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Small molecule synthesis via iterative cross-coupling (ICC) For this work, the Burke group was recently selected as one of the "World's 35 Top Innovator's Under 35" by Technology Review. For a slide show describing the ICC concept and its potential impact on medicine click here.
A new concept for controlling the reactivity of boronic acids
Selective cross-coupling with avariety of bifunctional haloboronic acids
Simple, efficient, and modular syntheses of natural products via ICC
These new building blocks have proven to be very powerful in the context of total synthesis of polyene natural products all trans-retinal (Scheme 4), beta-parinaric acid (Scheme 5). See section 2 for the use of this strategy en route to the total synthesis of the channel-forming polyene macrolide amphotericin B. 
It is our ultimate goal to harness the remarkable simplicity of these methods and
robust nature of the B-protected haloboronic acid building blocks to develop a fully-automated
small molecule synthesis process analogous to modern peptide coupling. Achieving
this goal has the potential to make this powerful discovery engine maximally accessible,
even to the non-chemist. Achieving this goal will broadly enable the more effective
study and widespread utilization of this extraordinary class of compounds.
1. E.P. Gillis, M.D. Burke. "Multistep Synthesis of Complex Boronic Acids from Simple MIDA Boronates" J. Am. Chem. Soc. 2008, ASAP.
2. S.J. Lee, K.C. Gray, J.S. Paek, M.D. Burke. "Simple, efficient, and modular syntheses
of polyene natural products via iterative cross-coupling" J. Am. Chem. Soc.
2008, 130, 466-468.
3. E.P. Gillis, M.D. Burke, "A simple and modular strategy for small molecule synthesis:
iterative Suzuki-Miyaura coupling of B-protected haloboronic acid building blocks"
J. Am. Chem. Soc. 2007, 129, 6716-6717.
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To most effectively harness the potential impact of complex small molecules on both
science and medicine, it is critical to maximize the simplicity, efficiency, and
flexibility with which these types of compounds can be synthesized in the laboratory.
In this regard, modern peptide synthesis (Fig. 1, left), involving the iterative
coupling of bifunctional amino acids represents an inspiring benchmark. Amino acid
building blocks are now commercially-available in suitably-protected form as stable,
crystalline solids, and the process of peptide synthesis is routinely automated.
As a result, this highly enabling methodology is accessible to a broad range of
scientists. In sharp contrast, the laboratory synthesis of small molecules remains
a relatively complex and non-systematized process. We are currently developing a
simple and highly modular strategy for making small molecules which is analogous
to peptide synthesis and involves iterative Suzuki-Miyaura cross-coupling of B-protected
haloboronic acids (Fig. 1, right). In this approach, building blocks are
prepared (or in the future simply purchased) having all of the required functional
groups preinstalled in the correct oxidation state and with the desired stereochemical
relationships. These building blocks are then brought together via the recursive
application of one mild reaction. Although certain small molecules are currently
more amenable to this approach than others, the rapidly expanding scope of the Suzuki-Miyaura
reaction, which increasingly includes sp3-sp3 couplings, suggests the potential
for broad generality. Our long term goal is to create a general and automated process
for the simple and flexible construction of a broad range of complex small molecules,
thereby making this powerful discovery engine widely accessible, even to the non-chemist.
Similar to the way an Fmoc or Boc protective group enables the controlled, iterative
coupling of bifunctional amino acid building blocks (i.e., by avoiding random
oligomerization), realizing the proposed iterative cross-coupling strategy required
the discovery of a ligand for boronic acids that can reversibly attenuate the reactivity
of this functional group under cross-coupling conditions. Current data suggest that
transmetalation in the Suzuki-Miyaura reaction requires a vacant and Lewis acidic
boron p-orbital (Fig. 2A).
Consistent with this, we recently discovered that the
rehybridization of a boron center from sp2 to sp3 via complexation
with the commercially-available trivalent ligand, N-methyliminodiacetic acid
(MIDA, Fig. 2B) inhibits its reactivity towards cross-coupling. X-ray crystallographic
analysis confirmed that the boron atom in these complexes is sp3-hybridized
(Fig. 3). Moreover, although MIDA boronate esters are protected from anhydrous Suzuki-Miyaura
coupling even under forcing conditions (sealed tube, elevated temperatures, long
reaction times), deprotection can be readily achieved at 23 °C in 10 minutes
using very mild aqueous base. This remarkable orthogonality is both surprising and
highly enabling for applications to complex molecule synthesis (see below).
A broad range of haloboronic acids have been complexed with MIDA to yield a series
of B-protected bifunctional building blocks (Table 2). In contrast to many
boronic acids, all of these boronate esters are indefinitely bench stable under
air. Remarkably, although the reactivity of aryl, heteroaryl, vinyl, and
alkylboronic acids can vary dramatically, the same protective group is effective
with all four classes of nucleophiles. All of these products are also deprotected
efficiently to using a standard set of mild aq. basic conditions (1M aq. NaOH/THF,
23 °C, 10 min). The extremely mild aq. NaHCO3 in MeOH is also effective.
As demonstrated below, these types of B-protected haloboronic acids have proven
to be very powerful building blocks for small molecule synthesis. Our future plans
involve dramatically expanding this pool of bifunctional reagents, focusing on the
key substructures that are common in a wide variety of natural products, pharmaceutical
agents, and specialized materials. We are especially interested in exploring new
building blocks with sp3-hybridized organohalide and boronic acid moieties,
which have the potential to dramatically expand the generality of this approach.
A major, international chemical company is planning to make a large collection of
these types of B-protected haloboronic acid building blocks commercially-available
to the scientific community within the coming year. We hope that this will dramatically
catalyze the utilization of this new chemistry.
The cross-coupling strategy described herein is distinguished by its theoretically
limitless potential for iteration. To begin exploration of this potential and the
compatibility of this mild protective group methodology with complex small molecule
substrates, we targeted the first total synthesis of the natural product ratanhine,
the most complex member of a large family of neolignans isolated from the medicinal
plant Ratanhiae radix. Retrosynthetic fragmentation of ratanhine into four
simpler building blocks A-D via recursive application of the Suzuki-Miyaura
transform is shown in Scheme 1. The synthesis (Scheme 2) commenced with a
selective cross-coupling between vinyl boronic acid A and bromoarylboronate
B. Strikingly, although the corresponding heteroarylboronic acids decompose
in one day, these benzofuranyl MIDA boronates were bench stable under air for several
months. After deprotection, cross-coupling with the electron-rich and sterically-bulky
aryl bromide C required both an elevated temperature (80 °C, sealed tube)
and extended reaction time (28 hours). Remarkably, the MIDA protective group was
found to be completely stable to these forcing conditions. A final sequence of B-deprotection,
cross-coupling with D, and cleavage of the two MOM ethers completed
the first total synthesis of ratanhine. As demonstrated with this first example,
the iterative cross-coupling strategy enables the use of a single mild reaction
to bring together a collection of easily synthesized, readily purified, and highly
robust building blocks. This synthesis is also short and highly modular.
The synthesis of polyenes is made challenging by the sensitivity of conjugated double
bond frameworks to light, oxygen, and many common synthetic reagents, especially
protic and Lewis acids. Controlling stereochemistry during the formation of each
double bond is also a critical issue. Syntheses based on palladium-mediated cross-coupling
are attractive due to the mild, non-acidic, and stereospecific nature of these methods.
Among these, the Suzuki-Miyaura (SM) reaction stands out due to its use of
non-toxic boronic acid reagents and extraordinary functional group compatibility.
However, polyenylboronic acids are notoriously unstable, which precludes their general
utilization. We recently reported a novel collection of B-protected haloalkenylboronic
acid building blocks that are strikingly stable to purification and storage, and
highly selective towards a wide range of cross-coupling reactions. This remarkable
stability is maintained in the resulting polyenyl MIDA-boronate ester intermediates,
thereby enabling the simple, efficient, and modular construction of a variety of
polyene natural products with higher-order functions.