Multistep synthesis of complex boronic acids from simple MIDA boronates

Article abstract of DOI:10.1021/ja8063759

Due to its sensitivity to most synthetic reagents, it is typically necessary to introduce the boronic acid functional group just prior to its utilization. Overcoming this important limitation, we herein report that air- and chromatographically stable MIDA boronates are compatible with a wide range of common reagents which enables the multistep synthesis of complex boronic acid building blocks from simple B-containing starting materials. X-ray and variable temperature NMR studies link the unique stability of MIDA boronates to a kinetic inaccessibility of the potentially reactive boron p-orbital and/or nitrogen lone pair. These findings were collectively harnessed to achieve a short and modular total synthesis of (+)-crocacin C via the iterative cross-coupling of a structurally complex, MIDA-protected haloboronic acid building block. Copyright

Full text of DOI:10.1021/ja8063759

Published on Web 10/07/2008
Multistep Synthesis of Complex Boronic Acids from Simple MIDA Boronates
Eric P. Gillis and Martin D. Burke*
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
Received August 12, 2008; E-mail: burke@scs.uiuc.edu
Boronic acids are tremendously useful building blocks for organic
synthesis.1 However, to avoid incompatibilities with most synthetic
reagents, it is typically necessary to introduce the boronic acid group
just prior to its utilization. Because most of the methods for achieving
this have limited functional group tolerance, accessing structurally
complex boronic acids can be very challenging. A variety of sterically
bulky boronic esters are more compatible with synthetic reagents than
their boronic acid counterparts.2 However, liberation of the boronic
acid usually requires harsh conditions that can be incompatible with
complex substrates. Trifluoroborate salts can in many cases serve as
highly effective surrogates for boronic acids.3 These compounds are
also stable to a variety of common reaction conditions and benchtop
storage, thus providing novel access to many important organoboranes.3,4
However, a lack of compatibility with chromatography can significantly
limit the utility of trifluoroborate salts in the multistep synthesis of
structurally and/or stereochemically complex building blocks.
In addition to being unreactive under anhydrous cross-coupling
conditions, we have recently reported that N-methyliminodiacetic acid
(MIDA) boronates5 are universally compatible with chromatography,
exceptionally stable to benchtop storage, and easily hydrolyzed using
mild conditions to liberate the corresponding boronic acids.6,7 MIDA
boronates thus represent a potentially general building block platform
with distinct advantages over boronic acids and other surrogates.
Greatly expanding access to these materials, we herein report the
discovery that MIDA boronates are compatible with a wide range of
common synthetic reagents. As demonstrated with the total synthesis
of (+)-crocacin C, this finding now makes it possible to reliably
transform simple B-containing starting materials into structurally
complex boronic acid building blocks via multistep synthesis pathways
(Scheme 1a).
oxidizing Jones conditions (H2SO4/CrO3). However, we were surprised
to find a 90% yield of benzoic acid 3. The corresponding boronic acid
1b, pinacol boronic ester 1c, 1,8-diaminonaphthalene adduct8 1d,
trifluoroborate salt4 1e, and N-methyldiethanolamine boronate9,10 1f
all decomposed under Jones conditions.8
To gain understanding of the dramatic difference in reactivity for
the structurally related MIDA (1a) and N-methyldiethanolamine (1f)
adducts, we carried out single crystal X-ray analysis of both complexes
which revealed no major differences in bond lengths, bond angles, or
tetrahedral character at the two boron centers (Supporting Information).
In contrast, and consistent with studies of related complexes,5,10
variable temperature NMR of a solution of 1f in d6-DMSO revealed
coalescence of the diastereotopic methylene protons of the diethanol-
amine backbone upon heating from 23 to 60 °C, while the same
experiment with the MIDA boronate 1a yielded no coalescence upon
heating to 150 °C. These data are consistent with the conclusion that
the NfB bond in 1f is dynamic which renders the boron p-orbital
and nitrogen lone pair vulnerable to attack, whereas in the MIDA
boronate 1a these potentially reactive sites are kinetically not accessible
at <150 °C.
Encouraged by the unique stability of the MIDA boronate group to
these strongly acidic and oxidative conditions, we explored its
compatibility with a variety of common reagents (Scheme 1b).
Remarkably, even TfOH (pKa -14) was tolerated, enabling the acid-
catalyzed p-methoxybenzylation of 1a to yield 4, which was then
smoothly debenzylated with DDQ to regenerate 1a. Alcohol 1a was
also reversibly silated under standard conditions (1a f 5; 5 f 1a) or
converted into the bifunctional halo MIDA boronate 6 upon treatment
with PPh3/I2. The compatibility with soft nucleophiles suggested by
the latter encouraged us to explore a series of C-C bond-forming
reactions with benzaldehyde 2. The Evans aldol, Horner-Wadsworth-
Emmons olefination, and Takai olefination reactions were all found
to be well-tolerated. Aldehyde 2 was also reductively aminated to form
10 or reduced with NaBH4 to regenerate 1a.
Due to a lack of the p-orbital that is typically involved in the
reactivity of boronic acids, we anticipated that pyramidalized MIDA
boronates might be relatively stable to some mild reagents. We first
explored the compatibility of the model substrate p-hydroxymeth-
ylphenyl MIDA boronate 1a to a range of oxidants and found the
conditions of Swern afforded the desired benzaldehyde 2 in good yield
(Scheme 1b). PDC, TPAP/NMO, and Dess-Martin periodinane were
also well-tolerated. Expecting to identify the limits of this stability,
we exposed MIDA boronate 1a to the very strongly acidic and
In the course of these studies, we found that MIDA boronates are
tolerant to a variety of workup/extraction solutions including water,
pH 7 buffer, brine, aq. HCl, aq. NH4Cl, aq. NaS2O3, and aq. hydrogen
peroxide at pH 6. Surprisingly, saturated aqueous NaHCO3 is also well-
tolerated, except in the presence of alcoholic solvents. Despite this
Scheme 1
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14084 J. AM. CHEM. SOC. 2008, 130, 14084–14085
10.1021/ja8063759 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
the synthesis of (+)-crocacin C (Scheme 4). Enabled by the ability to
carry a boron functional group through multiple synthetic steps, this
ICC-based route is short (nine steps in the longest linear sequence)
and readily amenable to analogue synthesis via incorporation of
modified building blocks into the same pathway.
As demonstrated herein, the stability of MIDA boronates to a broad
range of common reaction conditions and the unique compatibility of
these materials with chromatography collectively make it now possible
to reliably prepare complex boronic acid building blocks from simple
B-containing starting materials17 via multistep synthesis pathways.
Because of this and many other highly enabling features,6,7 MIDA
boronates represent a uniquely promising platform for the preparation,
storage, and utilization of organoborane building blocks in organic
synthesis.
Scheme 3
Acknowledgment. We gratefully acknowledge the NSF
(CAREER 0747778) and the Dreyfus Foundation for financial support,
Sigma-Aldrich for gifts of reagents, and S. Wilson for X-ray analysis.
M.D.B. is a Beckman Young Investigator.
Scheme 4
Supporting Information Available: Procedures, spectral data, spectra,
and X-ray crystallographic data (cif) for 1a and 1f. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
widespread stability, MIDA boronates 1-5 and 7-10 were all
conveniently transformed into the corresponding boronic acids using
mild aqueous base (aq. NaOH/THF, 23 °C, 10 min, or aq. NaHCO3/
MeOH, 23 °C, 3.5 h, Supporting Information).6-8 Consistent with a
focused sensitivity to hard nucleophiles, we found that MIDA boronates
are generally incompatible with LiAlH4, DIBAL, TBAF, and a variety
of metal alkoxides.11 Importantly, compounds 1a-10 are all crystalline
solids, compatible with chromatography, and stable to long-term
benchtop storage under air.
Inspired by the simplicity and flexibility of peptide coupling, we
recently reported a potentially general strategy for small molecule
synthesis involving the iterative cross-coupling (ICC) of MIDA-
protected haloboronic acids.6-8 In an ideal ICC-based pathway,
building blocks having all of the required functional groups preinstalled
in the correct oxidation state and with the desired stereochemical
relationships are brought together using only stereospecific cross-
coupling reactions. We recognized that the newfound reagent compat-
ibilities of MIDA boronates should enable structurally and/or stereo-
chemically complex haloboronic acid building blocks to be readily
prepared from simple MIDA boronate starting materials via multistep
synthesis. To evaluate this potential, we targeted the total synthesis of
the natural product (+)-crocacin C12 (11) via ICC.
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Retrosynthetic fragmentation of 11 via recursive cross-coupling
generates known building blocks 1212b and 14 and the structurally
complex, B-protected haloboronic acid 13 (Scheme 2). As shown in
Scheme 3, the synthesis of 13 commenced with acrolein MIDA
boronate 15, which was prepared from the known boronic acid.13
A
Paterson aldol reaction followed by diastereoselective reduction of the
resulting ꢀ-hydroxyketone12d yielded diol 16. Harnessing a key
advantage of MIDA boronates, silica gel chromatography was utilized
to remove the small amounts of diastereomeric byproducts that are
typically generated during these types of reactions. Permethylation of
16 with Meerwein’s salt and cleavage of the resulting PMB ether using
CAN afforded primary alcohol 17. DMP oxidation followed by Takai
olefination12d of the resulting aldehyde afforded bifunctional building
block 13. Notably, 15, 13, and all intermediates are crystalline solids,
compatible with chromatography, and stable to benchtop storage under
air. With building block 13 in hand, a CsF/CuI-promoted Stille
coupling14 with 12 followed by in situ boronic acid generation15 and
Pd/SPhos16-promoted cross-coupling between 18 and 14 completed
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(17) A large collection of MIDA boronates will soon be commercial.
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