Catalytic Lewis acid phosphorylation with pyrophosphates

Article abstract of DOI:10.1016/j.tet.2012.08.070

We report a method for the Lewis acid catalyzed phosphorylation of alcohols with pyrophosphates. Ti(O^tBu)₄ was found to be the most effective catalyst in the phosphorylation of both primary and secondary alcohols with tetrabenzylpyrophosphate, providing conversions between 54% and >98% and isolated yields between 50% and 97%. Other pyrophosphates with orthogonal protecting groups were synthesized and screened to validate the generality of the approach. This study will describe how benzyl, methyl, ethyl, allyl, and o-nitrobenzyl pyrophosphates are all effective phosphorylating agents under Lewis acid catalysis.

Full text of DOI:10.1016/j.tet.2012.08.070

Tetrahedron 68 (2012) 9023e9028
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic Lewis acid phosphorylation with pyrophosphates
y
y
y
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*
Owen S. Fenton, Emily E. Allen , Kyle P. Pedretty , Sean D. Till , Joseph E. Todaro , Bianca R. Sculimbrene
College of the Holy Cross, Department of Chemistry, 1 College St., Worcester, MA 01610, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2012
Received in revised form 17 August 2012
Accepted 22 August 2012
Available online 30 August 2012
We report a method for the Lewis acid catalyzed phosphorylation of alcohols with pyrophosphates.
Ti(OtBu)4 was found to be the most effective catalyst in the phosphorylation of both primary and sec-
ondary alcohols with tetrabenzylpyrophosphate, providing conversions between 54% and >98% and
isolated yields between 50% and 97%. Other pyrophosphates with orthogonal protecting groups were
synthesized and screened to validate the generality of the approach. This study will describe how benzyl,
methyl, ethyl, allyl, and o-nitrobenzyl pyrophosphates are all effective phosphorylating agents under
Lewis acid catalysis.
Keywords:
Phosphorylation
Catalytic
Ó 2012 Elsevier Ltd. All rights reserved.
Phosphates
Pyrophosphates
Alcohols
1. Introduction
reaction, which removes the need for a subsequent oxidation step.
Diphenylchlorophosphate,
a common, commercially-available
Phosphate is a ubiquitous functional group found in natural
products,1 drug candidates,2 and biological messengers.3 The de-
rivatization of alcohols is the primary method for the synthesis of
phosphates. Due to the unique oxidation states of phosphorus (P),
this can be accomplished with either P(III) reagents (such as
phosphoramidites,4 phosphites5 or phosphorochloridites6) fol-
lowed by oxidation7 or P(V) reagents (such as chlorophosphates8).
In recent years, most of the attention in phosphorylation has fo-
cused on P(III) reagents, particularly the use of phosphoramidites in
the synthesis of oligonucleotides.9
phosphorylating agent, has been used with great success in the
phosphorylation of alcohols with catalytic Lewis acids12 and
nucleophiles.8b Other commercially available chlorophosphates
(i.e., dimethyl and diethyl) have only been demonstrated to work
with Lewis acids.12 Benzyl protecting groups are widely used in
phosphate chemistry, however dibenzylchlorophosphate (DBCP)
must be synthesized from dibenzylphosphite.13 In our hands, DBCP
was not a competent phosphorylating agent with nucleophilic
catalysts14 and provided inconsistent results under Lewis acid ca-
talysis, most likely due to reagent purity.
Catalytic methods for the synthesis of any functional group are
beneficial because they can increase reaction rates, reduce the
quantity of waste products, and alter the distribution of reaction
products. Catalytic reactions for the phosphorylation of alcohols are
favorable because they do not require the activation of the alcohol
(i.e., formation of an alkoxide) and/or the use of highly reactive
phosphorylating reagents that can be difficult to synthesize or
handle. Chiral variants of the catalyst can also be developed to
desymmetrize or resolve meso or racemic alcohols, respectively,
providing enantioselective syntheses of phosphorylated mole-
cules.10 Our previous work in this area focused on phosphitylation
with phosphoramidites utilizing catalytic tetrazole and an iso-
cyanate additive to facilitate catalyst turnover.11 Recently, our ef-
forts have focused on developing a catalytic P(V) phosphorylation
In searching for a phosphorylating agent that would be easy to
synthesize and purify and available with a diverse range of or-
thogonal protecting groups, we turned our attention to pyrophos-
phates. The early literature on pyrophosphates explored the
synthesis of nucleotide diphosphates and their use as phosphory-
lating agents.15 Perhaps due to their lower reactivity, pyrophos-
phates have not been used as extensively as their chlorophosphate
analogs. We hypothesized that a catalyst could overcome the lower
reactivity of pyrophosphates, and that this increased stability
would be beneficial in their synthesis and purification. Two general
methods exist for the synthesis of pyrophosphates (Scheme 1). The
first approach relies on dehydrating a phosphate diester with re-
agents, such as DCC.16 Many phosphate diesters are commercially
available or can be synthesized in one-step from methyldi-
chlorophosphate.17 The second method couples a phosphate with
a chlorophosphate liberating HCl. This reaction can be accom-
plished in one pot from the corresponding phosphite with CCl4 as
the chlorinating agent in the presence of K2CO3 and a phase
* Corresponding author. Tel.: þ1 508 793 3425; fax: þ1 508 793 3530; e-mail
address: bsculimb@holycross.edu (B.R. Sculimbrene).
y
These authors contributed equally to this study.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.070

9024
O.S. Fenton et al. / Tetrahedron 68 (2012) 9023e9028
transfer catalyst.18 As is true in the first method, many phosphites
are commercially available or can otherwise be synthesized from
phosphorus trichloride.19 Recently, Han and co-workers published
an alternative method for the synthesis of pyrophosphates via
a copper catalyzed coupling of phosphites.20 The multitude of
synthetic methods to synthesize pyrophosphates made them an
attractive target for developing a phosphorylation reaction with
orthogonal protecting groups on the phosphorylating agent.
Table 1
Catalyst screen for phosphorylation with TBPPa
Entry
Catalyst
Conversionb
1
2
3
4
5
6
None
DMAP
0%
0%
67%
94%
9%
Ti(OiPr)4
Ti(OtBu)4
Sc(OTf)3
Bi(OTf)3
0%
a
€
Reactions performed with 1.2 equiv of TBPP and 1.5 equiv of Hunig’s base at
room termperature for 16 h.
b
Conversions obtained from integrations of 1H NMR of crude rxns.
Scheme 1. Synthesis of pyrophosphates.
in 80e88% yield (Table 2). In the absence of catalyst, all of the
secondary alcohols tested provided exclusively recovered starting
material by 1H and 31P NMR. Phenolic alcohols were also phos-
phorylated under these conditions though in lower yield (Table 2,
entry 5). Phosphorylation of primary alcohols with TBPP resulted in
26% conversion without catalyst and 98% conversion with 10 mol %
Ti(OtBu)4 (Table 2, entry 6). We attribute this to the higher innate
reactivity of primary alcohols in phosphorylation reactions.24 Un-
fortunately, we found tertiary alcohols did not perform well under
our reaction conditions. Butylcyclohexanol and 2-methyl-3-butyn-
2-ol did not generate high yields of phosphorylated product at
room temperature (negligible product detected by NMR and 26%
isolated yield, respectively). When these reactions were heated to
reflux in CH2Cl2, the reaction was accompanied by contaminant
phosphorylation of tert-butanol derived from ligand exchange with
the catalyst.
We were also interested to see if more functionalized alcohols
would be amendable to phosphorylation with Ti(OtBu)4. Boc-
protected amines, methyl esters and alkenes were all compatible
with the reactions conditions (Table 2, entries 7e10). The mono-
phosphorylation of a diol was readily achieved resulting in phos-
phate 7 in >98% conversion and 93% isolated yield. It should be
noted that no diphosphorylated product was isolated even when
2 equiv of pyrophosphate was used.25 The side chain hydroxyl of
the protected amino acids Serine and Tyrosine was phosphorylated
to generate 8 and 9 in 71% and 50% yield, respectively. Allylic al-
cohols were also suitable substrates, as was demonstrated by the
phosphorylation of geraniol in 86% yield (Table 2, entry 10).
We recognized an important aspect of this method was its use in
the synthesis of phosphorylated alcohols with diverse protecting
groups on the phosphate. Methyl phosphates have been selectively
deprotected in the presence of other alkyl and aryl groups on
phosphate with 1 M TMSOTfethioanisole in TFA.26 Under carefully
monitored conditions, ethyl phosphonates have been selectively
mono-deprotected under acidic and basic conditions.27 To study
these alkyl protecting groups, tetramethylpyrophosphate (TMPP)
and tetraethylpyrophosphate (TEPP) were synthesized from the
corresponding phosphite (Fig. 1).18 Phosphorylation of 2-dodecanol
with TMPP and 10 mol % Ti(OtBu)4 resulted in 91% isolated yield,
however conversion could not be obtained due to overlap in the 1H
NMR of 2-dodecanol and the product (Table 3, entry 1). Phosphor-
ylation with TEPP resulted in lower conversions and yields (Table 3,
entry 2), presumably due to the increased steric-bulk around the
electrophilic center. The allyl group has been used extensively as an
orthogonal protecting group for phosphate in nucleic acid and
peptide synthesis.28 To our knowledge, tetraallylpyrophosphate
(TAPP) was a new compound that had not been previously used as
a phosphorylating agent (Fig. 1). TAPP was synthesized via both
2. Results and discussion
Our pyrophosphate study began with tetrabenzylpyr-
ophosphate (TBPP, Fig. 1), a well-known compound first reported in
the 1940s.8c,21a Most examples of TBPP as a phosphorylating agent
rely on conversion of the alcohol substrate to an alkoxide.22 One
encouraging report used the chelation of a full equivalent of silver
oxide and a diol for the monophosphorylation of this diol with
TBPP.23 This stoichiometric reaction suggested to us the possibility
of utilizing catalytic Lewis acids with appropriate catalyst turnover.
We began our study by screening the phosphorylation of
2-dodecanol under a variety of catalytic conditions with TBPP
(Table 1). When no catalyst is added the reaction yields no product
as detected by 1H and 31P NMR (Table 1, entry 1). When 10 mol %
DMAP was used there was also no conversion to product; only
recovered starting material was isolated (Table 1, entry 2). Titanium
Lewis acids, which have previously been reported with chlor-
ophosphates,12 yielded 67% and 94% conversion to 1 with Ti(OiPr)4
and Ti(OtBu)4, respectively (Table 1, entry 3e4). The use of the
more common Ti(OiPr)4 resulted in lower yields due to competitive
phosphorylation of isopropanol formed during ligand exchange.
When other Lewis acids were examined, only trace amounts of
product or no product was observed (Table 1, entries 5e6).
Upon identifying a competent catalyst for phosphorylation with
TBPP, our attention then turned to screening other alcohols to de-
termine the generality of the phosphorylation method. When dif-
ferent secondary alcohols were treated with 10 mol % of Ti(OtBu)4,
€
TBPP and Hunig’s Base (as an acid scavenger), phosphorylated
products (1e4) were observed in 86e95% conversion and isolated
Fig. 1. Structure of pyrophosphates explored in this study.

O.S. Fenton et al. / Tetrahedron 68 (2012) 9023e9028
9025
Table 2
Phosphorylation of primary and secondary alcohols with TBPPa
Table 3
Phosphorylation with orthogonally protected pyrophosphates
Entry
1
Product
Conversionb
94%
Isolated yield
88%
Entry
1
Product
Conversionc
NAd
Isolated yield
91%a
49%a
84%a
2
3
90%
86%
86%
80%
2
3
54%
86%
4
95%
NAc
4
95%
92%b
5
6
NAd
54%
97%
a
€
Reactions performed with 1.5 equiv of pyrophosphate and 1.8 equiv of Hunig’s
base at room temperature for 16 h.
b
€
Reactions performed with 1.2 equiv of pyrophosphate and 1.5 equiv of Hunig’s
base at room temperature for 16 h.
98%
c
Conversions obtained from integrations of 1H NMR of crude rxns.
d
Conversion could not be obtained due to overlap in 1H NMR resonance.
7
8
>98%
93%
50%
as phosphate protecting groups that are removed under photoly-
sis.29 Since light is the only reagent necessary for the deprotection,
this type of ‘caging group’ has witnessed great success in blocking
biologically active molecules, such as phosphopeptides, and pro-
teins, nucleic acids, and small molecule messengers.30 In these
studies, the caged phosphate is released at specific times in cellular
or biochemical experiments. To our knowledge, tetra-o-nitro-
benzylpyrophosphate (TNPP) was also a new compound that we
attempted to synthesize via both pyrophosphate methods (Fig. 1). In
our hands, only the dehydration of di-o-nitrobenzylphosphate
resulted in good yields of TNPP. Once again, this new pyrophosphate
was successful in the phosphorylation of 2-dodecanol in the pres-
ence of 10 mol % catalyst yielding 95% conversion and 92% isolated
yield of the caged phosphorylated alcohol.
54%
9
77%
94%
71%
3. Conclusions
10
86%
This study has demonstrated that pyrophosphates are versatile
phosphorylating agents when combined with titanium Lewis acids.
Both primary and secondary alcohols were phosphorylated in good
conversions and yields using pyrophosphates protected with ben-
zyl, methyl, ethyl, allyl, and o-nitrobenzyl groups. Catalytic Lewis
acids facilitated the use of the less reactive but more robust pyro-
phosphates to serve as competent phosphorylating agents. All py-
rophosphates screened to date have been successful
phosphorylating agents under the conditions described. We will
continue to develop other pyrophosphates and screen catalysts
capable of performing this important transformation.
a
€
Reactions performed with 1.2 equiv of TBPP and 1.5 equiv of Hunig’s base at
room temperature for 16 h.
b
Obtained from 1H NMR of crude rxns.
c
From NMR analysis, product slowly decomposes during column chromatogra-
phy to styrene and dibenzyl phosphate.
d
Conversion could not be obtained due to overlap in 1H NMR resonance.
methods discussed in Scheme 1 and was used in the phosphoryla-
tion of 2-dodecanol with 10 mol % Ti(OtBu)4. This resulted in 86%
conversion and 84% yield to the desired diallyl protected phosphate
(Table 3, entry 3). o-Nitrobenzyl esters have been successfully used

9026
O.S. Fenton et al. / Tetrahedron 68 (2012) 9023e9028
4. Experimental
1498, 1455, 1380, 1264, 1214; TLC Rf 0.45 (30% ethyl acetate/hex-
anes); Exact mass calcd for [C26H39O4PþH]þ requires m/z 447.2664.
4.1. General procedures
Found 447.2676 (FAB).
Proton NMR spectra were recoded on Varian 400 spectrometer.
4.2.2. Cyclohexyl dibenzyl phosphate 2. 1H NMR (CDCl3, 400 MHz)
Proton chemical shifts are reported in parts per million (
to internal tetramethylsilane (TMS, 0.0) or with the solvent
reference relative to TMS employed as the internal standard
(CDCl3, 7.26 ppm; DMSO-d6, 2.50; C6D6 7.16 ppm; D2O,
4.79). Data are reported as follows: chemical shift (multiplicity
[singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m)],
coupling constants [Hz], integration). Carbon NMR spectra were
recorded on Varian 400 (100 MHz) with complete proton
d
) relative
d
7.36e7.31 (m, 10H), 5.03 (m, 4H), 4.36 (m, 1H), 1.88 (m, 2H), 1.71
d
(m, 2H), 1.54e1.43 (m, 3H), 1.33e1.20 (m, 3H); 13C NMR (CDCl3,
100 MHz)
d
136.3 (d, J¼6.8 Hz), 128.8, 128.6, 128.1, 77.9 (d,
d
d
d
J¼6.0 Hz), 69.2 (d, J¼6.1 Hz), 33.5 (d, J¼4.6 Hz), 25.3, 23.7; 31P NMR
d
(CDCl3, 162 MHz)
d
ꢁ0.6; IR (film, cmꢁ1) 2937, 2859, 1497, 1455,
1259, 1214; TLC Rf 0.31 (30% ethyl acetate/hexanes); Exact mass
calcd for [C20H25O4PþH]þ requires m/z 361.1569. Found 361.1536
(FAB).
decoupling. Carbon chemical shifts are reported in ppm (
tive to TMS with the respective solvent resonance as the internal
standard (CDCl3, 77.0). Phosphorus NMR spectra were recorded
on a Varian 400 (162 MHz) spectrometer with complete proton
decoupling. Phosphorus chemical shifts are reported in ppm (
d) rela-
4.2.3. 2-(4-Phenylbutyl) dibenzyl phosphate 3. 1H NMR (CDCl3,
400 MHz) d 7.37e7.31 (m, 10H), 7.28e7.13 (m, 5H), 5.05 (m, 4H),
4.55 (m, 1H), 2.66 (m, 2H), 1.96 (m, 1H), 1.81 (m, 1H), 1.35 (d,
d
d
)
J¼6.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 141.2, 135.9 (d,
relative to an 85% H3PO4 external standard. NMR data were col-
lected at 25 ꢀC, unless otherwise indicated. Infrared spectra were
obtained on a Perkin Elmer SpectrumOne FTIR spectrometer with
a universal ATR sampling accessory. Analytical thin-layer chro-
J¼8.4 Hz), 128.4, 128.3 (d, J¼3.1 Hz), 128.2, 127.7, 125.8, 75.8 (d,
J¼6.1 Hz), 69.0 (d, J¼2.3 Hz), 68.9 (d, J¼3.1 Hz), 39.0 (d, J¼6.8 Hz),
31.3, 21.4 (d, J¼2.3 Hz); 31P NMR (CDCl3, 162 MHz)
d
ꢁ0.4; IR (film,
cmꢁ1) 3030, 2931, 1497, 1455, 1381, 1263; TLC Rf 0.33 (50% ether/
petroleum ether); Exact mass calcd for [C24H27O4PþH]þ requires m/
z 411.1725. Found 411.1757 (FAB).
ꢀ
matography (TLC) was performed using Silica Gel 60 A F254
precoated plates (0.25 mm thickness). TLC Rf values are reported.
Visualization was accomplished by irradiation with a UV lamp
and/or staining with cerium ammonium molybdenate (CAM) so-
4.2.4. sec-Phenethyl dibenzyl phosphate 4. 1H NMR (CDCl3,
lution. Flash column chromatography was performed using Silica
400 MHz) d 7.35e7.27 (m, 13H), 7.19 (m, 2H), 5.49 (m, 1H), 4.98 (m,
m).31 High-resolution mass spectra were obtained
2H), 4.86 (d, J¼7.6 Hz, 2H), 1.59 (d, J¼6.6 Hz, 3H); 13C NMR (CDCl3,
ꢀ
Gel 60 A (40
m
at the Mass Spectrometry Facility at the University of Massachu-
setts at Amherst (Amherst, MA) or University of Illinois at Urbana
Champaign (Urbana, IL). The method of ionization is given in
parentheses. All reactions were carried out under a nitrogen at-
mosphere employing oven- and/or flame-dried glassware at room
temperature unless otherwise stated. All solvents were obtained
from a MBraun solvent purification system (MB-SPS). 2-((tert-
Butoxycarbonyl)amino)-2-ethyl-1,3-propanediol was synthesized
100 MHz)
d
141.2 (d, J¼2.3 Hz), 135.6 (d, J¼3.0 Hz), 135.5 (d,
J¼3.0 Hz), 128.3, 128.3, 128.2, 128.2, 128.1, 128.0, 127.6, 127.5, 125.7,
76.9, 76.5, 68.8, 68.8, 68.7, 23.9 (d, J¼5.3 Hz); 31P NMR (CDCl3,
162 MHz)
d
ꢁ0.6; IR (film, cmꢁ1) 3033, 1497, 1455, 1378, 1265, 1212;
TLC Rf 0.32 (30% ethyl acetate/hexanes); Exact mass calcd for
[C22H23O4PþH]þ requires m/z 383.1412. Found 383.1441 (FAB).
4.2.5. 2-Naphthyl dibenzyl phosphate 5. 1H NMR (CDCl3, 400 MHz)
following
a
literature procedure.32 Tetrabenzylpyrophosphate
d
7.81 (dd, J¼7.8 Hz, J¼1.2 Hz, 1H), 7.78 (d, J¼9.0 Hz, 1H), 7.71 (dd,
(TBPP) was synthesized following a modified literature procedure
from dibenzyl phosphate16 or dibenzylphosphite.18 Tetrae-
thylpyrophosphate (TEPP) and Tetramethylpyrophosphate (TMPP)
were synthesized from the corresponding phosphite.18 All other
chemicals were obtained from Aldrich and used without further
purification.
J¼7.8 Hz, J¼1.3 Hz, 1H), 7.57 (observed s, 1H), 7.46 (dquintets,
J¼7.6 Hz, J¼1.9 Hz, 2H), 7.33 (m, 10H), 7.28 (ddd, J¼8.9 Hz,
J¼2.5 Hz, J¼0.7 Hz, 1H) 5.16 (d, J¼8.3 Hz, 4H); 13C NMR (CDCl3,
100 MHz)
d
148.1 (d, J¼7.2 Hz), 135.5, 135.4, 138.8 (d, J¼0.8 Hz),
130.9 (d, J¼0.8 Hz), 129.8, 128.7, 128.6, 128.1 (2C), 127.7, 127.6,
126.7, 125.5, 70.1 (d, J¼5.5 Hz); 31P NMR (CDCl3, 162 MHz)
d
ꢁ6.1;
IR (film, cmꢁ1) 3034, 1632, 1599, 1510, 1497, 1464, 1456, 1381,
1279, 1244; TLC Rf 0.36 (30% ethyl acetate/hexanes); Exact mass
calcd for [C24H21O4PþH]þ requires m/z 405.1256. Found 405.1210
(FAB).
4.2. General procedure for the phosphorylation of alcohols
with TBPP
The alcohol (0.49 mmol) was dissolved in 1.0 mL of CH2Cl2. N,N-
Diisopropylethylamine (0.130 mL, 0.746 mmol) was added to the
solution, followed by tetrabenzylpyrophosphate (0.320 g,
4.2.6. 4-Phenylbutyl dibenzyl phosphate 6. 1H NMR (CDCl3,
400 MHz)
d
7.33 (m, 10H), 7.29e7.12 (m, 5H), 5.03 (m, 4H), 4.00 (m,
141.7,
0.594 mmol). Ti(OtBu)4 (19
mL, 0.049 mmol, 10 mol %) was added
2H), 2.59 (m, 2H), 1.64 (m, 4H); 13C NMR (CDCl3, 100 MHz)
d
and the reaction was stirred for 16 h at room temperature. The
solution was then vacuum filtered through a 20:1 Silica/MgSO4
plug and washed with 50 mL of 1:1 EtOAc/petroleum ether. The
filtrate was concentrated under reduced pressure and a crude NMR
was obtained for conversion. The crude product was purified using
silica gel chromatography. See Table 2 for conversion and yield
data.
135.7 (d, J¼6.9 Hz), 128.4, 128.3, 128.2 (d, J¼5.3 Hz), 127.8, 125.7,
69.0 (d, J¼5.4 Hz), 67.5 (d, J¼6.1 Hz), 35.1, 29.5, 29.4, 27.0; 31P NMR
(CDCl3, 162 MHz) d
0.3; IR (film, cmꢁ1) 3029, 2942,1496, 1454,1380,
1275; TLC Rf 0.27 (50% ether/petroleum ether); Exact mass calcd for
[C24H27O4PþH]þ requires m/z 411.1725. Found 411.1686 (FAB).
4.2.7. 2-(tert-Butoxycarbonyl)amino-2-ethyl-3-hydroxylpropyl di-
benzyl phosphate 7. 1H NMR (CDCl3, 400 MHz)
d 7.41e7.31 (m, 10H),
4.2.1. 2-Dodecyl dibenzyl phosphate 1. 1H NMR (CDCl3, 400 MHz)
5.05 (dd, J¼8.6 Hz, J¼2.4 Hz, 4H), 4.73 (s, NH), 4.10 (m, 2H), 3.54 (s,
d
7.35e7.33 (m, 10H), 5.03 (m, 4H), 4.50 (m, 1H), 1.61 (m, 1H), 1.48
2H), 1.75 (m, 1H), 1.47 (m, 1H), 1.42 (s, 9H), 0.81 (t, J¼7.4, 3H); 13C
(m,1H),1.37e1.23 (m,19H), 0.88 (t, J¼6.88 Hz, 3H); 13C NMR (CDCl3,
NMR (CDCl3, 100 MHz)
d
155.6, 135.5 (d, J¼3.9 Hz), 128.7, 128.6,
100 MHz)
d
139.5, 136.0, 136.0, 135.9, 128.7, 128.5, 128.3, 127.7, 127.7,
128.0, 79.8, 69.6 (d, J¼6.0 Hz), 67.9 (d, J¼6.0 Hz), 64.1, 58.9 (d,
122.2, 118.9, 76.7 (d, J¼6.1 Hz), 68.9 (d, J¼6.1 Hz), 37.4 (d, J¼3.1 Hz),
J¼6.4 Hz), 28.3, 24.4, 7.3; 31P NMR (CDCl3, 162 MHz)
d 0.2; IR (film,
31.9, 29.6, 29.5, 29.5, 29.3, 29.3, 25.1, 22.6, 21.5 (d, J¼3.1 Hz) 14.1; 31
P
cmꢁ1) 3417, 3314, 2971, 1712, 1497, 1456, 1391, 1366, 1247; TLC Rf
NMR (CDCl3, 162 MHz)
d
ꢁ0.5; IR (film, cmꢁ1) 2924, 2854, 1597,
0.29 (30% ethyl acetate/30% methylene chloride/40% toluene);

O.S. Fenton et al. / Tetrahedron 68 (2012) 9023e9028
9027
Exact mass calcd for [C24H34NO7PþH]þ requires m/z 480.2151.
J¼6.0 Hz), 63.4 (d, J¼2.8 Hz), 63.3 (d, J¼2.8 Hz), 37.4 (d, J¼6.4 Hz),
31.8, 29.6, 29.5, 29.4, 29.3, 29.2, 25.1, 22.6, 21.5 (d, J¼3.2 Hz), 16.1 (d,
Found 480.2145 (ESI).
J¼2.4 Hz), 16.0 (d, J¼2.4 Hz), 14.1; 31P NMR (CDCl3, 162 MHz)
ꢁ1.6;
d
4.2.8. (s)-Boc-Tyr(dibenzylphosphate)-methyl ester 8. 1H NMR
IR (film, cmꢁ1) 2924, 2854, 1466, 1380, 1262; TLC Rf 0.26 (30%
ethyl acetate/hexanes); Exact mass calcd for [C16H35O4PþH]þ re-
quires m/z 323.2351. Found 323.2366 (FAB).
(CDCl3, 400 MHz)
d 7.36e7.31 (m, 10H), 7.06 (m, 4H), 5.12 (dd,
J¼2.1 Hz, J,¼6.3 Hz, 4H), 4.97 (d, J¼8.2 Hz, 1H), 4.56 (m, 1H), 3.70 (s,
3H), 3.08 (dd, J¼12.5 Hz, J¼4.7 Hz, 1H), 3.01 (dd, J¼14 Hz, J¼6 Hz,
1H), 1.43 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d
172.1, 155.0, 149.6 (d,
4.4. Procedure for the phosphorylation of 2-dodecanol with
TAPP
J¼7.5 Hz), 135.4 (d, J¼5.2 Hz), 132.9, 130.5 (d, J¼24.3 Hz), 128.8 (d,
J¼3.2 Hz), 128.4 (d, J¼6.8 Hz), 128.1 (d, J¼29.6 Hz), 120.1 (d,
J¼29.1 Hz), 80.0, 69.9 (d, J¼5.6 Hz), 54.3, 52.3 (d, J¼19.5 Hz), 37.5,
Tetraallylpyrophosphate (TAPP) was synthesized according to the
following modified literature procedure and used directly in phos-
phorylation reactions: Diallyl phosphate (3.56 g, 19.97 mmol,
1 equiv) was dissolved in 70 mL of CH2Cl2. N,N-Dicyclohex-
ylcarbodiimide (2.268 g, 10.99 mmol, 0.55 equiv) was then added
and the reaction stirred for 4 h (dicyclohexylurea immediately be-
gins to precipitate). The reaction mixture was then vacuum filtered
to remove the dicyclohexylurea and the filtrate concentrated under
reduced pressure. The crude product was resuspended in 40 mL
ether, and submitted to a second vacuum filtration to remove any
residual DCC and Urea. The filtrate was concentrated under reduced
pressure to yield 3.362 g (99.5% yield) of tetraallylpyrophosphate.
Tetraallylpyrophosphate (0.254 g, 0.751 mmol, 1.5 equiv) was
then dissolved in 1 mL CH2Cl2. To this flask was added 2-dodecanol
28.3 (d, J¼17.6 Hz); 31P NMR (CDCl3, 162 MHz)
d
ꢁ6.3; IR (film,
cmꢁ1) 2976, 1747, 1712, 1507, 1456, 1366, 1250; TLC Rf 0.24
(65% ether/hexanes); Exact mass calcd for [C29H34NO8PþH]þ re-
quires m/z 556.2100. Found 556.2106 (ESI).
4.2.9. (s)-Boc-Ser(dibenzylphosphate)-methyl ester 9. 1H NMR
(CDCl3, 400 MHz)
d
7.37e7.32 (m, 10H), 5.42 (d, J¼8.2 Hz, 1H), 5.03
(d, J¼8.2 Hz, 2H), 5.01 (dd, J¼2.3 Hz, J¼8.2 Hz, 2H), 4.48 (m, 1H),
4.40 (m, 1H), 4.21 (m, 1H), 3.71 (s, 3H), 1.44 (s, 9H); 13C NMR (CDCl3,
100 MHz)
d
169.7, 155.2, 135.5, 128.8 (d, J¼2.5 Hz), 128.5 (d,
J¼5.2 Hz), 128.2, 127.8, 80.3, 69.6, 67.5 53.9, 52.7 (d, J¼21.9 Hz), 28.3
(d, J¼20.0 Hz); 31P NMR (CDCl3, 162 MHz)
d
ꢁ1.1; IR (film, cmꢁ1
)
3275, 3035, 2982, 2930, 2850, 1732, 1700, 1531, 1456, 1366; TLC Rf
0.32 (20% ethyl acetate/30% methylene chloride/50% toluene); Ex-
act mass calcd for [C23H30NO8PþH]þ requires m/z 480.1787. Found
480.1787 (ESI).
(110
m
L, 0.489 mmol), N,N-diisopropylethylamine (160
mL,
0.919 mmol, 1.9 equiv) and lastly Ti(OtBu)4 (19
mL, 0.05 mmol,
10 mol %). After 18 h, the reaction was vacuum filtered through
a 20:1 Silica/MgSO4 plug and washed with 50 mL of 1:1 EtOAc/
petroleum ether. The filtrate was concentrated under reduced
pressure and a crude NMR was obtained for conversion. The crude
product was purified using silica gel chromatography to yield
142 mg (84% yield) of 2-dodecanol diallyl phosphate as a viscous
oil.
4.2.10. Geranyl dibenzylphosphate 10. 1H NMR (CDCl3, 400 MHz)
d
7.35 (m, 10H), 5.34 (m, 1H), 5.04 (m, 1H), 5.03 (d, J¼7.9 Hz, 4H),
4.54 (t, J¼7.4 Hz, 2H), 2.04 (m, 4H), 1.67 (s, 3H), 1.64 (s, 3H), 1.59 (s,
3H); 13C NMR (CDCl3, 100 MHz)
d
142.9, 135.9 (d, J¼5.0 Hz), 131.9,
128.7 (d, J¼9.6 Hz), 128.3 (d, J¼10.3 Hz), 128.0, 127.7, 123.8, 123.4,
118.7 (d, J¼6.3 Hz), 118.5 (d, J¼6.8 Hz), 69.1 (d, J¼5.6 Hz), 64.4 (d,
J¼5.6 Hz), 39.4, 26.2; 31P NMR (CDCl3, 162 MHz)
d
ꢁ0.6; IR (film,
4.4.1. 2-Dodecyl diallyl phosphate 13. 1H NMR (CDCl3, 400 MHz)
cmꢁ1) 3034, 2920, 1669, 1498, 1455; TLC Rf 0.23 (40% ethyl ether/
pentane); Exact mass calcd for [C24H31O4PþH]þ requires m/z
415.2038. Found 415.2050 (ESI).
d
5.94 (m, 2H), 5.37 (dq, J¼1.5 Hz, J¼17.2 Hz, 2H), 5.24 (dq, J¼1.4 Hz,
J¼10.4 Hz, 2H), 4.51 (m, 5H),1.65 (m,1H),1.52 (m,1H),1.41e1.26 (m,
19H), 0.88 (t, J¼6.85 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 132.6 (d,
J¼7.6 Hz), 117.9 (d, J¼2.0 Hz), 76.5 (d, J¼6.4 Hz), 67.8 (d, J¼4.4 Hz),
4.3. Procedure for the phosphorylation of 2-dodecanol with
TMPP and TEPP
37.4 (d, J¼6.0 Hz), 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 25.1, 22.7, 21.5 (d,
J¼3.2 Hz), 14.1; 31P NMR (CDCl3, 162 MHz)
d
ꢁ1.5; IR (film, cmꢁ1
)
2926, 2854, 1461, 1425, 1381, 1266; TLC Rf 0.28 (20% ethyl acetate/
hexanes); Exact mass calcd for [C18H35O4PþH]þ requires m/z
347.2351. Found 347.2358 (FAB).
The pyrophosphate (0.734 mmol,1.5 equiv) was dissolved in 1 mL
CH2Cl2. To this flask was added 2-dodecanol (110
N,N-diisopropylethylamine (157 L, 0.901 mmol,1.8 equiv) and lastly
Ti(OtBu)4 (19
L, 0.05 mmol, 10 mol %). After 18 h, the reaction was
mL, 0.489 mmol),
m
m
4.5. Procedure for the phosphorylation of 2-dodecanol with
TNPP
vacuum filtered through a 20:1 Silica/MgSO4 plug and washed with
50 mL of 1:1 EtOAc/petroleum ether. The filtrate was concentrated
under reduced pressure and a crude NMR was obtained for con-
version. The crude product was purified using silica gel chroma-
tography to yield 0.131 g (91% yield) of 2-dodecyl dimethyl
phosphate and 0.077 g (49% yield) of 2-dodecyl diethyl phosphate.
Tetra-o-nitrobenzylpyrophosphate (TNPP) was synthesized
according to the following modified literature procedure and used
directly in phosphorylation reactions: di-o-nitrobenzylphosphate17
(1.00 g, 2.72 mmol) was dissolved in 20 ml of CH2Cl2. N,N0-Dicy-
clohexylcarbodiimide (0.340 mg, 1.65 mmol, 0.6 equiv) was added
to the solution and the reaction was heated to reflux. After 4 h the
reaction was cooled to room temperature and then cooled
to ꢁ20 ꢀC to ensure complete precipitation of the N,N-dicyclohex-
ylurea by-product. The precipitate was removed by vacuum filtra-
tion and the filtrate was concentrated under reduced pressure to
yield 0.860 g (88% yield) of tetra-o-nitrobenzylpyrophosphate.
4.3.1. 2-Dodecyl dimethyl phosphate 11. 1H NMR (CDCl3, 400 MHz)
d
4.49 (m, 1H), 3.77 (d, J¼2.8 Hz, 3H), 3.74 (d, J¼2.9 Hz, 3H), 1.65
(m, 1H), 1.53 (m, 1H), 1.40e1.26 (m, 19H), 0.88 (t, J¼6.85 Hz, 3H); 13
C
NMR (CDCl3, 100 MHz)
d
76.4 (d, J¼6.6 Hz), 54.0 (d, J¼3.6 Hz), 53.9
(d, J¼3.7 Hz), 37.4 (d, J¼5.9 Hz), 31.9, 29.6, 29.5, 29.4, 29.3, 29.3, 25.1,
22.6, 21.5 (d, J¼3.0 Hz), 14.1; 31P NMR (CDCl3, 162 MHz)
d 0.5; IR
(film, cmꢁ1) 2924, 2854, 1466, 1381, 1267; TLC Rf 0.26 (35%
ethyl acetate/hexanes); Exact mass calcd for [C14H31O4PþH]þ re-
quires m/z 295.2038. Found 295.2034 (FAB).
2-dodecanol (110
CH2Cl2. N,N-Diisopropylethylamine (130
di-o-nitrobenzyl pyrophosphate (427 mg, 0.594 mmol, 1.2 equiv)
and lastly Ti(OtBu)4 (19
L, 0.05 mmol, 10 mol %) was added to the
mL, 0.489 mmol) was dissolved in 1 ml of
m
L, 0.797 mmol, 1.5 equiv),
m
4.3.2. 2-Dodecyl diethyl phosphate 12. 1H NMR (CDCl3, 400 MHz)
reaction flask. After 18 h, the reaction was concentrated under re-
duced pressure and a crude NMR was obtained for conversion. The
crude product was purified with silica gel chromatography eluting
d
4.48 (m, 1H), 4.10 (m, 4H), 1.64 (m, 1H), 1.51 (m, 1H), 1.40e1.26 (m,
25H), 0.88 (t, J¼6.55 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 76.0 (d,

9028
O.S. Fenton et al. / Tetrahedron 68 (2012) 9023e9028
Nature 1945, 156, 604; (d) Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J. Chem.
Soc. 1945, 382e385.
with 30% ethyl acetate/hexane to yield 240 mg (92% yield) of
2-dodecyl di-o-nitrobenzylphosphate as a viscous oil.
9. Beaucage, S. L.; Iyer, R. P. Tetrahedron 1992, 48, 2223e2311.
8a
10. (a) Refs.
and.8b (b) Jordan, P. A.; Miller, S. J. Angew. Chem., Int. Ed. 2012, 51,
4.5.1. 2-Dodecyl di-o-nitrobenzylphosphate 14. 1H NMR (CDCl3,
2907e2911; (c) Jordan, P. A.; Kayser-Bricker, K. J.; Miller, S. J. Proc. Natl. Acad. Sci.
U.S.A. 2010, 107, 20620e20624; (d) Sculimbrene, B. R.; Xu, Y.; Miller, S. J. J. Am.
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400 MHz)
d
8.15 (d, J¼7.99 Hz, 2H), 7.81 (d, J¼7.99 Hz, 2H), 7.70 (dt,
J¼7.56 Hz, J¼1.60 Hz, 2H), 7.52 (t, J¼7.56 Hz, 2H), 5.55 (dd,
J¼2.80 Hz, 7.19 Hz, 4H), 4.65 (m, 1H) 1.67 (m, 1H), 1.56 (m, 1H),
1.41e1.23 (m, 19H), 0.88 (t, J¼6.80 Hz, 3H); 13C NMR (CDCl3,
11. Brady, P. B.; Morris, E. M.; Fenton, O. S.; Sculimbrene, B. R. Tetrahedron Lett.
2009, 50, 975e978.
12. Jones, S.; Selitsianos, D.; Thompson, K. J.; Toms, S. M. J. Org. Chem. 2003, 68,
5211e5216.
13. Acharya, J.; Gupta, A. K.; Shakya, P. D.; Kaushik, M. P. Tetrahedron Lett. 2005, 46,
5293e5295 and references therein.
14. This is due to nucleophilic attack on carbon instead of phosphorus, see: (a)
Modro, T. A.; Moorhoff, C. M. J. Phys. Org. Chem. 1989, 2, 263e270; (b) Zervas, L.;
Dilaris, I. J. Chem. Soc. 1954, 77, 5354e5357; (c) Kim, U. T.; Hajdu, J. J. Chem. Soc.,
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15. Clark, V. M.; Kirby, G. W.; Todd, A. J. Chem. Soc. 1957, 1497e1501.
16. (a) Nelson, T. D.; Rosen, J. D.; Bhupathy, M.; McNamara, J.; Sowa, M. J.; Rush, C.;
Crocker, L. S. Org. Synth. 2003, 80, 219e223; (b) Khorana, H. G.; Todd, A. R. J.
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100 MHz)
d
146.4, 134.1 (d, J¼2.3 Hz), 132.5 (d, J¼8.4 Hz), 128.7 (d,
J¼2.3 Hz), 128.1 (d, J¼5.3 Hz), 124.9, 77.6 (d, J¼6.0 Hz), 65.8, 65.8,
65.7, 37.3 (d, J¼6.0 Hz), 31.8, 29.5, 29.5, 29.4, 29.3, 29.2, 25.1, 22.6,
21.6, (d, J¼3.1 Hz) 14.1; 31P NMR (CDCl3, 162 MHz)
d
ꢁ1.1; IR (film,
cmꢁ1) 2924, 2854, 1614, 1579, 1524, 1448, 1340, 1271; TLC Rf 0.46
(50% ethyl ether/toluene); Exact mass calcd for [C26H37N2O8PþH]þ
requires m/z 537.2366. Found 537.2399 (FAB).
17. Rubinstein, M.; Patchornik, A. Tetrahedron 1975, 31, 2107e2110.
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Acknowledgements
This work was supported by the Camille and Henry Dreyfus
Foundation (New Faculty Award to B.R.S. and a Jean Dreyfus Bois-
sevain Summer Undergraduate Fellowship to O.S.F.).
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.08.070.
23. Takeda, S.; Chino, M.; Kiuchi, M.; Adachi, K.
24. Graham, S. M.; Pope, S. C. Org. Lett. 1999, 1, 733e736.
25. Future investigations will explore if this selectivity is general to other diols or
just 1,3-diols
26. Otaka, A.; Miyoshi, K.; Kaneko, M.; Tamamura, H.; Fujii, N. J. Org. Chem. 1995, 60,
3967e3974.
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