Titanium enolates synthesis

The addition of the titanium enolate 5 to 3-methylbutanal giving ferf-butyl 3-hydroxy-5-methyl-hexanoate with 99% ee, serves as the key step in a synthesis of optically pure (,Y)-ipsenol77. 

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)... 

Entry 8 in Scheme 2.1 is an example of this method. Titanium enolates are frequently employed in the synthesis of complex molecules and with other carbonyl derivatives,... 

The stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

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

A new and direct method for the synthesis a range of 2-azetidinones (/3-lactams) has been developed by Sharma and Kanwar via condensation of titanium enolate 83 of various mixed anhydrides with different imines (Scheme 33).116... 

As the t-butyl group can readily be removed upon acidic or basic hydrolysis, this method can also be used for //-hydroxyl acid synthesis. In analogy with allylation reactions, the enolate added preferentially to the Re-face of the aldehydes in aldol reactions. Titanium enolate 66 tolerates elevated temperatures, while the enantioselectivity of the reaction is almost temperature independent. The reaction can be carried out even at room temperature without significant loss of stereoselectivity. We can thus conclude that this reaction has the following notable advantages High enantiomeric excess can be obtained (ee > 90%) the reaction can be carried out at relatively high temperature the chiral auxiliary is readily available and the chiral auxiliary can easily be recovered.44... 

A rhodium-catalyzed asymmetric synthesis of chiral titanium enolates by 1,4-addition of aryltitanium reagents to a,p-enones under aprotic conditions has... 

Other examples of the uses of enolate derivatives of thioesters for highly diastereoselecave aldol reactions were reported by Gennari [373] and Hanaoka et al. [374. 375]. The latter reported the reaction between a chromium-complexed benzaldehyde (1) and the titanium enolate of a thioester (2) as the first step of sequences directed towards the synthesis of (+)-goniofufurone [374] and the taxol C13 side-chain [375]. They also used cobalt-complexed acetylenic aldehydes for the selective formation of syn-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... 

Crimmins s TiCL -mediated asymmetric aldol condensation protocol was used in the enantioselective total synthesis of (9S)-dihydroerythronolide A (68)25 (Scheme 2.lx). Swern oxidation of the primary alcohol 69 provided the aldehyde 70 in almost quantitative yield, which underwent asymmetric aldol condensation with the titanium enolate of (A )-4-bcnzyl-3-propionyloxa/,olidin-2-onc (26M) in the presence of (-)-sparteine to afford the aldol adduct desired (71) as a single diastereomer. 

The addition of a chiral ketone enolate to an aldehyde displays not only simple diastereoselectivlty, but also highly induced stereoselectivity, as shown by Fecik and coworkers for the formal total synthesis of the polyketide macrolactone narbonoMe (92, equation 27). This reaction demonstrates the successful application of titanium in aldol additions for the highly stereoselective construction of two new stereogenic centers by addition of aldehyde 90 to the titanium enolate of Evans S-keto imide 89 the iyw-aldol product 91 was obtained exclusively in 74% yield. Interestingly, there is no detectable loss of stereochemistry via enolization at the potentially labile C2-methyl-bearing stereocenter in 89 ... 

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. ... 

Transition metal enolates were introduced into organic synthesis in 1981 by Reetz and Peter, who reported that titanium enolates are easily accessible using cheap reagents, distillable and miscible in THF, ether, methylene chloride or pentane, and display pronounced erithro selectivity in reactions with aldehydes. Since then, the importance of these versatile nucleophiles has steadily increased and compounds which can be represented as 57 or 58 have been identified. 

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 first enantioselective total synthesis of (-)-denticulatin A was accomplished by W. Oppolzer. The key step in their approach was based on enantiotopic group differentiation in a meso dialdehyde by an aldol reaction. In the aldol reaction they utilized a bornanesultam chiral auxiliary. The enolization of A/-propionylbornane-10,2-sultam provided the (Z)-borylenolate derivative, which underwent an aldol reaction with the meso dialdehyde to afford the product with high yield and enantiopurity. In the final stages of the synthesis they utilized a second, double-dlastereoditferentiating aldol reaction. Aldol reaction of the (Z)-titanium enolate gave the anf/-Felkin syn product. The stereochemical outcome of the reaction was determined by the a-chiral center in the aldehyde component. 

The second total synthesis of swinholide A was completed by the Nicolaou group [51] and featured a titanium-mediated syn aldol reaction, followed by Tishchenko reduction, to control the C21-C24 stereocenters (Scheme 9-30). The small bias for anri-Felkin addition of the (Z)-titanium enolate derived from ketone 89 to aldehyde 90 presumably arises from the preference for (Z)-enolates to afford anti-Felkin products upon addition to a-chiral aldehydes [52], i.e. substrate control from the aldehyde component. 

Felkin product (69% ds, 2-anti). A (Z)-titanium enolate usually favours the anti-Felkin adduct, and the subsequent Oppolzer synthesis of denticulatins A (see Scheme 9-69) highlights this behaviour (see also Scheme 9-30) however, exceptions can be found (Scheme 9-45). Oxidation of the C3 and Cn hydroxyls of 258, and cyclization, under carefully controlled conditions to preserve the configuration of the Cio stereocenter, then allowed the selective synthesis of denticulatin B. 

The synthesis of dihydrofurans with an additional ester moiety and one or two quaternary centers are prepared from titanium enolates formed by reactions of 3,4-dienoates with Cp2TiCl2. Titanium enolate derivatives TiCl3[CH2CH2C(=0)0Et] and the Tebbe reagent compound have been applied in the synthesis of pumilio-toxin.1915 Chiral allyl and mono-Gp chloro enolato titanium compounds add with high enantioface discrimination to aldehyde.973... 

Schering-Plough Corp, has used an oxazolidinone in its synthesis of the cholesterol adsorption inhibitor (+)-SCH 54016 (24) (Scheme 7) [51], Condensation of an acid chloride intermediate with the (7 )-phenylglycine-derived Evans auxiliary followed by reaction of the titanium enolate with -(4-methoxybenzyh-dene)anihne gave the intermediate 25. This was silylated and treated with TBAF, resulting in removal of the auxiliary and cyclization to form the 2-azetidinone ring. The stereochemistry was exclusively trans. The azetidinone was then converted to the bromide, followed by intramolecular alkylation to form SCH 50416 in > 99% ee. 

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>. 

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