Sterically demanding substrates

The unique power of Hoveyda s recyclable ruthenium catalyst D in RCM with electron-deficient and sterically demanding substrates is illustrated in Honda s total synthesis of the simple marine lactone (-)-malyngolide (54), which contains a chiral quaternary carbon center (Scheme 10) [35]. Attempted RCM of diene 52 with 5 mol% of NHC catalyst C for 15 h produced the desired... 

Some of the more sterically demanding substrates such as 56h were reduced with a moderate loss of enantioselectivity. 

In 2000, Tanaka, Sakai, and Suemune expanded the scope of these desymmetrization reactions to more highly substituted substrates (Eq. 16) [19], The high selectivity of Rh(I)/BINAP for addition to one of the enantiotopic olefins leads to the generation of adjacent quaternary and tertiary stereocenters with excellent stereoselection. Unfortunately, for these more sterically demanding substrates, neutral Rh(l)/BINAP complexes furnish a poor yield of the desired cyclopentanone. 

A striking example of the power of A -heterocyclic carbene (NHC)-bearing catalysts with sterically demanding substrates was disclosed by Chavez and Jacobsen, " who presented a route to several iridoid natural products, exemplified by the enantio- and diastereoselective synthesis of boschnialactone 31 outlined in Scheme 5. Chiral aldehyde 27, available from citronellal by Eschenmoser-methylenation in a single step, reacted despite the presence of an isoprenyl moiety and a gi OT-disubstituted double bond, in the presence of catalyst C smoothly to form... 

The Schrock catalysts are more active and are useful in the conversion of sterically demanding substrates, while the Grubbs catalysts tolerate a wide variety of functional groups. 

Scheme8.21. Palladium-mediated C-C bond formation with sterically demanding substrates [152-155].

In principle, the screening concepts introduced here could be applied to other polymerases, and other activity. As yet, however, the contexts of low polymerase fidelity or of tolerance versus non-natural substrates have not been sufficiently targeted. In the course of our studies, we tackled these problems and presented solutions for both, selecting, or screening, polymerase libraries. Thereby, we detected an error-prone polymerase variant and polymerase activity in the sole presence of sterically demanding substrates. 

Most probably, the successful conversion of substrates on BDD cathodes requires access to the diamond surface without spatial restrictions. Consequently, more sterically demanding substrates are not suitable. 

Sterically demanding substrates are tolerated well and Suzuki coupling has been used in a wide range of aryl-aryl cross-couplings. This example has three ortho substituents around the newly formed bond (marked in black) and still goes in excellent yield. It also shows that borate esters can be used instead of boronic acids. 

Ir complexes gave high enantioselectivities for a range of tettasubstituted arylalkenes (Scheme 9) [23], For substtates with at least one methyl substituent essentially full conversion was obtained, whereas more sterically demanding substrates showed reduced reactivity. 

Nevertheless, in the case of sterically demanding substrates little or no reduction occured, indicating a substrate steieospecificity different from that observed in homogeneous catalysis or when using catalyst precursor belonging to the polymer backbone [32]. For the reduction of acetophenone, crosslinked templated polymers were studied. Optimization of the crosslinking ratio led to the best compromise between activity and selectivity (70% ee for a crosslinking ratio of 50/50 of triisocyanate/diisoc anate) [33, 34]. 

The scope was found to be quite broad with sterically demanding substrates or those that contain a P-leaving group (no elimination) or other a-acidic functionality (no enolate scrambling). An a-fluorine atom could also be tolerated (Fig. 4.3). 

Whereas secondary amines are suitable catalysts for activation of a,(3-unsaturated aldehydes, more difficulties are usually encountered with sterically demanding substrates, such as a,(5-unsaturated ketones. Primary amines can be useful catalysts in such cases. Yoshida et al. [52] reported an amino acid-catalyzed sulfa-Michael addition of arylmethyl mercaptans to cyclic enones. The proposed mechanism invokes the formation of an imine intermediate. However, even with the best screened catalyst, 5-trityl L-cysteine, the reaction proceeded with modest levels of enantioselectivity (8-58% ee). 

However, the most versatile catalyst system for sterically demanding substrates was reported by Nolan et al. [44]. The one-component catalyst 50, which consists of the l,3-bis(2,6-diisopropylphenyl)imidazolidene carbene ligand 19 and an aUyl-Pd species, promoted the coupling of dibutylamine with electron-rich and sterically demanding aryl chlorides at room temperature (Scheme 13.57). 

Complex 47 was also found to be more efficient in the CM of various substrates and in the formation of disubstituted olefins than complex 11 highlighting the advantage of tolyl-substituted NHC over mesityl-substituted NHC in these reactions [68]. The increased catalytic activity of these complexes was attributed to the significantly less hindered steric environment around the ruthenium center due to the more stable conformations where the tolyl groups rotate away from the incoming bulky olefins [69]. The idea of reducing steric hindrance of the NHC to achieve more efficient catalysis on sterically demanding substrates... 

With this catalyst the RCM of the sterically demanding substrate (see Scheme 9) was attempted. The recycling results were slightly improved with a conversion of 68% obtained on the fourth cycle but milder conditions were undoubtedly necessary to ensure a better recycling. Optimised conditions were found by using a biphasic media [bmim][PF6]/toluene (25 75) at room temperature for 3 h. Under these conditions up to eight runs were performed with conversions better than 95%. Furthermore the Ru content of the product was measured for each cycle and found to be between 2.3 and 16.9 ppm, which is among the lowest values obtained after an olefin metathesis reaction. 

With this new catalyst it has been possible to run 17 cycles of N,N-diallyltosylamide RCM with a conversion of 90% for the 17th run. A more sterically demanding substrate bearing a disubstituted olefin was also efficiently transformed with tiiis catalyst and six cycles performed with very good conversions (Table 8). 

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