Lucas Schreyer

Extremely Active Organocatalysts Enable a Highly Enantioselective Addition of Allyltrimethylsilane to Aldehydes

The enantioselective allylation of aldehydes to form homoallylic alcohols is one of the most frequently used carbon-carbon bond-forming reaction in chemical synthesis and, for several decades, has been a testing ground for new asymmetric methodology. However, a general and highly enantioselective catalytic addition of the inexpensive, nontoxic, air- and moisture-stable allyltrimethylsilane to aldehydes, the Hosomi-Sakurai reaction, has remained elusive. Reported herein is the design and synthesis of a highly acidic imidodiphosphorimidate motif (IDPi), which enables this transformation, thus converting various aldehydes with aromatic and aliphatic groups at catalyst loadings ranging from 0.05 to 2.0 mol % with excellent enantioselectivities. Our rationally constructed catalysts feature a highly tunable active site, and selectively process small substrates, thus promising utility in various other challenging chemical reactions.

Confined acids catalyze asymmetric single aldolizations of acetaldehyde enolates

An acid inaccessible to aldol products The aldol reaction is a venerable and widely applicable method for making carbon-carbon bonds. Ironically, it is most challenged by the simplest substrates. The trouble is that the product looks a lot like one of the reactants, and so it can latch onto the coupling partner instead. Schreyer et al. report that a bulky phosphorus-based acid catalyst alleviates this problem. The acidic site is buried in a pocket that is too small to activate the product for further reaction. The chiral geometry of the catalyst also induces high enantioselectivity. Science, this issue p. 216 A phosphorus-based acid catalyst envelops its substrate to form just one carbon-carbon bond selectively. Reactions that form a product with the same reactive functionality as that of one of the starting compounds frequently end in oligomerization. As a salient example, selective aldol coupling of the smallest, though arguably most useful, enolizable aldehyde, acetaldehyde, with just one partner substrate has proven to be extremely challenging. Here, we report a highly enantioselective Mukaiyama aldol reaction with the simple triethylsilyl (TES) and tert-butyldimethylsilyl (TBS) enolates of acetaldehyde and various aliphatic and aromatic acceptor aldehydes. The reaction is catalyzed by recently developed, strongly acidic imidodiphosphorimidates (IDPi), which, like enzymes, display a confined active site but, like small-molecule catalysts, have a broad substrate scope. The process is scalable, fast, efficient (0.5 to 1.5 mole % catalyst loading), and greatly simplifies access to highly valuable silylated acetaldehyde aldols.

Enzymatic Nitrene Transfer/Sigmatropic Rearrangement to Access Allylic Amines

Significance: Arnold and co-workers report an enzymatic synthesis of allylic amines through a sulfimidation/[2,3]-sigmatropic rearrangement of phenyl allyl sulfides with tosyl azide. A mutant variant of cytochrome P411 from Bacillus megaterium efficiently catalyzes a highly enantioselective nitrene transfer to the sulfides, and permits a subsequent rearrangement with partial retention of the stereochemical information. In a scale-up experiment with reduced catalyst loading, 0.1 mmol of substrate was converted into the corresponding allylic amine in 71% yield and a remarkable total turnover number of 6100. Comment: The authors have successfully employed directed evolution to achieve a chemoselective nitrene transfer over the competing reduction. Furthermore, they achieved a sigmatropic rearrangement of the intermediate allylic sulfimides, a process unknown in wild-type biological systems. N N N N Fe Ph S R1 Ph S R1 N Ts

Amine-Catalyzed Direct Vinylogous Michael Addition of Dienols to Enals

Significance: Xu and co-workers report a vinylogous Michael addition of acyclic alkyl and aryl allyl ketones to enals. The reaction is catalyzed by a chiral secondary amine (A) and a chiral hydrogen bond donor (B), which in combination enable the formation of the desired enones in moderate to excellent yields and regioselectivities, and with excellent enantioselectivities. The scalability of the reaction was proven in one experiment starting with 1.46 gram of phenyl allyl ketone. Comment: While the application of catalyst A in combination with a ‘regular’ Brønsted acid or base (e.g., benzoic acid or DABCO) already furnished small amounts of desired product with excellent enantioselectivity, it required a second, anion-binding catalyst (B) to enhance the reactivity of the proposed α,β-unsaturated iminium ion intermediate by ion pair separation and to shield the α-position of the nucleophile, effecting the desired γ-selectivity. The concept of supramolecular iminium ion catalysis was previously reported by the same group (Angew. Chem. Int. Ed. 2012, 51, 12339). R1 O