Total Synthesis of Crocagin A

Abstract

Crocagin A( 1)c ombines an attractive molecular structure with an unusual biosynthesis and bioactivity.A n efficient synthesis of crocagin Aispresented that hinges on an early formation of the heterotricyclic core,a ne lectrophilic amination, and the stereoselective hydrogenation of atetrasubstituted double bond. This synthesis confirms the absolute configuration of crocagin Aand provides access to the natural product and derivatives thereof for further biological testing. Scheme 1. Structure and biosynthetic origin of crocagin.Scheme 2. Retrosynthetic analysis of crocagin A.

Electrophilic Aminating Agents in Total Synthesis

“…[99,101] Tr auner and co-workers have demonstrated the power of this approach in the synthesis of crocagin A( 57), ab ioactive compound isolated from myxobacterium Chondromyces crocatus (Scheme 10). [114] It was hypothesized that the C( 14) À Nbond of 57 could be installed by electrophilic amination, prior to introduction of the N-methyl isoleucine side chain, 55.T oe xecute this strategy,p yrimidinone 51 was identified as as uitable precursor, and this was prepared in six steps from 50.T he installation of the desired CÀNb ond to 51 was challenging, likely due to the diminished nucleophilicity of the C( 14)-C( 15) alkene double bond as aresult of conjugation with the C(13) carbonyl. Indeed, several azodicarboxylate electrophiles were investigated without success.Subsequently,itwas found that amination could be achieved using copper(II) triflate as aLewis acidic catalyst in combination with dibenzyl azodicarboxylate 22,p roviding 52 in 86 %y ield.…”

“…Compound 103 was prepared by subjecting alkene 101 to the Cu I Hh ydroamination conditions,i nt he presence of the chiral ligand (S)-DTBM-SEGPHOS.I nt his particular case, 1,2-benzisoxazole (102)w as selected as the aminating agent and this provided the Schiff base product 103 in excellent yield and enantioselectivity.F rom here,h ydrolysis of the imine gave the desired chiral amine,w hich was advanced to the corresponding isocyanate, 105.T his can be coupled with known amide 104 to generate DMP 777 (106)i ne xcellent yield. [240] To demonstrate the applicability of Cu I H-catalyzed hydroamination to other types of p-unsaturated systems, Buchwald reported as uccinct two-step synthesis of rivastigmine (114), ad rug compound used for the treatment of Alzheimersa nd Parkinsonsd isease (Scheme 20). [230] The synthesis commenced with the formation of carbamate 108 by addition of N-ethyl-N-methylcarbamoyl chloride to commercially available 3-hydroxyphenylacetylene (107).…”

Electrophilic Aminating Agents in Total Synthesis

“…[99,101] Tr auner and co-workers have demonstrated the power of this approach in the synthesis of crocagin A( 57), ab ioactive compound isolated from myxobacterium Chondromyces crocatus (Scheme 10). [114] It was hypothesized that the C( 14) À Nbond of 57 could be installed by electrophilic amination, prior to introduction of the N-methyl isoleucine side chain, 55.T oe xecute this strategy,p yrimidinone 51 was identified as as uitable precursor, and this was prepared in six steps from 50.T he installation of the desired CÀNb ond to 51 was challenging, Scheme 9. Shibasaki's synthesis of mycestericin F (49).…”

“…[230] The synthesis commenced with the formation of carbamate 108 by addition of N-ethyl-N-methylcarbamoyl chloride to commercially available 3-hydroxyphenylacetylene (107). From here, the amino-bearing stereocenter was introduced by at andem process involving Cu I H-catalyzed reduction of the alkyne and hydroamination of the resulting alkene.T he reduction step required the addition of i-PrOH, which is postulated to protonate vinyl copper species 110,a nd thereby prevent formation of enamine 111.T he resulting alkene 112 then engages in another CuH-catalyzed hydroamination event via the alkylcopper species 113 to provide rivastigmine (114)i n excellent yield and enantioselectivity.…”