Enantioefficient Synthesis of α-Ergocryptine:  First Direct Synthesis of (+)-Lysergic Acid

Abstract

The first direct synthesis of (+)-lysergic acid (2a) suitable for scale-up has been achieved by the following reaction sequence. Bromoketones 4d or 4g were allowed to react with amine 5 followed by deprotection, and the resulting diketone 6c was transformed into the unsaturated ketone (+/-)-7 by the LiBr/Et(3)N system. Resolution afforded (+)-7, which was further transformed by Schöllkopf's method into the mixture of esters 2e and 2f. Upon hydrolysis the latter mixture afforded (+)-2a. The peptide part of alpha-ergocryptine (1) was prepared according to the Sandoz method; the stereoefficiency, however, has been significantly improved by applying a new resolution method and recycling the undesired enantiomer. Coupling the peptide part with lysergic acid afforded 1. Having synthetic (+)-7 in hand, we can claim the total synthesis of all the alkaloids which were prepared earlier from (+)-7 that had been obtained through degradation of natural lysergic acid.

Model Construction for the A–B–C Ring System of Lysergic Acid via Vilsmeier–Haack‐Type Cyclization of 1H‐Indole‐4‐propanoic Acid Derivatives

“…-Lysergic acid (1), a tetracyclic indole derivative with two stereogenic centers, is the core unit of ergot alkaloids showing wide spectra of biological activities [1] such as prolactin inhibition, anti-Parkinsonian effect, and depression of hypertension. The total synthesis of racemic 1 has been reported by nine research groups [2], and two groups have successfully achieved the asymmetric synthesis [3].Recently, we have explored a novel aziridination from guanidinium ylides and aromatic (or unsaturated) aldehydes, applicable to asymmetric synthesis [4], and designed the atom-economical synthesis of bioactive N-containing compounds using the formed aziridine as a key synthetic intermediate. Our retro-synthetic strategy of lysergic acid (1) is shown in Scheme 1, in which all the C-and the N-units of the aziridine 2, derived from guanidinium ylide 3 and 1H-indole-4-carboxaldehyde 4, are incorporated in the lysergic acid structure during the synthesis.…”

“…Although no improvement was observed when CHCl 3 was used as solvent in place of THF (Entry 2), the use of MeCN resulted in the formation of 10 not only in higher yield but also with shorter reaction time (Entry 3). Some time ago, we have reported the efficiency of K 2 CO 3 as an additive in the intramolecular Friedel -Crafts reaction of 2,4-diarylbutanoic acids using POCl 3 to give 2-aryl-3,4-dihydronaphthalen-1(2H)-one derivatives [7]. In the Vilsmeier -Haack reaction with 9, addition of K 2 CO 3 is also effective (Entries 4 -6), and the best yield (74%) was achieved under the conditions shown in Entry 5.…”

“…NaHCO 3 soln. (5 ml) and brine (7 ml), dried, and evaporated, and the residue purified by CC (CHCl 3 / 3 (53 mg, 0.383 mmol), and POCl 3 (53 ml, 0.569 mmol) in dry MeCN (0.65 ml) was stirred at 658 for 1 h, and the reaction was quenched with H 2 O (3 ml). The aq.…”

Synthetic Route to Ergot Alkaloids

“…The third route [22] finally has brought the desired results. 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).…”

Cyclopropanation of Carbon-Carbon Double Bonds in Ring D of Ergot Alkaloids

“…[5][6][7] For such transformation various techniques (Simmons-Smith reaction 8,9 transformation with dimethyloxosulfonium methylide, 10 and reaction with diazomethane 11 ) has been reported in the literature and, also, an extensive review have also been reported recently. In the course of our earlier research 13,14 we described the synthesis of lysergic acid derivatives 3-5. These compounds containing the C-9 = C-10 double bond seemed to serve as proper starting materials for the synthesis of new cyclopropane-fused derivatives.…”