Chem 316/422 Beauchamp 1 Match the step number in the synthesis with the letter of the reagents listed just below. O O O O H step 1 step 2 N N Ph step 3 N N Ph THPO HO step 4 O O Ph O O O step 6 N step 5 N Ph C Cl N N N Ph H step 7 O N OEt step 8 O step 9 O O N N Ph N N Ph N N Ph H H H step 10 N C I N C N step 11 step 12 O N O H O N N Ph N N Ph * H H N H step 13 N C H OH OH C O step 16 step 14 step 15 N N N H H N H H HN HN HN HN Reagents used in synthesis A B C D O E F NaCN 1. (i-Pr)2NLi (LDA)/THF O CH3 1. NaBH4, EtOH DMF (solvent) CH2 O 2. O O = THP 2. workup H C N Br Cl S CH3 2 H CH3 -78oC OoC H-Cl N CH3 O Cl O CH3 O CH3 Et3N / CH2Cl2 CH3 O (±)-goniomitine H3C S O S CF3 = (CH3)3Si-OTf Org. Lett., vol. 10, pp 157-9, 2008 C.L. Morales & B.L. Pagenkopf CH3 O K L M P G H I J N O Pd / C catalyltic TsO-H NaCN / CH CN 1. DIBAH, CH2Cl2 Na / NH / THF 1. 2 eqs. n-BuLi/THF catalytic TsO-H 1. POCl3 / toluene NaOH / H O / 3 3 CH3I / CH3OH 2 microwave 2. H2SO4 / H2O 2. CH3CH2-Br CH3OH 2. NaBH4 CH3OH / Et3N 3. C6H5CH2Br OH C:\Documents and Settings\psbeauchamp.WIN\My Documents\classes\synthesis literature articles\Org Letts, 2008, 157-9, (dl)-goniomitine.doc Chem 316/422 Beauchamp 2 Key – The reagents for each step are listed below. O O O O H step 1 step 2 N N Ph step 3 N N Ph THPO HO step 4 O O Ph O O O step 6 N step 5 N Ph C Cl N N N Ph H step 7 O N OEt step 8 O step 9 O O N N Ph N N Ph N N Ph H H H step 10 N C I N C N step 11 step 12 O N O H O N N Ph N N Ph * H H N H step 13 N C H OH OH C O step 16 step 14 step 15 N N N H H N H H HN HN HN HN step 1 step 2 step 3 step 4 step 5 step 6 step 7 step 8 1. 2 eqs. n-BuLi/THF 1. (i-Pr) NLi (LDA)/THF catalytic TsO-H O O 2 NaCN / CH3CN Pd / C 2. CH3CH2-Br NaOH / H2O / 2. O O = THP CH3OH microwave 3. C6H5CH2Br Cl S CH Br 3 OH o o -78 C O C O O O CH3 CH3 O Et3N / CH2Cl2 (±)-goniomitine H C S O S CF 3 3 = (CH3)3Si-OTf step 9 O Org. Lett., vol. 10, pp 157-9, 2008 CH O C.L. Morales & B.L. Pagenkopf 3 CH3 CH2 H2C N H CH3 H-Cl N step 10 step 11 step 12 step 13 step 14 step 15 step 16 Cl CH3 NaCN 1. NaBH4, EtOH catalyltic TsO-H CH3 CH3I / CH3OH Na / NH3 / THF 1. POCl3 / toluene 1. DIBAH, CH2Cl2 DMF (solvent) 2. NaBH 2. workup CH3OH / Et3N 4 2. H2SO4 / H2O C:\Documents and Settings\psbeauchamp.WIN\My Documents\classes\synthesis literature articles\Org Letts, 2008, 157-9, (dl)-goniomitine.doc Chem 316/422 Beauchamp 3 Synthesis of (±)-goniomitine (with comments) O O H N N Ph * Cl 1. 2 eqs. n-BuLi/THF step 1 2. CH3CH2-Br 3. C6H5CH2Br step 5 NaCN / CH3CN / microwave A dianion alkylates at the more reactive site, followed by alkylation at the less reactive site. O Cyanide is a good nucleophile and acetonitrile is a good SN2 * = chiral center solvent (polar, aprotic). SN2 reaction displaces the good chloride leaving group. The microwaves make the reaction work more efficiently by providing localized heating. N * CH3 O = (CH3)3Si-OTf H3C S O S CF3 1. (i-Pr)2NLi (LDA)/THF step 2 2. O O = THP CH3 O O Br -78oC OoC step 6 O O CH LDA removes an H to make an enolate, which is alkylated 3 (the 3rd time in a row). THP is tetrahydropyran, an alcohol (H3C)3SiO O protecting group. O O Ph N Ph * THPO Ph = phenyl N * O C N catalytic TsO-H / CH3OH step 3 Deprotection of THP group using catalytic toluenesulfonic acid. (H3C)3SiO O O O Ph N Ph N * * HO C N O O The trimethylsilyltriflate reacts with the C=O group lone pair Cl S CH (like a proton). Electron donation from the methoxy oxygen, step 4 3 breaks the cyclopropane ring and makes a silyl enol ether. Et3N / CH2Cl2 The positive charge that forms by the methoxy group is attacked O by the nitrile in a "Ritter" reaction. The new positive carbon Mesylate (like tosylate) makes OH into a good leaving group, (of the nitrile) is attacked by the enol ether, making a 5 atom and chloride leaving group turns into a nucleophile that ring. A tautomeric proton shift makes the new 5 atom heterocyclo ring. displaces the mesylate in an SN2 reaction. Continue at top of next column. Continue at top of next page. C:\Documents and Settings\psbeauchamp.WIN\My Documents\classes\synthesis literature articles\Org Letts, 2008, 157-9, (dl)-goniomitine.doc Chem 316/422 Beauchamp 4 O O N O O N N Ph * N N Ph * H H Reverse of hydrogenation (there's step 7 Pd / C no H2(g)). Pd is oxidizing instead of reducing. The driving force is step 10 CH3I / CH3OH aromatization. o SN2 methylation reaction by 3 amine on O iodomethane, makes ammonium ion OEt which becomes a good leaving group. O I N N N Ph * O H N N Ph * step 8 NaOH / H O / H 2 OH Hydrolysis of ester to carboxylate, followed by decarboxylation 2 (-CO2). The leaving group is the sp carbon of the indole ring, step 11 NaCN / DMF (solvent) which immediately protonates. O Cyanide does an SN2 reaction with trimethylamine leaving group. DMF (dimethylformamide) is a good SN2 solvent (polar, aprotic). N N Ph * N C H O O CH3 CH N N Ph 2 * step 9 H2C N H CH 3 H H-Cl N Cl CH3 step 12 Na / NH3 / THF CH3 o Enamine-like reaction with carbonyl-like protonated iminium Radical anion forms in phenyl part of benzyl 3 amide protecting o made from an aldehyde, secondary amine and some HCl. The group is reduced to the 2 amide group. Think "LAH-like SN2 reaction makes a 3o amine (called the "Mannich" reaction). reaction" at benzyl carbon, except LAH would react with the amide and nitrile. Continue at top of next column. Continue at top of next page. C:\Documents and Settings\psbeauchamp.WIN\My Documents\classes\synthesis literature articles\Org Letts, 2008, 157-9, (dl)-goniomitine.doc Chem 316/422 Beauchamp 5 N H C Redrawn structure with twisted single C bond to show more helpful O conformation leading to next reaction. N H O N O * H * * PCl2 Cl HN N H R 1. POCl / toluene step 13 3 2. NaBH 4 step 15 1. NaBH4, EtOH 2. workup R Sodium borohydride reduction of an aldehyde to a primary alcohol. NH R OH O O P * Cl2 N Cl H N POCl (think "acid-Cl") reacts with the amide C=O making an 3 H "imine-like" group that is attacked by the indole nitrogen atom in * * a carbonyl-like addition reaction. PO2Cl2 becomes a leaving HN group, leading to a C=N bond. NaBH4 reduces a C=N group to an acetal-like group, having two nitrogen atoms. N C catalyltic TsO-H / CH OH / Et N step 16 3 3 Epimerization of "nitrogen" acetal. Protonation of nitrogen, N ring makes a good leaving group. That ring opens and nitrogen comes back on the other side of the ring. Hyrogen atom is H * * epimerized (switched to opposite configuration). HN OH step 14 1. DIBAH, CH2Cl2 2. H2SO4 / H2O N Diisobutylaluminum hydride reduces nitrile to aldehyde, o H after aqueous workup. If they used LiAlH4 here, a 1 amine * * would have been the product. HN (±)-goniomitine Org. Lett., vol. 10, pp 157-9, 2008 Continue at top of next column. C.L. Morales & B.L. Pagenkopf C:\Documents and Settings\psbeauchamp.WIN\My Documents\classes\synthesis literature articles\Org Letts, 2008, 157-9, (dl)-goniomitine.doc .