Aza‐Piancatelli Cyclization as a Platform for the Preparation of Scaffolds of Natural Compounds: Application to the Total Synthesis of Bruceolline D

Abstract

The aza‐Piancatelli cyclization provides an expedient synthesis of 4‐aminocyclopentenone building blocks that may be converted into aminocyclopentitols, which are heavily represented motifs among natural products. However, its use as a key step in total synthesis was still unprecedented. Here, we disclose our in‐depth investigations regarding this reaction in order to access highly complex structures representing the core of some natural molecules. The applicability of the cyclization was highlighted by the 3‐step total synthesis of bruceolline D. Thus, we anticipate that this work will lay the ground for further applications in total synthesis.

Recent Advances on Piancatelli Reactions and Related Cascade Processes

“…43 Under the catalysis of Yb(OTf) 3 , this transformation allows for the efficient construction of hexahydro-2a,5-epoxycyclopenta[cd]isoindoles bearing six contiguous stereogenic centers in a highly stereoselective manner (Scheme 16). An alternative Ca(II)/HFIP-based catalyst system developed by Leboeuf (2020) enabled the resulting products to undergo further fragmentation reaction to form tetrahydro-1H-indenes. The reactivity can be further extended to the 1,3-diene to furnish the corresponding bicyclic compound (Scheme 17).…”

“…The reactivity can be further extended to the 1,3-diene to furnish the corresponding bicyclic compound (Scheme 17). 44…”

“…Utilizing 2-aminophenylboronic acid pinacol ester and 2-(4-bromofuran-2-yl)propan-2-ol as starting materials, Leboeuf (2020) 44 described the Ca(II) and Pd(II)-catalyzed sequential aza-Piancatelli rearrangement/Suzuki-Miyaura cross-coupling reaction to construct Bruceolline D, 45 a natural product with potential medicinal utility for the treatment of malaria (Scheme 18).…”

Efficient Piancatelli rearrangement on a large scale using the Zippertex technology under subcritical water conditions

“…A large number of chemical reactions have been based on this transformation over this decade, including oxa-, aza-, and carba-Piancatelli rearrangement, intramolecular reactions, asymmetric versions, and mechanistic studies. [18][19][20][21][22][23] Nevertheless, the development of this transformation still faces numerous difficulties, such as (i) harsh experimental conditions, (ii) high dilution reaction conditions (<0.005 M), (iii) long reaction periods, and (iv) formation of cyclopentenones in moderate yields due to multiple sidereactions. In fact, besides the Piancatelli rearrangement process, the furanic starting material might be involved in other reaction processes such as hydrolysis into levulinic acid, 24,25 formation of dimeric compounds, [26][27][28][29] formation of brown-black soluble oligomers, 30,31 and production of solid black humin matter as insoluble tarry carbonaceous materials, which were difficult to remove from the desired HCP (Scheme 2).…”

(1R,4S,5S)-5-((3-Hydroxypropyl)amino)-4-((1-methyl-1H-tetrazol-5-yl)thio)cyclopent-2-en-1-ol

“…Aziridines are recurrent motifs in anticancer compounds (Figure 1A) and are useful building blocks in organic synthesis, largely due to their ring strain [1]. [2][3][4].…”