Aldol absolute stereocontrol

These reactions imply an aldol condensation following the initial Michael addition. Two examples in which absolute stereocontrol over three or four new stereogenic centers is achieved in a single operation illustrate the potential of these methods. 

The key observation was that L-proline would catalyze the addition of a-hetero aldehydes to a-branched aldehydes such as 2 to give the aldol product 3 with high cnantio- and diastereocontrol. Even more exciting, in the absence of other acceptors the a-hetero aldehydes dimerize with high relative and absolute stereocontrol. Both alkoxy and silyloxy aldehydes worked efficiently. 

High anti-diastereoselectivity is observed for several aromatic imines for ortho-substituted aromatic imines the two newly formed stereocenters are created with almost absolute stereocontrol. Aliphatic imines can also be used as substrates and the reaction is readily performed on the gram scale with as little as 0.25 mol% catalyst loading. Furthermore, the Mannich adducts are readily transformed to protected a-hydroxy-/8-amino acids in high yield. The absolute stereochemistry of the Mannich adducts revealed that Et2Zn-linked complex 3 affords Mannich and aldol adducts with the same absolute configuration (2 R). However, the diastereoselectiv-ity of the amino alcohol derivatives is anti, which is opposite to the syn-l,2-diol aldol products. Hence, the electrophiles approach the re face of the zinc enolate in the Mannich reactions and the si face in the aldol reactions. The anti selectivity is... 

In addition to their use with the traditional enoxysilanes derived from ketones and esters, the bisoxazoline catalysts have been shown to mediate aldol-like additions between chelating aldehydes and 5-alkoxy-substituted ox-azoles to afford adducts such as 328 (Scheme 4.46) [165], Interestingly, the identification of aluminum salen complexes 330 as a viable catalyst expands the scope of the process to include aromatic aldehydes (Equation 31). The products are isolated as isoxazolines (cf. 331) with a high degree of relative and absolute stereocontrol. 

Researchers fundamentally interested in C-C bond-forming methods for polyketide synthesis have at times viewed allylation methods as alternatives, and maybe even competitors, to aldol addition reactions. Both areas have dealt with similar stereochemical problems simple versus absolute stereocontrol, matched versus mismatched reactants. There are mechanistic similarities between both reaction classes open and closed transition states, and Lewis acid and base catalysis. Moreover, there is considerable overlap in the prominent players in each area boron, titanium, tin, silicon, to name but a few, and the evolution of advances in both areas have paralleled each other closely. However, this holds for an analysis that views the allylation products (C=C) merely as surrogates of or synthetic equivalents to aldol products (C=0). The recent advances in alkene chemistry, such as olefin metathesis and metal-catalyzed coupling reactions, underscore the synthetic utility and versatility of alkenes in their own right. In reality, allylation and aldol methods are complementary The examples included throughout the chapter highlight the versatility and rich opportunities that allylation chemistry has to offer in synthetic design. 

One of the key features of such stereocontrolled aldol reactions is the predictability of the absolute stereochemistry of the enantiomers (or diastereo-mers) that will be formed as the major products. The preferred intermediate for an archetypal aldol reaction, proceeding by way of a metal enolate, can be tracked using the Zimmerman Traxler transition state and the results from the different variations of the aldol reaction can be interpreted from similar reasoning, and hence predictions made for analogous reactions1129]. 

Mukaiyama Aldol Condensation. As expected, the chiral titanium complex is also effective for a variety of carbon-carbon bond forming processes such as the aldol and the Diels-Alder reactions. The aldol process constitutes one of the most fundamental bond constructions in organic synthesis. Therefore the development of chiral catalysts that promote asymmetic aldol reactions in a highly stereocontrolled and truly catalytic fashion has attracted much attention, for which the silyl enol ethers of ketones or esters have been used as a storable enolate component (Mukaiyama aldol condensation). The BINOL-derived titanium complex BINOL-TiCl2 can be used as an efficient catalyst for the Mukaiyama-ty pe aldol reaction of not only ketone si ly 1 enol ethers but also ester silyl enol ethers with control of absolute and relative stereochemistry (eq 11). ... 

We have already seen how relative stereocontrol may be achieved in aldol reactions at the positions labelled 1 and 2 in 194 (chapters 4 and 27). One of these chiral centres is formed from the aldehyde electrophile and the geometry of the double bond of the enolate determined whether we got anti or syn geometry (chapters 4 and 21). The absolute stereochemistry at these centres could be controlled by a variety of methods (chapters 23-29), including the use of a chiral auxiliary (chapter 27). 

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