Yang Zhen / Gong Jianxian group of Shenzhen Graduate School of Peking University completed the stereoselective synthesis of (±) - 5-epi-cyanthiwigin I

The author: danyan Cyanthiwigins is a kind of Cyathane alkane type two terpenoids (Figure 1) with cycloheptane [e] - indene nucleus, which was isolated from Epipolasis reiswigi and Mermekioderma Styx Biological results showed that cyanthiwigin C (3) and cyanthiwigin f (4) were cytotoxic to human lung cancer cell A549 (IC50 = 4.0 mg / ml) and human primary tumor cell (IC50 = 3.1 mg / ml), respectively Cyanthiwigins contains the parent nucleus of three carbon rings (5-6-7) and four consecutive solid centers on the B ring, including the four all carbon substituted solid centers of CIS configuration on C6 and C9 (photo source: Organic letters) the complexity of molecular structure and special biological activity of the cyanthiwigins family have attracted the interest of organic chemists In 2005, Phillips and colleagues [1] reported the total synthesis of cyanthiwigin U (8) in this natural product family They constructed the three ring core (scheme 1, EQ 1) of the molecule by rom-rcm cascade reaction; in 2008, Stoltz and his collaborators [2] completed the asymmetric synthesis (scheme 1, EQ) of cyanthiwigins B (2) by double asymmetric catalytic alkylation and RCM reaction 2) In 2013, Gao and his colleagues [3] synthesized cyanthiwigin a (1), C (3), G (5) and H (6) (scheme 1, EQ 3) by using intermolecular [4 + 2] cycloaddition reaction and RCM reaction as key steps Recently, the use of pauson khand reaction (PKR), i.e., [2 + 2 + 1] cycloaddition reaction between alkynes, alkenes and Co, to synthesize cyclopentenone structure, is a newly developed and effective method to construct natural product skeleton Recently, Yang Zhen / Gong Jianxian group of Shenzhen Graduate School of Peking University completed the stereoselective total synthesis of (±) - 5-epi-cyanthiwigin I (scheme 1, EQ 4) with the intramolecular pauson khand reaction as the key step Relevant papers were published on organic letters by Professor Yang Zhen, Associate Professor Gong Jianxian and associate professor Hao Donghong (DOI: 10.1021 / ACS Orglett 8b00903) The specific synthesis route is as follows: in order to synthesize cyanthiwigin mother nucleus by PKR, the author developed the synthesis method of keto ester 9 to enyne 16 (scheme 2) Firstly, the enolates were treated with LDA and then reacted with allyl bromide 10 to form diene 11 Under the action of Grubbs II catalyst, the olefins were metabolized to form keto ester 12 After alkylation of 12 with potassium TERT butanol, the product reacted with 4-iodine-2-methyl-1-butene to obtain ketone 14 Compound 14 was transformed into corresponding enol by LDA treatment, and then reacted with Comins reagent 11 to obtain key intermediate vinyl trifluoromethanesulfonate 15 Then 15 and 3-methyl-1-butyne were coupled by Sonogashira to obtain enyne 16 and a small amount of cyclopropane 17 with three consecutive all carbon substituted chiral centers (photo source: Organic letters) next, the author tried to use PKR of enyne 16 to synthesize cyanthiwigins mother nucleus 18 The experimental results are as follows (Table 1): after many failed attempts, the author treated enyne 16 with CO 2 (CO) 8 in reflux toluene to obtain ring-forming product 18 (64%) and its C9 enantiomer 18a (6%) Furthermore, the alkyne 16 was treated by adding 4޹molecular sieve, and the single isomer 18 was obtained with 55% separation yield When NMO was used as the additive, the yield of 18 was 70%, and it was the only isomer Its structure was confirmed by X-ray crystallography analysis of derivative 19 Compound 18 has a 5-6-7 tricyclic framework and all the functional groups needed for the synthesis of cyanhiwigins (photo source: Organic letters) the total synthesis route of C5 EPI cyanthiwigini (29) is shown in the figure (scheme 3): at first, the author tried to use the birch reaction to 1,6-reduce the conjugated ketene 18, and then isomerize β, γ - ketene 20 to ketene 21 by alkali catalyzed double bond isomerization However, 20 was obtained in 40% yield In addition to the 1,6-reduction products of conjugated ketene, the C6 ester group in part 18 was reduced to the corresponding primary alcohol Then, enone 21 was obtained by further treating ketone 20 in MeOH with meona in 90% yield After removing c16-oh from 21, the product 22 was obtained, which was epoxidated selectively in m-CPBA region, and then treated with tbsotf in DCM in the presence of 2,6-dimethylpyridine to obtain the product 24 Ketene 24 was treated with KHMDS at -78 ℃, and the enolate reacted with Davis N sulfoxyaziridine to obtain unsaturated α - hydroxyketone 25 (dr=1:1), which was rearranged in alkaline condition to obtain two phenol 26 (its structure was confirmed by X ray crystallographic analysis) The corresponding trifluoromethylsulfonate 27 was obtained by the reaction of the alcohol salt of compound 26 treated by khmds with Comins reagent In the presence of LiCl, the product 28 was treated with PD (PPh3) 4 / ET 3sih to obtain c5-e pi-cyanthiwigin I (29) Conclusion: the author developed a co mediated pauson khand reaction as a key step to construct the 5-6-7 three carbon ring fused skeleton of cyanthiwigins, and applied this strategy to (±) - 5-epi-cyanthiwigin Among the total synthesis of I, it laid a foundation for the structural diversity synthesis of cyanthiwigins family natural products chem - EUR J 2011, 17, 9957 (c) Kim, K E.; Adams, A M.;Chiappini, N D.; Du Bois, J.; Stoltz, B M J Org Chem 2018 , 83 , 3023 [3] Wang, C.; Wang, D.; Gao, S H Org Lett 2013 , 15 , 4402.