Stereodivergent synthesis of 1,4-dicarbonyls by traceless charge–accelerated sulfonium rearrangement

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Science  17 Aug 2018:
Vol. 361, Issue 6403, pp. 664-667
DOI: 10.1126/science.aat5883

Four varieties of carbonyl sandwich

Compounds with adjacent carbons sandwiched between two carbonyl (C=O) centers turn up frequently in organic chemistry. When these central carbons each have a substituent, there are four possible mutual geometries, all with potentially distinct biochemical properties. Kaldre et al. present a single method to access each stereoisomer individually. The outcome depends on the straightforwardly tunable configuration of a sulfoxide group in a precursor, which guides a rearrangement. The versatility of the method should facilitate selective access to 1,4-dicarbonyl motifs in pharmaceutical research.

Science, this issue p. 664


The chemistry of the carbonyl group is essential to modern organic synthesis. The preparation of substituted, enantioenriched 1,3- or 1,5-dicarbonyls is well developed, as their disconnection naturally follows from the intrinsic polarity of the carbonyl group. By contrast, a general enantioselective access to quaternary stereocenters in acyclic 1,4-dicarbonyl systems remains an unresolved problem, despite the tremendous importance 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 rearrangement starting from vinyl sulfoxides and ynamides. The stereochemistry at sulfur governs the absolute sense of chiral induction, whereas the double bond geometry dictates the relative configuration of the final products.

Much of organic synthesis revolves around the chemistry of the carbonyl group. Concatenations of more than one carbonyl function are given special attention and referred to by the relative disposition of the two moieties (e.g., 1,3; 1,4; or 1,5), along with strategies for their direct preparation. Highly efficient approaches exist for the preparation of substituted, enantioenriched 1,3- or 1,5-dicarbonyls, as their disconnection naturally follows from the intrinsic polarity of the carbonyl group. By contrast, the 1,4-dicarbonyl pattern remains challenging to access, even though 2,3-substituted 1,4-dicarbonyl motifs are commonly found in numerous natural products (1) and drug scaffolds (2, 3) and are key synthons for many named reactions in organic chemistry (4, 5) (Fig. 1A). Most of the current methods for the synthesis of these motifs involve direct formation of the central, C2–C3 bond via oxidative coupling (1, 68) or Umpolung strategies (9, 10) involving enolate alkylation (11) (Fig. 1B). However, whereas the first family of methods fails to properly address stereoselectivity, the second one is limited in structural flexibility or requires multistep preparation of two chiral starting materials while being only moderately diastereoselective. Rearrangements have been used to access 1,4-dicarbonyls (12, 13), but these methods are strongly limited to certain molecular scaffolds. A general enantioselective route to quaternary stereocenters in acyclic 1,4-dicarbonyl systems remains an open problem (1, 1416).

Fig. 1 Relevance and synthesis of 1,4-dicarbonyls.

(A) 1,4-dicarbonyl motifs in bioactive substances. (B) Current strategies and common limitations. (C) Highly modular and stereoselective synthesis of vinyl sulfoxides. (D) Stereodivergent approach for the enantio– and diastereoselective synthesis of 1,4-dicarbonyls.

Here we report a broad strategy to access acyclic, polysubstituted 1,4-dicarbonyls via charge-accelerated sulfonium rearrangement (1719). Our approach uses highly enantioenriched alkenylsulfoxides—readily available substrates in two steps from commercially available menthyl sulfinates (Fig. 1C) (2023). In combination with ynamides (24) and a Brønsted acid catalyst, these undergo a [3,3]-sulfonium rearrangement to form a thionium intermediate that is hydrolyzed in situ to give the respective aldehydes or ketones in a traceless manner (Fig. 1D). This catalytic approach allows the preparation of tertiary and quaternary centers to access each and every diastereomer and enantiomer of the 1,4-dicarbonyl products at will and with high stereopurity.

Our investigation started with the use of (E)-vinyl sulfoxide 1a (22, 23), which enabled the selective formation of syn-2,3–disubstituted 1,4-dicarbonyls (Fig. 2A). During optimization studies, both the addition of water to the reaction mixture and the use of oxazolidinone-derived ynamides afforded superior results (see supplementary materials for more details). Several aliphatic ynamides afforded the desired aldehydes in good yields and high diastereomeric ratio (d.r.), and the stereoselectivity was further improved when aromatic ynamides were used (2d, 2e). Numerous base-sensitive functional groups such as esters (2f), nitriles (2g), imides (2h), and ketones (2i), as well as primary chlorides, aldehydes, and alkynes (see supplementary materials), were all well-tolerated. Sterically more demanding substituents on the sulfoxide greatly enhanced the stereoselectivity, delivering the desired products with high diastereoselectivity (2j and 2k). When using ynamides with a chiral auxiliary, we observed matched-mismatched pairings leading to diastereomeric ratios of 10:1 (matched, compare 2l) and 3:1 (mismatched, compare supplementary materials) respectively. The products were isolated as free aldehydes ready for further functionalization (see below), and ketones (2m) could also be accessed using an α-substituted sulfoxide (R2 ≠ H).

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. Unless otherwise indicated, reactions were run on 0.1- to 0.2-mmol scale. Yields were determined by 1H-NMR (nuclear magnetic resonance) using an internal standard (isolated yields shown in parentheses). Diastereomeric. ratios were determined by 1H-NMR analysis of the crude product. Enantiomeric excess (ee) determined via high-performance liquid chromatography (HPLC). * Isolated yield. Modified conditions used, see supplementary materials for details.

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 vinyl sulfoxides led to increased yields and stereoselectivities (see supplementary materials for details). Consistently high diastereo- and enantioselectivities were observed. Thus, all four possible isomers (2a, 2n, and their respective enantiomers) of a 1,4-dicarbonyl product are accessible by this stereodivergent approach, in high yield and stereoselectivity, by simply switching between double bond geometry and sulfoxide stereoisomers, as demonstrated in Fig. 2C (2529).

In our stereochemical model, the charge-accelerated sulfonium rearrangement is consistent with a chair-like transition state. The (E)-vinyl sulfoxides bias all substituents into a pseudoequatorial orientation, whereas their (Z)-counterparts mandate that the R1 substituent (Fig. 2C) occupies a pseudoaxial orientation directing the substituents to an anti-relationship in a final 1,4-dicarbonyl structure. The stereochemistry at sulfur governs the absolute sense of chiral induction, whereas the double bond geometry in turn dictates the relative stereochemistry of the final products.

Having successfully demonstrated diastereo- and enantiodivergence, we turned our attention to β,β-disubstituted alkenylsulfoxides to access all-carbon quaternary stereocenters in a stereoselective fashion. As shown in Fig. 3, A and B, the easily controlled sulfoxide double bond geometry correspondingly induces formation of the quaternary carbon stereocenter with high diastereoselectivity and perfect enantiocontrol.

Fig. 3 Synthesis of all-carbon quaternary products.

(A) Preparation of quaternary 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 by 1H-NMR using an internal standard. Isolated yields in parentheses. d.r. ratios were determined by 1H-NMR analysis of the crude product.

Exploring this approach further, we were able to install isopropyl (2ad), alkynyl (2ae), fluoro (-F) (2af), and trifluoromethyl substituents (2ag) on the newly formed quaternary center, all of which usually would require their own synthetic strategy (Fig. 3C) (3033).

Enantioenriched polysubstituted 1,4-dicarbonyls are important intermediates in synthesis. For example, diastereoselective nucleophilic additions to the aldehyde moiety easily afforded trisubstituted lactone 3 (Fig. 4A) (34) or the two-step protocol afforded γ-oxobutyric acid building block 4 (35). A direct comparison of our method to state-of-the-art enolate coupling highlights its advantages, in that both stereoisomers become available at will and in high purity under comparably mild, catalytic conditions. Several highly potent MMP inhibitors bear a 2,3-disubstituted 1,4-dicarbonyl backbone, and the simple access to fully functionalized succinate 6 with excellent stereocontrol (Fig. 4B) is representative of the synthetic value of this method (2, 36). That the fully annotated precursor 5 is elaborated in a single-step from the unconventional building blocks 1d and 7 is a hallmark of this strategy.

Fig. 4 Applications.

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

Supplementary Materials

Materials and Methods

Table S1 to S6

Figs. S1 to S8

NMR Spectra

HPLC Spectra

References (3752)

References and Notes

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

Correction (21 August 2018): Several minor structural and labeling errors in Figs. 1 to 4 have been corrected.

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