Copper-Catalyzed Enantioselective Synthesis of β-Boron β-Amino Esters

Article abstract of DOI:10.1021/acs.orglett.7b02784

In this report, the enantioselective, copper-catalyzed borylation of β-amidoacrylates is disclosed. A broad variety of biologically important α-aminoboronates has been prepared with consistently high levels of enantiocontrol using an inexpensive copper catalyst and a commercially available chiral ligand. The method can be applied to the synthesis of novel boron-containing dipeptides and hemiboronates.

Full text of DOI:10.1021/acs.orglett.7b02784

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Copper-Catalyzed Enantioselective Synthesis of β‑Boron β‑Amino
Esters
Aurora Lopez,† Timothy B. Clark,§ Alejandro Parra,*,†,‡ and Mariola Tortosa*,†,‡
́
†Department of Organic Chemistry and ‡Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Auton
de Madrid, 28049 Madrid, Spain
§Department of Chemistry and Biochemistry, University of San Diego, San Diego, California 92210, United States
́
oma
S
* Supporting Information
ABSTRACT: In this report, the enantioselective, copper-catalyzed borylation of β-amidoacrylates is disclosed. A broad variety of
biologically important α-aminoboronates has been prepared with consistently high levels of enantiocontrol using an inexpensive
copper catalyst and a commercially available chiral ligand. The method can be applied to the synthesis of novel boron-containing
dipeptides and hemiboronates.
Scheme 1. Enantioselective Catalytic Approaches to α-
Aminoboronates
hiral α-aminoboronic acids have become an important class
Cofbiologically active compounds, notablydue totheir use as
proteasome inhibitors.1 The α-aminoboronic acid motif is
present in the approved anticancer drugs bortezomib (Velcade)
and ixazomib (Ninlaro) or in phase I/II candidates such as
delanzomib (Figure 1). Additionally, these structures have also
been used as intermediates for the synthesis of enantiomerically
enriched amines or amino alcohols.2
compounds with dialkylamino groups can be prepared (Scheme
1, eq 2).7 However, α-aminoboronates shown in Figure 1 have
two structural features in common: a secondary amide with an
amino acid residue and an alkyl substituent α to the amino-
boronate moiety. Therefore, we realized that the development of
catalytic asymmetric methods to introduce these two structural
motifs simultaneously remains an important unmet challenge.
To address this task, we turned our attention to Z-enamides of
type A as potential precursors of α-aminoboronates B through an
enantioselective copper-catalyzed borylation (Scheme 1, eq 3).
We reasoned that the hydrogen bond between the N−H and the
carbonyl could provide a rigid template for the development of an
effective asymmetric transformation. Additionally, Z-enamides
can be easily prepared as single stereoisomers. The products
Figure 1. Biologically active α-aminoboronates.
Despite their biological relevance and synthetic interest, the
asymmetric synthesis of α-aminoboronates has been mostly
based on diastereoselective methods that involve the use of
stoichiometric amounts of chiral auxiliaries.3 Although a few
effective catalytic methods have been reported, they still present
structural limitations (Scheme 1). For instance, the metal-
catalyzed4 and metal-free borylation5 of imines and enamines6
only allow the preparation of aryl-substituted α-aminoboronates
(Scheme 1, eq 1). Alternatively, the copper-catalyzed hydro-
amination of alkenes overcomes this restriction, but only
Received: September 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02784
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Organic Letters
Letter
would be a novel class of α-aminoboronates that contain the two
structural motifs present in biologically active compounds: the
secondary amide moiety and analkyl substituent with a functional
group susceptible to further functionalization. Moreover, from a
biological point of view, they could also benefit from being β-
amino acid derivatives.8 Importantly, the transformation would
represent the first copper-catalyzed borylation of a β-
amidoacrylate.9,10
Table 1. Substrate Scope of Z-Enamides 1
To test our hypothesis, we prepared enamide 1a through
palladium-catalyzed addition of benzamide to ethyl propiolate.11
We next examined the copper-catalyzed borylation12 of 1a in the
presence of a variety of chiral phosphines.13 Enamide 1a was
treated in THF, at room temperature, with CuCl (10 mol %),
B2pin2 (1.1 equiv), NaOt-Bu (1 equiv), MeOH (4 equiv), and 11
mol % of a chiral ligand. After some optimization, we found that
(R)-Segphosprovidedthehighestyieldandthebestenantiomeric
ratio (Scheme 2).
Scheme 2. Optimized Copper-Catalyzed Borylation
Oneofthemain challengesweencountered duringthereaction
optimization was the moderate stability of compound 2a on silica
gel. Although the 1H NMR of the crude products showed clean
conversion, 2a was consistently obtained in low yields. Standard
deactivation of the silica gel with trimethylamine did not work.
After significant effort, we found that it was essential to deactivate
the silica gel with 35 wt % of water to obtain high yields.
We next explored the scope of the method with different Z-
enamides (Table 1). Aryl enamides with electron-donating
(Table 1, entry 2) and electron-withdrawing groups in the para,
meta, and ortho positions (Table 1, entries 3−6) afforded α-
aminoboronates 2b−f in high yields and excellent enantiomeric
ratios. Heteroaromatic substituted enamides, with coordinating
atoms suchas sulfur and nitrogen, were alsosuitable substrates for
the borylation. Importantly, alkyl amides such as 2j and N-Boc-
protected α-aminoboronate 2i could be also prepared with
excellent stereoselectivity (Table 1, entries 9 and 10). Finally, we
were pleased to find that this catalytic system also worked when
we substituted the ester moiety for a peptide bond (Table 1,
compounds 2k and 2l).14 On the contrary, the enantiomeric
excess dropped significantly when ketones were tested. Finally,
using 5 mol % of CuCl, we observed lower yields in most cases.
Next, we tested the present catalytic system with a more
challenging substrate such as 1m (Scheme 3), with a phenyl-
alanine fragment structurally close to the anticancer agent
bortezomib I (Scheme 1). Using the standard reaction conditions
and (R)-DM-Segphos as achiral ligand, the borylated product 2m
was obtained with moderate dr, revealing a possible mismatched
scenario (Scheme 3). Indeed, the use of (S)-DM-Segphos
provided the matched diastereomer 2m′ with improved
diastereomeric ratio.
a
Reaction conditions: 1 (0.2 mmol), B2pin2 (0.22 mmol, 1.1 equiv),
NaO-t-Bu (1.0 equiv), CuCl (10 mol %), L2 (11 mol %), MeOH (0.8
b
mmol, 4.0 equiv), THF (0.1 M). The er was determined by chiral
HPLC. Isolated yield. 1.5 equiv of B2pin2 was used. The reaction
time was 12 h.
c
d
e
and high enantiomeric ratio, with the opposite configuration at
the aminoboro stereocenter compared to compounds 2.15 Simple
alkyl chains on the nitrogen (4e) as well as β-carboxylate groups
(4f) were also tolerated. E-Enamides with a benzylic ester were
also suitable substrates for the copper-catalyzed borylation,
affording compounds 4g and 4h in good yields and high
stereocontrol. Finally, α-aminoboronate 4i was prepared in
moderate yield, showing that the benzoyl group on the nitrogen is
less efficient for the E-enamide series.
We further expanded the scope of our method to N-Boc-
protected E-enamides 3 with an alkyl substituent and a removable
protecting group on the nitrogen (Table 2). Gratifyingly, our
catalytic system proved to be robust despite the significant
structural changes. N-Boc-protected benzylic (4a,b) and
heterobenzylic (4c,d) derivatives were prepared in good yields
B
DOI: 10.1021/acs.orglett.7b02784
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Letter
Scheme 3. Synthesis of Boron-Containing Dipeptides
Scheme 4. Removal of the Pinacol Ester
Table 2. Substrate Scope of E-Enamides 3
Figure 2. Energy profile for the enantioselective borylation process.
M06-2X/6-31G(d,p)-cc-pVDZ-DK(Cu)-SMD(THF)//B3LYP/6-
31G(d)-cc-pVDZ-DK(Cu)-SMD(THF). C−H bonds were omitted for
clarity. All energies in kcal mol−1. For more details, see the Supporting
Information.
of the pinacol boronic ester in 2a resulted in formation of
hemiboronate 6. However, when the same hydrolysis conditions
were applied to amide 2j, boronic acid 7 was obtained in good
yield. Importantly, N-Bocprotectedderivative2iwastransformed
into primary α-aminoboronate 8.
Finally, we performed DFT calculations to gain insight into the
mechanism of the reaction and to account for the observed
stereoselectivity (Figure 2). We started from Cu(I)−boryl
complex C, using (R)-Segphos and (S)-Segphos as ligands, and
enamide E. We introduced a methyl group at the enamide instead
of an ethyl group to simplify the calculation. The reaction begins
with the initial endothermic complexation of chiral copper−boryl
complex C and enamide E. Two metal−η2-alkene complexes are
initially formed, with Complex-S resulting slightly lower in
energy than Complex-R. The borylation reaction is a highly
exoergic (−26.9 kcal mol−1) and, therefore, irreversible process
(Figure 2). Consequently, the enantioselectivity of the process is
kinetically controlled in the insertion step. Two transition states
for the boryl cupration (TS-R and TS-S) were located and
permittedthecalculationofthecorrespondingactivationenergies
for the formation of both enantiomers. Importantly, calculated
TS-R showed a 9.7 kcal mol−1 lower energetic barrier than TS-S
(Figure 2), consistent with the formation of the observed major
a
Reaction conditions: 3 (0.2 mmol), B2pin2 (0.22 mmol, 1.1 equiv),
NaOt-Bu (1.0 equiv), CuCl (10 mol %), L2 (11 mol %), MeOH (0.8
mmol, 4.0 equiv), THF (0.1 M). The er was determined by chiral
HPLC. Yield of isolated 4. The reaction time was 4 h. The reaction
time was 12 h. The reaction was performed at −20 °C.
b
c
d
e
f
To provide compounds more suitable for biological
applications, we removed the pinacol ester moiety (Scheme 4).
Treatment of α-aminoboronate 2a with KHF2 afforded
trifluoroborate salt 5 in excellent yield. Interestingly, hydrolysis
C
DOI: 10.1021/acs.orglett.7b02784
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Letter
enantiomer using ligand (R)-L2.16 Finally, once the C−B bond
andthestereochemistryweredefined, thecopperwasstabilizedto
form a copper enolate. These results suggest the insertion as the
rate-limiting step as well as the enantiodetermining step.
In summary, we have developed a novel catalytic approach for
the preparation of enantiomerically enriched α-aminoboronates.
Our method has proven to be general for a wide variety of
substrates, including the preparation of boryl-containing
dipeptides, using an inexpensive copper catalyst and a
commercially available chiral ligand. Biologically studies of the
prepared compounds are underway.
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b02784.
Experimental procedures, compound characterization
data, analytic details for all enantiomerically enriched
products, and crystal structural data (PDF)
́
(5) Sole, C.; Gulyas, H.; Fernandez, E. Chem. Commun. 2012, 48, 3769.
(6) Hu, N.; Zhao, G.; Zhang, Y.; Liu, X.; Li, G.; Tang, W. J. Am. Chem.
Soc. 2015, 137, 6746.
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15620.
(8) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101,
3219.
Accession Codes
CCDC 1514307 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
(9) For representative examples of enantioselective 1,4 copper-
catalyzed borylations, see: (a) Hornillos, V.; Vila, C.; Otten, E.;
Feringa, B. L. Angew. Chem., Int. Ed. 2015, 54, 7867. (b) Kobayashi, S.;
Xu, P.; Endo, T.; Ueno, M.; Kitanosono, T. Angew. Chem., Int. Ed. 2012,
51, 12763. (c) Molander, G. A.; Wisniewski, S. R.; Hosseini-Sarvari, M.
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Arrayas, R.;Carretero, J. C. Chem. Commun. 2011, 47, 6701. (f)Lee, J. C.;
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A.; Tatla, A.; Whiting, A.; Fernandez, E.; Gulyas, H. Chem. - Eur. J. 2011,
17, 14248. (h) O’Brien, J. M.; Lee, K. − S.; Hoveyda, A. H. J. Am. Chem.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: alejandro.parra@uam.es.
*E-mail: mariola.tortosa@uam.es.
ORCID
Mariola Tortosa: 0000-0002-5107-0549
Notes
The authors declare no competing financial interest.
(10) During the preparation of this manuscript, Xu et al. reported a
related transformation (published online June 21, 2017). Chen, L.; Zou,
X.; Zhao, H.; Xu, S. Org. Lett. 2017, 19, 3676. Most of the examples
reported by Xu contain α-aminoboronates with disubstitution on the
nitrogen. However, our catalytic system is general for the preparation of
α-aminoboronates that contain a secondary amide, which is an important
feature in biologically active compounds. Both methods are, therefore,
complementary.
ACKNOWLEDGMENTS
■
We thank the European Research Council (ERC-337776),
MINECO (CTQ2016-78779-R), and National Science Founda-
tion (1151092 and 1543699) for financial support. M.T. thanks
MICINN for aRyC contract. Weacknowledge Dr. Josefina Perles
for X-ray structure analysis (UAM). We acknowledge the
generous allocation of computer time at the Centro de
(11) Panda, N.; Mothkuri, R. J. Org. Chem. 2012, 77, 9407.
(12) For our previous work on copper-catalyzed borylations, see:
(a) Guisan-Ceinos, M.; Parra, A.; Martin-Heras, V.; Tortosa, M. Angew.
́
Computacion
(CCC-UAM).
́
Cientifica at the Universidad Auton
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oma de Madrid
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Cruz-Acosta, F.; Collado-Sanz, D.; Cardenas, D. J.; Tortosa, M. ACS
Catal. 2016, 6, 442. (c) Parra, A.; Amenos, L.; Guisan-Ceinos, M.; Lopez,
A.; Garcia-Ruano, J. L.; Tortosa, T. J. Am. Chem. Soc. 2014, 136, 15833.
(d) Alfaro, R.; Parra, A.; Aleman, J.; Garcia-Ruano, J. L.; Tortosa, M. J.
́
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(13) See the Supporting Information for details.
(14) The absolute configuration of 2b was established from single
crystal X-ray crystallography. The crystal structure of 2b shows a dative
bond between the carbonyl oxygen of the amide and the boron atom.
(15) The absolute configuration for the E-enamide series was
established for compound 4l by comparison of its optical rotation with
that of the product of benzylation of 2a. See the Supporting Information
for details.
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DOI: 10.1021/acs.orglett.7b02784
Org. Lett. XXXX, XXX, XXX−XXX