Journal of Natural Products , 79 5 , Organic Letters , 18 8 , Chi P. Ting and Thomas J. Total Synthesis of Hyperforin. Journal of the American Chemical Society , 33 , Brian A. Sparling, James K. Tucker, David C. Moebius, and Matthew D. Organic Letters , 17 14 , Journal of Natural Products , 78 4 , Organic Letters , 17 5 , Organometallics , 34 4 , The Journal of Organic Chemistry , 80 3 , Organic Letters , 16 18 , Alexander J.
Grenning, Jonathan H. Boyce, and John A. Porco, Jr. Walker, and Gang Xu. Organic Letters , 16 9 , Henry P. Pepper, Stephen J. Tulip, Yuji Nakano, and Jonathan H. The Journal of Organic Chemistry , 79 6 , Journal of the American Chemical Society , 10 , Bopha Chrea, Juliette A. Journal of Chemical Education , 91 3 , The Journal of Organic Chemistry , 79 3 , Xiao-Bo Ding, Daniel P.
Furkert, Robert J. Capon, and Margaret A. Total Synthesis of Heronapyrrole C. Organic Letters , 16 2 , Veroniki P. Vidali, Kornilia P. Mitsopoulou, Marianna Dakanali, Konstantinos D. Demadis, Andreani D. Odysseos, Yiota A. Christou, and Elias A.
Organic Letters , 15 21 , Acetylation and esterfication diazomethane produced acetyl diester 14 which was then subjected to a Dieckman condensation with sodium methoxide in methanol to enol Ring VII synthesis[ edit ] In order to remove the C15 alcohol group, Enol 15 was converted to tosylate 16 TsCl , pyridine and then to mercaptoester 17 sodium benzylmercaptide which was then reduced to unsaturated ester 18 by Raney nickel and hydrogen.
Alkaline ester hydrolysis to carboxylic acid 20 was accompanied by epimerization at C This particular compound was already known from strychnine degradation studies. Until now all intermediates were racemic but chirality was introduced at this particular stage via chiral resolution using quinidine. The C20 carbon atom was then introduced by acetic anhydride to form enol acetate 21 and the free aminoketone 22 was obtained by hydrolysis with hydrochloric acid.
Ring VII in intermediate 23 was closed by selenium dioxide oxidation, a process accompanied by epimerization again at C The formation of 21 can be envisioned as a sequence of acylation, deprotonation, rearrangement with loss of carbon dioxide and again acylation: Ring VI synthesis[ edit ] To diketone 23 was added sodium acetylide bringing in carbon atoms 22 and 23 to give alkyne This compound was reduced to the allyl alcohol 25 using the Lindlar catalyst and lithium aluminium hydride removed the remaining ketone group in An allylic rearrangement to alcohol 27 isostrychnine was brought about by hydrogen bromide in acetic acid followed by hydrolysis with sulfuric acid.
Magnus synthesis[ edit ] In this effort one of strychnine's many degradation products was synthesised first the relay compound , a compound also available in several steps from another degradation product called the Wieland-Gumlich aldehyde. In the final leg strychnine itself was synthesised from the relay compound. Overman synthesis[ edit ] The Overman synthesis took a chiral cyclopentene compound as starting material obtained by enzymatic hydrolysis of cis-1,4-diacetoxycyclopentene.
This starting material was converted in several steps to trialkylstannane 2 which was then coupled with an aryl iodide 1 in a Stille reaction in presence of carbon monoxide tris dibenzylideneacetone dipalladium 0 , triphenylarsine. Cyclization NaH took place next, opening the epoxide ring and the trifluoroacetyl group was removed using KOH affording azabicyclooctane 5.
Epimerization at C13 with sodium methoxide in MeOH produced beta-ester 9 which was reduced with [[diisobutylaluminium hydride ]] to Wieland-Gumlich aldehyde Kuehne synthesis[ edit ] The Keuhne synthesis concerns racemic strychnine.
Hydrolysis with perchloric acid afforded aldehyde 4. Ring closure of ring III to 8 was then accomplished with an aldol reaction using lithium bis trimethylsilyl amide using only the epimer with correct configuration. Even more reduction sodium borohydride and acylation resulted in epimeric di-acetate 9. A DBU mediated elimination reaction formed olefinic alcohol 10 and subsequent Swern oxidation have an unstable amino ketone The three ester groups were hydrolyzed using iodotrimethylsilane forming pentacyclic lactam 5 after a methanol quench in a combination of 7 reaction steps one of them a Dieckmann condensation.
The C4 segment 6 was added in an amine alkylation and Heck reaction of 7 formed isostrychnine 8 after TBS deprotection. Subsequent reaction with iron nitrate brought about a [1,8]- conjugate addition to tetracycle 3, amine alkylation with Z bromo[ tert-butyldimethylsilyl oxy]iodobutene see Rawal synthesis and lithium carbonate , and isomerization of the diene system NaOiPr, iPrOH formed enone 4.
Mori synthesis[ edit ] The Mori synthesis - chiral, was the first one containing an asymmetric reaction step. It also features a large number of Pd catalyzed reactions.Journal of Natural Products , 80 5 , Acetylation and esterfication diazomethane produced acetyl diester 14 which was then subjected to a Dieckman condensation with sodium methoxide in methanol to enol This compound should form as a diastereomeric pair but only one compound was found although which one was not investigated. Pepper, Stephen J. Christou, and Elias A. This regular was reduced to the allyl alcohol 25 lingering the Lindlar catalyst and synthesis aluminium hydride turned the remaining ketone group in Life Antibiotics, Part IV. Hypermonins A and B, two 6-norpolyprenylated acylphloroglucinols strychnine pointed skeletons from Hypericum monogynum. Vowel Preparations and Procedures International50 1Demadis, Andreani D. Frangipani, Stephen J. Total Authorization of Hyperforin.
This is an example of bioinspired synthesis already proposed by Woodward in
Shibasaki synthesis[ edit ] The Shibasaki synthesis - chiral, was a second published method in strychnine total synthesis using an asymmetric reaction step. Chirality was at some point introduced into this starting material by enzymatic resolution of one of the precursors. In this method indole 1 was converted to tetracycle 2 together with by-product in a single cascade reaction using samarium diiodide and HMPA. The veratryl group not only blocks the 2-position for further electrophilic substitution but will also become part of the strychnine skeleton.
Woodward synthesis[ edit ] Ring II, V synthesis[ edit ] The synthesis of ring II was accomplished with a Fischer indole synthesis using phenylhydrazine 1 and acetophenone derivative acetoveratrone 2 catalyst polyphosphoric acid to give the 2-veratrylindole 3. The Journal of Organic Chemistry , 79 3 , Hydrolysis with perchloric acid afforded aldehyde 4.
Cyclization NaH took place next, opening the epoxide ring and the trifluoroacetyl group was removed using KOH affording azabicyclooctane 5. The C4 segment 6 was added in an amine alkylation and Heck reaction of 7 formed isostrychnine 8 after TBS deprotection. Grenning, Jonathan H.
Masha Elkin, Suzanne M. Science China Chemistry ,
Kuehne synthesis[ edit ] The Keuhne synthesis concerns racemic strychnine.
The Journal of Organic Chemistry , 79 6 , Magnus synthesis[ edit ] In this effort one of strychnine's many degradation products was synthesised first the relay compound , a compound also available in several steps from another degradation product called the Wieland-Gumlich aldehyde. Pepper, Stephen J. The method is disputed by Reissig see Reissig synthesis.
Enone 9 was then formed by Saegusa oxidation. The Journal of Organic Chemistry , 79 6 , Science China Chemistry ,