Cornforth: Nature is an organic chemist with a preference for the aldol reaction.

Transcription

1 I. Basic Principles IC. The Aldol Reaction Cornforth: Nature is an organic chemist with a preference for the aldol reaction. Many natural products contain polyhydroxylated carbon arrays, usually a mix of 1,2- and 1,3-diols; biosynthetically, these compounds are related and are commonly referred to as polyacetates/polypropionates. Typical examples of polyether antibiotics isolated from Streptomyces are: 1

2 Most of these compounds are metal chelators (ionophores). Monensin as a food additive kills bacteria in poultry by the transporting Na + outside the cell, thus increasing the intracellular osmotic pressure and causing the coccidia to explode. Macrolide antibiotics are characterized by the macrocyclic lactone moiety and can be grouped into: polyoxo, polyene, ionophore, and ansamycin macrolides. 2

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4 Aldol Methodology Synthetic problem: control of aldol regio- and stereoselectivity. Heathcock s synthesis of ristosamine (THL 1983, 24, 4637). 4

5 The Ivanov Reaction rationalization: Zimmerman-Traxler, JACS 1957, 79, To achieve high diastereo- and enantioselectivity, it is necessary to: - control the enolization step - use an auxiliary with a large diastereofacial bias - control competing transition states, e.g. - half-chair vs. twist boat - closed vs. open - use metal-derivatives that have clearly defined coordination geometries. 5

6 The stereochemical implications of the Zimmerman-Traxler transition state model for the aldol reaction can be summarized as follows: Zimmerman-Traxler transition states represent the most frequently used models, but other possibilities have always to be considered as well: 6

7 Asymmetric Induction Arya, P.; Qin, H., "Advances in asymmetric enolate methodology." Tetrahedron 2000, 56, Heathcock/Masamune auxiliaries: 7

8 Highly selective additions of these auxiliaries have been achieved via all four of the postulated pathways (JOC 1991, 56, 2499): Evans Chiral Oxazolidinone Auxiliary D. A. Evans, JACS 1981, 103,

9 Smith, A. B.; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117, Crimmins, M. T.; King, B. W.; Tabet, E. A., "Asymmetric aldol additions with titanium enolates of acyloxazolidinethiones: Dependence of selectivity on amine base and Lewis acid stoichiometry." J. Am. Chem. Soc. 1997, 119,

10 Experiments employing N-acyloxazolidinethione auxiliaries (sulfur has a higher affinity to titanium than oxygen), 2 equiv of TiCl 4 and 1 equiv of Hünig s base gave excellent selectivity for the non-evans syn aldol product. Crimmins believes that the second equivalent of Lewis acid abstracts the chlorine ion and leads to a chelated transition state (in contrast to the acyclic transition state postulated by Heathcock). In addition, very high (>98:2) Evans syn aldol selectivities could be obtained by using 1 equiv of TiCl 4 in combination with sparteine (2.5 equiv). The role of sparteine is presently unknown. An added advantage of oxazolidinethiones is that they are easily removed under mild conditions: 10

11 Crimmins, M. T.; King, B. W., "Asymmetric total synthesis of callystatin A: Asymmetric aldol additions with titanium enolates of acyloxazolidinethiones." J. Am. Chem. Soc. 1998, 120, Oxazolidinethiones can be N-acylated by a variety of standard methods including acylation of the lithium salt or sodium salt by treatment with an acyl chloride or mixed anhydride or by acylation with an acid chloride in the presence of triethylamine. Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J. Am. Chem. Soc. 1993, 115, Yan, T.-H.; Hung, A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J. Org. Chem. 1995, 60, Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 4, 591. Crimmins, M. T.; She, J., "An improved procedure for asymmetric aldol additions with N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones." Synlett 2004,

12 indirect solution for anti-aldol (D. A. Evans, THL 1986, 27, 4957: 12