Aldol titanium-mediated

S)-2-/-Butyldimethylsilyloxypentan-3-one (46), a lactate-derived chiral ketone, undergoes titanium-mediated aldols giving all-vyn products in high de.121 Low-temperature (g) H and 13C NMR evidence suggests a likely TS to account for the selectivity. 

Hayward CM, Yohannes D et al (2002) Total synthesis of rapamycin via a novel titanium-mediated aldol macrocyclization reaction. J Am Chem Soc 115 9345-9346... 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

Acetals are a versatile alternative to aldehydes and ketones which have wide applicability in the titanium-mediated aldol reaction [51], Equation (10) shows the difference between an acetal and the parent aldehyde in the diastereoselective aldol reaction [52]. In this example the latter results in better diastereoselectivity than the former. The reactivity of an aldehyde and its acetal have been compared (Eq. 11) [53]. More examples of the directed aldol reaction starting from enol derivatives of aldehydes and ketones are summarized in Table 1. 

Mahrwald, R., Costisella, B. Titanium-mediated aldol-Tishchenko reaction. A stereoselective synthesis of differentiated anti 1,3-diol monoesters. Synthesis 1996, 1087-1089. 

The related lactate-derived ketones, 44 [27] and 45 [29], are useful auxiliaries for boron- and titanium-mediated syn aldol reactions, respectively (Scheme 9-14). The effect of the protecting group in both cases is notable. For ketone 44, the use of the boron chloride reagent unexpectedly afforded the syn adduct with good control... 

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. 

In the Evans synthesis of the polypropionate region (Scheme 9-45), the boron-mediated anti aldol reaction of -ketoimide ent-25 with a-chiral aldehyde 145 afforded 146 with 97% ds in what is expected to be a matched addition. Adduct 146 was then converted into aldehyde 147 in readiness for union with the C -Cs ketone. This coupling was achieved using the titanium-mediated syn aldol reaction of enolate 148 leading to the formation of 149 with 97% ds. 

TBS-protection, a second, boron-mediated, syn aldol reaction led to the formation of 277 with 95% ds. In this case, ketone 278 controlled the stereochemical outcome of the reaction, and chiral ligands on boron were not required. A simple steric model accounts for this selectivity (see Scheme 9-11), and a titanium-mediated aldol reaction would be expected to give the same product. Following elaboration, including an Ireland-Claisen rearrangement, aldehyde 279 was prepared. 

A chiral aldehyde, attached through a silyl linker to a hydroxymethyl Merrifield resin, was employed for expanding polyketide diversity. Aldol reaction with preformed (H)-enol borinate derived from a suitable chiral (R)-ketone afforded the anti-anti aldol product. Titanium-mediated enolization of the enantiomer (S)-ketone afforded the syn-syn product. 

Aldol reactions. A high degree of syn-diastereoselectivity is exhibited in the aldol reaction mediated by titanium(IV) alkoxides in the presence of a-hydroxy acids. With chiral a-hydroxy acids, asymmetric induction is observed.- ... 

Chiral 3,5,6-trihydroxyheptanoic acids are potentially useful intermediates for the synthesis of natural products. The backbone can be constructed by a titanium-mediated aldol reaction of silyl enol ether 536 with 929. The syn adduct 949 is formed exclusively, as predicted by the chelation-controlled Cram cyclic model. 

In the pivotal reaction, a titanium-mediated aldol condensation of enol silyl ether 545 produces tetrahydropyran-4-ones 547 (11%) and 548 (38%), which are separable by chromatography. Unfortunately, the product with the desired stereochemistry is the minor isomer 547. The synthesis is completed by benzoylation of the primary alcohol, reduction of the ketone with sodium borohydride, and benzoylation of the newly formed secondary alcohol [132]. 

The synthesis of the other building block, cyclic sulfone 157 (Scheme 22), was far more direct, with the critical operation being the coupling of ketone 153 with aldehyde 154 through a titanium-mediated aldol reaction. This event gave rise to 156 in 68% yield with 3 1 diastereoselectivity for its two new stereocenters,... 

In 1983, Winterfeld published the first synthesis of K252c as shown in Scheme 19 [52-53]. The synthesis of lactam 126 was successfully achieved by intramolecular aldol reaction of ketoa-mide 125 and then followed by titanium-mediated deoxygenation. Oxidative Photocyclization of 126 resulted in indolocarbazole 4 (staurosporinone). 

Scheme 4.70 Acetate aldol additions mediated via titanium enolates with chiral ligands derived from diacetone glucose and TADDOL 312 and 313, respectively.

Scheme 5.62 Enantioselective Mukaiyama aldol additions mediated by titanium-BINOL complexes 196 according to Mikami and Keck. Proposed Zimmerman-Traxler-type transition state model.

In 1991, Evans et al. reported on a more convenient method, the titanium-mediated aldol reaction (Scheme 8.7). ° Chiral imide 14 was treated with TiCLj and Hiinig base to react with isobutyraldehyde to afford syn adduct 41 in high selectivity. 

SCHEME 8.7. The titanium-mediated asymmetric aldol reactions. 

SCHEME 8.10. The titanium-mediated aldol reaction yielding the non-Evans -iy adduct. 

SCHEME 8.11. The titanium-mediated aldol reactions of lactate derivatives. 

A confusing picture emerges from the stereochemical outcome of the Mukaiyama variation of the aldol addition. The titanium(IV) chloride mediated addition of silylketene acetals to isobutyraldehyde confirms this statement while there is a reasonable correlation between the predominance of the (/t)-silylkctenc acetal 2 over the (Z)-acetal, and the favored formation of the an/t -carboxylic ester over the. svn-product, the pure (Z)-diastereomer displays no syn selectivity26. 

A combination of diethylzinc with sulfonamides 18 or 19 offers another possibility for the enantioselective acetate aldol reaction39,41. The addition of silyl enol ethers to glyoxylates can be directed in a highly enantioselective manner when mediated by the binaphthol derived titanium complex 2040. 

A titanium(iv) chloride mediated Baylis-Hillman-type or aldol reaction between a-ketoesters and cyclohex-2-enones has been studied (Equation (13)).77 The steric effect of the R2 substituent is crucial for the reaction pathway since the aldol reaction only proceeds with the unsubstituted cyclohexenone (aldol adduct 71 with R2 = H to a small extent the Baylis-Hillman reaction occurs), whereas with the substituted substrate (R2 = Me) gives exclusively the Baylis-Hillman adduct 72. 

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