Selective phosphorylation of diols with a Lewis acid catalyst

Article abstract of DOI:10.1016/j.tetlet.2014.05.047

We report a method for the Lewis acid catalyzed phosphorylation of diols with pyrophosphates. Titanium alkoxides were found to be effective catalysts in the selective mono-phosphorylation for a range of diols. Diols of varying chain lengths and substituents were screened, to study the factors that influence mono- versus di-phosphorylation. It was discovered that 2-alkyl-2-amino-1,3-propanediols can be selectively mono-phosphorylated in up to 97% isolated yield. This structural core is mono-phosphorylated in numerous immunomodulating compounds including the FDA-approved drug, FTY720.

Full text of DOI:10.1016/j.tetlet.2014.05.047

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective phosphorylation of diols with a Lewis acid catalyst
⇑
Kyle A. Coppola, Joseph W. Testa, Emily E. Allen, Bianca R. Sculimbrene
College of the Holy Cross, Department of Chemistry, 1 College Street, Worcester, MA 01610, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a method for the Lewis acid catalyzed phosphorylation of diols with pyrophosphates. Titanium
alkoxides were found to be effective catalysts in the selective mono-phosphorylation for a range of diols.
Diols of varying chain lengths and substituents were screened, to study the factors that influence mono-
versus di-phosphorylation. It was discovered that 2-alkyl-2-amino-1,3-propanediols can be selectively
mono-phosphorylated in up to 97% isolated yield. This structural core is mono-phosphorylated in numer-
ous immunomodulating compounds including the FDA-approved drug, FTY720.
Received 18 April 2014
Revised 2 May 2014
Accepted 7 May 2014
Available online xxxx
Keywords:
Phosphorylation
Diols
FTY720
Catalytic
Ó 2014 Elsevier Ltd. All rights reserved.
The mono-functionalization of polyols has been of particular
interest to synthetic chemists due to the plethora of natural prod-
ucts and pharmaceuticals that require this transformation for their
synthesis. These reactions are often hampered by low yields due to
reactivity at multiple hydroxyl groups, yet selective strategies exist
for the acylation,1 alkylation,2 benzoylation,3 phosphorylation,4
silyation,5 and tosylation6 of polyols. These reactions rely on
enzymes,7 organocatalysts8 or reagents such as silver(I) oxide,6a
organotin compounds,3a or borinic acids6b to facilitate the modifi-
cation of one hydroxyl group in the polyol.
that the key immunomodulating compound was not the diol
FTY720, but the mono-phosphate FTY720-P, which is generated
in vivo by sphingosine kinase (see Fig. 1).10 FTY720-P is a mimic
of spingosine-1-P and acts as a high affinity agonist for four of
the five spingosine-1-phosphate G-protein coupled receptors
resulting in the sequestration of lymphocytes in secondary lym-
phoid organs.11 FTY720 was generated as a structural analogue of
myriocin, a natural product with immunosuppressive activity
10-100 times greater than Cyclosporine A.12 Researchers found
that the key structural element for the immunomodulating
response was a 2-alkyl-2-amino-1,3-propanediol. Interestingly,
FTY720 was created as a simplified analogue of myriocin lacking
any stereogenic centers, however the active drug (FTY720-P) is
chiral upon mono-phosphorylation and only the (S)-enantiomer
is medicinally relevant.13 The reported chemical syntheses of
FTY720-P generate the compound as a racemate,4a utilize chiral
HPLC for enantiomer separation,14 use enzymatic acylation in the
The discovery of FTY720 (Fingolimod, Gilenya) highlighted the
need for synthetic methods for the functionalization of diols.
FTY720 is the first orally available drug approved for the treatment
of relapse-remitting Multiple Sclerosis.9 In 2002 it was discovered
⇑
Corresponding author. Tel.: +1 (508) 793 3425; fax: +1 (508) 793 3530.
E-mail address: bsculimb@holycross.edu (B.R. Sculimbrene).
http://dx.doi.org/10.1016/j.tetlet.2014.05.047
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Coppola, K. A.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.047

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K. A. Coppola et al. / Tetrahedron Letters xxx (2014) xxx–xxx
carbon chain is increased to four or five carbons, the yield of
mono-phosphate is decreased to 64% of 3 and 65% of 4, respec-
tively, (Table 1, entries 3 and 4). This is due to an increase in
di-phosphate yield of 26% and 22%, respectively. Takeda and
co-workers reported that a similar chain length screen using an
excess of silver(I) oxide, tetrahexylammonium iodide (THAI), and
TBPP resulted in comparable yields for 2 and 3 (69% and 71%,
respectively), but decreased yields of 1 and 4 (trace and 43%,
respectively).4a
To determine if the selectivity for mono-phosphorylation of
1,3-propane diols could be increased, we examined the effect of
methyl substitutions on the three-carbon chain (see Table 2). A
single methyl substitution on carbon-2 (C-2) increases the
mono-phosphorylation yield from 71% of 2 to 84% of 5 (Table 2,
entry 1). This trend can be further exploited by addition of a second
methyl substituent, which results in the selective formation of 6 in
90% yield. Adding methyl substituents adjacent to the hydroxyl
group (C-1 and/or C-3) also had an effect on the mono-phosphory-
lation selectivity. The addition of substituents at these positions
can break the symmetry and results in hydroxyl groups of differing
reactivity (primary, secondary, or tertiary alcohols). The primary
hydroxyl group is preferred in a ratio of 4:1 over the secondary
hydroxyl in the formation of 7 (Table 2, entry 3). In the case of
secondary versus tertiary alcohols, only the secondary alcohol is
phosphorylated to deliver 8 in 85% yield. We had previously
reported that tertiary alcohols are poor substrates for phosphoryla-
tion using Ti(OtBu)4, as witnessed by the low yield of 9.
Figure 1. FTY720, FTY720-P, and structurally related immuno modulating natural
products.
desymmetrization of the diol,15 or use a Sharpless asymmetric
epoxidation followed by functional group interconversions.16 We
sought a method for the direct phosphorylation of 2-alkyl-2-
amino-1,3-propanediols to facilitate a rapid synthesis of FTY720-
P and its analogues.
Catalytic methods for the phosphorylation of alcohols include
the use of P(III) reagents (such as phosphoramidites17) followed
by oxidation, or P(V) reagents (such as chlorophosphates18 or
pyrophosphates19). We sought to test our recently disclosed
method on the Lewis acid catalyzed phosphorylation of alcohols
with pyrophosphates on the mono-phosphorylation of diols.19
We began this study by examining if the carbon chain length
between the two hydroxyls of a diol would have an effect on the
selectivity of mono-phosphorylation (see Table 1). All reactions
were run with 10 mol % of the Lewis acid catalyst (Ti(OtBu)4),
1.2 equiv of phosphorylating agent (tetrabenzyl pyrophosphate
(TBPP)), and 1.5 equiv of proton scavenger (NiPr2Et) in CH2Cl2
and quenched after 4 h.20 When two or three carbon-bridged diols
were tested, 75% of 1 and 71% of 2 are isolated along with 8%
and 17% of the di-phosphate (Table 1, entries 1 and 2). As the
Table 2
Effect of substituents on the mono-phosphorylation of diols
Entry
1
mono-P product
Isolated yield mono-Pa
84%
Table 1
2
90%
Effect of chain length on the mono-phosphorylation of diols
3
4
5
90% (4:1 ratiob)
85%
Entry
1
Mono-P product
Isolated yield mono-Pa
75%
21%c
6
7
81%
2
3
71%
64%
84% (15:1 ratiob)
a
Reactions performed with 1.2 equiv of TBPP and 1.5 equiv of Hünig’s Base at
4
65%
room temperature for 4 h.
b
The major mono-phosphate product is depicted for unsymmetrical diols. The
product ratio was determined by 1H NMR.
a
Reactions performed with 1.2 equiv of TBPP and 1.5 equiv of Hünig’s Base at
room temperature for 4 h.
c
Compound slowly decomposes during isolation.
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K. A. Coppola et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Aromatic substituents were also examined for their effect on
selectivity. Phenyl substitution at C-2 did not alter the high yield
of mono-phosphorylation as witnessed by the 81% isolated yield
of 10 (Table 2, entry 6). We were also interested in studying the
competition between a phenolic and primary hydroxyl. When
3-(4-hydroxyphenyl)-1-propanol was subjected to the standard
reaction conditions, 84% yield of mono-phosphate was isolated in
a 15:1 ratio favoring phosphorylation of the primary hydroxyl (as
depicted in 11). This result is complimentary to the work of Takeda
and coworkers who report this same substrate reacts with silver(I)
oxide, THAI, and TBPP to yield a reaction at the phenolic hydroxyl,
exclusively.4a
In conclusion, we have demonstrated that titanium alkoxides
are effective catalysts for the mono-phosphorylation of diols. We
have found that the propensity to stop at mono-phosphorylation
is even greater when the carbon chain length separating the two
hydroxyls is two or three carbons and bears additional substitu-
ents. We have also demonstrated that this reaction can generate
up to 97% yield of a mono-phosphate in a model system for
FTY720-P. This method should aid in the selective chemical
mono-phosphorylation of FTY720-P and its analogues.23 We are
currently exploring the use of other Lewis acid catalysts including
chiral catalysts to enable a desymmetrization of FTY720 to form
(S)-FTY720-P.
With
a series of encouraging results for the selective
mono-phosphorylation of 1,3-propane diols, we turned our
attention to analogues of FTY720. Inexpensive and readily available
2-amino-2-ethyl-1,3-propanediol was amine protected with
tert-butoxycarbonyl (Boc) and carboxybenzyl (Cbz) protecting
groups (12 and 13).21 When either of these amine-protected diols
was subjected to our standard reactions conditions, 78% of the
mono-phosphate was formed (Table 3, entries 1 and 2). Analysis
of the crude NMR for both reactions showed recovered starting
material. We were excited to observe that by extending the dura-
tion of the reaction to 16 h, we could obtain 96% of 14 and 93% of
15, with no detectable di-phosphate. Takeda and co-workers found
that when Cbz-protected FTY720 was subjected to phosphoryla-
tion with silver(I) oxide, THAI, and TBPP, 60% of the desired
mono-phosphate was formed along with 22% di-phosphate and
12% of a cyclized byproduct.4a It is interesting to note that similar
yields of 14 are formed when 10 mol % of the more commonly
available Ti(OiPr)4 is used in the phosphorylation of 12 (generating
92% isolated yield of 14).22 We are hopeful that the use of titanium
alkoxides as Lewis acid catalysts will afford high levels of selectiv-
ity in the synthesis of FTY720-P and its analogues.
Due to the diverse solubility of potential FTY720 analogues, we
examined the effect of solvent on the reaction rate and selectivity.
(see Table 3, entries 5–10). We found that when 12 was subjected
to phosphorylation in CH2Cl2, toluene, THF, or DMF 14 was isolated
in high yield. There is a slight drop in yield when the reaction is
performed in Et2O, CH3CN, or pentane (77%, 80%, and 63%, respec-
tively). We were pleased that a variety of solvents with different
boiling points, polarity, and dielectric constants were suitable for
the mono-phosphorylation of 12.
Acknowledgments
This work was supported by the Camille and Henry Dreyfus
Foundation (New Faculty Award to BRS), the College of the Holy
Cross, and the Alumni Parent Fund at Holy Cross.
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.
05.047.
References and notes
1. (a) Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata, T.; Schedel, H. J. Am. Chem.
Soc. 2007, 129, 12890–12895; (b) Griswold, K. S.; Miller, S. J. Tetrahedron 2003,
59, 8869–8875; (c) Wang, Y.-F.; Lalonde, J. J.; Momongan, M.; Bergbreiter, D. E.;
Wong, C.-H. J. Am. Chem. Soc. 1988, 110, 7200–7205; (d) Therisod, M.; Klibanov,
A. M. J. Am. Chem. Soc. 1987, 109, 3977–3981.
2. Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945–5948.
3. (a) Iwasaki, F.; Maki, T.; Onomura, O.; Nakashima, W.; Matsumura, Y. J. Org.
Chem. 2000, 65, 996–1002; (b) Evtushenko, E. V. J. Carbohydr. Chem. 2010, 29,
369–378.
4. (a) Takeda, S.; Chino, M.; Kiuchi, M.; Adachi, K. Tetrahedron Lett. 2005, 46,
5169–5172; (b) Sculimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
10125–10126.
5. (a) Sun, X.; Worthy, A. D.; Tan, T. L. Angew. Chem., Int. Ed. 2011, 50, 8167–8171;
(b) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006, 443, 67–70.
6. (a) Bouzide, A.; Sauve, G. Org. Lett. 2002, 4, 2329–2332; (b) Lee, D.; Williamson,
C. L.; Chan, L.; Taylor, M. S. J. Am. Chem. Soc. 2012, 134, 8260–8267.
7. Pesti, A.; DiCosimo, R. Curr. Opin. Drug Discovery Dev. 2003, 6, 884–901.
8. Diaz-de-Villegas, M. D.; Galvez, J. A.; Badorrey, R.; Lopez-Ram-de-Viu, M. P.
Chem. Eur. J. 2012, 18, 13920–13935.
9. Chun, J.; Brinkmann, V. Discov. Med. 2011, 12, 213–228.
10. (a) Mandala, S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.; Xie, J.; Milligan, J.;
Thornton, R.; Shei, G.-J.; Card, D.; Keohane, C.; Rosenbach, M.; Hale, J.; Lynch, C.
L.; Rupprecht, K.; Parsons, W.; Rosen, H. Science 2002, 296, 346–349; (b) Billich,
A.; Bornancin, F.; Devay, P.; Mechtcheriakova, D.; Urtz, N.; Baumruker, T. J. Biol.
Chem. 2003, 48, 47408–47415.
11. Brinkmann, V.; Davis, M. D.; Heise, C. E.; Albert, R.; Cottens, S.; Hof, R.; Bruns,
C.; Prieschl, E.; Baumruker, T.; Hiestand, P.; Foster, C. A.; Zollinger, M.; Lynch, K.
R. J. Biol. Chem. 2002, 277, 21453–21457.
Table 3
Mono-phosphorylation of N-protected 2-amino-2-ethyl-1,3-propane diols
12. (a) Adachi, K.; Kohara, T.; Nakao, N.; Arita, M.; Chiba, K.; Mishina, T.; Sasaki, S.;
Fujita, T. Bioorg. Med. Chem. Lett. 1995, 8, 853–856; (b) Fujita, T.; Hirose, R.;
Yoneta, M.; Sasaki, S.; Inoue, K.; Kiuchi, M.; Hirase, S.; Chiba, K.; Sakamoto, H.;
Arita, M. J. Med. Chem. 1996, 39, 4451–4459.
13. Albert, R.; Hinterding, K.; Brinkmann, V.; Guerini, D.; Muller-Hartwieg, C.;
Knecht, H.; Simeon, C.; Streiff, M.; Wagner, T.; Welzenbach, K.; Zecri, F.;
Zollinger, M.; Cooke, N.; Francotte, E. J. Med. Chem. 2005, 48, 5373–5377.
14. (a) Hale, J. J.; Yan, L.; Neway, W. E.; Hajdu, R.; Bergstrom, J. D.; Milligan, J. A.;
Shei, G.-J.; Chrebet, G. L.; Thornton, R. A.; Card, D.; Rosenbach, M.; Rosen, H.;
Mandala, S. Bioorg. Med. Chem. 2004, 12, 4803–4807; (b) Ref. 13.
15. Kiuchi, M.; Adachi, K.; Tomatsu, A.; Chino, M.; Takeda, S.; Tanaka, Y.; Maeda, Y.;
Sato, N.; Mitsutomi, N.; Sugahara, K.; Chiba, K. Bioorg. Med. Chem. 2005, 13,
425–432.
Entry
PG
Solvent
Time (h)
Isolated yield 14 or 15a (%)
1
2
3
4
5
6
7
8
9
10
Cbz
Boc
Cbz
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Et2O
CH3CN
DMF
Pentane
THF
4
4
78
78
96
93
97
77
80
93
63
96
16
16
16
16
16
16
16
16
16. Bittman, R.; Lu, X. Tetrahedron Lett. 2006, 47, 825–827.
17. (a) Hayakawa, Y.; Kataoka, M. J. Am. Chem. Soc. 1997, 119, 11758; (b) Brady, P.
B.; Morris, E. M.; Fenton, O. S.; Sculimbrene, B. R. Tetrahedron Lett. 2009, 50,
975–978.
18. (a) Jones, S.; Selitsianos, D.; Thompson, K. J.; Toms, S. M. J. Org. Chem. 2003, 68,
5211–5216; (b) Ref. 4b.
19. Fenton, O. S.; Allen, E. E.; Pedretty, K. P.; Till, S. D.; Todaro, J. E.; Sculimbrene, B.
R. Tetrahedron 2012, 68, 9023–9028.
20. General procedure for the phosphorylation of diols. The diol (0.49 mmol) was
dissolved in 1.0 mL of CH2Cl2. N,N-Diisopropylethylamine (0.130 mL,
a
Reactions performed with 1.2 equiv of TBPP and 1.5 equiv of Hünig’s Base at
room temperature.
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K. A. Coppola et al. / Tetrahedron Letters xxx (2014) xxx–xxx
0.746 mmol) was added to the solution, followed by tetrabenzylpyrophosphate
(0.320 g, 0.594 mmol). Ti(OtBu)4 (19 L, 0.049 mmol, 10 mol %) was added and
22. In the phosphorylation of secondary alcohols, there is contaminant
l
phosphorylation of isopropanol when Ti(OiPr)4 is employed as the catalyst
(see Ref. 17a). None of this byproduct was detected in the phosphorylation of
12.
the reaction was stirred for 4 h at room temperature. To quench the reaction,
the crude solution was filtered through a 5 mL plastic syringe containing 2 mL
of 20:1 Silica/MgSO4 and washed with 60 mL of 75% EtOAc/hexanes. The
filtrate was concentrated under reduced pressure. The crude product was
purified using silica gel chromatography. See Supporting information for
characterization data and spectra.
23. (a) Ko, R. Y. Y.; Chu, J. C. K.; Chiu, P. Tetrahedron 2011, 67, 2542–2547; (b)
Briard, E.; Orain, D.; Beerli, C.; Billich, C.; Streiff, M.; Bigaud, M.; Auberson, Y. P.
ChemMedChem 2011, 6, 667–677; (c) Ma, B.; Guckian, K. M.; Lin, E. Y.-S.; Lee,
W.-C.; Scott, D.; Kumaravel, G.; Macdonald, T. L.; Lynch, K. R.; Black, C.;
Chollate, S.; Hahm, K.; Hetu, G.; Jin, P.; Luo, Y.; Rohde, E.; Rossomando, A.;
Scannevin, R.; Wang, J.; Yang, C. Bioorg. Med. Chem. Lett. 2010, 20, 2264–2269.
21. Honjo, T.; Nakao, M.; Sano, S.; Shiro, M.; Yamaguchi, K.; Sei, Y.; Nagao, Y. Org.
Lett. 2007, 9, 509–512.
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