Synthesis of Highly Functionalized Hydrindanes via Sequential Organocatalytic Michael/Mukaiyama Aldol Addition and Telescoped Hydrozirconation/Cross-Coupling as Key Steps: En Route to the AB System of Clifednamides

Abstract

The AB ring systems of the clifednamide family, polycyclic tetramate macrolactames (PoTeMs), were prepared by a new, convergent approach employing an intramolecular Diels−Alder (IMDA) reaction. Key steps comprise an organocatalytic Michael addition (>90% enantiomeric excess (ee)), a Mukaiyama aldol reaction for the convergent installation of a diene moiety, and a telescoped hydrozirconation/cross-coupling grafting an enone. The following IMDA furnished a highly functionalized hydrindane (diastereomeric ratio (dr) = 91:1) with the same configuration as the clifednamide scaffold. Advantages of this route are only one required protecting group, 13% overall yield over 9 steps (reduced from previously 17 steps/1.3% overall), and the potential access to the key intermediates in the clifednamide biosynthesis.

Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

“… Previous work of hydrozirconations with Schwartz's reagent and our work [ 54 – 55 57 – 58 61 – 62 ]. …”

“…It has been successfully employed in methodology studies [ 31 – 40 ] as well as in several total syntheses of natural products [ 41 – 46 ]. Especially the combination of hydrozirconation and Pd or Ni-catalyzed cross coupling was elaborated by several groups ( Scheme 3 ) [ 47 – 54 ].…”

“…The substrate scope required aryl units at either alkyne or acid chloride unit. Recently, we could extend this method to alkyl-substituted alkynes 16 and acetyl chloride ( 22 ), providing enone building blocks 23 for the synthesis of clifednamides [ 54 , 62 ]. The addition of Schwartz's reagent proceeds as a syn -addition affording ( E )-alkenylzirconocenes 24 from terminal alkynes [ 28 ].…”

Multifunctional P450 Monooxygenase CftA Diversifies the Clifednamide Pool through Tandem C–H Bond Activations

“…Synthetic access to PTMs is improving but remains challenging due to the structural complexity of this natural product class. ,, Accordingly, microorganismal sources of PTMs for discovery, characterization, and biocombinatorial production remain productive and important. Late-stage oxidation in PTM biosynthesis is used by producing microbes to diversify the product pool and improve water solubility in natural environments.…”

“…The clifednamide family of PTMs (clifednamides A–J, Figure S1) is an interesting system for the study of PTM site-selective late-stage oxidations and their structure–function consequences. ,− First discovered in 2010 in growth extracts of Streptomyces sp. strain JV178 isolated from Connecticut, USA, soils, clifednamides have now been rediscovered in several globally distributed Streptomyces strains. ,,, To date, clifednamide biosynthesis has been investigated by multiple research groups using a combination of genome mining, gene deletion, and synthetic biology approaches.…”