Strategies for the Synthesis of Cyclic Ethers of Marine Natural Products

Abstract

This account describes our studies on the synthesis of natural products that contain cyclic ethers in their structures. An overview of the main methodologies is presented and several total syntheses developed by the group are described. We also discuss new applications based on the use of Prins and Nicolas reactions as key steps in the preparation of oxygenated heterocyclic compounds.

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…Specific compounds or compound classes represented include: (1) tetrahydropyrans [53]; (2) cyclopentenones [54]; (3) 3,4,5-trisubstituted isoxazolines [55]; (4) carbocyclic nucleosides [56]; (5) lycopodium alkaloids [57,58]; (6) cyclic hydrazines and azo compounds [59]; (7) tropone and tropolone natural products [60]; (8) seven-membered ring natural products [61]; [62]; (9) tetrahydroisoquinoline-3-carboxylic acid derivatives [63]; (10) chalcones and their heterocyclic derivatives [64]; (11) marine-derived cyclic ethers [65]; (12) pericosine and related marinederived carbasugar natural products [66]; (13) carbohydrate derived macrocyclic compounds [67]; (14) neurotrophic natural products [68]; (15) isodon diterpenes [69]; (16) non-isoprenoid polyene natural products [70]; (17) heterophosphacyclanes [71]; (18) chlorosulfolipids [72]; (19) seven-membered ring sulfur heterocycles; (20) organic cage compounds [73]; (21) presilphiperfolanols [74]; (22) pleuromutilin [75]; (23) hyperforin [76]; (24)…”

Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing sidechain-functionalized tetrahydrofurans

“…In the contemporary organic synthesis, methods for preparing chiral cyclic ethers from alkenols in a diastereodivergent approach are a concern [19]. Oxepans, tetrahydropyrans, and particularly tetrahydrofurans pose key structures of many secondary metabolites ( Fig.…”

Stereoselective Synthesis of Highly Substituted Tetrahydropyrans through an Evans Aldol–Prins Strategy

“…5 (t, NCH2CH2OCOCH3), 45.2 (d, C8), 47.5 (d, C4a), 61.6 (t, NCH2CH2OCOCH3), 74.7 (d, C5), 76.7 (d, C8a), 76.9 (d, C7), 152.5 (s, C2), 169.5 (s, C4), 171.2 (s, OCOCH3); HRMS: calcd for C21H35NO6Na [(M + Na) + ] 420.2362, found 420.2361. (4a'S*,5'S*,8'S*,8a'S*)-8'-Ethyl-3'-(2-hydroxyethyl)-5'-methyltetrahydro-2'H-spiro[cyclohexane-1,7'-pyrano[3,4-e][1,3]oxazine]-2',4'(3'H)-dione (5l).Aldol 2b (30 mg, 0.13 mmol) and cyclohexanone (0.03 mL, 0.29 mmol, 2.2 equiv) were submitted to the general procedure for the Prins cyclization and yielded, after purification by flash chromatography (21 cm of height of silica gel, n-hexane/EtOAc 75/25), THF 8l (7.8 mg, 19%, 80:20 dr), title compound 5l (10 mg, 23%, >95:5 dr) and previously described bicycle 5b (8 mg, 45%, >95:5 dr). 5l was isolated as a colourless oil and its description is given below.…”

“…(4aS*,5S*,7R*,8R*,8aS*)-3-(2-Chloroethyl)-8-ethyl-5,7-diisobutyltetrahydro-2H,5H-pyrano[3,4-e][1,3]oxazine-2,4(3H)-dione (7a-Cl). To a suspension of bicycle 5a(86 mg, 0.24 mmol) in H2O (2.4 mL, 0.1 M) was added a 37% HCl aqueous solution (2.4 mL, 29 mmol, 121 equiv) and the mixture was heated at 100 ºC.…”

“…RF: 0.3 (nhexane/EtOAc 60/40); 1 H-NMR (500 MHz, δ, CDCl3): 0.84-0.88 (m, 3H, H2'''), 0.90-0.97 (m, 12H, 4x(CH3)2CH), 1.30-1.37 (m, 1H, H1''), 1.40-1.50 (m, 2H, H1', H1''), 1.52-1.65(m, 2H, H8, H1'''), 1.70-1.76 (m, 1H, H1'''), 1.85-1.96 (m, 2H, H2', H2''), 2.06-2.14 (m, 1H, H1'), 2.34-2.40 (m, 1H, H4a), 3.16-3.23 (m, 1H, H7), 3.49-3.56 (m, 3H, H5, NCH2CH2Br), 4.05-4.14 (m, 1H, NCH2CH2Br), 4.15-4.26 (m, 2H, H8a, NCH2CH2Br); 13 C-NMR (125 MHz, δ, CDCl3): 9.3 (q, C2'''), 18.5 (t, C1'''), 21.0 (q, (CH3)2CHCH2), 21.2 (q, (CH3)2CHCH2), 23.9 (q, (CH3)2CHCH2), 24.0 (q, (CH3)2CHCH2), 24.1 (d, (CH3)2CHCH2), 24.4 (d, (CH3)2CHCH2), 28.3 (t, NCH2CH2Br), 41.6 (t, (CH3)2CHCH2), 42.8 (t, NCH2CH2Br), 43.4 (t, (CH3)2CHCH2), 45.6 (d, C8), 48.1 (d, C4a), 72.9 (d, C5), 75.2 (d, C8a), 76.8 (d, C7), 151.3 (s, C2), 168.6 (s, C4); HRMS: calcd for C19H32BrNO4Na [(M + Na) + ] 440.1392, found 440.1410. (4aS*,5S*,7R*,8R*,8aS*)-3-(2-Chloroethyl)-8-ethyl-5,7-dimethyltetrahydro-2H,5H-pyrano[3,4-e][1,3]oxazine-2,4(3H)-dione (7b-Cl). To a solution of aldol 2b (37 mg, 0.16 mmol) in DCM (1.6 mL, 0.1 M) was sequentially added acetaldehyde (73 L of a 3.3 M solution in DCM, 0.24 mmol, 1.5 equiv), TMSCl (0.05 mL, 0.40 mmol, 2.5 equiv) and BF3•OEt2 (0.01 mL, 0.08 mmol, 0.5 equiv; lower amounts led to higher reaction times and worse yields of the bicycle).…”