Scheme 4. Preparation of Stable Imidazolin-2-ylidenes by Arduengo and Co-workers Scheme 5. Synthesis of the Stable Carbene 22 Developed by Enders and Teles and Co-workers Scheme 6. Postulated Mechanism of the Formoin Condensation Reported by Teles and Co-workers

Getting cross: Excellent asymmetric inductions and very good yields are achieved in the generation of a quaternary stereocenter in α‐hydroxy‐substituted tetralones by using chiral N‐heterocyclic carbene catalysts in an enantioselective intramolecular crossed‐benzoin reaction. The synthesis of the corresponding α‐hydroxyindanones with good ee values is also possible by this route.

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.

A s y m m e t r i c O r g a n o c a t a l y t i c S y n t h e s i s o f c i s -S u b s t i t u t e d D i h y d r o b e n z o f u r a n o l sAbstract: The diastereo-and enantioselective synthesis of 3-hydroxy 2,3-dihydrobenzofurans via an intramolecular cis-selective aldol reaction employing proline-type organocatalysts is described enabling a new entry to coumarine natural products.

The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron-zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.