I. Basic Principles IC. The Aldol Reactionccc.chem.pitt.edu/wipf/Courses/2320_07_files/Aldol_I.pdf · increasing the intracellular osmotic pressure and causing the coccidia to explode.

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

IC. The Aldol Reaction

I. Basic Principles

Many natural products contain polyhydroxylated carbon arrays, usually a mix of 1,2-and 1,3-diols; biosynthetically, these compounds are related and are commonlyreferred to as polyacetates/polypropionates.Typical examples of polyether antibiotics isolated from Streptomyces are:

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Most of these compounds are metal chelators (ionophores). Monensin as a foodadditive kills bacteria in poultry by the transporting Na+ outside the cell, thusincreasing the intracellular osmotic pressure and causing the coccidia to explode.

Macrolide antibiotics are characterized by the macrocyclic lactone moiety and canbe grouped into: polyoxo, polyene, ionophore, and ansamycin macrolides.

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Aldol Methodology

Synthetic problem: control of aldol regio- and stereoselectivity.

Heathcock’s synthesis of ristosamine (THL 1983, 24, 4637).

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The Ivanov Reaction

rationalization: Zimmerman-Traxler, JACS 1957, 79, 1920.

To achieve high diastereo- and enantioselectivity, it is necessaryto:

- 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.

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The stereochemical implications of the Zimmerman-Traxlertransition state model for the aldol reaction can be summarized asfollows:

Zimmerman-Traxler transition states represent the mostfrequently used models, but other possibilities have always to beconsidered as well:

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Arya, P.; Qin, H., "Advances in asymmetric enolate methodology." Tetrahedron2000, 56, 917-948.

Heathcock/Masamune auxiliaries:

Asymmetric Induction

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Highly selective additions of these auxiliaries have been achieved via all four ofthe postulated pathways (JOC 1991, 56, 2499):

Evans’ Chiral Oxazolidinone Auxiliary

D. A. Evans, JACS 1981, 103, 2127

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Smith, A. B.; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011.

Crimmins, M. T.; King, B. W.; Tabet, E. A., "Asymmetric aldol additions with titaniumenolates of acyloxazolidinethiones: Dependence of selectivity on amine base andLewis acid stoichiometry." J. Am. Chem. Soc. 1997, 119, 7883.

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Experiments employing N-acyloxazolidinethione auxiliaries (sulfur has a higheraffinity to titanium than oxygen), 2 equiv of TiCl4 and 1 equiv of Hünig’s base gaveexcellent selectivity for the “non-Evans” syn aldol product. Crimmins believes thatthe second equivalent of Lewis acid abstracts the chlorine ion and leads to achelated transition state (in contrast to the acyclic transition state postulated byHeathcock). In addition, very high (>98:2) “Evans” syn aldol selectivities could beobtained by using 1 equiv of TiCl4 in combination with sparteine (2.5 equiv). The roleof sparteine is presently unknown.

An added advantage of oxazolidinethiones is that they are easily removed under mild conditions:

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Crimmins, M. T.; King, B. W., "Asymmetric total synthesis of callystatin A: Asymmetricaldol additions with titanium enolates of acyloxazolidinethiones." J. Am. Chem. Soc.1998, 120, 9084.

Oxazolidinethiones can be N-acylated by a variety of standard methods includingacylation of the lithium salt or sodium salt by treatment with an acyl chloride ormixed anhydride or by acylation with an acid chloride in the presence oftriethylamine.

Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J. Am. Chem. Soc. 1993, 115, 2613.Yan, T.-H.; Hung, A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J. Org. Chem. 1995, 60, 3301.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-acyloxazolidinones, oxazolidinethiones, and thiazolidinethiones." Synlett 2004, 1371-1374.

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

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