In summary, we have developed an efficient Pd-catalyzed cascade alkoxycarbonylative macrolactonization to construct THP/THF-containing macrolactones with different ring sizes and substituents. Challenging macrolactones involving tertiary alcohols were synthesized efficiently as well. Mechanistically, experiments have been conducted to support a Wacker-type trans-oxypalladation step. The application of this method was demonstrated in the synthesis of 9-demethylneopeltolide.
A Synthesis of 4-Phenyl-2-phenylsulfonyl-3-vinylcyclopentanone via Palladium-catalyzed 1,3-Oxygen- to-Carbon Alkyl Shift, 1993,
Synthesis of Multisubstituted Allenes, Furans, and Pyrroles via Tandem Palladium-Catalyzed Substitution and Cycloisomerization 2017,
Synthesis of 2H-Indazoles via Tandem Palladium-Catalyzed Deacylative Cross-Coupling and Denitrogenative Cyclization of 2-Iodoazoarenes and 2-Iodoaryltriazenes with Acyldiazoacetates in One-Pot 2016,
Synthesis of Acyl Alkenylindium Reagents and Their Application in the Synthesis of (Z)-α,β-Unsaturated Ketones via Palladium-Catalyzed Cross-Coupling Reaction, 2015,
In Situ Generation of Phosphoryl Alkylindiums and Their Synthetic Application to Arylalkyl Phosphonates via Palladium-Catalyzed Cross-Coupling Reactions2014,
One-Pot Synthesis of Indolizines via Sequential Rhodium-Catalyzed [2 + 1]-Cyclopropanation, Palladium-Catalyzed Ring Expansion, and Oxidation Reactions from Pyridotriazoles and 1,3-Dienes 2017,
A novel Pd-catalyzed cascade alkoxycarbonylative macrolactonization to construct THP/THF-containing bridged macrolactones in one step from alkendiols is described. Products with various ring sizes and substituents were obtained. Challenging macrolactones involving tertiary alcohols were synthesized smoothly as well. Mechanistically, experimental evidence to support a trans-oxypalladation step has been provided. The method was applied to the synthesis of potent anticancer 9-demethylneopeltolide.
Transition metal-catalyzed carbonylation reactions are of broad applicability, in terms of both basic research and commercial applications.– This chemistry has been widely employed in organic synthesis, because it can be utilized on a wide variety of substrates to produce a wide range of carbonyl products and it generally proceeds smoothly under low pressures of carbon monoxide ().– Similarly, the palladium-catalyzed cyclocarbonylation/lactonization of organic halides is very useful synthetic methodology that has become an important tool in organic synthesis.– For example, we have reported that the coupling of o-iodophenols, internal alkynes, and carbon monoxide efficiently affords 3,4-disubstituted coumarins ().– Similarly, we have prepared coumestans and coumestrol by iodocyclization and subsequent palladium-catalyzed intramolecular lactonization using an acetoxy group as the nucleophile ().
Herein, we report an efficient method for the palladium-catalyzed intramolecular cyclocarbonylation and intermolecular carboalkoxylation of various hydroxyl-substituted 3-iodofurans to give lactone- and ester-containing furan products, respectively. The hydroxyl substituents present in the latter substrates can be critical for receptor binding in vitro due to their hydrophilicity and, thus, lipophobic nature. According to calculations using Lipinski’s rules, terminal hydroxyl-containing furans should be good drug candidates. Intramolecular cyclocarbonylation would also appear to provide an interesting set of lactones of potential biological interest. We anticipate that this chemistry should find broad applications in synthetic organic chemistry, as well as the pharmaceutical sciences.
Engle, Jin-Quan Yu
"Heterocycle Formation via Palladium-Catalyzed C-H Functionalization"
Synthesis 2012, 44, 1778.
The hydroxyl-containing 3-iodofurans 2 produced by this chemistry should be very useful for the synthesis of a wide variety of other substituted furans () as well. For example, the Sonogashira and Suzuki-Miyaura reactions have afforded the corresponding products 5 and 6 in good yields. In summary, we have developed a useful new synthetic route to lactone-containing furans 3 and ester-containing furans 4 by the palladium-catalyzed intramolecular cyclocarbonylation and intermolecular carboalkoxylation of hydroxyl-substituted 3-iodofurans 2, respectively. Various hydroxyl-containing 3-iodofurans 2 have been successfully prepared through the iodocyclization of 2-(1-alkynyl)-2-alken-1-ones by I2 in the presence of various diols. These iodine-containing furans can also be readily elaborated to more complex products using known organopalladium chemistry. The iodine-containing furans 2 have thus proven to be very useful intermediates for further diversification by known palladium-catalyzed chemistry, and are thus valuable building blocks for combinatorial chemistry.
In our preliminary studies on the synthesis of tetrahydrofurans via Pd-catalyzed carboetherification reactions, we examined the coupling of 4-penten-1-ol (10) with 2-bromonaphthalene. We initially surveyed the conditions employed by Trost that led to the formation of a tetrahydrofuran side product (16) during the transformation of 14 to 15 (). As shown in , these conditions provided only a trace amount of the desired product 17 (ca. 2-3% yield by GC). In order to optimize this transformation we first explored the use of different bases, as we felt that the nucleophilicity of the heteroatom may be important, and a stronger base could provide a greater equilibrium concentration of a nucleophilic alkoxide derived from 10. After surveying several bases we found that NaOtBu provided improved but still unsatisfactory results (20% yield). The main side product formed in this reaction was naphthalene, and it seemed likely that this product was generated via β-hydride elimination of a palladium(aryl)alkoxide complex such as 8a (). At this point it was unclear if 8a was along or outside of the catalytic cycle, but it seemed plausible that a chelating bis-phosphine ligand could diminish the rate of this side reaction and potentially provide improved yields. After some experimentation, we found that the bidentate ligand Dpe-phos provided significantly improved results (45% yield), and use of 2 equiv of both NaOtBu and 2-bromonaphthalene with this ligand afforded 17 in 76% yield.