Letter Cite This: Org. Lett. 2018, 20, 2876−2879
pubs.acs.org/OrgLett
Stereoselective Total Synthesis of (±)-5-epi-Cyanthiwigin I via an Intramolecular Pauson−Khand Reaction as the Key Step Yuanyuan Chang,† Linlin Shi,† Jun Huang,† Lili Shi,† Zichun Zhang,† Hong-Dong Hao,*,† Jianxian Gong,*,† and Zhen Yang*,†,‡,§ †
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China ‡ Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China § Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266071, China S Supporting Information *
ABSTRACT: A convenient approach to the construction of the 5−6−7 tricarbocyclic fused core structure of cyanthiwigins via a Co-mediated Pauson−Khand reaction as a key step has been developed. The cyathane core intermediate obtained by this strategy was used in the concise synthesis of (±)-5-epi-cyanthiwigin I. The developed chemistry paves the way for the total synthesis of structurally diverse cyanthiwigins.
C
yanthiwigins1 (Figure 1), which have a cyclohepta[e]indene core (as shown in Figure 1), are structurally
Biologically, cyanthiwigin C (3) and cyanthiwigin F (4) are cytotoxic against A549 human lung cancer cells (IC50 = 4.0 mg/mL)1c and human primary tumor cells (IC50 = 3.1 mg/mL),1b,d,e respectively. Cyanthiwigins contain a 5−6−7 tricarbocyclic core with carbons in various oxidation states and bear four contiguous stereocenters on their B ring, including two cis-configured quaternary all-carbon stereogenic centers at C6 and C9, unlike other cyathane-type diterpenoids, which have two trans-oriented quaternary centers. This intricate molecular architecture is a challenge for the existing synthetic methods, and the development of new synthetic strategies and tactics is needed. In 2005, Phillips and co-workers reported the total synthesis of a member of this class of natural products, namely cyanthiwigin U (8), using an elegant ROM−RCM cascade to construct its tricyclic core (Scheme 1, eq 1).3 In 2008, Stoltz and co-workers developed a concise approach, which featured double asymmetric catalytic alkylation and an RCM reaction as the key steps in the asymmetric syntheses of cyanthiwigins B (2), F (4), and G (5) (Scheme 1, eq 2).4 In 2013, Gao and co-workers reported a concise synthetic method that involved a formal intermolecular [4 + 2] cycloaddition and an RCM reaction as key steps in the total syntheses of cyanthiwigins A (1), C (3), G (5), and H (6) (Scheme 1, eq 3).5
Figure 1. Selected naturally occurring cyanthiwigins.
diverse cyathane-type diterpenes.2 They were isolated from the marine sponges Epipolasis reiswigi and Mermekioderma styx. © 2018 American Chemical Society
Received: March 19, 2018 Published: May 9, 2018 2876
DOI: 10.1021/acs.orglett.8b00903 Org. Lett. 2018, 20, 2876−2879
Letter
Organic Letters Scheme 1. Total Synthesis of Cyanthiwigins
Scheme 2. Synthesis of Enyne 16
Table 1. Diastereoselective Synthesis of 18 via the PKR Recently, the Pauson−Khand reaction (PKR),6 a [2 + 2 + 1] cycloaddition between an alkyne, an alkene, and CO to deliver cyclopentenone structures, has been regarded as a powerful tool for the construction of natural product skeletons.7 On this basis, we considered that the PKR could be used as a key step in the construction of the 5−6−7 tricarbocyclic cores of cyanthiwigins with two cis-configured all-carbon quaternary stereogenic centers at their ring junctions. To the best of our knowledge, the construction of such a scaffold via the PKR has not been reported. Here, we present our recently developed method, with the PKR as a key step, for the total synthesis of 5-epi-cyanthiwigin I. To achieve the envisaged PKR for formation of the cyanthiwigin core, we developed a route for the synthesis of enyne 16 from the commercially available ketoester 9 (Scheme 2). The enolate obtained by treatment of 9 with LDA reacted with allyl bromide 10 to give diene 11 in 82% yield.8 Further treatment of 11 with Grubbs II catalyst9 afforded ketoester 12, which was alkylated with potassium tert-butoxide in tert-butyl alcohol10 and then reacted with 4-iodo-2-methylbut-1-ene to give ketone 14 in 85% yield. The key intermediate 16 was obtained by converting the ketone group in 14 to the corresponding enolate by treatment with LDA, followed by reaction with Comins’ reagent11 to afford vinyl triflate 15 in 93% yield. A Sonogashira coupling reaction of 15 with 3-methylbut-1-yne gave enyne 16 in 48% yield, along with a 30% yield of cyclopropane 17, which has three contiguous all-carbon quaternary chiral centers. We performed a systematic optimization of the Sonogashira reaction to improve the yield of 16. We found that when the substrate concentration was increased to 1 mmol/mL, the coupling yield of 16 increased to 68%; 17 was formed in 14% yield. A possible mechanism12 for the formation of cyclopropane 17 is shown in Scheme 2. We then evaluated the PKR of enyne 16 for the formation of the indene core 18 of cyanthiwigins. The PKR test results are given in Table 1. Initial attempts to synthesize 18 by treatment of enyne 16 with Co2(CO)8 (0.5 equiv) or CoBr2 (0.1 equiv)/Zn (1.0 equiv) in
entry 1 2 3 4 5 6 7 a
reagent Co2(CO)8 (0.5 equiv) CoBr2(0.1 equiv)/ Zn (1.0 equiv) PdCl2 (0.15 equiv) [Rh(CO)2Cl]2 (0.1 equiv) Co2(CO)8 (1.2 equiv) Co2(CO)8 (1.2 equiv) Co2(CO)8 (1.2 equiv)
solvent
temp (°C)
yield (%) (18/18a)a
TMTU
benzene
110
0
TMTU
toluene
70
0
TMTU/ LiCl
THF
60
0
DCE
80
0
toluene
110
70 (10:1)
4 Å MS
toluene
110
55b
NMO
toluene
110
70b
additive
Isolated yield. b18 was isolated as single isomer.
the presence of tetramethylthiourea (TMTU)13 did not give the desired annulated product (entries 1 and 2). We next tested Pd/ TMTU-catalyzed14 and [Rh(CO)2Cl]2-catalyzed15 PKRs, but neither of them generated the desired product (entries 3 and 4). We then treated enyne 16 with Co2(CO)8 (1.2 equiv) in refluxing toluene; the annulated product 18 bearing two cis-configured all-carbon quaternary chiral centers (C6 and C9) and an isopropyl group16 (C2) was obtained in 64% yield, together with its C9 diastereoisomer 18a in 6% yield (entry 5). Further treatment of enyne 16 in the presence of 4 Å molecular sieves (4 Å MS) as an additive under the same conditions as those for entry 1 gave 18 in 55% isolated yield as a single isomer (entry 6). When NMO was used as the additive,17 18 was obtained as the sole isomer in 70% yield (entry 7). The structure of 18 was confirmed by X-ray crystallographic analysis of its derivative 19, which was prepared from 18 via a sequence of reduction (LiAlH4/AlCl3)18 and 2877
DOI: 10.1021/acs.orglett.8b00903 Org. Lett. 2018, 20, 2876−2879
Letter
Organic Letters
82% yield in two steps. A silyl oxide group was installed stereoselectively at C13 in 24 by regioselective epoxidation of 22 via treatment with m-CPBA; the resultant epoxide 23 was treated with TBSOTf in the presence of 2,6-lutidine22 in DCM to give product 24 in 65% yield in two steps. To complete the total synthesis, enone 24 was treated with potassium bis(trimethylsilyl)amide (KHMDS) at −78 °C. The resultant enolate was reacted with Davis’ N-sulfonyloxaziridine to give unsaturated α-hydroxy ketone 25 in 83% yield (dr = 1:1). Subsequent treatment with potassium tert-butoxide23 promoted rearrangement of the unsaturated hydroxy ketone 25, and diosphenol 26 was obtained in 94% yield. The structure of 26 was confirmed by X-ray crystallographic analysis. The C2 hydroxyl group was removed by converting substrate 26 to its corresponding vinyl triflate by treatment with KHMDS and reaction of the resultant alkoxide with Comins’ reagent to give triflate 27 in 77% yield. Treatment of 27 with Pd(PPh3)4/Et3SiH in the presence of LiCl in DMF24 at 80 °C provided product 28 in 86% yield. Removal of the TBS group in 28 by treatment with HF/pyridine in DCM at 0 °C gave C5-epi-cyanthiwigin I (29) in 92% yield. In summary, an intramolecular PKR was used for stereoselective construction of the cyanthiwigin core, which has two cisconfigured all-carbon quaternary chiral centers (C6 and C9) and an isopropyl group (C3). The developed chemistry enables the total synthesis of 5-epi-cyanthiwigin I (29) in 17 steps and can be used for the total synthesis of other cyanthiwigins. The observed Pd-catalyzed cyclopropanation of enyne 15 to give product 17 bearing three contiguous all-carbon quaternary chiral centers is noteworthy. Further investigation of the use of this chemistry to synthesize complex natural products is underway in our laboratories. The results will be reported in due course.
dihydroxylation (OsO4/NMO) reactions (Scheme 3). Compound 18 has the basic 5−6−7 tricarbocyclic skeleton and essential Scheme 3. Total Synthesis of C5-epi-Cyathniwigin I (29)
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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.8b00903. Experimental procedures, characterization for new compounds, including 1H and 13C NMR spectra (PDF)
functional groups needed for the total synthesis of cyanthiwigins; therefore, we initiated a program to achieve the total synthesis of cyanthiwigins. Scheme 3 shows our total synthesis of C5-epi-cyanthiwigin I (29). Initially, we expected that 1,6-reduction of conjugated enone 18 in the presence of a double bond (C12 and C13), ester group (C6), and keto group (C2) could be achieved by dissolving metal reduction (Li/NH3);19 isomerization of the resultant β,γ-ketone 20 to enone 21 could be achieved via a base-induced double-bond isomerization. However, when 18 was treated with Li/NH3 in THF at −20 °C, 20 was obtained in 40% yield. In addition to the expected 1,6-reduction of the conjugated enone, the C6 ester group in 18 was converted to the corresponding primary alcohol. Further treatment of ketone 20 with MeONa in MeOH20 gave enone 21 in 90% yield. However, the stereochemistry at the newly generated C5 stereogenic center was the opposite of desired. Intensive attempts to invert this stereogenic center failed. The configuration at C5 was established by NOE experiments (from the observed C5−C16 and C5−C9 proton correlations). The C16 hydroxyl group was removed by treating 21 with TsCl in the presence of DMAP and Et3N in DCM, and the resultant tosylate was subjected to reductive detosylation with Zn21 in the presence of NaI in DMF to give product 22 in
Accession Codes
CCDC 1590635 and 1823278 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 Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Zhen Yang: 0000-0001-8036-934X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge financial support from the National Science Foundation of China (Grant Nos. 21572009, 21632002, 2878
DOI: 10.1021/acs.orglett.8b00903 Org. Lett. 2018, 20, 2876−2879
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Organic Letters
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21772008, and U1606403), Guangdong Natural Science Foundation (Grant No. 2016A030306011), Shenzhen Peacock Plan (Grant No. KQTD2015071714043444), and Shenzhen Basic Research Program (Grant Nos. JCYJ2016033009562978, JCYJ20160226105337556, and JCYJ20170818090044432).
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DOI: 10.1021/acs.orglett.8b00903 Org. Lett. 2018, 20, 2876−2879
