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History and Development:
Named after Andreas Hafner and Rudolf O. Duthaler, the Duthaler-Hafner reagent is a cyclopentadienyldialkoxyallyltitanium reagent first described in 1992, available in both enantiomeric forms capable of highly stereoselective allylation of aldehydes. Though ƞ3-crotyl molybdenum complexes are capable of the same chemical transformation high enantioface differentiation, they tend to be sensitive, difficult to prepare, and display low solubility, slow reaction rates, while the sophisticated chiral auxiliaries hamper large-scale applications. Despite good results with simple aldehydes, the stereodifferentiation is often inadequate in the case of more complex, especially chiral, substrates. Hafner and Duthaler believed that further improvements could be achieved for enantioselective alkylating reagents in their ease of preparation, solubility, reaction rate, and access to sophisticated chiral auxiliaries.

Catalyst Screening Image HERE Caption: A variety of sugar-derived ligands were screened for enantioselective allyltitanation of benzaldehyde; xylose acetonide, diacetone idose, diacetone glucose, and diacetone allose.

With the exception of the highly stereocontrolled addition of chiral allyl-groups, few moderately successful allyl-titanium reagents with chiral ligands have been reported so far. This is astonishing, since high diastereocontrol has been observed for achiral allyl-titanates. Furthermore, these organo-titanium reagents are low in toxicity and highly available.

A variety of chiral cyclopentadienyldialkoxytitanium (IV) complexes were prepared and screened for enantioselective allyltitanation. These ligands were derivatives prepared from glucose, idose, allose, and xylose. Though the glucose-derived ligand showed the highest ee values (90% ee), it was only commercially available in the D form, restricting the enantioface discrimination to the "re"-side attack. However, particularly high ee values were observed when (TADDOL) ligands used. The marked influence on enantioselectivity is thought to be due to the steric bulk the phenyl substituents (Ph) exert on the carbinol group. Due to these promising findings and the ease of access to these ligands from the readily available natural (+)- or (-)-tartaric acid, Duthaler and Hafner further explored these catalysts.

Preparation
These chiral monochlorotitanates are readily prepared from CpTiCl3 or Cp*TiCl3 and chiral tartaric acid 1,4-diols, readily available nontoxic materials in both enantiomeric forms. Treatment of the resultant chiral monochlorotitanates with the desired allyl gringard provides the allyltitanium catalyst.

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Mechanism
Upon treatment of the allyltitanium reagent with the aldehyde, Si face attack of achiral aldehydes is preferred with the (R,R)-Duthaler-Hafner catalyst. Though the exact details of the mechanism are unclear, it is known that coordination of the aldehyde’s carbonyl to the metal center promotes occurs first which then promotes attack of the allyl olefin into the carbonyl. A carbon-carbon bond then forms between the carbonyl of the aldehyde and carbon of the olefin farthest from the metal center. as well as bond breakage between the allyl carbon-Ti bond. Treatment of the resulting intermediate with NH4F/H2O cleaves the Ti-O bond to release the desired product.

Insert mechanism Image here: Caption: An allyl transfer occurs from the "si"-face of the aldehyde substrate to form a new stereocenter. In the case of branched olefins, the allyltransfer inevitably results in the anti-configuration.

Like other allyltitanation reactions, the method is thus restricted to the preparation of branched regioisomers with the anticonfiguration. Irrespective of the geometry of the organometallic species used for the preparation of the allyl-titanate catalyst, the anti-product will always be obtained due to an observed rapid equilibration of the ƞ1-bound allyl-titanates to the most stable vans-isomer with titanium bound to the less substituted carbon.

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Applications in Total Synthesis
In their synthesis of Epothilones A and B, Mulzer and Martin et al. utilized the Duthaler-Hafner reagent provided an alternative with >98% ee and a yield of 61%. Previous routes towards this same intermediate devised by Nicalou et al. utilized Brown allylation with moderate ee values of ~84%.

Epothilones A and B Image Here:

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Duthner-Hanfer's allylation played a significant role in the synthesis of a monomeric counterpart of marinomycin A, a 44-membered C2-symmetrical dimeric macrodiolide marine natural product with antitumor and antibiotic activity. (10.1021/ol070240k) Throughout this synthesis, Janine Cossy et. al. utilized the Duthner-Hanfer reagent to establish 3 of the 5 stereocenters with high ee and dr values and in moderate yields.

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In further work by Janine Cossy and coworkers, the Duthaler-Hafner reagent was again used to establish the sole chiral center in their synthesis of the marine natural product, (-)-mycothiazole. In their synthesis, the ability of the Duthaler-Hafner reagent to establish this stereocenter are directly compared with a chiral allylic borane, also generated from the addition of an allylmagnesium bromide to the corresponding (+)-chlorodiisopinocampheyl borane ((+)-DIPCl). The figure below shows that in this case, both the yield and %ee of the resultant chiral secondary alcohol were notably higher when using the allyltitanium complex.