Abstract

Recently, the research teams of Prof. Henry N. C. Wong (CUHK, Hong Kong) and Prof. Xiao-Shui Peng (CUHK-Shenzhen) have completed the first total synthesis of cryptotrione. This synthetic route would be practical for synthesizing other members of the structurally unprecedented cryptotrione family and its analogs for further biological evaluation.

This work was supported by National Science Foundation of China and Research Grants Council of Hong Kong, Shenzhen Science and Technology Innovation Committee, and the University Development Fund Grants from CUHK-Shenzhen and was published on Angew. Chem. Int. Ed. 2020, 10.1002/anie.202009255.

Research Background

Cryptotrione (1), a novel C35-terpene, was isolated from the bark of Cryptomeria japonica in 2010. On one hand, cryptotrione has an unprecedented skeleton possessing an abietane-type diterpene quinone methide spiro-annulated with a thujone-type bicyclo[3.1.0]hexane ring system. On the other hand, cryptotrione exhibits anticancer activity against human oral epidermoid carcinoma KB cells with an IC50 value of 6.44 ± 2.23 μM, only slightly weaker than that of the clinically used anticancer drug, etoposide (VP-16, IC50~2.0 μM).

About the Research

Recently, the research teams of Prof. Henry N. C. Wong (CUHK, Hong Kong) and Prof. Xiao-Shui Peng (CUHK-Shenzhen) have completed the first total synthesis of cryptotrione. 

Firstly, indane 10 was readily prepared from commercially available homoveratric acid (11). Then the bicyclo[3.1.0]hexane moiety was assembled via enyne cycloisomerization, and abietane-type diterpene skeleton was assembled via Lewis acid-mediated cyclization. Subsequent installation of the side chain and generation of the relevant quinone methide species eventually afforded synthetic cryptotrione (1).

The synthesis commenced with 1,5-enyne precursor 12, which could be prepared from commercially available homoveratric acid (11). Next, authors focused on the conversion of enynes into the desired bicyclo[3.1.0]hexene species. As mentioned in their previous work, 1,5-enyne precursor also could undergo another kind of cycloisomerization (Angew. Chem. Int. Ed. 2018, 57, 11365-11368). After optimization of reaction conditions and reactants, using enyne 12e as reactant, 10 mol% of PtCl4 as catalyst and 1,4-dioxane as the solvent,  gave the best result of 75% isolated yield to generate the desired bicyclo[3.1.0]hexene 13e.

Desilylation of 13e followed by hydrogenation yielded alcohol 14 in 75% yield and X-ray crystallographic analysis showed the bicyclo[3.1.0]hexane skeleton to have the same relative configuration as in natural cryptotrione (1). Oxidation of 14 with Dess-Martin periodinane furnished the corresponding ketone, which then underwent monoalkylation to afford polyene ketones 15. Screening of various reducing reagents showed ketone 15 was reduced diastereoselectively by L-selectride at low temperature, affording alcohol 17 as a major diastereomer (dr = 13:1) in 33% yield (48% brsm), as well as alcohol 16 as a single isomer in 35% yield. Alcohol 16 was able to undergo oxidation followed by epimerization to regenerate ketones 15 (dr = 1:1) in 88% yield.

Lewis acid-induced polyene cyclization of the acetate of alcohol 17 yielded the trans-decalin product 18. Bromide 19 was produced from 18 in 53% yield (69% brsm) employing two equivalents of NBS in the co-solvents hexafluoroisopropanol (HFIP) and DMF. The efforts to direct isopropylation of bromide 19, using direct isopropylation conditions, yielded only reductive product 18 and n-propyl-substituted product. Then the authors tried to introduce the isopropyl group stepwise under Stoltz’s conditions. As expected, bromide 19smoothly underwent sterically hindered Suzuki-Miyaura coupling with potassium isopropenyltrifluoroborate to produce the alkene 20 in 80% yield as an inseparable atropisomeric mixture (ca. 3:1). Attempts at direct hydrogenation of alkene 20 using a variety of classic protocols were completely unsuccessful, probably retarded by the steric hindrance from acetyl and pivaloyl groups. Reduction of 20 with DIBAL-H to relieve this steric hindrance, followed by subsequent hydrogenation, however, successfully led to diol 21 in 91% yield over the two steps.

After establishment of the structural framework of cryptotrione (1), the authors then focused on the installation of the side chain. Selective oxidation of the primary hydroxyl group of 21 using PIDA-TEMPO led to its aldehyde in 92% yield, which subsequently underwent Knoevenagel condensation with dimethyl malonate to afford α,β-unsaturated malonate 22, the precursor for conjugated addition, in 80% yield. When two equivalents Li2CuCl4 were used as the copper source in the presence of 20 equivalents of homoallylmagnesium bromide (22a) at –78 °C, the desired conjugated addition product 23 was smoothly achieved in 80% yield with dr > 20:1. Interestingly, further optimizations showed that the stereoselectivity of the conjugated addition was totally reversed in the presence of 10 equivalents of homoallylmagnesium bromide (22a) and Li2CuCl4 (2 equivalents) at –78 °C with different reagent addition mode, forming 24 (C7'-epimer of 23) with excellent dr (> 20:1 at C7').

Upon treatment of 23 with LiAlH4, subsequent selective tosylation and hydride replacement of the resulting tosylate, alkene 6 was formed in 30% yield over the 3 steps. Demethylation of 6 under alkaline conditions then afforded the dihydroxyl intermediate, which unfortunately could not be auto-oxidized in air to its corresponding ortho-quinone. Instead, this dihydroxyl phenol intermediate was treated with MnO2, generating the para-quinone methide 6a, which was directly subjected to Wacker oxidation without further purification, eventually affording synthetic cryptotrione (1) in 40% yield. Moreover, subjection of alkene 24 to the similar aforementioned procedures from alkene 23to cryptotrione (1), 7'-epi-cryptotrione (25) was successfully achieved in 18% yield over 5 steps. The structure of 7'-epi-cryptotrione (25) was unambiguously confirmed using X-ray crystallographic analysis.

This synthetic protocol features with a novel platinum(IV) chloride-catalyzed diastereoselective cycloisomerization of 1,5-enynes to construct the bicyclo[3.1.0]hexane core, a Lewis acid-induced diastereoselective polyene cyclization to construct abietane-type diterpene skeleton, and a stereo-divergent conjugated addition to construct the tertiary carbon center of the side chain with full stereocontrol. This synthetic route would be practical for synthesizing other members of the structurally unprecedented cryptotrione family and its analogs for further biological evaluation.

About the Professor

Prof. Xiao-Shui Peng

Associate Professor

Xiao-Shui Peng received his BSc and MSc degrees from Lanzhou University in 1999 and 2002, respectively, under the guidance of Professor Xin-Fu Pan. In 2006, he obtained his PhD from The Chinese University of Hong Kong, where he worked on the total synthesis of pallavicinin under the supervision of Henry N. C. Wong. After completing his postdoctoral research fellowship with Professors K. C. Nicolaou and David Y. K. Chen on the cortistatin project at CSL@Biopolis, Singapore, he returned to CUHK as a Research Assistant Professor (2009-2015) and Research Associate Professor (2015-2020). 

In 2020, he joined School of Science and Engineering as Associate Professor at The Chinese University of Hong Kong (Shenzhen), and is focusing his research themes on the development of eco-friendly synthetic methodologies and novel “bio-inspired” strategies  for the total synthesis of structurally complex and biologically significant natural products, as well as natural product-derived drug discovery. 

He is looking for PhD Students, Postdoctoral Fellows with research background in Organometallic, Synthetic Methodology, Natural Product Synthesis, Drug Discovery, and will provide full financial support to the successful applicants. Applicants should send the application package to Prof. Peng at xspeng@cuhk.edu.cn.