Professor Dong guangbin's research group completed the synthesis of natural products enmein, isodocarpin and sculponin R

The author: danyan enantiomer kaurene diterpenoids are an important family of natural products isolated from Theaceae, which have rich biological activity and unique chemical structure Due to the limited natural resources, the efficient chemical synthesis of these diterpenoids has attracted the interest of synthetic chemists (Figure 1a) Enmein (1) was first separated from I japonica in 1958, and its structure was determined in 1966 So far, researchers have found more than 90 kinds of natural products, such as isodocarpin (2), sculponin R (3), MACROCALYXIN a, isorothornin g, etc (Figure 1b), but there are few researches on total synthesis Only Fujita and his colleagues reported the synthesis of enmein (1) (Figure 1C) in 1972 Recently, Professor Dong guangbin's research group at the University of Chicago reported the total synthesis of natural products (-) - enmein, (-) - isodocarpin and (- - sculponin R (DOI: 10.1002 / anie 201803709) in angew Chem Int ed (image source: angelw Chem Int ed.) the structure of natural products of phloroglucins is very unique, so its total synthesis faces many challenges Firstly, there are many oxygen-containing functional groups with different oxidation states, such as free alcohol, acetal or hemiacetal, lactone and ketone Secondly, it is very difficult to construct C8-10 fragment which consists of two all carbon substituted quaternary carbon chiral centers Moreover, it is necessary to determine a common intermediate for the development of divergent synthesis routes of a variety of natural products However, due to the different substitution methods of D / E ring, the selection of intermediate becomes quite complex Based on the study of molecular structure, the author proposed the following synthesis strategy (scheme 1): using the precursor 5 containing cyclohexanone structure as a general intermediate, enmein, isodocarpin and sculponin R can be synthesized The ketene part provides reaction sites for the construction of E-ring and the introduction of C11 hydroxyl in the late stage of sculponin r synthesis The C8 substituted quaternary carbon centers in intermediate 5 can be constructed by continuous acylation, alkylation and lactonization of intermediate 6 There are two advantages in the early construction of cage ketal skeleton: 1) it can protect C3 hydroxyl and hemiacetal, thus reducing the use of protective groups; 2) the rigid cage structure will be helpful for the non enantioselective construction of C8 and C9 chiral centers Cage compound 6 can be prepared from Diels alder adduct (7) by oxidation state regulation and dearylation (picture source: angelw Chem Int ed.) the specific synthesis route is as follows: scheme 2: danishefsky diene 8 and anhydride 9 undergo Diels alder cycloaddition reaction to obtain dicyclone product 10 in 91% yield; then lactone 11 is obtained in 90% yield after selective reduction of carbonyl by LiAlH 4 Next, 11 was reduced to 1,4-diene by Li / NH 3, while lactone was reduced to hemiacetal and benzyl protecting group was removed; under the action of HCl aqueous solution, alkene ether hydrolysis and olefin isomerization took place to obtain cyclohexene ketone part, and cage acetal was formed at the same time Because cyclohexanone can rotate freely, the direct hydrogenation of compound 13 has almost no enantioselectivity Therefore, the author tried to protect C1 hydroxyl with TMS to limit the rotation of c9-c10 bond, and then obtained C9 stereo center with Dr value of 4.8-8.7:1 by Pd / C hydrogenation It is worth mentioning that the reaction can be expanded to the scale of 10 grams Subsequently, alkanone 6 was synthesized by Newhouse palladium catalytic dehydrogenation method, and β - keto ester intermediate was successfully obtained by treating alkanone 6 with LiHMDS / Mander reagent Under most conditions, O-alkylation is easier than c-alkylation, which makes α - alkylation of 2,3-dibromopropylene challenging Finally, the author successfully carried out c-alkylation with NAH as base and HMPA: THF = 1:5 as mixed solvent (the ratio of C to O-alkylation is 6:1, Dr > 10:1) The structure and stereochemistry of compound 5 were confirmed by X-ray crystallography (scheme 3) (image source: angelw Chem Int ed.) after the synthesis of key intermediate 5, the author started the divergent synthesis of sculponin R, isodocarpin and enmein (scheme 3) Compound 5 was treated with LiHMDS / tbscl to form vinyl enol ether, then oxidized by dmdo to get γ - hydroxyalkanone, and then protected by acetyl group to get ester 18 in 72% yield Next, 18 was reduced by luche and cyclized by free radicals to construct [3.2.1] skeleton to obtain compound 19; then, compound 20 was obtained by Barton McCombie deoxidization in 78% yield; further, ketene 21 was obtained by SEO 2 allyl oxidation and des Martin oxidation Subsequently, the author used Mukaiyama hydration and me 3 snnme 2 deacetylation to complete the total synthesis of sculponin R the spectral data are consistent with those reported in the literature (photo source: angelw Chem Int ed.) the total synthesis of enmein and isodocarpin (scheme 3): the author developed a unique method of reducing alkenylation to construct D / E ring After the intermediate 5 was reduced by l-selectride to produce lithium enolate 22, the palladium catalyzed alkenylation resulted in [3.2.1] bicyclic skeleton 23 Then, the C14 oxygen was removed by reduction / Barton McCombie, and the cage like structure of alcohol 25 was obtained by acid post-treatment in methanol The compound is a common intermediate for the preparation of enmein and isodocarpin On the one hand, the intermediate 25 was oxidized by DES Martin and reduced by l-selectride to realize the differential isomerization of C3 hydroxyl group, and then the target product enmein (1) was obtained by allyl oxidation, acid mediated acetal hydrolysis and TMS deprotection On the other hand, 25 was deoxidized by Barton McCombie to remove C3 hydroxyl, and then hydrolyzed by allyl oxidation / acetal to isocarocarpin (2) The structures of enmein and isodocarpin were confirmed by X-ray crystallography In order to develop the asymmetric synthesis methods of these natural products, the author tried to control the stereochemistry (scheme 4) in Diels alder reaction by using the chiral diene 28 prepared by (s) - 1-phenylethanol Although the enantioselectivity of the reaction is not ideal, the two enantiomers 29 and 30 can be separated, and 29 is the target isomer The cage compound (+) - 13 was obtained by reduction and acid treatment of anhydride 29, which is the same as the intermediate in the above synthesis route Because the cost of (s) - 1-phenylethanol is relatively low, this route provides a fast and cheap way to obtain the synthesis intermediates rich in enantiomers According to the synthesis route described in schemes 2 and 3, the author has finally realized the synthesis of (–) - enmein, (–) - isodocarpin and (–) - sculpoin R the optical rotation data of the synthesis is consistent with the reported results of natural samples Conclusion: the author developed a simple method of divergent synthesis, and completed the total synthesis of (- - enmein, (-) - isodocarpin and (-) - sculpoin R The main features of the strategy include: (1) controlling the subsequent enantioselectivity through the formation of early cage like skeleton; (2) constructing C-ring and C8 quaternary carbon stereocenters through acylation / alkylation / lactonization "one pot method"; (3) constructing enmaind / E ring by reductive alkenylation; (4) designing flexible routes to complete the divergent synthesis of three natural products In addition, this synthesis strategy will be of great significance for the preparation of other enantiomeric kaurene diterpenoids.