Ephedradine synthesis

A very impressive application of this chemistry is the total synthesis of (—)-ephedradine A 102.222 The key intermediate /rcarboxylic acid ester 101 was synthesized by intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh2(Y-DOSP)4, aryl diazo ester 100 possessing a chiral auxiliary underwent a C-H insertion reaction to give 101 in 63% yield and 86% de (Equation (83)). 

Synthesis of Heterocyclic Natural Products (-)-Ephedradine A, (-)-a-Tocopherol, (-)-Lepadin D, and (-)-Phenserine... 

In the first synthesis of the hypotensive alkaloid (-)-ephedradine A 3 (Tetrahedron 2004,60, 9615), Tohru Fukuyama of the University of Tokyo faced the challenging of constructing the central five-membered ring ether with control of relative and absolute configuration. While neither chiral Rh catalysts nor chiral auxiliaries alone gave satisfactory results, a combination of the two worked efficiently, yielding the two trans diastereomers of 2 in a 13 1 ratio. 

Intramolecular C-H insertions of aryldiazoacetates have been effectively achieved with high asymmetric induction by using either Rh2(S-DOSP)4[13] or Rh2(S-PTLL)4[14] as catalyst. An impressive recent example is a key step (18 to 19) in the synthesis of (-)-ephedradine A (20) (Scheme 8) [15]. In this particular case, a double stereodifferentiation with a chiral catalyst and auxiliary gave the best asymmetric induction. 

The fruit, leaves, and root bark of Lycium chinenese (Solanaceae) are used mainly as a tonic. The methanol extract of the root bark of L. chinense is used as an antipyretic and has shown remarkable hypotensive activity in animals. The active components were isolated and were determined to be alkaloids, named kukoamines A and B [5,6]. Kuko is the Japanese name for L. chinense. These alkaloids are composed of a spermine unit and two molecules of dihydrocaffeic acid, as in the case of the ephedradines described above. The total synthesis of kukoamine A was independently achieved by two groups [7,8]. 

Construction of the macrocycllc ring of ephedradIne-A was carried out under Mitsunobu conditions (eq 15). Upon treatment of 31 with DEAD and PPha In 0.05 M toluene solution at room temperature, the desired cycllzatlon proceeded smoothly to afford 32 in 77% yield. Since ephedradIne-A possessed the acid- and/or base-labile dihydrobenzofuran and 8-amlno ester moieties, the synthetic utility of the Ns strategy for secondary amines was also demonstrated by this total synthesis. 

Synthesis of (-)-Ephedradine A, (-)-Serotobe-nine, and (+)-LithospemUc Acid Fukuyama et al. developed a new approach based on the asymmetric C H functionalization reaction with rhodium carbenoid reagents to prepare optically active 2,3-dihydrobenzofuran, a common skeleton that is found in numerous natural and bioactive compounds.By combination of the chiral... 

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