Stereoselective Synthesis of Amino Alcohols Applications to Natural Product Synthesis

Sammanfattning: This thesis is divided into four separate parts with amino alcohols as the common feature.The first part of the thesis describes the development of an efficient three-component approach to the synthesis of ?-hydroxy-?-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-?-hydroxy-?-amino esters are formed in high yields and excellent diastereoselectivities. An asymmetric version was also developed by employing chiral ?-methylbenzyl imines as dipolarophiles yielding enantiomerically pure syn-?-hydroxy-?-amino esters. This methodology was also applied on a short asymmetric synthesis of the paclitaxel side-chain as well as in an asymmetric synthetic approach towards the proteasome inhibitor omuralide. Furthermore, the use of chiral Rh(II) carboxylates furnishes the syn-?-hydroxy-?-amino esters in moderate enantioselectivity (er up to 82:18), which indicates that the reaction proceeds via a metal-associated carbonyl ylide.The second part describes the development of a 1,3-dipolar cycloaddition reaction of azomethine ylides to aldehydes for the synthesis of ?-amino-?-hydroxy esters. Different methods for the generation of the ylides, including Vedejs’ oxazole methology and an Ag(I)/phosphine-catalyzed approach have been evaluated. The best results were obtained with the Ag(I)/phosphine approach, which yielded the desired ?-amino-?-hydroxy ester in 68% yield and 3.4:1 syn:anti-selectivity.The last two parts deals with the total synthesis of the amino alcohol-containing natural products D-erythro-sphingosine and (?)-stemoamide. The key transformation in the sphingosine synthesis is a cross-metathesis reaction for the assembly of the polar head group and the aliphatic chain. In the stemoamide synthesis, the key feature is an iodoboration/Negishi/RCM-sequence for the construction of the ?,?-unsaturated azepine core of stemoamide followed by a stereoselective bromolactonization/1,4-reduction strategy for the installation of the requisite C8-C9 trans-stereochemistry.