Secondary aryl alkyl

Moreover, reduction of alkyl aryl ketones can be used to access optically pure secondary aryl alkyl amines, as illustrated in an enantioselective synthesis of SDZ-ENA-713 (ll)60 and as we have demonstrated in a related process (Scheme 16.8). 

Scheme 41.2 Kinetic resolution of secondary aryl alkyl alcohols by Birman et al.

Building upon the results obtained by Birman and coworkers. Smith et al. set out to develop an isothiourea-based catalyst that could promote the KR of secondary aryl alkyl alcohols [58]. After screening a range of DHIP catalysts, (2S,3R)-2-phenyl-3-isopropyl-substituted isothiourea (56) proved to be ideal as it afforded high levels of selectivity (s > 17) under low catalyst loadings (<1 mol%) (Scheme 41.12). To explain the enantiodiscrimination, the authors proposed a model where the N-acylated catalyst adopts a conformation that places the phenyl substituent in a pseudo-axial position to minimize 1,2-strain, resulting in a preferential attack of the (R)-enantiomer of the alcohol due to favorable n-n and/or cation-Jt interactions of the TT-system of the alcohol with the acylated isothiouronium catalyst intermediate. 

In 2010, Fossey et al. developed a new class of planar chiral ferrocene nucleophilic catalysts combining both central and planar chirality [59]. Inspired by Fu s planar chiral DMAP and by Birman s 2-phenyl-2,3-dihydroimidazo[l,2-a]pyridine, Rp-57 proved to be a remarkably effective catalyst for the KR of various racemic secondary aryl alkyl alcohols, particularly bulky aryl alkyl alcohols, which are usually difficult to resolve. Typically, by performing the reaction in the presence of Rp-57 (2mol%), propionic anhydride (0.75 equiv.) and i-Pr2NEt (0.75 equiv.) in toluene at 0°C, selectivity factors ranging from s = 31 for substrates such as a-methyl benzyl alcohol to s = 534 in the case of the more bulky a-tert-butyl benzyl alcohol could be obtained (Scheme 41.13). Remarkably, the selectivity could be further increased by running the reaction at lower temperatures (s = 801 at -20 °C and up to s = 1892 at -40 °C), albeit with a concomitant loss in activity. 

Scheme 41.13 Ferrocene-based planar chiral PIP catalyst for the KR of racemic secondary aryl alkyl alcohols by Fossey et ol.

In 2006, Connon et al. [61] developed a new class of chiral 4-pyrrolidinopyridine (4-PPY) catalysts, which also operate via an induced-fit mechanism. This new catalyst allowed the attainment of moderate to good selectivities (s factors ranging from s = 14 to 30) on a wide range of secondary aryl alkyl alcohols, including Baylis-Hillman adducts, which are typically difficult to obtain in an enantiomerically enriched form (Scheme 41.17) [6lb]. 

Scheme 41.18 Carbety s helicenoidal DMAP catalyst for the KR of secondary aryl alkyl...

Unfortunately, as none of these catalysts induced useful levels of selectivity in the KR of secondary aryl alkyl alcohols. Miller et al. set out to identify specific peptide-catalysts for specific applications using automated peptide synthesis and high-throughput fluorescent screening. This allowed them to unveil some particularly effective catalysts for various transformations such as the KR of an intermediate in the synthesis of aziridomitosane [22h, k], the KR of a series of tertiary alcohols [22i], the regioselective acylation of carbohydrates [22k], and the KR of N-acylated tert-amino alcohols [22ij. 

Subsequently, Birman et al. tested various amidine-based catalysts, including commercially available tetramisole (45) and its benzaimellated analog benzote-tramisole (BTM) (23) in the KR of secondary aryl alkyl alcohols and propargylic alcohols (Figure 41.3). Both catalysts displayed far superior enantioselectivity although BTM proved to be more reactive [27c, 50, 51],... 

Carbery et al. also used the DMAP scaffold to develop the first hehcenoidal asymmetric organocatalyst, which proved to be a particularly selective acylation catalyst for the KR of secondary aryl alkyl alcohols [64]. Catalyst 67 offered good to excellent selectivity factors ranging from s = 17 to 116 at catalyst loadings as low as 0.5mol% (Scheme 41.18). 

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