Syn-Selective Aldol Additions

Syn selective aldol additions of titanated aldehyde hydrazones and ketone hydrazones have been reported by Reetz. The observed syn selectivity parallels the syn selectivity seen in titanium ketone eno-iates, and the intermediate titanium aldehyde hydrazone derivatives were seen to have ( )c—c geometry (equation 17). 

Titanium enolates have also been obtained by direct deprotonation from ketones and imides upon treatment of titanium tetrachloride in the presence of tertiary amines, preferably, Hiinig s base. As they have been found to be efficient in syn-selective aldol additions [120], their configuration has been assumed to be cis, but they were rarely characterized by NMR spectroscopy. For the titanium enolate derived from Evans-type auxiliaries, the relative ratio of base to titanium tetrachloride was found to have a distinct impact on the selectivity in the addition to aldehydes. This effect has been rationalized by postulating an equilibrium between the tetrachlorotitanate 106/titanium tetrachloride and the titanium enolate 107/pentachlorotitanate, as supported by NMR studies (Scheme 2.30) [121]. Several chiral ketones have been converted into the corresponding cis-enolates by treatment with TiClgOiPr in the presence of Hiinig s base [122]. Titanium tetrachloride and trialkylamines also lead to aldehyde enolates and enable directed aldol additions between aldehydes. This is remarkable in view of the fact that preformed enolates of aldehydes are not readily accessible [123]. 

Scheme 4.46 Evans-syn" selective aldol addition of valine-derived N-propionyl oxazolidinone 48 via boron enolate 208. Dipole-minimized transition state model 210.

Ruiz, M., Ojea, V., Quintela, J. M. Computational study of the syn,anti-selective aldol additions of lithiated bis-lactim ether to 1,3-dioxolane-4-carboxaldehydes. Tetrahedron Asymmetry 2002,13, 1863-1873. 

Gosh has independently reported a second and-selective aldol addition process (Eq. (8.4)) [6]. Amino indanol derived esters such as 11 are enolized with excess TiCl4 (2 equiv) and Hiinig s base to furnish a brown solution consisting exclusively of the Z-enolate as determined by H NMR spectroscopy. Addition of aldehyde (2 equiv) at -78 °C affords the corresponding aldol adducts 12/13 in 44-97% yield and up to 99 1 antitsyn diastereoselectivity. The optimal substrates in the addition reaction include aliphatic and unsaturated aldehydes. It is interesting to note that the only aromatic aldehyde examined, benzaldehyde, yielded products as a 1 1.l mixture of antv.syn diastereomers. 

Trichlorotitanium enolates are formed in variable yield from trimethylsilyl enol ethers and an equivalent of TiCU in dichloromethane at 20-35 C. These highly Lewis acidic preformed enolates then undergo aldol reactions at -70 C to give moderate levels of syn selectivity, as in equation (13). Trichlorotitanium enolates have also been used by Reetz et al. in their studies on diastereofacially selective aldol additions to a-alkoxy aldehydes.Trichlorotitanium enolates are formed in situ in the aldol reaction of aromatic ketones and aldehydes using TiCU and EtsN. ... 

In 2007, Barbas III and co-workers reported the 5y -selective aldol addition of DHA 55 to various aldehydes catalyzed by 0-fBu-threonine [105]. It should be noted that products were acetylated brfore purification and according to the authors modifications to the product isolation procedure would increase yields. The reaction worked nicely for aromatic aldehydes but not for aliphatic analogs. Through the optimization of the reaction conditions, Gong and Cheng used amine 84 to generate. syw-aldols syn-56 from aromatic aldehydes in a stereoselective manner (Chart 3.12). [97, 106, 76]. 

Chiral alcohol 73 was synthesized using the Evans aldol reaction and provided the syn-selective aldol adduct (95 5) in 52% yield in the haloacetyl aldol reaction during the total synthesis of (-)-clavosolide B. The chlorine atom was removed by treatment of Zn/NH4C1 in methanol, providing an additional example of an acetate aldol equivalent. 

A highly diastereoselective anti aldol addition utilizing a variety of N-glycolyloxazolidinethiones has been developed by Crimmins. Enolization of an Atglycolyoxazlidinethione with titanium(IV) chloride and (-)-sparteine followed by the addition of an aldehyde activated with additional TiCU resulted in highly anti-selective aldol additions, typically with no observable syn isomers. 

Gosh independently reported another anti-selective aldol addition process employing aminoindanol-derived esters 114 (Equation 11) [72]. These were subjected to enolization with excess TiCl, and Hiinig s base to furnish titanium 2-enolates, as determined by NMR spectroscopy. Addition reactions with a variety of aliphatic and unsaturated aldehydes, precomplexed with TiCl4, furnished the anti aldol adducts such as 116 in 44—97% yields and up to 99 1 anti/syn ratios of diastereomers. The stereochemical outcomes of the reactions have been attributed to chelated Zimmerman-Traxler transition state structures, such as 115. It is interesting to note that benzaldehyde, as the only aromatic aldehyde examined, yielded a 1 1.1 mixture of antijsyn products. 

Tin enolates are also used in aldol reactions.27 Both the Sn(II) and Sn(IV) oxidation states are reactive. Tin(II) enolates can be generated from ketones and Sn(II)(03SCF3)2 in the presence of tertiary amines.28 The subsequent aldol addition is syn selective and independent of enolate configuration.29 This preference arises from avoidance of gauche interaction of the aldehyde group and the enolate P-substituent. The syn stereoselectivity indicates that reaction occurs through an open TS. 

In the case of methyl vinyl ketone (MVK), similar reactivity is observed. Exposure of MVK (150 mol%) and p-nitrobenzaldehyde to basic hydrogenation conditions provides the corresponding aldol product in good yield, though poor dia-stereoselectivity is observed [24a]. Remarkably, upon use of tris(2-furyl)phos-phine as ligand and Li2C03 as basic additive, the same aldol product is formed with high levels of syn-selectivity [24 e]. Addition of MVK to activated ketones such as l-(3-bromophenyl)propane-l,2-dione is accomplished under similar con-... 

From these and related examples, the following generalizations have been drawn about kinetic stereo selection in aldol additions.9 (1) The chair transition-state model provides a basis for explaining the stereoselectivity observed in aldol reactions of ketones having one bulky substituent. The preference is Z-enolate —> syn aldol E-enolate —> anti aldol. (2) When the enolate has no bulky substituents, stereoselectivity is low. (3) Z-Enolates are more stereoselective than E-enolatcs. Table 2.1 gives some illustrative data. 

Aldol reactions.1 Several exotic boron derivatives have been used to prepare boron enolates, of particular interest because of their use for selective syn-aldol reactions. Actually boron enolates can be generated using BC13 and Hiinig s base. Dichloroboron enolates are unusually reactive even at -95°, and show syn-selectivity of 80-95%. Aldol reactions are carried out in CH2C12 by mixing the ketone and BC13 (1 2 equiv.) followed by addition of the base (2 equiv.) and the aldehyde (1 equiv.). Yields are 80-95%. 

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. 

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