2), −35 °C, 1 h, 90%; (b) Pd(PPh3)2Cl2 (0.05 equiv), CuI (0.03 equiv), DIPA (5.0 equiv), HCCTMS (3.0 equiv), THF, 50 °C, 16 h, 93%; (c) TBSCl (1.3 equiv), imidazole (2.5 equiv), DMF, rt, 15 h, 95%; (d) mCPBA (2.0 equiv), DCM, −30 to 0 °C; then BF3·Et2O (0.05 equiv), DCM, 0 °C, 1 h, 65%, 2 steps; (e) CeCl3 (1.5 equiv), Grignard reagent 7 (1.5 equiv), THF, 0 °C, 30 min; (f) K2CO3 (5.0 equiv), MeOH, rt, 16 h; (g) TBSOTf (1.5 equiv), Et3N (3.0 equiv), DCM, −78 °C to rt, 3 h, 76%, 3 steps.

Scheme 2. Pauson−Khand Reaction of Enyne 8a

aReagents and conditions: (a) nBuLi (1.2 equiv), NCS (1.2 equiv), THF, −78 °C to rt, 87%; (b) [Rh(CO)2Cl]2 (0.5 equiv), CO (1.0 atm), nBu2O, 160 °C, 48 h, 33%; (c) [Rh(CO)2Cl]2 (0.5 equiv), CO (1.0 atm), DCE, 65 °C, 48 h, 67%.

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desilylation to remove its TMS via treatment with tBuOK,33

and the resultant cyclopropane then participated in a Pd/C- catalyzed regioselective hydrogenation to afford ketone 17. 17 was then subjected to a Li/NH3-mediated regioselective reductive ring-opening reaction followed by aprotic-quench- ing34 with dichloroethane (DCE) to afford 18 bearing the trans-fused bicyclic CD ring with the desired C13 stereogenic center in 76% yield over three steps. To regioselectively install the trans-double bond between

C17−C20, 18 was reacted with nBu2BOTf/DIPEA, and the resultant enolate participated in an enol-borane-mediated aldol reaction35 with TBS-stabilized furyl acetaldehyde 19 to afford 20 as a sole isomer in 97% yield. The observed excellent diastereoselectivity should be attributed to the formation of the chairlike transition state TS-A36 in the presence of bulky DIPEA,37 and the structure of 20 was confirmed by X-ray crystallographic analysis of its ester derivative (see SI for details). Thus, further reaction of 20 with 2-fluoro-1- methylpyridin-1-ium tosylate38 followed by a neutral Al2O3- mediated syn-elimination afforded enone 21 in 75% yield. The trans-configurated C17−C20 double bond in 21 was confirmed by 2D-NMR analysis. To diastereoselectively generate the allylic alcohol in 23,

enone 21 underwent a cuprate-mediated 1,4-addition via treatment with Me2CuLi, and the resultant ketone was methylated (MeI/KH) to give ketone 22 bearing the desired C17 and C20 stereogenic centers (see SI for a DFT experiment to account for the diastereoselectivity). Thus, further treatment of 22 with LDA followed by reaction with PhSeCl gave a selenide, which was then selectively oxidized

with m-CPBA and reduced with DIBAL to afford 23 in 66% yield over three steps.

Scheme 3. Synthesis of Cyclopentenones 15a and 15ba

aReagents and conditions: (a) CeCl3 (1.3 equiv), lithium reagent 13 (1.3 equiv), pentane/Et2O = 3:2, −98 °C to −60 °C, 2.5 h, 75%; (b) TESOTf (1.2 equiv), Et3N (3.0 equiv), DCM, −78 to 0 °C, 2 h; then MeOH, K2CO3 (10.0 equiv), rt, 24 h, 98%; (c) W(CO)3(MeCN)3 (1.5 equiv), EtOH/HMPA = 20:1, CO (1.0 atm), rt to 80 °C, 61% (15a:15b = 1:1); (d) Ni(COD)2 (1.1 equiv), 2,2′-bipyridine (1.2 equiv), toluene, CO (1.0 atm), rt, 84%, 15a:15b = 1:4; (e) Mo(CO)3(DMF)3 (1.5 equiv), toluene, 60 °C, 30 min, 70%, 15a:15b = 1:2.

Scheme 4. Synthesis of Spirochensilide A 1a

aReagents and conditions: (a) SmI2 (2.0 equiv), THF/HMPA = 10:1, rt, 30 min, 77%; or nBu3SnH (5.0 equiv), AIBN (0.5 equiv), PhH, 80 °C, 6 h, 44%; (b) tBuOK (7.5 equiv), tBuOH, 85 °C, 4 d, 95%; (c) 5% Pd/C (0.2 wt., type 87L), H2 (balloon), EtOH/EA = 1:1, rt, 12 h; (d) Li-NH3, THF, −78 °C, 15 min; then quenched with DCE, 80%, 2 steps; (e) nBu2BOTf (2.0 equiv), DIPEA (2.5 equiv), DCM, −78 °C, then furyl acetaldehyde 19 (4.0 equiv), −78 °C to −50 °C, 1.5 h, 97%; (f) 2-fluoro-1-methylpyridin-1-ium tosylate (3.0 equiv), Et3N (10 equiv), DCM, rt, 12 h; then neutral Al2O3, rt, 1 h, 75%; (g) Me2CuLi (2.0 equiv), Et2O, −78 °C to −30 °C, 5 h, 86%; (h) KH (1.5 equiv), MeI (4.0 equiv), THF, rt to −78 °C, 81%; (i) LDA (1.2 equiv), THF, −78 to 0 °C; then PhSeCl (1.3 equiv), −98 °C, 15 min, 46% (77% brsm); (j) m-CPBA (1.05 equiv), Et3N (3.5 equiv), DCM, −78 °C to rt, 87%; (k) DIBAL (2.0 equiv), DCM, −78 °C to −10 °C, 3 h, 98%; (l) methylene blue (MB) (10−4 M), O2 (bubble), DCM, hv (tungsten lamp), 0 °C, 2.5 min; then ClCH2CO2H, H2O, MeCN, rt, 1 h, 88%; (m) TBAF·3H2O (3.0 equiv), THF, rt, 15 min, 97%; (n) DMP (2.0 equiv), NaHCO3 (20 equiv), pyridine (15 equiv), DCM, rt, 20 min, 95%; (o) aq. 48%−51% HF, DCM/MeCN = 1:4, rt, 4 h, 94%.

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To complete the total synthesis, 23 bearing a TBS group39

was first oxidized by singlet oxygen (generated by irradiation of oxygen with tungsten lamp in the presence of methylene blue), and the resultant 4-oxo-2-alkenoic acid intermediate40 was then treated with ClCH2CO2H in MeCN to afford 24 in 88% yield. Selective desilylation of 24 with TBAF·3H2O followed by DMP-oxidation of the newly generated secondary alcohol afforded a C9-ketone, which was further subjected to a desilylation with HF to afford 1 in 87% yield over three steps. The structure of synthetic spirochensilide A was confirmed by single-crystal X-ray diffraction, and its NMR and optical rotation data were in agreement with those reported in the literature. More than 150 mg of 1 were made in our first round of synthesis. In summary, the total synthesis of (−)-spirochensilide A (1)

has been accomplished for the first time in 22 steps from epoxide 2, with a total yield up to 2.2%. The keys to the success of the synthesis were the use of (1) a semipinacol rearrangement of epoxide 2 to stereoselectively generate the chiral aldehyde 6; (2) a rarely investigated tungsten-mediated cyclopropene-based PK reaction to form 15a, bearing the spiro-bicyclic core of 1; and (3) singlet oxygen-mediated oxidative cyclization of furyl alcohol 23 to form the anomeric spiroketal motif of 1. The developed chemistry paves the way to the stereoselective construction of this unprecedented triterpenoid scaffold, which bears two spirocyclic systems and up to four all-carbon quaternary chiral centers.

■ ASSOCIATED CONTENT *sı Supporting Information The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.0c02522.

Experimental procedures and compound characteriza- tions (PDF) X-ray diffraction of compound 11 (CIF) X-ray diffraction of compound 12 (CIF) X-ray diffraction of compound 15a (CIF) X-ray diffraction of compound 15b (CIF) X-ray diffraction of compound 20 ester derivative (CIF) X-ray diffraction of spirochensilide A (CIF)

■ AUTHOR INFORMATION Corresponding Authors Zhen Yang − Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science, and Peking- Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; State Key Laboratory of Chemical Oncogenomics and Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Shenzhen Wan Laboratory, Shenzhen 518055, China; orcid.org/0000-0001-8036-934X; Email: zyang@ pku.edu.cn

Jia-Hua Chen − Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science, and Peking- Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Email: [email protected]

Author Xin-Ting Liang − Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing

National Laboratory for Molecular Science, and Peking- Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China

Complete contact information is available at: https://pubs.acs.org/10.1021/jacs.0c02522

Notes The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS This work is supported by National Science Foundation of China (Grant Nos. 21772004, 21632002, and 21871012). We thank Dr. Jie Su and Mr. Yuan-He Li from Peking University for the X-ray crystallographic detection and analysis. We also thank Mr. Zhong-Chao Zhang from Peking University Shenzhen Graduate School for DFT analyses. This paper is dedicated to Professor Henry N. C. Wong on the occasion of his 70th birthday.

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