Glycerol conversion to high-value chemicals: The implication of unnatural α-amino acid syntheses using natural resources

Article abstract of DOI:10.1039/c9gc00755e

Glycerol derivatives are an important class of compounds, which have great applications as basic structural building blocks in organic synthesis. O-Benzylglycerol was oxidised to produce a high-value compound in high yield using a NaOtBu-O₂ system. Furthermore, the synthetic utility of the resulting product was demonstrated by its transformation into unnatural α-amino acids, thus showing the valorisation of glycerol biomass.

Full text of DOI:10.1039/c9gc00755e

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DOI: 10.1039/C9GC00755E
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ARTICLE
Glycerol conversion to high-value chemicals: Implication of
unnatural -amino acids syntheses using natural resources
Yun Ji Park and Jung Woon Yang*
Received 00th January 20xx,
Accepted 00th January 20xx
Glycerol derivatives are an important class of compounds, which have great applications as basic structural building blocks
in organic synthesis. O-Benzylglycerol was oxidised to produce a high-value compound in high yield using a NaOtBu-O2
system. Furthermore, the synthetic utility of the resulting product was demonstrated by its transformation into unnatural
α-amino acids, thus showing the valorisation of glycerol biomass.
DOI: 10.1039/x0xx00000x
www.rsc.org/
under an oxygen atmosphere. Further transformation of 3 to
the unnatural -amino acid 2812 was investigated using
potentially infinite natural resources, such as sodium and (S)--
amino acids, which are derived from the electrolysis of sodium
chloride in seawater and common components of chiral pool
from nature, respectively (Scheme 1c). Therefore, this protocol
may provide an opportunity for new categories of biomass
conversions using natural resources and non-depleting
molecular oxygen as a terminal oxidant.
Introduction
Glycerol, known as glycerine, is a triol that can be generated as
a by-product during the synthesis of biodiesel from vegetable
oils, such as soybean and sunflower oils.1 Nowadays, there have
been made efforts to synthesise renewable materials utilising
biomass derivatives containing overproduced glycerol in
industrial research.2 Glycerol is no longer considered a by-
product of biodiesel production and is recognised as a privileged
scaffold due to its potential as a high-value carbon and oxygen
source and alternative to our gradually depleting existing
natural resources. Therefore, a diverse range of organic
transformations are needed for glycerol conversion.3 O-
Benzylglycerol (1), as a non-viscous glycerol derivative, is one of
the most valuable synthons in a variety of applications,
including solvents, cosmetics, pharmaceuticals, creams,
detergents, and additives for printing inks, lubricants, and
fuels.4 To date, the most common use of glycerol and its
derivatives reported in the literature is in transition-metal-
catalysed oxidation reactions (Scheme 1). Research on these
reactions is at an early stage and is mainly focused on
synthesising various chemical feedstocks rather than controlling
the selectivity of the products formed using precious transition
metal catalysts (e.g., Co, Au, Cu, Pt, and Ag).5 According to the
trend shown in a previous study, bimetallic systems6 exhibit
superior selectivity during the selective oxidation of glycerol
when compared to monometallic systems7 (Scheme 1a and
1b).8,9
Previous works:
a)
O
O
O
O
O
CuO
HO
+
+
+
HO
OH
HO
HO
OH
OH
OH
O
H
OH
H2O2, 80 °C
OH
OH
O
HO
HO
H
OH
OH
b)
Au/TiO2
O
O
O2 (1 atm)
+
HO
OH
OH
HO
OH
OH
OH
OH
OH
This work:
c)
NaOtBu (5 equiv)
O2 (1 atm)
O
OH
+
Ar
O
OH
toluene, 60 °C
Ar
OH
Ar
O
O
1
2
3
(S)-valine-based
R
Br / LDA
chiral oxazolidinone
NH2
R
OMe
Herein, we describe a transition-metal-free chemoselective
oxidative dehomologation of 2-O-benzylglycerol (Ar = Ph, 1) to
give aromatic carboxylic acid (2)10 and 2-(aryloxy)acetic acid
(3)11, which represents an unprecedented product pattern,
(R)
O
28
Potentially infinite natural resources
(Unnatural -amino acid synthesis)
Scheme 1. Previous reports on the oxidation of glycerol using monometallic
and bimetallic catalysts (a-b). Our current work on the transition-metal-free
oxidative dehomologation reaction of glycerol under an O2 atmosphere and
its application to unnatural -amino acid synthesis using a chiral auxiliary
approach (c).
Department of Energy Science, Sungkyunkwan University, Suwon 16419, South
Korea. E-mail: jwyang@skku.edu; Fax: +82-31-299-6505; Tel: +82-31-299-4276
†Electronic Supplementary Information (ESI) available: Detailed experimental
procedures, characterisation data and copies of 1H and 13C NMR spectra. See
DOI: 10.1039/x0xx00000x
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both the yield and ratio of the target products, which are the
Results and discussion
View Article Online
same outcomes as observed in the prevDioOuI:s1e0.x1p03e9r/imC9eGnCt0u07s5in5gE
2-O-benzylglycerol 1a (Table 2, entries 5-15). After screening
parameters including the adjustment of NaOtBu equivalents,
reaction temperature, and reaction time, the optimal
conditions were found to be include 1’a (0.5 mmol), NaOtBu (5
equiv) and O2 (1 atm) in THF at 30 oC for 18 h (Table 2, entry 11).
As the reaction temperature increased, the yield of the product
decreased (Table 2, entries 14 and 15). A trace amount of the
target products (2% yield) was obtained when the reaction was
carried out under solvent-free conditions (Table 2, entry 16).
We began our study by examining the transformation of two
different types of O-benzylglycerol derivatives (1a and 1’a) to
high-value chemicals, such as benzoic acid 2a and 2-
(phenyloxy)acetic acid 3a under the reaction conditions
previously established for the oxidative cleavage of alcohols13
or lignin model compounds14 utilising a NaOtBu-O2 system
(Table 1 and 2).
Table 1. Screening of the reaction parameters used for the oxidative
dehomologation of 2-O-benzylglycerol (1a)a
OH
NaOtBu / O2 (1 atm)
O
Table 2. Screening of the reaction parameters used for the oxidative
dehomologation of 1-O-benzylglycerol (1’a) a
OH
+
Ph
O
OH
Ph
OH
solvent, 60 °C
Ph
O
O
OH
NaOtBu / O2 (1 atm)
O
1a
2a
3a
Ph
O
OH
+
Ph
O
Ph
OH
solvent, 30 °C
OH
O
Equiv. of
NaOtBu
Time
(h)
18
18
18
18
18
18
18
18
18
18
18
12
24
18
18
18
Ratio of
2a:3ab
-
-
-
Yield
(%)c
n.d
n.d
n.d
53
37
28
55
29
29
64
90
78
86
69
80
39
1'a
2a
3a
Entry
Solvent
1
2
3
4
5
6
7
8
MeOH
EtOH
5
5
5
5
5
5
5
5
3
4
5
5
5
5
5
5
Equiv. of
NaOtBu
Time
(h)
18
18
18
18
18
18
18
18
18
18
18
12
24
18
18
18
Ratio of
2a:3ab
-
Yield
(%)c
n.d
n.d
n.d
76
75
60
65
89
64
85
85
82
71
75
68
2
Entry
Solvent
n-BuOH
t-BuOH
CH2Cl2
DMSO
THF
1
2
3
4
5
6
7
8
MeOH
EtOH
n-BuOH
t-BuOH
CH2Cl2
DMSO
DMF
Toluene
THF
THF
THF
THF
THF
5
5
5
5
5
5
5
5
3
4
5
5
5
5
5
5
64:36
>99:n.d
86:14
56:45
83:17
55:45
66:34
76:24
80:20
78:22
72:28
75:25
90:10
-
-
34:66
61:39
80:20
85:15
67:33
22:78
71:29
79:21
72:28
84:16
76:24
83:17
33:67
DMF
9
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
-
10
11
12
13
14d
15e
16
9
10
11
12
13
14d
15e
16
THF
THF
-
a General conditions: 1a (0.5 mmol), NaOtBu (5 equiv), solvent (4 mL), O2 (1 atm),
18 h, 60 oC. Determined by 1H NMR spectroscopy. Isolated yield. Reaction
b
c
d
performed at 30 oC. e Reaction performed at 100 oC.
a General conditions: 1’a (0.5 mmol), NaOtBu (5 equiv), solvent (4 mL), O2 (1 atm),
18 h, 30 oC. Determined by 1H NMR spectroscopy. Isolated yield. Reaction
b
c
d
In the presence of alcoholic solvents, the target products were
not detected in the reaction mixture with the exception of t-
BuOH (Table 1, entries 1-4 and Table 2, entries 1-4). In the case
of 1a, the selectivity toward benzoic acid (2a) was extremely
high, but the product yield was low when using CH2Cl2 as the
reaction solvent (Table 1, entry 5). The selectivity observed
between products 2a and 3a was low when using THF, but high
in DMSO and DMF although in low yield (Table 1, entries 6-8).
After screening parameters including the adjustment of NaOtBu
equivalents, reaction temperature, and reaction time (Table 1,
entries 9-10 and 12-15), the optimal result was obtained using
performed at 60 oC. e Reaction performed at 100 oC.
The substrate scope of the oxidative dehomologation of O-
benzylglycerol (1a and 1’a) was then explored under the
optimal conditions and the results are summarised in Table 3.
The highest yields (81-90%) were obtained with substrates 1a
and 1’a (Table 3, entries 1 and 2). Substrates bearing electron-
donating substituents on the aromatic ring gave high yields (81-
83%; Table 3, entries
5 and 6). Electron-withdrawing
substituents at the para-position (62-86%; Table 3, entries 7-12)
showed better results than with substituents at the meta-
position (20-36%; Table 3, entries 13 and 14).
o
5 equivalents of NaOtBu in toluene at 60 C for 18 h (Table 1,
entry 11). Upon lowering the reaction temperature to 30 oC, the
ratio of 2a and 3a was not significantly different, but the target
products were obtained in low yield (Table 1, entry 14). The
reaction was also investigated under solvent-free conditions,
which resulted in the formation of the target products in 39%
yield (Table 1, entry 16). In the case of 1'a, the reaction was
carried out in CH2Cl2, DMSO, THF, DMF, toluene, and THF.
Among these solvents, THF gave the best results in terms of
Based on our previous 18O-isotope labelling experiments on the
oxidative cleavage reaction of alcohols13 or direct oxidation of
allylic alcohols,15 the reaction mechanism was proposed, as
shown in Scheme 2. 2-O-Benzylglycerol (1a) was oxidised to
aldehyde 4 with the release of hydroperoxide anion 5 in the
NaOtBu-O2 system.
2 | J. Name., 2012, 00, 1-3
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Table 3. Substrate scope for the oxidation of various O-benzylglycerol derivativesa
The subsequent ring-opening reaction of 8 takesVpielwacAerticdleuOenlitnoe
ring strain to give formyl ester 10 and formate 9. Formyl
DOI: 10.1039/C9GC00755E
OH
OH
carbonate 12 may be formed as a transient intermediate by
nucleophilic addition of hydroperoxide anion to aldehyde 10
followed by Baeyer-Villiger rearrangement16 with acyl group
migration. Formyl carbonate 12 may decompose to benzyl
alkoxide 14 with the loss of formic acid 13 and carbon dioxide
in the presence of hydroxide ion. Benzoic acid 2a was then
obtained via -hydride transfer from 14 to molecular oxygen
and Dakin-type oxidation reaction17 of 16 followed by an acidic
work-up procedure. In Path II, 2-(benzyloxy)malonic acid 18 was
Ar
Ar
O
1
NaOtBu, O2 (1 atm)
Condition A or B
O
OH
or
+
Ar
O
OH
OH
Ar
OH
O
O
2
3
1'
Products
(2 and 3)
Yields of
2:3 (%) b
76:24
63:18
59:8
57:15
70:13
65:16
74:12
64:11
57:6
50:12
62:17
63:12
19:17
16:5
Entry Substrate Ar
Condition
1
1a
Ph
A
B
A
B
A
B
A
B
A
B
A
B
A
B
1
serendipitously isolated and confirmed using H and 13C NMR
2a + 3a
2b+ 3b
2c + 3c
2d + 3d
2e + 3e
2f + 3f
2
3
4
5
1’a
1b
1’b
1c
spectroscopy, which allowed a better understanding of the
following reaction mechanism. Di-aldehyde 4 was oxidised to
the di-carboxylic acid using 2 equivalents of hydroperoxide
anion, which then formed the final target compound 3a via the
mono-decarboxylation of 19 followed by an acidic work-up
procedure.
The mechanism for oxidative dehomologation of 1-O-
benzylglycerol 1'a was also determined using a competing
reaction between the deprotonation of 4’ by NaOtBu and the
nucleophilic addition of 4’ with hydroperoxide anion, as shown
in Scheme 2. As a result, benzoic acid 2a and 2-(benzyloxy)
acetic acid 3a, which are the same products formed in the
previous experiments using 2-O-benzylglycerol (1a), were
produced (Scheme 3). Similar to Path I in Scheme 2, enolate 6’
was formed by the abstraction of the -acidic proton in the
ketone by tert-butoxide base. Benzyl formate 10’, as a transient
β-Naphthyl
3-OMe-C6H4
4-Cl-C6H4
4-Br-C6H4
4-CF3-C6H4
3-NO2-C6H4
6
7
8
9
10
11
12
13
14
1’c
1d
1’d
1e
1’e
1f
1’f
1g
1’g
2g + 3g
a Condition A: 1 (0.5 mmol), NaOtBu (5 equiv), toluene (4 mL), O2 (1 atm), 18 h, 60
oC; Condition B: 1’ (0.5 mmol), NaOtBu (5 equiv), THF (4 mL), O2 (1 atm), 18 h, 30
oC. b Isolated yield.
The next step was determined to follow either Path I or Path II.
In Path I, treating aldehyde 4 with NaOtBu forms nucleophilic
enolate 6, which attacks molecular oxygen to afford 1,2-
dioxetan-3-olate 8 via the intramolecular nucleophilic addition
of the hydroperoxyl anion to the carbonyl group.
intermediate,
can
be
generated
via
consecutive
transformations including the nucleophilic addition of
hydroperoxyl anion to the carbonyl group 7’ and ring-opening
of 1,2-dioxetan-3-olate (8’) with the release of glyoxylate 9’.
OH
H
O
O
NaOtBu / O2
- HO2 (5)
OH
O
Ph
O
Ph
1a
4
H
[Path I] deprotonation by base
[Path II] nucleophilic addition

NaOtBu O2
2 HO2
tBuO
H
O
O
H
O
O
H
O
O
O
H
O
O
O
O
OH
O
O
NaOtBu
H
O

Ph
Ph
O
O
O
O
- HCO2
OH
OH
O
Ph
Ph
Ph
Ph
Ph
O
(9)
O
O
O
10
O
H
H
O
19
7
18
O
8
6

HO2
O
- CO2
O
O
H
O
O
H
H
OH
HCl (aq)
OH
Ph
O
O
OH
Ph
Ph
O
O
H
O

- HO
- HO2
Ph
O
Ph
O
- HCO2H (13)
OH - CO2
O
3a
O
O
20
14
11
12
15

HO2
OH
O
O
HCl (aq)
OH
Ph
O
Ph
O
- HO
Ph
O
H
2a
17
16
Scheme 2. Proposed mechanism for the oxidative dehomologation of 2-O-benzylglycerol 1a.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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DOI: 10.1039/C9GC00755E
H
OH
OH
NaOtBu / O2
- HO2 (5)
O
H
Ph
O
Ph
O
4'
O
1'a
[Path I] deprotonation by base
[Path II] nucleophilic addition
HO2 (5)
NaOtBu O2
O
O
O
O
O
O
O
O
O
O
O
Ph
O
Ph
O
O
- HO
O
H
O
H
OH
O
O
- glyoxylate
Ph
O
H
Ph
O
Ph
O
O
Ph
O
O
O
13'
14'
(9')
10'
H
8'
7'
6'
O
H
HO
O
H

HO2
O
- HCO2H (13)
O
H
H
H
OH
O
HCl (aq)
Ph
O
H
Ph
O
O

- HO
OH
Ph
O
Ph
O
Ph
O
Ph
Ph
O
- HO2
- CO2
O
14
15
OH
3a
O
O
11'
12'
15'

HO2
OH
O
H
O
HCl (aq)
OH
Ph
O
- HO
O
Ph
O
2a
17
16
Scheme 3. Plausible mechanism for the oxidative dehomologation of 1-O-benzylglycerol 1'a.
Benzyl oxide 14 can be produced after the 1,2-hydride shift of one] to give acylated derivative 22. Reaction of the
11’ and decarboxylation of 12’. Subsequently, the target corresponding lithium enolate, which was generated from 22
product (2a) was formed via the iterative routes from 14 to 17 using LDA at -78 oC, with benzyl bromide gave the
as described in Scheme 2. In Path II, the nucleophilic addition corresponding -alkylated adduct 23 as a single diastereomer
reaction takes place by the hydroperoxide anion 5 with more (>99% de). The pure diastereomer 23 was cleaved from the
electrophilic aldehyde 4’ to give tetrahedral intermediate 13’. chiral auxiliary upon treatment with LiOH/H2O2 (aq) to give the
O-Formyl ester 14’ and hydroxide ion are formed via Baeyer- (R)-configured carboxylic acid 24. The chiral oxazolidinone was
Villiger rearrangement16 with acyl group migration. recovered almost quantitatively and can be recycled (see ESI).19
Deformylation can be promoted by hydroxide ion and thus, α-Hydroxy acid 25,20 as a versatile chiral building block and
release carboxylate 15’ and formic acid 13. After an acidic work- intermediate, was obtained via debenzylation of 24 using 10%
up procedure, carboxylate 15’ was converted into 2- Pd/C with H2 gas. The absolute configuration of product 25 was
(phenyloxy)acetic acid 3a.
determined by comparison of optical rotation with the
Further transformation of 2-(benzyloxy) acetic acid 3a to an literature and assigned to be (R)-configuration.21 Methyl ester
unnatural -amino acid utilising a diastereoselective alkylation 26 was synthesized using a conventional Fischer esterification
reaction of a chiral metal enolate was carried out using Evans’ reaction of compound 25. A series of stepwise transformations
chiral auxiliary18, as shown in Scheme 4. Acid chloride 21 was starting from 26 enable its elaboration into unnatural -amino
coupled with the chiral auxiliary [(S)-4-isopropyloxazolidin-2- acid 28 and potential unnatural -amino acid 30, depending on
R
R
OH
O
O
OH
Cl
OH
i
ii
iii
iv
v
N
N
R
OH
Ph
O
Ph
O
Ph
O
Ph
O
Ph
>99% de
O
O
O
O
O
O
O
O
O
25
23
24
3a
21
22
(R = Ph)
-Hydroxy acid
N3
NH2
ix
vii, viii
R
OMe
vi
Route to (R)--amino acid synthesis
Route to (S)--amino acid synthesis
R
OMe
OMe
(R)
OH
O
28: 89% ee
O
O
27
R
OMe
NH2
N3
xi
x
R
R
OMe
O
26
(S)
30: 92% ee
O
29
Scheme 4. Reagents and conditions: i) SOCl2, CH2Cl2, reflux, 4 h, 99%; ii) (S)-4-isopropyloxazolidin-2-one, n-BuLi, THF, -78 oC to 0 oC, 4.5 h, 70%; iii) BnBr, LDA, THF, -78
oC to -45 oC, 3.5 h, 74%; iv) 28% H2O2 (aq), LiOH, THF, 0 oC, 1 h, 84%; v) 10% Pd/C, H2, EtOH, rt, 12 h, 84%; vi) H2SO4 (cat.), MeOH, reflux, 3.5 h, 87%; vii) Tf2O, pyridine,
LiBr, CH2Cl2, (CH3)2CO, -45 oC to 0 oC, 1 h, 90%; viii) NaN3, DMF, 40 oC, 1 h, 92%; ix) 10% Pd/C, H2, EtOH, rt, 12 h, 78%; x) DBU, DPPA, THF, 0 oC to 40 oC , 1d, 89%; xi) 10%
Pd/C, H2, EtOH, rt, 12 h, 85%.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9GC00755E
3
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the R group used and the stereochemistry of the chiral
secondary alcohol 26 formed via an inversion or retention step.
The (R)-configured hydroxy group in 26 was readily converted
into (R)-configured azido group in 27 via a double inversion of
stereochemistry involving bromination [reaction conditions:
Tf2O, pyridine, LiBr, CH2Cl2, (CH3)2CO, -45 C to 0 C, 1 h]22 and
azidonation [reaction conditions: NaN3, DMF, 40 oC, 1 h]23.
Catalytic hydrogenation of 27 gave (R)-phenylalanine methyl
ester 28 in 89% ee. The absolute configuration of (R)--amino
acid 28 was established based on a comparison of its specific
optical rotation {[α] 2D0 -26.2° (c 4.0, EtOH)} with reported in the
literature {[α] 2D3 -25.0° (c 4.04, EtOH)}24.
4
5
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o
o
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6
7
(R)-configured hydroxy group in 26 was readily converted into
an (S)-configured azido group in 29 via a Mitsunobu inversion
reaction using diphenylphosphoryl azide (DPPA) and 1,8-
diazabicyclo[5.4.0]undec-7-ene
(DBU).25
Catalytic
hydrogenation of 29 using 10% Pd/C and H2 gas, gave the
potential unnatural -amino acid 30 in 92% ee. The absolute
stereochemistry of (S)-30 was determined by comparison of its
specific optical rotation {[α] 2D0 +26.5° (c 4.0, EtOH)} with that
previously reported {[α] 2D3 +25.0° (c 4.04, EtOH)}24.
8
9
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In summary, O-benzylglycerol derivatives have been
synthesised from glycerol, which can act as a promising carbon
source from a myriad of biomass obtained from nature. These
derivatives were subjected to a transition-metal-free oxidative
dehomologation reaction using a NaOtBu-O2 system, leading to
the two different carboxylic acid products. The use of 1-O-
benzylglycerol enables the construction of unnatural -amino
acids utilising potentially infinite natural resources, such as
sodium and (S)--amino acid, thereby contributing to a new
type of glycerol valorisation.
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We gratefully acknowledge the National Research Foundation
(No. 2016R1A2B4010181 and No. 2019R1A4A2001440) and
NRF Nano.Material Technology Development Program
(2012M3A7B4049652) for financial support of this work.
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