Dynamic Kinetic Resolution of Azlactones by a Chiral N, N-Dimethyl-4-aminopyridine Derivative Containing a 1,1′-Binaphthyl Unit: Importance of Amide Groups

Article abstract of DOI:10.1021/acs.orglett.8b01960

A dynamic kinetic resolution (DKR) of azlactones in the presence of benzoic acid and a binaphthyl-based N,N-4-dimethylaminopyridine (DMAP) derivative 1i having two amide groups at the 3,3′-positions of a binaphthyl unit is developed. The reaction proceeded smoothly with a wide range of azlactones to provide α-amino acid derivatives with good to high enantiomeric ratios (er's). A multigram-scale reaction (2.5 g) for the DKR of azlactone 2d was also demonstrated, and the resulting product was converted to unnatural α-amino acid 6d′.

Full text of DOI:10.1021/acs.orglett.8b01960

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Dynamic Kinetic Resolution of Azlactones by a Chiral N,N‑Dimethyl-
4-aminopyridine Derivative Containing a 1,1′-Binaphthyl Unit:
Importance of Amide Groups
Hiroki Mandai,* Kohei Hongo, Takuma Fujiwara, Kazuki Fujii, Koichi Mitsudo, and Seiji Suga*
Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka,
Kita-ku, Okayama 700-8530, Japan
S
* Supporting Information
ABSTRACT: A dynamic kinetic resolution (DKR) of azlactones in the presence of benzoic acid and a binaphthyl-based N,N-4-
dimethylaminopyridine (DMAP) derivative 1i having two amide groups at the 3,3′-positions of a binaphthyl unit is developed.
The reaction proceeded smoothly with a wide range of azlactones to provide α-amino acid derivatives with good to high
enantiomeric ratios (er’s). A multigram-scale reaction (2.5 g) for the DKR of azlactone 2d was also demonstrated, and the
resulting product was converted to unnatural α-amino acid 6d′.
rearrangement,4 the kinetic resolution of benzylic carbinols5
N,N-Dimethyl-4-aminopyridine (DMAP) and 4-pyrrolidino-
and d,l-1,2-diols,6 and the desymmetrization of meso-1,2-diols7
pyridine (PPY) are powerful acylation catalysts that have been
used in organic synthesis for several decades.1,2 Chiral variants of
these catalysts have also been well-studied and used in various
enantioselective acyl transfer processes.3 Very recently, we
reported extremely active and enantioselective chiral nucleo-
philic catalysts (Figure 1a), binaphthyl-based chiral DMAP
derivatives having tert-alcohol groups, for Steglich-type
(Figure 1b−d). According to various control experiments and
DFT calculations, tert-alcohol units [-C(OH)Ar2] were
responsible for the high catalytic activity and enantioselectivity
as a result of hydrogen bonding interaction between the reaction
substrate and tert-alcohol unit(s) of the catalyst.4 These
enantioselective acyl transfer reactions developed by our
group required only an achiral acylating agent (e.g., (i-
PrCO)2O) with a prochiral or racemic nucleophile, while the
reactions of a racemic acylating agent (not an achiral variant)
and an achiral nucleophile have not been examined. To further
explore the utility of binaphthyl-based chiral DMAP derivatives
in enantioselective transformations, we sought to elucidate their
roles in different modes of the reaction (i.e., other than the
enantioselective acylation of alcohol). We thought that the
dynamic kinetic resolution (DKR) of azlactones, which gives an
α-amino acid derivative, is a benchmark reaction for evaluating
the catalyst capability. With regard to such transformations,
several organocatalytic approaches to the DKR of azlactones
have been reported (using a planar chiral DMAP derivative,8
benzotetramisole,9 urea-based bifunctional catalysts,10,11 chiral
phosphoric acid,12 a peptide catalyst,13 and a chiral bisguanidi-
nium salt catalyst14), but some of the reported methods resulted
in only moderate enantioselectivity (<95:5 er) and required a
high catalyst loading (5−20 mol %) with a longer reaction time
Figure 1. (a) General structure of binaphthyl-based chiral DMAP
derivatives with two tert-alcohol units. (b) Schematic representation of
Steglich-type rearrangement. (c, d) Schematic representation of the
acylation of alcohols.
Received: June 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01960
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
(>24 h). Thus, there is still room for improvement regarding
increased enantioselectivity (>95:5 er) and reduced catalyst
loading (<5 mol %) and reaction time.
Table 1. Screening of Nucleophile in the DKR of 2a
In this letter, we report the DKR of azlactones with
binaphthyl-based chiral DMAP derivatives having two amide
groups, which are critical substituents for achieving high
catalytic activity and enantioselectivity. We also demonstrate
that a multigram-scale reaction (2.5 g) proceeds to deliver an
unnatural α-amino acid precursor in good yield with high
enantioselectivity.
We began by identifying the optimal catalyst from a selected
library 1a−l15 for the DKR of azlactone 2a in the presence of 5
equiv of methanol (nucleophile) and 10 mol % of benzoic acid
cocatalyst8 in toluene at 25 °C for 15 h (Figure 2). The reactions
b
c
entry
ROH
MeOH
EtOH
n-PrOH
i-PrOH
i-BuOH
allyl-OH
BnOH
1-NaphCH2OH
Ph2CHOH
product
conv (%)
er
1
2
3
4
5
6
7
8
9
3a
4a
5a
6a
7a
8a
9a
10a
11a
>98
>98
>98
77
>98
>98
>98
90
72:28
82:18
82:18
94:6
83:17
72.5:27.5
70:30
75:25
82:18
28
a
Reactions were performed on a 0.1 mmol scale in toluene (0.2 M)
b
under an argon atmosphere. Conversion was determined by 1H
NMR analysis based on consumption of the starting material.
c
Enantioselectivities were determined by HPLC analysis.
accelerate the DKR of 2a. Furthermore, the use of a bulkier α-
branched alcohol, benzhydryl alcohol, resulted in significant
decreases in conversion and enantioselectivity (28% conv.,
82.5:17.5 er, entry 9). Accordingly, we selected isopropyl
alcohol as the optimal nucleophile in terms of high
enantioselectivity of desired product 6a.
Next, we screened various solvents for the DKR of 2a with 1i
at 25 °C for 15 h (Table 2). The reactions in common organic
a
Table 2. Screening of Solvent in the DKR of 2a
b
c
entry
solvent
conv (%)
er
94:6
91:9
d
1
toluene
Et2O
THF
EtOAc
CH2Cl2
CHCl3
i-PrOH
77
29
29
36
39
74
91
2
3
4
5
6
7
86.5:13.5
86:14
92:8
Figure 2. Initial screening of catalyst for the DKR of azlactone 2a.
96:4
with 3 mol % of catalysts 1a−d, which have alkyl ethers or ethyl
esters at the 3,3′-positions of the binaphthyl unit, led to a nearly
racemic mixture of 3a (up to 53:47 er), and those with 1e−h,
which have tert-alcohol units,16 resulted in a slight improvement
in the enantioselectivity of 3a (up to 39:61 er). On the other
hand, catalysts 1i−l having amide groups afforded 3a with
moderate enantioselectivity (up to 72:28 er). Based on these
results, 1i was selected as an optimal catalyst for further
optimization of the reaction conditions.
To verify the effect of the nucleophile on the DKR of 2a,
reactions with various alcohols were carried out in the presence
of 3 mol % of 1i at 25 °C for 15 h (Table 1). Although most of
the tested alcohols showed >98% conversion (conv.) with
moderate enantioselectivities of the products (entries 1−3 and
5−8), isopropyl alcohol (α-branched alcohol) gave the highest
enantioselectivity (entry 4, 77% conv., 94:6 er). Although
isopropyl alcohol is a less reactive nucleophile in the DKR of
azlactones (<5% conv.9 or t1/2 ∼1 week8 of azlactone), probably
due to steric hindrance, catalyst 1i was active enough to
63:37
a
Reactions were performed on a 0.1 mmol scale in solvent (0.2 M)
b
under an argon atmosphere. Conversion was determined by 1H
NMR analysis based on consumption of the starting material.
c
d
Enantioselectivities were determined by HPLC analysis. The same
data as in Table 1, entry 4.
solvents (Et2O, THF, EtOAc, and CH2Cl2) afforded 5a in low
conversion (29−39% conv.) with good enantioselectivity (up to
92:8 er, entries 2−5), while the reaction in chloroform (CHCl3)
showed slightly improved conversion and enantioselectivity
(74% conv., 96:4 er, entry 6). The reason for this improvement is
not yet clear. Furthermore, the use of isopropyl alcohol also
improved the conversion to the product, but resulted in
moderate enantioselectivity (91% conv., 63:37 er, entry 7).
Presumably, the protic solvent prevents the formation of an
effective hydrogen bonding network between the catalyst and
the substrate,17,18 which should be responsible for achieving
B
DOI: 10.1021/acs.orglett.8b01960
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
loading; see the Supporting Information for details), we selected
the following optimal conditions: 3 mol % of 1i, 3 equiv of i-
PrOH, 10 mol % benzoic acid in CHCl3 at 25 °C for 24 h.
With the optimal reaction conditions in hand, the DKR of
various azlactones was examined (Scheme 1). The reactions of
(hetero)aryl alanine derivatives 2a−e gave the products 6a−e in
good yields with excellent enantioselectivities (66−89% isolated
yields19 with 95.5:4.5 to 96:4 er20). On the other hand, the
results obtained using 2f having an −NH functionality
(tryptophan derivative) were worse in terms of both product
yield and enantioselectivity (28% yield with 62:38 er),
presumably because the hydrogen bonding donor (−NH)
inhibits the effective formation of a hydrogen bonding network
between the catalyst and substrate. Furthermore, the reactions of
substrates 2g−n with a simple or functionalized alkyl chain,
involving allyl, thiomethyl, and ester groups, were also carried
out. The desired products 6g, 6h, and 6j−n were obtained in
good yields with good to excellent enantioselectivities (58−91%
isolated yields with 86:14 to 95:5 er). In some cases (2h−m),21
the reaction required a slightly modified procedure (MS 3A as an
additive and/or a longer reaction time [48 h]) to achieve an
acceptable yield of the product. Among them, substrate 2i
having an α-branched alkyl group (i-Pr) was unreactive under
the reaction conditions due to steric hindrance around the
electrophile. Interestingly, the reaction of 2n with a hydrogen
bonding acceptor (vs hydrogen bonding donor, see 2f) had no
significant impact on the enantioselectivity of the product (95:5
er), and 2o mainly gave an unidentifiable side product.
According to these experiments, the current DKR process
allowed us to access various natural and unnatural α-amino acid
derivatives with good yields and enantioselectivities within 24−
48 h. Although such transformation generally required a higher
catalyst loading (5−20 mol %) and/or a longer reaction time
(>48 h),8−11 it is worth noting that the amide catalyst 1i showed
excellent catalytic activity (3 mol % of 1i and reaction time of
<48 h) in the DKR of azlactone, even though a sterically
demanding nucleophile (i-PrOH) was used.
Scheme 1. Dynamic Kinetic Resolution of Various Azlactones
with Catalyst 1i
DKR and deprotection leading to an amino acid were also
carried out on a multigram scale (Scheme 2). DKR of 2d (2.5 g)
Scheme 2. DKR of 2d on a Gram Scale and Deprotection of
6d
a
Reactions were performed on a 0.1 mmol scale in CHCl3 (0.4 M)
b
under an argon atmosphere for 24 h unless otherwise noted. NMR
yield was determined by H NMR analysis using 1,1,2,2-tetrachloro-
1
ethane as an internal standard, and the isolated yield is shown in
c
d
parentheses. MS 3A was used as an additive. The reaction time was
48 h.
under the modified reaction conditions (1 mol % of 1i [50 mg]
and substrate concentration 0.6 M) proceeded smoothly to give
6d (2.7 g, 91% yield with 96:4 er), and catalyst 1i was recovered
in 83% yield. After recrystallization, a pure enantiomer of 6d was
obtained (2.42 g, 81% yield, >99:1 er). Deprotection of the
resulting product 6d was successively achieved by treatment of
high enantioselectivity according to our previous studies.4−7
After taking into account these results and extensive screening of
the reaction conditions (reaction temperature, concentration of
substrate, acid additive, equivalents of nucleophile, and catalyst
C
DOI: 10.1021/acs.orglett.8b01960
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
HBr aq in refluxed acetic acid to give the desired unnatural α-
amino acid salt 6d′ in 43% yield without a decrease in the
enantiomeric ratio.
Experimental procedures and copies of 1H and 13C NMR
spectra for substrates and products (PDF)
To gain further insight into the high catalytic activity of 1i
having two amide units, we conducted additional control
experiments using other pyridine-based nucleophilic catalysts
(Figure 3). DKR of 2a with C1-symmetric catalyst 1m (lack of
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mandai@cc.okayama-u.ac.jp.
*E-mail: suga@cc.okayama-u.ac.jp.
ORCID
Hiroki Mandai: 0000-0001-9121-3850
Koichi Mitsudo: 0000-0002-6744-7136
Seiji Suga: 0000-0003-0635-2077
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by a Grant-in-Aid for
Young Scientists (B) (17K17903) from JSPS, a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts,” and the JGC-S Scholar-
ship Foundation.
REFERENCES
■
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Korenaga, T.; Suga, S. Nat. Commun. 2016, 7, 11297.
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2016, 89, 1081.
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359, 2778.
Figure 3. Effects of amide group(s) of the catalyst in the DKR of 2a.
(7) Mandai, H.; Yasuhara, H.; Fujii, K.; Shimomura, Y.; Mitsudo, K.;
Suga, S. J. Org. Chem. 2017, 82, 6846.
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one amide group) gave 6a in 78% conv. with 91.5:8.5 er. The
yield and enantioselectivity of 6a were somewhat lower than
those from 1i (an optimal catalyst) having two amide groups
(87% conv., 94:6 er). The reaction with catalyst 1n without
amide groups at the 3,3′-positions of the binaphthyl unit
resulted in 51% conv. with 45.5:54.5 er, and the catalytic activity
of 1n was almost identical to that of DMAP (51% conv. vs 56%
conv.). Although at least one amide group is required for
enantioselective transformation, two amide groups play
important roles in acceleration of the rate of the reaction and
achieving high enantioselectivity.
(15) 1-Naph indicates a 1-naphthyl group.
(16) According to our previous studies, catalysts 1e and 1f showed
excellent catalytic activity and enantioselectivity in Steglich-type
rearrangement, kinetic resolution of benzylic alcohol and d,l-1,2-diols,
and desymmetrization of meso-1,2-diols. See refs 4−7.
(17) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus, P. J.;
Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638.
(18) Vasbinder, M. M.; Jarvo, E. R.; Miller, S. J. Angew. Chem., Int. Ed.
2001, 40, 2824.
(19) Due to the highly crystalline nature of the products, purification
of the product (0.1 mmol scale) by column chromatography on SiO2
was rather difficult. Accordingly, we give the NMR yield and isolated
yield.
(20) The absolute configuration of 6a was determined to be S in
comparison to 6a prepared from L-phenylalanine. Other products 6b,
6e, and 6g were also assigned S with comparison to the reported values
of specific optical rotation. Other products were also assigned S by
analogy. See the Supporting Information for details.
(21) See the Supporting Information for details.
In conclusion, we have developed a dynamic kinetic
resolution of azlactones using a binaphthyl-based DMAP
derivative 1i having two amide groups. As little as 3 mol % of
the catalyst facilitates the reactions within a relatively short
reaction time (<48 h), as compared to the previously reported
methods, to afford a variety of natural and unnatural
enantioenriched α-amino acid derivatives in moderate to good
yields (up to 91% isolated yield) with high enantioselectivities
(up to 96:4 er). Control experiments revealed that the amide
group(s) of catalyst 1i play a significant role in achieving high
catalytic activity and enantioselectivity. Further mechanistic and
computational studies are now underway to elucidate the
reaction mechanism, including the role of the amide group(s).
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01960.
D
DOI: 10.1021/acs.orglett.8b01960
Org. Lett. XXXX, XXX, XXX−XXX