Homologation of α-aryl amino acids through quinone-catalyzed decarboxylation/Mukaiyama-Mannich addition

Article abstract of DOI:10.1039/c7cc00485k

A new method for amino acid homologation by way of formal C-C bond functionalization is reported. This method utilizes a 2-step/1-pot protocol to convert α-amino acids to their corresponding N-protected β-amino esters through quinone-catalyzed oxidative decarboxylation/in situ Mukaiyama-Mannich addition. The scope and limitations of this chemistry are presented. This methodology provides an alternative to the classical Arndt-Eistert homologation for accessing β-amino acid derivatives. The resulting N-protected amine products can be easily deprotected to afford the corresponding free amines.

Full text of DOI:10.1039/c7cc00485k

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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DOI: 10.1039/C7CC00485K
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Homologation of α-Aryl Amino Acids through Quinone-Catalyzed
Decarboxylation/Mukaiyama−Mannich Addition
Benjamin J. Haugeberg,† Johnny H. Phan, †b Xinyun Liu, Thomas J. O’Connorc and Michael D. Clift*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new method for amino acid homologation by way of formal C–C renewable starting materials (Scheme 1). Classical methods,
bond functionalization is reported. This method utilizes a 2- such as the Arndt−Eistert homologation,5 the Kowalski ester
step/1-pot protocol to convert α-amino acids to their homologation6 and the Kolbe reaction,7 have proven to be
corresponding N-protected β-amino esters through quinone- useful tools for converting α-amino acids into their
catalyzed oxidative decarboxylation/in situ Mukaiyama−Mannich corresponding β-amino esters. While these reactions, and their
addition. The scope and limitations of this chemistry are contemporary counterparts,8 have been broadly employed,
presented. This methodology provides an alternative to the they typically require many synthetic operations, utilize costly
classical Arndt–Eistert homologation for accessing β-amino acid or toxic reagents, and proceed through highly reactive
derivatives. The resulting N-protected amine products can be intermediates. We sought to develop an alternative protocol
easily deprotected to afford the corresponding free amines.
to promote such homologations by utilizing quinone
organocatalysis to facilitate the transformation of α-amino
acids into their corresponding N-protected β-amino ester
derivatives by way of decarboxylative functionalization.9
Arndt–Eistert Homologation
In recent years, research focused on the utilization of β-
amino acid derivatives has received significant attention owing
to their unique ability to resist degradation by proteases and
stabilize protein secondary structure. β-amino acids are used
to synthesize designer β-peptides (many of which are regarded
as promising antibacterial1 and anti-HIV agents2) and a wide
range of FDA-approved pharmaceutical agents (Figure 1). The
increasing importance of these molecules has fueled a growing
interest in the development of new methods for their
preparation.3, 4
PG
PG
O
1. PG on
2. SOCl2
4. Ag2O, −N2,
H2N
CO2H
HN
HN
OMe
MeOH
R
O
R
R
N2
3. CH2N2
β-amino acid
derivative
α-amino acid
This work
H2N
α-diazoketone
PG
N
PG
HN
SEt
SEt
CO2H
quinone
OTMS
CF3
O
R
R
O
R
catalysis
N
H
H
N
H
N
S
−CO2
H
H2N
N
R
Me
Me
imine
electrophile
β-amino acid
derivative
N
α-amino acid
N
OMe
F
F
O
O
Scheme 1. Classical Amino Acid Homologation and This Work.
O
CO2H
sitagliptin
DPP-IV inhibitor
methylphenidate
CNS stimulant
penicillins
antibacterials
F
In nature, quinone cofactors are commonly employed by
copper amine oxidases to enable the conversion of primary
amine substrates to their corresponding carbonyl
derivatives.10,11 Several recent reports have highlighted the
ability of quinone cofactor mimics to enable the catalytic
aerobic oxidation of primary amines.12,13,14 We sought to
explore the possibility of using quinone catalysis to promote a
Figure 1. β-Amino Acid Derivatives in FDA-Approved Therapeutics.
Among the established methodologies for β-amino acid
synthesis, α-amino acid homologation is the most commonly
employed, presumably because it utilizes inexpensive, bio-
formal
C–C
functionalization
through
oxidative
decarboxylation of α-amino acids,15 followed by sequential
nucleophilic addition to yield β-amino ester derivatives
(Scheme 2). In such a process, we envisioned that a quinone
catalyst (2) and an α-amino acid (1) would condense to
generate iminoquinone 4. This intermediate would undergo
quinone-enabled oxidative decarboxylation to deliver N-aryl
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imine 5, which would in turn participate in transimidation with imine formation at slightly higher temperatures (entries 12
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an appropriately selected amine (H2N−PG) to furnish N- and 13) and it could be easily remDoOvIe:d10.1u0n3d9/eCr7CrCe0d0u4c8e5dK
protected imine 7. The reduced catalyst (6) would then be pressure prior to imine additions. Unfortunately, all natural
returned to the catalytic cycle through reaction with molecular amino acids tested failed to provide the desired imine under
oxygen and 1 (or oxygen and water, both possibilities are the current reaction conditions.19 Examination of a range of
shown). Imine 7 could then participate in a subsequent quinone catalysts failed to improve this result.20 p-Anisidine
reaction with silyl ketene (thio)acetal 8 to deliver, after can be replaced by a variety of N-protected amines to allow
removal of the protecting group, the desired homologation access to a wide range of imine products; these studies are
product (3). The proposed reaction represents a significant detailed in the supporting information.
departure from traditional cofactor chemistry wherein
Table 1. Optimization of Quinone-Catalyzed Oxidative Decarboxylation
pyridoxal phosphate-type catalysts are employed in amino acid
Protocol.19
decarboxylation events.16 Herein we report the development
OMe
O
PMP
of this method and its application to the efficient synthesis of
β-amino ester derivatives.
t-Bu
t-Bu
H2N
CO2H
catalyst 2 (x mol %)
N
+
base (2 equiv.),
solvent, 24 h,
temperature, O2
Ph
Ph
NH2
quinone-catalyzed
amino acid homologation
O
H2N
CO2H
H2N
SEt
phenyl
glycine (1a)
p-anisidine
(2.0 equiv)
imine
electrophile (7a)
2
O
R
O
R
entry
solvent
temperature
catalyst
base
yielda
oxidation and
hydrolysis
t-Bu
t-Bu
α-amino acid
substrate (1)
β-amino acid
derivative (3)
1
2
3
4
1,4-Dioxane
THF
CH3CN
50oC
50oC
50oC
50oC
50oC
80oC
80oC
80oC
80oC
50oC
50oC
50oC
70oC
5%
5%
5%
5%
-
-
-
-
0%
0%
0%
O2, H2O
O
H2O
DMSO
DMSO
39%
catalyst
Et3N
Et3N
Et3N
5
6
7
5%
5%
5%
42%
68%
63%
74%
90%
O
2
OH
DMSO
H2O
t-Bu
t-Bu
t-Bu
t-Bu
O2, then 1
SEt
Et3N
Et3N
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
8
9
5%
10%
OH
O
1)
N
8
OTMS
Et3N
Et3N
Et3N
Et3N
CH3CN:H2O (1:1)
CH3CN:H2O (1:1)
10
11
12
13
5%
10%
10%
10%
84%
91%
70%
92%
4
6
NH2
R
2) deprotection
EtOH
EtOH
OH
PG
t-Bu
t-Bu
a Determined by 1H NMR using methyl benzoate as an internal standard.
N
oxidative
decarboxylation
R
Next we investigated in situ Mukaiyama−Mannich addition21
using silyl ketene (thio)acetal 8 and the imine generated
through oxidative decarboxylation of phenylglycine. After
evaluating a variety of Lewis and Brønsted acid catalysts, we
found that tetrafluoroboric acid was an effective promoter of
the desired addition,22 providing thioester 9a in 74% yield from
H2N PG
N
imine
electrophile (7)
CO2
R
5
Scheme 2. Proposed Method for Quinone-Catalyzed Amino Acid Homologation.
We began by examining the potential of amino acid
substrates to undergo oxidative decarboxylation in the
presence of a quinone catalyst (Table 1). Quinone 2 was
selected for initial studies because of it’s established ability to
enable the aerobic oxidation of amines.17 Valine,
phenylalanine, serine and phenylglycine were first tested
(entries 1−4, only phenylglycine results shown) with entry 4
providing initial conditions to promote imine formation for
only the α-aryl amino acid. The addition of triethylamine as a
base resulted in a slight improvement in reaction efficiency
(entry 5, 42% yield) that was furthered by elevation of the
reaction temperature (entry 6, 68% yield). With this result in
hand, we sought to address issues with substrate solubility
under these initial conditions. Not surprisingly, the use of polar
organic solvents (entries 1−6) or water (entry 7) failed to
dissolve the entire reaction mixture. This led us to explore the
use of biphasic conditions (entries 8−11). Increasing the
catalyst loading to 10 mol% provided imine 7a in 91% yield
(entry 9). The temperature could be reduced under these
conditions, with no loss of reaction efficiency (entries 10 and
11). While there was some evidence to the contrary,18 we
anticipated that water may interfere with subsequent
Mukaiyama−Mannich additions. Fortunately, ethanol proved
to be an equally viable solvent for promoting decarboxylative
phenylglycine
(eq.
1).
This
sequential
oxidative
decarboxylation/ Mukaiyama−Mannich addition protocol
provides a new methodology for amino acid homologation via
decarboxylative functionalization.
O
PMP
HN
1. 2 (10 mol%), O2, Et3N,
t-Bu
t-Bu
H2N
CO2H
p-anisidine, EtOH, 70oC
SEt
(1)
Ph
SEt
2.
HBF4,
THF, 0oC
Ph
O
O
2
8
OTMS
1a
9a, 74% yield
With optimized conditions for the oxidative decarboxylation/
Mukaiyama−Mannich sequence in hand, we examined the
substrate scope by assessing the efficiency of this process
using a variety of amino acids (Table 2). A wide range of
phenylglycine derivatives with variable substitution patterns
was subjected to the optimal reaction conditions. The 2-
methyl derivative displays significantly reduced reaction
efficiency, presumably due to the steric hindrance caused by
the methyl substituent (entry 2, 56%). The 2-chloro derivative
delivered the homologation product in excellent yield (entry 3,
95% yield), presumably owing to an attenuation of the steric
effect noted in entry 2 by replacement with a smaller chlorine
atom.21 Meta- and para- substituted aryl glycine derivatives
generally afforded good to excellent yields (entries 4−9, 72−
94% yield). Notably, electronic effects do not appear to
2 | J. Name., 2012, 00, 1-3
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influence reaction efficiencies as electron-rich and electron-
COMMUNICATION
Diastereoselective decarboxylative functionalizations have
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poor substrates all provided good yields of the desired product also been explored (eq. 2). Here, sDteOrI:e1o0c.1h0e3m9/Cic7aCllCy00p4u85rKe
(entries 5, 6 and 7–9, respectively, 72−94% yield). 2- (thio)silyl ketene acetal (12) couples with phenylglycine to
thiophenylglycine is also compatible under the optimized provide thioester 13 in good yield with modest
conditions (entry 10, 77% yield), proving that electron-rich stereoselectivity (70% yield, 4:1 dr).
heteroaryl glycine derivatives are also suitable substrates,
1. 2 (10 mol%), O2, Et3N,
O
despite the potential for competitive arene oxidation.24
p-anisidine, EtOH, 70oC
PMP
HN
Me
t-Bu
t-Bu
H2N
CO2H
(2)
St-Bu
Me
2.
HBF4,
THF, 0oC
Ph
1a
St-Bu
Ph
O
Table 2. Amino Acid Scope using Silyl Ketene (Thio)acetal Nucleophile 8.
O
12
2
OTMS
13, 70%, 4:1 dr
In order to carry out a true amino acid homologation, we
sought to transform the N-PMP protected β-amino ester
products 9a and 11a into synthetically useful derivatives 14
and 15, respectively (eq. 3). These transformations were
accomplished in high yields by using CAN to promote cleavage
the PMP group,25 thereby delivering the corresponding
products of direct amino acid homologation (14 and 15).
O
PMP
HN
1. 2 (10 mol%), O2, Et3N,
H2N
CO2H
t-Bu
t-Bu
p-anisidine, EtOH, 70oC
SEt
Ar
SEt
2.
HBF4,
Ar
O
THF, 0oC
8
OTMS
1
9
O
2
yielda
yielda
entry
entry
product
PMP
product
PMP
HN
5
6
7
8
9
9e, R = Me, 89%
9f, R = OMe, 88%
9g, R = F, 84%
9h, R = Cl, 94%
9i, R = Br, 72%
SEt
HN
SEt
1
2
3
9a, R = H, 74%
9b, R = Me, 56%
9c, R = Cl, 95%
O
R
O
R1 R1
Me Me
PMP
HN
CAN, rt, 2 hr
SEt
CAN, rt, 2 hr
H2N
R2
H2N
OMe
(3)
R
Ph
O
94% yield
89% yield
Ph
O
Ph
15
O
PMP
HN
PMP
HN
14
9a or 11a
SEt
SEt
4
9d, 78%
10
9j, 77%
In conclusion, we have demonstrated that sequential
quinone-catalyzed oxidative decarboxylation/Mukaiyama−
Mannich addition provides an efficient method for α-amino
acid homologation under mild reaction conditions（20
substrates, 15–95% yield). By employing different silyl ketene
acetal nucleophiles, a variety of β-amino ester derivatives can
be readily prepared. Notably, this is the first example of
O
O
S
F
a Isolated yields.
Encouraged by these results, we next extended the scope of
the oxidative decarboxylation/Mukaiyama−Mannich addition
sequence by employing gem-dimethyl silyl ketene acetal
nucleophile 10 (Table 3). To our delight, when phenylglycine
was employed as the substrate, the corresponding β-amino
ester 11a was obtained in excellent yield (entry 1, 89% yield).
Similar substituent effects on reaction efficiency were
observed in this series when compared to those above (Table
2). Interestingly, ortho-substitution has a more prominent
influence on the efficiency observed in this series of reactions
(entry 2 and entry 3, 15% yield and 65% yield, respectively).
This likely results from increased steric bulk of the silyl ketene
acetal nucleophile leading to a reduced rate of addition,
thereby enabling competitive proto-desilylation. Once again,
electron-rich and electron-poor aryl glycines are well tolerated
(entries 4−10, 80−94% yield).
quinone-catalyzed C−C bond cleavage,
a reaction that
represents significant departure from biochemical
a
transformations that utilize quinone cofactors to convert α-
amino acids into the corresponding α-keto acids. Future work
will focus on the development of quinone catalysts that will
address current limitations in the substrate scope.
Notes and references
Financial support from the NSF (EPS-0993806) and The
University of Kansas is gratefully acknowledged. Additional
support for this work was provided by the National Institutes
of Health Graduate Training Program in Dynamic Aspects of
Chemical Biology Grant T32 GM08545 from NIGMS (to B. J.
H.). Support for NMR instrumentation was provided by NIH
Shared Instrumentation Grants No. S10OD016369 and
S10RR024664, and NSF Major Research Instrumentation
Grant No. 0320648. We thank Dr. Justin Douglas for helpful
discussions.
Table 3. Amino Acid Scope using Silyl Ketene Acetal Nucleophile 10.
1. 2 (10 mol%), O2, Et3N,
p-anisidine, EtOH, 70oC
O
PMP
HN
Me Me
H2N
CO2H
t-Bu
t-Bu
OMe
Me
2.
Me
HBF4,
THF, 0oC
Ar
Ar
O
OMe
1
11
O
2
10 OTMS
1
2
3
For a related review, see: Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. Rev. 2001, 101, 3219.
yielda
yielda
entry
entry
product
product
Me Me
PMP
HN
Stephens, O. M.; Kim, S.; Welch, B. D.; Hodsdon, M. E.; Kay,
M. S.; Schepartz, A. J. Am. Chem. Soc. 2005, 127, 13126.
For selected reviews, see: (a) Juaristi, E.; Soloshonok, V. A.
Enantioselective Synthesis of β-Aminoacids, 2nd ed.; Wiley-
Interscience: New York. 2005; (b) Bandala, Y.; Juaristi, E.;
Wiley-VCH Verlag GmbH & Co. KGaA: 2009; Vol. 1, p 291; (c)
Sleebs, B. E.; Van Nguyen, T. T.; Hughes, A. B. Org. Prep.
Proced. Int. 2009, 41, 429; (d) Weiner, B.; Szymanski, W.;
Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev.
2010, 39, 1656; (e) Chhiba, V.; Bode, M.; Mathiba, K.; Brady,
D.; Wiley-VCH Verlag GmbH & Co. KGaA: 2014, p 297.
5
6
7
8
9
11e, R = Me, 80%
11f, R = OMe, 83%
11g, R = F, 80%
11h, R = Cl, 87%
11i, R = Br, 85%
PMP
HN
Me Me
O
OMe
OMe
OMe
1
11a, R = H, 89%
11b, R = Me, 15%
11c, R = Cl, 65%
O
2b
R
3
R
PMP
HN
Me Me
O
PMP
HN
Me Me
OMe
4
11d, 94%
10
11j, 82%
O
S
F
a Isolated yields. b Determined by 1H NMR using methyl benzoate as an internal standard.
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4
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