Direct Synthesis of N-Alkyl Arylglycines by Organocatalytic Asymmetric Transfer Hydrogenation of N-Alkyl Aryl Imino Esters

Article abstract of DOI:10.1021/acs.orglett.7b02627

The organocatalytic asymmetric transfer hydrogenation of N-alkyl aryl imino esters for the direct synthesis of N-alkylated arylglycinate esters is reported. High yields and enantiomeric ratios were obtained, and tolerance to a diverse set of functional groups facilitated the preparation of more complex molecules as well as intermediates for active pharmaceuticals. A simple recycling protocol was developed for the Br?nsted acid catalyst which could be reused through five cycles with no loss of activity or selectivity.

Full text of DOI:10.1021/acs.orglett.7b02627

Letter
pubs.acs.org/OrgLett
Direct Synthesis of N‑Alkyl Arylglycines by Organocatalytic
Asymmetric Transfer Hydrogenation of N‑Alkyl Aryl Imino Esters
Javier Mazuela,*,† Thomas Antonsson,† Magnus J. Johansson,† Laurent Knerr,†
and Stephen P. Marsden‡
†Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca R&D, Pepparedsleden 1,
Molndal, SE-431 83, Sweden
̈
‡School of Chemistry, University of Leeds, Leeds, LS2 9JT, U.K.
S
* Supporting Information
ABSTRACT: The organocatalytic asymmetric transfer hydrogenation of N-alkyl aryl imino esters for the direct synthesis of N-
alkylated arylglycinate esters is reported. High yields and enantiomeric ratios were obtained, and tolerance to a diverse set of
functional groups facilitated the preparation of more complex molecules as well as intermediates for active pharmaceuticals. A
simple recycling protocol was developed for the Brønsted acid catalyst which could be reused through five cycles with no loss of
activity or selectivity.
espite considerable recent interest in peptides as
Dcandidate drugs thanks to their potential for tackling
complex targets (e.g., protein−protein interaction modulation)
and improved selectivity and toxicity profiles, their use is
strongly hampered by their poor pharmacokinetic profile,
including short circulating plasma half-life and poor potential
for oral absorption. Thus, the development of novel chemical
strategies to stabilize peptides and improve their pharmacoki-
netic properties has gained in profile.1 Among the strategies
developed to circumvent these limitations,1,2 the incorporation
of N-alkylated amino acids is considered an effective way to
enhance metabolic stability, lipophilicity, and membrane
permeability.2 For example, the clinically used immunosup-
Figure 1. Arylglycine-containing pharmaceutical agents.
pressive natural product cyclosporine A features seven N-
methylated residues and, although violating the Lipinski rules
for oral bioavailability, has an excellent pharmacokinetic
profile.3 N-Alkylation modifies the steric constraints of the
peptide chain and the hydrogen bond patterns, offering
opportunities for broader conformational design.2,4 Moreover,
N-allylated amino acids have been used in approaches to
stabilize secondary structures such as Arora’s hydrogen bond
surrogate strategy,5 and in the preparation of stapled peptides.6
In view of these developments, there is significant interest in
the development of new methods to provide optically pure N-
alkyl amino acids.
Arylglycines belong to a family of nonproteinogenic amino
acids7 which are present in a wide range of natural products of
pharmaceutical relevance (such as the pristinamycines8 and
ramoplanines9 Figure 1) as well as semisynthetic drugs (such as
penicillins and cephalosporins, Figure 1).10 Classical method-
ologies for the preparation of N-alkylated arylglycines can be
grouped into three processes: reductive amination, reductive
ring opening of 5-oxazolidinones, and N-alkylation.2a However,
many of these methods either are lengthy and/or involve
protection/deprotection sequences often associated with
racemization of the sensitive stereocenter.7 To our knowledge,
only two asymmetric catalytic methodologies have been
reported toward the direct synthesis of N-alkyl arylglycines.11
Organocatalytic hydrosilylation of N-benzyl imino esters was
reported with moderate enantioselectivity (up to 71% ee,
Scheme 1),11a while an asymmetric Rh-catalyzed hydrogenation
of aldimines proceeding via dynamic kinetic resolution gave
moderate-to-low enantiomeric ratios.11b In this context, the
development of a modular asymmetric catalytic methodology
for the preparation of a wide range of arylglycines bearing
different N-alkyl chains is still needed.
BINOL-derived chiral Brønsted acids have proved to be
efficient catalysts for asymmetric imine transfer hydrogenation
and reductive aminations of carbonyl compounds.12 The
Received: August 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02627
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Asymmetric Catalytic Synthesis of Arylglycines
Table 1. Optimization of the Reaction Conditions
b
c
entry cat
Ar
solvent
yield (%)
er
1
3a
3a
3a
3a
3a
3a
4a
5a
3b
3c
3d
3e
3f
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
4-CF3-C6H4
toluene
mesitylene
DCM
95
94
95
48
55
0
81:19
81:19
70:30
75:25
73:27
−
53:47
51:49
86:14
89:11
82:18
80:20
89:11
84:16
90:10
93:7
2
3
4
Et2O
groups of You13b and Antilla13c reported the organocatalytic
transfer hydrogenation of protected α-imino esters, obtaining
α-amino esters with high yields and enantioselectivities
(Scheme 1), but the substrate scope was limited to N-aryl
imines. Inspired by the work of List using BINOL-derived
disulfonimides 3 to promote the asymmetric transfer hydro-
genation of N-alkyl ketimines,14 we set out to examine the use
of chiral Brønsted acids as catalysts for the transfer hydro-
genation of N-alkyl aryl imino esters 1. We report herein the
successful direct synthesis of enantioenriched arylglycines 2
bearing diverse functionalized N-alkyl substituents (Scheme 1).
Gratifyingly, we found that reduction of aryl imino ester 1aa
using 3a as the catalyst, Hantzsch ester 6 as a hydrogen donor,
and Boc2O in toluene in the presence of 5 Å molecular sieves
furnished the desired Boc-protected N-methyl amino ester in a
95% NMR yield with a high enantiomeric ratio (e.r. = 81:19,
Table 1, entry 1). It was observed that apolar solvents are
needed to obtain both high yields and enantiomeric ratios, but
the best result was obtained in toluene (Table 1, entries 1−6).
Different hydrogen donors were also tested, and the best results
were obtained using Hantzsch ester 6 (see Supporting
Information). As reported by List, the presence of Boc2O as
a trapping agent is needed to achieve high yields.14 Other
trapping groups could be used maintaining comparable levels of
selectivity (see Supporting Information).
BINOL-derived phosphoric acid 4a and triflyl phosphor-
amide 5a gave only moderate yields and low selectivities
(entries 7−8). The effect of the substituent in the 3/3′-position
of the binaphthyl moiety of the catalyst was investigated. Aryl
substituents with electron-withdrawing groups in the para
position gave the highest levels of enantioselectivity (entries 1,
9−14), with the best result obtained with para-nitrophenyl
substituted disulfonimide 3h, affording the Boc-protected
amino ester in a 95% NMR yield and 90:10 enantiomeric
ratio; deprotection gave a 90% isolated yield of N-methyl amino
ester 2aa.15 The e.r. could be further increased by decreasing
the reaction temperature to 0 °C (entry 15).
5
cC6H12
MeOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
6
7
57
85
97
84
85
68
87
66
8
9
10
11
12
13
14
14
15
4-CN-C6H4
4-SF5-C6H4
3,5-Ph2-C6H3
4-Me-3,5-(NO2)2-C6H2
4-OMe-C6H4
3g
3h
3h
d
4-NO2-C6H4
95 (90)
e
4-NO2-C6H4
47
a
Reactions conditions: (1) 1aa (0.1 mmol), 1aa/cat/6/Boc2O
(1:0.05:1.4:1.2) with 50 mg 5 Å molecular sieves in 3 mL solvent
b
for 16 h at room temperature. (2) TFA/DCM 3:1 for 2 h at rt. 1H
NMR yield of the corresponding Boc-protected amino ester using
c
dibromomethane as internal standard. Determined by 1H NMR
d
e
adding (R)-TBPTA. Isolated yield of the amino ester. Reaction run
at 0 °C for 24 h.
a tert-butyl substituent in the para position performed
particularly well, and the N-methyl arylglycine 2ea could be
prepared on gram scale, maintaining the excellent yield and
enantioselectivities (Supporting Information). Electron-donat-
ing groups on the aryl ring led to an increase in the
enantiomeric ratio while electron-withdrawing substituents
decreased both activity and selectivity (Figure 2). Finally, the
organocatalytic transfer hydrogenation was compatible with the
introduction of heteroaromatic rings into the imino ester;
however, only moderate enantioselectivities were obtained
(Figure 2).
The effect of various N-alkyl groups was then investigated
(Figure 3). Pleasingly a range of substituents with different
chain lengths and bearing a variety of functional groups (allyl,
homopropargyl, azide, bromo, silyl ether) were very well
tolerated, maintaining excellent enantioselectivities albeit longer
reaction times were needed. Notably, the ready access to N-
allyl, homopropargyl, and azidoalkyl amino acids will facilitate
the preparation of stapled peptides. Together, these results
represent the first asymmetric transfer hydrogenation of N-
alkylated aryl imino esters, delivering varied N-alkyl arylglycine
esters directly with good to excellent selectivities.
With the optimal reaction conditions in hand, we next
examined the generality of this transformation, commencing
with reduction of various N-methyl aryl imino esters. Different
ester groups were well tolerated, with ethyl esters affording the
best results (Figure 2). The replacement of the ester
functionality by a tertiary amide gave the corresponding
amide but with low yield and enantioselectivity. Variation in
the aryl substituent was probed. Both para and meta
substituents on the aryl ring were well tolerated, but the
introduction of ortho substituents led to a decrease in both
activity and enantioselectivity (Figure 2). Imino ester 1ea with
Furthermore, the functional groups present on the N-alkyl
substituents could be used for further transformations to
construct more complex chiral compounds. For example, ester
reduction afforded amino alcohol 7 in good yield, while the
Fmoc-protected amino acid 8, which could potentially be
B
DOI: 10.1021/acs.orglett.7b02627
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 4. Preparation of diverse building blocks from functionalized
N-alkylated arylglycine derivatives. Conditions: (i) LiAlH4, THF (from
2ea). (ii) (a) FMOC-Cl, DIPEA, THF. (b) MgI2, THF (from 2ea).
(iii) Na-ascorbate, CuSO4, tBuOH, H2O (from 2qa). (iv) DIPEA,
CAN (from 2ta). (v) Pd/C, H2, MeOH (from 2sa).
chemical biology (Figure 4).17 N-Heterocycles could also be
elaborated from N-alkyl amino esters. Azetidine containing
amino ester 10 was generated by internal nucleophilic
substitution of an alkyl bromide, while piperazone 11 was
obtained by reductive cyclization of azido ester 2sa. In all cases
the products were obtained, maintaining the excellent
enantioselectivities (Figure 4).
Finally, we demonstrated the applicability of our method to
the direct synthesis of a marketed drug, by completing the
synthesis of morpholinone 12c which is an intermediate for the
preparation of the antiemetic drug Aprepitant (Figure 5).18,19
This is the first catalytic asymmetric method developed to date
for the preparation of compound 12c.20
Figure 2. Substrate scope in the transfer hydrogenation of N-methyl
aryl imino esters. Reaction conditions: (1) 1 (0.2 mmol), 1/3h/6/
Boc2O (1:0.05:1.4:1.2) with 100 mg 5 Å molecular sieves in 6 mL of
toluene for 16 h at rt. (2) TFA/DCM 3:1 for 2 h at rt. a Reaction run
for 3 d. b Reaction run for 2 d.
Figure 5. Formal asymmetric synthesis of Aprepitant. Conditions: (i)
(a) 3h, 6, 5 Å molecular sieves, Boc2O, toluene; (b) TFA, DCM; (ii)
BnBr, TBAI, K2CO3, DMF; (iii) ref 19.
Figure 3. Substrate scope in the transfer hydrogenation of N-alkyl aryl
imino esters. Reactions conditions: (1) 1 (0.2 mmol), 1/3h/6/Boc2O
(1:0.05:1.4:3) with 100 mg 5 Å molecular sieves in 6 mL of toluene for
3 d at rt. (2) TFA/DCM 3:1.
In our effort to increase the applicability and sustainability of
the process, we developed a protocol for the recovery and reuse
of the chiral Brønsted acid catalyst (Table 2). Simply by
transferring the crude reaction mixture to a commercially
available anion exchange resin column followed by solvent
elution allowed us to recover the Boc-protected amino ester. A
final acid wash of the column eluted the Brønsted acid catalyst,
which could be recovered nearly quantitatively. In this way, the
catalyst was reused up to five times while maintaining excellent
yields and selectivities. This represents the first successful
directly used in the construction of synthetic peptides, was
easily prepared from amino ester 1ea (Figure 4).16 We were
also able to perform a Cu-catalyzed click reaction of azide
containing amino ester 1sa to afford the biotinylated
compound 9 in high yield, offering the potential for
incorporation in bioactive peptides and use as a tool in
C
DOI: 10.1021/acs.orglett.7b02627
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Organic Letters
Letter
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88
90
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95:5
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94:6
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95
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95
90
95
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In summary, we have developed an organocatalytic transfer
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direct access to N-alkyl arylglycines. Excellent yields and
enantiomeric ratios were achieved for a wide range of substrates
with a range of (hetero)aryl substituents as well as diverse
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of these products, combined with the opportunity for catalyst
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02627.
■
S
(13) (a) Eftekhari-Sis, B.; Zirak, M. Chem. Rev. 2017, 117, 8326−
8419. (b) Kang, Q.; Zhao, Z.-A.; You, S.-L. Adv. Synth. Catal. 2007,
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(15) Boc-group cleavage was observed during purification of the Boc-
protected amino ester, leading to a decrease in the isolated yield.
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(b) Sheppard, R. J. Pept. Sci. 2003, 9, 545−552.
Experimental methods, materials used, synthetic charac-
terization, and data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Javier.MazuelaAragon@astrazeneca.com.
ORCID
(17) For example: (a) Viens, A.; Harper, F.; Pichard, E.; Comisso,
M.; Pierron, G.; Ogryzko, V. J. Histochem. Cytochem. 2008, 56, 911−
919. (b) Howarth, M.; Chinnapen, D. J.; Gerrow, K.; Dorrestein, P. C.;
Grandy, M. R.; Kelleher, N. L.; El-Husseini, A.; Ting, A. Y. Nat.
Methods 2006, 3, 267−273.
Javier Mazuela: 0000-0002-3678-9045
Laurent Knerr: 0000-0002-4810-8526
Stephen P. Marsden: 0000-0002-2723-8954
Notes
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M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.;
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Strader, C. D.; MacIntyre, D. E.; Metzger, J. E. J. Med. Chem. 1996, 39,
1760−1762. (c) Dorn, C. P.; Hale, J. J.; MacCoss, M.; Mills, S. G.;
Ladduwahetty, T.; Shah, S. K. Eur. Pat. Appl. 577394A1, 1994.
(19) Zhao, M. M.; McNamara, J. M.; Ho, G.-J.; Emerson, K. M.;
Song, Z. J.; Tschaen, D. M.; Brands, K. M. J.; Dolling, U.-H;
Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 2002, 67, 6743−6747.
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Mathad, V. T. Org. Process Res. Dev. 2007, 11, 455−457. (c) Dorn, C.
P.; Finke, P. E.; Hale, J. J.; Gills, S. G.; Williams, B. J. U.S. Patent
5,719,147, 1998. (d) Sorbera, L. A.; Castaner, J.; Bayes, M.; Silvestre, J.
Drugs Future 2002, 27, 211−222.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank AstraZeneca Gothenburg and the
AstraZeneca PostDoc programme for financial support. Dr.
Thomas Cogswell (AstraZeneca) is acknowledged for the help
in the preparation of chiral Brønsted acids.
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DOI: 10.1021/acs.orglett.7b02627
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