Iridium-catalysed C-H borylation of β-aryl-aminopropionic acids

Article abstract of DOI:10.1039/d0ob01495h

Iridium-catalysed catalytic, regioselective C-H borylation of β-aryl-aminopropionic acid derivatives gives access to 3,5-functionalised protected β-aryl-aminopropionic acid boronates. The synthetic versatility of these new boronates is demonstrated through sequential one-pot functionalisation reactions to give diverse building blocks for medicinal chemistry. The C-H borylation is also effective for dipeptide substrates. We have exemplified this methodology in the synthesis of a pan αv integrin antagonist.

Full text of DOI:10.1039/d0ob01495h

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DOI: 10.1039/D0OB01495H
Iridum-catalysed C–H Borylation of β-aryl-aminopropionic acids
Henry Robinson,† Joe Stillibrand,† Klemensas Simelis,† Simon J. F. Macdonald‡ and Andrew
Nortcliffe†*
†GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of
Chemistry, University of Nottingham, Triumph Road, Nottingham, NG7 2TU, United
Kingdom.
‡GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY,
United Kingdom.
CF3
N
O
N
BocHN
OEt
R1
R1
BPin
O
Ir-catalyzed
C-H borylation
drug-like molecules
O
Br
O
BocHN
OR
BocHN
OR
Highly functionalised monomers
for medicinal chemistry
NH
O
H
N
H2N
N
H
O
N
OH
H
Biologically active molecules

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DOI: 10.1039/D0OB01495H
Abstract
Iridium-catalysed catalytic, regioselective C–H borylation of β-aryl-aminopropionic acid
derivatives gives access to 3,5-functionalised protected β-aryl-aminopropionic acid boronates.
The synthetic versatility of these new boronates is demonstrated through telescoped
functionalisation reaction to give diverse building blocks for medicinal chemistry. The C-H
borylation is also effective for dipeptide substrates. We have exemplified this methodology in
the synthesis of a pan v integrin antagonist.
Introduction
Natural and non-natural amino acids are widespread and have been extensively exploited in the
synthesis of therapeutic molecules.1 As a result, there is a continued need to develop novel
strategies for the synthesis of these fundamentally important building blocks. Of particular
importance in the context of medicinal chemistry is the development of methods for the
construction of structurally diverse β-aryl-aminopropionic acids. This motif is present in
biologically active molecules with activity against Chagas disease,2 breast cancer,3 and in αv
integrin antagonists as potential treatments for osteoporosis,4 melanoma5 and idiopathic
pulmonary fibrosis.6 Additionally, β-phenyl-aminopropionic acid is an intermediate in the
synthesis of Maraviroc,7 a CCR-5 receptor antagonist used for the treatment and prevention of
HIV. Therefore, a unified strategy to the synthesis of functionalised β-aryl-aminopropionic
acid would be of significant value.
Three general strategies have been developed for the synthesis of β-aryl-aminopropionic acids
to date (Scheme 1). The Rodionov reaction (Scheme 1A) represents the simplest option and
involves the multicomponent coupling of an aldehyde, malonic acid and ammonium acetate to
generate racemic β-aryl-aminopropionic acids.8–10
A
second protocol involves

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diastereoselective Reformatsky reactions of sulfinimines (Scheme 1B).11 An alternative
DOI: 10.1039/D0OB01495H
auxiliary-based approach is depicted in Scheme 1C and involves the addition of chiral lithium
amides to cinnamic acid derivatives (Scheme 1C).12–14 These strategies for the synthesis of β-
aryl-aminopropionic acids are dependent on the availability of highly functionalised starting
aldehydes (Scheme 1A and B) or aryl bromides (Scheme 1C). While some of these are
commercially available, they are available in limited supply and, since the diversity is
introduced in the first step, a multistep synthesis is required for each different β-aryl-
aminopropionic acid. This makes the exploration of structure-activity relationships around the
aryl ring time and resource consuming.
Scheme 1: Common approaches to β-aryl-aminopropionic acids.

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DOI: 10.1039/D0OB01495H
NH4OAc
O
O
R1
R2
R1
R2
O
A
HO
OH
Rodionov reaction
O
H2N
OH
- simple reaction conditions
- expensive 3,5-substituted aldehydes
- restricted by aldehyde availability
O
R1
R2
R1
O
R2
O
B
BrZn
OR3
Reformatsky
S
*
N
S
t-Bu
N
H
OR
*
*
t-Bu
O
- moisture sensitive conditions
- stoichiometric zinc waste
- expensive 3,5-substituted aldehydes
- restricted by aldehyde availability
O
R1
R2
O
R1
R2
C
[Pd]
OR3
Ph
Br
Ph
N
OR
*
Ph
N
*
*
Li
Ph
Heck, 1,4-addition
- air/moisture sensitive conditions
- Pd waste
- expensive 3,5-substituted aryl bromides
As part of our research into novel biologically active peptidomimetics for therapeutic
application we sought to incorporate β-aryl-aminopropionic acids with diverse substituents in
the 3- and 5-positions. Given that existing methods, require a bespoke aldehyde or aryl bromide
for every new compound and we designed an alternative method based on a late-stage
functionalisation approach. Specifically, we envisioned that an appropriately pre-
functionalised 3-substituted β-aryl-aminopropionic acid derivative, accessed via a Rodionov
multicomponent reaction from more widely available 3-substituted aldehyde, could undergo a
C–H functionalisation reactions (Scheme 2) providing a platform for further chemistry.

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DOI: 10.1039/D0OB01495H
Scheme 2: C-H functionalisation to diverse β-aryl-aminopropionic acids
NH4OAc
O
O
- simple reaction conditions
- scalable
- cheap 3-substituted aldehydes
- highly functionalised products
- opportunity for one-pot
diversification
R1
R1
H
BPin
O
R1
R2
HO
OH
C-H borylation
O
Rodionov reaction
BocHN
OR
BocHN
OR
O
In the past decade C–H activation chemistry emerged into the forefront of modern organic
chemistry. The innovative work of Hartwig and Miyaura,15 and Smith and Maleczka16 in
iridium-catalysed aromatic C–H borylation offers a potentially powerful method for
functionalisation given that the synthetic versatility of boronate groups is ever increasing.17,18,19
Encouraged by previous examples of C–H borylation on simple phenylalanine20 and
tryptophan21 derivatives we now report the substrate directed iridium borylation of β-3-aryl-
aminopropionic acid precursors together with examples of “one-pot” transformations to
diversely functionalised 3,5-substituted products and implementation of this methodology in
the preparation of an integrin antagonist bearing a β-3,5-aryl-aminopropionic acid motif.
Results and Discussion
A series of 3-substituted β-aryl-aminopropionic acid derivatives were prepared by Rodionov
multicomponent reaction or addition of the bromozincacetate to the corresponding sulfinimine
followed by suitable protection as the N-Boc esters. Using 1d as a model substrate we
performed a brief screen of previously reported ligands and solvents to determine the optimum
conditions.22 Methoxy(cyclooctadiene)iridium(I) dimer ([Ir(OCH3)COD)]2) was chosen as the
catalyst with bis(pinacolato)diboron (B2pin2) as the boron source. We evaluated three solvents
(MTBE, THF and iPrNEt2) with two ligands – 4-4’-di-tert-butyl-2,2’-bipyridine (dtbpy) and

Organic & Biomolecular Chemistry
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3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen). The reactions were heated at 80 ºC forV2ie4w Ahrticle Online
DOI: 10.1039/D0OB01495H
and a qualitative assessment of conversion determined by LCMS. The reaction did not reach
completion when iPrNEt2 was used a solvent. Conversion was comparable for both ligands and
when ether solvents were used. Under standard heating conditions, shortening the reaction time
from 24 h reduced the conversion, but complete conversion could be achieved using microwave
irradiation in three hours. Based on this screen we selected MTBE and dtbpy to pair with
([Ir(OCH3)COD)]2) and B2Pin2. Under these conditions a range of β-aryl-aminopropionic acid
derivatives were converted into the corresponding borylated derivatives (Scheme 3). As
predicted, the reaction predominantly or exclusively yielded the 3,5-substituted products, in
accordance with the reported directing regiochemistry of iridium-catalysed borylation
reactions.23

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Scheme 3: Substrate scope of iridium-catalysed C–H borylation of β-aryl-aminopropionic
DOI: 10.1039/D0OB01495H
acids.
B2Pin2 (1.2 equiv.)
[Ir(OMe)(cod)2]2 (2.5 mol%)
dtbpy (5 mol%)
X
X
BPin
O
MTBE
O
80 °C, µW, 3 h
BocHN
OR
BocHN
OR
1a-l
2a-l
H
BPin
O
Cl
BPin
O
F
BPin
O
BocHN
OEt BocHN
OEt BocHN
OEt
64%,a 2a
71%, 2b
40%,b 2c
MeO
BPin
O
Me
BPin
O
Br
BPin
O
BocHN
OEt BocHN
OEt BocHN
OEt
71%, 2d
51%, 2e
86%, 2f
2g scale, 5.4 mmol
CF3
BPin
O
NC
BPin
O
BPin
O
BocHN
OEt
BocHN
OEt
BocHN
OEt
85%, 2h
2g scale, 6.5 mmol
69%, 2g
55%, 2i
PinB
R1
BPin
O
N
S
O
O
BocHN
OtBu
OEt
BocHN
OEt
BocHN
30%,c 2k
31%,d 2l
38%, 2j
a1:1:3 mixture of regioisomers (2a:4-substitued:3,5-substituted), b2:1 mixture of regioisomers (2c:3,4-
substituted), cborylated product (R1 = Bpin) unstable to column chromatography; yield over two steps following
d
Suzuki coupling with p-nitroiodobenzene to yield product 2k (R1 = p-nitrophenyl) reaction conducted at room
temperature.

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The reaction of unsubstituted β-aryl-aminopropionic acid derivative (X = H) yieldDeOdI:a10m.10i3x9t/Du0rOeB01495H
of 3- and 4-isomers along with and 3,5-diborylated product in a ratio of 1:1:3, as determined
1
by H NMR. 3-Substituted substrates were readily tolerated in the reaction delivering the
corresponding 3,5-substituted products in 38-86% yield (Scheme 3). 3-Fluorosubstituted
substrate 1c yielded a 2:1 mixture of 3,5 (2c) and 3,4-isomers that were inseparable by column
chromatography. This is consistent with observations by other workers.20,24 The borylated
products were stable and could be readily purified by column chromatography to isolate them.
Furthermore, the 3-trifluoromethyl 2f and 3-bromo 2h derivatives could be prepared on
multigram scale with improved isolated yields. Under the standard borylation conditions, 2-
thienyl derivative 1l yielded exclusively the 3,5-diborylated product. The 5-borylated product
2l was produced exclusively by conducting the reaction at room temperature. C–H borylation
of the 3-pyridyl derivative 1k yielded the desired product, however, attempts to purify the
compound by chromatography resulted in protodeborylation and recovery of starting material
1k. The yield reported is for the two-step procedure, involving Suzuki-Miyaura coupling of the
unstable boronate ester with 4-nitroiodobenzene (R1 = 4-nitrophenyl). When the
enantioenriched substrate (S)-1f was subjected to C–H borylation followed by oxidation,
phenol (S)-3 was obtained with an 97% ee indicating no racemisation occurs in the borylation
process (Scheme 4).

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Scheme 4: Iridium-catalysed C–H borylation of enantiopure β-aryl-aminopropionic
DOI: 10.1039/D0OB01495H
acids.
B2Pin2 (1.2 equiv.)
[Ir(OMe)(cod)2]2 (2.5 mol%)
dtbpy (5 mol%)
Br
Br
BPin
O
Br
OH
O
aq. Oxone®
MTBE
O
80 °C, µW, 3 h
acetone
rt, 0.75 h
BocHN
OEt
BocHN
OEt
BocHN
OEt
33% over 2 steps
(S)-1f
97% ee
(S)-2f
(S)-3
97% ee
To demonstrate the versatility of these β-aryl-aminopropionic acid boronate derivatives in
synthesis we have exemplified their applicability in typical reactions used in the synthesis of
biologically active molecules (Scheme 5). In each example, the 3-substituted β-aryl-
aminopropionic acid derivative was borylated under the previously described conditions and
then telescoped into functionalisation without purification of the boronate. Oxidation of the
boronate with aqueous Oxone® provided the phenols 3-6.16 3-Trifluoromethyl derivative 1h
was borylated and transformed into biaryl ether 7 under standard Suzuki-Miyaura conditions.
Attempts to alkylate the phenols under standard conditions (RBr, Cs2CO3) were unsuccessful,
resulting in ester hydrolysis and transesterification only. To circumvent this and access ether
containing products we utilised the Chan-Lam coupling to provide phenyl ethers 8 and 9.25 The
Chan-Lam coupling was also an effective methodology to access N-linked heteraraomatic β-
aryl-aminopropionic acid derivatives, the 1,3-dimethylpyrazole derivates 10 and 11 were
accessed in 74 and 68% yield respectively over two steps.26 These transformations are further
examples of the Chan-Lam coupling as a viable sustainable alternative to Pd-catalysed
etherification and amination and are compatible with tandem iridium borylation. Bromination
of 2i with CuBr2 provided the 3-bromo-5-tert-butyl derivative 12, this motif is featured in
recently reported selective integrin antagonists.27,28 3-Bromo-5-fluoroderivative 13 was

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prepared via metallation of the intermediate boronate to the organosilver reagent DaOnId: 10r.e10a3c9t/Dio0OnB01495H
with Selectfluor®.29
Scheme 5: One-pot functionalisation of BPin-β-aryl-aminopropionic acids
X
OH
O
NO2
CF3
BocHN
OEt
3, X = Br
4, X = Cl
5, X = F
O
BocHN
OEt
6, X = CF3
7
b
c
X
O
O
X
X
BPin
a
d
O
O
BocHN
OEt
BocHN
OEt
BocHN
OEt
8, X = Br
9, X = CF3
e
g
f
X
N
N
Br
F
O
Br
O
BocHN
OEt
BocHN
OEt
10, X = Br
11, X = CF3
O
13
H2N
OEt
12
Reagents and conditions. (a) standard conditions Scheme 2; (b) Oxone®, aq. acetone, r.t., 0.75 h, 3 = 52%, 4 =
77%, 5 = 33%, 6 = 92% over two steps; (c) 1-iodo-4-nitrobenzene, Pd(dppf).CH2Cl2, K3PO4, 1,2-DME:H2O, 70
°C, 4.5 h, 93% over two steps; (d) phenol, CuOAc2, B(OH)3, 4Å molecular sieves, 70 °C, 16 h, 8 = 36%, 9 = 34%
over two steps; (e) 1,4-dimethylpyrazole, Cu(OAc)2, B(OH)3, 4Å molecular sieves, 80 °C, 16 h, 10 = 74%, 11 =
68% over two steps; (f) CuBr2, MeOH:H2O (2:1), 70 °C, 16 h, 39%; (g) i. AgOTf, NaOH, MeOH, 0 °C, 0.5 h; ii.
Selectfluor®, 3Å MS, acetone, r.t., 3 h, 59%.

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While tert-butoxycarbonyl groups present a robust, stable protecting group for thDeOsI:u10b.1s0t3r9a/tDe0sO,B01495H
further N-functionalisation requires deprotection before further reaction. To demonstrate the
utility of the C–H borylation in peptidomimetics, we replaced the tert-butoxycarbonyl group
with an α-amino acid (Scheme 6). Under the established C–H borylation conditions the amino
acid derived substrates 14a-c were converted to the corresponding dipeptide boronates 15a-c
in good yield showing the tolerance of the conditions to more complex conditions with
additional hydrogen bond donors.
Scheme 6: Iridium-catalysed C–H borylation of β-aryl-aminopropionic dipeptides.
B2Pin2 (1.2 equiv.)
[Ir(OMe)(cod)2]2 (2.5 mol%)
Br
Br
BPin
O
dtbpy (5 mol%)
MTBE
O
80 °C, µW, 3 h
AA
AA
N
OEt
N
OEt
H
H
15a-c
14a-c
Br
BPin
O
Br
BPin
O
O
O
BocHN
BocHN
N
OEt
N
OEt
H
H
69%, 15a
50%, 15b
Br
BPin
O
O
N
OEt
H
NBoc
39%a, 15c
AA = amino acid aextended reaction time of 6 h.

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Finally, we used this C–H borylation strategy to prepare a reported selective integrin
DOI: 10.1039/D0OB01495H
antagonist.27,28 Utilising the C–H borylation strategy to prepare 3-bromo-5-tert-butyl derivative
12 (Scheme 5) we converted this through to dipeptide 16 by amide coupling with Boc-glycine
in 50% yield (Scheme 7). Further acidic deprotection and coupling with 3-guanidinobenzoic
acid and final ester hydrolysis provided the integrin antagonist 17. While comparable in step
count to the reported, this approach allows installation of the stereocenter by Reformatsky
addition of ethyl bromozincacetate to the chiral sulfinamide, obviating a chiral HPLC
separation as previously reported. The reported synthetic procedures for similar compounds
require a bespoke aldehyde synthesis for each target compound, whereas a C–H borylation
strategy allows a more sustainable synthesis of similar analogs by functionalizing a common
intermediate.
Scheme 7: Application of C–H borylation chemistry in the synthesis of an integrin
antagonist.
Br
Br
Br
a
b, c, d
NH
O
O
O
O
O
H
N
BocHN
H2N
N
N
OH
N
OEt
H2N
OEt
H
H
H
O
12
16
17
Reagents and conditions. (a) Boc-glycine, HATU, iPr2EtN, MeCN, 0 °C to r.t., 16 h, 50%; (b) 4M HCl in dioxane,
5 h; (c) 3-guanidinobenzoic acid, diisopropylcarbodiimide, HOBt, CH2Cl2:DMF (1:1), r.t., 64 h; (c) 1M aq. LiOH,
THF, r.t., 64 h, 52% over three steps.
In conclusion, we have developed an efficient iridium-catalysed C–H borylation procedure of
β-aryl- and heteroaryl-aminopropionic acids and explored the scope of the procedure with

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Organic & Biomolecular Chemistry
respect to functional group tolerance and retention of enantiointegrity. We have fuVritehweArrticle Online
DOI: 10.1039/D0OB01495H
explored the C–H borylation procedure in dipeptide substrates further demonstrating its
synthetic utility. By applying telescoped “one-pot” reaction conditions we have shown that the
C–H borylation approach allows an effective route to diversely functionalised β-aryl-
aminopropionic acids across chemical space relevant to medicinal chemistry.
Supporting information
Experimental procedures, NMR spectra and chiral HPLC chromatograms are available in
Supporting Information.
Author information
Corresponding author: Email: andrew.nortcliffe@nottingham.ac.uk, Phone +44(0)1158
466887
Funding
We thank GlaxoSmithKline and the University of Nottingham for providing funds for
consumables associated with this work, including a part-studentship for H. Robinson.
Notes
The authors declare no competing financial interest.
#J.S. Deceased December 2018

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DOI: 10.1039/D0OB01495H
ORCID
Henry Robinson 0000-0002-3318-653X
Andrew Nortcliffe 0000-0002-3371-390X
Acknowledgements
We thank Thomas McInally and Prof. Christopher J. Moody for helpful discussions.
Determination of chiral purity was undertaken by Reach Separations, Bio City, Nottingham,
UK.
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