Chiral Phosphoric Acid Catalyzed Addition of Dihydropyrans to N-Acyl Imines: Stereocontrolled Access to Enantioenriched Spirocyclic Oxazoletetrahydropyrans with Three Contiguous Stereocenters

Abstract

Dihydropyran derivatives readily undergo addition to N-acyl imines in the presence of chiral Phosphoric acids. This addition process yields an attractive product that is capable of a tandem oxidative-cyclization via an epoxide intermediate. ChiralBrønsted acids have been shown as highly effective catalysts for stereocontrolled additions to imines. 1 The use of N-acyl imines, in particular, has been a very successful substrate for activation by chiral phosphoric acid (PA) based catalysis. 2 As part of our ongoing efforts in the chiral PA activation of N-acyl electrophiles, 3 we have been continually interested in establishing new stereocontrolled C-C bond forming reactions. During the course of our investigation into the use of dihydropyran (DHP) as a substrate for aza-Diels-Alder 4 chemistry, a report by Mead and coworkers 5 described the achiral Mannich-type addition of DHP and derivatives to N-acyl imines catalyzed by trifluoroacetic acid or BF 3 -OEt 2 . Concurrent with the Mead study, we observed that the chiral PA-catalyzed reaction of DHP with N-acyl imine 1 also provided the direct Mannich product, rather than the [4+2] adduct (Scheme 1). We were excited because the addition, if rendered highly enantioselective, would have the following unique features: a) it is a relatively novel carbon-carbon bond forming reaction, which could provide synthetically useful chiral allyl amines (or amides); b) functionalized chiral dihydropyran derivatives, are found in numerous bioactive natural products and compounds with medicinal interest. 6 We report herein, to the best of our knowledge, the first catalytic jantilla@cas.usf.edu. Supporting Information Available Experimental procedures, characterization, and spectra. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2011 May 7. We initiated our studies with VAPOL phosphoric acid 3a (5 mol % catalyst loading) as the catalyst, and toluene as the solvent. The reaction was run at room temperature and yielded the addition product in 45% yield and 37% ee. This result encouraged us to further explore the reaction conditions. Catalyst screening showed that (R)-TRIP-PA 7 gave the best result in terms of enantioselectivity and yield. Therefore, (R)-TRIP-PA was used to evaluate the effect of solvent on the reaction. As shown in Table 1, coordinating solvents such as THF and ether (entries 3and 5) gave poor results. Chloroform provided the best yield at 85% and ee at 71% (entry 8).Decreasing the temperature lowered the yield and ee dramatically (entry 9). Increasing the temperature to 50°C afforded a lower yield of the major product, due in part to the formation of more side products, while providing only modest ee. We then turned our attention to the effect of different substituents on the phenyl ring of the benzoyl group. As shown in Table 1, introduction of a methoxy or methyl group in the ortho or meta positions of the phenyl ring did not induce a positi...

Recent Developments in the Stereoselective Synthesis of Nitrogen‐Containing Heterocycles using N‐Acylimines as Reactive Substrates

“…Reaction of dihyropyrans with N ‐acylimines catalyzed by a chiral phosphoric acid is able to produce the corresponding adducts in good yield (72–95%) and enantioselectivity ( ee 76–92%) . Subsequent oxidation of the dihyropyran ring using 3‐chloroperoxybenzoic acid affords stereoselectively spirocyclic oxazoletetrahydropyrans having three contiguous stereocenters.…”

Chiral BINOL-derived phosphoric acids: privileged Brønsted acid organocatalysts for C–C bond formation reactions

“…The group of Antilla developed the addition reaction of hydroxypyrans to N-acyl imines. 65 The preferred catalyst was found to be 16. The respective products can be oxidatively coupled, using MCPBA, to form a spirocyclic compound while completely retaining enantioselectivity.…”

Alkyl Enol Ethers: Development in Intermolecular Organic Transformation

“…The addition reaction of dihydropyran 29 to N ‐acyl imines 202 has been developed by Antilla and co‐workers. Reaction proceeds in the presence of chiral phosphoric acid in chloroform as solvent at room temperature provide compound 203 with good yield (Scheme 65), which is further treated with m ‐CPBA to give highly selective spirocyclic oxazoletetrahydropyrans 204 via tandem epoxidation/ring‐opening reaction [97] …”