A Convergent Total Synthesis of 19‐Hydroxysarmentogenin

Abstract

Crossopetalum gaumeri (Loes.), a medical plant among the Yucatec Mayan community, contains various highly cytotoxic natural products, including 19-hydroxysarmentogenin-3b-Ob-6-deoxyguloside (Figure 1). [1] This compound belongs to a family of cardenolides and bufadienolides, which are Scheme 2. Reagents and conditions: a) toluene, reflux; HCl (1 m), THF, RT, 78 %; b) LiAlH 4 , Et 2 O, À78 8C to RT; c) MnO 2 , CH 2 Cl 2 , RT, 66 % (2 steps); d) Ac 2 O, Et 3 N, CH 2 Cl 2 , RT, 99 %; e) OsO 4 , NaIO 4 , 2,6lutidine, H 2 O, dioxane, RT, 94 %; f) m-CPBA, CH 2 Cl 2 , RT, 67 %; g) K 2 CO 3 , MeOH, RT, 92 %; h) TBSOTf, 2,6-lutidine, CH 2 Cl 2 , RT; i) PPTS, H 2 O, MeOH, 0 8C, 99 % (2 steps); j) DIBAL-H, CH 2 Cl 2 , À78 8C, 63 %; k) TBSOTf, 2,6-lutidine, CH 2 Cl 2 , RT, 96 %; l) O 3 , CH 2 Cl 2 , À78 8C; Ph 3 P, RT, 80 %; m) A, LDA, THF, RT, 71 % (E/Z = 1:1.2); n) TBAF, THF, 60 8C; o) Ac 2 O, pyridine, DMAP, RT, 84 % (2 steps). DIBAL-H = diisobutylaluminum hydride, DMAP = N,N-dimethyl-4-amino pyridine, LDA = lithium diisopropylamide, m-CPBA = meta-chloroperoxybenzoic acid, PPTS = pyridinium p-toluenesulfonate, TBAF = tetra-n-butylammonium fluoride, TBS = tert-butyldimethylsilyl. AngewandteChemie 5301

Development of a Concise Synthesis of Ouabagenin and Hydroxylated Corticosteroid Analogues

“…More recently, an elegant total synthesis of 19-hydroxysarmentogenin starting from carvone was disclosed by Inoue and co-workers. 16 …”

Concise Approach to (ent)‐14 β‐Hydroxysteroids through Highly Diastereo‐/Enantioselective Diels–Alder Reactions

“…Furthermore, the synthetic routes that were developed are highly efficient because five steps are sufficient to get the compounds of interest. Finally, the presence of the 3‐isopropenyl group (compounds 10 – 13 ) is potentially highly valuable for the introduction of a 3β‐hydroxyl group as has already been shown . Thus, synthetic approaches to ( ent )‐cardenolides using our methodology will be described in the near future.…”

“…Particularly, cardenolides, belonging to the 14β‐hydroxysteroid family, are well known as cardiotonic steroids (i.e. digitoxin, ouabain, 19‐hydroxysarmentogenin) and were utilized for the treatment of congestive heart failure . More recently, novel therapeutic applications as potential use for cancer therapies were developed .…”

Metal‐Catalyzed Asymmetric Michael Addition in Natural Product Synthesis

“…[47] The synthesis of 19-hydroxysarmentogenin 21 was first reported by Inoue and co-workersi n2 013. [48] In 2016, Nagorny and coworkers publishedt he enantioselective total syntheses of 21 and 22,w hich is the diastereomer of 21 at the C5 position. [7j] In this work, Nagornya nd co-workerse stablished an efficient protocolf or the construction of the ABCD-ring structural motif using Cu(OTf) 2 -catalyzed asymmetric Michael addition followed by aldol condensation (i.e., 126)( Scheme 15).…”

“…In addition to their cardiac activity, other biological activities of these molecules include their cytotoxic activity against various cultured human cancer cells . The synthesis of 19‐hydroxysarmentogenin 21 was first reported by Inoue and co‐workers in 2013 . In 2016, Nagorny and co‐workers published the enantioselective total syntheses of 21 and 22 , which is the diastereomer of 21 at the C5 position .…”