Stereoselective Synthesis of Amino Alcohols: Applications to Natural Product Synthesis
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
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 α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters are formed in high yields and excellent diastereoselectivities. An asymmetric version was also developed by employing chiral α-methylbenzyl imines as dipolarophiles yielding enantiomerically pure syn-α-hydroxy-β-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-α-hydroxy-β-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 α-amino-β-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 α-amino-β-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 β,γ-unsaturated azepine core of stemoamide followed by a stereoselective bromolactonization/1,4-reduction strategy for the installation of the requisite C8-C9 trans-stereochemistry.
Place, publisher, year, edition, pages
Stockholm: KTH , 2007. , 71 p.
Trita-CHE-Report, ISSN 1654-1081 ; 2007:52
Amino alcohol, asymmetric 1.3-dipolar cycloaddition, azomethine ylide, carbenoid, carbonyl ylide, cross-metathesis, omuralide, oxazolidine, rhodium, sphingosine, stemoamide, stereoselective synthesis, total synthesis.
IdentifiersURN: urn:nbn:se:kth:diva-4472ISBN: 978-91-7178-734-7OAI: oai:DiVA.org:kth-4472DiVA: diva2:12426
2007-09-14, F3, Lindstedtsvägen 26, Stockholm, 10:00
Andersson, Pher G, Professor
QC 201008202007-08-232007-08-232010-08-20Bibliographically approved
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