An Efficient Synthetic Strategy for Introduction of C₃‐C₄ Double Bond into Eudesmane Skeleton: First Total Synthesis of (+)‐Chrysanthemol

Abstract

The first enantioselective syn the sis of (+)-chrysanthemol 1 was car ried out start ing from (+)-dihydrocarvone in ten steps. In our stud ies, a fac ile syn thetic strat egy has been de vel oped for in t ro duc tion of C3-C4 dou ble bond into a eudesmane skel e ton. IN TRO DUC TION Chry san the mum indicum L1 is a tra di tional Chi nese med i cine com monly used. It ex hib its con sid er able bi o log i cal ac tiv i ties such as antipyretion, de tox i fi ca tion, and re duc ing blood pres sure. Re cently, a clin i cal study has in di cated that Chry san the mum indicum L has fairly good ef fects on chronic pel vic carity in flam ma tion, pel vic carity tu ber cu lo sis and pros trate gland in flam ma tion. A pharmacodynamics study dem on strates that it can re sist bac te ria, con trol blood platelet ag gre ga tion, ex pand cor o nary, and re duce blood pres sure. In 1987, Yu and Xie iso lated (+)-chrysanthemol 1 from the flower of Chry san the mum indicum L and elu ci dated its struc ture on the ba sis of spec tral and chem i cal ev i dence.1 At the same time, El-Ghazouly and co-workers iso lated sesquiterpene -xylopyranosides 2 and 4 from the ae rial parts of Iphiona scarbra. 2 Herein we de scribe the first to tal syn the sis of (+)-chrysanthemol 1 start ing from (+)-dihydrocarvone in ten steps. In our syn the sis, the nat u ral prod uct (+)--eudesmol was also ob tained as a key in ter me di ate. 3 RE SULTS AND DIS CUS SIONIn our syn thetic strat egy, a dou ble bond at the C-3, C-4 po si tion is pref er a ble. Pre vi ously, there have been many attempts for the in tro duc tion of C-3, C-4 dou ble bond in a eudesmane skel e ton.4 Sev eral of these meth ods have been applied for the syn the sis of eudesmol. But it is im prac ti cal to ap ply these meth ods in the syn the sis of the eudesma acid functionalized at C-3, C-4 due to some draw backs. These short com ings en tail de vel op ing a more ef fi cient syn thetic route to in tro duce a dou ble bond into a eudesmane skel e ton. In this pa per we also pro vided an ef fi cient, con ve nient syn thetic ap proach to wards the in tro duc tion of C3-C4 dou ble bond into a eudesmane skel e ton. Em ploying this strat egy, we com pleted the to tal syn the sis of (+)-chrysanthemol 1 as shown in the fol low ing scheme.By the pub lished method, 5 ( )--cyperone 6 was eas ily pre pared from (+)-dihydrocarvone 5 in 50% yield. Lith iumliquid am mo nia re duc tion of 6, us ing am mo nium chlo ride as the pro ton do nor, af forded the dihydro--cyperone 7 stereospecificly. 4a Uti lizing the steric hin drance of 10 -methyl, stereoselective re duc tion of 7 by tri-t-butoxyaluminium hydride gave al co hol 8 in high yield. By a stereospecific manner, al co hol 8 was con verted into its 3 -chloro de riv a tive 9 by PPh 3 -NCS in THF un der mild con di tions. 6 Epoxidation of 9 with m-CPBA, fol lowed by LiAlH4 re duc tion af forded alco hol 11. (+)--Eudesmol 3 was ob tained af ter elim i na tion of the ha lide of com pound 11 with LiBr-LiCO 3 /DMF in high yield (90%). 7 Con se quentl...