Enantiodivergent Approach to the Synthesis of Cis-2,6-Disubstituted Piperidin-4-ones

Abstract

Enantiopure β-amino ketone derivatives were synthesized by decarboxylative Mannich reaction of chiral N-tert-butanesulfinyl imines with β-keto acids, and were subsequently transformed into cis-2,6-disubstituted piperidin-4-ones through an organocatalyzed condensation with aldehydes. Both enantiomers were accessible from the same precursors by inverting the order in the reaction sequence of the aldehydes involved in the imine formation and the intramolecular Mannich condensation. The synthesis of the piperidine alkaloids (+)-241D, (−)-epimyrtine and (−)lasubine II demonstrated the utility of this methodology.

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

“…On the other hand, aliphatic aldehydes gave in general excellent enantiomeric ratios (>90:10). It is important to note that the order of reaction of carbonyl compounds R 1 CHO and R 2 CHO with tert-butanesulfinamide to form chiral imine 14, or in the intramolecular organocatalyzed condensation, determined the absolute configuration of compounds 201 [141]. The usefulness of this methodology was demonstrated in the synthesis of the alkaloid (+)-241D (202), isolated from the skin of the Panamanian poison frog Dendrobates speciosus, through the reduction of piperidin-4-one 201 (R 1 = Me, R 2 = n-C 9 H 19 ) with lithium borohydride (Scheme 49).…”

“…A straightforward synthesis of the alkaloids (−)-epimyrtine (300a) and (−)-lasubine II (ent-302) from β-amino ketone derivatives 204 was reported by Lahosa et al These compounds participate in a ʟ-proline organocatalyzed intramolecular Mannich reaction with a second aldehyde (R 2 CHO) to give cis-2,6-disubstituted piperidin-4-ones 205 (see above Scheme 49 [141]). However, when one of the aldehydes involved in the formation of β-amino ketone 204 (R 1 CHO) or in the intramolecular Mannich reaction (R 2 CHO) which is 5-chloro-or 5-bromopentanal, quinolizidinone derivatives 299 or 300 are formed.…”

“…In both cases, after formation of the piperidine ring through the expected Mannich condensation, a subsequent intramolecular N-alkylation involving the carbon-halogen bond occurred to produce the quinolizidinic systems. The natural alkaloid (−)-epimyrtine (300a), isolated from bilberry (Vaccinium myrtillus) was prepared following this methodology, along with ent-299b, which was transformed in a single step into (−)-lasubine II (ent-302), by diastereoselective reduction with ʟ-selectride (Scheme 66) [141].…”

Pyrrolidine and Indolizidine Alkaloids from Chiral N-tert-Butanesulfinyl Imines Derived from 4-Halobutanal

“…The base-promoted decarboxylative-Mannich coupling of 3-oxobutanoic acid (13a) and N-tert-butanesulfinyl imine 1b, derived from 4chlorobutanal, gave -amino ketone derivative 18 in 81% yield. This compound participated in an L-proline organocatalyzed intramolecular Mannich reaction with an aldehyde (R 2 CHO: n-butanal and n-heptanal) to give cis-2,6disubstituted piperidin-4-ones, 20 first, followed by a subsequent intramolecular N-alkylation involving the carbonchlorine bond, leading finally to the corresponding indolizidine 19, in moderate yields (Scheme 5). Importantly, when the reaction was performed with bromine derivative 14a, the expected indolizidines 19 were obtained in less than 10% yield, and a significant amount of (-)-norhygrine (15) was also formed.…”

Stereoselective Synthesis of δ- and ε-Amino Ketone Derivatives from N-tert-Butanesulfinyl Aldimines and Functionalized Organolithium Compounds

“…For instance, our research group have also accomplished the stereoselective synthesis of α-amino ketone derivatives in moderate yields from β-nitro amine derivatives that were obtained by a coupling reaction of N-tertbutanesulfinyl imines and nitroethane under basic conditions [17] (Scheme 1). On the other hand, we reported the synthesis of β-amino ketones through the nucleophilic addition to these chiral imines of enolates obtained by a copper-catalyzed addition of dialkylzinc reagents to α,β-unsaturated cyclic enones [18][19][20], and more recently by a decarboxylative Mannich coupling with β-keto acids under mild basic conditions [21,22], proceeding these reactions in excellent yields and diastereoselectivities (Scheme 1). Continuing our interest in the stereoselective synthesis of amino ketone derivatives from chiral N-tert-butanesulfinyl imines, and being aware of the potential interest as synthetic intermediates of these compounds, we decide to explore a new synthetic pathway to access to γ-, δ-and ε-amino ketone derivatives in an enantioenriched form, by performing a diastereoselective addition of a functionalized organolithium compound to these imines.…”