Appreciate the art of organic synthesis: the synthesis of natural products by Hughes and gleasond, virosaine a

Securinega alkaloids are a series of natural products of indoleazide The typical characteristics of the alkaloids are the bridged four ring structure containing α, β - unsaturated γ - lactone Many members of the natural product family have strong biological activities, such as antimalarial, antibacterial, GABA receptor antagonistic and so on These properties make the synthesis of alkaloids from Phyllanthus attractive Since the first alkaloid of Phyllostachys was isolated more than 60 years ago, new members have been added to the family Two of the most complex compounds, virosaines a (1) and B (2), were reported by Ye et al in 2012 (org Lett 2012, 14, 3096 – 3099) Virosaines was isolated from the branches and leaves of fluega virosa Its molecular structure is similar to birdcage It is the first alkaloid of Phyllostachys with 7-oxo-1-azabicyclo [3.2.1] octane structure It is worth mentioning that baifanshu is widely used in traditional Chinese medicine to treat dermatitis and eczema The biosynthesis of virosaines is believed to be realized by 1,3-dipolar cycloaddition of nitrone / olefin (Fig 1), which has a guiding role in its total synthesis Fig 1 Biosynthesis sources of virosaines A and B: in 2013, Li and his colleagues reported the first synthesis of natural products of virosaine (angelw Chem Int ed 2013, 52, 620 – 624; angelw Chem 2013, 125, 648 – 652) They used D-proline derivative 3 as raw materials, after N-oxidation, σ - migration rearrangement and the last 1, Compound 2 was synthesized by a series of reactions such as 3-dipolar cycloaddition (Fig 2a) However, a month later, the gademann group reported the synthesis of compound 1 (chem Commun 2013, 49, 1921-1923) Their synthesis route was very similar to that of Li et al (Fig 2b) Figure 2 Full synthesis source of virosaines A and B: angel Chem Int ed this paper focuses on the synthesis of virosaines a (1) by Gleason and Hughes (angel Chem Int ed 2017, 56, 10830 – 10834; angel Chem 2017, 129, 10970 – 10974) They also used 1,3-dipolar cycloaddition to build the core structure of compound 1 Different from the previous work, they carried out this step in the previous step to realize the rapid construction of carbon ring skeleton They hypothesized that the butenolide structure in the target product 1 can be obtained by functionalization of the intermediate 11; while 11 can be formed by relatively simple oxime / epoxy compound 12 through epoxy ring opening / nitrone, and 1, 3-dipolar cycloaddition can be obtained; precursor 12 can be obtained by simple molecules 2-bromoacrolein 13, furan 14 and acetal compound 15 through Diels alder cycloaddition, carbonyl addition, epoxy formation and oxime formation grade coupling reaction (Fig 3) Fig 3 Gleason and Hughes' analysis source of reverse synthesis of virosaine A: angelw.chem.int.ed in the actual synthesis process, Diels alder cycloaddition process has enantioselectivity and oxazaborolidone catalyst 16 is required; however, furan 14 does not have functional group compatibility in this catalytic process, which is a defect of this synthesis route However, the process from 12 to 11 is very simple and beautiful With the selective functionalization of C14, it can completely make up for the previous shortcomings After Diels alder cycloaddition and in-situ addition with 15, acetal 17 can be obtained in 30% yield and excellent selectivity (> 20:1 D.R.; > 99% ee) through recrystallization In this paper, the author describes this one pot synthesis as "building all the atoms except two carbon atoms in the target natural product" Next, the precursor 18 was formed by oxime and epoxy with a total yield of 91% in three steps, which provided abundant raw materials for the next key ring opening / nitrone cycloaddition of epoxy The next key step is the short-time high temperature reaction (120 ℃) under weak acid condition In general, the author obtained the key five membered ring precursor 11 with a total yield of 25% in six steps, which is a great feat considering the structural complexity of the product Figure 4 Rapid construction of precursor 11 source: after angelw.chem.int.ed had the key five membered ring, the author began to investigate the feasibility of selective functionalization of C14 After fully understanding the reaction demand, they chose to use the hydroxyl group on C10 as the key point to limit the activation of C2, C9 and C14 At first, they tried to insert carbene directly into C14, but they got the functionalized product 22 of methylene c9-h bond The author also tried to use carbene, and the result was not satisfactory The product 23 of c2-h insertion was obtained (Fig 5, top) After many experimental failures, Hughes and Gleason turned to theoretical calculation, hoping to solve the problem of activation of different sites Combined with DFT calculation, NMR chemical shift analysis and natural population analysis (NPA) results, they found that C14 has a relatively large positive charge distribution, and the Homo level of c14-h bond is the lowest of all C-H bonds in the five membered ring intermediate Therefore, they speculated that the selective functionalization of C14 could be realized by site deprotonization In the actual experiment, after the urethane 24 is deprotonated by s-buli, it reacts with br 2 to obtain bromine 25, the yield can reach 70%, and the remaining raw material is 20% (Fig 4, bottom) The target product 1 was obtained by allylation, oxidation / cyclization and elimination of the intermediate 25 So far, the total yield of virosaine a (1) is 9.7% in the 11 step synthesis route with furan as the starting material Figure 5 Source of C14 functionalization: angel Chem Int ed when the field of natural product synthesis is struggling with various imperfect indicators to define the synthesis efficiency, and it is widely considered that efficiency is a perfect measure, an elegant and bold synthesis route is always refreshing and memorable Li and gademann have done pioneering research on the complex natural products of virosaines, but Hughes and gleasond can find another way and give another attractive synthetic route Most researchers engaged in complex molecular synthesis will not only be attracted by beautiful molecular structure and synthesis challenges, but also be interested in aesthetic synthesis routes If we rely too much on metrics, we may miss the opportunity to appreciate the beauty of complex molecules The synthesis of Hughes and Gleason, as well as other similar examples, provides us with an opportunity to focus on the synthesis of inner art Paper link: http://onlinelibrary.wiley.com/doi/10.1002/anie.201708051/abstract author information: Professor Bryan D Ellis and Christopher D vanderwal, Department of chemistry, University of California, the vanderwal group: http://factory.sites.uci.edu/cdv/