Evans aldol addition

One of the most successful and widely used methods for diastereoselective aldol addition reactions employs Evans imides 17 and the derived dialkyl boryleno-lates [8J. The 1,2-svn aldol adducts are typically isolated in high diastereoisomeric purity (>250 1 dr) and useful yields. More recent investigations of Ti(IV) and Sn(II) enolates by Evans and others have considerably expanded the scope of the aldol process [9], In 1991, Heathcock documented that diverse stereochemical outcomes could be observed in the aldol process utilizing acyl oxazolidinone imides by variation of the Lewis acid in the reaction mixture [10]. Thus, for example, in contrast to the, l-syn adduct (21) isolated from traditional Evans aldol addition, the presence of excess TiCL yields the complementary non-Evans 1,2-syn aldol diastereomer. This and related observations employing other Lewis acids were suggested to arise from the operation of open transition-state structures wherein a second metal independently activates the aldehyde electrophile. 

In 1988 Heathcock reported the Johnson, Eschenmoser and Ireland-Claisen rearrangements of ketene acetals derived from chiral non-racemic allyUc alcohols (Scheme 4.23) [25]. The alcohols were themselves derived from Evans aldol additions. While the Johnson and Eschenmoser rearrangements were used to iUus-... 

Scheme 4.47 Evans aldol addition with phenylalanine-derived imide 73 and cleavage of...

Scheme 5.69 Stereodivergent Evans aldol addition mediated by copper complex 216a and tin complex 218. Model 233 for rationalizing the topicity in the copper-BOX-catalyzed aldol...

Related catalytic enantioselective processes [84] As the examples in Scheme 6.26 show, a wide variety of catalytic asymmetric aldol additions have been reported that can be considered as attractive alternatives to the Zr-catalyzed process summarized above. The Ti-cata-lyzed version due to Carreira (84) [85], the Cu-catalyzed variant of Evans (85) [86], and the protocol reported by Shibasaki (86) [87] have all been used in syntheses of complex molecules. More recently, Trost (87) [88] and Shibasaki (88) [89] have developed two additional attractive asymmetric catalytic aldol protocols. Other related technologies (not represented in Scheme 6.26) have been described by Morken [90] and Jorgensen [91]. 

Scheme 10. Cu-catalyzed asymmetric aldol addition used in the enantioselective total synthesis of bryostatin 2 by Evans (1998).

D. A. Evans, P. H. Carter, E M. Carreira, J. A. Pmnet, A. B. Charette, M. Lautens Asymmetric Synthesis of Bryosta-tin 2 , Angew. Chem, Int. Ed. Engl. 1998,37,2354-2359. For methodological studies on asymmetric Cu-catalyzed aldol addition, see D. A. Evans, J. Murry, M. C. Koz-lowski C2-Symmetric Cu(II) Complexes as Chiral Lewis Adds. Catalytic Enantiosdective Aldol Additions of Silylketene Acetals to (Benzyloxy)acetaldehyde , J. Am Chem. Soc 1996,118,5814-5815. 

Alkylation of Enolates Asymmetric syntheses involving enolate reactions such as alkylations, aldol additions and acylations in which the chiral auxiliary A -H is both readily obtained and easily recoverable after the desired bond construction had been achieved by Evans et al.175). 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

Cu(II) and Sn(II) Bisoxazolinc Complexes. Evans has prepared and studied a family of Cu(II) complexes prepared from bisoxazoline ligands [8]. Utilizing these complexes a number of different addition reactions can be successfully conducted on pyruvate, benzyloxyacetalde-hyde, and glyoxylates. Whereas the focus of the work in the context of aldol addition reactions has been on the use of silyl ketene acetals (vide infra), the addition of ketone-derived enoxy silanes 8a-b with methyl pyruvate has been examined (Eq. 8B2.1). The additions of 8a-b proceed in the presence of 10 mol % Cu(II) catalyst at -78°C in CH2Cl2, affording adducts of acetophenone 9a and acetone 9b with 99% and 93% ee, respectively. 

Impressive advances in catalytic, enantioselective propionate aldol addition reactions have also been documented since 1992. Mikami has described a Ti(lV) catalyst readily prepared from BINOL and TiC O Pr. A propionate aldol addition process by Evans utilizes complexes prepared with bisoxazoline ligands and Sn(II) and Cu(II). In analogy to the acetate aldol... 

The Evans Cu(II)- and Sn(II)-catalyzed processes are unique in their ability to mediate aldol additions to pyruvate. Thus, the process provides convenient access to tertiary a-hydroxy esters, a class of chiral compounds not otherwise readily accessed with known methods in asymmetric catalysis. The process has been extended further to include a-dike-tone 101 (Eqs. 8B2.22 and 8B2.23). It is remarkable that the Cu(II) and Sn(II) complexes display enzyme-like group selectivity, as the complexes can differentiate between ethyl and methyl groups in the addition of thiopropionate-derived Z-silyl ketene acetal to 101. As discussed above, either syn or anti diastereomers may be prepared by selection of the Cu(II) or Sn(II) catalyst, respectively. 

This reaction is a formal asymmetric aldol addition following a modified Evans protocol. The enolate 26 is formed at 0 °C in the presence of one equivalent of titanium tetrachloride as Lewis acid and two equivalents diisopropylethylamine (Hunig s base) as proton acceptor. Selectively the Z-enolate is formed. The carbon-carbon bond formation takes place under substrate control of the Tvan.v-auxiliary, whose benzyl group shields the, v/-face of the enolate. 

The addition of a chiral ketone enolate to an aldehyde displays not only simple diastereoselectivlty, but also highly induced stereoselectivity, as shown by Fecik and coworkers for the formal total synthesis of the polyketide macrolactone narbonoMe (92, equation 27). This reaction demonstrates the successful application of titanium in aldol additions for the highly stereoselective construction of two new stereogenic centers by addition of aldehyde 90 to the titanium enolate of Evans S-keto imide 89 the iyw-aldol product 91 was obtained exclusively in 74% yield. Interestingly, there is no detectable loss of stereochemistry via enolization at the potentially labile C2-methyl-bearing stereocenter in 89 ... 

Non-Evans Aldol Reactions. Either the syn- or onri-aldol adducts may be obtained from this family of imide-derived eno-lates, depending upon the specific conditions employed for the reaction. Although the illustrated boron enolate affords the illustrated jyn-aldol adduct in high diastereoselectivity, the addition reactions between this enolate and Lewis acid-coordinated aldehydes afford different stereochemical outcomes depending on the Lewis acid employed (eq 35). Open transition states have been proposed for the Diethylaluminum Chloride mediated, anti-selective reaction. These anfi-aldol reactions have been used in kinetic resolutions of 2-phenylthio aldehydes. ... 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

To date, two total syntheses of myriaporone 4 are known. This chapter is based on the total synthesis of myriaporone 4 published by Taylor et al. in 2004. The synthesis of a chiral precursor, which has also been employed for the total synthesis of related compounds, was published by the same group in 1998. The linear total synthesis starts with an enantiomerically pure molecule from the chiral pool that delivers the stereogenic center at C-12 of the final product, employs Evans aldol reactions as key steps for stereoselective chain elongations and additionally includes reduction/oxidation steps as well as protecting group chemistry. 

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply demonstrated in a recent enantioselective synthesis of apoptolidinone. This synthesis features three thiazolidinethione propionate aldol reactions for controlling the configuration of 6 of 12 stereogenio centers <05JA13810>. For example, addition of aldehyde 146 to the enolate solution of A -propionyl thiazolidinethione 145 produces aldol product 147 with excellent selectivity (>98 2) for the Evans syn isomer. Compound 145 also undergoes diastereoselective aldol addition with bisaryl aldehyde 148 to give the Evans syn product 149, which is converted to eupomatilone-6 in 6 steps <05JOC9658>. 

Though either enantiomer of a yyn-aldol can be made by using the right auxiliary in an Evans aldol reaction the anti aldols cannot be made this way. The addition of a Lewis acid catalyst transforms the situation.13 Using the valine-derived chiral auxiliary 89, the same Z-boron enolate 111 is used but the aldehyde is added in the presence of a threefold excess of the Lewis acid Et2AlCl. The product is predominantly one enantiomer of an anh-aldol 112. 

In suitable cases the application of stoichiometric chiral auxiliaries may be advantageous even on the industrial kilogram-scale. Scheme 49 provides as an example the synthesis of a thromboxane antagonist (ICI D1542) via the Evans aldol strategy [114]. Thus, the chiral auxiliary 49-1 is converted into the amide 49-3 and then submitted to a boron mediated aldol addition leading to 49-4 in dias-tereomerically pure crystalline form. The auxiliary is removed by reduction and... 

The use of Cu(II) complexes as Lewis acid catalysts for the Mukaiyama aldol addition reaction has been documented and studied by Evans [120a, 120b, 121a,... 

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