A Modular Approach to Angularly Fused Polyquinanes via Ring-Rearrangement Metathesis: Synthetic Access to Cameroonanol Analogues and the Basic Core of Subergorgic Acid and Crinipellin

Abstract

We describe a modular approach to angularly fused polyquinanes that are core units of many natural products such as cameroonanol, subergorgic acid, and crinepellin, etc. in excellent yields by employing atom-economic ring-rearrangement metathesis as a key step. Our work highlights, the synthesis of cameroonanol analogues 1–6 and their ester derivatives by using the stereoselective reduction of the carbonyl group by using DIBAL-H- and DCC-mediated coupling as the key reactions. The subergorgic acid core 7 was produced by LDA-mediated kinetically controlled regio- and stereoselective ring-junction allylation as a critical step. Moreover, it is worth mentioning that the present strategy relies on a less explored exo-dicyclopentadiene-1-one (8) and produces highly congested polycyclic frameworks containing up to seven contiguous stereogenic centers including quaternary carbons up to two. All of the new molecules were characterized by NMR data. The structure and relative stereochemistry of some compounds were confirmed by chemical methods and further supported by single-crystal X-ray diffraction studies. The newly reported tri- and tetraquinane skeletons are present in many naturally occurring bioactive polyquinanes. Hence, this strategy is useful for designing various “druglike molecules” and expands the chemical space of cyclopentanoids that are useful in medicinal chemistry.

Synthetic Improvements and an Alternative Synthetic Approach to exo‐Dicyclopentadiene‐1‐one: A Useful Building Block for Cyclopentanoids

“…The exo-DCPD-1-one 4 can serve as a key building block in the synthesis of several naturally occurring natural and unnatural compounds (Figure 4). [13][14][15] Therefore, exo-DCPD-1-one 4 occupies a unique place in organic synthesis.…”

“…The organic layer was washed with aqueous saturated NaHCO 3 solution (200-300 mL) twice. The [13][14][15] organic layer was concentrated to get crude compound and which was purified by column chromatography (2-4% EtOAc/PE as an eluent) to afford 4 (2%), 7 (50 g, 32%), and 8 (28%) as liquids.…”

“…[14] Whereas, 5/5-exo (exo-isomer) stereochemistry is favorable for the synthesis of polyquinanes and some fused cyclic molecules, and not favorable for the [2 + 2]-cycloaddition sequence. [14,15] Also, the exo-isomer undergoes ring-open metathesis polymerization (ROMP) at a faster rate as compared to the endo-isomer. [11] After establishing the structure of endo-DCPD 1 by Alder and Stein (1933), [16] many groups reported interesting studies to convert the endo-DCPD into its isomer, exo-DCPD 2.…”

An Intramolecular Cycloetherification of Unactivated Olefinic Substrates Bearing endo‐Alcohol: Access to Diversely Alkylated Oxa‐Cage Derivatives Useful for Olefin‐Metathesis

“…Note : Experimental procedures for methylation, allylation, [22d] DIBALH reduction, Grignard reaction, Hydrogenation, DCC‐coupling, and the key starting materials are described in supporting information . Data of respective compounds are also well documented.…”

A Single-Atom Upgrade to Polydicyclopentadiene

“…Seeking to combine the positive attributes of 2 (easy monomer synthesis) and 3 (desirable polymer properties), while eliminating the disadvantages noted above (e.g., the use of toxic oxidants or the need to purify away regioisomers at the monomer stage), we were attracted to the possibility of polymerizing dicyclopentadien-1-one (oxaDCPD; 4 m ). Ketone 4 m has long been known (in both endo and exo diastereomeric forms) as an intermediate in complex-molecule synthesis, − but its polymerization by ring-opening metathesis polymerization (ROMP) methods has not previously been described. − Compellingly, the one-step oxidation of DCPD ( 1 m ) to 4 m has been reported previously under photocatalytic conditions and is known to afford only a single regioisomer of the target compound, in good yield. − If this reaction could be adapted toward large-scale production, it could provide an attractive monomer synthesis that is both economically and environmentally sustainable. Moreover, if polymerization of 4 m were to proceed similarly to the previously known functionalized monomers 2 m and 3 m , this could afford a novel functionalized polydicyclopentadiene ( 4 p and/or 4 p,c ) that has a somewhat increased surface energy relative to the parent PDCPD (due to the polar ketone group), while also encoding a useful synthetic handle for further derivatization and avoiding the labile allylic alcohol (or allylic ester) functionality that limited the high-temperature performance and T g in polymer 2 p .…”