Regioselective Synthesis of Indanones

Abstract

Abstract:The degree of hydrolysis of polyphosphoric acid (PPA) has a crucial effect on the regioselectivity of the PPA-mediated synthesis of indanones. It was found that the regioselectivity can be switched by employing PPA with either a high or low content of P 2 O 5 . This methodology was used for the regioselective synthesis of a range of electron-rich indanones, including a natural sesquiterpene.Key words: indanones, polyphosphoric acid, electrophilic aromatic substitution, total synthesis, regioselectivity Indanones are an important class of compounds due to their widespread occurrence in natural products and the biological activity associated with both natural and synthetic indanones. For example, indanones belonging to the Pterosin sesquiterpene family exhibit antimicrobial, 1 antispasmodic 2 and cytotoxic activity, 3 while the synthetic indanocine shows antiproliferative activity 4 ( Figure 1). The development of chemo-and regioselective synthetic methodology toward indanones is therefore of considerable importance.The main methods for the synthesis of indanones are (intramolecular) Friedel-Crafts acylation, 5 Nazarov cyclization, 6 and various transition-metal-catalyzed ring-closing reactions. 7 Indanones can also be accessed by the one-pot reaction of α,β-unsaturated carboxylic acids with benzene derivatives using polyphosphoric acid (PPA). 8,9 This protocol is frequently used in our laboratory for the synthesis of indanones, which serve as building blocks en route to overcrowded alkenes. 10 The main advantage of this method is the use of simple substrates that are often commercially available. However, the lack of control over the regioselectivity severely decreases the efficiency of the indanone synthesis. In some cases, these reactions generate mixtures of regioisomers that are difficult to separate, while in other cases, certain regioisomers cannot be accessed at all with this method.We envisioned that the P 2 O 5 content in PPA can be a key control parameter in the selective alkylation versus acylation in the PPA-mediated synthesis of indanones. 11 A change in the regioisomer ratio, depending on the polyphosphoric acid concentration, has been observed for a perimidine heterocycle. 12Figure 1 Natural and synthetic indanones with biological activity Scheme 1 Regioselective synthesis of two indanone isomers depending on the P 2 O 5 content in PPA In this letter, the effect of the P 2 O 5 content in PPA on the regioselectivity for the synthesis of indanones is examined. It was found that the regioselectivity can be effectively switched, depending on the degree of hydrolysis of PPA (Scheme 1). A mechanistic rational is given for the observed change in regioselectivity, together with supporting 31 P NMR spectroscopic studies. Additionally, the natural product sesquiterpene 19a and its unnatural regioisomer 19b were synthesized selectively by using the developed protocol to demonstrate its synthetic value. The condensation of 2,5-dimethylanisole (1) with methacrylic acid (2) was conducted by using PPA wi...

Total Synthesis of Cephanolide A and Harringtonolide: A Unified Strategy Connecting Benzenoid and Troponoid Cephalotaxus Diterpenoids

“…The indanone fragment 9 was prepared from commercially available phenol 10 by methyl protection (K2CO3, MeI in DMF) following a one-step Friedel-Craft alkylation/acylation reaction (acrylic acid, PPA 100 o C) in 53% yield over two steps. 14 Subsequently, the union between fragment 8 and 9 was achieved by palladium-catalyzed Csp 2 -Csp 3 cross coupling through the intermediacy of alkyl indium reagent developed by Loh, 15 providing pyrone 16 in 73% yield. Oxidation of 16 by IBX in DMSO 16 directly afforded the desired Diels-Alder product 7 in ~30% yield as a single diastereomer, with fully established Cephalotaxus diterpenoid carbon skeleton.…”