Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan‐CDK inhibitor), BAY 1143572 (P‐TEFb inhibitor), and AZD 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal‐chemistry‐relevant properties of sulfoximines. Herein we report the synthesis and in vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery.

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Indium-mediated allylation of N-tert-butanesulfinyl ketimines afforded in high yields and diastereoselectivities homoallylic amine derivatives with the nitrogen atom bonded to a quaternary stereocenter.

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The palladium-catalyzed allylation of N-tert-butanesulfinyl imines with allylic alcohols in the presence of InI as reducing reagent takes place with high diastereoselectivity in reasonable yields. The reaction with crotyl alcohol is totally regioselective, leading to the antidiastereomer as the main reaction product.The stereoselective allylation of imines using organometallic compounds is of great interest in synthetic organic chemistry because the resulting homoallylic amines are valuable building blocks. 1 For instance, the double bond of the allylic moiety can participate in a number of further synthetically useful transformations: hydroboration, hydration, epoxidation, hydroformylation, ozonolysis, olefin metathesis, etc. 2 Among the stereoselective methodologies, the catalytic enantioselective allylations 3 rely on the use of chiral Lewis acids or chiral Lewis bases. In addition, double activation could be also achieved by using chiral bifunctional catalysts 4 by the simultaneous activation of both electrophilic and nucleophilic reaction partners through a cooperative action of different functionalities of the ligand. However, and in spite of the rapid evolution of catalytic methods in recent years, the use of stoichiometric reagents (including substrates and/or allylic organometallic partners) is still the favourite choice of organic chemists in the synthesis of key intermediates of natural products. In these diastereoselective allylations, 5 the stereochemical information can be transferred by substrate control, including chiral auxiliaries, or through the use of chiral reagents (reagent control). Sometimes a double induction could also be involved in the process, a match/mismatch effect being possible. Performing the stereoselective allylation of imine derivatives with allylic halides in the presence of reducing metals under Barbier-type reaction conditions (metalation in the presence of the electrophile) is also of interest, because this strategy circumvents the need of isolating allyl metal species (the real nucleophiles), which usually are sensitive, and in many cases also toxic. The most commonly used metals in these transformations are chromium, 6 indium 7 and zinc. 8 Particularly noteworthy is the use of allylic alcohols as allylating reagents of carbonyl compounds and imines under palladium catalysis in the presence of a reducing reagent. 9 More recently, the use of the Kulinkovich reagent in the coupling of allylic alcohols with aldimines provides an alternative approach to regio-and stereodefined homoallylic amines. 10 On the other hand, in the growing field of the synthetic applications of chiral N-tert-butanesulfinyl derivatives, 11 we reported the diastereoselective allylation 12 of N-tert-butanesulfinyl aldimines 13 and ketimines 14 with in situ generated allylindium reagents, and the first one-pot a-aminoallylation of aldehydes with chiral tert-butanesulfinamide, allylic bromides, and indium, which provides homoallylic amines with high chemoand stereoselectivities. 15 The chiral auxiliar...

Chiral tert‐butylsulfinyl imines 3, which are easily prepared from the corresponding bromo carbonyl compounds 1 and tert‐butanesulfinamide (2), undergo a diastereoselective allylation by using indium metal and allyl bromide to give the corresponding homoallyl sulfinylamines 4. Treatment of compounds 4 with a catalytic amount of palladium acetate and triphenylphosphane gives exo‐methylene‐substitutedsulfinylamino)benzocycloalkenes 5 (five‐ to seven‐membered rings) that are easily deprotected with hydrochloric acid to give chiral primary amines 6.

LiOt-Bu (3 equiv) CPME, 110 °C

The front cover picture shows the general structure of a sulfoximine group in front of a charge density distribution from a computational modeling study, surrounded by a puzzle of tablets that is still being assembled. Sulfoximines, the monoaza‐analogues of sulfones, have been neglected in the life sciences for a long time but have gained considerable recognition as a new and versatile structural motif just recently. The synthetic methodology for sulfoximines has progressed significantly; however, the general understanding of this functional group regarding the medicinal‐chemistry‐relevant properties is still limited. To contribute novel pieces to the emerging picture of sulfoximines in drug discovery, researchers at Bayer AG prepared a set of direct sulfoximine analogues of marketed drugs and advanced clinical candidates to compare the in vitro properties of the matched molecular pairs with respect to biological activity, pharmacokinetics, and physicochemistry. More information can be found in the Full Paper by Ulrich Lücking and Juan Alberto Sirvent on page 487 in Issue 7, 2017 (DOI: 10.1002/cmdc.201700044).