Catalytic Asymmetric Synthesis of Phosphine Boronates

Article abstract of DOI:10.1002/anie.201502987

The first catalytic enantioselective synthesis of ambiphilic phosphine boronate esters is presented. The asymmetric boration of α,β-unsaturated phosphine oxides catalyzed by a copper bisphosphine complex affords optically active organoboronate esters that bear a vicinal phosphine oxide group in good yields and high enantiomeric excess. The synthetic utility of the products is demonstrated through stereospecific transformations into multifunctional optically active compounds. Ambiphilic phosphine boronate esters are obtained by the asymmetric boration of α,β-unsaturated phosphine oxides with a copper/bisphosphine catalyst in good yields and high enantioselectivity. The synthetic utility of the products is demonstrated through stereospecific transformations into multifunctional optically active compounds.

Full text of DOI:10.1002/anie.201502987

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502987
German Edition: DOI: 10.1002/ange.201502987
Borylation
Catalytic Asymmetric Synthesis of Phosphine Boronates**
Valentꢀn Hornillos,* Carlos Vila, Edwin Otten, and Ben L. Feringa*
Abstract: The first catalytic enantioselective synthesis of
ambiphilic phosphine boronate esters is presented. The
asymmetric boration of a,b-unsaturated phosphine oxides
catalyzed by a copper bisphosphine complex affords optically
active organoboronate esters that bear a vicinal phosphine
oxide group in good yields and high enantiomeric excess. The
synthetic utility of the products is demonstrated through
stereospecific transformations into multifunctional optically
active compounds.
C
hiral organophosphorus compounds play a prominent role
in many areas, including organometallic chemistry, chemical
biology, and the production of pharmaceuticals or agro-
chemicals.[1] In homogeneous catalysis, chiral phosphines are
essential in the field of asymmetric catalysis as we take
advantage of their ability to serve as ancillary ligands with
tunable steric and electronic properties.[2] More recent
applications in the rapidly emerging field of frustrated
Lewis pair (FLP) chemistry have led to new catalytic systems
for small-molecule activation.[3] In particular, phosphine-
substituted borane and boronate esters have gained increas-
ing interest for their applications in intramolecular FLP
chemistry[4] and as organocatalysts or ligands in metal-
catalyzed transformations.[5] In these systems, the boron
atom also has the ability to bind transition metals by acting
as a s-acceptor ligand, offering new fascinating possibilities in
terms of controlling reactivity.[6] Furthermore, the boronate
group enables a variety of transformations by virtue of its
ability to undergo stereospecific transformations to form
Scheme 1. Methods for the synthesis of chiral phosphine boronates.
Important procedures for the asymmetric synthesis of
chiral organoboranes are transition-metal- and organocata-
lyzed additions of diboron reagents, such as bis(pinacolato)-
diboron, to electron-deficient alkenes.[9] In particular, the use
of copper catalysts[10] has been highly successful, and a variety
of cyclic or acyclic chiral b-boron-substituted carbonyl
derivatives can now be obtained with excellent levels of
enantiopurity. We questioned whether a related process
involving the copper-catalyzed conjugate boration of alkenyl
phosphine oxides could be developed despite the fact that the
use of these substrates in catalytic asymmetric conjugate
additions (ACAs) with organometallic reagents has remained
a major challenge to date.[11] The corresponding enantiomer-
ically enriched vicinal phosphine oxide boronates could then
also be derivatized through stepwise stereospecific trans-
formations at both the boron and phosphorus functional
groups. Herein, we report an efficient catalytic method using
a chiral copper(I) complex to produce optically active vicinal
ambiphilic phosphine oxide boronates with excellent enan-
tioselectivity (up to 98:2 e.r., Scheme 1b).
C O, C N, or C C bonds.[7] Despite the promising reactivity
of these compounds, a catalytic asymmetric method to readily
access phosphine-substituted chiral boronates has not been
described, and to the best of our knowledge, only a limited
range of these chiral structures have been explored because of
a lack of methods for their synthesis (Scheme 1a).[8]
À
À
À
We started our study with the evaluation of various
common chiral bisphosphine ligands (L1–L7) in the reaction
of (E)-oct-1-enyldiphenylphosphine oxide 1a (readily
obtained by hydrophosphinylation of 1-octyne)[12] with
B2(pin)2 in the presence of catalytic amounts of
[Cu(CH3CN)4]PF6 and LiOtBu at room temperature. Under
these conditions, the use of L1, which has previously been
shown to be effective for the enantioselective boration of
cyclic b,b-disubstituted enones,[10a] led to 74% conversion
with 90:10 e.r. (Table 1, entry 1). Using other bisphosphines
with different steric and electronic properties, we found that
the conversion and e.r. values were highly dependent on the
nature of the ligand. To our delight, the use of (R,S)-Josiphos
L4 led to chiral phosphine oxide boronate ester 2a with
excellent conversion and enantioselectivity (96:4 e.r.,
[*] Dr. V. Hornillos, Dr. C. Vila, Dr. E. Otten, Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry
University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: v.hornillos.gomez.recuero@rug.nl
b.l.feringa@rug.nl
[**] The Netherlands Organization for Scientific Research (NWO-CW),
the National Research School Catalysis (NRSC-C), the European
Research Council (ERC Advanced Grant 227897 to B.L.F.), the Royal
Netherland Academy of Arts and Sciences (KNAW), and the
Ministry of Education, Culture and Science (Gravitation program
024.601035) are acknowledged for financial support. C.V. was
supported by an Intra-European Marie Curie fellowship (FP7-
PEOPLE-2011-IEF-300826).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502987.
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accordance with previous findings,[9c,d,10d,k] the addition of two
equivalents of MeOH markedly improved the rate of the
reaction, providing full conversion in three hours, and the
desired product was isolated in 89% yield (entry 15). The
absolute configuration of the stereogenic center was deter-
mined to be R by X-ray crystallographic analysis of compound
2a.[13]
Table 1: Optimization of the reaction conditions.
We next investigated the substrate scope under the
optimized reaction conditions. As shown in Scheme 2, sub-
strates bearing different linear aliphatic substituents provided
the desired products in high yields and enantiomeric ratios
(compounds 2b and 2c). An important feature is that the
reaction may also be performed on a larger scale. The
reaction of 1a on a 4.0 mmol scale provided 1.62 g (92%
yield) of 2a with similar enantioselectivity.[13]
Entry[a]
Ligand
Variations in the
Conv.[b] [%]
e.r.[c]
reaction conditions
1
2
3
L1
L2
L3
L4
L5
L6
L7
L4
L4
L4
L4
L4
L4
L4
L4
–
–
–
–
–
–
–
74
20
90:10
50:50
66:34
96:4
66:34
72:28
78:22
96:4
68:32
78:22
58:42
89:11
92:8
>95
>95
>95
>95
90
95
78
>95
5
4[d]
5
6
7
8[d]
9
NaOtBu
CuBr·SMe2
in DMSO
in CH2Cl2
in toluene
in dioxane
[CuL] (10 mol%)
[CuL] (10 mol%) and
MeOH (2 equiv)
10
11
12
13[d]
14
15
>95
>95
99
96:4
99 (89)[e]
97:3[f]
Scheme 2. Catalytic enantioselective boration of b-substituted a,b-
unsaturated phosphine oxides. Conditions: 1 (0.2 mmol), B2(pin)2
(0.3 mmol), THF (500 mL). The e.r. ratios were determined by HPLC
analysis on a chiral stationary phase. Yields refer to the isolated
materials after purification. [a] On a 4 mmol (1.25 g) scale. [b] Reaction
time: 48 h. [c] (S,R)-Josiphos was used instead. [d] Reaction time: 30 h.
[e] In DME. TBS=tert-butyldimethylsilyl.
[a] Reaction conditions: 1a (0.2 mmol), B2(pin)2 (0.3 mmol), THF
(500 mL). [b] Determined by 31P NMR spectroscopy and GC analysis.
[c] Determined by HPLC analysis on a chiral stationary phase. [d] Con-
version and e.r. values were poorly reproducible, varying inconsistently
from 66 to 97% conversion and 82:18 to 96:4 e.r. [e] Full conversion was
reached in 3 h. [f] The absolute configuration was determined to be R by
X-ray crystallographic analysis.
a,b-Unsaturated phosphine oxides with aromatic or
saturated carbocycles in the alkyl chain (compounds 2d–2 f)
as well as branching at the g-position (2g) also displayed high
reactivity and enantioselectivity regardless of the nature of
the cyclic structure. Importantly, it was found that the reaction
tolerates the presence of ester and silyl ether functional
groups, although longer reaction times were needed to reach
full conversion (2h and 2i).
A limitation for the Josiphos-based catalytic system is that
more sterically demanding electrophiles, such as b-aryl- and
trimethylsilyl-substituted substrates, suffered from lower
reactivity and diminished selectivity as seen for compounds
entry 4). The use of other ferrocenyl-type ligands (entries 2, 3,
and 5), BINAP- or BIPHEP-derived ligands (entries 6 and 7)
as well as variations in the copper salt, base, or solvents did
not improve these results (entries 8–13). Despite the excellent
selectivity achieved with L4, using 5 mol% of catalyst
(entry 4), we observed a lack of reproducibility of both the
enantiomeric ratio (varying from 82:18 to 96:4 e.r.) and
conversion (from 66 to 97%). However, we could consistently
obtain the desired product with excellent selectivity by
increasing the catalyst loading (entry 14). Furthermore, in
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2j (74:26 e.r.) and 2k (57:43 e.r.). To solve this problem, we
examined various chiral phosphine ligands but the enantio-
selectivity remained unsatisfactory (Table 2, entries 1 and 2
and results not shown). When exploring other chiral ligands,
Table 2: Optimization of the reaction conditions for sterically demand-
ing b-substituted phosphine oxides.
Scheme 3. Methylboration of a,b-unsaturated phosphine oxide 1. Con-
ditions: 1a (0.5 mmol), B2(pin)2 (0.75 mmol), THF (1.5 mL). Full
conversion; 2l/2a=71:29 as determined by 31P NMR spectroscopy
and GC analysis.
rate[9d] led to chiral b-hydroxyphosphine oxide 3 in high yield
without racemization (Scheme 4a). By exploiting the propen-
sity of organoboronates to undergo stereospecific 1,2-metal-
late rearrangements, the chiral secondary boronic ester[15] in
Entry[a]
Ligand
Variations in the
reaction conditions
Conv.[b] [%]
e.r.[c]
1
2
3
4
5
L4
L1
L8
L8
L8
–
–
–
85
15
ca. 80
ca. 80
ca. 80
74:26
76:24
81:19
90:10
91:9
2
3
À
2a was subjected to an oxidative C(sp ) C(sp ) cross-coupling
in DME
substrate 1a
[a] Conditions: 1a (0.2 mmol), B2(pin)2 (0.3 mmol), THF (500 mL).
[b] Determined by 31P NMR spectroscopy and GC analysis. [c] Deter-
mined by HPLC analysis on a chiral stationary phase.
we found that the use of L8, which contains a 1,2-dipheny-
lethylenediamine scaffold, enhanced the enantioselectivity
(entry 3). Solvent effects were also examined, and the use of
1,2-dimethoxyethane (DME), which has been shown to be
effective for the enantioselective boration of linear b,b-
disubstituted enones,[10b] improved the e.r. to 90:10 without
affecting the reactivity. Under these conditions, the more
sterically demanding substrate 1k was converted into b-
boryltrimethylsilyl phosphine oxide 2k in good yield and high
selectivity (Scheme 2). The use of ligand L8 in the boration
reaction of phosphine oxide 1a afforded the desired com-
pound 2a (entry 5), but with decreased conversion and
enantioselectivity in comparison with the use of L4.
It has been proposed that in the copper(I)-catalyzed
boration of a,b-unsaturated acceptors, following the initial
conjugate addition of a copper boryl complex, the resulting
enolate reacts with MeOH to yield the protonated product
and regenerate the catalytically active copper alkoxide.[9c,d,f–h]
Based on this mechanistic proposal, we wondered if the
boration reaction in the presence of CH3I as an electrophile
(instead of MeOH) would allow for a catalytic three-
Scheme 4. Stereospecific transformations at the boron and phospho-
rus functional groups. [a] Conditions A: HSiCl3, Et3N, toluene, 908C,
16 h, 66% yield; conditions B: bis(4-nitrophenyl) hydrogen phosphate
(7.5 mol%), (EtO)2MeSiH (4 equiv), toluene, 1108C, 16 h, 77% con-
version, 58% yield.
À
À
component reaction in which a C B and a C C bond are
created in a single catalytic process.[14] The use of stoichio-
metric amounts of base would in this case be required to
transform the CuI formed by reaction of the copper ylide with
CH3I into the catalytically active CuOtBu.[14] To our delight,
the use of CH3I (4 equiv) and LiOtBu (1.1 equiv) at room
temperature gave product 2l, which features a boron and
a methyl moiety, in 5.2:1 d.r., along with a minor amount of
the hydroborated product 2a (Scheme 3).
with furyllithium, under conditions recently described by the
group of Aggarwal,[16] delivering the cross-coupled product 4
with preserved stereochemical integrity (Scheme 4b). It
should be noted that this transformation would be difficult
to achieve in the corresponding b-boron-substituted carbonyl
derivatives owing to the reactivity of a carbonyl group
towards organolithium reagents.
Finally, 2a was reduced to the corresponding chiral
phosphine 5 without affecting the boronate group by using
either classical conditions (HSiCl3/Et3N) or with
(EtO)2MeSiH in the presence of catalytic amounts of
a Brønsted acid, as recently described by the group of
Beller[17] (Scheme 4c). A phosphine borane complex was
To further demonstrate the synthetic potential of this new
method, compound 2a was used as a platform for the
synthesis of various new chiral building blocks that are
otherwise difficult to access. Oxidation with sodium perbo-
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In conclusion, we have developed the first catalytic
asymmetric b-boration of a,b-unsaturated phosphine oxides
that provides ready access to chiral ambiphilic phosphine
oxide and phosphine boronates in good yields under mild
conditions. Broad structural scope, functional group toler-
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a chiral catalytic system based on copper(I) and L4 or L8 at
room temperature. Stereospecific transformations to new
optically active products and metal complexes demonstrate
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tions and extensions of this process are currently under
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Keywords: asymmetric catalysis · borylation · copper catalysis ·
phosphine boronates · organophosphorus compounds
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Received: March 31, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Borylation
V. Hornillos,* C. Vila, E. Otten,
B. L. Feringa*
&&&& — &&&&
Catalytic Asymmetric Synthesis of
Phosphine Boronates
Ambiphilic phosphine boronate esters are
obtained by the asymmetric boration of
a,b-unsaturated phosphine oxides with
a copper/bisphosphine catalyst in good
yields and high enantioselectivity. The
synthetic utility of the products is dem-
onstrated through stereospecific trans-
formations into multifunctional optically
active compounds.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!