hem 316/422 Beauchamp 1 Match the step number in the synthesis with the letter of the reagents listed just below. TP l Et step 8 4 5 eagents used in synthesis A B D E F a DMF (solvent) 1. (i-pr) 2 Li (LDA)/TF -78 o o rg. Lett., vol. 10, pp 157-9, 2008.L. Morales & B.L. Pagenkopf TP l 3 Et 3 / 2 l 2 2 l 3 3 -l 2 3 3 1. ab 4, Et 3 3 3 3 F 3 ( 3 ) 3 i-tf G 1. Pl 3 / toluene ab 4 Pd / a / 2 / J catalyltic Ts- 3 / Et 3 K a / 3 microwave L 1. DBA, 2 l 2 2 4 / 2 M a / 3 / TF 1. 2 eqs. n-buli/tf 3 2-3. 6 5 2 catalytic Ts- 3 P 3 / 3 :\Documents and ettings\psbeauchamp.w\my Documents\classes\synthesis literature articles\rg Letts, 2008, 157-9, (dl)-goniomitine.doc
hem 316/422 Beauchamp 2 Key The reagents for each step are listed below. TP l Et step 8 4 5 1. 2 eqs. n-buli/tf 3 2-3. 6 5 2 2 l 3 3 -l 1. (i-pr) 2 Li (LDA)/TF -78 o o 2 3 3 3 / 3 TP catalytic Ts- 3 rg. Lett., vol. 10, pp 157-9, 2008.L. Morales & B.L. Pagenkopf a DMF (solvent) l 3 Et 3 / 2 l 2 a / 3 / TF a / 3 microwave 3 1. Pl 3 / toluene ab 4 3 3 4 1. DBA, 2 l 2 2 4 / 2 3 F 3 ( 3 ) 3 i-tf 5 1. ab 4, Et step 8 Pd / a / 2 / catalyltic Ts- 3 / Et 3 :\Documents and ettings\psbeauchamp.w\my Documents\classes\synthesis literature articles\rg Letts, 2008, 157-9, (dl)-goniomitine.doc
hem 316/422 Beauchamp 3 ynthesis of (with comments) l 1. 2 eqs. n-buli/tf 3 2-3. 6 5 2 A dianion alkylates at the more reactive site, followed by alkylation at the less reactive site. chiral center yanide is a good nucleophile and acetonitrile is a good 2 solvent (polar, aprotic). 2 reaction displaces the good chloride leaving group. The microwaves make the reaction work more efficiently by providing localized heating. 3 a / 3 / microwave 1. (i-pr) 2 Li (LDA)/TF -78 o o LDA removes an to make an enolate, which is alkylated (the 3rd time in a row). TP is tetrahydropyran, an alcohol protecting group. TP 3 3 ( 3 ) 3 i F 3 ( 3 ) 3 i-tf 3 TP catalytic Ts- / 3 phenyl Deprotection of TP group using catalytic toluenesulfonic acid. ( 3 ) 3 i l 3 Et 3 / 2 l 2 Mesylate (like tosylate) makes into a good leaving group, and chloride leaving group turns into a nucleophile that displaces the mesylate in an 2 reaction. ontinue at top of next column. The trimethylsilyltriflate reacts with the group lone pair (like a proton). Electron donation from the methoxy oxygen, breaks the cyclopropane ring and makes a silyl enol ether. The positive charge that forms by the methoxy group is attacked by the nitrile in a "itter" reaction. The new positive carbon (of the nitrile) is attacked by the enol ether, making a 5 atom ring. A tautomeric proton shift makes the new 5 atom heterocyclo ring. ontinue at top of next page. :\Documents and ettings\psbeauchamp.w\my Documents\classes\synthesis literature articles\rg Letts, 2008, 157-9, (dl)-goniomitine.doc
hem 316/422 Beauchamp 4 Pd / Et everse of hydrogenation (there's no 2 (g)). Pd is oxidizing instead of reducing. The driving force is aromatization. 3 / 3 2 methylation reaction by 3 o amine on iodomethane, makes ammonium ion which becomes a good leaving group. step 8 a / 2 / ydrolysis of ester to carboxylate, followed by decarboxylation (- 2 ). The leaving group is the sp 2 carbon of the indole ring, which immediately protonates. a / DMF (solvent) yanide does an 2 reaction with trimethylamine leaving group. DMF (dimethylformamide) is a good 2 solvent (polar, aprotic). 2 l ontinue at top of next column. 3 3 -l 2 3 Enamine-like reaction with carbonyl-like protonated iminium made from an aldehyde, secondary amine and some l. The reaction makes a 3 o amine (called the "Mannich" reaction). 3 a / 3 / TF adical anion forms in phenyl part of benzyl 3 o amide protecting group is reduced to the 2 o amide group. Think "LA-like 2 reaction" at benzyl carbon, except LA would react with the amide and nitrile. ontinue at top of next page. :\Documents and ettings\psbeauchamp.w\my Documents\classes\synthesis literature articles\rg Letts, 2008, 157-9, (dl)-goniomitine.doc
hem 316/422 Beauchamp 5 edrawn structure with twisted single bond to show more helpful conformation leading to next reaction. l Pl 2 1. Pl 3 / toluene ab 4 P l 2 5 1. ab 4, Et odium borohydride reduction of an aldehyde to a primary alcohol. Pl 3 (think "acid-l") reacts with the amide making an "imine-like" group that is attacked by the indole nitrogen atom in a carbonyl-like addition reaction. P 2 l 2 becomes a leaving group, leading to a bond. ab 4 reduces a group to an acetal-like group, having two nitrogen atoms. l catalyltic Ts- / 3 / Et 3 Epimerization of "nitrogen" acetal. Protonation of nitrogen, ring makes a good leaving group. That ring opens and nitrogen comes back on the other side of the ring. yrogen atom is epimerized (switched to opposite configuration). 4 1. DBA, 2 l 2 2 4 / 2 Diisobutylaluminum hydride reduces nitrile to aldehyde, after aqueous workup. f they used LiAl 4 here, a 1 o amine would have been the product. ontinue at top of next column. rg. Lett., vol. 10, pp 157-9, 2008.L. Morales & B.L. Pagenkopf :\Documents and ettings\psbeauchamp.w\my Documents\classes\synthesis literature articles\rg Letts, 2008, 157-9, (dl)-goniomitine.doc