Hirsutine Tietze

The alkaloids hirsutine (1) and its 3or-epimer dihydrocorynantheine (2a) belong to the corynanthe group of indole alkaloids. They have been isolated from the plant Uncaria rhynchophylla MIQ, which was used for the preparation of the old Chinese folk medicine kampo . Nowadays, 1 and related compounds attract great attention in medicine because of their growth inhibition of the influenza A subtype H3N2 virus. With an EC50 value of 0.40-0.57 ig/mL 1 has shown itself to be 10-20 times more active than the clinically used drug ribavirine (3).1,2 Furthermore, 1 is known for its antihypertensive and antiarrhythmic activity.3 

The absolute configuration of 1 was established in 1967.4 Since then, l5 and 2a6 have been the subject of several syntheses. A challenge in both cases was the stereochemistry at the three stereogenic centers of the quinolizidine subunit. Tietze and co-workers have previously synthesized indole alkaloids of the corynanthe group,7 this problem is based on the recent enantioselective total synthesis of 1.2,8,12 

Hints The basic conditions are used for the cleavage of esters. Selectively, only one ester group is removed. 

Discussion Starting from the commercially available sodium salt of diethyl 

Problem 1- HCI °YC°2H H 6 X02Et EtOH, reflux, 48 h 60 % (over two steps) 5 

Starting from the commercially available sodium salt of diethyl oxalacetatc (4) partial alkaline saponilieation results in carbethoxypyruvic acid (5). Because of the activation by tile cr-substituent one ester group is more reactive than the other thus cleavage of only one ester group is achieved selectively. After acidic work-up an equilibrium mixture of the solid enolic form 17 (ca. 10 %) and the liquid ketonic form 5 is gained. 

Like /f-keto carboxylic acids 5 undergoes decarboxylation at high temperatures. As a result 5 is transformed into 18 by setting free CO. Aldehyde 18 reacts with the hydrochloride salt 6 to iminium ion 19. The. subsequent Pictet-Spengler reaction provides tetrahydro-/ -carboline 7.  

The mechanism of this reaction is still not dear. It has always been thought that the Pictet-Spengler reaction proceeds via a spiroindolenine intermediate 20 followed by a Wagner-Meemein rearrangement to 21 (way A). On the other hand in the case of very reactive eleetrophile.s it was shown that the cyclization can occur by direct attack at the C-2 po.sition of the indole (way B). However, after deprotonation of 21 compound 7 i.s I ormed.  

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Scheme 12.25. Syntheses of hirsutine and dihydrocorynantheine using a three-component Knoevenagel/hetero[4+2] cycloaddition/ retro[4+2] fragmentation, by Tietze and Zhou...

The domino Knoevenagel condensation hetero-Diels-Alder reaction was used for the enantioselective total synthesis of the active anti-influenza A virus indole alkaloid hirsutine and related compounds by L.F. Tietze and co-workers. The Knoevenagel condensation was carried out between an enantiopure aldehyde and Meldrum s acid in the presence of ethyienediamine diacetate. The resulting highly reactive 1-oxa-1,3-butadiene underwent a hetero-Diels-Alder reaction with 4-methoxybenzyi butenyl ether ElZ = 1 1) in situ. The product exhibited a 1,3-asymmetric induction greater than 20 1. 

Scheme 3. Tietze s biomimetic synthesis of the alkaloid hirsutine (20) through a domino Knoevenagel/ hetero-Diels-Alder sequence.

The tandem Knoevenagel-Diels-Alder sequence is well known, and has been extensively studied by Tietze and others. The Knoevenagel products have been shown to be active as dienophiles in normal-electron-demand Diels-Alder reactions, as well as heterodienes in inverse-electron-demand hetero-Diels-Alder reactions. One of the most elegant examples of a tandem Knoevenagel-hetero-Diels—Alder sequence is Tietze s synthesis of hirsutine 76. In this sequence, a mixture of aldehyde 70, Meldrum s acid 71, enol ether 73 (a mixture of isomers) and a catalytic amount of ethylenediamine diacetate were sonicated in Benzene for 12 h at 60 °C. This effected a cascade sequence that began with Knoevenagel condensation to form the heterodiene 72, followed by intermolecular hetero-Diels-Alder reaction with enol ether 73 to lead to 74, which underwent in situ hydrolysis and decarboxylation to yield intermediate 75 in 84% yield. 

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