Catalytic enantioselective aldol addition

The advances that have taken place over the past five years in catalytic, enantioselective aldol addition reactions is evident in a number of important respects. The types of transition metals and their complexes that function competently as catalysts have been expanded considerably. Thus, in addition to B(III), Ag(I), Au(I), Sn(II), and La(III), chiral catalysts prepared from Cu(II), Ti(IV), Ln(III), Si(IV), Pt(II) and Pd(II) have been introduced. The expansion in the use of transition metals has taken place hand-in-hand with the design and synthesis of new bidentate and tridentate organic ligands based on nitrogen, oxygen, and phosphorus donors. Additionally, whereas the older methods primarily relied on the use of Lewis-acids for the activation of... 

Some of the most impressive advances in the area of catalytic, enantioselective aldol addition reactions have taken place in the development of catalytic methods for enantioselective acetate aldol additions, a reaction type that has long been recalcitrant. Thus, although prior to 1992 a number of chiral-auxiliary based and catalytic methods were available for diastereo- and enantiocontrol in propionate aldol addition reactions, there was a paucity of analogous methods for effective stereocontrol in the addition of the simpler acetate-derived enol silanes. However, recent developments in this area have led to the availability of several useful catalytic processes. Thus, in contrast to the state of the art in 1992, it is possible to prepare acetate-derived aldol fragments utilizing asymmetric catalysis with a variety of transition-metal based complexes of Ti(IV), Cu(II), Sn(II), and Ag(I). 

The BINAP silver(I) complex can be further applied as a chiral catalyst in the asymmetric aldol reaction. Although numerous successful methods have been developed for catalytic asymmetric aldol reaction, most are the chiral Lewis acid-catalyzed Mukaiyama aldol reactions using silyl enol ethers or ketene silyl acetals [32] and there has been no report which includes enol stannanes. Yanagisawa, Yamamoto, and their colleagues found the first example of catalytic enantioselective aldol addition of tributyltin enolates 74 to aldehydes employing BINAP silver(I) complex as a catalyst (Sch. 19) [33]. 

Carreira, E. M., Singer, R. A., Lee, W. Catalytic, Enantioselective Aldol Additions with Methyl and Ethyl Acetate 0-Sllyl Enolates A Chiral Tridentate Chelate as a Ligand for Titanium(IV). J. Am. Chem. Soc. 1994, 116, 8837-8838. 

In a landmark study of Mukaiyama aldol addition reactions, Heathcock proposed that the observed stereochemical outcome of the products in the Lewis acid-mediated addition of silyl ketene acetals to aldehydes was consistent with extended, open transition-state structures [38a, 38b]. This analysis has gained wide acceptance as a consequence of its predictive power. Alternative models involving cyclic, closed structures have also been postulated, in particular, the latter have been invoked with increasing regularity in the analyses of catalytic, enantioselective aldol addition reactions [7,30b,39a,39b. ... 

Recently, catalytic, enantioselective aldol addition reactions have been reported which are proposed to proceed through mechanistic pathways involving... 

In contrast to the mechanism discussed in the previous section, catalytic, enantioselective aldol addition processes have been described which proceed through an intermediate aldolate that undergoes subsequent intermolecular silylation. Denmark has discussed this possibility in a study of the triarylmethyl-cation-catalyzed Mukaiyama aldol reaction (Scheme 10) [73]. The results of exploratory experiments suggested that it would be possible to develop a competent catalytic, enantioselective Lewis-acid mediated process even when strongly Lewis acidic silyl species are generated transiently in the reaction mixture. A system of this type is viable only if the rate of silylation of the metal aldolate is faster than the rate of the competing silyl-catalyzed aldol addition reaction (ksj>> ksi-aidoi Scheme 10). A report by Chen on the enantioselective aldol addition reaction catalyzed by optically active triaryl cations provides support for the mechanistic conclusions of the Denmark study [74]. 

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]. 

Preliminary examples of catalytic enantioselective aldol additions using rhodium complexes with chiral phosphine ligands attached, e.g. (42), have been disclosed by Reetz and Vougioukas (equation 15) although the low level of asymmetric induction so far obtain in the silylated aldol adduct (43) requires substantial enhancement before this reaction has any synthetic value. However, there is ample scope for future improvement by the use of more effective chiral diphosphine- odium complexes. 

Evans DA, Kozlowski MC, Bnrgey CS, MacMillan DWC (1997) C2-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Catalytic Enantioselective Aldol Additions of Enolsilanes to Pyruvate Esters. J Am Chem Soc 119 7893... 

Evans, D.A., Kozlowski, M.C., Murry, J.A., Burgey, C.S., Campos, K.R., Connell, B.T., and Staples, R.J. (1999) C-2-symmetric copper(ll) complexes as chiral Lewis acids. Scope and mechanism of catalytic enantioselective aldol additions of enolsilanes to (benzyloxy)acetaldehyde. /. Am. Chem. Soc.. 121, 669-685. 

Evans DA, Murry JA. Kozlowski MC. C2-symmetric copper (II) complexes as chiral Lewis acids. Catalytic enantioselective aldol additions of silylketene acetals to (benzyloxy)acet-aldehyde. 7. Aw. Chem. Soc. 1996 118 5814-5815. 

Hayashi s and Ito s 1986 disclosure of a catalytic, enantioselective aldol addition involving isocyanoacetates represents an important landmark in the field (Scheme 4.3) [18, 40). The gold-catalyzed process was revealed to pro-... 

In 1991, Yamamoto reported a simple catalyst for aldol reactions consisting of a chiral (acyloxy)borane (CAB) complex of tartrate-derived ligands (241, Scheme 4.28) [120-122]. This work, along with that of Mukaiyama and Kobayashi, stunningly showed that remarkably simple complexes for catalytic enantioselective aldol addition reactions could be identified. Both enantiomers of the catalyst are readily accessible from the enantiomers of tartaric acid. The syn aldol adducts were observed to be preferentially formed regardless of the enolate geometry (242 vs. 244) with high levels of enantios-... 

The enantioselective aldol addition reactions mediated by BINOL/TiCl (Ot-Pr)4, j complexes as catalysts are highly attractive because of the convenient accessibility of the catalyst components along with the unique substrate scope they display [130-135]. These were developed by Keck and Mikami. Two catalyst preparations, involving BINOL and either TiCl2(Oi-Pr)2 [130] or Ti(Oi-Pr)4 [133], have been dociunented. Both of these furnish aldol adducts with excellent yields and enantioselectivities (Scheme 4.31). The fact that these compounds can mediate aldol additions to a wide range of functionalized aldehydes, such as trifluoroacetaldehyde [132] and chloroacetalde-hyde [131], is impressive, as these are rare substrates in catalytic, enantioselective aldol addition reactions (Scheme 4.32). Additionally, aldehydes such... 

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