A practical and scalable process to selectively monofunctionalize water-soluble α,ω-diols

Article abstract of DOI:10.1016/j.tetlet.2014.04.066

A practical protocol for rapid and scalable synthesis of monofunctionalized α,ω-diols using a simple and inexpensive THP ether protection/deprotection strategy was described. Use of inexpensive DHP source and ease to remove excess water-soluble α,ω-diols

Full text of DOI:10.1016/j.tetlet.2014.04.066

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A practical and scalable process to selectively monofunctionalize
water-soluble
a,x-diols
Quanxuan Zhang a, , Hong Ren b,c, Gregory L. Baker a
⇑
a Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
b Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
c Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical protocol for rapid and scalable synthesis of monofunctionalized a,x-diols using a simple and
inexpensive THP ether protection/deprotection strategy was described. Use of inexpensive DHP source
Received 5 April 2014
Accepted 17 April 2014
Available online xxxx
and ease to remove excess water-soluble -diols and THP ether after deprotection render the process
a,x
scale-friendly without need of column chromatographic separation. The application of present method
was also illustrated in the preparation of heterobifunctional diols and well-defined extended oligo
(ethylene glycol).
Keywords:
Monofunctionalization
Water-soluble a,x-diols
Ó 2014 Elsevier Ltd. All rights reserved.
THP ether protection and deprotection
Scalable
Introduction
expensive and freshly prepared silver(I) oxide (1.5 equiv). Column
chromatography was also required to separate the desired
Water-soluble
organic synthesis and material science. A crucial step in application
of those -diols is to differentiate the reactivity of two chemi-
cally equivalent terminal hydroxyl groups for selective monofunc-
tionalization.1 A stoichiometric amount of water-soluble
-diols
a
,
x
-diol is an important family of synthons in
products. All these reported methods failed to deliver a practical
and scalable process for the synthesis of monofunctionalized
a,x
a,x
-diols.
In our endeavor to prepare clickable polylactide biomaterials, it
is crucial to establish a library of -hydroxy acids (1) bearing
oligo(ethylene glycol) (OEG) spacer between terminal alkyne and
-hydroxy acid moiety. And we envisioned that a practical and
scalable process to monofunctionalize OEGs (4, a family of water-
a
,x
a
relative to the functional/protective reagents usually generates a
mixture of unreacted, monofunctionalized and bis-functionalized
a
a,x
-diols in a statistical distribution of 1:2:1.2 To favor the forma-
tion of monofunctionalized
a,x
-diols selectively, a large excess of
soluble -diols) is highly desirable to scale up the synthesis of
a
,
x
starting
a
,
x
-diols is usually utilized compared to the functional/
desired a-hydroxy acids 1 (Scheme 1). Herein, we report a practical
protective reagents.1d–f,3 Use of catalysts or additives, such as
and scalable method for monofunctionalization of water-soluble
-diols using a simple and inexpensive THP-protection/depro-
strongly acidic ion exchange resins,4 polymer supports,5 and
a,x
cesium base,6 in stoichiometric feeding of
a,x
-diols and the func-
tection strategy. The synthesis proceeded in high yields of readily
tional/protective reagents is required for selective monofunction-
purified products without need of column chromatography.
alization. However, these methods all produced a mixture of
monofunctionalized and bis-functionalized
a,x-diols. In addition,
these methods all required employing column chromatography
to separate target monofunctionalized products for further elabo-
ration, which is costly and time-consuming. Silver(I) oxide medi-
ated selective monotosylation and monoalkylation of diols under
mild condition were reported to be a great protocol with excellent
functional group tolerance in the presence of a catalytic amount of
potassium iodide.7 However, it requires using a large amount of
OH
O
OH
COOH
OH
CN
Br
H
O
R
R
5
O
R
O
1
2
3
O
m
OH
O
O
R:
m
4
⇑
Corresponding author. Tel.: +1 517 355 9715; fax: +1 517 353 1793.
E-mail address: zhangqua@msu.edu (Q. Zhang).
Scheme 1. Retrosynthetic analysis of a-hydroxy acids (1).
http://dx.doi.org/10.1016/j.tetlet.2014.04.066
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhang, Q.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.066

2
Q. Zhang et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
Differentiation and functionalization of
a,x-diols (6)
Functionalization
or Protection
HO
R
OTHP
OTHP
PO
R
OTHP
OTHP
DHP/H
7
9
HO
R OH
H2O wash
α,ω-Diol
THPO
R
8
THPO
R
6
8
P = Ts, Bn and CH2CH(OCH2CH3)2
Entry
Diol (6)
Ratio (7:8)a
7a:8a8:1
Products (8+9)b
Yieldc (8+9) (%)
1
2
3
4
5
6
7
HO(CH2CH2O)4H (6a)
TsO(CH2CH2O)4THP (9a)
BnO(CH2CH2O)4THP (9b)
(CH3CH2O)2CHCH2O(CH2CH2O)4THP(9c)
TsO(CH2)4OTHP (9d)
(CH3CH2O)2CHCH2O(CH2)4OTHP (9e)
TsO(CH2)6OTHP (9f)
97.0
92.8
92.1
85.0
84.1
86.7
83.5
HO(CH2)4OH (6b)
HO(CH2)6OH (6c)
7b:8b10:1
7c:8c9:1
(CH3CH2O)2CHCH2O(CH2)6OTHP (9g)
a
b
c
Calculated from 1H NMR.
Tosylation was conducted in a mixture of aqueous KOH solution and THF. Alkylation was completed in THF in the presence of NaH.
Isolated yield of the mixture.
Results and discussion
Table 3
THP protection/tosylation of pure monofunctional diols (10)
Two chemically equivalent hydroxyl groups of water-soluble
a,x-diols (6a–c, Table 1) were differentiated with dihydropyran
(DHP) using a ꢀ5-fold excess of 6 in THF or CH2Cl2 in the presence
of a catalytic amount of p-toluenesulfonic acid (TsOH). A mixture
of 7 and 8 with mono-THP protected 7 as major product was
obtained. This mixture of 7 and 8 was used directly in the next step
without purification. Due to their high polar nature and high solu-
DHP/TsOH
PO
10: Pure
R OH
PO
9: Pure
R OP1
or TsCl
P = Ts, Bn; P1: THP, Ts
Entry
Substrate (10)a
Productb
Yieldc (%)
bility in water, excess of a,x-diols was simply removed by washing
1
2
3
4
5
TsO(CH2CH2O)4H (10a)
BnO(CH2CH2O)4H (10b)
TsO(CH2)4OH (10d)
TsO(CH2)6OH (10f)
BnO(CH2CH2O)4H (10b)
TsO(CH2CH2O)4THP (9a)
BnO(CH2CH2O)4THP (9b)
TsO(CH2)4OTHP (9d)
TsO(CH2)6OTHP (9f)
98.3
94.0
91.1
92.9
91.0
a CH2Cl2 solution of 7 and 8 with water and saturated aqueous
NaCl solution. THP is demonstrated to be an efficient alcohol pro-
tecting group due to its excellent stability towards neutral and
basic conditions. This would allow for incorporating suitable func-
tional groups (P) to mono-THP protected 7 under neutral or basic
condition in our synthesis. The mixture of 7 and 8 was then tosy-
lated with tosyl chloride (Table 1, entries 1, 4 and 6) or alkylated
upon reaction with benzyl bromide (Table 1, entry 2) or bromo-
acetaldehyde diethyl acetal (5, Scheme 1; Table 1, entries 3, 5
and 7) to quantitatively provide bifunctional diols (9a–g). The
bis-THP protected a,x-diols (8) were carried over to the next step
without separation (Table 1).
When a mixture of 8 and 9 was subjected to acidic conditions,
analytically pure monofunctionalized diols (10a–g, Table 2) includ-
ing tosylates, benzylate and diethyl acetals were obtained after
BnO(CH2CH2O)4Ts (9h)
a
Pure monofunctionalized diols (10) were subjected to THP protection or
tosylation.
b
Pure bifunctional diols (9) were prepared from 10.
Isolated yield.
c
removal of THP protecting groups. The complete cleavage of THP
ethers was accomplished via transacetalization reaction between
THP ethers and methanol or ethanol solvent in the presence of a
catalytic amount of TsOH.8 To avoid potential impurities from
methanolysis of diethyl acetal,9 it is important to note that ethanol
was used solely as acetal exchange solvent in the deprotection of
Table 2
Synthesis of analytically pure monofunctionalized diols (10)
PO
R
OTHP
OTHP
TsOH
9
PO
R
10
OH
+
R
8
Solvent
24h, rt
H2O wash
THPO
Pure
P = Ts, Bn and CH2CH(OCH2CH3)2
Entry
Substrate (8+9)a
Solventb
Product
Yieldc (%)
1
2
3
4
5
6
7
TsO(CH2CH2O)4THP (9a)
BnO(CH2CH2O)4THP (9b)
(CH3CH2O)2CHCH2O(CH2CH2O)4THP (9c)
TsO(CH2)4OTHP (9d)
(CH3CH2O)2CHCH2O(CH2)4OTHP (9e)
TsO(CH2)6OTHP (9f)
(CH3CH2O)2CHCH2O(CH2)6OTHP (9g)
MeOH
MeOH
EtOH
MeOH
EtOH
10a
10b
10c
10d
10e
10f
97.0
90.0
87.0
84.5
90.5
85.5
85.9
MeOH
EtOH
10g
a
b
c
A mixture of 8 and 9 was subjected to THP deprotection.
Anhydrous MeOH or absolute EtOH from bottle was used.
Isolated yield.
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Q. Zhang et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
THP
OTs
O
4
Bn
Bn
Bn
OTHP
OH
OH
9a
1. MeOH/TsOH
O
O
O
4
8
8
NaH, THF
Quant. yield
2. 55 °C in vacuo
10b
12
11
90%
Scheme 2. Synthesis of octa(ethylene glycol) derivatives from mono- and bifunctional diols 10b and 9a.
THP ethers for substrates 9c, e and g (Table 2, entries 3, 5, and 7).
Due to their relatively low boiling points,10 THP ethers of methanol
or ethanol after deprotection step via acetal exchange were readily
removed in vacuo using rotary evaporator. Bis-THP protected diols
(8) released hydrophilic diols after THP deprotection in alcoholic
solvents under acidic condition. The hydrophilic diols were simply
removed by washing a CH2Cl2 or CHCl3 solution of product 10 with
aqueous NaCl solution to afford pure monofunctional product
via heterobifunctionalization and thus the chain-length extension
of OEGs, which demonstrated its significance in preparing useful
synthetic building blocks.
Acknowledgement
This manuscript is in memory of my advisor, Prof. Gregory L.
Baker, who passed away unexpectedly while this paper was under
preparation. The authors are grateful to Prof. William D. Wulff at
Michigan State University for his invaluable guidance, discussions
and assistance during preparation of this manuscript.
10a-g.11 The ease of removing water-soluble
a,x-diols and THP
derivatives after deprotection of THP groups of 8 and 9 in methanol
or ethanol is the key step to enable a simple and scalable synthesis
of monofunctionalized diols (10a–g) without need of column chro-
matography. The judicious choice of DHP for its inexpensive
source, easy installation and facile deprotection under mild acidic
condition12 further render large-scale synthesis of monofunction-
alized diols practical with low cost.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
04.066.
Heterobifunctional
a,x-diol represents an important family of
building blocks in organic synthesis and material science. To fur-
ther extend the application of current methodology for monofunc-
Reference and notes
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11. It is worth mentioning that product 10c, 10e, and 10g could not be completely
dried (Table 2, entries 3, 5, and 7). Instead, they were stored as solutions in
CHCl3 under nitrogen to prevent inter- or intramolecular transacetalization
until subjected for further functionalization. However, it was found that pure
products 10c, 10e, and 10g can be rapidly recovered by dissolving them in
ethanol and stirring the resulting mixtures under nitrogen (100 psi) if inter- or
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14. Tosylated bifunctional diol (9a, 1.1 equiv) was optimized to afford 11 in a form
which can be easily purified in our case.
monofunctional diols (10) were readily converted to useful hetero-
bifunctional diols following known procedures. To avoid undesired
deprotection of
heterobifunctional diols, the stability of existing
groups under reaction conditions leading to the -functional group
a-functional groups during the preparation of
a
-functional
x
formation should be taken into account. For example, monofunc-
tional diols (10a, 10b, 10d and 10f) were readily transformed into
pure THP-protected bifunctional diols (9a, 9b, 9d and 9f) in the
presence of catalytic amount of TsOH in high yield (Table 3, entries
1–4). Tetraethylene glycol monobenzyl ether (10b) was also tosy-
lated with tosyl chloride to provide valuable heterobifunctional
derivative 9h in a simple manner (Table 3, entry 5).3b Moreover,
monofunctional diol (10b) was deprotonated by NaH and coupled
with tosylated heterobifunctional diol (9a) to afford chain-length
extended octa(ethylene glycol) derivative (11) quantitatively
(Scheme 2).1b,13 Column chromatography is not required to purify
11 since only negligible amount of by-product was formed at a rel-
atively large scale (0.25 mol of 10b) after optimization.14 The
transacetalization of THP-protected 11 in methanol further pro-
vided pure monofunctional octa(ethylene glycol) monobenzyl
ether (12). These results clearly indicate that the presented method
can be used to rapidly synthesize monofunctional and bifunctional
diol derivatives in large quantity with high purity as useful syn-
thetic building blocks.
In conclusion, we have developed a practical and scalable proto-
col for the synthesis of monofunctionalized
a,x-diols. Due to its
operational simplicity, the current process can be readily scaled
up to afford monofunctional diols efficiently without need of col-
umn chromatographic separation. The current method paved the
road for further versatile elaboration of monofunctionalized diols
Please cite this article in press as: Zhang, Q.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.066