Diastereoselection, crystallization-induc

Diastereoselective Slrecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an In situ crystallization-induced asymmetric transformation, whereby one diastereomer selecliveiy precipitates and can be isolated in 76-33% yield and dr > gsti. The diastereomeilcaily pure a-amino nitrtie obtained from pivaidehyde (R, = t-Bu, Rj = H) was converted in three steps to (S)-tert-leucine in 73% yieid and >98% ee. 

The observed diastereoselectivity in the asymmetric Strecker step via the crystallization-induced asymmetric transformation can be explained as shown in Figure 2. Apparently, the re face addition of CN to the intermediate imine 4 is preferred at room temperature in methanol and results in a dr 65/35. At elevated temperatures in water, the diastereomeric outcome and yield of the process are controlled by the reversible reaction of the amino nitriles 3 to the intermediate imine and by the difference in solubilities of both diastereomers under the applied conditions. . .. 

Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and... 

A novel application of this chemistry to a short synthesis of enantiomeri-cally pure 2-hydroxymorpholine 136, an intermediate in the synthesis of the substance P antagonist Apprepitant 138 (Scheme 7.18), was reported by a group from Merck [64]. Interestingly, despite the initial formation of a complex diastereo-meric mixture, compound 136 was isolated in high yield and enantioselectivity via a crystallization-induced diastereoselection and could be completely isomerized to 137, a precursor to 138. 

The desired oxazinone was created by the condensation of 4-fluorophenylglyoxal hydrate 59 with amino alcohol 58. The initial diastereoselectivity of this condensation was 2 1 (60 61). A number of crystallization-induced resolution conditions were examined. The 2 1 mixture could be treated with HCl in IPAC at 70 °C to selectively crystallize the desired diastereomeric hydrochloride salt 61-HCI and concomitantly epimerize the undesired oxazinone diastereomer 60. Overall, the process afforded a 90% yield of oxazinone hydrochloride 61-HCI (98% de). 

Highly diastereoselective alkylation at C-2 of benzo-l,4-diazepin-3-ones 41 was accomplished in 40-85% chemical yield using an (R)-phenylglycinol moiety at N-4, as the chirality-inducing element (Scheme 10) <2005EJ01590>. The optimum conditions involve deprotonation of 41 with 2 equiv of -BuLi at — 40 °C and alkylation at — 78 °C to give products 42 with 86-96% de. A single crystal X-ray diffraction analysis of the methylated derivative determined that the major product formed was the 2-(R)-isomer, as depicted in the product 42. 

Dr Reddy s Laboratories claimed the diastereoselective hydroformylation of an enantiopure bicyclic lactam by means of a Rh[(/ ,/ )-Kelliphite] catalyst (Scheme 4.59) [18]. The olefinic substrate that is produced on a multi-ton scale by Chirotech gives after hydroformylation and a single crystallization step the almost pure aldehyde. Noteworthy, (S,S)-Kelliphite or other ligands, such as (/J,/ ,S)-Bisdiazaphos or (achiral) BIPHEPHOS, induced mainly the formation of the undesired regioisomeric aldehyde. The reaction has been upscaled to 15 g of substrate and used eventually for the production of multifunctionalized... 

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