Chromenes enantioselective synthesis

Keywords Catalytic metathesis, Enantioselective synthesis, Catalytic kinetic resolution, Catalytic carbomagnesation, Catalytic rearrangement, 2-Substituted chromenes, Catalytic m aero cyclization... 

Organocatalytic enantioselective aza-Michael reactions 12COC521. Organocatalytic C—H activation reactions 12BJ01374. Organocatalytic tandem Michael addition reactions A powerful access to the enantioselective synthesis of functionahzed chromenes, thiochro-menes, and 1,2-dihydroquinohnes 12BJ01668. 

SCHEME 16.41. Oxa-Michael/aldol/dehydration organocascade for the enantioselective synthesis of chromenes. 

A procedure for the highly enantioselective synthesis of chiral chromenes and tetrahydroquinolines was achieved in 2012 by Feringa and co-workers. By combining asymmetric copper-catalyzed allylic substitution with Grignard reagents and an efficient palladium-catalyzed intramolecular Heck... 

P. Kotame, B.-C. Hong, J.-H. Liao, Tetrahedron Lett. 2009, 50, 704—707. Enantioselective synthesis of the tetrahydro-6//-benzo[c]chromenes via domino Michael-aldol condensation control of five stereocenters in a quadruple-cascade organocatalytic multi-component reaction. 

G. Zhang, Y. Zhang, J. Yan, R. Chen, S. Wang, Y. Ma, R. Wang, One-pot enantioselective synthesis of functionalized pyranocoumarins and 2-amino-4H-chromenes discovery of a type of potent antibacterial agent, J. Org. Chem. 77 (2012) 878-888. 

Scheme 17. The tandem Zr-catalyzed kinetic resolution and Mo-catalyzed conversion of styrenyl ethers to chromenes is used in the first convergent and enantioselective total synthesis of the antihypertensive agent (S,R,R,R) nebivolol...

C. W. Johannes, M. S. Visser, G. S. Weatherhead, A H. Hoveyda Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Mo-Catalyzed Chromene Formation in Synthesis. Enantioselective Total Synthesis of the Antihypertensive Agent (SJUUD-Nebivolol J. Am Chem Soc 1998, 120, 8340-8347. For development of the enantioselective methodology, see M. S. Visser, J. P. A. Harrity, A. H. Hoveyda Zirconium-Catalyzed Kinetic Resolution of Cyclic Allylic Ethers. An Enantioselective Route to Unsaturated Medium Ring Systems , J. Am Chem Soc 1996,118, 3779-3780. 

The six-membered ring 85 is obtained from the allylamine 84 [31]. The sulfur-containing ring 87 was obtained from 86 using the Mo catalyst. The Ru catalyst is not active for this reaction [32]. The (S, f )-chromene derivative 89 was obtained in 97% yield by the Mo-catalysed intramolecular metathesis of (S,f )-cycloheptenyl styrenyl ether 88 under an atmosphere of ethylene. In the absence of ethylene, 89 and its dimer were obtained. The enantioselective total synthesis of (.S, / ,/ , / )-ncbivoIoI (90) has been carried out from 89 [33]. No cyclization of the cyclopentene 91 was observed, because the highly strained cyclobutane intermediate 92 is difficult to form. 

Due to the demand for inexpensive anti-HIV agents, several reactions for the synthesis of Indinavir (70, an HIV protease inhibitor of Merck Co.) have been reported. Enantioselective epoxidation of simple alkenes with bleach is achievable in the presence of the Mn " complex 69 possessing a well-designed chiral salen ancillary [69]. Scheme 20 exemplifies its application to the synthesis of Indinavir (70), by way of indene oxide (68) in 88 % ee [69]. This method is also useful for the asymmetric synthesis of a chromene epoxide in 97 % ee serving as an intermediate for Lemakalim, a K" -channel opening agent [70]. 

The [Mn(salen)]-catalyzed epoxidation of chromene derivatives was discovered to occur with exceptional enantioselectivity [74]. Chromene derivatives bearing 2,2-disubstitution appear to combine all the important substrate characteristics required for a highly enantioselective epoxidation. The synthetic utility of the enantioenriched epoxychroman products is increased by the predictable regio- and stereochemical outcome of epoxide ring opening with a variety of nucleophiles. These two features were highlighted in the synthesis of the selective potassium channel activator BRL 55834 [78]. Catalyst loadings as low as... 

To examine and challenge the utility of the two-step catalytic resolution-chromene synthesis process in synthesis [28], we undertook it convergent and enantioselective total. synthesis of the potent antihypertensive agent (,S .R./f,R)-nebivolol (63) 29. As illustrated in, Scheme4.12. the two... 

The reaction started with the tandem oxa-Michael-Michael reaction of 83 and 84 to give 87 in 76% yield and greater than 99% ee. The following Michael-aldol condensation with 4,4-dimethoxy-but-2-enal 85 works nicely in 69% yield and also excellent enantioselectivity. The obtained hexahydro-6//-benzo[c]chromene 88 is a highly functionalized intermediate in the total synthesis of (+)-conicol 89. The two-step reaction could be achieved in one pot from 83 and 84, without isolation of the intermediate 87, with a 55% overall isolated yield of 88. 

The same research group applied the above methodology for the synthesis of valuable 4//-chromenes 43 in good yields and with excellent enantioselectivities. The approach consists of a dual light and Br0nsted acid mediated isomerization-cyclization reaction starting from enones 41 to yield 27f-chromen-2-ol intermediates A. The subsequent Brpnsted acid catalyzed elimination of water leads to an... 

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