Synthesis of the 1,6,8-trioxadispiro[4.1.5.2]tetradec-11-ene ring system present in the spirolide family of shellfish toxins and its conversion into a 1,6,8-trioxadispiro[4.1.5.2]-tetradec-9-en-12-ol via base-induced rearrangement of an epoxide

Abstract

The synthesis of the 1,6,8-trioxadispiro[4.1.5.2]tetradec-11-enes 12 present in the shellfish toxins spirolides B and D 2, is reported. The two spirocentres were constructed via iterative radical oxidative cyclization of hydroxyalkyl dihydropyran 14 and hydroxyalkyl spiroacetal 13 using iodobenzene diacetate and iodine. This procedure initially afforded a 1 : 1 : 1 : 1 mixture of bis-spiroacetals 12a : 12b : 12c : 12d, however subsequent acid catalysed equilibration afforded a 3 : 1 : 0.9 thermodynamic mixture of 12a : 12b : 12c. The major bis-spiroacetal 12a underwent stereoselective epoxidation using dimethyldioxirane to alpha-epoxide 33a. Subsequent base induced rearrangement of this epoxide 33a using lithium diethylamide in pentane afforded allylic alcohol 34a, that was converted to the more thermodynamically favoured homoallylic alcohol 11a upon treatment with lithium pyrrolidinylamide in tetrahydrofuran. Homoallylic alcohol 11a possesses a hydroxyl group at C-12 as required for introduction of the tertiary alcohol group present at this position in spirolides B 1 and D 2.

Dictating Thermodynamic Control through Tethering: Applications to Stereoselective Bis‐Spiroketal Synthesis

“…The stereochemical outcome of this reaction was determined through a NOESY experiment and from the observation of a 0.6 Hz coupling constant for the axial methyl group in the 1 H NMR spectrum, consistent with the known W‐coupling of axially‐oriented methyl groups adjacent to a carbon with an axially oriented hydrogen . This is consistent with previous related examples . The phthalate diester was cleaved under standard conditions to deliver 39 in good yield.…”

Synthesis of spiroacetal-triazoles as privileged natural product-like scaffolds using “click chemistry”

“…Due to the instability of the resultant Grignard reagent, 20 utilisation of Barbier conditions was implemented under the reaction conditions that have been successfully used for related reactions by our research group. 17, 21 After activation of the magnesium turnings with iodine and 1,2dibromoethane, Weinreb amide 11 and bromide 10 were added sequentially and the reaction was triggered with the addition of iodine. Initially, the reaction afforded ketone 9 in only 42-65% yield when the reaction temperature was not carefully controlled.…”

Synthesis of the Bis-spiroacetal Moiety of Spirolides B and D

“…In addition to our work on the synthesis of model spiroimines related to the spirolides, we have previously also reported the synthesis of a C10−C22 bis-spiroacetal fragment that lacked the C19 tertiary alcohol group using a double oxidative radical cyclization . However, problems were encountered during the introduction of functionality at C19 and extension of the carbon framework at C22, thus prompting adoption of a modified synthetic plan in which disconnection of the C23−C24 bond rather than the C22−C23 bond was a pivotal step.…”

“…With alcohol 12 in hand, attention was turned to the iterative oxidative radical cyclization steps (Scheme ) …”