Total Synthesis of Stenine

Abstracted with permission from Tetrahedron, 1994, SO, 10083 1994 Elsevier Science Ltd 

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The first total synthesis of (+)-stenine has been accomplished in the laboratory of D.J. Hart/ The key steps were an intramolecular DIels-Alder reaction, an amidine variant of the Curtius rearrangement, an Eschenmoser-Clalsen rearrangement, a halolactonization, and a Keck allylation. The allylic alcohol precursor and A/,A/-dimethylacetamide dimethyl acetal was heated to reflux in xylenes for 4h to afford the desired amide in 93% isolated yield. The transition state most likely adopted a boatlike conformation. 

Scheme 4.R Total synthesis of (+)-stenine via an intermolecular Diels-AIder/Schmidt sequence.

Aube and collaborators reported an expeditious total synthesis of ( )-stenine in only nine steps and 14% overall yield through a cascade intermolecular Diels-Alder reaction/intramolecular Schmidt reaction sequence (Scheme 13.17) [20]. The cascade sequence allowed the construction of the BCD ring system of the natural product in one step, and the routine was also the shortest one among all the completed synthetic strategies so far. 

Scheme 13.17 Total synthesis of ( )-stenine (117) by using cascade intermolecular Diels-Alder reaction/intramolecular Schmidt reaction sequence.

In another example, the asymmetric total synthesis of (—)-stenine relied on both a regio- and stereoselective reduction of the more hindered tertiary bridgehead carbon in 44, and although considerable optimization was required to minimize the formation of 46 and 47, conditions were identified facilitating a high yielding synthesis of the key frans-hexahydroindole intermediate 45 strictly anaerobic conditions were required. Hydride transfer occurs stereoselectively as a result of direct intramolecular addition in Pd(II) intermediate 48 overall inversion occurs (eq 26). 

Chen C, Hart DJ. A Diels-Alder approach to Stemona alkaloids total synthesis of stenine. J. Org. Chem. 1993 58 (15) 3840-3849. 

Quite recently, a domino Diels-Alder/Prins/pinacol reaction was reported by Barriaulfs group [38]. This novel method is very reliable and efficient for the synthesis of highly functionalized bicyclo[m.n.l]alkanones. In addition, Aube and coworker [39] used a combination of a Diels-Alder and a Schmidt reaction within the total synthesis of the Stemona alkaloid stenine [40]. 

An interesting approach toward the total synthesis of the Stemona alkaloid, (-)-stenine (25), which have been used in Chinese and Japanese folk medicine as insecticides, as drugs for the treatment of respiratory diseases, via spirolactone... 

During the endgame of the total synthesis of the stemona alkaloid (-)-stenine, Y. Morimoto and co-workers utilized the Finkelstein reaction to prepare a primary alkyl iodide from a primary alkyl mesylate. The mesylate was prepared from the corresponding primary alcohol with MsCI/EtsN. The resulting primary alkyl iodide was used in the subsequent intramolecular N-alkylation to construct the final perhydroazepine C-ring of the natural product. 

Further manipulation of 239 led to stenine (240), whereas 235 was converted to neostenine (236) and the synthetic analog 13-epi-neostenine (237). During the last 20 years, several syntheses of stenine have been reported, but this is the first total synthesis of neostenine. 

The first total synthesis of (—)-tuberostemonine (4) was described by Wipf and coworkers 66). The oxidation of IV-carbobenzyloxy tyrosine with hypervalent iodine afforded, after benzoylation of the tertiary hydroxyl group, bicyclic 113 which was employed by Wipf and coworkers in their synthesis of (—)-stenine (Scheme 2) and served here as the scaffold for the installation of the stereogenic centers of (—)-tuberostemonine (4) (Scheme 6). Substitution of PBnj for the previously used PBuj allowed them to... 

The power of the intramolecular Schmidt reaction is demonstrated in the concise synthesis of the Stemona alkaloid stenine. Reaction of trimethylsilyloxy diene 79 with cyclohexenone 80 and tin(IV) tetrachloride brings about a tandem Diels-Alder/Schmidt reaction to give adducts 82 and 83 in 52% and 17% yields, respectively, with the exo addition product 83 predominating. Adduct 83 contains three rings and four stereocenters present in stenine. The intramolecular Schmidt reaction is also employed as a key step in the total syntheses of 251 F (84 to 85) and (+)-aspidospermidine (87 to 88). ... 

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