Organic Chemistry Portal
Organic Chemistry Highlights

Wednesday, April 5, 2006
Vasco D. B. Bonifacio
New University of Lisbon

Asymmetric Hetero-Diels-Alder Reactions

The asymmetric hetero-Diels-Alder (HDA) reaction is among the most powerful available methodologies for the construction of optically active six-membered heterocycles, with extensive synthetic applications in natural or unnatural products with a wide range of biological activity. The DA reaction has high regioselectivity and endo-stereoselectivity. This Highlight reviews recent developments from 2005 to present (for comprehensive reviews on asymmetric DA reaction see a) Angew. Chem. Int. Ed. 2002, 41, 1650. DOI: 10.1002/1521-3773(20020517)41:10%3C1650::AID-ANIE1650%3E3.0.CO;2-B; b) Angew. Chem. Int. Ed. 2002, 41, 1668. DOI: 10.1002/1521-3773(20020517)41:10%3C1668::AID-ANIE1668%3E3.0.CO;2-Z; c) Mini-Reviews in Organic Chemistry, 2004, 1, 41. Link). Some of the examples presented here use organocatalysis, which is a rapidly growing research field.

Kobayashi and co-workers
(Tetrahedron Lett. 2005, 45, 1803. DOI: 10.1016/j.tetlet.2005.01.111)
Dubernet and co-workers
(Bioorg. Med. Chem. Lett. 2006, 16, 1172. DOI: 10.1016/j.bmcl.2005.11.100)

Burke and co-workers
(J. Org. Chem. 2005, 70, 3757. DOI: 10.1021/jo050034v)
Fig. 1 Recent examples using the HDA methodology.

1. aza-Diels-Alder Reactions

Timmons and co-workers reported the first aza-DA reaction using a new class of iododiene 1 and chiral imines 2 (Tetrahedron 2005, 61, 11837. DOI: 10.1016/j.tet.2005.10.018). The methodology was used in the synthesis of dihydropyridones 3 (3:1 to 4.5:1 de, 61-85% yield).

Córdova and co-workers reported the first one-pot three-component direct catalytic enantioselective aza-DA reaction. This organocatalysed reaction was tested using different ketones 4 (40-90% yield, 94-99% ee), formaldehyde (5) and anilines 6 (20-70% yield, 96-99% ee) in the presence of (S)-proline. The reaction occurs via a transition state in which the in situ-generated imine attacks the si face of the proline-derived catalyst. The reaction is simple, can be performed in wet solvents, and is environmentally friendly (Angew. Chem. Int. Ed. 2005, 44, 4877. DOI: 10.1002/anie.200500811).

a) 4 (2 mmol, 2 equiv.), aqueous 5 (1 mmol), 6 (1.1 mmol), (S)-proline (30 mol%), DMSO, rt, 20-72 h.

2. oxo-Diels-Alder Reactions

Ding and coworkers successfully developed a catalytic oxo-DA reaction for the synthesis of 2,3-dihydro-4H-pyran-4-one derivatives 8 in excellent yields and high enantioselectivity. The authors used chiral zinc catalysts containing ligand 9, various diimine activators (the best results were obtained using 10 and 11), Danishefsky’s-type diene 12 and aromatic aldehydes 13 through a combinatorial approach (Tetrahedron 2005, 61, 9465. DOI: 10.1016/j.tet.2005.08.007).

a) 1. ligand/Et2Zn/diimine (10 mol%), toluene, -20°C ; 2. CF3CO2H

Using chiral lanthanide complexes with (R,R)-DPENTf (14) Tonoi and Mikami report a catalytic oxo-DA reaction between Danishefsky’s-type diene 15 and glyoxylate 16 (23-87% yield, 23-86% ee). The reaction proceeds through double hydrogen bonding using bis-triflylamide as chiral Brønsted acid catalyst (Tetrahedron Lett. 2005, 46, 6355. DOI: 10.1016/j.tetlet.2005.07.043).

a) 15 (0.12 mmol), 16 (0.1 mmol), 14 (10 mmol%), toluene, -20 or -78ºC, 4 h.

Rajaram and Sigman developed a new class of hydrogen bond catalysts 18 that activate aldehydes 13 through hydrogen bonds. These rigid oxazolines successfully (42-80% yield) promote highly enantioselective (71-92% ee) oxo-DA reactions (Org. Lett. 2005, 7, 5473. DOI: 10.1021/ol052300x). The authors found that both hydrogen bond donors in the organocatalyst are necessary for effective catalysis.

a) 1. 18 (20 mol%), toluene; 2. CH2Cl2, CH3COCl, -78ºC.

Rawal and co-workers reported an oxo-DA organocatalysed reaction between aminosiloxydiene 19 and a wide variety of unactivated aldehydes 21 with useful yields (42-99% yield) and excellent enantioselectivities (84-99% ee) using axially chiral diols 22 of the BAMOL family (J. Am. Chem. Soc. 2005, 127, 1336. DOI: 10.1021/ja044076x). The authors show that the diols function in the same capacity as Lewis acids, by activating the aldehyde carbonyl group through hydrogen bonding.

a) 1. 19 (0.5 mmol), 21 (1 mmol), 22 (0.1 mmol), toluene, -40 or -80ºC; 2. CH3COCl, CH2Cl2-toluene, -78ºC, 30 min.

3. Other Hetero Diels-Alder Reactions

Kumawat and co-workers developed a regioselective (4:1 de, 50% yield) HDA reaction between isoprene (24) and [1,4,2]diazaphospholo[4,5-a]pyridines 25 in the presence of selenium (Tetrahedron 2005, 61, 10521. DOI: 10.1016/j.tet.2005.08.045). The weaker C=P π-bond, relatively to the C=C π-bond, lowers the activation energy needed for the cyclisation and favours the HDA reaction.

V. D. B. Bonifacio, Org. Chem. Highlights 2006, April 5.