Site-selective C-H hydroxylation of pentacyclic triterpenoids directed by transient chiral pyridine-imino groups

Abstract

Pentacyclic triterpenoids (PTs) constitute one of the biggest families of natural products, many with higher oxidation state at the D/E rings possess a wide spectrum of biological activties but are poorly accessible. Here we report a site-selective C-H hydroxylation at the D/E rings of PTs paving a way toward these important natural products. We find that Schönecker and Baran's Cu-mediated aerobic oxidation can be applied and become siteselective on PT skeletons, as being effected unexpectedly by the chirality of the transient pyridine-imino directing groups. To prove the applicability, starting from the most abundant triterpenoid feedstock oleanane, three representative saponins bearing hydroxyl groups at C16 or C22 are expeditiously synthesized, and barringtogenol C which bears hydroxyl groups at C16, C21, and C22 is synthesized via a sequential hydroxylation as the key steps.

Facile Synthesis of Saikosaponins

“…Since the 2-O-acetyl group might result in orthoester formation or migration to the aglycone during the glycosylation reactions [27][28][29], 2,4-di-O-benzoyl o-alkynylbenzoate 12 was also prepared (77% for 3 steps). The synthesis of saikogenins commenced with known compound 13, which was readily prepared from oleanolic acid in 7 steps (Scheme 3) [20]. Desilylation with the Olah reagent, oxidation of the resultant 3-OH, and subsequent oxime formation with hydroxylamine hydrochloride afforded oxime 14 (84%).…”

“…The synthesis of saikogenins commenced with known compound 13 , which was readily prepared from oleanolic acid in 7 steps ( Scheme 3 ) [ 20 ]. Desilylation with the Olah reagent, oxidation of the resultant 3-OH, and subsequent oxime formation with hydroxylamine hydrochloride afforded oxime 14 (84%).…”

“…Chemical synthesis of saikosaponins is also a challenging task, given the scarce availability of the triterpene aglycones that bear high oxidation state at the D/E rings [ 16 , 17 , 18 , 19 ]. Very recently, we disclosed a site-selective C-H hydroxylation reaction at the D/E rings of pentacyclic triterpenoids, thus paving a venue for the synthesis of saikosaponins [ 18 , 20 ]. Herein, we report the synthesis of saikosaponin A ( 1 ), D ( 2 ), and their congeners ( 3 – 7 ), using the largely available oleanolic acid as a starting material.…”

A Relationship between NTP and Cell Extract Concentration for Cell-Free Protein Expression

“…Because of its easiness of handling and ability to express wide varieties of proteins, CFPS is widely applied to protein engineering including directed evolution of proteins and synthesis of cytotoxic proteins [ 2 , 3 , 4 , 5 , 6 , 7 ]. Since CFPS has the ability to reconstitute biochemical systems from DNA mixtures, it has been also featured as an important material for research toward rebuilding living cells in vitro [ 8 , 9 , 10 , 11 , 12 , 13 ]. As another application, CFPS has been utilized for protein folding studies [ 14 , 15 ], membrane insertion analysis [ 16 , 17 ], and elucidation of molecular machinery in living cells such as translational arrest [ 18 ].…”

Facile Synthesis of Oleanane‐type Pentacyclic Triterpenoids Bearing Hydroxy Groups on D/E Rings

“…[18,19] Thus, starting from the abundant oleanolic acid, we were able to prepare 22α-ol and 16β-ol derivatives 7 and 8 effectively, and thereafter we have managed to synthesize barringtogenol C and a panel of saikosaponins bearing 16β/αÀ OH or 22αÀ OH group. [17,20] Herein, we report the synthesis of chichipeginin (1) and PTs 2-6, where hydroxy groups are further introduced into C15 and C21 on the D/E rings of the oleanane scaffold (Figure 2). The transposition of 22αÀ OH in PT 7 to 21À OH was firstly examined (Scheme 1).…”