Enantioselective synthesis of structurally intricate and complementary polyoxygenated building blocks of Spongistatin 1 (Altohyrtin A)

Abstract

Enantioselective approaches to the construction of four complex building blocks of the structurally intricate marine macrolide known as spongistatin 1 are presented. The first phase of the synthetic effort relies on a practical approach to a desymmetrized, enantiomerically pure spiroketal ring system incorporating rings A and B. Concurrently, the C17–C28 subunit, which houses one-fifth of the stereogenic centers of the target in the form of rings C and D, was assembled via a composite of stereocontrolled aldol condensations. Once arrival at the entire C1–C28 sector had been realized, routes were devised to provide two additional highly functionalized sectors consisting of C29–C44 and C38–C51. A series of subsequent transformations including cyclization of the E ring and hydroboration to afford the B-alkyl intermediate for the key Suzuki coupling to append the side chain took advantage of efficient stereocontrol. Ultimately, complete assembly and functionalization of the western EF sector of spongistatin was thwarted by an inoperative Suzuki coupling step intended to join the side chain to the C29–C44 sector, and later because of complications due to protecting groups, which precluded the complete elaboration of the late stage C29–C51 intermediate.

Effect of Partially Fluorinated N‐Alkyl‐Substituted Piperidine‐2‐carboxamides on Pharmacologically Relevant Properties

“…( R )‐1‐Benzyloxy‐2,3‐difluoropropane (52) : Triethylamine trihydrofluoride (1.00 mL, 6.01 mmol, 0.820 equiv) was added to ( S )‐2‐((benzyloxy)methyl)oxirane 50 (1.20 g, 7.31 mmol, 1.00 equiv), then the vessel was sealed and the mixture was heated at 150 °C and stirred for 1.5 h. The reaction was then quenched with water (10 mL) and the mixture extracted with EtOAc (3×40 mL). The collected organic layers were washed with saturated NaHCO 3 (50 mL), dried over Na 2 SO 4 and concentrated in vacuo.…”

“…Terminal vicinal difluorides 6 and 7 were synthesized starting from ( R )‐glycidol 47 and its enantiomer 48 , respectively. Following benzyl protection with benzyl bromide and sodium hydride the epoxide was opened by treatment with Et 3 N⋅3HF at 150 °C to give regioisomeric mixtures of fluorohydrins, which were converted in good yields to vicinal difluorides 51 and 52 (Scheme ). Hydrogenolysis of the benzyl ether and nosylation of the primary alcohols gave nosylated difluorides 53 and 54 , which could be readily coupled with carboxamide 22 to produce the targeted difluorides 6 and 7 in high yields.…”

Electrochemical Vicinal Difluorination of Alkenes: Sustainable, Scalable, and Amenable to Electron-rich Substrates

“…This product, 3f, was synthesised from 10-undecen-1-ol using 'in-cell' procedure 1 and purified using silica gel chromatography (20% EtOAc:Hexane) to yield a viscous colourless oil (125 mg, 50 %) which solidified over the course of several weeks. C 3 ), 29.5 (1C, C [4][5][6][7][8][9] ), 29.4 (1C, C 4-9 ), 28.9 (1C, C 4-9 ), 28.9 (1C, C [4][5][6][7][8][9] ), 26.1 (1C, C 4-9 ), 24.9 (1C, C [4][5][6][7][8][9] ). These data are consistent with that previously reported.…”

Asymmetric total synthesis strategies of halichlorine and pinnaic acid

“…The addition product 5.6 was reduced with sodium borohydride to nitroalcohols 5.7 , followed by iodization to form iodide 5.8 . Dithione 5.9 was coupled with iodide 5.8 afforded 5.10 , 14 and then the thioketal hydrolysis to ketone obtained compound 5.11 .…”

“…The nitroester was reduced with LiBH 4 , followed by mesylation and iodination to obtaine iodide 22.8 . Subsequently, dithiane 22.9 was subjected to metallization using t -BuLi, 14 and then alkylated with iodide 22.8 . 12 a ,53 Dithiane was then deprotected in the presence of I 2 and NaHCO 3 in acetone to obtaine ketone 22.10 , which served as a crucial precursor for the cyclization of the piperidine ring.…”