P. Wipf - Chem /29/2006. To achieve high diastereo- and enantioselectivity, it is necessary to:

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1 P. Wipf - Chem /29/2006 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. 1

2 P. Wipf - Chem /29/2006 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: 2

3 P. Wipf - Chem /29/2006 Enolization a. Lithium enolates 3

4 P. Wipf - Chem /29/2006 Transition states for enolization: Kinetic ratios for LDA/THF enolization: 4

5 P. Wipf - Chem /29/2006 Busch-Petersen, J.; Corey, E. J., "Sterically shielded secondary N-tritylamines and N-tritylamide bases, readily available and useful synthetic reagents." Tetrahedron Lett. 2000, 41, Heathcock s synthesis of ristosamine (THL 1983, 24, 4637; see also: JOC 1989, 54, 2936). 5

6 P. Wipf - Chem /29/2006 b. Boron enolates Selectivities: The boron-halide coordinates to the carbonyl oxygen, thereby increasing the acidity of the α- proton so that it can be removed by amine bases. * but: w/ Chx 2 B(OTf)/NEt 3 : E : Z = 20 : 80 data from: Evans, JACS 1981, 103, 3099; Brown, JOC 1993, 58, 147. at least a partial rationalization of these results is provided by the following transition state models: 6

7 P. Wipf - Chem /29/2006 Asymmetric Induction Arya, P.; Qin, H., "Advances in asymmetric enolate methodology." Tetrahedron 2000, 56, Heathcock/Masamune auxiliaries: Highly selective additions of these auxiliaries have been achieved via all four of the postulated pathways (JOC 1991, 56, 2499): 7

8 P. Wipf - Chem /29/2006 Evans Chiral Oxazolidinone Auxiliary D. A. Evans, JACS 1981, 103, 2127 Smith, A. B.; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117,

9 P. Wipf - Chem /29/2006 Abiko, A.; Liu, J.-F.; Wang, G.; Masamune, S. Tetrahedron Lett. 1997, 38,

10 P. Wipf - Chem /29/2006 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,

11 P. Wipf - Chem /29/2006 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: 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,

12 P. Wipf - Chem /29/2006 Two methods for the synthesis of 4-benzyloxazolidine-2-thione from 2-amino-3- phenyl-1-propanol (phenylalaninol) have been described. The appropriate amino alcohol is readily prepared from (R)-phenylalanine or (S)-phenylalanine by reduction with sodium borohydride and iodine in THF. Exposure of phenylalaninol to carbon disulfide and aqueous sodium carbonate for 15 min at 100 C provided 4-benzyloxazolidine-2-thione in 63% yield. Alternatively, treatment of the amino alcohol with thiophosgene and triethylamine in dichloromethane for 30 min at 0 C provided 95% of the oxazolidinethione. The former method often results in the oxazolidinethione contaminated with varying amounts of the corresponding thiazolidinethione. Delaunay, D.; Toupet, L.; Le Corre, M. J. Org. Chem. 1995, 60, Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 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,

13 P. Wipf - Chem /3/2006 Tin(II) Enolates of N-acyloxazolidinethiones. Tin(II) enolates of oxazolidinethiones show moderate diastereoselectivity for the non-evans aldol products presumably proceeding through a chelated transition state. The N- acetyl oxazolidinethiones are generally less selective than the corresponding thiazolidinethiones in diastereoselective acetate aldol reactions. Nagao, Y.; Fujita, E. J. Chem. Soc., Chem. Commun. 1985, Boron enolates of N-acyloxazolidinethiones. Boron enolates of N- propionyloxazolidinethiones can be generated under standard enolization conditions with dibutylboron triflate and diisopropylethylamine. The boron enolates react with aldehydes to provide the Evans syn-aldol products with excellent diastereoselectivity. No oxidative workup was necessary in the examples reported. Hsiao, C. Miller, M. Tetrahedron Lett. 1985, 26, ; Hsiao, C. Miller, M. J. Org. Chem. 1987, 52, Guz, N. R.; Phillips, A. J., "Practical and highly selective oxazolidinethione-based asymmetric acetate aldol reactions with aliphatic aldehydes." Org. Lett. 2002, 4,

14 P. Wipf - Chem /29/2006 The use of excess titanium (IV) chloride with N-glycolyloxazolidinethiones leads to the anti aldol adducts selectively. These aldol additions most likely proceed through an open transition state where the additional Lewis acid serves to activate the aldehyde for the aldol addition reaction. indirect solution for anti-aldol (D. A. Evans, THL 1986, 27, 4957: 14

15 P. Wipf - Chem /29/2006 For important modern concepts on selective anti-aldol processes, see work by Masamune (Tetrahedron Lett. 1992, 33, 1729) Mikami (J. Am. Chem. Soc. 1994, 116, 4077) Denmark (J. Am. Chem. Soc. 1999, 121, 4982) Evans (J. Am. Chem. Soc. 1997, 119, 10859) Kobayashi (Ishitani, H.; Yamashita, Y.; Shimizu, H.; Kobayashi, S., "Highly anti-selective catalytic asymmetric aldol reactions." J. Am. Chem. Soc. 2000, 122, ) and others: Corey, E. J.; Li, W.; Reichard, G. A. "A new magnesium-catalyzed doubly diastereselective antialdol reaction leads to a highly efficient process for the total synthesis of lactacystin in quantity." J. Am. Chem. Soc. 1998, 120, Gosh, A. K.; Fidanze, S. "Asymmetric synthesis of (-)-tetrahydrolipstatin: An anti-aldol-based strategy." Org. Lett. 2000, 2, Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. "Diastereoselective magnesium halidecatalyzed anti-aldol reactions of chiral N-acyloxyoxazolidinones." J. Am. Chem. Soc. 2002, 124, Chow, K. Y.-K.; Bode, J. W. "Catalytic generation of activated carboxylates: Direct, stereoselective synthesis of β-hydroxyesters from epoxyaldehydes." J. Am. Chem. Soc. 2004, 126, Assumed catalytic cycle: 15

16 P. Wipf - Chem /29/2006 Double Diastereoselectivity D. A. Evans, JACS 1985, 107, Note: Reagent-based stereocontrol does not always superseed substrate control: from: cytovaricin synthesis; Paterson, THL 1988, 29,

17 P. Wipf - Chem /29/2006 Evans Bispropionate Synthon Keck, G. E.; Lundquist, G. D., "Synthetic studies toward the total synthesis of swinholide. 1. Stereoselective construction of the C 19 -C 35 subunit." J. Org. Chem. 1999, 64,

18 P. Wipf - Chem /29/2006 Paterson s Ipc-Enolate (TH 1990, 46, 4663): This strategy is particularly useful for aldol reactions of large, chiral fragments in macrolide synthesis. Catalytic Asymmetric Aldol: Eder-Sauer-Wiechert-Hajos Process For a further development, see: List, B.; Lerner, R. A.; Barbas, C. F., "Proline-catalyzed direct asymmetric aldol reactions." J. Am. Chem. Soc. 2000, 122, Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F. "Organocatalytic direct asymmetric aldol reactions in water." J. Am. Chem. Soc. 2006, 128, Storer, R. I.; Macmillan, D. W. C., "Enantioselective organocatalytic aldehyde-aldehyde cross-aldol couplings. The broad utility of α-thioacetal aldehydes." Tetrahedron 2004, 60, Houk, K. N.; List, B., "Asymmetric organocatalysis." Acc. Chem. Res. 2004, 37, 487. Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N., "Theory of asymmetric organocatalysis of aldol and related reactions: Rationalizations and predictions." Acc. Chem. Res. 2004, 37,