Synthesis of (S)-3-hydroxytetrahydropyran from L-glutamic acid

Article abstract of DOI:10.1016/j.tetlet.2017.09.008

A concise synthesis of (S)-3-hydroxytetrahydropyran from natural L-glutamic acid has been developed. The intramolecular etherification starting from 1,5-diol was promoted by trifluoromethanesulfonic anhydride. The clinnamates of the alcohols were prepared

Full text of DOI:10.1016/j.tetlet.2017.09.008

Accepted Manuscript
Synthesis of (S)-3-Hydroxytetrahydropyran from L-glutamic Acid
Yang Geng, Maolin Zheng, Jingya Li, Dapeng Zou, Yusheng Wu, Yangjie Wu
PII:
S0040-4039(17)31115-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.008
TETL 49278
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 June 2017
27 August 2017
4 September 2017
Please cite this article as: Geng, Y., Zheng, M., Li, J., Zou, D., Wu, Y., Wu, Y., Synthesis of (S)-3-
Hydroxytetrahydropyran from L-glutamic Acid, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.09.008
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Synthesis of (S)-3-Hydroxytetrahydropyran from
L-glutamic Acid
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Yang Geng, Maolin Zheng, Jingya Li, Dapeng Zou,* Yusheng Wu,* and Yangjie Wu*
OH
OBn
OBn
Pd(OH)2/H2
Tf2O
(S)
(S)
HO
OH
(S)
O
O
> 95% ee

1
Tetrahedron Letters
Synthesis of (S)-3-Hydroxytetrahydropyran from L-glutamic Acid
Yang Geng,a Maolin Zheng,b Jingya Li,b Dapeng Zou,a* Yusheng Wu,a, b, c* and Yangjie Wua, b*
a The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450052, People’s Republic of China
b Tetranov Biopharm, LLC. and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450052, People’s Republic of China
c Tetranov International, Inc. 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise synthesis of (S)-3-hydroxytetrahydropyran from natural L-glutamic acid has been
developed. The intramolecular etherification starting from 1, 5-diol was promoted by
trifluoromethanesulfonic anhydride. The clinnamates of the alcohols were prepared for
accurately determining the optical purity by HPLC method.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
(S)-3-hydroxytetrahydropyran
Trifluoromethanesulfonic anhydride
Intramolecular etherification
have been developed.8 Hydroboration-oxidation of 3, 4-dihydro-
Introduction
2H-pyran
can
afford
dozens
of
grams
of
3-
hydroxytetrahydropyran.9 However, the enantiomers of 3-
hydroxytetrahydropyran with high optical purity are not easily
synthesized. So far, utilizing the asymmetric hydroboration-
oxidation of 3, 4-dihydro-2H-pyran with optically pure
organoboranes as reductive agent has been the major way for
preparing chiral 3-hydroxytetrahydropyran.10 In the 1980s,
Brown and co-workers10a-f made outstanding works in the
As major components of the chiral drugs, the chiral organic
molecules play an increasingly important role in pharmaceutical.
The enantiomers of a chiral drug have shown different
pharmacokinetic,
pharmacodynamics
and
toxicological
properties in human body.1 The demand for chiral compounds is
dramatically increasing accompany with the rapid growth of
pharmaceutical research and development. This has brought
prosperity in asymmetric synthesis2 and resolution methodology.3
Preparing target chiral compounds from natural chiral materials,
affords a facile and economic solution for chiral synthesis.
preparation
of
high
enantiomeric
purity
diisopinocampheylborane, and using them in asymmetric
hydroboration of cyclic olefin, ketones and so on. Among them,
the method10a for the synthesis of (R)-3-hydroxytetrahydropyran
was described as follows (Scheme 1): Hydroboration-oxidation
of 3, 4-dihydropyran with (-)-diisopinocampheylborane gave the
(R)-3-hydroxytetrahydropyran in 83% ee.10b Treatment of the 3-
tetrahydropyrandiisopinocampheylborane with acetaldehyde
provides the diethyl boronate. Then, iminodiacetic acid converts
this boronate into a crystalline chelate. After recrystallizations
twice from DMSO, the optical purity was up to 99% ee. Then,
the crystalline chelate was acidification, followed by oxidation to
give the crude product. The alcohol was distilled and purified by
preparative GC to afford the (R)-3-hydroxytetrahydropyran in >
99% ee. This method has some advantages for the synthesis of
high optical purity 3-hydroxytetrahydropyran. However, the high
optical purity diisopinocampheylborane was expensive and not
stable to moisture. Besides Brown's method, Jacobsen and
coworkers reported a synthesis of (S)-3-hydroxytetrahydropyran
through a intramolecular kinetic resolution of epoxy alcohols
catalyzed by a [CoIII(salen)] complex, and this method gave (S)-
3-hydroxytetrahydropyran in 46% yield with 95% ee.11
3-Hydroxytetrahydropyran forms an important substructure of
some pharmacologically active compounds. These compounds
seem to confer certain valuable properties on potential drugs. For
examples, 3-hydroxytetrahydropyran containing compounds
(Figure 1) are potential Soft ROCK inhibitor (A),4 glucokinase
activator (B),5 Mnk2 kinases inhibitors (C and D),6 respectively.
O
O
O
F
O
O
HN
O
OH
S
O
N
NH
O
O
S
O
O
NH2
O
N
O
A
B
F
O
F
O
O
O
NH
NH
N
O
O
N
N
S
S
N
N
N
N
N
H
H
C
D
Using the chiral amino acids to prepare chiral pyran12 and
furan13 derivatives in kilograms scale have been reported with
high optical purity. Herein, we report a protocol to prepare (S)-3-
hydroxytetrahydropyran through intramolecular etherification of
Figure 1. 3-Hydroxytetrahydropyran containing drugs
The racemic 3-hydroxytetrahydropyran was firstly synthesized
in the year of 1959 by Barker and co-workers.7 To date, various
methods for the synthesis of racemic 3-hydroxytetrahydropyran

2
Tetrahedron
1, 5-diol which can be transformed from available chiral
diol was treated with 1.0 eq. of trifluoromethanesulfonic
starting material L-glutamic acid.
anhydride, 3.0 eq. of triethylamine in dichloromethane at 0 °C to
25 °C for 3 h (entry 6), the compound 2 was isolated in 40%
yield. Further investigation indicated that the addition of a
catalytic amount of DMAP promoted the reaction and gave the
compound 2 with 48% yield.
Brown and co-worker's work
OH
83% ee
O
OBn
COOH
COOH
oxidation
(-)-(Ipc)2BH
OBn
a
b
Ipc
OEt
B
NH
O
O
L-Glutamic Acid
HO
OH
B
CH3CHO
Ipc
OEt
O
O
O
O
O
1-1
1
O
83% ee
OEt
B
O
B
OBn
OH
OH
3 M NaOH, 30% H2O2
Preparative GC
c
N
H
d
6 M HCl
Crystallize
OEt
O
O
O
O
O
O
O
> 99% ee
2
3
> 99% ee
Reagents and conditions: (a) HCl (conc.), NaNO2, H2O, -5 °C, 16 h; HCl
(conc.), MeOH, reflux, 12 h; BnBr, Ag2O, EtOAc, rt, 48 h; 65% yield (3
steps). (b) LiAlH4, Et2O, 24 h, 85% yield; (c) Tf2O, DMAP, Et3N, CH2Cl2,
25 °C, 0.5 h, 49% yield; (d) Pd(OH)2, H2 (1 atm), MeOH, 40 °C, 20 h, 82%
yield.
This work
OBn
OH
OBn
HO
OH
L-Glutamic Acid
O
O
Scheme 1. Synthesis of 3-hydroxytetrahydropyran with high
optical purity
Scheme.
2
Preparation
of
grams
of
(S)-3-
hydroxytetrahydropyran.
Results and Discussion
Next, the grams scale of (S)-3-hydroxytetrahydropyran was
prepared as shown in Scheme 2. Compound 1-1 was synthesized
with yield of 65% in 3 steps from L-glutamic acid according to
the literatures. Then compound 1-1 was treated with 2.0 eq. of
LiAlH4 in ether, and transformed into (S)-2-(benzyloxy)pentane-
1, 5-diol in 85% yield.15 Treatment of 21.0 g of 1, 5-diol with the
optimum conditions afforded the cyclization product 2 9.4 g
(49% yield). The benzyl protective group was removed using
palladium hydroxide in MeOH at 40 °C under 1 atm H2 to give
the compound 3 with 85% yield. Determination of chiral purity
of the product was achieved via chiral HPLC using the
cinnamamide derivative11 of the (S)-3-hydroxytetrahydropyran as
illustrated in Figure 2. The results revealed that this method
afforded the (S)-3-hydroxytetrahydropyran with high optical
purity (> 95% ee) without other purification.
In general, the process begins with the transformation of L-
glutamic acid into a crucial intermediate (S)-2-(benzyloxy)
pentane-1, 5-diol (Table 1, compound 1) which then undergoes
cyclization and debenzylation to isolate the product (S)-3-
aminotetrahydrofuran.
At the outset of our studies, the (S)-2-(benzyloxy)pentane-1,5-
diol was prepared from L-glutamic acid according to the
15
literature.14, The benzyl was chosen as the protecting group
because of its stability under LiAlH4 reduction condition and
easy removal under mild conditions. To go insight of the crucial
intramolecular etherification, some common closed loop methods
were tried. When 1, 5-diol was treated with 0.2 eq. p-
toluenesulfonic acid (entry 1), refluxed in toluene for 18 h with
the water diversion device, no product was detected. Mitsunobu
cyclization (entry 2) was tried and afforded the cyclization
product 2 in the low yield of 15%. Intramolecular nucleophilic
substitution reaction (entry 3) also used for the cyclization, but
the yield was also unsatisfactory.
Table 1. Intramolecular etherification of 1, 5-diol.a, b, c
OBn
OBn
(S)
1
(S)
HO
OH
O
2
entry
conditions
yield (%)
n.d.
15
1
2
3
4
5
6
7
0.2 eq. TsOH, tolune, reflux, 18 h
1.1 eq. DEAD, 1.1 eq. PPh3, THF, 20 h
Regents and Conditions: (a) Cinnamyl chloride, DMAP, Et3N, DCM. (b)
HPLC conditions: Daicel AD-H column (4.6×250 mm, 5 μm), mobile phase:
n-heptane: i-PrOH = 0.9 : 0.03 (v/v); detector: UV, λ = 254 nm.
1.0 eq. TsCl, 1.0 eq. NaH, THF, 0–25 °C, 4 h
10
1.0 eq. TFAA, 3.0 eq. Pyridine, DCM, 0–25 °C, 1 h
1.0 eq. Tf2O, 3.0 eq. Pyridine, DCM, 0 °C, 1 h
1.0 eq. Tf2O, 3.0 eq. Et3N, DCM, 0–-25 °C, 3 h
1.0 eq. Tf2O, 5% DMAP, 3.0 eq. Et3N, DCM, 25 °C, 1 h
n.d.
n.d.
40
Figure 2. HPLC of cinnamamide derivatives.
Conclusion
In summary, (S)-3-hydroxytetrahydropyran with grams scale
was prepared from inexpensive natural chiral L-glutamic acid.
The intramolecular etherification was promoted by
trifluoromethanesulfonic anhydride in mild conditions. This
facile method affords a convenient way for the synthesis of other
similar chiral derivatives.
48
aConditions: compound 1 (1 mmol). b The isolated yield was obtained via
silica gel column. cn.d. = not detected by GC–MS.
Trifluoroacetic
anhydride
(entry
4)
and
trifluoromethanesulfonic anhydride (entry 5) were designed as
dehydration agents with excess of pyridine as base, but only the
esterification reaction was detected. To our delight, when 1, 5-
Acknowledgements

3
We are grateful to the National Natural Science Foundation of
China (21172200) for financial support
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4
Tetrahedron
Highlights
. (S)-3-hydroxytetrahydropyranwas synthesized
frominexpensive L-glutamic acid.
. One step intramolecular etherification was
promoted by Tf2Ounder mild conditions.
. The product was prepared with >95% ee in a
gram-scale without recrystallization.