In 1991, we discovered that alkyl azides react with carbonyl compounds in a process reminiscent of the Schmidt reaction of hydrazoic acid with ketones. Despite early failures in replacing hydrazoic acid with an alkyl azide under the strong protic acid conditions of the classical Schmidt reaction, it was learned that highly efficient conversions are possible when carried out intramolecularly or using a strong Lewis acid, such as TiCl4.
Current work is directed toward mechanistic studies and expansion of the methodology to embrace a group of related reactions. A particularly useful modification involves the use of an in situ-generated hemiacetal as a temporary tethering device, which renders the azide addition intramolecular and greatly expands the scope of the “intermolecular” reaction. For example, this trick permits the efficient ring expansion of cyclopentanones and moderately hindered cyclohexanones (both of which are impervious to the TiCl4-promoted reaction above) and installs a functionalized side chain.
We have also demonstrated that a variant using a chiral azido alcohol is capable of effecting enantioselective ring-expansion reactions, which have themselves been a long-standing interest of the group. The particular example noted is cool because it represents an unusually efficient example of 1,7-diastereoselectivity.
In addition, we have applied these new variants of the Schmidt reaction to total synthesis. Asymmetric synthesis of indolizidine 209B, a rare frog toxin, and aspidospermidine has been published. Other molecules currently slated for synthesis using asymmetric Schmidt technology are shown below.
Lead References
Anyone interested in the use of alkyl azides in organic synthesis ought also to look at Will Pearson's work carried out with azides and carbocations, which is very elegant and complements our own efforts.
1. Intramolecular Schmidt Reaction of Alkyl Azides. Aubé, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965-8966.
2. TiCl4-Mediated Reactions of Alkyl Azides with Cyclic Ketones. Aubé, J.; Milligan, G. L.; Mossman, C. J. J. Org. Chem. 1992, 57, 1635-1637.
3. Application of the Intramolecular Schmidt Reaction to the Asymmetric Synthesis of (–)-Indolizidine 209B from Pulegone. Aubé, J.; Rafferty, P. S.; Milligan, G. L. Heterocycles 1993, 35, 1141-1147.
4. Efficient Nitrogen Ring-Expansion Process Facilitated by in situ Hemiketal Formation. An Asymmetric Schmidt Reaction. Gracias, V.; Milligan, G. L.; Aubé, J. J. Am. Chem. Soc. 1995, 117, 8047-8048.
5. Ring Expansion by in situ Tethering of Hydroxy Azides to Ketones: The Boyer Reaction. Gracias, V.; Frank, K. E.; Milligan, G. L.; Aubé, J. Tetrahedron 1997, 53, 16241-16252.
6. Regiocontrol in an Intramolecular Schmidt Reaction: Total Synthesis of (+)-Aspidospermidine. Iyengar, R.; Schildknegt, K.; Aubé, J. Org. Lett. 2000, 2, 1625-1627.
7. Reactions of Alkyl Azides and Ketones as Mediated by Lewis Acids: Schmidt and Mannich Reactions Using Azide Precursors. Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman, C.; Milligan, G. L.; Aubé, J. J. Am. Chem. Soc. 2000, 122, 7226-7232.
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