Stereodivergent Total Syntheses of Precoccinelline, Hippodamine, Coccinelline, and Convergine

Abstract

[structure: see text] A stereodivergent approach toward total syntheses of Coccinellidae defensive alkaloids is described. These syntheses feature a highly diastereoselective intramolecular aza-[3 + 3] annulation strategy, which represents a de novo approach to this family of natural products.

Asymmetric Construction of Alkaloids by Employing a Key ω‐Transaminase Cascade

“…β‐Enaminones are vinylogous amides with unique reactivity and represent important intermediates in the synthesis of a variety of N ‐heterocyclic compounds . Specifically, six‐membered cyclic variants have been exploited for the preparation of a diverse array of bioactive piperidine alkaloids (Figure ), including pinidinone and related 2,6‐piperidine derivatives, apomitomycin, mesembrenone, desoxoprosophylline, cassine, deoxyfebrifugine, sedacryptine, selenopsine and the Coccinellidae defensive alkaloids, including hippodamine . However, despite their importance, there have been limited strategies reported for the enantioselective construction of chiral β‐enaminones.…”

“…[1] Specifically,s ix-membered cyclic variants have been exploited for the preparation of ad iverse array of bioactive piperidine alkaloids (Figure 1), including pinidinone and related 2,6-piperidine derivatives, [2] apomitomycin, [3] mesembrenone, [4] desoxoprosophylline, [5] cassine, [6] deoxyfebrifugine, [7] sedacryptine, [8] selenopsine [9] and the Coccinellidae defensive alkaloids, including hippodamine. [10] However,d espitet heir importance,t here have been limited strategies reported for the enantioselectivec onstruction of chiral b-enaminones. Traditional approaches for their synthesis rely on the sulfidec ontraction methodology originally reported by Eschenmoser, [11] modified Knoevenagel-type reactions on (alkylth-io)alkylideniminiums alts, [12] lactam-derived iminium chlorides [13] or relatedc ompounds.…”

Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

“…In the forward direction to synthesize 17 , we used the approach developed in our model study for the synthesis of precoccinelline, hippodamine and myrrhine alkaloids [30–31]. Specifically, TBDPS-protected 3-butyne-2-ol 18 was converted to bromoalkene 19 in two steps involving alkylation with an excess of dibromopropane and subsequent Lindlar’s hydrogenation (Scheme 5).…”

“…Based on our previous experience with precarious annulation products, in situ hydrogenation was then carried out, and we managed to track down ~30% of the desired reduced aza - annulation product 26 , although stereoselectivity for the reduction was modest. We ultimately elected not to force our way toward propyleine using the enone aza-[3 + 3] annulation, as we succeeded in total syntheses of other members of the azaphenalene alkaloid family through annulations with enals [30–31]. While it is disappointing that this particular system may have lacked sufficient stability for this to be a suitable synthetic approach, success in an enone version of intramolecular aza-[3 + 3] annulation will allow us to find future applications.…”

“…While seemingly an insignificant perturbation, the ability to employ enones in aza-[3 + 3] annulations can generate a vast array of opportunities, including the case where R is as small and simple as a Me group, which would already represent a facile entry to aza-phenylene alkaloids [30–31 38–45], such as propyleine [46–48], as well as lycopodium alkaloids that are rich in bioactivities [49–51] (Fig. 2).…”