Please cite this article in press as: Ma et al., A General Approach to Stereospecific Cross-Coupling Reactions of Nitrogen-Containing Stereo-
centers, Chem (2020), https://doi.org/10.1016/j.chempr.2020.02.002
Article
A General Approach to Stereospecific
Cross-Coupling Reactions
of Nitrogen-Containing Stereocenters
Xinghua Ma,1,2 Haoran Zhao,1,2 Meruyert Binayeva,1,2 Glenn Ralph,1,2 Mohamed Diane,1,2
Shibin Zhao,1,2 Chao-Yuan Wang,1,2 and Mark R. Biscoe1,2,3,
*
SUMMARY
The Bigger Picture
A novel strategy employing cyclohexyl spectator ligands in Stille cross-coupling
reactions has been developed as a general solution to the long-standing chal-
lenge of conducting stereospecific cross-coupling reactions at nitrogen-contain-
ing stereocenters. This method enables direct access to enantioenriched prod-
ucts that are difficult (or impossible) to obtain via alternative preparative
methods. Selective and predictable transfer of a single secondary alkyl unit
can be achieved under reaction conditions that exploit subtle electronic differ-
ences between activated and unactivated alkyl units. Through this approach,
enantioenriched a-stannylated nitrogen-containing stereocenters undergo
Pd-catalyzed arylation and acylation reactions with exceptionally high stereofi-
delity in all instances investigated. We demonstrate this process by using a-stan-
nylated pyrrolidine, azetidine, and open-chain (benzylic and non-benzylic)
nucleophiles in stereospecific reactions. This process will facilitate rapid and
reliable access to enantioenriched compounds possessing nitrogen-substituted
stereocenters, which constitute ubiquitous structural motifs in biologically
active compounds emerging from the drug-discovery process.
Two molecules that have the same
structure and composition but are
mirror images of each other can
produce very different biological
responses. Therefore, control of
the 3D atomic arrangement in
molecules is critical in the drug-
discovery process. Because
biologically active molecules tend
to contain C–N bonds, a general
method to control the 3D
structure of nitrogen-substituted
carbon atoms would be
particularly useful toward
facilitating the discovery and
development of new medicines. In
this report, we detail a general
method to modify the 3D
INTRODUCTION
structure of nitrogen-containing
carbon centers. We employ
palladium-catalyzed cross-
The biological properties of organic molecules are greatly influenced by the presence of
1
nitrogen atoms within their molecular architectures. Nitrogen-containing stereocenters
are particularly common structural motifs within biologically active molecules that
emerge from the drug-discovery process. Indeed, four of the top five most commonly
encountered nitrogen-containing heterocycles in FDA-approved drugs contain satu-
coupling reactions in C–C bond-
forming reactions where the initial
3
D structure of the reactant is
2
rated rings and therefore the possibility of stereoisomers. When preparing such mole-
predictably transferred to the final
product. With this new method,
scientists will now be able to use
cross-coupling reactions to
cules, control of the absolute and relative stereochemistry of the nitrogen-containing
stereocenter is a vital concern. Thus, the development of general synthetic strategies
that enable precise stereochemical control of nitrogen-containing stereocenters consti-
tutes an essential goal in organic chemistry.
rapidly generate libraries of new
compounds while controlling the
Over the past decade, stereospecific cross-coupling strategies have emerged as
viable synthetic options to achieve precise stereocontrol of carbon-carbon
3
D architecture of the
compounds.
3
–9
bonds.
tioenriched organotin
We, and others, have demonstrated that configurationally stable, enan-
1
0–22
23–37
and organoboron
may be employed in Pd-catalyzed
cross-coupling reactions where transmetallation proceeds primarily through a ster-
eoretentive or stereoinvertive mechanism, leading to predictable stereochemical
outcomes (Figure 1A). Commonly, the use of alkyl nucleophiles that bear specific
2
modes of activation, such as a-C(sp ) groups, a-heteroatoms, ring strain, and/or
Chem 6, 1–11, March 12, 2020 ª 2020 Elsevier Inc.
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