Asymmetric rhodium-catalysed addition of arylboronic acids to acyclic unsaturated esters containing a basic γ-amino group

Article abstract of DOI:10.1055/s-0032-1317512

Application of the Miyaura-Hayashi rhodium-catalysed addition of aryl boronic acids to acyclic unsaturated esters featuring basic centres to yield γ-amino butyric acids incorporating a substituted β-phenyl group is described. Unoptimised isolated yields and enantiomeric excesses vary from moderate to excellent, and the method tolerates a variety of substitution patterns and a range of functionality. Copyright

Full text of DOI:10.1055/s-0032-1317512

LETTER
▌2817
lAettserymmetric Rhodium-Catalysed Addition of Arylboronic Acids to Acyclic
Unsaturated Esters Containing a Basic γ-Amino Group
Addition of Arylboronic Acids to Acyclic Unsaturated Esters
Niall A. Anderson,*a Brendan J. Fallon,a Elena Valverde,a Simon J. F. MacDonald,a John M. Pritchard,a Colin
J. Suckling,b Allan J. B. Watsonb
a
Department of Medicinal Chemistry, Fibrosis DPU, Respiratory CEDD, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road,
Stevenage, Hertfordshire, SG1 2NY, UK
Fax +44(1438)768302; E-mail: niall.a.anderson@gsk.com
b
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK
Received: 30.08.2012; Accepted after revision: 05.10.2012
ronic acids.10 In an N-benzylpyrroline carboxylic acid eth-
Abstract: Application of the Miyaura–Hayashi rhodium-catalysed
yl ester system, Belyk et al. developed a rhodium-
addition of aryl boronic acids to acyclic unsaturated esters featuring
catalysed asymmetric 1,4-addition in good to excellent
basic centres to yield γ-amino butyric acids incorporating a substi-
tuted β-phenyl group is described. Unoptimised isolated yields and
enantioselectivities (up to 96%).4 Collier identified a prac-
enantiomeric excesses vary from moderate to excellent, and the tical route to 3-aryl-3-azetidinyl acetic acid esters via the
method tolerates a variety of substitution patterns and a range of
functionality.
rhodium-catalysed 1,4-addition of boronic acids to α,β-
unsaturated azetidinyl esters protected with either a diphe-
Key words: rhodium, asymmetric 1,4-addition, drugs, γ-amino-
butyric acid, synthesis
nylmethyl or a tert-butoxycarbonyl (Boc) nitrogen pro-
tecting group.5 Reactions affording enantiomerically pure
products were not described. These are the only examples
in the literature of rhodium-catalysed 1,4-addition reac-
γ-Aminobutyric acid (GABA) is the most abundant inhib- tions where a γ-amino group is present of which we are
itory neurotransmitter in the central nervous system and aware. Note in both these examples, the basic functional-
its derivatives are important intermediates and targets for ity is γ to the ester and within a cyclic system.
therapeutic agents.1 Therefore, GABA analogues are
compounds with exceptional therapeutic potential to alle-
O
O
viate several neurological disorders.2 For this reason, ef-
fective synthetic routes that afford GABA derivatives
stereoselectively and in high yields may be of consider-
able utility and value. For example, related analogues
have also been made for therapeutic uses on up to kilo-
gram scale.3–5
Rh(acac)(C2H4)2 (3 mol%)
(S)-BINAP (3 mol%)
99% yield
97% ee
PhB(OH)2
1,4-dioxane–H2O (10:1)
100 °C, 5 h
Ph
1
2
Scheme 1 Rh-catalysed conjugate 1,4-addition of phenylboronic
acid to cyclohexenone (1) under the Hayashi–Miyaura protocol
Since the first report by Hayashi and Miyaura in 1997,6
the rhodium-catalysed addition of aryl and alkenyl boron-
ic acids to activated alkenes in the presence of the ligand
1,4-bis(diphenylphosphino)butane (dppb) has emerged as
important methodology in organic synthesis.7 A detailed
review of the mechanism has very recently been pub-
lished.7 Replacing the dppb ligand with a chiral ligand
rhodium(I) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
(BINAP) results in an asymmetric procedure giving the
desired addition products in high yields (up to 99%) and
excellent ee (up to 99%) (Scheme 1).8
In contrast, in our work, the unsaturated ester motif is not
part of a cyclic ring system. We were interested in the syn-
thesis of piperazine analogues of γ-amino butyric acids
featuring a substituted β-phenyl group (such as 4a). A ver-
satile route was required that would allow (i) the presence
of a basic γ-amino group; (ii) variation of this γ-amine;
(iii) variation of the aryl group; and (iv) introduction of
the aryl group in an asymmetric fashion.
We describe here the successful application of the
Hayashi–Miyaura procedure to the synthesis of a range of
γ-amino butyric acids allowing access to biologically in-
teresting structures with varying physicochemical proper-
ties. In particular, we demonstrate that both the racemic
and the asymmetric Hayashi–Miyaura protocols are effec-
tive with a range of acyclic and basic γ-amino unsaturated
esters giving products, without optimisation, in moderate
to good yields and enantiomeric excesses, which to the
best of our knowledge, is without precedent.
The Hayashi–Miyaura protocol has been successfully ap-
plied to the preparation of biologically active target struc-
tures including β-phenylalanine derivatives.9 For
example, elegant syntheses of the GABA analogues
baclofen and rolipram were developed by Helmchen et al.
in good yields and enantiomeric excesses (up to 92%)
from nonbasic protected γ-aminocrotonates and arylbo-
SYNLETT 2012, 23, 2817–2821
Advanced online publication: 31.10.2012
DOI: 10.1055/s-0032-1317512; Art ID: ST-2012-D0728-L
© Georg Thieme Verlag Stuttgart · New York
We started by demonstrating that a variety of analogues
could be synthesised in the racemic Hayashi–Miyaura re-
action. Using the commercially available piperazinyl un-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2818
N. A. Anderson et al.
LETTER
saturated ester 3a, a range of aryl boronic acids in the We then investigated the asymmetric version of the reac-
presence of rhodium chloride cyclooctadiene catalyst tion by the addition of a catalytic amount of the chiral li-
{[RhCl(cod)]2}, moderate to good yields of products 4a– gand (R)-BINAP in place of dppb (Table 2).
f were obtained (Table 1).
Table 2 Development of an Asymmetric 1,4-Addition Protocola
Table 1 Piperazine Template for the Rh-Catalysed 1,4-Additiona
Cl
O
Ar
O
O
O
OMe
OMe
Rh (cat.)
*
Rh (cat.)
(R)-BINAP
Ar B(OH)2
N
N
N
OMe
OMe
conditions
B(OH)2
N
N
conditions
N
Boc
Boc
Cl
N
N
Boc
Boc
rac-4a–f
3a
3a
4a
Entry
1
Boronic acid
Product 4
Yield (%)b
Entry Rh (cat.)
Temp (°C) Yield (%)b ee (%)c
Cl
1
2
3
4
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(acac)(C2H4)2
[Rh(cod)Cl]2
95
60
95
95
37
29
49
64
85
83
84
86
rac-4a
79
B(OH)2
t-Bu
2
3
rac-4b
rac-4c
61
63
a Reaction conditions: [RhCl(cod)]2 (5 mol%), (R)-BINAP (20
mol%), aq KOH (2 equiv), ArB(OH)2 (3 equiv), 1,4-dioxane, 95 °C,
4 h.
B(OH)2
Br
b Isolated yield of pure products.
c Determined by chiral HPLC analysis.
B(OH)2
Applying the conditions used for the synthesis of the race-
mic analogues with the addition of 20 mol% (R)-BINAP,
gave the addition product 4a in moderate yield and good
enantiomeric excess (Table 2, entry 1). Reducing the tem-
perature to 60 °C decreased the yield (Table 2, entry 2)
whereas changing the catalyst to Rh(acac)(C2H4)2 (Table
2, entry 3) improved the yield to 49% whilst maintaining
good enantiomeric excess. Ultimately, however, the high-
est yield (64%) and enantiomeric excess (86%) was ob-
tained by premixing the reagents at room temperature for
30 minutes before addition of the alkene (Table 2, entry
4). This premixing may allow the catalytic system to form
prior to the coordination of the α,β-unsaturated ester, al-
though this has not been fully elucidated.
4
rac-4d
60
B(OH)2
5
6
rac-4e
rac-4f
31
43
B(OH)2
Br
Hayashi et al. have shown that increasing the steric bulk
of the ester group increased the enantiomeric excess for a
(E)-methyl hex-2-enoate template.11 We therefore synthe-
sised the isopropyl and tert-butyl ester analogues of 3a in
a straightforward manner (3b and 3c, respectively,
Scheme 2) and reacted these with 3-chlorobenzene boron-
ic acid using our preferred conditions. Gratifyingly, the
desired 1,4-addition products 7a and 7b were obtained in
high yields (78% and 81%) and very good enantiomeric
excesses (93% and 96%, respectively).
B(OH)2
a Reaction conditions: [RhCl(cod)]2 (5 mol%), aq KOH (2 equiv),
ArB(OH)2 (3 equiv), 1,4-dioxane, 95 °C, 4 h.
b Isolated yield of pure products.
Note the 3- and 4-bromo-substituted aryls (rac-4c and
rac-4f, respectively, Table 1, entries 3 and 6) can be fur-
ther modified by palladium-catalysed chemistry (not de-
scribed here) which are useful for lead optimisation
programmes. Compounds 4e and 4f (Table 1, entries 5
and 6) gave lower than expected yields due to issues en-
countered during purification by silica chromatography.
After chiral chromatographic separation of compound 4a,
the same single enantiomer as compound 7b was then hy-
drolysed and deprotected to give the amino acid 8. Crys-
tals suitable for X-ray diffraction were generated from
isopropyl alcohol and water and allowed the stereo-
Synlett 2012, 23, 2817–2821
© Georg Thieme Verlag Stuttgart · New York

LETTER
Addition of Arylboronic Acids to Acyclic Unsaturated Esters
2819
O
Table 3 Enantioselective 1,4-Addition of a Range of Aryl Boronic
Acids to 3a and 3ca
O
O
i
ii
OR
OR
Me
OR
O
Ar
O
N
Br
Rh (cat.)
(R)-BINAP
OR
OR
5a: R = i-Pr
5b: R = t-Bu
6a: R = i-Pr, 45% yield
6b: R = t-Bu, 50% yield
N
Ar B(OH)2
N
N
N
Boc
conditions
3b: R = i-Pr, 87% yield
3c: R = t-Bu, 78% yield
N
Boc
Boc
Cl
O
3a,c
(S)-9a–f, 7c
Entry Ar
Product 9
(S)-9a
Yield (%)b ee (%)c
iii
7a: R = i-Pr, 78% yield, 93% ee
7b: R = t-Bu, 81% yield, 96% ee
*
OR
N
N
1
42d
75
Boc
Scheme 2 Synthesis and use of isopropyl and tert-butyl ester ana-
logues of 3 in the asymmetric Rh-catalysed 1,4-addition. Reagents
and conditions: (i) NBS (0.7 equiv), AIBN (0.1 equiv), CCl4,
80 °C, 3.5 h; (ii) Boc-piperazine (1.1 equiv), i-Pr2NEt (2 equiv),
CH2Cl2, 25 °C; (iii) [RhCl(cod)]2 (5 mol%), aq KOH (2 equiv),
ArB(OH)2 (3 equiv), (R)-BINAP (20 mol%), 1,4-dioxane, 95 °C, 4
h. Yields are isolated yields of pure products.
2
3
(S)-9b
(S)-9c
73d
61d
80
62
NO2
OMe
chemistry of the asymmetric rhodium-catalysed conjugate
addition product to be identified via a small-molecule
crystal structure (Scheme 3).14 As illustrated, the absolute
configuration of 8 was shown to be S and by correlation
with chiral HPLC,12 we confirmed that the use of (R)-BI-
NAP delivers the S-addition product, for example 7b.
4
(S)-9d
75d
57
OH
Me
5
6
7
(S)-9e
(S)-9f
(S)-7c
54d
43d
63e
33
82
91
Br
Br
Scheme 3 Confirmation of the enantioselectivity of the Rh-catalysed
1,4-addition: crystal structure of 8. Reagents and conditions: (i) chiral
HPLC separation (25 cm Chiralpak IA); (ii) 4 M HCl, MeOH, 50 °C,
78% yield; (iii) 10 M NaOH, MeOH, 25 °C, 32% yield.
a Reaction conditions: [RhCl(cod)]2 (5 mol%),), (R)-BINAP (20
mol%), aq KOH (2 equiv), ArB(OH)2 (3 equiv), 1,4-dioxane, 95 °C,
4 h.
b Isolated yield of pure products.
c Determined by chiral HPLC analysis.
d R = Me.
The next part of our investigation was to explore the scope
of the asymmetric 1,4-addition reaction using a variety of
aryl boronic acids. Without optimisation, the desired
products were obtained in moderate to good yields and in
moderate to high enantiomeric excesses (Table 3).
e R = t-Bu.
the steric hindrance of the methyl group.13 As before,
when the substrate ester group was changed from methyl
(Table 3, entry 6) to the larger tert-butyl group (Table 3,
entry 7), an increase in yield and enantiomeric excess was
observed.
The reaction works well with a range of boronic acids
bearing a range of electron-donating and electron-with-
drawing groups and is tolerant of a good range of func-
tionality. Thus, boronic acids containing a nitro group
(Table 3, entry 2), unprotected phenol (Table 3, entry 4),
and bromine atom (Table 3, entries 6 and 7), were all cou-
pled in good yields and high enantiomeric excesses. The
o-methylphenyl boronic acid (Table 3, entry 5) gave a
lower than expected enantiomeric excess probably due to
Finally, we replaced the piperazine moiety of the substrate
with other amines (Table 4). The substrates 3d–f were
prepared according to step (ii) of Scheme 2 and in high
yields (84–100%).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2817–2821

2820
N. A. Anderson et al.
LETTER
the reaction mixture was stirred at r.t. under nitrogen. tert-Butyl pi-
perazine-1-carboxylate (5.91 g, 31.7 mmol) dissolved in DMF (100
mL) was added dropwise, and the solution was stirred at r.t. for 2 h.
Table 4 Rh-Catalysed Asymmetric 1,4-Addition with Variation of
the Basic Residuea
Cl
The reaction mixture was then concentrated in vacuo, partitioned
between CH2Cl2 (500 mL) and H2O (250 mL). The aqueous phase
was separated and washed with further CH2Cl2 (250 mL). The com-
bined organic phases were then dried over MgSO4, filtered, and
concentrated in vacuo to give a brown oil. This was purified by sil-
ica chromatography eluting with EtOAc–cyclohexane (25–100%
EtOAc). The appropriate fractions were combined and concentrated
in vacuo to give a brown oil (6.66g, 71%).
1H NMR (400 MHz, CDCl3): δ = 6.78–6.87 (m, 1 H), 5.85–5.95 (m,
1 H), 3.43–3.47 (m, J = 4.78 Hz, 4 H), 3.11 (dd, J = 1.76, 6.29 Hz,
2 H), 2.38–2.43 (m, J = 5.04 Hz, 4 H), 1.49 (s, 9 H), 1.46 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 165.4, 154.7, 143.1, 125.5, 80.5,
79.7, 76.7, 59.3 (2 C), 53.1 (2 C), 28.4 (3 C), 28.1 (3 C). HRMS: m/z
calcd for C17H30N2O4: 327.2284; found: 327.2270.
O
Rh (cat.)
Cl
(R)-BINAP
R
O
Ot-Bu
conditions
R
Ot-Bu
B(OH)2
3d–f
(S)-10a–c
Entry
1
R
Product
Yield (%)b
ee (%)c
HO
(S)-10a
60
88
N
PhHN
Me2N
2
3
(S)-10b
(S)-10c
76
47
67
(S)-tert-Butyl 4-[4-(tert-Butoxy)-2-(3-chlorophenyl)-4-oxobu-
tyl]piperazine-1-carboxylate (7b)
n.d.d
(3-Chlorophenyl)boronic acid (302 mg, 1.93 mmol) was dissolved
in 1,4-dioxane (3 mL) under an atmosphere of nitrogen. (R)-BINAP
(80 mg, 0.13 mmol), 3.8 M aq KOH (0.34 mL, 1.29 mmol) and [Rh-
Cl(cod)]2 (16 mg, 0.032 mmol) were added, and the solution was
stirred at r.t. for 0.5 h. (E)-tert-Butyl 4-[4-(tert-butoxy)-4-oxobut-2-
en-1-yl]piperazine-1-carboxylate (210 mg, 0.643 mmol) in 1,4-di-
oxane (3 mL) was added, and the solution was heated to 95 °C for
4 h. The reaction mixture was then concentrated in vacuo, parti-
tioned between CH2Cl2 (10 mL) and H2O (10 mL), and the aqueous
phase was separated and washed with further CH2Cl2 (10 mL). The
combined organic phases were concentrated in vacuo and purified
by silica chromatography eluting with EtOAc–cyclohexane (0–
100% EtOAc). The appropriate fractions were combined and con-
centrated in vacuo to give the title compound as a clear gum (228
mg, 81%).
a Reaction conditions: [RhCl(cod)]2 (5 mol%), (R)-BINAP (20
mol%), aq KOH (2 equiv), ArB(OH)2 (3 equiv), 1,4-dioxane, 95 °C,
4 h.
b Isolated yield of pure products.
c Determined by chiral HPLC analysis.
d n.d. = not determined; separation conditions for the enantiomers un-
able to be found.
3-Hydroxyprolyl (3d), aniline (3e), and dimethylamino
(3f) substrates, groups with different functionalities and
degrees of basicity, also coupled in reasonable to good
isolated yields and enantiomeric excesses.
In conclusion, a method for coupling aryl boronic acids to
acyclic α,β-unsaturated esters containing a basic γ-amino
group has been described. The reaction is catalysed by a
[RhCl(cod)]2 catalyst and can generate enantiomerically en-
riched products by the addition of 20 mol% of (R)-BINAP.
A variety of functional groups, and of particular note, unpro-
tected alcohols and amines, are tolerated, and the reaction
proceeds in moderate to very good yields (up to 81%) and
enantiomeric excesses (up to 96%).
1H NMR (400 MHz, CDCl3): δ = 7.16–7.22 (m, 3 H), 7.06–7.10 (m,
1 H), 3.37 (t, J = 4.91 Hz, 4 H), 3.24–3.32 (m, 1 H), 2.80 (dd, J =
5.92, 15.49 Hz, 1 H), 2.37–2.51 (m, 5 H), 2.28–2.35 (m, 2 H), 1.45
(s, 9 H), 1.32 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 171.8,
155.0, 145.3, 134.4, 129.9, 128.1, 127.0, 126.2, 80.7, 79.8, 77.6,
77.3, 77.0, 64.4, 53.6, 40.3, 40.0, 28.7 (3 C), 28.3 (3 C). HRMS: m/z
calcd for C23H35ClN2O4: 439.2364; found: 439.2356.
Acknowledgment
Mr. Ian Campbell is acknowledged for generating helpful discus-
sions. Dr. P. A. Procopiou is gratefully acknowledged for providing
useful feedback during manuscript revisions. Professor William
Clegg and Dr. Ross Harrington (University of Newcastle) are than-
ked for the GlaxoSmithKline funded X-ray crystallographic analy-
sis of 8.
Typical Procedure
(E)-tert-Butyl 4-Bromobut-2-enoate (6b)
(E)-tert-Butyl but-2-enoate (10 g, 70.3 mmol) was dissolved in
CCl4 (250 mL) and NBS (8.76 g, 49.2 mmol) was added. The reac-
tion mixture was stirred under nitrogen at r.t. for 5 min before AIBN
(1.16 g, 7.03 mmol) was added. The reaction mixture was then heat-
ed to 80 °C for 3.5 h. H2O (250 mL) was added and the organic
phase separated and dried over MgSO4, filtered, and concentrated in
vacuo to give a yellow oil that was purified by silica chromatogra-
phy eluting with EtOAc–cyclohexane (0–25% EtOAc). The appro-
priate fractions were combined and concentrated in vacuo to give
the title compound as a clear oil (7.75 g, 50%).
References and Notes
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1 H), 3.99 (dd, J = 1.26, 7.30 Hz, 2 H), 1.48 (s, 9 H). 13C NMR (100
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1-carboxylate (3c)
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PEA (10.08 ml, 57.7 mmol) were dissolved in DMF (150 mL), and
(7) Tian, P.; Dong, H. Q.; Lin, G. Q. ACS Catal. 2012, 2, 95.
Synlett 2012, 23, 2817–2821
© Georg Thieme Verlag Stuttgart · New York

LETTER
Addition of Arylboronic Acids to Acyclic Unsaturated Esters
2821
(8) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Miyaura, N.
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isomer 1 elutes ca. 21 min, isomer 2 elutes ca. 30 min.
(14) Crystallographic data (excluding structural factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC897927. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, [fax: +44(1223)336033 or
e-mail: deposit@CCDC.cam.ac.uk].
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Synlett 2012, 23, 2817–2821

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