Anti conformation ethers

Typical carbon-oxygen bond distances m ethers are similar to those of alcohols (—142 pm) and are shorter than carbon-carbon bond distances m alkanes (—153 pm) An ether oxygen affects the conformation of a molecule m much the same way that a CH2 unit does The most stable conformation of diethyl ether is the all staggered anti conformation Tetrahydropyran is most stable m the chair conformation—a fact that has an important bearing on the structures of many carbohydrates... 

The inside alkoxy effect is useful for predicting the stereoselectivity of nitrile oxide cycloaddition reactions with chiral lylic ethers. The hypothesis states that allylic ethers adopt the inside position and alkyl substituents prefer the sterically less-crowded anti conformation in transition states for these electrophilic cycloadditions . The terms inside and outside are defined in (17) for a hypothetical nitrile oxide cycloaddition transition state. Both ab initio (Gaussian 80 with 3-2IG basis set) and molecular mechanics calculations agree, each predicting the lowest-energy transition state to be the one described, i.e. (18 H outside) just above it lies one where the alkyl group is anti, OR outside and H inside (19 ). As illustrated, the former leads to a product wherein OR and the nitrile oxide oxygen are anti, the latter to one with them syn (Scheme 19). 

Table 5.13 B3LYP/aug-cc-pvdz intramolecular interaction in anti-conformers of methyl ethers of 2 -deoxyribonucleotides in Z-DNA like conformations. True hydrogen bonds are underlined...

Anti conformation of diethyl ether Chair conformation of tetrahydropyran... 

Substituents at C9 play a key role in determining the conformation of cinchona alkaloids. For example, esters are present in the anti-closed form in solution, while C9 methyl ethers prefer an anti-open conformation. Recently, the conformations of cinchona alkaloids with a CF3 and a hydroxyl group at the C9 position were examined with NMR spectroscopy [16]. The CF3 group was observed to act as a conformational stabilizer by decreasing the rate of rotation around the C4 -C9, thus allowing the syn and anti conformers to be differentiated at room temperature. The anti conformer was observed to be stabilized by polar solvents with the exception of D2O, in which the syn conformer appeared to be preferred. As found for natural cinchona alkaloids, the syn conformer dominates in apolar solvents. 

In each instance, the silyl enol ether approaches anti to the methyl substituent on the chelate. This results in a 3,4-syn relationship between the hydroxy and alkoxy groups for a-alkoxy aldehydes and a 3,5-anti relationship for (3-alkoxy aldehydes with the main chain in the extended conformation. 

Z)-enolates. The product was subjected to selective deprotection of the C4,C4 -methyl ethers with Mgl2, providing the natural structure of hypocrellin A as the major product. The two newly formed stereocenters in the 7-membered ring were determined to conform to the predicted helical (/ -stereochemistry and the syn-aldol stereochemistry. The minor ( )-enolate afforded the anti aldol product, which matched the diastereomeric natural product shiraiachrome A (8). With this step, the first total syntheses of hypocrellin A and shiraiachrome A (symanti = 10 1 syn diastereomer, 92 % ee) were completed. 

---