Total Synthesis Of The Marine Natural Product Callipeltin B

A number of bioactive natural products were found from marine sponges.In the last decade,a class of cyclopeptides with unique structure have been isolated.The structural characteristics of this family of cyclopeptides include some commonunusual amino acid residues and unique N-terminal polyketide-derived moieties.These cyclopeptides include Papuamides,Callipeltins,Mirabamides,Neamphamides and Theopapuamides et al.They show cytoprotective activity against HIV-1,anti-tumor and antifungal activity.Callipeltins have been isolated from the sponge of Callipelta sp.and Latrunculia sp.by Zampella and co-workers.Callipeltin B,as a member of Callipeltins,displays a broad range of anticancer activity.Callipeltin B possesses a 22-membered macrolactone composed of the unique,non-proteinogenic amino acids(2R,3R)-β-methoxytyrosine,(3S,4R)-3,4-dimethyl-L-pyroglutamic acid and D-allothreonine as well as one D-Arginine and two N-methylated amino acids and one L-Leu.It is a very challenging task to synthesize(2R,3R)-β-methoxytyrosine,(3S,4R)-3,4-dimethyl-L-pyroglutamic acid and D-allothreonine.In this paper,we developed three expeditious and novel routes for the synthesis of these nonproteinogenic amino acids and then accomplished the total synthesis of Callipeltin B.The main contents and results are focused as following:1.A novel method for synthesis of enantiopure β-hydroxy-p-arylalanine and β-methoxy-β-arylalanine was developed.(1)erythro-β-Hydroxy-β-arylalanine derivatives were prepared by diastereoselective hydrogenation of ethyl 2-(hydroxyimino)-3-oxo-3-arylpropanoates,which were in turn acquired by the oximation of ethyl 3-oxo-3-arylpropanoates with ethyl nitrite in the presence of nano-K2CO3 with yields of 72%to 80%;(2)β-Methoxy-β-arylalanine derivatives were synthesized through Williamson reactions between the corresponding N-actely-acetyl-β-hydroxy-β-arylalanine ester and iodomethane with silver oxide as base.(3)threo-N-Acetyl-β-hydroxy-β-phenylalanine was prepared selectively through the thermodynamically controlled aldol reaction between glycine and benzaldehyde.The two erythro isomers were prepared by L-or D-aminoacylase-catayzed resolution of the corresponding N-acetyl derivatives,whereas the two threo isomers were obtained only by D-aminoacylase-catalyzed resolution of the derivatives.Chiral β-hydroxy-β-arylalanine and β-methoxy-β-arylalanine derivatives were stereoselectively synthesized with 99%ee values by this method and prepared on a multigram scale;(4)Further,the synthesis of(2R,3R)-β-methoxytyrosine was accomplished according to the above method.erythro-β-Methoxytyrosine derivatives protected by MEM was prepared firstly.(2S,3S)-β-Methoxytyrosine was obtained by L-aminoacylase-catalyzed resolution of the corresponding N-acetyl derivatives,and then(2R,3R)-β-Methoxytyrosine was obtained by the removal of acetyl group using chemical method.2.A novel method for synthesis of optically pure 3-methylglutamic acid and 3.4-dimethylglutamic acid was developed.Highly stereoselective Michael addition of camphor-based tricyclic iminolactones 57 and 58 to α,β-unsaturated ester respectively was accomplished without using any chiral catalyst,which afforded adducts with two or three newly formed stereogenic centers in one step in good yields(78-81%)and excellent diastereoselectivities(dr>95:5).The effects of reaction temperature,ester groups of electrophile and inorganic ions on the synthesis were investigated.The synthesis of 3,4-dimethylglutamic acids were achieved through only 5 steps,starting from commercially available camphorquinone.It is a simple and practical method because the synthetic route was shorten drastically compared with the reported approaches.Optically pure spirocyclic products containing multichiral centers were obtained by cascade addition of iminolactone 58 to crotonate.Optical purity(3S,4R)-3,4-dimethyl-L-pyroglutamic acid was obtained through the racemization of a-C,cyclization and then chromatographic separation.The configurations of products were unambiguously ascertained by NMR and X-ray crystallography.3.A novel and practical approach for preparation of L-allothreonine and D-allothreonine was designed.The optical purity L-allo-Thr(or D-allo-Thr)compound was obtained by using the L-(or D-)aminoacylase to resolute the α-C racemic threonine of N-acetylation.The resolution conditions were optimized by assessing pH,temperature and the amount of Co2+ for obtaining the maximum yield.The optimal condition was that pH is 7.5,reaction temperature is 37 ℃,and concentration of Co2+ is 0.1 g/L.The yield was 93.8%for L-allo-Thr.89.8%for D-allo-Thr.and de>99%.This method showed some advantages such as high stereoselectivity,simple operation and mild conditions.4.This subject choosed 2-Chlorotrityl chloride resin(1.1 mmol/g)as the carrier,anchored the C-terminal of β-OMeTyr to the resin.The synthesis of line peptide of’Callipeltin B was achieved using Discover SPS by a standard Fmoc-based,C-to-N synthesis approach.Finally,the total synthesis of Callipeltin B was accomplished through the cyclization using PyAOP as coupling reagents at room temperature in overall yield 1.1%.5.A novel method for preparation nano-K2CO3 was developed.Nano-K2CO3 was prepared by ultrafine wet milling.The surface properties and the reactive activities of nano-K2CO3 were characterized.The material was endowed with a small average particle size and strong basicity compared with normal K2CO3.It was found that such base showed higher basicity than normal K2CO3 and could replace sodium(or potassium)alkoxide to carry out monoalkylation and oximation of active methylene compounds.