REPORT◥

ORGANIC CHEMISTRY

Stereodivergent synthesis of1,4-dicarbonyls by traceless charge–accelerated sulfonium rearrangementDainis Kaldre*, Immo Klose*, Nuno Maulide†

The chemistry of the carbonyl group is essential to modern organic synthesis. Thepreparation of substituted, enantioenriched 1,3- or 1,5-dicarbonyls is well developed, astheir disconnection naturally follows from the intrinsic polarity of the carbonyl group. Bycontrast, a general enantioselective access to quaternary stereocenters in acyclic1,4-dicarbonyl systems remains an unresolved problem, despite the tremendousimportance of 2,3-substituted 1,4-dicarbonyl motifs in natural products and drug scaffolds.Here we present a broad enantioselective and stereodivergent strategy to access acyclic,polysubstituted 1,4-dicarbonyls via acid-catalyzed [3,3]-sulfonium rearrangementstarting from vinyl sulfoxides and ynamides. The stereochemistry at sulfur governs theabsolute sense of chiral induction, whereas the double bond geometry dictates the relativeconfiguration of the final products.

Much of organic synthesis revolves aroundthe chemistry of the carbonyl group. Con-catenations of more than one carbonylfunction are given special attention andreferred to by the relative disposition of

the two moieties (e.g., 1,3; 1,4; or 1,5), along withstrategies for their direct preparation. Highly effi-cient approaches exist for the preparation of sub-stituted, enantioenriched 1,3- or 1,5-dicarbonyls,as their disconnection naturally follows from theintrinsic polarity of the carbonyl group. By con-trast, the 1,4-dicarbonyl pattern remains chal-lenging to access, even though 2,3-substituted1,4-dicarbonyl motifs are commonly found innumerous natural products (1) and drug scaf-folds (2, 3) and are key synthons formany namedreactions in organic chemistry (4, 5) (Fig. 1A).Most of the current methods for the synthesis ofthese motifs involve direct formation of the cen-tral, C2–C3 bond via oxidative coupling (1, 6–8)or Umpolung strategies (9, 10) involving enolatealkylation (11) (Fig. 1B). However, whereas thefirst family of methods fails to properly addressstereoselectivity, the second one is limited instructural flexibility or requires multistep prep-aration of two chiral startingmaterialswhile beingonlymoderatelydiastereoselective.Rearrangementshave been used to access 1,4-dicarbonyls (12, 13),but these methods are strongly limited to certainmolecular scaffolds. A general enantioselectiveroute to quaternary stereocenters in acyclic

1,4-dicarbonyl systems remains an open problem(1, 14–16).Herewe report a broad strategy to access acyclic,

polysubstituted1,4-dicarbonyls viacharge-acceleratedsulfonium rearrangement (17–19). Our approach

uses highly enantioenriched alkenylsulfoxides—readily available substrates in two steps from com-mercially available menthyl sulfinates (Fig. 1C)(20–23). In combination with ynamides (24) anda Brønsted acid catalyst, these undergo a [3,3]-sulfonium rearrangement to form a thioniumintermediate that is hydrolyzed in situ to give therespective aldehydes or ketones in a tracelessman-ner (Fig. 1D). This catalytic approach allows thepreparation of tertiary and quaternary centers toaccess each and every diastereomer and enantio-mer of the 1,4-dicarbonyl products at will andwithhigh stereopurity.Our investigation started with the use of

(E)-vinyl sulfoxide 1a (22, 23), which enabledthe selective formation of syn-2,3–disubstituted1,4-dicarbonyls (Fig. 2A). During optimizationstudies, both the addition of water to the reactionmixture and the use of oxazolidinone-derivedynamides afforded superior results (see supple-mentary materials for more details). Several ali-phatic ynamides afforded the desired aldehydesin good yields and high diastereomeric ratio (d.r.),and the stereoselectivity was further improvedwhen aromatic ynamides were used (2d, 2e).Numerous base-sensitive functional groups suchas esters (2f), nitriles (2g), imides (2h), andketones(2i), as well as primary chlorides, aldehydes, and

RESEARCH

Kaldre et al., Science 361, 664–667 (2018) 17 August 2018 1 of 4

Institute of Organic Chemistry, University of Vienna,Währinger Strasse 38, 1090 Vienna, Austria*These authors contributed equally to this work.†Corresponding author. Email: nuno.maulide@univie.ac.at

Fig. 1. Relevance and synthesis of1,4-dicarbonyls. (A) 1,4-dicarbonyl motifs inbioactive substances. (B) Current strategies andcommon limitations. (C) Highly modular andstereoselective synthesis of vinyl sulfoxides.(D) Stereodivergent approach for the enantio– anddiastereoselective synthesis of 1,4-dicarbonyls.

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Kaldre et al., Science 361, 664–667 (2018) 17 August 2018 2 of 4

Fig. 2. Substrate scope. (A) syn-1,4-dicarbonyls. (B) anti-1,4-dicarbonyls.(C) Access to all possible stereoisomers of a 1,4-dicarbonyl product. Unlessotherwise indicated, reactions were run on 0.1- to 0.2-mmol scale. Yields weredetermined by 1H-NMR (nuclear magnetic resonance) using an internal

standard (isolated yields shown in parentheses). Diastereomeric. ratios weredetermined by 1H-NMRanalysis of the crude product. Enantiomeric excess (ee)determined via high-performance liquid chromatography (HPLC). * Isolatedyield. Modified conditions used, see supplementary materials for details.

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alkynes (see supplementary materials), were allwell-tolerated. Sterically more demanding sub-stituents on the sulfoxide greatly enhanced thestereoselectivity, delivering the desired productswith high diastereoselectivity (2j and 2k). Whenusing ynamides with a chiral auxiliary, we ob-served matched-mismatched pairings leading todiastereomeric ratios of 10:1 (matched, compare2l) and 3:1 (mismatched, compare supplemen-tary materials) respectively. The products wereisolated as free aldehydes ready for further func-tionalization (see below), and ketones (2m) couldalso be accessed using an a-substituted sulfoxide(R2 ≠ H).Conversely, the use of (Z)-sulfoxides resulted

in the formation of anti-1,4-dicarbonyl products(Fig. 2B). In this case, the use of alkyl vinylsulfoxides led to increased yields and stereo-selectivities (see supplementary materials fordetails). Consistently high diastereo- and enan-tioselectivities were observed. Thus, all fourpossible isomers (2a, 2n, and their respectiveenantiomers) of a 1,4-dicarbonyl product areaccessible by this stereodivergent approach, in

high yield and stereoselectivity, by simply switch-ing between double bond geometry and sulfoxidestereoisomers, as demonstrated in Fig. 2C (25–29).In our stereochemical model, the charge-

accelerated sulfoniumrearrangement is consistentwith a chair-like transition state. The (E)-vinylsulfoxides bias all substituents into a pseudoequa-torial orientation, whereas their (Z)-counterpartsmandate that the R1 substituent (Fig. 2C) occupiesa pseudoaxial orientation directing the substitu-ents to ananti-relationship in a final 1,4-dicarbonylstructure. The stereochemistry at sulfur governsthe absolute sense of chiral induction, whereasthe double bond geometry in turn dictates therelative stereochemistry of the final products.Having successfully demonstrated diastereo-

and enantiodivergence, we turned our attentionto b,b-disubstituted alkenylsulfoxides to accessall-carbon quaternary stereocenters in a stereo-selective fashion. As shown in Fig. 3, A and B, theeasily controlled sulfoxide double bond geometrycorrespondingly induces formation of the quater-nary carbon stereocenter with high diastereose-lectivity and perfect enantiocontrol.

Exploring this approach further, we were ableto install isopropyl (2ad), alkynyl (2ae), fluoro(-F) (2af), and trifluoromethyl substituents (2ag)on the newly formed quaternary center, all ofwhich usually would require their own syntheticstrategy (Fig. 3C) (30–33).Enantioenrichedpolysubstituted 1,4-dicarbonyls

are important intermediates in synthesis. Forexample, diastereoselective nucleophilic additionsto the aldehyde moiety easily afforded trisubsti-tuted lactone 3 (Fig. 4A) (34) or the two-step pro-tocol afforded g-oxobutyric acid building block 4(35). A direct comparison of our method to state-of-the-art enolate coupling highlights its advan-tages, in that both stereoisomers become availableat will and in high purity under comparably mild,catalytic conditions. Several highly potent MMPinhibitors bear a 2,3-disubstituted 1,4-dicarbonylbackbone, and the simple access to fully function-alized succinate 6 with excellent stereocontrol (Fig.4B) is representative of the synthetic value of thismethod (2, 36). That the fully annotated precursor5is elaborated in a single-step from the unconventionalbuilding blocks 1d and7 is a hallmark of this strategy.

Kaldre et al., Science 361, 664–667 (2018) 17 August 2018 3 of 4

Fig. 3. Synthesis of all-carbon quaternary products. (A) Preparation ofquaternary centers. (B) Scope of ynamides. (C) Scope of vinyl sulfoxides,including fluorine and trifluoromethyl derivatives. Unless otherwise indicated,

reactions were run on 0.1- to 0.2-mmol scale. Yields were determined by1H-NMR using an internal standard. Isolated yields in parentheses. d.r. ratioswere determined by 1H-NMR analysis of the crude product.

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ACKNOWLEDGMENTS

I.. A Roller (University of Vienna) is acknowledged for assistancewith crystallographic structure determination and E. Macoratti(University of Vienna) for HPLC analysis. Funding: We are grateful tothe ERC (CoG VINCAT), the FWF (P30226), and the DFG (grantMA 4861/4-2) for financial support of this research. Generouscontinued support by the University of Vienna is acknowledged.Author contributions: N.M. conceived the project; D.K. andI.K. carried out the experiments; N.M., D.K., I.K. wrote the manuscript.Competing interests: The authors declare no competing financialinterests. Data and materials availability: X-ray structural data areavailable free of charge from the Cambridge Crystallographic DataCentre under CCDC 1828062. Other characterization data, optimizationtables, and additional substrates are in the supplementary materials.Requests for materials should be addressed to N.M.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/361/6403/664/suppl/DC1Materials and MethodsTable S1 to S6Figs. S1 to S8NMR SpectraHPLC SpectraReferences (37–52)

15 March 2018; accepted 12 June 201810.1126/science.aat5883

Kaldre et al., Science 361, 664–667 (2018) 17 August 2018 4 of 4

Fig. 4. Applications. (A) Diastereoselective transformations. (B) Direct stereoselective access to succinate building blocks. Yields refer to isolatedmaterial. d.r. ratios were determined by 1H-NMR analysis of the crude product.

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rearrangementaccelerated sulfonium−Stereodivergent synthesis of 1,4-dicarbonyls by traceless charge

Dainis Kaldre, Immo Klose and Nuno Maulide

originally published online August 16, 2018DOI: 10.1126/science.aat5883 (6403), 664-667.361Science 

, this issue p. 664Scienceresearch.rearrangement. The versatility of the method should facilitate selective access to 1,4-dicarbonyl motifs in pharmaceuticalThe outcome depends on the straightforwardly tunable configuration of a sulfoxide group in a precursor, which guides a

present a single method to access each stereoisomer individually.et al.potentially distinct biochemical properties. Kaldre chemistry. When these central carbons each have a substituent, there are four possible mutual geometries, all with

Compounds with adjacent carbons sandwiched between two carbonyl (C=O) centers turn up frequently in organicFour varieties of carbonyl sandwich

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MATERIALSSUPPLEMENTARY http://science.sciencemag.org/content/suppl/2018/08/15/361.6403.664.DC1

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