A catalytic enantiotopic-group-selective Suzuki reaction for the construction of chiral organoboronates

Article abstract of DOI:10.1021/ja500029w

Catalytic enantiotopic-group-selective cross-couplings of achiral geminal bis(pinacolboronates) provide a route for the construction of nonracemic chiral organoboronates. In the presence of a chiral monodentate taddol-derived phosphoramidite ligand, these reactions occur with high levels of asymmetric induction. Mechanistic experiments with chiral ¹⁰B-enriched geminal bis(boronates) suggest that the reaction occurs by a stereochemistry-determining transmetalation that occurs with inversion of configuration at carbon.

Full text of DOI:10.1021/ja500029w

Communication
pubs.acs.org/JACS
A Catalytic Enantiotopic-Group-Selective Suzuki Reaction for the
Construction of Chiral Organoboronates
Chunrui Sun, Bowman Potter, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
Scheme 1
ABSTRACT: Catalytic enantiotopic-group-selective
cross-couplings of achiral geminal bis(pinacolboronates)
provide a route for the construction of nonracemic chiral
organoboronates. In the presence of a chiral monodentate
taddol-derived phosphoramidite ligand, these reactions
occur with high levels of asymmetric induction. Mecha-
nistic experiments with chiral 10B-enriched geminal
bis(boronates) suggest that the reaction occurs by a
stereochemistry-determining transmetalation that occurs
with inversion of configuration at carbon.
he versatility of nonracemic chiral organoboronates has
Tmade them sought after intermediates in asymmetric
synthesis.1 Recent catalytic enantioselective strategies for
constructing such compounds include hydroboration,2 con-
jugate borylation,3 allylic borylation,4 conjugate addition and
a
Table 1. Catalytic Enantioselective Suzuki Reaction
allylic substitution with borylated electrophiles,5 and cyclo-
additions with vinyl boronate derivatives.6 Also developed are
conjugate reduction7 and hydrogenation of vinyl boronates,8
and diborylation of alkenes9 and alkynes.10 In this connection,
our laboratory has pursued the enantioselective construction
and transformation of vicinal diboronates with the notion that
selective mono-cross-coupling reactions result in products
wherein the remaining boronate can be used in subsequent
strategically useful chemical transformations.11 It was consid-
ered that a similarly useful strategy for construction of
organoboronates might arise by the mono-cross-coupling of
geminal bis(boronates). These reactions have been extensively
studied by Shibata and Endo who employed Pd(PtBu3)2 as an
effective catalyst for a range of such reactions.12 While related
reactions of chiral nonracemic geminal bis(boronates) have
been developed by Hall13 and Yun14 (Scheme 1), we
considered that readily accessed symmetric geminal bis-
(boronates), reacting in the presence of an appropriately
designed chiral catalyst, might participate in an enantiotopic-
group-selective Suzuki reaction and that such a strategy might
provide a useful new route to nonracemic organoboronate
derivatives that are not readily prepared by other methods.15 In
this manuscript, we present such a process and show that it can
be employed to prepare a range of chiral boronates in an
enantioselective fashion; we also provide mechanistic insight
about critical steps in the catalytic cycle.
a
b
entry
ligand
none
Ar
R1
R2
yield (%)
er
1
2
3
4
5
6
7
−
−
−
Ph
−
−
−
Me
−
−
−
98
78
−
binap
JosiPhos
L1
50:50
50:50
75:25
77:23
94:6
55
Ph
80
L2
Ph
H
NMe2
NMe2
NMe2
74
L3
p-tol
Me
Me
>98
92
L4
4-t-BuPh
92:8
a
Yield was determined by NMR in comparison to an internal standard.
Enantiomer ratio (er) determined by chiral SFC analysis.
b
the absence of ligand (entry 1), as well as nonselective reaction
in the presence of bidentate phosphines (entries 2−3) or with a
preformed JosiphosPdCl2 complex. These observations sug-
gested a catalytic reaction pathway requiring access to three-
coordinate L1PdAr(X), ostensibly as a precursor to trans-
metalation with bis(boronate), and it was suspected that that
complexes derived from bidentate ligands might prove
sufficiently unreactive that nonselective background reactions
could prevail. In line with this hypothesis, reactions with chiral
monodentate ligands proved more selective with L3 being most
Our preliminary experiments surveyed the cross-coupling
reaction between geminal bis(boronate) 1 and p-iodoanisole in
the presence of Pd(OAc)2 and selected ligands (Table 1).
Initial observations revealed a high background reaction rate in
Received: January 2, 2014
Published: February 19, 2014
© 2014 American Chemical Society
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effective. A survey of reaction conditions showed the following
to be most critical: first, reactions of aryl iodides are
significantly more selective than bromides (chlorides and
triflates are unreactive); second, high concentrations of KOH
are critical (reaction with 4.5 equiv of KOH results in 79:21 er);
third, an excess of monodentate ligand is critical for highest
selectivity (65:35 er was obtained with 1:1 L3/Pd), presumably
as a result of competing background nonligated pathways at
lower ligand loading. Lastly, it was found (vide infra) that aryl
bromides can also be employed as electrophiles in asymmetric
Suzuki reactions but require the addition of sodium iodide for
high selectivity.
shown), this problem could be ameliorated for the case of
ketone substrates by the use of ketal protection (product 11).
Lastly, it was found that neither heterocycles (products 9, 14)
nor an electron-withdrawing p-fluoro group (product 12)
interfered in the process. In terms of the scope of geminal
bis(boronates), the reaction applies to linear aliphatic substrates
(products 16, 17), as well as more hindered substrates (product
18), although the larger substituent appears to retard the
reaction rate.
The utility of the asymmetric cross-coupling reaction for the
enantioselective construction of pharmaceutically relevant
benzhydryl derivatives was examined by targeting the
construction of (R)-tolterodine (Detrol LA), a therapeutic
used for the treatment of urinary incontinence (Scheme 2).17
The substrate scope of enantiotopic-group-selective cross-
couplings involving geminal bis(boronates) was surveyed with a
number of aryl halides and geminal bis(boronates) (Figure
1).16 The reactions with either p-iodoanisole (method A) or p-
Scheme 2. A Route for the Synthesis of (R)-Tolterodine with
the Enantiotopic-Group-Selective Suzuki Reaction
Construction of substrate 22 was accomplished by deprotona-
tion and alkylation of 1,1-di(pincolatoboryl)methane (21).16a
Subsequent Suzuki reaction provided 23 in 74% yield and 93:7
enantiomer ratio. Subsequent stereoretentive cross-coupling of
23 with 2-iodo-4-methylanisole employing conditions similar to
those developed by Crudden18 occurred with some erosion of
enantiomeric excess, but in very good yield. Lastly, depro-
tection of 23 furnished 24, a known precursor19 to the clinically
used therapeutic.
To provide insight into the processes that underlie the
enantiotopic-group-selective Suzuki reaction, the cycle in
Scheme 3 was considered. On the basis of findings that Suzuki
Scheme 3
Figure 1. Substrate scope of the enantioselective Suzuki coupling.
bromoanisole combined with sodium iodide (method B)
provide comparable yield and selectivity in the production of
2, although it should be noted that with other substrates
(product 4) there is a moderate difference between the two
methods. Also of note, electron-neutral electrophiles (products
5−7), as well as more hindered ortho substituted electrophiles
(products 10, 13), also couple with good enantioselection.
While protodeboronation occurred when conjugating groups
were present at the para position (CN, CO2Et; data not
reactions in the presence of base and water may occur through
the intermediacy of Pd(hydroxide) intermediates,20 it was
considered that, subsequent to oxidative addition, substitution
of halide for hydroxide might occur. Next, transmetalation
might furnish α-borylorganopalladium complex 25; reductive
elimination would then furnish the product. Other possibilities
notwithstanding, in this scenario the stereoselectivity-determin-
ing step might be transmetalation, or if the intermediate 25 is
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Communication
subject to isomerization, reductive elimination might control
the product outcome.
One possible mechanism for equilibration of intermediate 25
involves reversible deprotonation.21 This possibility was
excluded by examination of the reaction run in the presence
of D2O: less than 5% deuterium was incorporated in the
product (eq 1, Scheme 4). While other mechanisms might
reactants in the transmetalation. Thus the stereoselective
transmetalation might occur either by a desymmetrization if
both boronates are equivalent or by a dynamic kinetic
resolution if the geminal boron atoms are not substituted
equivalently.
Stereoinversion has been observed in other transmetalations
and is most often associated with an open transition state that
does not involve preassociation between Pd and the reacting
organometallic reagent.23 This feature was unanticipated in the
present reaction and will be the subject of forthcoming studies.
Further studies on expanding the scope of this reaction to the
construction of other chiral boron derivatives and on further
elucidation of catalytic mechanisms is in progress.
Scheme 4
ASSOCIATED CONTENT
* Supporting Information
Procedures, characterization and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
morken@bc.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The NIH (GM-59471) is acknowledged for financial support;
AllyChem (B2(pin)2) and BASF (pinacolborane) are acknowl-
edged for donations of reagents.
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