The stereoselective synthesis of tetrahydrofurans from diazoesters and glyceraldehyde derivatives

Tetrahydrofurans possessing a wide variety of functionality and substitution patterns can be found in nature. Therefore, novel methodologies that incorporate desired functionality and set multiple stereogenic centers are in high demand. The extension of novel methodology, discovered in these laboratories, for the stereoselective synthesis of substituted tetrahydrofurans is described herein.; The first part of this work describes the synthesis of tetrahydrofurans from simple β-hydroxyaldehydes. In this section we investigated the effect various alcohol protecting groups had on the product and yield of the reaction. We discovered that silyl protecting groups provided the highest yield of tetrahydrofurans. In particular, triethylsilyl (TES) was determined to be the optimal protecting group in our tetrahydrofuran forming reaction. Addition of boron trifluoride etherate to a solution of β-triethylsilyloxy aldehyde and benzyl diazoacetate in CH₂Cl₂ at −78°C, afforded us optimized yields of tetrahydrofurans as single stereoisomers. With optimized conditions in hand, we then explored the effect of α-alkyl groups on the yield and stereoselectivity of the reaction. In general, as the steric bulk of the α-alkyl group increased, the yield and stereoselectivity of the tetrahydrofuran product increased.; In the second part of this work, we developed an efficient synthesis of tetrahydrofurans incorporating oxygen functionality at the 3- and 4-positions of the tetrahydrofuran ring. Our tetrahydrofuran synthesis hinged on the successful preparation of the requisite glyceraldehydes derivatives possessing a triethylsilyl protecting group on the β-hydroxyl. Since these types of derivatives had not been reported, we developed an efficient synthesis of them. Treating these derivatives under our optimized conditions for tetrahydrofuran formation afforded tetrahydrofurans in good yield as single stereoisomers. The stereochemistry of these products was determined by conversion to a known tetrahydrofuran.; Finally, we carried out a number of reactions with tetrahydrofuran products from above, in an attempt to synthesize tetrahydrofuran containing natural products. Our progress toward natural products Sphydrofuran and Secosyrin 1 is reported.