Strychnine Diels-Alder reaction

An elegant and efficient stereocontrolled total synthesis of strychnine has been achieved by applying intramolecular Diels Alder and Heck reations as key reactions [47]. An unusual exo-Diels-Alder reaction of 102 afforded 103, which was converted to the vinyl iodide 104. The Heck reaction of 104 using Pd(OAc)2 gave the hexacyclic strychnan system 105 smoothly in 74% yield. Hydrolysis of 105 afforded isostrychnine, which was isomerized to strychnine (106) under basic conditions. 

Fused carbazoles related to pyrido[4,3-6]carbazole alkaloids were prepared by a Diels-Alder route, and a 3-aza bioisostere of the antitumor alkaloid olivacine was synthesized <02CPB1479>. Indoloid [3.3]cyclophane 40a gave the pentacyclic indoloid 41a upon heating <02OL127>. This led to a concise formal total synthesis of ( )-strychnine in 12 facile steps from tryptamine when a similar transannular inverse-electron-demand Diels-Alder reaction of indoloid [3.3]cyclophane 40b gave 41b <02AG(E)3261>. 

In 2002, Bodwell and Li reported an elegant and efficient total synthesis of strychnine based on an intramolecular inverse-electron-demand Diels-Alder reaction that involves a pyridazine as diene. The required cyclophane 91 was built up via hydroboration of A-[2-(l-allyl-l/7-indol-3-yl)ethyl]-6-iodopyridazin-3-amine (90) followed by an intramolecular sp —sp coupling reaction [55]. 

Total syntheses of the complex molecule of strychnine have been carried out by several groups applying intramolecular HR as key reactions. The first elegant Pd-based total synthesis of stryclmine (237) has been achieved by Rawal. An intramolecular Diels-Alder reaction and HR were key reactions. The Pd-catalyzed cyclization of the pentacyclic lactam 238 under Jeffery s conditions gave isostrychnine 239 in 74% yield. Conversion of 239 to 237 is known [106]. 

In a concise formal total synthesis of strychnine, the cyclophane 108 was prepared in 65% yield by applying the hydroboration-intramolecular coupling method to 107 under high dilution conditions, and converted to the pentacycle 109 by transannular inverse-electron-demand Diels-Alder reaction [88]. 

Bodwell (2002) plan for strychnine tandem Diels-Alder—retro-Diels-Alder reaction in step 8. 

Owing to their structural complexity, Strychnos alkaloids, especially strychnine itself, are a benchmark in synthetic organic chemistry and have been prepared numerous times ]92]. Another alkaloid of the Strychnos family that enjoys increasing popularity nowadays is (+)-minfiensine. It was isolated from Strychnos minfimsis and features a l,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole motif, and hence is closely related to echitamine and vincorine [93]. A total synthesis of this beautiful structure was accomplished by MacMillan and coworkers [94]. Their key step was a highly efficient enantioselective domino Diels-Alder/isomerization/amine cycHzation reaction (Scheme 14.35). In this process, the chiral organocatalyst 226-TBA (TBA, tribromoacetic acid) was used, which reacted first with propargyl aldehyde 225 to form i minium ion 229 as intermediate, which underwent an endo-selective Diels-Alder reaction with 224... 

Very recently, Padwa reported a total synthesis of strychnine based on an intramolecular Diels-Alder reaction/rearrangement cascade, which was previously developed in his group to assemble the tetracyclic core ring system of indole alkaloids (Scheme 16) (174-178). Intramolecular cycloaddition reactions often benefit from higher reactivity and greater control of stereoselectivity relative to their intermolecular counterparts. Unlike Bodwell s lEDDA reaction (Scheme 13), the reaction of an electron-rich furan moiety with an N-acyl indole moiety required only a single tether. His synthesis also involved... 

An interesting transannular Diels-Alder/retro-Diels-Alder reaction cascade was employed in a formal total synthesis of ( )-strychnine by Bodwell and Li (Scheme 20.5). ° The reaction cascade involved a transannular inverse-electron-demand Diels-Alder (lEDDA) reaction of cyclophane 12 to form 13, which spontaneously expelled a molecule of nitrogen by the retro-Diels-Alder reaction to give 14 in quantitative yield. This led to a formal total synthesis of strychnine after 14 was converted into a common... 

SCHEME 20.5. The transannular Diels-Alder/retro-Diels-Alder reaction cascade in the synthesis of ( )-strychnine. 

In our efforts toward strychnine, we have integrated an intramolecular Diels-Alder approach to its tetracyclic core with an organometallic D-ring closure. Both of these key reactions were certainly inspired by the previous accomplishments of others as described above. 

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