C O M M U N I C A T I O N S
Table 2
a The same yield was observed whether this reaction was set up in the
As demonstrated herein, this iterative cross-coupling strategy can
dramatically simplify the process of small molecule synthesis. This
natural product was prepared using a single mild reaction iteratively
to bring together a collection of easily synthesized, readily purified,
and highly robust building blocks. The synthesis is short16 and
highly modular, and thus a variety of derivatives should be readily
accessible simply by substituting modified building blocks into the
same pathway. Further studies will pursue the inherent adaptability
of these methods to solid-phase and/or automated techniques.
Although certain small molecules are at present more amenable to
this approach than others, the rapidly expanding scope of the SM
reaction, which increasingly includes sp3-sp3 couplings,17 suggests
significant potential for broad generality.
glovebox or in the air. b B-Deprotection was also achieved with aq NaHCO3/
MeOH, 23 °C, 6 h, 85%. c 2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropyl-
1,1′-biphenyl was used instead of 4b.
The potential of the MIDA ligand to enable selective cross-
couplings was probed by reacting each of these B-protected
bifunctional building blocks with p-tolylboronic acid (Table 2).
Although the reactivity of aryl, heteroaryl, vinyl, and alkyl boronic
acids can vary dramatically,6 the same protectiVe group was
effectiVe with all four classes of nucleophiles yielding selective
cross-coupling products 9a-f. All four classes of nucleophiles were
also efficiently deprotected using a standard set of mild aqueous
basic conditions (1 M aq NaOH/THF, 23 °C, 10 min). Aqueous
NaHCO3 is also effective (entry 3).
Acknowledgment. We gratefully acknowledge the Dreyfus
Foundation and UIUC for funding, F. Sun and S. Mullen for MS
studies, and S. Wilson for X-ray analysis.
The strategy described herein is distinguished from related
lynchpin-based approaches by its theoretically limitless potential
for iteration. To begin exploration of this potential and the compati-
bility of this mild protective group methodology with small molecule
substrates, we targeted the first total synthesis of the natural product
ratanhine (11) (eq 4), the most complex member of a large family
of neolignans isolated from the medicinal plant Ratanhiae radix.14
Retrosynthetic fragmentation of 11 into four simpler building
blocks 12-15 was achieved via recursive application of three SM
transforms (eq 4). There were several challenges associated with
this plan that were anticipated to provide rigorous tests for the new
methodology. For example, cross-coupling of aryl boronic acids
tends to be more facile than that of their vinyl counterparts,6a making
the selective cross-coupling between vinyl boronic acid 12 and
bromoaryl boronate 13 unsecured. In addition, heteroaromatic
boronic acids, such as the deprotected version of 13, can be very
sensitive to decomposition.15 Moreover, cross-coupling with the
highly electron-rich and sterically encumbered aryl bromide 14 was
expected to require elevated temperatures and/or long reaction times
that would test the limits of stability for the MIDA ligand.
With building blocks 12-15 in hand (see eq 5 and SI), the
synthesis commenced with a successful selective cross-coupling
between 12 and 13 to yield intermediate 16. Strikingly, benzofuranyl
boronates 13 and 16 were bench stable under air for at least 1
month. In contrast, the 2-benzofuranyl boronic acid that resulted
from deprotection of 16 rapidly decomposed over the course of a
few days. This challenge was overcome simply by deprotecting 16
just prior to cross-coupling with 14. As expected, this electron-
rich and sterically bulky aryl bromide 14 required both an elevated
temperature (80 °C, sealed tube) and extended reaction time (28
h). Remarkably, the MIDA protective group was found to be
completely stable to these forcing conditions, yielding advanced
intermediate 17. A final sequence of B-deprotection, cross-coupling
with 15, and cleavage of the two MOM ethers completed the first
total synthesis of ratanhine.16
Supporting Information Available: Procedures, spectral data,
spectra, and X-ray crystallographic data (cif); full citations for refs 4a,
4b, 6a, 6b, 6c, 6d, 12b, 12c, 14 and 17. This material is available free
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