Adventures and Detours in the Synthesis of Hydropentalenes

Abstract

Functionalized hydropentalenes (i.e., bicyclo[3.3.0]octanones) constitute important building blocks for natural products and for ligands for asymmetric catalysis. The assembly and tailored functionalization of this convex roof-shaped scaffold is challenging and has motivated a variety of synthetic approaches including our own contributions, which will be presented in this account.1 Introduction2 Biosynthesis of Hydropentalenes3 Hydropentalenes through the Pauson–Khand Reaction4 Hydropentalenes through Transannular Oxidative Cyclization of Cycloocta-1,4-diene5 Functionalization of Bicyclo[3.3.0]octan-1,4-dione to Dodecahydrocyclopenta[a]indenes6 Functionalization of Bicyclo[3.3.0]octan-1,4-diones to Crown Ether Hybrids7 Functionalization of Bicyclo[3.3.0]octan-1,4-dione to Cylindramide8 Tandem Ring-Opening Metathesis/Ring-Closing Metathesis/Cross-Metathesis of Bicyclo[2.2.1]heptanes9 Functionalization of Bicyclo[3.3.0]octan-1,4-dione to Geodin A10 Hydropentalenes through Enantioselective Desymmetrization of Weiss Diketones11 Functionalization of Weiss Diketones by Carbonyl Ene Reactions12 Functionalization of the Weiss Diketone to Cylindramide and Geodin A Core Units13 Biological Properties of Bicyclo[3.3.0]octanes14 Hydropentalenes through Vinylcyclopropane Cyclopentene Rearrangement15 Functionalization of Bicyclo[3.3.0]octanes toward Chiral Dienes16 Miscellaneous Syntheses of Hydropentalenes17 Conclusion and Outlook

Nature-Inspired Tetrahydropentalene Building Blocks: Scalable Synthesis for Medicinal Chemistry Needs

“…After that, the catalyst was filtered off, the filtrate was concentrated in vacuo, and the residue was used in further transformations with no additional treatment. 1 H NMR of the material obtained was not characteristic due to the partial deprotection of ketone and complexity of the spectrum. The yield was calculated as quantitive, ~5.1 g.…”

“…Yield -37.4 g (91 %). 1 H NMR (400 MHz, CDCl 3 ), δ, ppm: 0.93 (8H, d, J = 7 Hz), 1.41 -1.53 (3H, m), 1.96 -2.04 (3H, m), 2.04 -2.10 (1H, m), 2.22 -2.34 (2H, m), 2.41 (2H, s), 2.47 -2.57 (2H, m), 3.44 (dd, J = 16.9, 6.7 Hz, 5H), 4.79 (2H, s).…”

“…The quest to harness the potential of tetrahydropentalene (THP) derivatives in medicinal chemistry is driven by the remarkable biological activities observed for natural products featuring the bicyclo [3.3.0]octane core, such as carbacyclin (1,Figure), and clinprost (3). These compounds show prostaglandin analogs and platelet aggregation inhibitory properties, along with others displaying the anticancer activity like cylindramide (2), and antibiotic potential like geodin A (4).…”

“…These compounds show prostaglandin analogs and platelet aggregation inhibitory properties, along with others displaying the anticancer activity like cylindramide (2), and antibiotic potential like geodin A (4). In general, they exemplify the diverse biological actions -from antimicrobial to enzyme-inhibiting activities -that THP structural motif offers [1]. The synthetic analogs of tetrahydropentalenes, thus, emerge as formidable scaffolds in the drug development, opening the opportunities for finding new therapeutic agents capable of targeting a broad spectrum of diseases.…”

“…An in-depth review of the methodologies used for synthesizing tetrahydropentalene derivatives reveals a dynamic landscape marked by both tradition and novelty [1]. Each strategy offers unique advantages, such as enhanced yields and selectivity, yet often contends with the need for specialized reagents and stringent conditions, reflecting the evolving sophistication in the tetrahydropentalene synthesis.…”