David Y. - K. Chen, National University of Seoul, Korea, completed reserpine synthesis based on desymmetry

Sixty years ago, Woodward first completed the total synthesis of reserpine (Figure 1, 1) It is characterized by the arrangement of functional groups and three-dimensional centers in the molecule 1 The most challenging problem in the synthesis process is to construct the intensively substituted cyclohexyl "e" ring In the past synthesis research, researchers have done a lot of research on the stereo control of E-ring precursor in reserpine, and developed a variety of ring addition methods (image source: angelw Chem Int ed.) based on the previous experience, the David Y - K Chen research group of Seoul National University in South Korea considered to simplify the synthesis of E-ring precursors in reserpine The author thinks that the symmetric cyclohexanone 3 (single ring or bridged double ring) is a suitable intermediate (scheme 1) After the introduction of tryptamine, a new C3 stereocenter is formed in tetrahydro - β - carboline 4, which can distinguish C16 and C20 from each other (local desymmetry) In addition, the intramolecular differentiation of C16 / C20 by the secondary nitrogen Center (N1) in 4 can be directly introduced into the five ring parent core structure of reserpine (e.g 5) Finally, the whole synthesis of reserpine can be completed by solving the late stage of C17 regioselective oxidation and C18 keto carbonyl stereoselective reduction The relevant research results were recently published on angelw Chem Int ed (DOI: 10.1002 / anie 201810974) (picture source: angelw Chem Int ed.) first, the preparation process of bicyclone aldehyde 9 is shown in scheme 2 By using acetoxyfullerene 6 and tetrabromoacetone 7 as reductive [4 + 3] cycloaddition, dicyclonenol acetate 8 was obtained, followed by hydrolysis of vinyl acetate and differential isomerization of aldehydes to obtain 9 Then, the aldehyde group in 9 was homogeneized to get methylenol ether 10 The intermediate 12 produced by the reaction of 10 with tryptamine 11 was protected by CBZ and BOC to obtain tetrahydro - β - carboline 14 At this point, the author considers breaking the [3.2.1] bicyclic fragment in 14 and carrying out the intramolecular desymmetry In this case, the double bond in 14 is converted into diol 15 by Sharpless dihydroxylation On the contrary, when 14 is dihydroxylated by NMO, the reaction will lead to over oxidation of the substrate due to the rich electricity of the methoxy substituted tetrahydro - β - carboline Under the action of Pb (OAC) 4, a mixture of diol cracking products, mainly bishemiacetal 16, was produced, which was hydrogenated to ketal 19 by Pd / C-H 2 19 was oxidized by NaCl 2 and methylated by trimethylsilylated diazomethane to obtain keto ester 21 The stereochemical structure of 21 was determined by NMR and spectral correlation It is C3 / C15 syn, C15 / C16 syn and C16 / C20 syn In addition, 21 can be converted into keto ester 22 with C3 / C15 anti stereochemical structure, and 22 and 3-epi-22 can be separated by column chromatography (image source: angelw Chem Int ed.) the author found that in addition to the enantiomeric dialdehyde in 17 by selective imine formation, it can also be distinguished by the indole nitrogen Center (N4) (scheme 3a) In this case, the dihydroxylation of tetrahydro - β - carboline 13A can be carried out under the condition of oso 4-nmo The cracking process of diol 28 mediated by Pb (OAC) 4 can generate hemiacetal 30, which can be further oxidized to a single stereoisomeric amide 31 The results show that the desymmetrization of dialdehyde intermediate 29 produced by oxidative cleavage of 28 is selective The relative stereochemistry of 31 can be determined According to the experimental results and literature reports (Scheme 3B), the two hydrogen atoms marked by arrows in 32 are in the trans position (image source: angelw Chem Int ed.) next, the authors performed regionally and stereoselective C17 oxidation of 3-epi-21 to construct E-ring In the model reaction, the author tried several alkene alcoholization oxidation schemes, and obtained the mixed products However, α - hydroxyketone 23 was obtained from L-proline / nitroso benzene, which is a single domain and stereoisomer On the contrary, C3 isomer 21 can also be oxidized by L-proline / nitroso benzene, but the yield is significantly reduced (scheme 4a) Therefore, C3 isomerization must be carried out on the pre oxidized intermediate 21 Then, the author uses the Pummerer type condition (DMSO, AC 2O) to carry on the sulfur methylation to 23, obtains the methylthiomethyl ether 24, which further reduces the desulfurization to realize the oxygen methylation (scheme 2) The author used Raney Ni / H 2 to desulfurize 24 and reduce C18 ketone to get hydroxymethyl ether 26, which is a single stereoisomer, and NaBH 4 to reduce ketone 25 to get C18 non enantiomer alcohol, which is a scheme 4B Subsequently, the author acylated 26 with 3,4,5-trimethoxybenzoyl chloride 27, then removed its BOC carbamate to obtain reserpine (1) (scheme 2) The bocrmoval conditions (silica gel, toluene, reflux) developed by the author have realized "one pot" acylation and deboc (image source: angelw Chem Int ed.) finally, the author obtained the protected 6-methoxytryptamine (scheme 5a) by iridium catalyzed C-H activation / boration sequence reaction In addition, as a supplement to the conversion from 1 to deerpidine (36), this method first proved the feasibility of preparing 1 from 36 by later C-H activation, and may be suitable for the total synthesis of unsubstituted tryptamines (scheme 5b) The optically active 12 can be used to synthesize the desymmetric compound 1, while 12 can be prepared from imine 37 by Noyori transfer hydrogenation (scheme 5C) (picture source: angelw Chem Int ed.) conclusion: David Y - K Chen team completed the total synthesis of reserpine (1) through a reasonably designed strategy of intramolecular desymmetry, which greatly simplified the synthesis of E-ring precursor in reserpine, and successfully introduced other three-dimensional centers on E-ring by using the three-dimensional control of substrate C3 three-dimensional center.