Exploration of chiral Lewis acid Mg2+ catalysts in the synthesis of aryl organophosphate triesters from phosphorus oxychloride through a three-step, two-pot substitution sequence

Article abstract of DOI:10.1016/j.tetlet.2018.02.066

A variety of nucleophilic and Lewis acid catalysts were examined for use in promoting the synthesis of organophosphate triesters. Eight novel organophosphate triesters are reported here for the first time. MgSO₄ was discovered as an inexpensive catalyst capable of improving the synthesis of a variety of aryl organophosphate triesters from the readily available and low cost precursor phosphorus oxychloride in a three-step, two-pot sequence. Yields for this method improve upon the uncatalyzed method by 8–36%. Several chiral catalysts were tested, but none were able to induce enantioselectivity in the reaction.

Full text of DOI:10.1016/j.tetlet.2018.02.066

Accepted Manuscript
Exploration of Chiral Lewis Acid Mg2+ Catalysts in the Synthesis of Aryl Or-
ganophosphate Triesters from Phosphorus Oxychloride through a Three-step,
Two-pot Substitution Sequence
Emily Granger, Kasia Solomianko, Cori Young, Jeremy Erb
PII:
S0040-4039(18)30268-5
https://doi.org/10.1016/j.tetlet.2018.02.066
TETL 49751
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 January 2018
21 February 2018
23 February 2018
Please cite this article as: Granger, E., Solomianko, K., Young, C., Erb, J., Exploration of Chiral Lewis Acid
Mg2+ Catalysts in the Synthesis of Aryl Organophosphate Triesters from Phosphorus Oxychloride through a Three-
step, Two-pot Substitution Sequence, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.066
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Exploration of Chiral Lewis Acid Mg2+ Catalysts in the
Synthesis of Aryl Organophosphate Triesters from
Phosphorus Oxychloride through a Three-step, Two-pot
Substitution Sequence
Leave this area blank for abstract info.
Emily Granger; Kasia Solomianko; Cori Young; Jeremy Erb*

1
Tetrahedron Letters
Exploration of Chiral Lewis Acid Mg2+ Catalysts in the Synthesis of Aryl
Organophosphate Triesters from Phosphorus Oxychloride through a Three-step, Two-
pot Substitution Sequence
Emily Granger; Kasia Solomianko; Cori Young; Jeremy Erb*
The Integrative Science and Engineering Center, Department of Chemistry, University of Dayton, 300 College Park, Dayton, Ohio 45469-2357
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A variety of nucleophilic and Lewis acid catalysts were examined for use in
promoting the synthesis of organophosphate triesters. eight novel organophosphate
triesters are reported here for the first time. MgSO4 was discovered as an inexpensive
catalyst capable of improving the synthesis of a variety of aryl organophosphate
triesters from the readily available and low cost precursor phosphorus oxychloride in a
three-step, two-pot sequence. Yields for this method improve upon the uncatalyzed
method by 8-36%. Several chiral catalysts were tested, but none were able to induce
enantioselectivity in the reaction.
Available online
Keywords:
aryl organophosphate triester
catalysis
magnesium
Lewis acid
2009 Elsevier Ltd. All rights reserved.
1. Introduction
although stereospecific methods have been noticeably
rare.37,46,75,85–87 In general, reaction of P(V) compounds equipped
Synthetic strategies for the construction of
with labile groups with nucleophilic attachments remains a
popular method for construction of OPs.1,46,47,67,75,77,84–89 Villard et
al. used a typical non-catalytic method to synthesize phenyl
phosphorotriester derivatives in good yield (63-76%) through use
of a phosphorochloridate with a labile chlorine as a leaving
group, but needed 3 equivalents of the P(V) phosphorochloridate
organophosphates and their derivatives (OPs) are reported in the
literature, but have seen a lack of attention over the past
century.1–3 However, new synthetic efforts4–41 have created a
resurgence for the “13th” element and have found great utility in
the pharmaceutical industry and medicinal chemistry ever since
OPs were recognized as a major class of medicinal agents.42–48
This is largely due to phosphorus being a key element in nature,
and use of phosphorylation or dephosphorylation reactions has
allowed control over many life processes such as the regulation
of proteins, nucleosides (DNA and RNA), and steroids.49–61 As
such, phosphorus chemistry can be used to treat different types of
human ailments such as cancer, Hepatitis C, and AIDS.42–45,47,62–78
Nothing seems to demonstrate the importance of
organophosphate derivatives in the pharmaceutical industry more
than the wildly successful drug Sofosbuvir (also known as
Sovaldi) that has earned $10. 3 billion in 2014 for the treatment
of Hepatitis C.42,43 It represents a transformational shift in
strategy for nucleoside-based pharmaceuticals that currently treat
HIV, Hepatitus B and C, herpes, and ebola.62–64,66,68,79 Central to
the success of Sofosbuvir is the chiral organophosphate center,
which allows for the delivery of a nucleoside 5’-monophosphate
in a prodrug fashion that increases absorption and bypasses the
slow monophosphorylation step.40,80–83 Like other chiral drugs,
absolute configuration of stereochemistry (in this case at
phosphorus) has immense ramifications for drug performance.84
Figure 1. Known catalytic methods with using electrophilic
Creative efforts have been taken to improve upon the
synthetic methodology for the construction of phosphate triesters,
P(V) starting materials.

2
Tetrahedron
and 6 equivalents of N-methyl imidazole (NMI) per equivalent
contains a reactive phosphorus with three leaving groups present.
Other alternatives are outlined in the literature, but require prior
reaction and purification.1,11,16 The nucleophile of choice was
chosen to be phenol since TLC can easily monitor the reaction,
products that form from these two reagents have reported
chemical shift values in the literature98–101, it is inexpensive, it
should limit any complications from dealkylation side reactions,
and is present in many biologically active OPs already in use in
medicine.40
of the alcohol. Others report control over chirality at phosphorus,
but installation of a chiral auxiliary is the most common way to
promote
a
stereoselective process.75,86,90 Alternatively,
chromatographic enrichment can be used as a crutch since
catalytic chiral methods have been lacking.75 However, the
removal of the chiral auxiliary can be problematic and creates a
need for a catalytic method. DiRocco et al. have recently
reported the use of a chiral nucleophilic catalyst with success87
(Figure 1). Unfortunately, not only is the catalyst difficult and
expensive to synthesize (requiring separation by preparative
chiral SFC), but the work did not demonstrate the synthesis of a
P-(S) stereocenter in high yield and selectivity. Additionally,
their reported yields were not based on isolated chemical yields
Initial experiments were aimed at identifying ideal conditions
when starting from 1 and forming achiral 4a through three
sequential nucleophilic additions of phenol. We were able to
isolate triphenylphosphate 4a in 55% yield with no catalyst and
triethylamine (TEA) as a base. We tested a series of bases in the
reaction for comparison (Table 1). Interestingly, all inorganic
bases that were tested failed to produce the phosphate triester in
useful quantities. The results for organic bases were mixed, with
triethyl amine (TEA) performing the best and Proton Sponge
disappointingly producing the phosphate triester in only trace
amounts. Hunig’s base, despite a structure similar to TEA, was
lower in yield of the triester, 4a, and showed a larger quantity of
Ph2POCl (3a) and more side product by NMR. Based on these
results, TEA was used for further experiments. Though a method
exists of high yields of 4a at higher temperatures, we were more
interested in lower temperature conditions that might eventually
prove more conducive to stereospecific catalysis.102
but relied on internal calibration by H NMR (literature91 shows
1
some drastic decreases in yield between NMR yield vs. isolated
yield) or HPLC. Also notable is the requirement to prepare a
chlorophosphate starting material in a separate step because it is
not commonly commercially available, something that is all too
common in the literature. Along the same lines, Pertusati and
McGuigan promoted the formation of a phorsphoramidate
through catalysis with Cu(OTf)2 using a prefunctionalized
phosphochloridate.83 While the reaction did not proceed at all in
the absence of a catalyst, inclusion of Cu(OTf)2 was only able to
provide an isolated yield of 35% as a mixture of diastereomers.
Surprisingly, McGuigan’s work is reflective of the literature as a
whole in that only achiral Lewis acids have been tested in this
framework.92–95
Nucelophilic organocatalysts were also tested alongside TEA
as seen in Table 1. In each case, the catalyst was added before
the first nucleophilc addition to the reaction pot containing 1. We
were especially interested to see whether a catalyst could
promote the third nucleophilic step since it did not go to entirely
to completion to produce 4a (entry 1). DABCO, DMAP,
HyperBTM, and N-methyl imidazole (NMI) were all added prior
In light of these shortcomings in the literature, we
sought to develop a catalyzed enantioselective reaction using
either a Lewis acid or nucleophilic catalyst from the inexpensive
and easily accessible POCl3 that did not require excessive
equivalents of reagents. We envisioned that one, two, or three
different nucleophilic appendages can be added during the course
of three subsequent nucleophilic substitutions, thereby creating a
flexible path for organophosphate (OP) construction (Figure 2).
Table 1. Screening of bases and catalysts in model reaction.
Figure 2. General strategy for the synthesis of
organophosphate triesters.
Herein, we report a three-step, two-pot reaction sequence
catalyzed by magnesium sulfate that can generate
organophosphate triesters using three different phenolic
nucleophiles in yields 8-36% higher than the non-catalyzed
reaction. These triesters contain a stereocenter at phosphorus,
which makes our method distinct from other Lewis acid
catalyzed reactions that simply aim to transfer achiral
phosphates.92,96,97 Apart from triphenyl phosphate, we produced
eight new organophosphate triesters in this work. In order to
continue to fill in the missing gap in the literature, exploration of
chiral versions of these metal catalysts is reported.
Unfortunately, while we were able to produce the desired
phosphorus compounds in higher yields vs. the uncatalyzed
reaction, we were unable to do so enantioselectively.
2. Results and Discussion
As stated above, phosphohorus oxychloride (1) is an
obvious choice of starting material because it is simple,
inexpensive, relatively reactive, easy to purify and obtain, and

3
Table 2. Comparison of catalyzed vs. uncatalyzed yields of
OPs 4b-i.
to the nucleophilic additions at room temperature. While NMI
proved to be the best of the organocatalyst group when used in
catalytic amounts (0.1 equiv.) with a 27% yield of 4a (entry 9),
this was much lower than the 55% yield for the uncatalyzed
reaction (entry 1). The crude 31P NMR spectra collected for
entries 6-10 showed the phosphochloridate diester 3, the product
4a, and a side product peak at -25.4 ppm. We believe this side
product may be an anhydride based on literature
comparisons103,104, but unfortunately it could not be isolated nor
confirmed by comparison to reported 31P NMR chemical shift
data.
Subsequent to nucleophilic catalyst screening, Lewis acid
catalysts were examined (entries 11-21, Table 1). We had an
initial predisposition toward using magnesium salts because of
their well known role in life processes,105–109 as well as their
availability, price, and previous literature detailing coordination
of Mg2+ with chiral ligands.110,111 However, other metal cations
could be potential candidates, as evidenced with Cu2+ from
McGuigan’s work.83 Out of those tested, MgSO4 and MgCl2 gave
good results with an equal yield of 70% for each reaction (entries
12 and 13). TiO2 gave a slightly higher yield for 4a at 80%
(entry 11), but further experiments revealed that it gave similar
yields when compared to magnesium-catalyzed reactions for the
synthesis of other organophosphates. The other Lewis acids,
including copper, gave lower yields compared to the uncatalyzed
reaction. In addition to these catalysts, we used 3 equivalents of
Ag2O and Tl(PF6) to forcibly remove the chlorides from the
phosphate center. Interestingly, the silver gave results akin to
magnesium as a catalyst, while thalium did not yield an
appreciable amount of product. Addition of both a Lewis acid
and nucleophilic catalyst (MgSO4 and NMI, 0.1 equiv and 0.4
equiv. respectively) gave a 67% yield of 4a. So, when NMI is
used in excess of catalytic quantities, it can be combined with a
Mg2+ Lewis acid in a bifunctional system without much
detriment, but also without a benefit to the yield. Because of this,
NMI was omitted in subsequent reactions and MgSO4 was used
as the sole catalyst unless otherwise specified.
synthesizing phosphate triesters with three different attachments
to phosphorus. As for the choice of which nucleophiles to choose
instead of phenol, we ultimately decided that substituted phenol
derivatives would be a convenient choice since we already knew
how to interpret the chemical shift data in the phosphorus NMR
and they are easy to monitor by TLC. While these compounds are
not of significant medicinal value, they allowed for investigation
of simple P-stereogenic compounds before pursuit of complex
pharmaceuticals. Phosphate triesters 4 were also synthesized in
the absence of a catalyst for comparison. Unlike the previous
model reaction in which three equivalents of phenol were added,
Next, we turned our attention to other OPs (Figure 3 and
Table 2). We had the ultimate goal of testing the viability of our
method as an enantioselective catalytic process, so we began
Figure 3. Aryl phosphate triesters synthesized using 3 different phenols.

4
Tetrahedron
the additional complication of three different nucleophiles
observed in the 31P NMR spectrum upon addition of the soluble
magnesium salt MgI2. This supports the idea that magnesium
binds to the organophosphate and increases its electrophilicity.
We also chose to examine the effect of magnesium on other
reaction components. Addition of MgI2 to triethyl amine did not
needed to be managed. Addition of MgSO4 to a reaction of 1 with
different phenols was expected to increase the yield of other
phosphate triester derivatives 4b-i, as had been the case for the
model reaction. However, the reactions performed worse with
the catalyst at room temperature as revealed by 31P NMR, with
multiple substitutions occurring instead of the intended single
substitution per nucleophile. Therefore, MgSO4 was removed
from the first step and (PhO)POCl2 was prepared and distilled in
bulk as a preliminary step to simplify the reaction sequence.
Lowering the reaction temperature to -78 °C, adding the
nucleophile slowly in the second step over the course of 2 hours,
and letting the reaction warm up slowly overnight halted the over
addition as evidenced by 31P NMR and produced the intended
diester with few side products. MgSO4 can be added either before
the second nucleophilic addition or before the last nucleophilic
addition to give organophosphates 4b-I in increased yields.
Addition of MgSO4 at the start of the third nucleophilic addition
increased the yield of organophosphates by 8-36% as shown in
Table 2.
1
show any significant shift in its H NMR peaks. On the other
hand, addition of MgI2 to p-methoxyphenol induces several
changes in the NMR spectrum such as a downfield shift of some
aromatic hydrogen atoms by 0.11 ppm and a downfield shift of
the OH signal by nearly 2 ppm. Based on the NMR data, we
propose that magnesium is serving two functions: first, the
magnesium is coordinating to the OP and increasing its
electrophilicity; secondly, the Lewis acid is also coordinating to
the phenolic nucleophile and bringing it in closer proximity to the
electrophile. This is depicted with MgI2 in Figure 5.
I
I
Mg
Lewis acid binding
to substrate
and coordinating attack
O
P
Cl
ArOH
OPh
Cl
Now that a yield increase was seen for the synthesis of both
achiral and chiral organophosphate triesters, we turned our
attention to evaluation of chiral catalysts. Figure 4 shows
several magnesium catalysts equipped with chiral ligands.
Figure 5. Possible binding modes for magnesium.
In conclusion, we have developed a new catalytic method for
the synthesis of organophosphates. This new method uses
MgSO4 as an inexpensive catalyst and was able to synthesize 8
new aryl organophosphate triesters from the readily available and
low cost precursor phosphorus oxychloride in a three-step, two-
pot sequence. Yields for this method improve upon the
uncatalyzed method by 8-36%. Based on NMR data, we propose
that magnesium increases the electrophilic strength of
organophosphates by binding to the phosphoryl oxygen and also
brings oxygen-based nucleophiles in close proximity for reaction.
Although none of our chiral catalysts provided any
enantioselectivity, we propose that MgSO4 could be used in
tandem with chiral nucleophilic catalysts to activate
organophosphates and improve reaction yields.
Acknowledgments
We would like to thank the University of Dayton for
providing generous startup funds for this project.
References and notes
Figure 4. Chiral magnesium catalysts examined for
organophosphate synthesis.
These catalysts were added to 2 before the second nucleophilic
addition. While the chiral catalysts gave yields comparable to
those catalyzed by MgSO4, only racemic mixtures were observed
by chiral HPLC (RegisPack 5 Micron, 25cm x 4.6 mm). For
example, catalyst 9 gave a 62% yield of 4i as a racemic mixture
vs. 26% yield without magnesium. Thus, while the use of
magnesium can enhance the yield of organophosphate triesters, it
seems incapable of imparting stereochemical information.
1. Montchamp J-L, Ed. Phosphorus Chemistry I, Springer
International Publishing: Cham, 2015, vol. 360.
2. Petroianu GA. Pharm- Int J Pharm Sci. 2010; 65: 306–311.
3. Montchamp J-L, Ed. Phosphorus Chemistry II, Springer
International Publishing: Cham, 2015, vol. 361.
4. Marinozzi M, Pertusati F, Serpi M. Chem Rev. 2016; 116:
13991–14055.
5. Gavara L, Gelat F, Montchamp J-L. Tetrahedron Lett. 2013;
54: 817–820.
6. Li X-S, Han Y-P, Zhu X-Y, Li M, Wei W-X, Liang Y-M. J
Org Chem. 2017; 82: 11636–11643.
7. Ashmus RA, Lowary TL. Org Lett. 2014; 16: 2518–2521.
8. Ortial S, Montchamp J-L. Org Lett. 2011; 13: 3134–3137.
9. Abrunhosa-Thomas I, Coudray L, Montchamp J-L.
Tetrahedron. 2010; 66: 4434–4440.
10. Zhang J-Q, Chen T, Zhang J-S, Han L-B. Org Lett. 2017;
19: 4692–4695.
We hypothesized that the phosphoryl chlorides were being
activated by coordination of the metal center to the phosphoryl
oxygen. This type of activation would be expected to increase
the electrophilicity of the organophosphate towards both the
second and third nucleophilic additions, which is in agreement
with our experimental observations. An NMR experiment was
performed on a sample containing (PhO)POCl2 and MgSO4 in
CDCl3, but no change in the 31P chemical shift value was
observed indicating that the reaction may be occurring by
heterogeneous catalysis. However, when (PhO)POCl2 was
dissolved in CDCl3, a change from 4.56 ppm to 4.31 ppm was
11. McGuigan C, Derudas M, Gonczy B, Hinsinger K, Kandil
S, Pertusati F, Serpi M, Snoeck R, Andrei G, Balzarini J,

5
McHugh TD, Maitra A, Akorli E, Evangelopoulos D,
Bhakta S. Bioorg Med Chem. 2014; 22: 2816–2824.
12. Berger O, Petit C, Deal EL, Montchamp J-L. Adv Synth
Catal. 2013; 355: 1361–1373.
Subramanian GM, Hyland RH, Arterburn S, Jiang D,
McNally J, Brainard D, Symonds WT, McHutchison JG,
Sheikh AM, Younossi Z, Gane EJ. N Engl J Med. 2013;
368: 1878–1887.
13. Berger O, Montchamp J-L. Beilstein J Org Chem. 2014; 10:
732–740.
14. Montchamp J-L. Acc Chem Res. 2014; 47: 77–87.
15. Jessen HJ, Ahmed N, Hofer A. Org Biomol Chem. 2014; 12:
3526–3530.
43. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM,
Rodriguez-Torres M, Sulkowski MS, Shiffman ML, Lawitz
E, Everson G, Bennett M, Schiff E, Al-Assi MT,
Subramanian GM, An D, Lin M, McNally J, Brainard D,
Symonds WT, McHutchison JG, Patel K, Feld J, Pianko S,
Nelson DR. N Engl J Med. 2013; 368: 1867–1877.
44. Congiatu C, Brancale A, Mason MD, Jiang WG, McGuigan
C. J Med Chem. 2006; 49: 452–455.
45. Vernachio JH, Bleiman B, Bryant KD, Chamberlain S,
Hunley D, Hutchins J, Ames B, Gorovits E, Ganguly B,
Hall A, Kolykhalov A, Liu Y, Muhammad J, Raja N,
Walters CR, Wang J, Williams K, Patti JM, Henson G,
Madela K, Aljarah M, Gilles A, McGuigan C. Antimicrob
Agents Chemother. 2011; 55: 1843–1851.
16. Ma Y-N, Zhang H-Y, Yang S-D. Org Lett. 2015; 17: 2034–
2037.
17. Deal EL, Petit C, Montchamp J-L. Org Lett. 2011; 13:
3270–3273.
18. Janesko BG, Fisher HC, Bridle MJ, Montchamp J-L. J Org
Chem. 2015; 80: 10025–10032.
19. Weinschenk L, Schols D, Balzarini J, Meier C. J Med
Chem. 2015; 58: 6114–6130.
20. Meier C. Antivir Chem Chemother. 2017; 25: 69–82.
21. Rozniewska M, Stawinski J, Kraszewski A. Org Lett. 2013;
15: 4082–4085.
46. Pertusati F, McGuigan C. Chem Commun. 2015; 51: 8070–
8073.
22. Foust BJ, Poe MM, Lentini NA, Hsiao C-HC, Wiemer AJ,
Wiemer DF. ACS Med Chem Lett. 2017; 8: 914–918.
23. Richard V, Fisher HC, Montchamp J-L. Tetrahedron Lett.
2015; 56: 3197–3199.
24. Gollnest T, de Oliveira TD, Schols D, Balzarini J, Meier C.
Nat Commun. 2015; 6: 8716.
47. McGuigan C, Thiery J-C, Daverio F, Jiang WG, Davies G,
Mason M. Bioorg Med Chem. 2005; 13: 3219–3227.
48. McGuigan C, Madela K, Aljarah M, Bourdin C, Arrica M,
Barrett E, Jones S, Kolykhalov A, Bleiman B, Bryant KD,
others. J Med Chem. 2011; 54: 8632–8645.
49. Treviño LS, Wang Q, Walker CL. Prog Biophys Mol Biol.
25. Ortial S, Fisher HC, Montchamp J-L. J Org Chem. 2013;
78: 6599–6608.
26. Stawinski J, Kraszewski A. Acc Chem Res. 2002; 35: 952–
960.
2015; 118: 8–13.
50. Johnson LN, Lewis RJ. Chem Rev. 2001; 101: 2209–2242.
51. Sawicka A, Seiser C. Biochim Biophys Acta BBA - Gene
Regul Mech. 2014; 1839: 711–718.
27. Zhu Y, Chen T, Li S, Shimada S, Han L-B. J Am Chem Soc.
52. Van Rompay AR, Johansson M, Karlsson A. Pharmacol
2016; 138: 5825–5828.
Ther. 2000; 87: 189–198.
28. McGuigan C, Bourdin C, Derudas M, Hamon N, Hinsinger
K, Kandil S, Madela K, Meneghesso S, Pertusati F, Serpi M,
Slusarczyk M, Chamberlain S, Kolykhalov A, Vernachio J,
Vanpouille C, Introini A, Margolis L, Balzarini J. Eur J Med
Chem. 2013; 70: 326–340.
29. Gavara L, Petit C, Montchamp J-L. Tetrahedron Lett. 2012;
53: 5000–5003.
30. Yang J, Chen T, Han L-B. J Am Chem Soc. 2015; 137:
1782–1785.
53. Rossetto D, Avvakumov N, Côté J. Epigenetics. 2012; 7:
1098–1108.
54. Bourdais J, Biondi R, Sarfati S, Guerreiro C, Lascu I, Janin
J, Véron M. J Biol Chem. 1996; 271: 7887–7890.
55. de Oliveira PSL, Ferraz FAN, Pena DA, Pramio DT, Morais
FA, Schechtman D. Sci Signal. 2016; 9: re3–re3.
56. Wang X, Chuang H-C, Li J-P, Tan T-H. Front Immunol.
2012; 3.
57. Humphrey SJ, James DE, Mann M. Trends Endocrinol
31. Shen R, Luo B, Yang J, Zhang L, Han L-B. Chem Commun.
2016; 52: 6451–6454.
Metab. 2015; 26: 676–687.
58. Hunter T. Cell. 1995; 80: 225–236.
32. Szymańska A, Szymczak M, Boryski J, Stawiński J,
Kraszewski A, Collu G, Sanna G, Giliberti G, Loddo R,
Colla PL. Bioorg Med Chem. 2006; 14: 1924–1934.
33. Kolodziej K, Romanowska J, Stawinski J, Boryski J,
Dabrowska A, Lipniacki A, Piasek A, Kraszewski A,
Sobkowski M. Eur J Med Chem. 2015; 100: 77–88.
34. Kolodiazhnyi OI, Kolodiazhna A. Tetrahedron Asymmetry.
2017; 28: 1651–1674.
35. Kolodiazhnyi OI. Tetrahedron Asymmetry. 2005; 16: 3295–
3340.
36. Kolodiazhnyi OI, Kukhar VP, Kolodiazhna AO.
Tetrahedron Asymmetry. 2014; 25: 865–922.
37. Simmons B, Liu Z, Klapars A, Bellomo A, Silverman SM.
Org Lett. 2017; 19: 2218–2221.
38. Kolodiazhnyi OI. Tetrahedron Asymmetry. 2012; 23: 1–46.
39. Oka N, Wada T. Chem Soc Rev. 2011; 40: 5829.
40. Pradere U, Garnier-Amblard EC, Coats SJ, Amblard F,
Schinazi RF. Chem Rev. 2014; 114: 9154–9218.
41. Huchting J, Meier C. Eur J Org Chem. 2014; 2014: 3423–
3429.
42. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M,
Hassanein T, Gordon SC, Schultz M, Davis MN, Kayali Z,
Reddy KR, Jacobson IM, Kowdley KV, Nyberg L,
59. WEIGEL NL. Biochem J. 1996; 319: 657–667.
60. Marmiroli S, Fabbro D, Miyata Y, Pierobon M, Ruzzene M.
BioMed Res Int. 2015; 2015: 1–3.
61. Weigel. Nucl Recept Signal. 2007; 4.
62. Kang L, Pan J, Wu J, Hu J, Sun Q, Tang J. Viruses. 2015; 7:
4960–4977.
63. Kukhanova MK. Mol Biol. 2012; 46: 768–779.
64. De Clercq E, Li G. Clin Microbiol Rev. 2016; 29: 695–747.
65. Schlesinger E, Johengen D, Luecke E, Rothrock G,
McGowan I, van der Straten A, Desai T. Pharm Res. 2016;
33: 1649–1656.
66. De Clercq E. Rev Med Virol. 2015; 25: 254–267.
67. Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang
L, Neville S, Carra E, Lew W, Ross B, Wang Q, Wolfe L,
Jordan R, Soloveva V, Knox J, Perry J, Perron M, Stray
KM, Barauskas O, Feng JY, Xu Y, Lee G, Rheingold AL,
Ray AS, Bannister R, Strickley R, Swaminathan S, Lee WA,
Bavari S, Cihlar T, Lo MK, Warren TK, Mackman RL. J
Med Chem. 2017; 60: 1648–1661.
68. Gao J, Yin L. Drug Discov Ther. 2014; 8: 229–231.
69. Dore GJ, Cooper DA, Pozniak AL, DeJesus E, Zhong L,
Miller MD, Lu B, Cheng AK. J Infect Dis. 2004; 189:
1185–1192.

6
Tetrahedron
70. Birkus G, Bam RA, Willkom M, Frey CR, Tsai L, Stray
89. Cavalier J-F, Fotiadu F, Verger R, Buono G. Synlett. 1998;
1998: 73–75.
KM, Yant SR, Cihlar T. Antimicrob Agents Chemother.
2015; 60: 316–322.
90.
71. Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL,
Van Tongeren SA, Dong L, Retterer CJ, Eaton BP, Pegoraro
G, Honnold S, Bantia S, Kotian P, Chen X, Taubenheim
BR, Welch LS, Minning DM, Babu YS, Sheridan WP,
Bavari S. Nature. 2014; 508: 402–405.
91. Romanowska J, Szymańska-Michalak A, Boryski J,
Stawiński J, Kraszewski A, Loddo R, Sanna G, Collu G,
Secci B, Colla PL. Bioorg Med Chem. 2009; 17: 3489–
3498.
92. Jones S, Selitsianos D, Thompson KJ, Toms SM. J Org
72. Golla VM, Kurmi M, Shaik K, Singh S. J Pharm Biomed
Anal. 2016; 131: 146–155.
73. Uckun FM, Pendergrass S, Venkatachalam TK, Qazi S,
Richman D. Antimicrob Agents Chemother. 2002; 46: 3613–
3616.
Chem. 2003; 68: 5211–5216.
93. Jones S, Selitsianos D. Org Lett. 2002; 4: 3671–3673.
94. Brown RS, Neverov AA. J Chem Soc Perkin Trans 2. 2002:
1039–1049.
95. Brown RS, Neverov AA, Tsang JS, Gibson GT, Montoya-
Pelaez PJ. Can J Chem. 2004; 82: 1791–1805.
96. Liu C-Y, Pawar VD, Kao J-Q, Chen C-T. Adv Synth Catal.
2010; 352: 188–194.
97. Jones S, Selitsianos D. Org Lett. 2002; 4: 3671–3673.
98. Shakya PD, Dubey DK, Pardasani D, Palit M, Gupta AK. J
Chem Res. 2005; 2005: 821–823.
74. Venkatachalam TK, Samuel P, Uckun FM. Bioorg Med
Chem. 2005; 13: 1763–1773.
75. Rios Morales EH, Balzarini J, Meier C. J Med Chem. 2012;
55: 7245–7252.
76. Wang G, Boyle N, Chen F, Rajappan V, Fagan P, Brooks
JL, Hurd T, Leeds JM, Rajwanshi VK, Jin Y, Prhavc M,
Bruice TW, Cook PD. J Med Chem. 2004; 47: 6902–6913.
77. Pradere U, Garnier-Amblard EC, Coats SJ, Amblard F,
Schinazi RF. Chem Rev. 2014; 114: 9154–9218.
78. McGuigan C, Wang Y, Riley PA. FEBS Lett. 1995; 372:
259–263.
99. Chernyshev KA, Krivdin LB. Russ J Org Chem. 2011; 47:
355–362.
100. Pinkus AG, Waldrep PG. J Org Chem. 1966; 31: 575–581.
101. Acharya J, Gupta AK, Shakya PD, Kaushik MP.
Tetrahedron Lett. 2005; 46: 5293–5295.
79. De Clercq E. Rev Med Virol. 2015; 25: 254–267.
80. Časar Z, Ed. Synthesis of Heterocycles in Contemporary
Medicinal Chemistry, Springer International Publishing:
Cham, 2016, vol. 44.
81. Singh H, Bhatia H, Grewal N, Natt N. J Pharmacol
Pharmacother. 2014; 5: 278.
102. Kudryavtsev IY, Baulina TV, Pasechnik MP, Aisin RR,
Matveev SV, Petrovskii PV, Nifant’ev EE. Russ Chem Bull.
2013; 62: 1086–1090.
103. Ramirez F, Marecek JF. J Org Chem. 1983; 48: 847–850.
104. Muller N, Lauterbur PC, Goldenson J. J Am Chem Soc.
1956; 78: 3557–3561.
82. James E, Pertusati F, Brancale A, McGuigan C. Bioorg Med
105. Souza DO, de Meis L. J Biol Chem. 1976; 251: 6355–6359.
106. Romani AM, Maguire ME. Biometals. 2002; 15: 271–283.
107. Adams JA. Chem Rev. 2001; 101: 2271–2290.
108. Lusk JE, Williams RJP, Kennedy EP. J Biol Chem. 1968;
243: 2618–2624.
109. Cowan JA. Biometals. 2002; 15: 225–235.
110. Hatano M, Horibe T, Ishihara K. Org Lett. 2010; 12: 3502–
3505.
Chem Lett. 2017; 27: 1371–1378.
83. Pertusati F, McGuigan C. Chem Commun. 2015; 51: 8070–
8073.
84. Barth R, Rose CA, Schöne O. In Synthesis of Heterocycles
in Contemporary Medicinal Chemistry; Z. Časar, Ed.;
Springer International Publishing: Cham, 2015; Vol. 44, pp
51–88.
85. Hayakawa Y, Hyodo M, Kimura K, Kataoka M. Chem
111. Evans DA, Nelson SG. J Am Chem Soc. 1997; 119: 6452–
Commun. 2003; 0: 1704–1705.
6453.
86. Nakayama K, Thompson WJ. J Am Chem Soc. 1990; 112:
6936–6942.
87. DiRocco DA, Ji Y, Sherer EC, Klapars A, Reibarkh M,
Dropinski J, Mathew R, Maligres P, Hyde AM, Limanto J,
Brunskill A, Ruck RT, Campeau L-C, Davies IW. Science.
2017; 356: 426–430.
Supplementary Material
Supplementary data associated with this article can be found
in the online version.
88. Montchamp J-L. Acc Chem Res. 2014; 47: 77–87.

7
Highlights



Eight new aryl organophosphate triesters
were synthesized with a MgSO4 catalyst.
Yields of phosphates were improved by 8-
36% over uncatalyzed reaction.
Chiral magnesium catalysts did not produce
phosphates enantioselectively.