Since the seminal work of Butlerov (1863)[1a] and Grignard (1900),[1b] the addition of
preformed organometallic reagents to carbonyl compounds has played
a central role in chemical synthesis.[2] While
this technology has opened vast volumes of chemical space, the basicity
of most organometallic reagents mandates “protection”
of acidic substructures, including the ubiquitous hydroxyl group.
For the synthesis of carbohydrates, polyhydroxylated compounds bearing
multiple stereogenic centers, catalyst-directed stereoselective carbonyl
addition in the absence of protecting groups has only been achieved
using enzymes. In a groundbreaking advance, Shimizu and Kanai have
devised conditions for the direct anomeric propargylation of unprotected
aldoses with excellent levels of catalyst-directed diastereoselectivity.[3] This technology enables concise access to diverse
sialic acids (important cell-surface signaling molecules) and represents
a powerful addition to the lexicon of methods for protecting-group-free
chemical synthesis.[4]The anomeric propargylation of Shimizu and Kanai relies on three
key features. First, the use of allenylboronates as terminal propargyl
donors is essential, as such compounds are relatively nonbasic and
do not contribute significantly to an unselective background reaction.
Second, transmetalation must generate a chiral propargylmetal species
that is more reactive toward carbonyl addition, yet retains low basicity.
Further, this species must exert a diastereofacial bias that is strong
enough to overcome the intrinsic preference of the aldehyde. Soft
copper catalysts bound by state-of-the-art chiral phosphine ligands
meet this requirement. Finally, as aldoses prefer to reside in their
cyclic forms, a ring-opening additive, B(OMe)3, is needed
to increase the concentration of the “hidden aldehyde”.
Taking these factors into account, unprotected monosaccharides such
as d-mannose are subject to homologation with complete levels
of catalyst-directed diastereoselectivity.In summary, concise atom-efficient[5] chemical synthesis using carbohydrate building blocks has long been
impeded by the need to install and remove protecting groups.[6] While remarkable progress has been made on the
development of nonenzymatic catalysts for the site-selective modification
of diols and higher polyols (including sugars),[7] methods for their direct C–C coupling remain highly
uncommon, especially when delivering nonstabilized carbanion equivalents
with high levels of catalyst-directed stereoselectivity.[8] The anomeric propargylation developed by Shimizu
and Kanai expands the lexicon of catalytic asymmetric C–C bond
formations that may be deployed in the absence of protecting groups.
As demonstrated by the concise construction of various sialic acids,
such methodology streamlines de novo chemical synthesis. Of perhaps
greater significance, one can now easily imagine use of this technology
in combination with “click chemistry” to label and interrogate
the function of biomolecules that incorporate reducing sugars.[9]