JACS: the Newhouse group of Yale University uses CAD to complete the total synthesis of paspaline A and eindole PB

With the development of computer technology, more and more chemists hope to use computers to solve the problem of synthetic route design (inverse synthetic analysis), which needs human creativity most Recently, Timothy R Newhouse group of Yale University completed the total synthesis of paspaline a (1) and eindole Pb (2) by using DFT algorithm, which was recently published on J am Chem SOC (DOI: 10.1021 / JACS 8b13127) Paspaline a (1) and enindole Pb (2) are complex indole diterpene natural products Among them, paspaline a (1) contains six ring skeleton, including pyran ring and indole fused cyclopentane, and its molecule also contains two ortho quaternary carbon centers There is no report on the synthesis of enindole Pb (2) Paspaline a (1) and its related natural products have significant biological activities, such as regulating the anti proliferation and anti metastasis activities of Wnt / β - Catenin in MDA-MB-231 mammalian breast cancer cell line Previous studies on the synthesis of indole diterpenoids mainly depended on the introduction strategy of indole ring Inspired by the formation of indole diterpenoid skeleton through the polyene cascade reaction in the biogenic pathway of indole diterpenoids, the author attempts to introduce indole fragment directly and construct C-ring by its inherent nucleophilic property (Figure 1) Among them, paspaline a (1) can be obtained by Friedel crafts cyclization of carbon positive ion 4, or eindole Pb (2) can be obtained by methyl transfer, or natural products such as antholorin can be produced by elimination (photo source: J am Chem SOC.) the author hopes to use DFT algorithm to select the key positive ion rearrangement mode with the most favorable energy, so as to guide the inverse synthesis analysis Firstly, a group of substructures with obvious structural and energy differences were identified: the intermediate 4a of acyclic biosynthesis, monocyclic tetrahydropyran 4B and bicyclic ketal 4C (Figure 2); then, by comparing the energy barriers of the two possible processes of enantiomeric cyclization and methyl transfer, the precursor of carbon positive ion rearrangement was selected by DFT calculation (photo source: J am Chem SOC.) in the study of mechanism, the author thinks that 1,2-methyl migration may go through a synergistic or step-by-step way, while the cyclization of adjacent quaternary carbon centers may go through a carbon positive ion way Through DFT modeling analysis, the author found that 4C has the largest energy deviation (4.5 kcal / mol) The limitation of this method is that the error degree of correlation calculation is uncertain Because cyclization usually produces CIS condensed ring system, it is a challenge to construct trans condensed five membered ring by indole cyclization However, by DFT analysis of four non enantiomeric cyclized intermediates of precursor 4C, it is found that the expected stereochemistry (trans-c / d-condensation) has more energy advantages According to the above calculation and the structure target strategy, the Wieland Miescher ketone derivative 9 was determined as the starting material (Figure 3), which was alkylated with iodide 10 to obtain diketone 11 (3:1 D.R.) Then, 11 was dihydroxylated and ketalized to 12, and then Fe (ACAC) 3 / phsih 3 was used to reduce to tricyclic 13; 13 was alkylated with indole iodide 14, then deprotected and reacted with Meli to form axial tertiary alcohol 16 A mixture (3:1) of homologues 17 and 18 was obtained by cyclization Finally, paspaline a (1) was obtained by the reduction of cyclized product 18 with TiCl4 / ET 3sih The total synthesis of 1 was completed by 9 steps of reaction from the commercially available raw materials, which is two-thirds shorter than Smith's 25 steps or Johnson's 27 steps In addition, alkanol ether 19 was obtained by treating 17 with (i-pr 2n) AlMe 2 β, γ - unsaturated ketone was obtained by rubottom oxidation and DESs Martin oxidation, and then 20 was obtained by HBr initiated olefin isomerization Then, the author reduced alkene ketone 20 to alkene propanol 21, and then reduced alkene propanol and ketal to obtain 22 Its structure was confirmed by X-ray single crystal diffraction Finally, according to N - reverse isopentenation reported by Baran, the author obtained enindole Pb (2), whose spectral data is consistent with that reported by Kawai group (photo source: J am Chem SOC.) conclusion: Newhouse group completed the total synthesis of indole diterpene natural products paspaline A and enindole Pb through 9 and 13 steps respectively, among which enindole Pb was the first time to be fully synthesized and its stereoscopic structure was confirmed The key process of carbon positive ion rearrangement is predicted by density functional theory calculation to help select the most favorable precursor substrate The inverse synthesis analysis is strengthened by quantum chemistry calculation, and the feasibility of bond breaking is predicted by energy analysis results, which reduces time-consuming and expensive experience evaluation to the greatest extent.