Aldol addition reaction stereoselectivity

Despite the ability to control ester enolate geometry, the aldol addition reactions of unhindered ester enolate are not very stereoselective.37... 

Among the most useful carbonyl derivatives are (V-acyloxazolidinones, and as we shall see in Section 2.3.4, they provide facial selectivity in aldol addition reactions. l,3-Thiazoline-2-thiones constitute another useful type of chiral auxiliary, and they can be used in conjunction with Bu2B03SCF3,44 Sn(03SCF3)2,45 or TiCl446 for generation of enolates. The stereoselectivity of the reactions is consistent with formation of a Z-enolate and reaction through a cyclic TS. 

The Mukaiyama aldol reaction can provide access to a variety of (3-hydroxy carbonyl compounds and use of acetals as reactants can provide (3-alkoxy derivatives. The issues of stereoselectivity are the same as those in the aldol addition reaction, but the tendency toward acyclic rather than cyclic TSs reduces the influence of the E- or Z-configuration of the enolate equivalent on the stereoselectivity. 

A DFT study found a corresponding TS to be the lowest energy.167 This study also points to the importance of the solvent, DMSO, in stabilizing the charge buildup that occurs. A further computational study analyzed the stereoselectivity of the proline-catalyzed aldol addition reactions of cyclohexanone with acetaldehyde, isobu-tyraldehyde, and benzaldehyde on the basis of a similar TS.168 Another study, which explored the role of proline in intramolecular aldol reactions, is discussed in the next section.169... 

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. 

In several recent applications of enzyme catalysis, the snbstrates on which the enzymes act are not the kind of snbstrates that are natnral to the enzyme. However, enzyme catalysed synthesis of hexoses in the laboratory depends solely on enzymes acting on natural or near natnral snbstrates. The relevant enzymes are the aldolases (EC 4.1.2 aldehyde-lyases) since they catalyse an aldol type of C-C bond forming aldol addition reaction. The aldolases most commonly join two C-3 units, called donor and acceptor, and two new stereocentra are formed with great stereoselectivity. 

These reactions are divided into two sections. In the former, representative examples of organic electrophiles, which can be used in reactions with magnesium ketone enolates, are summarized. The second section shows that magnesium ketone enolates can be employed as interesting alternatives to their more known lithium counterparts in aldol addition reactions. This part is discussed in terms of regio- and stereoselectivity. 

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. 

Methyl-2-trimethylsilyloxypentan-3-one (1) is the prototype member of a series of a-trimethyls1lyloxy ketones that are useful for stereoselective aldol addition reactions (eq l).2 6-Hydroxy ketones 2 may be converted into 6-hydroxy acids,2 g-hydroxy aldehydes, and other e-hydroxy ketones. ... 

A number of methods have been developed for accomplishing aldol addition reactions in a stereoselective manner. The preformed lithium enolates of alkyl esters normally react with aldehydes to give mixtures of the two diastereomeric g-hydroxy esters (eq 1). However, the enolates derived from... 

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. 

The pioneering discovery by Mukaiyama in 1974 of the Lewis acid mediated aldol addition reaction of enol silanes and aldehydes paved the way for subsequent explosive development of this innovative method for C-C bond formation. One of the central features of the Mukaiyama aldol process is that the typical enol silane is un-reactive at ambient temperatures with typical aldehydes. This reactivity profile allows exquisite control of the reaction stereoselectivity by various Lewis acids additionally, it has led to the advances in catalytic, enantioselective aldol methodology. Recent observations involving novel enol silanes, such as enoxy silacyclobutanes and O-si-lyl M(9-ketene acetals have expanded the scope of this process and provided additional insight into the mechanistic manifolds available to this versatile reaction. 

A series of innovative investigations by Kiyooka and co-workers have introduced the use of tandem reaction processes that commence with a stereoselective aldol addition reaction and are followed by C=0 reduction [13]. A chiral oxazaboroli-dine complex prepared from BH3-THF and A-/ -toluenesulfonyl (L)-valine controls the absolute stereochemical outcome of the aldol reaction. In a subsequent reaction, the /i-alkoxyboronate effects intramolecular reduction of the ester to furnish the corresponding /i-hydroxy aldehyde. 

Many interesting, powerful applications of inter- and intra-molecular aldol addition reactions have been reported in the context of complex molecule synthesis. These demonstrate the power of aldol bond construction in providing rapid access to stereochemically complex fragments in a stereocontrolled manner. While a comprehensive review of these is well beyond the scope of any one chapter, some recent examples merit examination as they provide insight into interesting and unusual reaetivities that may result in the design of novel stereoselective aldol processes. 

Danishefsky has proposed that the unusual behavior of the unsaturated aldehyde as substrate is accounted for by an energetically stabilizing interaction between polarized aldehyde carbonyl and olefin Ti-electrons. The seemingly parallel behavior of similarly functionalized aldehydes Is consistent with this proposal. This type of electronic stabilization may prove general, offering innovative avenues for the future design of stereoselective aldol addition reactions. 

The same bisoxazoline Cu(II) and Sn(II) complexes have been utilized successfully in the corresponding propionate aldol addition reactions (Scheme 8-7). A remarkable feature of these catalytic processes is that either syn or anti simple dia-stereoselectivity may be accessed by appropriate selection of either Sn(II) or Cu(II) complexes. The addition of either - or Z-thiopropionate-derived silyl ke-tene acetals catalyzed by the Cu(II) complexes afford adducts 78, 80, and 82 displaying 86 14-97 3 syn anti) simple diastereoselectivity. The optical purity of the major syn diastereomer isolated from the additions of both Z- and i -enol silanes were excellent (85-99% ee). The stereochemical outcome of the aldol addition reactions mediated by Sn(Il) are complementary to the Cu(U)-catalyzed process and furnish the corresponding anp -stereoisomers 79, 81, and 83 as mixtures of 10 90-1 99 syn/anti diastereomers in 92-99% ee. 

Evans has recently reported the use of structurally well-defined Sn(II) Lewis acids 119 and 120 (Fig. 9)for the enantioselective aldol addition reactions of a-heterosubstituted substrates [83]. These complexes are easily assembled from Sn(OTf)2 and C2-symmetric bisoxazoline Hgands 124 and 126 (Fig. 10). The facile synthesis of these ligands commences with optically active 1,2-amino alcohols 122, which are themselves readily available from the corresponding a-amino acids 121 [84, 85]. The Sn(II) bis(oxazoHne) 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, using 10 mol % of 119, thioacetate and thiopropionate derived silyl ketene acetals add at -78 °C in CH2CI2 to glyoxaldehyde to give hydroxy diesters 130 in superb yields and enantioselectivities as well as diastereo-selectivities (Eq. 12). The process represents an unusual example wherein 2,3-anti-aldol adducts are obtained in a stereoselective manner. 

The addition reaction of fert-butyl thioacetate-derived silyl ketene acetal produces the corresponding aldol adducts in 84% yield and up to 96% enantiomeric excess (Eq. 16). The enantioselectivity of the products was observed to be optimal with toluene as solvent the use of the more polar dichloromethane consistently produced adducts with 10-15% lower enantiomeric excess. The bulkier ferf-butylthioacetate-derived enol silane was found to lead to uniformly higher levels of enantioselectivity than the smaller S-ethyl thioketene acetal. This process is impressive in that it tolerates a wide range of aldehyde substrates for instance, the aldol addition reaction has been successfully conducted with aldehydes substituted with polar functionaUty such as N-Boc amides, chlorides, esters, and 0-benzyl ethers. A key feature of this system when compared to previously reported processes was the abiUty to achieve high levels of stereoselectivity at 0 °C, in contrast to other processes that commonly prescribe operating temperatures of -78 °C. 

The catalytic, enantioselective aldol addition reaction generates products that can serve as versatile precursors to useful building blocks for asymmetric synthesis (Eq. 26). For example, treatment of cinnamaldehyde adduct 177 with LiAl(HNBn)4178 afforded the crystalline amide 179 (73%). Heating in -BuOH converted 177 to ester 180 (81%). Heating in alkaline methanol yielded (79%) the crystalline lactone 181. The synthetic utility of adducts 179 and 180 is enhanced by the stereoselective reaction methods that have been developed for their reduction to the corresponding syn and anti 3,5-diols [103,104]. 

The aldol addition reaction, and the related crotyl metal additions (section 5.1), have figured prominently in the total synthesis of a number of complex natural products (reviews [48,140-142]). Figure 5.8 illustrates those mentioned in the preceding discussion, along with others selected from the recent literature, with the stereocenters formed by stereoselective aldol addition indicated ( ). For the Prelog-Djerassi lactone and ionomycin, recall (Figure 3.8) that most of the other stereo-centers were formed by asymmetric enolate alkylation. 

Aldolases are a group of C—C bond forming enzymes with widespread applications. The stereoselective aldol addition reaction catalyzed by aldolases represents an attractive alternative to conventional chiral organic chemistry methods for chemical and pharmaceutical industries. Aldolases are classified according to both their proposed catalytic mechanism and the structure of the donor substrate, their sources and microbial production processes being presented in this chapter. To design appropriate bioreactors for aldol synthesis, the characteristics of aldolase biocatalysts obtained after purification procedures in free and immobilized form are discussed. 

Asymmetric C-C bond formation based on catalytic aldol addition reactions remains one of the most challenging subjects in synthetic organic chemistry. Although many successful nonbiological strategies have been developed [1355, 1356], most of them are not without drawbacks. They are often stoichiometric in auxiliary reagent and require the use of a metal or organocatalytic enolate complex to achieve stereoselectivity [1357-1360]. Due to the instability of such complexes... 

Control of Enantioselectivity. In the previous sections, the most important factors in determining the syn or anti stereoselectivity of aldol and Mukaiyana reactions were identified as the nature of the transition state (cyclic versus acyclic) and the configuration (E or Z) of the enolate. Additional factors affect the enantioselectivity of aldol additions and related reactions. Nearby chiral centers in either the carbonyl compound or the enolate can impose facial selectivity. Chiral auxiliaries can achieve the same effect. Finally, use of chiral Lewis acids as catalysts can also achieve enantioselectivity. Although the general principles of control of the stereochemistry of aldol addition reactions have been developed for simple molecules, the application of the principles to more complex molecules and the selection of the optimum enolate system requires analysis of the individual cases.Not infrequently, one of the enolate systems proves to... 

Here we recount the latest research on chemoenzymatic multistep and cascade strategies for the synthesis of iminocyclitols, carbohydrates, and deoxysugars from N-protected ami noaldehydes, hydroxyaldehydes, and simple alkylaldehydes, respectively. The key step in all of them is the stereoselective aldol addition reaction of dihydroxyacetone phosphate (DHAP) and its unphosphorylated analogs to the acceptor aldehydes using DH AP-dependent and dihydroxyacetone- (DH A)-utilizing aldolases, respectively, as biocatalysts. 

The aldol reaction is one of the most useful carbon-carbon bond forming reactions in which one or two stereogenic centers are constructed simultaneously. Diastereo-and enantioselective aldol reactions have been performed with excellent chemical yield and stereoselectivity using chiral catalysts [142]. Most cases, however, required the preconversion of donor substrates into more reactive species, such as enol silyl ethers or ketene silyl acetals (Scheme 13.45, Mukaiyama-type aldol addition reaction), using no less than stoichiometric amounts of silicon atoms and bases (Scheme 13.45a). From an atom-economic point of view [143], such stoichiometric amounts of reagents, which afford wastes such as salts, should be excluded from the process. Thus, direct catalytic asymmetric aldol reaction is desirable, which utilizes unmodified ketone or ester as a nucleophile (Scheme 13.45b). Many researchers have directed considerable attention to this field, which is reflected in the increasing... 

The topic of the stereoselectivity of aldol condensation reactions has received much attention recently owing to efforts directed toward the total synthesis of macrolide antibiotics. The carbon backbone of many of these substances may be viewed as capable of being derived by combinations of several aldol additions. Because of the number of chiral centers, it is necessary that a high level of stereochemical control be achieved in the carbon-carbon bond-forming steps. Hence, a number of fundamental studies have been concerned with stereoselection in aldol addition reactions. 

DHAP-dependent aldolases constitute a set of four stereocomplementary enzymes that catalyze stereoselectively the reversible aldol addition reaction of DHAP to a large variety of aldehyde acceptors. Among them, D-fructose-l,6-phosphate aldolase... 

---