Stereodiverse Iterative Synthesis of 1,3-Polyol Arrays through Asymmetric Catalytic Hydrogenation. Formal Total Synthesis of (−)-Cyanolide A

Abstract

An iterative protocol was developed for highly diastereo-and enantioselective construction of high-order 1,3polyols via iridium-catalyzed asymmetric hydrogenation of βalkyl-β-keto esters. The protocol involves four operations asymmetric hydrogenation, hydroxy protection, ester hydrolysis, and C-acylationand the catalyst loading can be as low as 0.005 mol %. The configurations of all stereogenic centers of 1,3-polyols are controlled by the catalyst. By the use of this protocol, a formal total synthesis of the polyketide cyanolide A was achieved with high diastereoselectivity and enantioselectivity.

Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation

“…The corresponding cyclohexyl-fused SpiroPAP ligand PNN-L7 gave almost the identical performance in this transformation . Subsequently, Zhou , developed sulfur chelated complexes PNS-Ir-1 and PNS-Ir-2 in 2015. Employing PNS-Ir-2 in ADH of β-keto ester was found to be more efficient: up to 99.9% ee and 355,000 TON were achieved.…”

General chemoenzymatic route to two-stereocenter triketides employing assembly line ketoreductases

“…Commercially-available 10 was hydrogenated at 100 atm using (S a )-Ir-spiroSAP or (R a )-Ir-spiroSAP as the catalyst to give enantiomers 11a or 11b, respectively. 31,32 11a and 11b were hydrolyzed by heating overnight in a solution of 5 M NaOH to generate 4a and 4b. Protection and extension of 4a and 4b into 6a and 6b were performed as in the chemoenzymatic route.…”

“…12a was reduced using (S a )-Ir-spiroSAP or (R a )-Ir-spiroSAP and hydrolyzed to provide 9aa or 9ab, (77% and 97% yields, respectively, through two steps). 31,32 Likewise, 12b was reduced using (S a )-Ir-spiroSAP or (R a )-Ir-spiroSAP and hydrolyzed to provide 9ba or 9bb (83% and 86% yields, respectively, through two steps). Coupling with NAC yielded 8aa, 8ab, 8ba, and 8bb.…”

“…KRs thus have an advantage over most asymmetric catalysts in the reduction of 1,3 polyol substrates in that they override the influence of neighboring stereocenters which commonly affect stereocontrol. 32,34 The chemoenzymatic synthesis of a library of two-stereo-center triketide fragments was accomplished with overall yields of 2.0% for 9aa, 1.3% for 9ab, 1.7% for 9ba, and 0.9% for 9bb (in each case the targeted stereoisomer comprises at least 90% of all possible stereoisomers; stereoisomeric compositions are reported in Table S1, ESI †). This marks an initial success for the described general polyketide synthesis and a starting point for optimization.…”

Resolution of Halogenated Mandelic Acids through Enantiospecific Co-Crystallization with Levetiracetam

“…Synthesis routes include chiral pool synthesis (using enantiopure starting materials) and asymmetric synthesis (using chiral auxiliary or catalyst) [ 5 , 6 , 7 , 8 , 9 ]. Although these two synthetic methods have obvious advantages in obtaining a single enantiomer, the limited number of sources of enantiopure starting materials and high cost are not conducive to a wide application of chiral pool synthesis, while asymmetric synthesis requires a long development time and high cost [ 10 , 11 , 12 , 13 , 14 , 15 ]. Chiral resolution is a method of selectively separating one enantiomer from the racemate to obtain the target enantiomer by various techniques, such as inclusion resolution [ 16 ], liquid–liquid extraction [ 17 ], electrophoresis [ 18 ], biological resolution [ 19 ], and membrane technology [ 20 ].…”