Synthesis of (+)-Conagenin

Abstract

An efficient total synthesis of (+)-conagenin was achieved. The right fragment of conagenin, alpha-methylserine containing a quaternary stereocenter attached to nitrogen, was synthesized using allyl cyanate-to-isocyanate rearrangement. The left fragment, 2,4-dihydroxy-3-methylpentanoic acid, has three contiguous stereogenic centers, which was efficiently constructed by enantioselective monoreduction of 2-alkyl-1,3-diketones reported by Cossy, and chelation-controlled stereoselective reduction of beta-hydroxy ketone. These two fragments were coupled through intramolecular amide bond formation with high efficiency.

The Allyl Cyanate/Isocyanate Rearrangement: An Efficient Tool for the Stereocontrolled Formation of Allylic C–N Bonds

“…Carbamate 75 , synthesized from methyl d ‐lactate ( 74 ), was subjected to Appel's conditions to give the isocyanate 76 , which was trapped with sodium phenylmethoxide (Scheme ) . The resulting N ‐protected allylamine 77 , obtained in 90 % yield over two steps, was further used as precursor of (+)‐conagenin, a secondary metabolite isolated from culture broths of Streptomyces roseosporus .…”

1,2,3-Triazoles

“…Combinations of HOBt with dehydrating agents, especially DIC 2005JOC9622 , 2005TL7443 , 2006JCO150 , 2006JME1833 , 2006JME2388 , HBTU 2005AGE2534 , 2005JCO697 , 2005JOC7654 , 2005TL4053 , 2006TL2671 and BOP 2002BML2855 , 2005AGE2887 , 2005JCO703 are common reagents in solid-phase synthesis of peptides. Use of HOBt together with DCC 2005CEJ6666 , 2005JOC5339 , 2005JOC6313 , 2005TL4377 , 2005TL6791 , EDC 2005AGE5710 , 2006JME2333 , 2006OL531 , 2006OL797 , 2006SC1317 or HBTU 2001NN1347 , 2006JME2593 in preparation of carboxylic esters is also relatively common. HOBt can likewise promote formation of C–C bonds in coupling of carboxylic acids with cyanoacetates <2002BCJ2691> and acetoacetates <2002SL1736> .…”

Evolution, Development and Personal Experience in Studies of the Allyl Cyanate-to-Isocyanate Rearrangement

“…The nitrogen-substituted quaternary stereocenter in the right a-methylserine moiety of conagenin was stereoselectively constructed by using [3.3]-sigmatropic rearrangement of an allyl cyanate (Scheme 21). 34 The pentanoic acid 89 and a-methylserine 88 fragments were joined by employing an intramolecular ester-toamide exchange reaction (Scheme 22). Thus, esterification of 89 with 88, removal of the Cbz group in 90 by hydrogenolysis and subsequent treatment of the resultant ester 91 with aqueous sodium bicarbonate gave rise to the amide 92 in 90% yield over three steps.…”