Use of chiral-pool approach into epi-thieno analogues of the scarce bioactive phenanthroquinolizidine alkaloids

Abstract

Diastereoselective reduction ThienoquinolizidinePhenanthroquinolizidine alkaloids a b s t r a c tThe stereoselective synthesis of epi-thieno analogues of the phenanthroquinolizidine bioactive alkaloids (À)-Cryptopleurine and (À)-(15R)-Hydroxycryptopleurine was achieved in five steps starting from easily available enantiopure (S)-2-aminoadipic acid used as chiral pool and nitrogen atom source. During these investigations, both p-cationic cyclization of chiral N-thienylmethyl-6-oxopipecolinic acids into pure (S)keto-lactams and theirs regioselective and diastereoselective reduction, considered as key steps of this sequence, were studied. Of particular interest, the FriedeleCrafts cyclization using (CF 3 CO) 2 O/BF 3 $Et 2 O show that near the expected keto-lactams, enamides and enamidones containing trifluoromethyl residue were isolated. A mechanism leading to the latter products with high synthetic potential was discussed.

The Reactivity of Enantiopure (S)‐6‐Oxopipecolic Acid and Corresponding Pyridoisoquinolines Under Acidic Conditions

“…The product 16 was formed by acylation of the enamide 15 with TFAA. Similarly, the course of this reaction was also observed with the N ‐thienylmethyl‐6‐oxopipecolic acid …”

“…On the other hand, the reaction of the nucleophilic enamide 15 with TFAA leads to the trifluoroacetyl ketone 16 (Method C ). Related reactions were already observed when chlorosulfonyl isocyanate was opposed to dihydropyridone 15 as a partner as well as in the N ‐thienyl‐methyl tetrahydropyridone series …”

“…We then turned our attention to intramolecular Friedel–Crafts acylation of the acid 8 . We have found that, contrary to the ( S )‐ N ‐thienylmethyl pipecolic acids, with ( S )‐ N ‐benzyl 6‐oxopipecolic acid ( 8 ), the best results were obtained with SOCl 2 and AlCl 3 (Method A ), giving the expected ketone 9 in good yield (71 %). Under these conditions, the AlCl 3 ‐catalyzed cyclization reaction of the non‐isolated acid chloride B needs only fifteen minutes of time.…”

“…Alternatively, when the starting compound was ketone 9 , we have obtained after heating with PPA lactam 11 as the sole reaction product in good yield (72 % after crystallization). Previously, we have found that in the case of N ‐thienylmethyl‐6‐oxopipecolic acids, the corresponding ketones are not susceptible for transformations to thieno analogues of dienone 11 , owing to their higher stability in acidic reaction conditions …”

“…We are strongly implicated in γ‐ and δ‐lactams reactivity and in that context, we have found that an important part of the chemistry of N ‐benzyl pyroglutamic acid (γ‐lactams), and corresponding ketone obtained after Friedel–Crafts cyclization, is governed by the formation of N ‐acyliminium salts followed by a hydride transfer during acid treatment. The chemistry of δ‐lactam containing acid has been, for its part, much less studied since only the results of the behavior of N ‐arylmethyl piperidone‐6‐carboxylic acid under acid conditions in benzene[6a], [6b], series and thiophene series were reported, however with different reactivity profile. Because the importance of the exposed scaffolds, γ‐lactams and δ‐lactams containing heterocycle for pharmaceutical and agrochemical industry, we describe herein our finding on the reactivity of enantiopure ( S )‐1‐benzyl‐6‐oxopipecolic acid ( 8 ) and corresponding tricyclic ketone 9 .…”