Diastereoselective synthesis titanium enolates

Among the preformed enol derivatives used in this way have been enolates of magnesium, lithium, titanium, zirconium, and tin, ° silyl enol ethers, enol borinates,and enol borates, R CH=CR"—OB(OR)2. The nucleophilicity of silyl enol ethers has been examined. In general, metallic Z enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. The ( ) isomers generally react nonstereoselectively. However, anti (or threo) stereoselectivity has been achieved in a number of cases, with titanium enolates, with magnesium enolates, with certain enol bor-inates, and with lithium enolates at — 78°C. ... 

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

Finally, several diastereoselective aldol reactions using titanium enolates and carbonyl electrophiles have also been applied to the total synthesis of natural products.69-72... 

Other examples of the uses of enolate derivatives of thioesters highly diastereoselective aldol reactions were reported by Gennari [3 and Hanaoka et al. [374, 375]. The latter reported the reaction between chromium-complexed benzaldehyde (1) and the titanium enolate of thioester (2) as the first step of sequences directed towards the synthesis (+)-goniofufurone [374] and the taxol C13 side-chain [375]. They also u cobalt-complexed acetylenic aldehydes for the selective formation of sy aldols [376]. 

Stacking interactions in the transition state are one factor suggested for the highly diastereoselective synthesis of syn- and anfr-aldols from the reaction of an arylsulfonamidoindanyl titanium enolate with bidentate aldehydes.56... 

The synthesis of eight isomers of maurenone 116 proceeded by coupling of each of the four aldehyde isomers 110, ewt-llO, 112 and ent-112 with the two ketone isomers 113 and 114. Attempts to couple the titanium enolate (TiCU, i-Pr2NEt) of ketone 113 with aldehyde 110 proved troublesome, because of desilylation taking place during enolization of ketone 113. Better results were achieved by means of lithium enolates, on treatment of ethyl ketone 113 with LiHMDS and subsequent addition of aldehyde 110, yielding the isomer 115 with an acceptable diastereoselectivity of 74% ds (equation 34). Separation of the isomers and further transformations gave (—)-maurenone (116), which NMR data showed to be an almost perfect correlation with all the peaks reported for the natural product maurenone. ... 

A two step synthesis of the first p-aminophosphotyrosyl mimetic (360) was carried out. Addition of (—)(R)-tert-butanesulfinylamide to 4-phosphonome-thyl benzaldehyde (361) gave chiral aldimine (362) which under treatment with the titanium enolate of methyl acetate produced the target compound with high diastereoselectivity (Figure 60). ... 

The oxidation of titanium enolato complexes, derived from a transmetallation reaction of the corresponding lithium enolates with Cp2TiCl2, by dimethyldioxirane has been investigated as a general, convenient, effective, and chemo- and diastereoselective synthesis of cr-hydroxy carbonyl compounds. The Cp derivative shown in Scheme 601 results in much higher diastereoselectivities than other enolato complexes studied.1556... 

Addition of the titanium enolate of Af-acetyl-4-isopropyl-l,3-thiazohdme-2-thione 150 to the A-acyl iminium ions from 151 furnishes the corresponding Mannich-type adducts 152 and 153 with good diastereoselectivity <05JOC4214>. A similar diastereoselective addition of the titanium enolate derived from Af-4-chlorobutyryl-l,3-thiazolidine-2-thione 154 to A -Boc-2-methoxypyrrohdine 155 has been used to provide 2-substituted pyrrolidine 156, a key intermediate in the synthesis of (+)-isoretronecanol <05TL2691>. 

Titanium enolate aldol reactions have been shown to be very effective for control of relative and absolute stereochemistry in acetate aldol and both syn and anti aldol reactions. The use of readily available and inexpensive titanium reagents make these methods convenient for large-scale synthesis. The synthetic potential of a variety of aldol reactions has been demonstrated by highlighting the synthesis of numerous bioactive complex natural products. The significance of enantio- and diastereoselection in synthesis, particularly in this pharmaceutical age, ensures that titanium enolate aldol reactions will remain an important part of organic synthesis for years to come. There is no doubt that unprecedented success has been achieved in the development of a variety of titanium enolate aldol reactions in the past decade. Much new potential and other exciting possibilities remain to be... 

So far only one example for the successful use of acetals in diastereoselective a-functionalization of chiral isotopically labeled imides has been published. Though this reaction was performed with carbon-13 material, there is little doubt that it is also applicable in carbon-14 synthesis. The titanium enolate prepared from (45)-4-benzyl-3-[(2R)-2-[ C, H3]methylpropionyl]-l,3-oxazolidin-2-one (111) reacted with trioxane to afford the corresponding a-hydroxymethyl derivative 112 in 83% yield and >96%... 

As can be seen from the developments described above, the control of both relative and absolute acyclic stereochemistry in a variety of syn aldol reactions can now be achieved highly stereoselectively. Both boron and titanium enoiate-based syn aldol reactions have gained svidespread popularity and are frequently used in synthesis. Whereas anti-a-alkyl-/i-hydroxycarbonyl units are inherent to numerous bioactive natural products, there are relatively fesv effective synthetic processes that are convenient, operationally simple, and afford high diastereoselectivity for a svide range of aldehydes. Early examples of anti-selective aldol reactions, reported by Meyers in 1984, svere based upon oxazoline-derived boron enolates [60]. Several other methods based upon metal enolates other than titanium have subsequently been developed. In this chapter, ho vever, we vill focus on titanium enoiate-based methods. 

Researehers at Schering-Plough have demonstrated the use of Evans ehiral oxazolidinone in their synthesis of the potent 2-azetidinone cholesterol inhibitor ezetimibe (Scheme 14.71). Reaetion of oxazolidinone 193 with imine 194 led to formation of the requisite antz-Evans-aldol product 196 in an impressive 95% de. Subsequent recrystallisation increased the de to 99%. Initial treatment of 193 with TiCU and DIPEA led to (Z)-enolate formation. It has been proposed that faeial seleetivity in the anfr-Evans aldol reaction is controlled through a boat transition state, ° and this may be facilitated by the ability of titanium to eoordinate to three heteroatoms. The combination of these two factors account for the high diastereoselectivity observed in this reaction. Silylation followed by fluoride eatalysed cyclisation afforded azetinone 197 in 85% yield whieh was subsequently transformed... 

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