Diastereoselective aldol addition

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

Scheme 6.32 y-Butenolides obtained from diastereoselective aldol addition of 2-trimethylsilyloxyfuran to aldehydes catalyzed by urea 32. 

With meso-conflgured dialdehyde precursors, the enantiotopic nature of the termini must give rise to a conflgurational terminus differentiation upon twofold chain extension because the catalyst-controlled diastereoselective aldol additions will break the inherent o symmetry. While the two enantiotopic termini cannot... 

To connect the C2 and C3 atoms of the 1-hydroxyethylene moiety, Wuts et al.[341 and Poss and Reid 35 used the Wadsworth-Emmons reaction between a (3-amino-a-hydroxy-aldehyde and a phosphonate (two-carbon fragment) to give the desired isostere after reduction of the alkene. In the synthesis reported by Poss and Reid (Scheme 17) the stereochemistry of the hydroxyl group at C4 is established by a highly diastereoselective aldol addition to furan. A slight modification was employed by Chakravarty et all36 and Plata et al.[37 where 4-amino-3-oxo phosphonates were reacted with an aldehyde or ketone form of the two-carbon fragment. 

The problem of diastereoselective aldol addition has been largely solved48,108). Under kinetic control Z enolates favor erythro adducts and E enolates the threo diastereomers, although exceptions are known. This has been explained on the basis of a six-membered chair transition state in which the faces of the reaction partners are oriented so as to minimize 1,3 axial steric interactions 481108). This means that there is no simple way to prepare erythro aldols from cyclic ketones, since the enolates are geometrically fixed in the E geometry. 

Highly diastereoselective acetate aldol additions using chlorotitanium enolates of mesityl-substituted JV-acetylthiazolidinethione 136 has been documented <07OL149>. These aldol reactions proceed in high yields and diastereoselectivities (94/6 to 98/2) for aliphatic, aromatic, and a,P-unsaturated aldehydes. Compound 136 also undergoes double diastereoselective aldol additions with chiral aldehyde 139 to give adduct 140 in high yields. 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

New auxiliaries and reaction methods are now available for the stereoselective synthesis of all members of the stereochemical family of propionate aldol additions. These also include improvements on previously reported methods that by insightful modification of the original reaction conditions have led to considerable expansion of the versatility of the process. In addition to novel auxiliary-based systems, there continue to be unexpected observations in diastereoselective aldol addition reactions involving chiral aldehyde/achiral enolate, achiral aldehyde/chir-al enolate, and chiral aldehyde/chiral enolate reaction partners. These stereochemical surpri.ses underscore the underlying complexity of the reaction process and how much we have yet to understand. 

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. 

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>. 

The most intensely studied aldol addition mechanisms are those beUeved to proceed through closed transition structures, which are best understood within the Zimmerman-Traxler paradigm (Fig. 5) [Id]. Superposition of this construct on the Felkin-Ahn model for carbonyl addition reactions allows for the construction of transition-state models impressive in their abiUty to account for many of the stereochemical features of aldol additions [50a, 50b, 50c, 51]. Moreover, consideration of dipole effects along with remote non-bonding interactions in the transition-state have imparted additional sophistication to the analysis of this reaction and provide a bedrock of information that may be integrated into the further development and refinement of the corresponding catalytic processes [52a, 52b]. One of the most powerful features of the Zimmerman-Traxler model in its application to diastereoselective additions of chiral enolates to aldehydes is the correlation of enolate geometry (Z- versus E-) with simple di-astereoselectivity in the products syn versus anti). Consequently, the analyses of catalytic, enantioselective variants that display such stereospecificity often invoke closed, cyclic structures. Further studies of these systems are warranted, since it is not clear to what extent such models, which have evolved in the context of diastereoselective aldol additions via chiral auxiliary control, are applicable in the Lewis acid-catalyzed addition of enol silanes and aldehydes. 

Diastereoselective Aldol Additions of Chiral Silyl Ketene Acetals and Chiral Silyl Enol Ethers... 

Solladie-Cavallo, A. and Crescenzi, B. (2000) Full conversion in diastereoselective aldol additions using naked enolates under catal3dic amount of phosphazene base the hydroxypi-nanone as chiral auxiliary. Synlett, 327-330 Sohadie-Cavallo, A., Koessler, J.-L., Isarno, T. et al. (1997). The hydrox3fpinanone as chiral auxiliary in Michael additions an inversion of diastereoselectivity at low concentration of enolate, a substrate-directed approach. Synlett, 217-218. 

Reaction of 132 with the esterenolate 137 results in diastereoselective aldol addition, which is followed by a Brook rearrangement and cyclization to yield... 

Denmark SE, Fujimori S (2002) Diastereoselective aldol additions of chiral beta-hydroxy ethyl ketone enolates catalyzed by Lewis bases. Org Lett 4 3473-3476... 

Denmark SE, Pham SM (2001) Highly diastereoselective aldol additions of a chiral ethyl ketone enolate under lewis base catalysis. Org Lett 3 2201-2204... 

Denmark SE, Fujimori S (2000) Diastereoselective aldol addition reactions of a chiral methyl ketone trichlorosilyl enolate under lewis base catalysis. Synlett 1024—1029... 

Diastereoselective aldol addition of lithiated (pentafluorophenyl)diphenyl-substituted acetyl iron complexes 78. Transition state model 81. 

B. Development of kinetic diastereoselective aldol addition variants through the discovery of optimal metal architectures [B(III), Ti(IV), Sn(II)]. 

---