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

Article abstract of DOI:10.1126/science.aat5883

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.

Full text of DOI:10.1126/science.aat5883

RESEARCH
◥
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) 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 man-
ner (Fig. 1D). This catalytic approach allows the
preparation of tertiary and quaternary centers to
access each and every diastereomer and enantio-
mer 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 supple-
mentary materials for more details). Several ali-
phatic 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
REPORT
ORGANIC CHEMISTRY
Stereodivergent synthesis of
1,4-dicarbonyls by traceless charge–
accelerated sulfonium rearrangement
Dainis Kaldre*, Immo Klose*, Nuno Maulide†
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.
uch of organic synthesis revolves around
the chemistry of the carbonyl group. Con-
catenations of more than one carbonyl
function are given special attention and
referred to by the relative disposition of
1,4-dicarbonyl systems remains an open problem
(1, 14–16).
Here we report a broad strategy to access acyclic,
polysubstituted 1,4-dicarbonyls via charge-accelerated
sulfonium rearrangement (17–19). Our approach
Institute of Organic Chemistry, University of Vienna,
Währinger Strasse 38, 1090 Vienna, Austria
*These authors contributed equally to this work.
M
†Corresponding author. Email: nuno.maulide@univie.ac.at
the two moieties (e.g., 1,3; 1,4; or 1,5), along with
strategies 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 the
intrinsic polarity of the carbonyl group. By con-
trast, the 1,4-dicarbonyl pattern remains chal-
lenging to access, even though 2,3-substituted
1,4-dicarbonyl motifs are commonly found in
numerous natural products (1) and drug scaf-
folds (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 cen-
tral, C2–C3 bond via oxidative coupling (1, 6–8)
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 prep-
aration 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
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.
Kaldre et al., Science 361, 664–667 (2018)
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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.
Kaldre et al., Science 361, 664–667 (2018)
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| REPORT
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.
alkynes (see supplementary materials), were all
well-tolerated. Sterically more demanding sub-
stituents 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 ob-
served matched-mismatched pairings leading to
diastereomeric ratios of 10:1 (matched, compare
2l) and 3:1 (mismatched, compare supplemen-
tary materials) respectively. The products were
isolated as free aldehydes ready for further func-
tionalization (see below), and ketones (2m) could
also 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 vinyl
sulfoxides led to increased yields and stereo-
selectivities (see supplementary materials for
details). Consistently high diastereo- and enan-
tioselectivities 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 switch-
ing between double bond geometry and sulfoxide
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) (30–33).
stereoisomers, as demonstrated in Fig. 2C (25–29).
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 pseudoequa-
torial orientation, whereas their (Z)-counterparts
mandate that the R1 substituent (Fig. 2C) occupies
a pseudoaxial orientation directing the substitu-
ents 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 b,b-disubstituted alkenylsulfoxides to access
all-carbon quaternary stereocenters in a stereo-
selective fashion. As shown in Fig. 3, A and B, the
easily controlled sulfoxide double bond geometry
correspondingly induces formation of the quater-
nary carbon stereocenter with high diastereose-
lectivity and perfect enantiocontrol.
Enantioenriched polysubstituted 1,4-dicarbonyls
are important intermediates in synthesis. For
example, diastereoselective nucleophilic additions
to 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 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 function-
alized 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.
Kaldre et al., Science 361, 664–667 (2018)
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Fig. 4. Applications. (A) Diastereoselective transformations. (B) Direct stereoselective access to succinate building blocks. Yields refer to isolated
1
material. d.r. ratios were determined by H-NMR analysis of the crude product.
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15 March 2018; accepted 12 June 2018
10.1126/science.aat5883
Kaldre et al., Science 361, 664–667 (2018)
17 August 2018
4 of 4

Stereodivergent synthesis of 1,4-dicarbonyls by traceless charge−accelerated sulfonium
rearrangement
Dainis Kaldre, Immo Klose and Nuno Maulide
Science 361 (6403), 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
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