Upload
phamngoc
View
213
Download
0
Embed Size (px)
Citation preview
1
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:
P. Wipf Chem 2320 1/10/2007
2
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.
P. Wipf Chem 2320 1/10/2007
4
Aldol Methodology
Synthetic problem: control of aldol regio- and stereoselectivity.
Heathcock’s synthesis of ristosamine (THL 1983, 24, 4637).
P. Wipf Chem 2320 1/10/2007
5
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.
P. Wipf Chem 2320 1/10/2007
6
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:
P. Wipf Chem 2320 1/10/2007
7
Arya, P.; Qin, H., "Advances in asymmetric enolate methodology." Tetrahedron2000, 56, 917-948.
Heathcock/Masamune auxiliaries:
Asymmetric Induction
P. Wipf Chem 2320 1/10/2007
8
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
P. Wipf Chem 2320 1/10/2007
9
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.
P. Wipf Chem 2320 1/10/2007
10
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:
P. Wipf Chem 2320 1/10/2007
11
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.
P. Wipf Chem 2320 1/10/2007