Asymmetrische Synthese von 2-Methyl-substituierten 1,3-Diolen

Nature employs dihydroxyacetonephosphate (DHAP) as a C3-building block for carbohydrate synthesis via enzyme catalyzed aldol reactions. Accordingly many groups focussed on broadening the scope of that enzyme catalyzed reaction. On the other hand a chiral, synthetic DHAP equivalent would not only be suitable for aldol type reactions but would open up the possibility of a wide range of stereoselective derivatisations. We found, that condensation of commercially available 2,2-dimethyl-1,3-dioxan-5-one with (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) to the respective SAMP-hydrazone proved to be an excellent platform for general asymmetric synthesis. Consequently in 1989 we published a stereoselective a-alkylation of the respective SAMP-hydrazone followed by oxidative auxiliary cleavage to the corresponding chiral, a-substituted acetonide protected ketodiols with good yields and excellent enantiomeric excesses. Since we were looking for new synthetically challenging and pharmacologically interesting targets, we thought about investigating the development of a new reliable method for the asymmetric synthesis of 2-methyl substituted 1,3-diols. Therefore, a novel asymmetric synthesis of pseudo C2-symmetric, 2-methyl substituted 1,3-diols was developed. Virtually diastereo- and enantiomerically pure 4,6-disubstituted 2,2-dimethyl-1,3-dioxan-5-ones were synthesized based on the SAMP/RAMP-hydrazone method in moderate to good overall yields starting from 2,2-dimethyl-1,3-dioxan-5-one-SAMP-hydrazone. a-Substituted ketones were converted into methylenated, 4,6-disubstituted 2,2-dimethyl-1,3-dioxan-5-ones by epimerization-free Wittig-reaction in good to excellent yields. Hydrogenation led to 4,6-disubstituted 2,2,5-trimethyl-1,3-dioxanes in good to excellent yields by using PtO2·H2O as well as Wilkinson´s catalyst. Finally, hydrolytic cleavage was demonstrated to afford the deprotected, pseudo C2-symmetric diols in almost quantitative yield (de >= 96%; ee >= 98%). However, if two different substituents R were introduced, again virtually diastereo- and enantiomericially pure acetonide protected keto diols and exo-methylene derivatives could be obtained with very good chemical yields, but the stereoselective hydrogenation could only be conducted with a diastereomeric excess up to 88% ( >= 96%). A modification of that method to the monoalkylated, exo-methylene derivatives did open up the possibility for the stereoselective hydrogenation of the prochiral double bond to give acetonide protected diols in excellent yields (de up to 90% (>= 96%), ee = 90-94%). Again, subsequent hydrolytic cleavage was demonstrated to obtain the deprotected diols in very good yields. As the double allylic alcohol moiety is a crucial structural feature of many natural products, found for example in metabolites of marine sponges and microorganisms with ionophoric activity, a further extension of the method would make those compounds easily available. Therefore, a straight forward five step synthesis of monoprotected, double allylic alcohols with very good overall yields and enantiomeric excesses (ee = 90-94%) was developed, which allow for an enantioselective approach to these versatile building blocks for asymmetric synthesis. Another application of the basic methodology has been shown by the diastereoselective synthesis of acetonide protected, 1,3-syn-diols by utilizing the respective achiral N,N-dimethylhydrazone as starting material. The protected ketodiols have then been olefinated and hydrogenated to give 2-methyl substituted 1,3-syn-diols in good yields and diastereomeric excesses up to 90% (>= 96%). The current research is directed towards the asymmetric synthesis of carbocyclic nucleosides and is most focused on the synthesis of neplanocin A analogues which shows remarkable high antitumor activity. Hence, a four step asymmetric synthesis of cyclic olefins was developed. Starting again from the respective SAMP-hydrazone, the a-substituted keto diols were synthesized in good yields over two steps and very good enantiomeric excesses (ee = 96%) using olefinic electrophiles for the stereoselective a-alkylation and utilizing aqueous oxalic acid for hydrolytic auxiliary cleavage. After Wittig-olefination, the cyclic olefins were obtained with very good yields by ring closing metathesis (RCM) using first generation Grubbs catalyst. Following the described synthesis route, a deoxyneplanocin A analogue should be obtaind by using a serin derived, nitrogen containing, chiral eletrophile. Besides, neplanocin A analogue should be obtained by an aldol route starting from the respective SAMP-hydrazone and adjacent ring closing metathesis (RCM). In summary, we have developed a novel and efficient method for the stereoselective synthesis of pseudo C2-symmetric as well as mono- and bisalkylated 2-methyl substituted 1,3-diols starting from commercially available 2,2-dimethyl-1,3-dioxan-5-one and employing the SAMP/RAMP-hydrazone method as stereoselective key step with very good to excellent asymmetric induction or utilizing the respective N,N-dimethylhydrazone as starting material with high diastereoselectivity. This method has been extended to an efficient five step asymmetric synthesis of monoprotected, double allylic alcohols in good overall yields and very good enantiomeric excesses. Furthermore, the asymmetric synthesis of 2-hydroxymethyl-3-hydroxy cyclic olefins with very good yields and enantiomeric excesses has been developed and will be used as the basis for neplanocin A analogues synthesis.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2003

Author dc:creator

• Voith, Matthias

Contributors dc:contributor

• Enders, Dieter

• info:eu-repo/classification/ddc/540
• Diole
• Methylgruppe
• Asymmetrische Synthese
• Dioxanone
• Chemie

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-120963%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:59153