Catalytic Enantioselective Biltz Synthesis

Abstract

The Biltz synthesis establishes straightforward access to 5,5‐disubstituted (thio)hydantoins by combining a 1,2‐diketone and a (thio)urea. Its appealing features include inherent atom and step economy together with the potential to generate structurally diverse products. However, control of the stereochemistry of this reaction has proven to be a daunting challenge. Herein, we describe the first example of enantioselective catalytic Biltz synthesis which affords more than 40 thiohydantoins with high stereo‐ and regio‐control, irrespective of the symmetry of thiourea structure. A one pot synthesis of corresponding hydantoins is also documented. Remarkably, experimental studies and DFT calculations establish the reaction pathway and origin of stereoselectivity.

Catalytic Asymmetric Cyclizative Rearrangement of Anilines and Vicinal Diketones to Access 2,2‐Disubstituted Indolin‐3‐ones

“…To understand the possible reaction mechanism, a series of control experiments were performed (Scheme 2). Initially, 13 Clabeled 2,3-diketoester 2a' was synthesized to undergo this asymmetric cyclizative 1,2-rearrangement. Significantly, the isotopically labeled carbon exists as the aza-quaternary stereocenter rather than the carbonyl moiety in the product 13 C-3a (see Sup-porting Information for details), which suggests that the reaction proceeds via a 1,2-ester shift instead of a 1,2-phenyl migration (Scheme 2a).…”

“…Initially, 13 Clabeled 2,3-diketoester 2a' was synthesized to undergo this asymmetric cyclizative 1,2-rearrangement. Significantly, the isotopically labeled carbon exists as the aza-quaternary stereocenter rather than the carbonyl moiety in the product 13 C-3a (see Sup-porting Information for details), which suggests that the reaction proceeds via a 1,2-ester shift instead of a 1,2-phenyl migration (Scheme 2a). Importantly, it also implies that this CACR might be initiated by the nucleophilic 1,2-addition of C(sp 2 )-H to the central carbonyl group of 2,3-diketoester 2.…”

“…A crucial 𝛼-hydroxyl iminium intermediate C was then generated from the intramolecular cyclizative condensation of B in the presence of 4f. Finally, a stereospecific 1,2-ester shift [13,14] afforded the desired product 3 with the observed stereocontrol.…”

“…Recently, we disclosed a novel strategy of catalytic asymmetric cyclizative rearrangement (CACR) which enabled the efficient construction of a series of synthetically challenging heterocycles bearing aza-quaternary stereocenters (Scheme 1C). [12][13][14] Aimed toward a general and flexible strategy for the synthesis of enantiopure 2,2-disubstituted indolin-3-ones, we decided to pursue an alternative approach, that is, the development of a CACR of aniline derivatives and vicinal diketones. This strategy can in principle operate on diverse substituted substrates, and the resulting products are synthetically versatile due to the presence of functionalizable ester derivatives.…”