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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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Enolization

a. Lithium enolates

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Transition states for enolization:

Kinetic ratios for LDA/THF enolization:

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Busch-Petersen, J.; Corey, E. J., "Sterically shielded secondaryN-tritylamines and N-tritylamide bases, readily available anduseful synthetic reagents." Tetrahedron Lett. 2000, 41, 2515-2518.

Heathcock’s synthesis of ristosamine (THL 1983, 24, 4637; seealso: JOC 1989, 54, 2936).

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b. Boron enolates

Selectivities:

* but:w/ Chx2B(OTf)/NEt3: E : Z = 20 : 80

The boron-halidecoordinates to thecarbonyl oxygen,thereby increasingthe acidity of the α-proton so that it canbe removed byamine bases.

data from: Evans,JACS 1981, 103,3099; Brown, JOC1993, 58, 147.

at least a partial rationalization of these results is provided by thefollowing transition state models:

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

Heathcock/Masamune auxiliaries:

Asymmetric Induction

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

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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, 12011.

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Abiko, A.; Liu, J.-F.; Wang, G.; Masamune, S. Tetrahedron Lett. 1997, 38, 3261.

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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:

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.

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Two methods for the synthesis of 4-benzyloxazolidine-2-thione from 2-amino-3-phenyl-1-propanol (phenylalaninol) have been described. The appropriate aminoalcohol is readily prepared from (R)-phenylalanine or (S)-phenylalanine byreduction with sodium borohydride and iodine in THF. Exposure of phenylalaninolto carbon disulfide and aqueous sodium carbonate for 15 min at 100 °C provided4-benzyloxazolidine-2-thione in 63% yield. Alternatively, treatment of the aminoalcohol with thiophosgene and triethylamine in dichloromethane for 30 min at 0 °Cprovided 95% of the oxazolidinethione. The former method often results in theoxazolidinethione contaminated with varying amounts of the correspondingthiazolidinethione.Delaunay, D.; Toupet, L.; Le Corre, M. J. Org. Chem. 1995, 60, 6604-6607.Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894-902.McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 3568-3571.

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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Tin(II) Enolates of N-acyloxazolidinethiones. Tin(II) enolates ofoxazolidinethiones show moderate diastereoselectivity for the non-Evans aldolproducts presumably proceeding through a chelated transition state. The N-acetyl oxazolidinethiones are generally less selective than the correspondingthiazolidinethiones in diastereoselective acetate aldol reactions.

Nagao, Y.; Fujita, E. J. Chem. Soc., Chem. Commun. 1985, 1418-1419.

Boron enolates of N-acyloxazolidinethiones. Boron enolates of N-propionyloxazolidinethiones can be generated under standard enolizationconditions with dibutylboron triflate and diisopropylethylamine. The boron enolatesreact with aldehydes to provide the Evans syn-aldol products with excellentdiastereoselectivity. No oxidative workup was necessary in the examples reported.Hsiao, C. Miller, M. Tetrahedron Lett. 1985, 26, 4855-4858; Hsiao, C. Miller, M. J.Org. Chem. 1987, 52, 2201-2206.

Guz, N. R.; Phillips, A. J., "Practical andhighly selective oxazolidinethione-basedasymmetric acetate aldol reactions withaliphatic aldehydes." Org. Lett. 2002, 4,2253.

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The use of excess titanium (IV) chloride with N-glycolyloxazolidinethiones leads tothe anti aldol adducts selectively. These aldol additions most likely proceed throughan open transition state where the additional Lewis acid serves to activate thealdehyde for the aldol addition reaction.

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

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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-selectivecatalytic asymmetric aldol reactions." J. Am. Chem. Soc. 2000, 122, 5403-5404)and others:Corey, E. J.; Li, W.; Reichard, G. A. "A new magnesium-catalyzed doubly diastereselective anti-aldol reaction leads to a highly efficient process for the total synthesis of lactacystin in quantity."J. Am. Chem. Soc. 1998, 120, 2330.Gosh, A. K.; Fidanze, S. "Asymmetric synthesis of (-)-tetrahydrolipstatin: An anti-aldol-basedstrategy." Org. Lett. 2000, 2, 2405-2407.Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. "Diastereoselective magnesium halide-catalyzed anti-aldol reactions of chiral N-acyloxyoxazolidinones." J. Am. Chem. Soc. 2002, 124,392-393.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, 8126-8127.

Assumed catalytic cycle:

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Double Diastereoselectivity

D. A. Evans, JACS 1985, 107, 4346.

Note: Reagent-based stereocontrol does not always superseedsubstrate control:

from: cytovaricin synthesis; Paterson, THL 1988, 29, 585.

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Evans Bispropionate SynthonKeck, G. E.; Lundquist, G. D., "Synthetic studies toward the total synthesis ofswinholide. 1. Stereoselective construction of the C19-C35 subunit." J. Org. Chem.1999, 64, 4482-4491.

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Paterson’s Ipc-Enolate (TH 1990, 46, 4663):

→ This strategy is particularly useful for aldol reactions of large, chiral fragments in macrolidesynthesis.

Catalytic Asymmetric Aldol: Eder-Sauer-Wiechert-Hajos Process

For a further development, see: List, B.; Lerner, R. A.; Barbas, C. F., "Proline-catalyzed direct asymmetricaldol reactions." J. Am. Chem. Soc. 2000, 122, 2395-2396.Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F. "Organocatalytic directasymmetric aldol reactions in water." J. Am. Chem. Soc. 2006, 128, 734-735.Storer, R. I.; Macmillan, D. W. C., "Enantioselective organocatalytic aldehyde-aldehyde cross-aldolcouplings. The broad utility of α-thioacetal aldehydes." Tetrahedron 2004, 60, 7705-7714.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 asymmetricorganocatalysis of aldol and related reactions: Rationalizations and predictions." Acc. Chem. Res. 2004, 37,558-569.

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