Kuehne s synthesis

The preparation of 18-methyIenevincadifformine (384) by H jicek and Troj nek (255) is a straightforward application of Kuehne s synthesis, in which 2-allyl-5-chloropentanal (577) was reacted with the tetrahydro-j8-carboline ester 578, first in boiling toluene, and subsequently in the presence of base. 18-Methylenevincadifformine (384) was thus obtained in essentially a one-pot preparation. 

In Kuehne s total synthesis of vincadifformine (89), the pentacyclic natural product was obtained when tetracyclic phenylselenide 88 was treated with 2.5 equivalents of n-Bu SnH and the radical initiator AIBN in refluxing benzene [52]. The stereochemistry of the phenylselenyl substituent in the tetracyclic precursor had no impact on the product yield. After the tertiary radical intermediate 90 was generated (Scheme 17), the 5-exo-trig cyclization was prohibited... 

Kuehne s remarkable synthesis of the vincadifformine group of alkaloids has been extended,107 and an alternative mechanism for the crucial complex stage in the synthesis has been proposed. 

Kuehne s prodigious output on the synthesis of the anilinoacrylate alkaloids began with a sjmthesis of vincadifformine (76) and its 11-methoxy derivative, ervinceine (87) (328,329). The basic strategy involved the construction of a spirocyclic ammonium salt 552 from either the tetrahydro-iS-carboline derivative 553 (328) or the isomeric y-carboline derivative 554 (329), presumably via the common intermediates 555 and 556. When treated with base, ring C in the spirocyclic ammonium salt 552 was opened by... 

The next target for synthesis by Kuehne s group was tabersonine (78), and three syntheses were recorded (134,323,332-334). Following the synthesis of racemic tabersonine (332) from the indoloazepine ester 560 and the lactol chloride 563, the procedure was refined by use of the chiral epoxyaldehyde 564 (333,334), which eventually afforded enantioselective syntheses of both (-)-vincadifformine (76) and (-)-tabersonine (78). Subsequently (323),... 

The immediate biogenetic precursor of minovincine may well be the biological equivalent of 20,21-didehydro-19-oxosecodine (401). The synthesis of such a base is therefore of considerable interest, and Kuehne s second... 

Szdntay s later synthesis (343) of 3-oxovincadifformine consisted essentially of an independent synthesis (Scheme 75) of Kuehne s tetracyclic aminoester 562a, which on debenzylation cyclized to 3-oxovincadifformine (97). The double bond was then introduced at the 14,15-position via the thiolactam, in a procedure reminiscent of that adopted by Magnus in his synthesis of 3-oxotabersonine (107). Desulfurization of the intermediate unsaturated thiolactam 586 gave yet another synthesis of tabersonine, whereas oxidative removal of the si r atom gave 3-oxotabersonine (107). Alternatively, condensation of the starting tryptamine derivative 587 with... 

Kuehne s biomimetic approach has also been applied to syntheses in this group, and inevitably several variations on this theme have been published, which have allowed almost all the alkaloids of this group to be synthesized. The first synthesis 387) involved the condensation of the ubiquitous indo-loazepine ester (560) with S-bromo-4-ethylpentanal, which gave a mixture of the crystalline C-20 epimeric pseudovincadifformines 666 and 667, presumably via the intermediate secodine 688 (Scheme 98). 

Kuehne s second synthesis of ( )-pseudovincadifformine (666) (389) is distinctly longer than the first one and was achieved in the course of a... 

The most recent synthesis of pseudovincadifformlne consists of yet another distinguished contribution from Kuehne s laboratory (346) and offers... 

Condensation of the unstable, highly functionalised aldehydo-ester (162) with 2-hydroxytryptamine gave a mixture of three stereo-isomeric, tetracyclic oxindole esters (163). The major isomer, when heated with polyphosphoric acid, underwent cyclisation, hydrolysis, decarboxylation, and further cyclization, to give the hexacyclic ketone (164), reduction of which gave (+)-19-hydroxyaspidofractinine (Scheme 29), identical (except in optical rotation) with an authentic sample prepared from minovincine. Kuehne s versatile biomimetic synthesis has been further... 

Bandarage, U.K., Kuehne, M.E., GUck, S.D. (2001) Chemical Synthesis and Biological Evaluation of 18-Methoxycoronaridine (18-MC) as a Potential Anti-Addictive Agent. Current Medicinal Chemistry Central Nervous System Agents, 1, 113-123. 

For a closely related example of stereochemical scrambling reported in the synthesis of the Strychnos alkaloid mossambine, see Kuehne, M. E., Wang, T. S., Seraphin, D., J. Org. Chem. 1996,61,7873. 

---