1,3,4,5-Tetrahydrobenz[c,d]indoles and related compounds. Part IV. Attempted syntheses of lysergic acid

Abstract

Road, Pontypool, Monmouthshire N P4 8YH Attempts to devise a synthesis of lysergic acid from 3,4-dihydrobenz[c,d]indol-5(1H)-one (I) via methy\ Nacetonyl-N-(I ,3,4,5-tetrahydro-5-oxo-l -(p-tolylsulphonyl)benz[c,d]indol-4-yl)carbamate (23) failed owing to difficulties in cyclising the latter to the tetracyclic ketone (4).Several alternative routes were examined and, inter alia, 4,8,9,1 Oa-tetrahydro-9-(hydroxymethyl) -9-methyl-6Hindolo [3,4-gh] [I ,4] benzoxazinium chloride (30) and 4-acetyl-6.6a.7.8-tetrahydro-8-imino-4H-indolo [6,5,4-cd] indolium acetate (40) have been prepared.

Experiments Towards the Synthesis of the Ergot Alkaloids and Related Structures. Part 8.17 The Total Synthesis of 4-Methyl-2,3,4,4a,5,6-hexahydro-benzo[f]quinoline-2-carbonitrile Hydrochloride Hemihydrate, an Immediate Precursor of the Despyrrole Analogues of Lysergic Acid and Its Amides

“…Progress 15 towards a novel general synthesis of lysergic acids capable of scale-up came to an abrupt halt when cyclisation of the des-pyrrole analogue N-methoxycarbonyl-tricyclic-diketone 1a to the crucial tetracyclic monoketone 2a under basic conditions failed despite the successful cyclisation of the related N-methylindoline-diketone 1b to the corresponding tetracyclic ketone 2b under the same conditions. 16 More recently, the cyclisation problem was solved in the model 1-tetralone series starting from the N-acyl-keto-acids 3, 4 and 5 followed by cyclisation via the bis-sodium salts of the corresponding diketo-acids 6 to give the tricyclicketones 7, 8 and 9 in 31-36% yield 17 (Scheme 1).…”

Synthetic Route to Ergot Alkaloids

“…To our pleasant surprise, we found that, contrary to [9], bromo ketone 4d [19] can be subjected to a substitution reaction with amine 26 providing us with the so far unknown but much sought-after, even mistakenly claimed [8], product 27a (yield 35%) if one has the patience to allow the reaction to proceed at room temperature in toluene (Scheme 5). The amine component 26 was already known and could easily be prepared [3].…”

“…Uhle started his synthesis of the ergoline skeleton with acetylation and subsequent bromination, and he claimed that the first obtained bromo derivative 4b could be subjected successfully to a substitution reaction with various amines [8]. Early in the seventies, Bowman and co-workers reinvestigated a few results of Uhles synthesis and established that one of the key steps, alkylation of several types of amines with 4b, always failed [9]. The approach starting from 4a by Stoll and co-workers used the Stobbe condensation as a key step, but the reaction sequence could not be carried out [10], thus the synthesis of lysergic acid starting from Uhles ketone 4a remained a challenge.…”

“…Though Wittig ± Horner reaction of the unsubstituted Uhle ketone with ethyl (diethylphosphinyl)acetate [20] or Knoevenagel ± Doebner-type condensation of Uhles ketone [20] or 4-acetamido-Uhles ketone [9] with malononitrile or ethyl cyanoacetate could be performed in reasonably good yield, similar processes with our N-acylated, N'-alkylated intermediate 20 failed. However, using methyl or ethyl acetate lithiated with (Me 3 Si) 2 NLi at À 788 [21], we were at last successful in achieving our goal and preparing hydroxy diester 21 from the freshly prepared base of HCl salt 20 (Scheme 4).…”

“…In connection with the intramolecular aldol cyclization step of the synthesis, it is worth mentioning and emphasizing the difficulties encountered by both the Bowman group [9] and ourselves. The former succeeded in preparing the doubly protected diketone intermediate 33 which seemed to be suitable for the above cyclization process as well.…”