The first asymmetric total synthesis of diterpene alkaloid (–) - arcutinine

The author: the diterpenoid alkaloids of Nie Wei are a kind of natural products with extensive physiological activity and complex chemical structure, which are mainly distributed in Aconitum, delphinium and Spiraea According to the number of carbon atoms contained in the skeleton, the natural products of the family can be divided into three categories: C20 -, C19 - and C18 Among them, C 20 - diterpene alkaloids have the most abundant skeleton types, which attracts the attention of synthetic chemists Arcutine C 20 diterpene alkaloids are natural products with highly condensed six ring core skeleton They are characterized by two units of tetracycline [5.3.3.04,9.04,12] tridecane and azabicyclo [4.3.0] nonane At the same time, there are three all carbon quaternary carbon chiral centers (C4, C5 and C8) in the molecule In terms of biogenesis, the artidine alkaloids can be obtained by C20 transfer from C10 to C5 Two alkaloids, arcutine (1) and arcuinine (2), were isolated from Aconitum arcuatum by saidkhodzhaeva and his collaborators in 2000 and 2001 Arcuinidine (3) is the hydrolysate of the two alkaloids In 2017, the research team of researcher Shi Jiangong separated aconicarcialcutiniuma (4) from Aconitum carmichaelii These diterpenoid alkaloid related diterpenoid compounds atropurpuran were isolated from Aconitum palmatum by Professor Wang Fengpeng of Sichuan University in 2009 Synthetic chemists have completed the complete synthesis of most types of C 20 - two terpene alkaloids and their related two terpene compounds, however, the complete synthesis of arcutine two terpene alkaloids has not been reported Professor Qin Yong's research group of Sichuan University has been committed to the total synthesis of complex diterpene and diterpene alkaloids Recently, the team has completed the first asymmetric synthesis of diterpene alkaloid arcutinine, and the related achievements have been published in j.am.chem.soc (j.am.chem.soc 2019, 141, 9712-9718) Fig 1 A) biogenic association between arcutine and hetidine diterpenoid alkaloids; b) structure of arcutine diterpenoid alkaloids (1-4) and related diterpene compounds atropuran (5) (source: j.am Chem SOC.) in 2016, Professor Qin Yong's research group completed the first total synthesis of natural diterpene product atropuran (5)（ Nat.Commun   2016 ,  7 ,12183 ）。 As shown in Fig 2, in this synthesis study, firstly, dicyclic [2.2.2] octane (6) was constructed by oxidative dearomatization / intramolecular Diels alder cycloaddition series reaction, and then five ring skeleton (8) was efficiently synthesized by aldol addition reaction and ketone olefin free radical addition reaction, and then target natural product atropuran (5) was obtained by functional group modification Due to the low efficiency of introducing methyl group at C4 position in this synthesis, and the initial attempt to introduce nitrogen atom on the basis of compound 9, and the route is not suitable for enantioselective synthesis, various factors prompted the author to develop a new strategy for asymmetric synthesis of arcutinine (2) Figure 2 The team's previous attempts (source: j.am Chem SOC.) to synthesize and pre synthesize arcutine are shown in Figure 3 B-ring can be constructed by ketone olefin free radical cyclization (10 to 2), and C / D / F three ring systems (11 to 10) can be assembled by oxidative de aromatization / intramolecular Diels alder cycloaddition series reaction The key nitrogen-containing five membered E-ring can be constructed by palladium catalyzed intramolecular oxidation of AZA Wacker (12-11) The reaction precursor alkene 12 is obtained by functional group conversion of cyano compound 13 Palladium catalyzed decarboxyallylation can convert carbonate 14 to olefin 13 and construct C5 quaternary carbon center The key C4 quaternary carbon chiral center of enol ester 14 was established by conjugation addition of enol compound 15 Finally, ketone 16 was prepared by the reductive Knoevenagel condensation of 1,3-cyclohexanedione (17) and known aldehyde compound 18, and then ketene 15 was synthesized by methyl addition and acid hydrolysis Fig 3 The first stage of reverse synthesis analysis (source: j.am Chem SOC.) is to construct A-ring compound 13 containing C4 and C5 consecutive chiral centers As shown in Fig 4, 1,3-cyclohexanedione and aldehyde 18 undergo reductive Knoevenagel condensation, and then ketene 15 can be obtained by addition of methyl lithium The next step is the formation of quaternary carbon center at C4 site Through the conjugation addition reaction of tmscn to ketene (15 → 20), enol carbonate 21 is prepared Finally, A-ring compound 13 containing continuous quaternary carbon center is successfully synthesized by palladium catalyzed decarboxylation allylation Fig 4 Preparation of key intermediate 13 containing 4,5 consecutive quaternary carbon chiral centers (source: j.am Chem SOC.) the next stage of the synthesis is the synthesis of five ring intermediate 10 using azawacker oxidation cyclization reaction and oxidative de aromatization / intramolecular Diels alder reaction (Fig 5) The substrate 23 of azawacker reaction can be prepared by palladium catalyzed isomerization of olefins, reduction of tetrahydroaluminum lithium and TS protected amino group When alcohol 23 was used as the substrate of Wacker reaction, a pair of non enantiomers 24a / B were obtained Two end o cycloaddition products 10 and 25 were obtained by direct DMP oxidation, trifluoroacetic acid removal of mom protecting group and iodobenzene acetate oxidation and aromatization The structures of the two five ring compounds were identified by X-ray single crystal diffraction The results show that in Wacker oxidation, the product with α - hydrogen at C20 can be converted to the required cycloaddition product 25 Through further study, the author found that the conversion of reaction substrate from alcohol 23 to silicon ether 26 could increase the proportion of products needed in Wacker cyclization Fig 5 Synthesis of pentacyclic intermediate 10 (source: j.am Chem SOC.) the next work is to construct B-ring using samarium diiodide mediated ketone olefin free radical cyclization (Fig 6) The results show that the target product 32 can be obtained by two ways Among them, in THF / MeOH solvent system, prolonging the reaction time can successfully synthesize the six ring intermediate 32 in one step Fig 6 The final step of the construction of six ring skeleton (source: j.am Chem SOC.) is to complete the synthesis of natural product arcutinine by proper functional group transformation As shown in Fig 7, the hexacyclic framework 32 is synthesized by the operation of α - methylation of carbon group, stereoselective reduction of carbonyl group, esterification and removal of TS protecting group to obtain secondary amine 35 In the last step of the oxidation of secondary amines to imines, the author found that increasing the reaction temperature can increase the proportion of the natural product arcutinine Figure 7 Synthesis of racemate arcuinine (source: j.am Chem SOC.) after the complete synthesis of racemate of natural product arcuinine, the author began to study the asymmetric synthesis of diterpene alkaloid arcuinine (Figure 8) Starting from the known alkene ketone compound 41, the compound 44 with C4 quaternary carbon center was prepared by series catalytic asymmetric conjugation addition reaction and aldol reaction, and the chiral cyano compound 20 could be obtained by further functional group adjustment Fig 8 Asymmetric synthesis of intermediate 20 (source: j.am Chem SOC.) starting from chiral compound 20, repeat the route in the racemic synthesis to complete the asymmetric synthesis of arcutinine (Fig 9) Two of the key intermediates, pentacyclic compound 10 and hexacyclic compound 32, were confirmed by single crystal X-ray diffraction Figure 9 Asymmetric synthesis of arcutinine (source: j.am Chem SOC.) conclusion: Professor Qin Yong's research group has realized the first full synthesis of diterpene alkaloid arcutinine The key synthesis steps include: 1) catalytic asymmetric conjugation addition / aldol series reaction to construct the quaternary carbon chiral center at C4 position; 2) palladium catalyzed decarboxyallylation to form the quaternary carbon center at C5 position; 3) azawacker oxidation and cyclization to synthesize the nitrogen-containing five membered ring; 4) oxidative de aromatization / intramolecular Diels Alder reaction to synthesize the C / D double ring The synthetic work provides the possibility for the study of the activity of related alkaloids and their derivatives.