Visible-Light-Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ-Amino Boronic Esters

Article abstract of DOI:10.1002/anie.201712186

The synthesis of alkyl boronic esters by direct decarboxylative radical addition of carboxylic acids to vinyl boronic esters is described. The reaction proceeds under mild photoredox catalysis and involves an unprecedented single-electron reduction of an α-boryl radical intermediate to the corresponding anion. The reaction is amenable to a diverse range of substrates, including α-amino, α-oxy, and alkyl carboxylic acids, thus providing a novel method to rapidly access boron-containing molecules of potential biological importance.

Full text of DOI:10.1002/anie.201712186

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Accepted Article
Title: Visible-Light-Mediated Decarboxylative Radical Additions to Vinyl
Boronic Esters: Rapid Access to γ-Amino Boronic Esters
Authors: Adam Noble, Riccardo S. Mega, Daniel Pflästerer, Eddie L.
Myers, and Varinder Kumar Aggarwal
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Angewandte Chemie International Edition
10.1002/anie.201712186
COMMUNICATION
Visible-Light-Mediated Decarboxylative Radical Additions to Vinyl
Boronic Esters: Rapid Access to γ-Amino Boronic Esters
†
†
Adam Noble, Riccardo S. Mega, Daniel Pflästerer, Eddie L. Myers, and Varinder K. Aggarwal*
Abstract: The synthesis of alkyl boronic esters by direct
decarboxylative radical addition of carboxylic acids to vinyl boronic
esters is described. The reaction proceeds under mild photoredox
catalysis and involves an unprecedented single-electron reduction of
an α-boryl radical intermediate to the corresponding anion. The
reaction is amenable to a diverse range of substrates, including α-
amino, α-oxy, and alkyl carboxylic acids, thus providing a novel
method to rapidly access boron-containing molecules of potential
biological importance.
wide substrate scope and good regiocontrol, the xanthate starting
materials need to be prepared and the dithiocarbonyl group next
to boron ultimately transformed into something more useful.
We reasoned that photoredox catalysis would allow direct
access to γ-amino organoborons through the radical-based
decarboxylative union of readily available α-amino acids and vinyl
boronic esters, where the nature of the photocatalyst could be
used to ensure good yield and wide substrate scope.[
MacMillan and co-workers reported related reactions with
acrylates and other electron-deficient olefins (Scheme 1c, X =
13]
CO
2
R).[14] In their process, following addition of the nucleophilic
Boronic acids and their derivatives occupy a central position
α-amino radical (generated by decarboxylation of a carboxylic
acid) to the acrylate, the resulting α-carboxyl radical intermediate
was reduced by the photocatalyst to give an enolate, which was
then protonated to give the γ-amino butyric acid derivative. It was
unclear whether vinyl boronic esters would participate in a similar
transformation as they are only weakly electron-deficient and the
photocatalyst-mediated single-electron reduction of an α-boryl
radical, which should be stabilized through π-donation,[11a] is
[
1]
in the chemical sciences, with broad applications in synthesis,
[
2]
polymer chemistry, and as chemical receptors.[4] They also
[3]
play an increasingly important role in medicinal chemistry since
they can act as carboxylic acid bioisosteres.[5] For example,
peptidylboronic acids can function as inhibitors of serine
proteases, an attribute that has led to the commercialization of the
peptidyl boronic acid antineoplastic drug, bortezomib, for the
treatment of relapsed and refractory multiple myeloma (Scheme
2
unknown (Scheme 1c, X = B(OR) ). We hereby report that
1
a).[6] Whilst boronic acid analogues of α-amino acids are now
well established, there have been very few investigations into the
use of boron analogues of other biologically important amino
[
7-
acids, such as the neuromodulator γ-amino butyric acid (GABA).
9
]
The paucity of such investigations could be due to the lack of
availability of these molecules, we therefore decided to address
this by developing new methodologies.
We wondered whether γ-amino boronic esters could be
accessed through the addition of α-amino radicals to vinyl boronic
esters. The addition of carbon-centered radicals to vinyl
organoboron molecules has been reported.[10-12] However, the
yield of desired product, regiochemistry (addition at the α or the β
carbon of the vinyl substrate) and the ability to suppress
deleterious polymerization is highly dependent on the nature of
the two substrates. Recently, Zard and co-workers addressed
some of these issues through the addition of a variety of carbon-
centered radicals to tetracoordinate N-methylimidodiacetate
[
11a]
(
MIDA)-ligated vinyl organoborons (Scheme 1b).
Accessing
the carbon-centered radicals via the fragmentation of xanthates
resulted in a group transfer reaction, with the dithiocarbonyl
moiety ending up at the position α to the boron atom. Despite the
[*]
Dr. A. Noble, R. S. Mega, Dr. D. Pflästerer, Dr. E. L. Myers, Prof. Dr.
V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
[†]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Boronic acids as carboxylic acid bioisosteres and proposed
synthesis of γ-amino boronic acid derivatives.
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photoredox-catalyzed decarboxylative radical addition of α-amino
acids (and a variety of other acids) to vinyl boronic esters is
feasible, providing rapid access to novel organoborons for
augmenting medicinal chemistry libraries.
Table 1. Optimization studies.[a]
To investigate our proposed reaction, initial studies focused
on the reaction between Boc-Pro-OH (1) and commercially
available vinyl boronic acid pinacol ester (2) (Table 1). We were
delighted to discover that the cesium salt formed by deprotonation
3 (%)[b]
Entry
Photocatalyst
Solvent
Light Source
1
2
A
B
DMF
DMF
DMF
DMA
DMSO
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
24 W blue LED strips
24 W blue LED strips
24 W blue LED strips
24 W blue LED strips
24 W blue LED strips
24 W blue LED strips
20 W CFL
44
62
0
of acid 1 with Cs
irradiation with 24 W blue LED strips in the presence of
Ir[dF(CF )ppy] (dtbbpy)PF (A) in DMF to yield γ-amino boronic
2 3
CO reacted with vinyl boronic ester 2 upon
3
C
3
2
6
4
B
29
39
5
ester 3 in 44% yield (entry 1). A significant increase in yield was
observed upon switching to the more reducing photocatalyst
5
B
6
B
Ir(ppy)
2
(dtbbpy)PF
6
(B), likely due to the more favorable SET
II
7
B
8
between the Ir state of the photocatalyst and the intermediate α-
boryl radical, whereas using ruthenium photocatalyst C proved
ineffective (entries 2–3). Evaluation of other solvents (entries 4–
8
B
40 W blue LED lamp
40 W blue LED lamp
40 W blue LED lamp
40 W blue LED lamp
None
82
66
1
9[c]
10[d]
11
D
6
) and bases gave no improvements in yield.[15] We next
B
investigated the effect of the light source on the reaction outcome.
While compact fluorescent light (CFL) was relatively ineffective
none
B
0
12
0
(
entry 7), the use of a more powerful 40 W blue LED lamp gave a
dramatic improvement in reaction efficiency, with 3 being formed
in 82% yield (entry 8). In addition, the use of the organic
photocatalyst 4CzIPN (D) under the optimized conditions afforded
[a] All reactions were carried out with 1 (0.050 mmol), 2 (0.075 mmol),
Cs CO (0.050 mmol), photocatalyst (0.50 μmol), and solvent (1.0 mL). [b]
Determined by GC using 1,2,4-trimethoxybenzene as an internal standard.
c] Using 5.0 mol% of photocatalyst D. [d] Reaction performed without
Cs CO . A = Ir[dF(CF )ppy] (dtbbpy)PF , B = Ir(ppy) (dtbbpy)PF , C =
2
3
[
3
in 66% yield, demonstrating that D is a viable alternative to the
2
3
3
2
6
2
6
iridium photocatalyst (entry 9).[16] Finally, control experiments
were performed to confirm the essential roles of the base,
photocatalyst and light (entries 10–12).
3 2 2
Ru(phen) Cl •xH O, D = 4CzIPN.
efficiency (8–10, 60–72%). When these conditions were applied
Having
established
optimal
conditions
for
the
to substrates bearing free N–H groups, dramatically reduced
decarboxylative radical addition to vinyl boronic esters, we
explored the scope of the transformation (Table 2). Various cyclic
amino acids possessing different carbamoyl protecting groups
and different ring sizes gave the corresponding products in
moderate to good yields (3–7, 38–78%). Protected acyclic amino
acids, including secondary and tertiary, also reacted with good
yields were observed.[
15]
However, slight modification of the
reaction conditions (using photocatalyst A and DMA as the
solvent) allowed these important substrates to participate (Table
, Conditions B). While primary carboxylic acids reacted with low
efficiency (11, 26%), secondary and tertiary substrates gave the
corresponding products in good yields (12–16, 52–67%). Various
2
Table 2. Scope of the synthesis of γ-amino boronic esters from α-amino acids.[a]
[
a] Reactions were carried out on a 0.30 mmol scale with irradiation times of between 30 and 72 h. See Supporting Information for exact experimental procedures.
Yields are of isolated product after chromatographic purification. [b] Reactions were carried out on a 0.20 mmol scale.
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COMMUNICATION
Table 3. Alkenyl boronic ester substrates.[a]
Table 4. Alkyl carboxylic acid substrates.[a]
[
a] Reactions were carried out on a 0.30 mmol scale. Yields are of isolated
product after chromatographic purification. [b] Undetermined d.r. [c] Formed
with 44:33:19:4 d.r. [d] Protodeboronation occurred under the reaction
conditions, the yield of the corresponding product is given in parenthesis.
functional groups, including aromatic and heteroaromatic rings,
thioethers, esters and primary amides were tolerated (17–21, 54–
69%). Furthermore, the dipeptides Z-Gly-Phe-OH and Z-Phe-
Leu-OH gave the γ-amino boronic esters 22 and 23 in 48% and
63% yields, respectively.
Next, we investigated the use of different alkenyl boronic
esters in the reaction with Boc-Pro-OH (1) (Table 3). Both 1- and
2-propenyl boronic esters reacted with high yields (24 and 25,
87% and 68%), whereas the products from the reactions with
trisubstituted alkenyl boronic esters were formed in lower yields
26 and 27, 49% and 28%), presumably due to the increased
steric hindrance. Pleasingly, protected alcohols could be
[a] Reactions were carried out on a 0.20 mmol scale. Yields are of isolated
product after chromatographic purification. [b] Reactions were carried out on a
(
0.30 mmol scale with photocatalyst A.
incorporated into the vinyl boronic ester (28 and 29, 57% and
Our proposed mechanism for this decarboxylative
5
3%). Surprisingly, however, when an α-styrenyl boronic ester
conjugate addition reaction is outlined in Scheme 2a. Initial SET
between the photoexcited iridium catalyst and the carboxylate
formed upon deprotonation of 1 generates a carboxyl radical that
undergoes decarboxylation to form α-amino radical 48. Conjugate
was employed, the desired product 30 was not obtained due to
rapid protodeboronation under the reaction conditions.[15]
To further demonstrate the utility of this decarboxylative
alkyl boronic ester synthesis we wanted to extend the scope to
include simple alkyl carboxylic acids (Table 4). Although initial
attempts demonstrated that photocatalyst A could promote the
desired reaction, it was found that optimum yields were obtained
addition to vinyl boronic ester 2 produces the stabilized α-boryl
radical 49, which undergoes SET with the reduced IrII
[18]
photocatalyst to give α-boryl anion 50. Final protonation then
furnishes the γ-amino boronic ester product 3. Support for the
when
Ir[dF(Me)ppy]
using
the
more
reducing
photocatalyst
proposed single-electron reduction of 49 to 50 was provided by
performing deuterium labeling studies (Scheme 2b).[15] When the
(dtbbpy)PF
6
(E).[17] We were delighted to discover
2
that simple cycloalkane carboxylic acids of various ring sizes and
acyclic secondary carboxylic acids reacted to give the
corresponding alkyl boronic esters in moderate to good yields
reaction of vinyl boronic ester 2 was carried out with the
preformed cesium salt 51 in the presence of deuterium oxide the
desired product 3 was formed with 58% D-incorporation α to the
boronic ester group, confirming the formation of α-boryl anion 50.
Calculation of the single-electron reduction potential for 49 using
DFT gave a value of –1.25 V vs. SCE in MeCN,[19,20] thus
(
31–35, 25–67%). Carboxylic acids with α-oxy groups, including
both cyclic and acyclic examples, also performed well (36 and 37,
2% and 47%), with photocatalyst A being optimal. Furthermore,
6
cyclic and acyclic tertiary carboxylic acids reacted to give the
corresponding products with moderate to excellent yields (38–41,
suggesting that thermodynamically favorable SET will occur with
III II
both photocatalyst A (E1/2 [Ir /Ir ] = –1.37 V vs. SCE in MeCN) and
46–75%). Finally, this methodology was applied to a variety of
III II
[13a]
B (E1/2 [Ir /Ir ] = –1.51 V vs. SCE in MeCN).
carboxylic acid natural products and drugs, including
dehydroabietic acid (42, 63%, >95:5 d.r.), the vitamin E analogue
Trolox (43 and 44, 55% and 56%), the fibrate drugs bezafibrate
In conclusion, a novel visible-light-mediated decarboxylative
radical addition to vinyl boronic esters has been developed for
synthesizing alkyl boronic esters from abundant alkyl carboxylic
acid substrates. A mechanism involving an unprecedented single-
electron reduction of an α-boryl radical by the reduced-state
photocatalyst was supported by deuterium labeling studies and
DFT calculations. Excellent functional-group tolerance was
demonstrated through application to a vast array of substrates,
including various natural products and drug scaffolds. Importantly,
(
(
45, 40%) and gemfibrozil (46, 68%), and a tartaric acid derivative
47, 29%, >95:5 d.r.). Importantly, the successful application of
these substrates demonstrates the potential for late-stage
introduction of an alkyl boronic ester group into complex
molecules possessing diverse functionality, including aryl ethers,
phenols, aryl halides, amides and esters.
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COMMUNICATION
the rapid access to structurally diverse alkyl boronic esters
provided by this methodology will likely be of significant value to
medicinal chemists, both as an end-point and as a site for
subsequent diversification.
[7]
a) M. Ordonez, C. Cativiela, Tetrahedron: Asymmetry 2007, 18, 3–99; b)
K. Gajcy, S. Lochynski, T. Librowski, Curr. Med. Chem. 2010, 17, 2338–
2347.
[
8]
For examples of bioactive γ-amino boronic acid derivatives, see: a) M. J.
Luderer et al. Pharm. Res. 2016, 33, 2530–2539; b) A. Maynard et al. J.
Med. Chem. 2013, 57, 1902–1913; c) L. L. Johnson Jr., T. A. Houston,
Tetrahedron Lett. 2002, 43, 8905; d) C. P. Decicco et al. Bioorg. Med.
Chem. Lett. 2001, 11, 2561–2564.
[
[
9]
For a recent investigation into β-amino boronic acids, see: J. Tan, A. B.
Cognetta III, D. B. Diaz, K. M. Lum, S. Adachi, S. Kundu, B. F. Cravatt,
A. K. Yudin, Nat. Commun. 2017, 8, 1760.
10] For radical additions to vinyl boronic esters, see: a) D. S. Matteson, J.
Am. Chem. Soc. 1959, 81, 5004–5005; b) D. S. Matteson, J. Am. Chem.
Soc. 1960, 82, 4228–4233; c) D. S. Matteson, G. D. Shaumberg, J. Org.
Chem. 1966, 31, 726–731; d) N. Guennouni, F. Lhermitte, S. Cochard,
B. Carboni, Tetrahedron 1995, 51, 6999–7018; e) E. Lee, K. Zong, H. Y.
Kang, J. Lim, J. Y. Kim, Bull. Korean Chem. Soc. 2000, 21, 765–766; f)
H. Lopez-Ruiz, S. Z. Zard, Chem. Commun. 2001, 2618–2619; g) M. R.
Heinrich, L. A. Sharp, S. Z. Zard, Chem. Commun. 2005, 3077–3079.
11] For radical additions to vinyl boronate complexes, see: a) B. Quiclet-Sire,
S. Z. Zard, J. Am. Chem. Soc. 2015, 137, 6762–6765; b) M. Kischkewitz,
K. Okamoto, C. Mück-Lichtenfeld, A. Studer, Science 2017, 355, 936–
[
938; c) M. Silvi, C. Sandford, V. K. Aggarwal, J. Am. Chem. Soc. 2017,
139, 5736–5739; d) G. J. Lovinger, J. P. Morken, J. Am. Chem. Soc.
2017, DOI: 10.1021/jacs.7b10519.
[
12] For radical additions to vinyl boronate complexes with regioselectivity for
addition α to boron, see: a) H. Kim, D. W. C. MacMillan, J. Am. Chem.
Soc. 2008, 130, 398–399; b) Y. Yasu, T. Koike, M. Akita, Chem.
Commun. 2013, 49, 2037–2039; c) D. F. Reina, A. Ruffoni, Y. S. S. Al-
Faiyz, J. J. Douglas, N. S. Sheikh, D. Leonori, ACS Catal. 2017, 7, 4126–
4130.
Scheme 2. Proposed mechanism and deuterium labeling studies.
[13] For selected reviews on photoredox catalysis, see: a) C. K. Prier, D. A.
Rankic, D. W. C. MacMillan, Chem. Rev. 2013, 113, 5322–5363; b) M.
H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org. Chem. 2016, 81, 6898–
6
926; c) J. W. Tucker, C. R. J. Stephenson, J. Org. Chem. 2012, 77,
617–1622; d) D. M. Schultz, T. P. Yoon, Science 2014, 343, 1239176.
Acknowledgements
1
[
14] a) L. Chu, C. Ohta, Z. Zuo, D. W. C. MacMillan, J. Am. Chem. Soc. 2014,
136, 10886–10889; b) S. Bloom, C. Liu, D. K. Kölmel, J. X. Qiao, Y.
Zhang, M. A. Poss, W. R. Ewing, D. W. C. MacMillan, Nat. Chem. 2018,
DOI: 10.1038/nchem.2888; For related examples, see: c) Y. Miyake, K.
Nakajima, Y. Nishibayashi, Chem. Commun. 2013, 49, 7854–7856; d) A.
Millet, Q. Lefebvre, M. Rueping, Chem. Eur. J. 2016, 22, 13464–13468;
e) N. P. Ramirez, J. C. Gonzalez-Gomez, Eur. J. Org. Chem. 2017,
2154–2163.
We thank EPSRC (EP/I038071/1) and H2020 ERC (670668) for
financial support. D.P. is in receipt of
a
Deutsche
Forschungsgemeinschaft (DFG) fellowship. We also thank Prof.
David Fermin for assistance with cyclic voltammetry.
Keywords: Photoredox catalysis • vinyl boronic esters • amino
boronic acids • radical reactions • decarboxylative coupling
[
15] See Supporting Information for details.
[16] H. Uoyama, K. Goushi, K. Shizu, H. Nomura, C. Adachi, Nature 2012,
4
92, 234–238.
17] S. Ladouceur, D. Fortin, E. Zysman-Colman, Inorg. Chem. 2011, 50,
1514–11526.
[
[
1]
2]
Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, Vols. 1 and 2; D. G. Hall, Ed.; Wiley-VCH:
Weinheim, 2011.
[
[
1
18] The generation of α-boryl anion 50 should be facilitated by the stabilizing
effect the tricoordinate boron atom has on the adjacent carbanion, see:
K. Hong, X. Lin, J. P. Morken, J. Am. Chem. Soc. 2014, 136, 10581–
a) A. Suzuki, Angew. Chem. Int. Ed. 2011, 50, 6722–6737; Angew. Chem.
2011, 123, 6854–6869; b) D. Leonori, V. K. Aggarwal, Angew. Chem. Int.
Ed. 2015, 54, 1082–1096; Angew. Chem. 2015, 127, 1096–1111; c) C.
Sandford, V. K. Aggarwal, Chem. Commun. 2017, 53, 5481–5494. For
use in Lewis acid catalysis, see: a) E. Dimitrijević, M. S. Taylor, ACS
Catal. 2013, 3, 945–962; b) H. Zheng, D. G. Hall, Aldrichimica Acta 2014,
1
0584.
19] a) Y. Fu, L. Liu, H. Yu, Y. Wang, Q. Guo, J. Am. Chem. Soc. 2005, 127,
227–7234. See also: b) H. G. Roth, N. A. Romero, D. A. Nicewicz,
[
7
Synlett 2016, 27, 714–723.
47, 41–51.
[
20] Attempts to measure this reduction potential by cyclic voltammetry using
a model α-iodo boronic ester showed only a single irreversible reduction
peak at –2.0 V vs. SCE in MeCN, corresponding to the two-electron
reduction process. See Supporting Information for details.
[
[
3]
4]
W. L. A. Brooks, B. S. Sumerlin, Chem. Rev. 2015, 116, 1375–1397.
a) S. D. Bull, M. G. Davidson, J. M. H. Ven Den Elsen, J. S. Fossey, A.
T. A. Jenkins, Y.-B. Jiang, Y. Kubo, F. Marken, K. Sakurai, J. Zhao, T. D.
James, Acc. Chem. Res. 2013, 46, 312–326; b) G. F. Whyte, R. Vilar, R.
Woscholski, J. Chem. Biol. 2013, 6, 161–174.
[
5]
6]
a) W. Yang, X. Gao, B. Wang, Med. Res. Rev. 2003, 23, 346–368; b) P.
C. Trippier, C. McGuigan, Med. Chem. Commun. 2010, 1, 183–198; c)
C. Ballatore, D. M. Huryn, A. B. Smith III. ChemMedChem 2013, 8, 385–
395; d) D. B. Diaz, A. K. Yudin, Nat. Chem. 2017, 9, 731–742.
[
a) D. S. Matteson, Med. Res. Rev. 2008, 28, 233–246; b) R. Smoum, A.
Rubinstein, V. M. Dembitsky, M. Srebnik, Chem. Rev. 2012, 112, 4156–
4220.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
The synthesis of alkyl boronic esters by
direct decarboxylative radical addition
of carboxylic acids to vinyl boronic
esters is described. The reaction
proceeds under mild photoredox
catalysis and is amenable to a diverse
range of substrates, including α-amino,
α-oxy, and alkyl carboxylic acids.
A. Noble, R. S. Mega, D. Pflästerer, E.
L. Myers, V. K. Aggarwal*
Page No. – Page No.
Visible-Light-Mediated
Decarboxylative Radical Additions to
Vinyl Boronic Esters: Rapid Access
to γ-Amino Boronic Esters
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