The Reggelin group

Sulfoximines – Auxiliaries

Based on a serendipitous discovery at the beginning of the 90ies we developed a method to prepare enantiomerically pure allylic sulfoximines 2. Later, we used this building blocks to synthesize highly substituted hetero(poly)cyclic ringsystems 1 via a diastereoselective γ-hydroxyalkylation with (chiral), heteroatom substituted aldehydes 3, followed by a Michael addition.

Key intermediate is the cyclic sulfonimidate 4 whose stereogenic centers are defined by the choice of the amino acid (here: valine) folloewd by a separation of the S-epimers. In case of the lk-configured diastereomers, we developed a dynamic diastereomer differentiating cyclisation reaction which enables us to prepare enantiomerically pure R,R-4 and S,S-4 on a larger scale (more than 100g).

Two procedures to remove the auxiliary have been developed. On the one hand by the application of aluminum amalgame, lithium naphthalenide or samarium(II)-iodide it is possible to effect a methylenating desulfurization (not shown). On the other hand, reaction of the α-deprotonated sulfoximine with a carbenoid generates a species which, via β-elimination, delivers a sulfur free, angular vinylated product.

Review: M. Reggelin, C. Zur, “Sulfoximines: Structures, properties and synthetic applications”, Synthesis 2000, 1-64. DOI: 10.1055/s-2000-6217.

Synthese der Sulfonimidate: M. Reggelin, H. Weinberger, “One-Pot Synthesis of (S)-4-Isopropyl-2-P-Toluene-4,5-Dihydro-[1,2-Lambda-6,3]Oxathiazole 2-Oxides – Efficient Precursors of Optically-Active Sulfoximines”, Tetrahedron Lett. 1992, 33, 6959-6962. DOI: 10.1016/S0040-4039(00)60906-1.

M. Reggelin, R. Welcker, “New stereocontrolled synthesis of cyclic sulfonimidates”, Tetrahedron Lett. 1995, 36, 5885-5886. DOI: 10.1016/0040-4039(95)01195-N.

M. Reggelin, H. Weinberger, M. Gerlach, R. Welcker, “Metalated 2-Alkenylsulfoximines: Efficient Solutions for Asymmetric d3-Synthons”, J. Am. Chem. Soc. 1996, 118, 4765-4777. DOI: 10.1021/ja9530735.

M. Reggelin, B. Junker, “Cyclic sulfonimidates by dynamic diastereomer-differentiating cyclisation: Large-scale synthesis and mechanistic studies”, Chem. Eur. J. 2001, 7, 1232-1239. DOI: 10.1002/1521-3765(20010316)7:6<1232::AID-CHEM1232>3.0.CO;2-L

γ-Hydroxyalkylierung und Heterocyclensynthesen:

M. Reggelin, H. Weinberger, “Diastereoselective hydroxyalkylation of enantiomerically pure 2-alkenylsulfoximides”, Angew. Chem. Int. Ed. 1994, 33, 444-446. DOI: 10.1002/anie.199404441.

M. Reggelin, H. Weinberger, M. Gerlach, R. Welcker, “Metalated 2-Alkenylsulfoximines: Efficient Solutions for Asymmetric d3-Synthons”, J. Am. Chem. Soc. 1996, 118, 4765-4777. DOI: 10.1021/ja9530735.

M. Reggelin, M. Gerlach, M. Vogt, “Metallated 2-alkenyl sulfoximines in asymmetric synthesis. Regio- and stereoselective synthesis of highly substituted oxabicyclic ethers and studies towards the total syntheses of the euglobals G1 and G2 and arenaran A”, Eur. J. Org. Chem. 1999, 1011-1031. DOI: 10.1002/(SICI)1099-0690(199905)1999:5<1011::AID-EJOC1011>3.0.CO;2-H.

M. Reggelin, B. Junker, T. Heinrich, S. Slavik, P. Bühle, “Asymmetric synthesis of highly substituted azapolycyclic compounds via 2-alkenyl sulfoximines: Potential scaffolds for peptide mimetics”, J. Am. Chem. Soc. 2006, 128, 4023-4034. DOI: 10.1021/ja057012a.