One-pot synthesis of phosphate diesters and phosphonate monoesters via a combination of microwave-CCl3CN-pyridine coupling conditions

Article abstract of DOI:10.1016/j.tetlet.2011.11.032

Simple and convenient one-pot synthesis of a phosphorus-oxygen bond in phosphate diesters and phosphonate monoesters using trichloroacetonitrile as an activating agent and pyridine as a solvent under microwave irradiation conditions was described. This me

Full text of DOI:10.1016/j.tetlet.2011.11.032

Tetrahedron Letters 53 (2012) 243–246
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One-pot synthesis of phosphate diesters and phosphonate monoesters via
a combination of microwave-CCl3CN–pyridine coupling conditions
Hao-Wei Shih a, Kuo-Ting Chen b, Wei-Chieh Cheng a,
⇑
a Genomics Research Center, Academia Sinica, No. 128, Academia Road Sec. 2, Nankang District, Taipei 11529, Taiwan
b School of Pharmacy, College of Medicine, National Taiwan University, No. 1, Jen Ai Road Sec. 1, Taipei 10051, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple and convenient one-pot synthesis of a phosphorus–oxygen bond in phosphate diesters and phos-
phonate monoesters using trichloroacetonitrile as an activating agent and pyridine as a solvent under
microwave irradiation conditions was described. This method is useful for the preparation of various bio-
logically interesting glycophospholipids and also phosphate diesters or phosphonate monoesters con-
taining diverse moieties such as alkyl, prenyl, and benzyl substituents.
Received 8 September 2011
Revised 1 November 2011
Accepted 7 November 2011
Available online 15 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Microwave chemistry
Phosphorylation
Phosphate alcohol coupling
Glycophospholipid
O
Numerous biologically interesting natural products possess a
phosphate diester moiety.1 For example, b-
-mannosyl
CH2 CH3
O
HO
HO
HO
D
16
O
O
P
OH
phosphomycoketide (MPM), isolated from the cell walls of
Mycobacterium tuberculosis or Mycobacterium avium, is a CD1c-
presented antigen for T cells. Phosphatidylglucoside (PtdGlc),
isolated from Staphylococcus aureus and mammalian cell, plays an
important role in glial cell development and differentiation.
O
O
O
CH2 CH3
OH
16
O
PtdGlc
b-D-Arabino-furanosyl-1-monophosphoryl-decaprenol (DPA) is a
key substrate for arabinogalactan (AG) and lipoarabinomannan
(LAM) in mycobacterium cell wall biosynthesis (Fig. 1).
O
P
OH
O
O
O
HO
One of our research interests is to synthesize key bacterial or
mycobacterial cell wall components, such as DPA or Lipid II, and
study their biological functions.2 Based on the preliminary
literature study, our model glycophospholipid 3 might be prepared
through the phosphoramidite–phosphotriester approach.1a How-
ever, this reagent, 2-cyanoethyl N,N-diidopropylchlorophosph-
oramidite, is quite expensive so this method is limited to scale
up. General esterification of phosphoric acids with alcohols by
coupling reagents under thermal conditions has been extensively
studied; however, our initial attempts to utilize these known
coupling reagents such as dicyclohexylcarbodiimide (DCC) or
triisopropylbezenesulfonyl chloride (TPSCl) to prepare glyco-
phospholipid 3, one of the phosphate diesters (Scheme 1, Table
1) from protected sugar 1 and long chain alcohol 2 were not
satisfactory because of low yields (<10%) and elongated reaction
8
OH
HO
DPA
OH
O
HO
O
P
OH
R
∗
HO
O
O
HO
R = n-heptylor n-pentyl
MPMs
O
P
OH
O
P
OH
R O
O R'
R
O
OH
R'OH
+
⇑
Corresponding author. Tel.: +886 02 2789 8761; fax: +886 02 2789 8771.
E-mail address: wcheng@gate.sinica.edu.tw (W.-C. Cheng).
Figure 1. Natural products containing a phosphate diester and its retrosynthesis.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.032

244
H.-W. Shih et al. / Tetrahedron Letters 53 (2012) 243–246
Table 2
OAc
O
AcO
AcO
AcO
Examination of reaction factors (solvent and time)a
O
P
+
Yieldb (%)
O
OH
OH
Entry
Solvent
T (°C)
Time (min)
HO
2
1
2
3
4
5
6
7
8c
Toluene
Acetone
1,4-Dioxane
THF
Acetonitrile
DMF
100
100
100
100
100
100
90
60
60
60
60
60
60
15
60
13
7
6
17
28
45
89
11
α:β = 10:1
1
2
OAc
O
AcO
AcO
AcO
conditions
in Table 3
O
O
O P
OH
Pyridine
Pyridine (80 W)
2
90
a
3
Reagents and conditions: 1 (0.4 mmol), 2 (1.5 equiv) and CCl3CN (2 mL) in the
desired solvent (entries 1–7) was irradiated at 120 W in a sealed tube.
b
Scheme 1. Model reaction used for the screening of coupling conditions.
Isolated yield.
The reaction was irradiated at 80 W.
c
Table 1
Examination of coupling conditions for the preparation of glycophospholipid 3a
This encouraging observation promoted us to further
investigate various solvent systems, and the results were shown
in Table 2. Polar aprotic solvents such as DMF, pyridine and aceto-
nitrile (Table 2, entries 5–7) gave better yields than less polar ones.
These results can be rationalized by higher dielectric constants of
solvents and easy charge separation of the phosphate anion from
its counter ion in polar solvents. Notably, pyridine was the best
Entry
Reagents and conditions
T (°C)
Time
Yieldb (%)
1
2
3
4
5
6
7
8
TPSCl/py.
DCC/py.
80
80
80
90
80
80
90
90
>72 h
>72 h
>72 h
48 h
60 min
60 min
60 min
15 min
64
9
5
PPh3/DIAD/py.
CCl3CN/py.
TPSCl/py. (
PPh3/DIAD/py. (
DCC/py. ( w 120 W)
CCl3CN/py. ( w 120 W)
47
41
l
w 120 W)
c
lw 120 W)
—
solvent in our study to prepare glycophsopholipid
3 under
l
13
89
microwave irradiation (120 W, 90 °C, 15 min, Table 2, entry 7). In
contrast, changing irradiation power from 120 to 80 W, a signifi-
cant decrease in reaction yield was obtained (Table 2, entry 7 vs 8).
To demonstrate the efficiency and the scope of the microwave-
assisted synthesis, various sugar phosphates and alcohols were
chosen to investigate the reaction feasibility to form glycophosp-
holipids or phosphate diesters using CCl3CN as an activating re-
agent in weak basic conditions (pyridine). As shown in Table 3,
the reaction’s progress was strongly dependent on the electronic
or steric property of the alcohol. For example, farnesol (4, entry
2) was converted to the corresponding glycophospholipid 5 at
80 W within 15 min, but solanesol (6, C45H73OH, entry 3) required
a longer time (60 min) to consume all the starting materials. Pre-
sumably, this long-chain lipid in 6 did not make the reaction mix-
ture homogeneous to perform a uniform heating pattern. Besides,
uridine-50-monophosphate glucopyranoside (12) could also be pre-
pared by microwave-assisted conjugation of 8 and 11 in 71% with-
in 15 min (Table 3, entry 5). Notably, when an alcohol such as 14
containing a labile tetrachlorophthalic (TCP) moiety was coupled
with a phosphate (entry 6), the reaction conditions should be
milder (70 °C, 60 W) in order to obtain a reasonable yield (62%, en-
try 6). Secondary alcohols such as benzyl 2-hydroxypropanoate
(16) and 1-phenylpropan-2-ol (29) were also applied to success-
fully generate desired adducts 17 and 30, respectively (entries 7
and 12). Excitingly, diverse phosphonate monoesters could also
be smoothly prepared via this method (Table 3, entries 9–11). As
we know, during the preparation of glycophospholipids via a
typical glycosylation reaction from activated sugars and lipid-
phosphates, the neighboring participation could affect the anomer-
ic selectivity. Thus, more synthetic steps might be required to
prepare specific sugar building blocks in order to control the de-
sired anomeric selectivity.12 In contrast, the fixed ratio of anomers
in our starting glycophosphates such as 1, 8, and 13 would directly
convert to the corresponding glycophospholipid products without
changing their anomeric ratio (see in Table 3).
l
a
Reagents and conditions: 1 (0.4 mmol), 2 (1.5 equiv) and coupling reagents
(3.0 equiv) in pyridine.
b
Isolated yield.
Not detected.
c
times required (>72 h).1,3 These poor results urged us to develop a
more practical method for the preparation of glycophospholipids.
Recently, Kalek and Stawinski have reported the synthesis of
mono- and di-arylphosphinic acids via microwave-assisted palla-
dium-catalyzed cross coupling.4 Their work inspired us to evaluate
microwave conditions to prepare our target molecules. Theoreti-
cally, a phosphorus–oxygen bond formation by the coupling of
phosphates or phosphonates to alcohols might be suitable under
microwave irradiation because these molecules can absorb the
microwave energy more efficiently through the ionic conduction
mechanism.5 Over the last two decades, microwave-assisted or-
ganic synthesis (MAOS) has become a powerful technique to boost
the reaction rates and to reduce the reaction time with an
improvement in the yield and quality of the product.5 However,
to the best of our knowledge, a microwave-assisted phosphorus
oxygen bond formation in a one-pot manner has not been studied
yet. Herein, we report the development of simple and convenient
method for the synthesis of structurally diverse glycophospholi-
pids, phosphate diesters, and phosphonate monoesters via micro-
wave irradiation with specific coupling conditions.
Our investigation was started from evaluating the efficiency of
coupling reagents for the assembly of mannopyranosidyl mono-
phosphate (1)6 with 3,7,11-trimethyl-dodecan-1-ol (2) under ther-
mal and microwave-assisted conditions (Scheme 1 and Table 1).
As shown in Table 1, under thermal conditions (entries 1–4),
better yields were given by using TPSCl and CCl3CN as coupling re-
agents instead of DCC or PPh3/DIAD but a longer time (>48 h) was
required in all reactions. With the assistance of microwave irradi-
ation, the yields were still too low (<13%) and messy results were
showed in either DCC-mediated conditions or Mitsunobu reaction
(entries 6 and 7).3,7 Fortunately, when CCl3CN-mediated condi-
tions8 were applied with pyridine as the solvent, the yield was dra-
matically improved to 89% within 15 min at 120 W (Table 1, entry
8). Presumably, the mechanism of this one-pot synthesis could be
proposed to generate an iminophosphate as a key intermediate.8
Next, D-arabinofuranosyl-1-monophosphorylsolanesol (31, DPA
analogue), a key natural product-like compound for mycobacte-
rium cell wall biosynthesis, was synthesized to demonstrate the
efficiency of our methodology (Scheme 2). The TBS protected
D
-arabinose-monophosphate 1810 was chosen as our starting
material to conjugate with a polyisoprenol, solanesol 6, at 90 °C
for 60 min under 80 W irradiation, followed by global desilylation

H.-W. Shih et al. / Tetrahedron Letters 53 (2012) 243–246
245
Table 3
Microwave assisted one-pot synthesis of phosphate diester and phosphonate monoester analogues9
Entry Phosphate/Phosphonate
Alcohol
Conditions (°C/W/
min)
Products
Yielda
(%)
OAc
O
OAc
O
AcO
AcO
AcO
O
P
O
P
OH
AcO
HO
AcO
O
O
OH
OH
AcO
O
O
1
2
3
4
90/120/15
80/80/15
80/80/60
80/80/15
89
86
82
89
2
2
2
2
8
OH
α:β = 10:1
2
1
α:β = 10:1
3
OAc
O
OAc
O
AcO
AcO
AcO
O
P
OH
O
AcO
HO
AcO
AcO
O P O
OH
α:β = 10:1
α:β = 10:1
1
4
Z,E-farnesol
5
OAc
O
OAc
O
AcO
AcO
AcO
O
P
OH
O
AcO
HO
AcO
O
O
OH
AcO
O P O
OH
α:β = 10:1
8
α:β = 10:1
1
6
solanesol
7
AcO
AcO
AcO
HO
O
P
OH
O
O
O
AcO
AcO
OH
AcO
O P O
OAc
9
OAc
OH
α:β = 1:1
8
α:β = 1:1
10
AcO
AcO
AcO
O
O
O
P
O
O
P
OH
O
O
O
O
N
AcO
N
N
N
HO
HO
AcO
O
OH
AcO
O
O
PMB
PMB
5
90/120/15
70/60/60
80/120/15
71
62
78
OAc
OH
O
OAc
O
O
O
O
O
α:β = 1:1
8
α:β = 1:1
11
12
OAc
O
AcO
AcO
AcO
O
P
OH
O
O
P
O
AcO
OBn
NTCP
AcO
O
O
OBn
NTCP
O
O
OH
OH
6b
O
O
OAc
OAc
α:β = 1:20
13
14
α:β = 1:20
15
OAc
O
O
AcO
AcO
AcO
O
P
OH
O
O
O
P
AcO
OBn
AcO
O
O
OH
OH
OBn
7
OH
OAc
OAc
16
α:β = 1:20
13
α:β = 1:20
17
O
O
O
O
O
P
OH
O
P
O
HO
HO
TBSO
TBSO
TBSO
8
OH
OH
8
8
9
80/80/60
84
73
OTBS
TBSO
OTBS
6
solanesol
α:β = 2:1
α:β = 1.8:1
18
O
P
19
O
P
OH
OH
O
OH
90/120/15
21
20
22
O
O
HO
O
P
OH
O
P O
OH
N
OH
N
10
11
80/80/15
68
83
24
O
O
23
25
O
O
O
O
HO
8
AcO
P
AcO
AcO
P
OH
OH
O
8
90/120/15
OH
27
n-decanol
AcO
OAc
OAc
26
28
(continued on next page)

246
H.-W. Shih et al. / Tetrahedron Letters 53 (2012) 243–246
Table 3 (continued)
Entry Phosphate/Phosphonate
Alcohol
Conditions (°C/W/
min)
Products
Yielda
(%)
O
P
OH
O
P
OH
OH
OH
O
12
90/120/15
81
29
20
30
a
Isolated yield.
Compound was decomposed at 90 °C.
b
Supplementary data
O
O
O
P(OH)2
TBSO
TBSO
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.032.
HO
+
8
OTBS
6
18
References and notes
1. CCl3CN, py.,
μw 80 W, 90 °C, 60 min
1. (a) Lee, R. E.; Mikusova, K.; Brennan, P. J.; Besra, G. S. J. Am. Chem. Soc. 1995, 117,
11829–11832; (b) de Jong, A.; Arce, E. C.; Cheng, T. Y.; van Summeren, R. P.;
Feringa, B. L.; Dudkin, V.; Crich, D.; Matsunaga, I.; Minnaard, A. J.; Moody, D. B.
Chem. Biol. 2007, 14, 1232–1242; (c) van Summeren, R. P.; Moody, D. B.;
Feringa, B. L.; Minnaard, A. J. J. Am. Chem. Soc. 2006, 128, 4546–4547; (d)
Greimel, P.; Lapeyre, M.; Nagatsuka, Y.; Hirabayashi, Y.; Ito, Y. Bioorg. Med.
Chem. 2008, 16, 7210–7217.
2. NH4F, MeOH,
μw 120 W, 80 oC, 30 min
64% for 2 steps
2. Shih, H. W.; Chen, K. T.; Cheng, T. J.; Wong, C. H.; Cheng, W. C. Org. Lett. 2011,
13, 4600–4603.
3. (a) Warren, C. D.; Liu, I. Y.; Herscovics, A.; Jeanloz, R. W. J. Biol. Chem. 1975, 250,
8069–8078; (b) Dinev, Z.; Gannon, C. T.; Egan, C.; Watt, J. A.; McConville, M. J.;
Williams, S. J. Org. Biomol. Chem. 2007, 5, 952–959; (c) Zhou, D.; Staake, M.;
Patterson, S. E. Org. Lett. 2008, 10, 2179–2182.
O
P
OH
O
O
O
8
HO
OH
HO
4. Kalek, M.; Stawinski, J. Tetrahedron 2009, 65, 10406–10412.
5. (a) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57,
9225–9283; (b) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Mingos, D.
M. P. Chem. Soc. Rev. 1998, 27, 213–223; (c) Polshettiwar, V.; Varma, R. S. Acc.
Chem. Res. 2008, 41, 629–639; (d) Wolkenberg, S. E.; Shipe, W. D.; Lindsley, C.
W.; Guare, J. P.; Pawluczyk, J. M. Curr. Opin. Drug Discov. Devl. 2005, 8, 701–708.
6. Sim, M. M.; Kondo, H.; Wong, C. H. J. Am. Chem. Soc. 1993, 115, 2260–2267.
7. (a) Jacob, A. M.; Moody, C. J. Tetrahedron Lett. 2005, 46, 8823–8825; (b)
Lampariello, L. R.; Piras, D.; Rodriquez, M.; Taddei, M. J. Org. Chem. 2003, 68,
7893–7895.
8. (a) Cherbuliez, E.; Rabinowitz, J. Helv. Chim. Acta. 1956, 39, 1461–1467; (b)
Myers, T. C. Ann. N.Y. Acad. Sci. 1969, 159, 221–233.
9. General procedure for generation of phosphate diester and phosphonate
monoester analogues. Discover™ Focused Microwave Synthesis (CEM
31
Scheme 2. Microwave-assisted synthesis of 31.
under fluoride-mediated microwave conditions to directly gener-
ate the desired product 31 in a 64% overall yield for two steps.11
In summary, we have successfully developed a simple and
convenient method for the formation of phosphorus–oxygen bond
to prepare various glycophospholipids, phosphate diesters, and
phosphonate monoesters under the assistance of microwave
irradiation. The optimized conditions we discovered were to utilize
trichloroacetonitrile as an activating reagent and pyridine as a
solvent for the conjugation of a phosphate or phosphonate with
an alcohol. In addition, the fixed ratio of anomers in our starting
glycophosphates would directly convert to the corresponding
glycophospholipids without changing their anomeric ratio. Struc-
turally diverse functional groups, including an electron-withdraw-
ing and electron-donating moiety, can be applied in these clean
and economic microwave-assisted reactions.
Corporation) was used for focused microwave irradiations.
A vessel
containing phosphate (or phosphonate) (0.4 mmol), alkyl alcohol (0.6 mmol,
1.5 equiv), CCl3CN (2 mL) and dried pyridine (2 mL) was sealed with Teflon
septum and irradiated in microwave reactor (the microwave power, reaction
temperature and time was shown in Table 3). After cooling, the reaction
mixture was evaporated to dryness and purified by flash column
chromatography.
10. Liav, A.; Brennan, P. J. Tetrahedron Lett. 2005, 46, 2937–2939.
11. Typical
procedure
for
generation
of
D-arabinofuranosyl-1-
monophosphorylsolanesol (31). In a vessel, 18 (0.23 g, 0.4 mmol), 6 (0.46 g,
0.6 mmol, 1.5 equiv) and CCl3CN (2 mL) were added to dried pyridine (2 mL).
The tube was sealed and irradiated in microwave reactor (80 W) for 60 min at
90 °C. After cooled to rt, the reaction was evaporated to dryness and treated
with ammonium fluoride (0.15 g, 4 mmol) and methanol (4 mL), and irradiated
again in microwave reactor (120 W) for 30 min at 80 °C. The mixture after
cooling was evaporated to dryness and purified by flash column
chromatography to afford 31 (0.25 g, 64%).
Acknowledgment
12. Martin, T. J.; Dufner, G.; Kratzer, B.; Schmidt, R. R. Glycoconjugate J. 1996, 13,
547–553.
This work was supported by the National Science Council and
Academia Sinica.