Enantioselective synthesis of the phosphate esters of the immunosuppressive lipid FTY720

Article abstract of DOI:10.1016/j.tetlet.2005.11.092

The enantiomers of FTY720-phosphate (3) were synthesized via 2-methylene-4-(4-octylphenyl)butan-1-ol (7), 2,3-epoxy alcohol 8, and Δ²-oxazoline 10. These compounds have potential use in the treatment of autoimmune diseases and prevention of kid

Full text of DOI:10.1016/j.tetlet.2005.11.092

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 825–827
Enantioselective synthesis of the phosphate esters of
the immunosuppressive lipid FTY720
Xuequan Lu and Robert Bittman*
Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, NY 11367-1597, USA
Received 12 October 2005; revised 9 November 2005; accepted 11 November 2005
Available online 6 December 2005
Abstract—The enantiomers of FTY720-phosphate (3) were synthesized via 2-methylene-4-(4-octylphenyl)butan-1-ol (7), 2,3-epoxy
alcohol 8, and D2-oxazoline 10. These compounds have potential use in the treatment of autoimmune diseases and prevention of
kidney transplant rejection.
Ó 2005 Elsevier Ltd. All rights reserved.
The sphingolipid FTY720 (2-amino-[2-(4-n-octylphen-
yl)ethyl]-1,3-propanediol, 1; Fig. 1) modulates the
recirculation of lymphocytes between the blood and
lymphoid tissues, and is currently in clinical studies to
evaluate its effects on prevention of kidney transplant
rejection in humans.1 FTY720 is also efficacious against
autoimmune diseases, including multiple sclerosis,2a
rheumatoid arthritis,2b and type 1 diabetes.2c FTY720
is phosphorylated in vivo by endogenous sphingosine
kinases3 to afford (S)-3, which is a structural analogue
of the lysophospholipid sphingosine 1-phosphate (S1P,
2).1b,4 Compound 2 interacts with G-protein coupled
receptors that are involved in emigration of thymocytes
and lymphocytes.5 (S)-3 binds tightly to S1P1 (one of the
five known G protein-coupled receptors for S1P) in thy-
mocytes and lymphocytes, rendering the cells unrespon-
sive to 2 and blocking lymphocyte egress from lymph
nodes.1b,6 Additional beneficial features of 1 are that
sphingolipid biosynthesis is not inhibited and that host
immune defense responses to most infections are not
decreased by administration of 1.1
To further elucidate the mechanisms of action of
FTY720, the availability of (S)-3 is required. In fact, a
practical route to both enantiomers is desired, since
(R)-3 may serve as an agonist or antagonist ligand of
some of the G-protein coupled receptors, such as S1P1,
for 2. Previous preparations of the enantiomers of 3
were accomplished by a lipase-catalyzed asymmetric
acylation of the prochiral hydroxymethyl groups,7 by
C8H17
O
P
OH
HO
O
C13H27
HO
OH
H2N
OH
NH2
FTY720 (1)
S1P (2)
C8H17
C8H17
O
P
O
P
HO
O
HO
O
OH
OH
HO
NH2
)-3
Figure 1. Structures of FTY720 (1), S1P (2), and FTY720 phosphate analogues 3.
NH2
HO
(
S
(R)-3
*
Corresponding author. Tel.: +1 718 997 3279; fax: +1 718 997 3349; e-mail: robert.bittman@qc.cuny.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.092

826
X. Lu, R. Bittman / Tetrahedron Letters 47 (2006) 825–827
chiral HPLC separation of fully protected derivatives,4,8
and by a lengthy synthesis starting with a L-serine-
derived oxazolidine.8 Syntheses of analogues of 3 have
also been reported,9 some of which start with the
precious compound 1.
yl)triphenylphosphonium bromide, which was ob-
tained from 1,3-propanediol in three steps,11 followed
by reduction of the double bonds and hydrogenolysis
of the O-benzyl group in the presence of Pd(OH)2/C
(PearlmanÕs catalyst),12 furnished alcohol 5. PCC oxida-
tion of alcohol 5 provided aldehyde 5a, which was con-
verted to a-methylene aldehyde 6 in good yield by
Mannich reaction with EschenmoserÕs salt13 in the pres-
ence of Et3N. Reduction of aldehyde 6 with NaBH4 in
the presence of CeCl3 (to suppress conjugate reduction)
gave allylic alcohol 7.14 Asymmetric Sharpless epoxida-
tion of allylic alcohol 7 with (+)-diisopropyl tartrate
(DIPT, 0.5 equiv), Ti(OPr-i)4 (0.5 equiv), and cumene
hydroperoxide provided epoxy alcohol (S)-8, and reac-
tion with trichloroacetonitrile in the presence of catal-
ytic DBU gave trichloroacetimidate 9. Treatment with
0.6 equiv of Et2AlCl in methylene chloride resulted in
intramolecular cyclization at the quaternary stereocen-
ter with inversion to afford oxazoline (S)-10 in 74%
overall yield.15 The overall yield of 10 for the seven steps
from aldehyde 4 was 33%.
Thus, in view of the drawbacks and limitations noted
above, we sought to develop an enantioselective method
to prepare the enantiomers of 3. We report here the appli-
cation of asymmetric Sharpless epoxidation10 for the
preparation of 2,3-epoxy alcohol (R)- and (S)-8, which
was converted to 2,3-epoxy-1-trichloroacetimidate 9.
After a Lewis-acid mediated cyclization furnished 2-tri-
chloromethyloxazoline 10, the oxazoline group was used
to mask the C(1)-hydroxy and C(2)-amino groups of one
of the prochiral hydroxymethyl groups of 1, allowing the
installation of the phosphate group into the unprotected
hydroxymethyl group, affording (R)- and (S)-3 in good
overall yields.
As illustrated in Scheme 1, Wittig reaction of 4-bromo-
benzaldehyde with the ylide of n-heptyltriphenylphos-
phonium bromide, followed by lithium–halogen
exchange and reaction with DMF, afforded aldehyde
4. Another Wittig reaction with (3-(benzyloxy)prop-
The unmasked hydroxyl group of chiral oxazoline 10
was converted to phosphate ester 11 with di-tert-butyl
diisopropylphosphoramidite in the presence of 1H-tetra-
(i) BnO(CH2)3PPh3Br
(i)
n-C7H15PPh3Br
C8H17
C6H13
n
-BuLi, THF
n
-BuLi, THF
4-BrC6H4CHO
(ii) -BuLi, THF,
DMF
n
(ii) H2, Pd(OH)2/C,
MeOH
HO(CH2)4
C8H17
OHC
4 (57%)
5 (81%)
C8H17
NaBH4, CeCl3
PCC, NaOAc
MS, CH2Cl2
[(CH3)2N=CH2]+ I-
Et3N, CH2Cl2
O
OHC(CH2)3
MeOH
5a
6 (76%)
C8H17
C8H17
(+)-DIPT, Ti(OPr-i)4, CH2Cl2
Cl3CCN, DBU
CH2Cl2
cumene hydroperoxide, MS, -20 °C
HO
HO
O
°
0 C, 1.5 h
S
( )-8 (83%)
7 (87%)
C8H17
C8H17-n
Et2AlCl
NH
CH2Cl2
0 ° C -rt
Cl3C
O
O
O
OH
( )-10 (85%)
N
Cl3C
( )-9 (87%)
R
S
Scheme 1. Synthesis of D2-oxazoline (S)-10.
C8H17-n
(t-BuO)2PN(Pr-i)2
(i)
1H-tetrazole, CH2Cl2/CH3CN, 6 h
2 M HCl
THF, rt
O
(R)-3 (81%)
(S)-10
O
OBu-t
OBu-t
N
(ii) t-BuOOH, rt, overnight
P
Cl3
O
11 (78%)
Scheme 2. Conversion of (S)-10 to FTY720 and (R)-3.

X. Lu, R. Bittman / Tetrahedron Letters 47 (2006) 825–827
827
C8H17-n
(-)-DIPT, Ti(OPr-i)4, CH2Cl2
cumene hydroperoxide, MS, -20 °C
See
(S)-3
7
HO
O
Schemes 1 and 2
(R)-8 (83%)
Scheme 3. Synthesis of (S)-3.
zole,16 followed by oxidation of the phosphite triester
with tert-butyl hydroperoxide (Scheme 2).17 Finally, a
one-pot reaction to hydrolyze the tert-butyl ester groups
and release the hydroxy and amino groups provided (R)-
3 in 63% overall yield from 10.18
349; (c) Matloubian, M.; Lo, C. G.; Cinamon, G.;
Lesneski, M. J.; Xu, Y.; Brinkmann, V.; Allende, M. L.;
Proia, R. L.; Cyster, J. G. Nature 2004, 427, 355–360; (d)
Brinkmann, V.; Cyster, J. G.; Hla, T. Am. J. Transplant.
2004, 4, 1019–1025.
7. 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.
The target compound (S)-3 was prepared by Sharpless
epoxidation of allylic alcohol 7 with (ꢀ)-DIPT, afford-
ing 2,3-epoxy alcohol (R)-8 (Scheme 3). The methodol-
ogy outlined above was used to convert (R)-8 to (S)-3
via (R)-10.19
8. 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.
9. (a) Kiuchi, M.; Adachi, K.; Kohara, T.; Teshima, K.;
Masubuchi, Y.; Mishina, T.; Fujita, T. Bioorg. Med.
Chem. Lett. 1998, 8, 101–106; (b) Hinterding, K.; Cottens,
S.; Albert, R.; Zecri, F.; Buehlmayer, P.; Spanka, C.;
Brinkmann, V.; Nussbaumer, P.; Ettmayer, P.; Hoe-
genauer, K.; Gray, N.; Pan, S. Synthesis 2003, 1667–
1670; (c) Foss, F. W., Jr.; Clemens, J. J.; Davis, M. D.;
Snyder, A. H.; Zigler, M. A.; Lynch, K. R.; Macdonald,
T. L. Bioorg. Med. Chem. Lett. 2005, 15, 4470–
4474.
In summary, a convenient method for the preparation of
both enantiomers of 3 from p-bromobenzaldehyde has
been described. D2-Oxazoline 10 was obtained by intra-
molecular cyclization at the quaternary stereocenter of
9, enabling the construction of (R)-3 from (S)-10 and
(S)-3 from (R)-10.
Acknowledgements
10. For a review of the Sharpless epoxidation, see: Katsuki,
T.; Martin, V. S. Org. React. 1996, 48, 1–299.
11. Ziegler, F. E.; Klein, S. I.; Pati, U. K.; Wang, T.-F. J. Am.
Chem. Soc. 1985, 107, 2730–2737.
We gratefully acknowledge the NIH and the City
University of New York (grant RF80209) for financial
support of this research.
12. King, A. O.; Shinkai, I. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester,
1995; pp 3888–3889.
13. Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A.
Angew. Chem., Int. Ed. Engl. 1971, 10, 330–331.
14. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
15. Hatakeyama, S.; Matsumoto, H.; Fukuyama, H.;
Mukugi, Y.; Irie, H. J. Org. Chem. 1997, 62, 2275–2279.
No by-product (i.e., dihydrooxazine, which has a six-
membered ring) was observed by TLC.
References and notes
1. (a) Brinkmann, V. Yonsei Med. J. 2004, 45, 991–997; (b)
Chiba, K. Pharmacol. Ther. 2005, 108, 308–319.
2. (a) Gonsette, R. E. J. Neurol. Sci. 2004, 223, 87–93; (b)
Matsuura, M.; Imayoshi, T.; Chiba, K.; Okumoto, T.
Inflamm. Res. 2000, 49, 404–410; (c) Maki, T.; Gottschalk,
R.; Ogawa, N.; Monaco, A. P. Transplantation 2005, 79,
1051–1055.
3. (a) Billich, A.; Bornancin, F.; Devay, P.; Mechtcheria-
kova, D.; Urtz, N.; Baumruker, T. J. Biol. Chem. 2003,
278, 47408–47415; (b) Paugh, S. W.; Payne, S. G.;
Barbour, S. E.; Milstien, S.; Spiegel, S. FEBS Lett. 2003,
554, 189–193.
16. Durgam, G. G.; Virag, T.; Walker, M. D.; Tsukahara, R.;
Yasuda, S.; Liliom, K.; van Meeteren, L. A.; Moolenaar,
W. H.; Wilke, N.; Siess, W.; Tigyi, G.; Miller, D. D. J.
Med. Chem. 2005, 48, 4919–4930.
25
17. Data for 11: Rf 0.15 (EtOAc/hexane 1:3); ½aꢁD ꢀ10.8 (c
3.6, CHCl3); 1H NMR (CDCl3) d 0.88 (t, J = 6.8 Hz,
3H), 1.22–1.36 (m, 10H), 1.54–1.64 (m, 20H), 1.86–2.04
(m, 2H), 2.57 (m, 2H), 2.64 (m, 2H), 4.06 (m, 2H), 4.42
(d, 1H, J = 8.8 Hz), 4.72 (d, 1H, J = 8.8 Hz), 7.11 (m,
4H); 13C NMR (CDCl3) d 14.1, 22.7, 28.9, 29.3, 29.5,
29.9, 31.6, 31.9, 35.5, 37.8, 61.2, 73.9, 74.7, 82.8, 100.0,
128.2, 128.6, 138.2, 140.8, 162.5; 31P NMR (CDCl3) d
ꢀ9.80.
4. 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.
5. Rosen, H.; Goetzl, E. Nat. Rev. Immunol. 2005, 5, 560–
570.
18. Data for (R)-3 and (S)-3: Rf 0.30 (CHCl3/MeOH/H2O/
AcOH 65:25:4:1); 1H NMR (CD3OD) d 0.88 (t, 3H,
J = 6.8 Hz), 1.22–1.36 (m, 10H), 1.54–1.64 (m, 2H), 1.86–
2.04 (m, 2H), 2.52 (m, 2H), 2.68 (m, 2H), 3.60 (m, 2H),
3.90 (m, 2H), 7.07 (m, 4H); 31P NMR (CD3OD) d 0.28;
MS (ESI, MH+) m/z calcd for C19H35NO5P 388.2, found
388.2.
6. (a) 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; (b) Mandala,
S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.; Xie, J.;
Milligan, J.; Thornton, R.; Shei, G.-J.; Card, D.; Keo-
hane, C.; Rosenbach, M.; Hale, J.; Lynch, C. L.; Rupp-
recht, K.; Parsons, W.; Rosen, H. Science 2002, 296, 346–
25
25
19. (S)-10: ½aꢁD +24.9 (c 1.60, CHCl3); (R)-10: ½aꢁD ꢀ25.0 (c
2.75, CHCl3).