Weinreb amide based new synthetic equivalents for convenient access to immunosuppressive agent FTY720 and analogues

Article abstract of DOI:10.1055/s-2007-990961

Three new synthetic equivalents containing Weinreb amide functionality for the central core of FTY720, an immunosuppressive agent, have been developed. These synthetic equivalents enabled incorporation of the polar head group of FTY720, through Julia, Wit

Full text of DOI:10.1055/s-2007-990961

LETTER
2841
Weinreb Amide Based New Synthetic Equivalents for Convenient Access to
Immunosuppressive Agent FTY720 and Analogues
A
ccess to Im
m
i
unosu
v
A
g
a
ent FTY72
r
A
n
a
alogues man Balasubramaniam, Senthilmurugan Annamalai, Indrapal Singh Aidhen*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
Fax +91(44)22574202; E-mail: isingh@iitm.ac.in
Received 3 August 2007
Dedicated to Professor Shoichi Kusumoto
A new strategy based on a disconnection represented in
Abstract: Three new synthetic equivalents containing Weinreb
amide functionality for the central core of FTY720, an immunosup-
pressive agent, have been developed. These synthetic equivalents
enabled incorporation of the polar head group of FTY720, through
Figure 2 was envisaged. The importance of the target, our
continued interest in developing synthetic equivalents
based on the Weinreb amide functionality,5,6 increasing
Julia, Wittig, and Horner–Wadsworth–Emmons reactions and also confidence of this functionality being used industrially on
kilogram scale,7 and the absence of a strategy based on the
allowed for variation in the chain length of the lipophilic side chain
in target, through the Weinreb amide functionality therein. The use
proposed disconnection herein were the main reasons
of tris(hydroxymethyl)aminomethane, commercially available at
justifying our synthetic efforts. The proposed synthetic
low cost for the polar head group offers a distinct advantage. Con-
scheme has two distinct and prominent advantages. First-
venient reactions and simple functional group interconversions in
ly, for the hydrophilic head group in FTY720, it envisages
the use of N-Boc-protected aldehyde 2,8 conveniently pre-
pared in two steps from inexpensive and commercially
available tris(hydroxymethyl)aminomethane (TRIS, 3) as
the starting substrate.
good to high yield highlight the strength of the new route developed
for the synthesis of clinically important FTY720.
Key words: FTY720, Weinreb amide, sulfone, olefination
FTY720 (1, Figure 1) is a novel and promising immuno-
suppressant that is currently in phase III clinical trials for
the prevention of allograft rejection.1 It is a synthetic
analogue of sphingosine ISP-I (myriocin), a fungal meta-
bolite of Chinese herb Iscaria sinclarri.2 The known syn-
thetic schemes3,4 for FTY720 start with octylbenzene,3b,c
4-octylbenzaldehyde,3d,4b 4-octyliodobenzene,4a or 2-(4-
hydroxyphenyl)ethanol,4c as the starting building block.
Fürstner’s approach banking on the use of 2-(4-hydroxy-
phenyl) ethanol as the starting material has great potential
in varying the lipophilic side chain with the use of envi-
ronmentally benign Fe(acac)3 during cross-coupling reac-
tion between aryl triflate and alkylmagnesium halide. In
contrast to acetaminomalonate, the use of tris(hydroxym-
ethyl)aminomethane (TRIS), for incorporating the polar
head group of FTY720, has been reported only recently.4a
HO
HO
FTY720 (1)
HCl·H2N
HO
HO
n-C7H15MgBr
5
NH2
X
Y
O
O
OMe
O
O
N
NHBoc
2
Me
O
N
S
HO
HO
O
S
OH
OH
O
NH2
HOOC
3
4
HOH2C
4
6
H2N
OH
myriocin
Figure 2
Secondly, it allows for convenient structural variations at
the lipophilic side chain of FTY720 through a robust
Weinreb amide functionality in the central building block
4 (Figure 2). The coupling of compound 4 with aldehyde
2 banks on the efficiency and success of Julia olefination
protocol. The absence of compound 4 in the literature,
which combines potentials of Julia olefination9 and Wein-
reb amide chemistry, further prompted this investigation.
Analytically pure compound 410 was conveniently pre-
pared in three steps using easily available amide 511 as the
HO
HO
HCl·H2N
FTY 720 (1)
Figure 1
SYNLETT 2007, No. 18, pp 2841–2846
Advanced online publication: 19.10.2007
DOI: 10.1055/s-2007-990961; Art ID: G26607ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
7

2842
S. Balasubramaniam et al.
LETTER
O
O
Table 1 Julia Olefination of Aldehydes 7a–h with Sulfone 4
OMe
OMe
O
N
N
b, c
a
4
OMe
Me
Me
N
Me
6
Br
5
R
O
OMe
RCHO
Product (% yield,a E/Z ratio)
8a (72, 2:1)
N
d
Me
4
+
RCHO
CHO
R
7a–h
8a–h
Scheme 1 Reagents and conditions: (a) NBS (1.1 equiv), Bz2O2,
CCl4, reflux, 16 h, 62–65%; (b) 2-mercaptobenzothiazole (1.1 equiv),
K2CO3 (1.5 equiv), acetone, reflux, 10 h, 60%; (c) Na2WO4·2H2O (0.5
equiv), 30% H2O2 (4.0 equiv), MeOH, 0 °C to r.t., 6 h, 77%; (d)
K2CO3 (3.0 equiv), THF–DMF (3:1), 70 °C, 17 h.
7a
CHO
8b (57, 9:1)
8c (64, 3:1)
OHC
7b
starting substrate (Scheme 1). It involved facile benzylic
bromination followed by nucleophilic substitution with 2-
mercaptobenzothiazole and oxidation of the resulting sul-
fide to sulfone 4.
The successful use of Cs2CO3 as a base in the literature12
for Julia olefination prompted the possible use of cheaper
K2CO3, particularly in conjunction with DMF as an ad-
junct solvent. To our satisfaction, a variety of aldehydes
cleanly reacted with the sulfone 4 in THF–DMF mixture
(3:1) at 70 °C when three equivalents of K2CO3 were used
as a base. The obtained alkenes 8a–h13 in moderate to
good yields contained E as the major geometrical isomer
(Table 1).
CHO
O
O
7c
CHO
NO2
8d (70, 9:1)
8e (66, 3:1)
7d
CHO
Towards the synthesis of FTY720, the sulfone 4 was then
reacted with aldehyde 2 under similar reaction conditions.
Clean reaction ensued furnishing the desired product 914
after silica gel chromatography in an isolated yield of
55%. Realizing the importance of 9 as a key building
block towards FTY720 and its analogues, attempts to in-
crease the yield of this reaction were made. After a few
variations in the nature of reaction solvent, it was ob-
served that good yield of 70% was obtained when DMF
alone was used as the solvent. The convenient availability
of 9 and subsequent facile addition of alkylmagnesium ha-
lides of varying lengths, proves the importance of scaffold
9 as a key building block for FTY720 and the significance
of the Weinreb amide functionality therein (Scheme 2).
All the ketones, 10a–e,15 were obtained in moderate yields
(Table 2).
MeO
OMe
7e
CHO
8f (56, 3:2)
N
Boc
7f
CHO
8g (75, 5:4)
8hb (78, 2:1)
O
7g
n-Butyraldehyde
7h
Given the fact that arylmagnesium halides are prone to
oxidative homodimerization as a parasitic side reaction
under Fe(acac)3-catalyzed cross-coupling reactions of
Grignard reagents with electron-deficient aromatic sub-
strates,16 the successful addition of phenylmagnesium
bromide and obtainment of ketone 10e, substantiate the
promise of this new strategy towards incorporation of the
aryl residue in the lipophilic side chain for FTY720 ana-
logues. With the facile conversion of 10d to 11,4a a formal
total synthesis of target molecule FTY720 has been
achieved. Compound 11 obtained in high yield of 85%
over two steps from 10d is an advanced and ultimate pre-
cursor in the recently reported synthesis of FTY720.4a
a Yield of isolated product after flash chromatography. All isolated
new compounds exhibited satisfactory analytical and spectral details.
The E/Z isomers were characterized using 1H NMR.
b Reaction was carried out using NaH in DMF at 0 °C.
Successful coupling of the sulfone 4 with aldehyde 2 and
the achieved synthesis of FTY720 hinted at the possible
use of Wittig or Horner–Wadsworth–Emmons (HWE)
based central units 12 and 13, respectively. Interestingly,
both of these compounds, although not in the literature,
were easily prepared17 using the bromo amide 6. Heating
of the Wittig salt 12 along with the aldehyde 2 in the pres-
ence of K2CO3 in THF–DMF mixture at 70 °C led to in
Synlett 2007, No. 18, 2841–2846 © Thieme Stuttgart · New York

LETTER
Access to Immunosuppressive Agent FTY720 and Analogues
2843
O
O
O
OMe
OMe
N
OMe
O
N
N
a
O
Me
Me
P
+
2
4
O
Me
EtO
OEt
NHBoc
9
12
13
Ph3P
Br
O
b
9 + Z-
isomer
OMe
O
N
12
b
a
O
2
Me
R1
O
13
9
O
BocHN
14
O
c
NHBoc
10a–e
O
6
d, e
6
c, d
O
11
O
10d
O
O
BocHN
15
NHBoc
11
Scheme 3 Reagents and conditions: (a) K2CO3 (3.0 equiv), 2 (1.0
equiv), THF–DMF (3:1), 70 °C, 18 h, 70% from 12 and 60% from 13;
(b) H2, 10% Pd/C (25 wt%); EtOAc, r.t., 24 h, 95%; (c) n-C7H15MgBr
(6.0 equiv), THF, –10 °C to 0 °C, 3 h, 70%; (d) NaBH4 (3.0 equiv),
MeOH, 0–10 °C, 2 h; (e) H2, 10% Pd/C (25 wt%); EtOAc, AcOH
(5 equiv), r.t., 24 h, 90% (2 steps).
Scheme 2 Reagents and conditions: (a) K2CO3 (3.0 equiv), 2 (1.0
equiv), THF–DMF (3:1), 70 °C, 18 h, 55%; DMF, 70%; (b) R1MgX
(6.0 equiv), THF, –10 °C to 0 °C, 3 h; (c) NaBH4 (3.0 equiv), MeOH,
0 °C, 2 h; (d) H2, 10% Pd/C (30 wt%), EtOAc, AcOH (5 equiv), r.t.,
24 h, 85% (2 steps).
functionality for the central core of FTY720 have been de-
veloped from commercially available p-toluic acid. These
synthetic equivalents enabled incorporation of the polar
head group of FTY720, through Julia, Wittig, and HWE
reactions and also allowed for complete control at the
length of the lipophilic side chain through the robust
amide functionality therein. All the reactions and con-
ditions en-route to the target molecule are simple and
good-yielding and therefore hold significant promise for
industrial application.
Table 2 Addition of Various Organometallic Reagents to Weinreb
Amide 9
Entry R1M
R1 in the product (yield, %a)
1
2
3
4
5
Me(CH2)3MgBr
10a
10b
10c
10d
10e
(CH2)3Me (70)
(CH2)5Me (65)
(CH2)7Me (68)
(CH2)6Me (75)
Ph (72)
Me(CH2)5MgBr
Me(CH2)7MgBr
Me(CH2)6MgBr
PhMgBr
a Yield of isolated product after flash chromatography. All isolated
new compounds exhibited satisfactory analytical and spectral details.
Acknowledgment
We thank DST-New Delhi for the funding towards 400 MHz NMR
machine to the Department of Chemistry, IIT-Madras under the
situ formation of the phosphorane and subsequent reac- IRPHA scheme and ESI-MS facility under the FIST program.
CSIR-New Delhi is acknowledged for funding of project 01(1971)/
05/EMR-II during 2005. B.S.R. is thankful to IIT-Madras for
tion with aldehyde 2. The reaction furnished the desired
product 9 along with the Z-isomer (E/Z = 3:1)18 in an iso-
Fellowship, A.S.M. is thankful for a JRF Fellowship under the
lated yield of 70%. However, under similar reaction con-
above project.
ditions the phosphonate 13 gave the E-isomer 9 as the
exclusive product in 60% yield. Simple hydrogenation of
References and Notes
the E/Z product mixture from the Wittig reaction and con-
vergence to alkane amide 1419 makes the obtainment of
geometrical isomers with building block 12 inconsequen-
tial. Compound 14, a stable crystalline solid is yet another
building block for the synthesis of FTY720 and ana-
logues. Addition of n-C7H15MgBr, at –10 °C furnished the
ketone 1520 in 70% yield. Finally, successful conversion
of 15 to 11 in high yield demonstrates the usefulness of
compound 14 as a key building block, not only for
FTY720, but for its analogues as well (Scheme 3).
(1) (a) Taha, T. A.; Argraves, K. M.; Obeid, L. M. Biochim.
Biophys. Acta: Mol. Cell Biol. Lipids 2004, 1682, 48.
(b) Praditpornsilpa, K.; Avihingsanon, Y. Transplant Proc.
2004, 36, 1228. (c) Kahan, B. D. Transplant Proc. 2004, 36,
S531. (d) Martini, S.; Peters, H.; Bohler, T.; Budde, K.
Expert Opin. Investig. Drugs 2007, 16, 505.
(2) (a) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki,
S.; Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. J.
Antibiot. 1994, 47, 208. (b) Adachi, K.; Kohara, T.; Nakao,
N.; Arita, M.; Chiba, K.; Mishina, T.; Sasaki, S.; Fujita, T.
Bioorg. Med. Chem. Lett. 1995, 5, 853. (c) Kiuchi, M.;
Adachi, K.; Kohara, T.; Minoguchi, M.; Hanano, T.; Oki, Y.;
Mishina, T.; Arita, M.; Nakao, N.; Ohtsuki, M.; Hoshino, Y.;
Teshima, K.; Chiba, K.; Sasaki, S.; Fujita, T. J. Med. Chem.
2000, 43, 2946.
To conclude, a successful strategy for the synthesis of
FTY720, an immunosuppressive agent based on an unex-
plored disconnection has been realized. For this, three
new synthetic equivalents containing the Weinreb amide
Synlett 2007, No. 18, 2841–2846 © Thieme Stuttgart · New York

2844
S. Balasubramaniam et al.
LETTER
(3) For previous syntheses of FTY720, see: (a) Adachi, K.;
Kohara, T.; Nakao, N.; Arita, M.; Chiba, K.; Mishina, T.;
Sasaki, S.; Fujita, T. Bioorg. Med. Chem. Lett. 1995, 5, 853.
(b) Kiuchi, M.; Adachi, K.; Kohara, T.; Inoguchi, M.;
Hanano, T.; Aoki, Y.; Mishina, T.; Arita, M.; Nakao, N.;
Ohtsuki, M.; Hoshino, Y.; Teshima, K.; Chiba, K.; Sasaki,
S.; Fujita, T. J. Med. Chem. 2000, 43, 2946. (c) Durand, P.;
Peralba, P.; Sierra, F.; Renaut, P. Synthesis 2000, 505.
(d) Kalita, B.; Barua, N. C.; Bezbarua, M.; Bez, G. Synlett
2001, 1411.
(4) For recent syntheses of FTY720, see: (a) Kim, S.; Lee, H.;
Lee, M.; Lee, T. Synthesis 2006, 753. (b) Sugiyama, S.;
Arai, S.; Kiriyama, M.; Ishii, K. Chem. Pharm. Bull. 2005,
53, 100. (c) Seidel, G.; Laurich, D.; Fürstner, A. J. Org.
Chem. 2004, 69, 3950. For FTY720-related compounds,
see: (d) 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.
(e) 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. (f) Hale, J. J.; Neway,
W.; Mills, S. G.; Hajdu, R.; Keohane, C. A.; Rosenbach, M.;
Milligan, J.; Shei, G.-J.; Chrebet, G.; Bergstrom, J.; Card,
D.; Koo, G. C.; Koprak, S. L.; Jackson, J. J.; Rosen, H.;
Mandala, S. Bioorg. Med. Chem. Lett. 2004, 14, 3351.
(g) Hinterding, K.; Cottens, S.; Albert, R.; Zecri, F.;
Buehlmayer, P.; Spanka, C.; Brinkmann, V.; Nussbaumer,
P.; Ettmayer, P.; Hoegenauer, K.; Gray, N.; Pan, S. Synthesis
2003, 1667. (h) Hinterding, K.; Albert, R.; Cottens, S.
Tetrahedron Lett. 2002, 43, 8095.
(5) Sivaraman, B.; Aidhen, I. S. Synlett 2007, 959.
(6) N-Methoxy-N-methyl amides are popularly called as
Weinreb amides. For reviews on Weinreb amide chemistry,
see: (a) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt.
Chem. 2000, 342, 340. (b) Mentzel, M.; Hoffmann, H. M. R.
J. Prakt. Chem. 1997, 339, 517. (c) Sibi, M. P. Org. Prep.
Proced. Int. 1993, 25, 15.
(7) Mickel, S. J.; Niederer, D.; Daeffler, R.; Osmani, A.;
Kuesters, E.; Schmid, E.; Schaer, K.; Gamboni, R.; Chen,
W.; Loeser, E.; Kinder, F. R. Jr.; Konigsberger, K.; Prasad,
K.; Ramsey, T. M.; Repic, O.; Wang, R.-M.; Florence, G.;
Lyothier, I.; Paterson, I. Org. Process Res. Dev. 2004, 8,
122.
(11) (a) Tunoori, A. R.; White, J. M.; Georg, G. I. Org. Lett. 2000,
2, 4091. (b) p-Toluic acid was converted to its acid chloride
using more economical SOCl2 and reacted with N-methoxy-
N-methyl amine hydrochloride in the presence of 3.0 equiv
of Et3N, yield 88–92%.
(12) Aïssa, C. J. Org. Chem. 2006, 71, 360.
(13) General Procedure for Olefination
A suspension of sulfone (0.3 mmol), aldehyde (0.33 mmol,
1.1 equiv), and K2CO3 (0.9 mmol, 3 equiv) in a mixture of
THF (1.8 mL) and DMF (0.6 mL; 3:1 mixture) was heated at
70 °C for 17 h. After completion of the reaction, THF was
evaporated and the reaction mixture was quenched with H2O
and then extracted with EtOAc. The washed organic layer
was dried over anhyd Na2SO4, filtered, concentrated, and
then purified by silica gel flash chromatography. The
spectral and analytical details for selected compounds are
given below.
4-[4-(5,5-Dimethyl-1,3-dioxan-2-yl)styryl]-N-methoxy-
N-methylbenzamide (8c)
Yield 64% (E:Z = 3:1). E-Isomer: Rf = 0.35 (hexane–EtOAc,
7:3); white crystalline solid, mp 121–124 °C. 1H NMR (400
MHz, CDCl3): d = 0.73 (s, 3 H), 1.22 (s, 3 H), 3.28 (s, 3 H),
3.48 (s, 3 H), 3.58 (d, 2 H, J = 10.8 Hz), 3.70 (d, 2 H,
J = 11.2 Hz), 5.32 (s, 1 H), 7.03 (d, 1 H, J = 16.0 Hz), 7.10
(d, 1 H, J = 16.4 Hz), 7.41–7.46 (m, 6 H), 7.62 (d, 2 H,
J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): d = 20.8, 22.0,
29.2, 32.8, 60.0, 76.7, 100.4, 125.0, 125.6, 127.1, 127.6,
127.8, 129.1, 131.9, 136.5, 137.2, 138.6, 168.5. Z-Isomer:
Rf = 0.42 (hexane–EtOAc, 7:3); colorless viscous liquid. 1H
NMR (400 MHz, CDCl3): d = 3.27 (s, 3 H), 3.49 (s, 3 H),
3.57 (d, 2 H, J = 10.4 Hz), 3.69 (d, 2 H, J = 11.2 Hz), 5.28
(s, 1 H), 6.51 (d, 1 H, J = 12.4 Hz), 6.57 (d, 1 H, J = 12.4
Hz), 7.17–7.21 (m, 4 H), 7.30 (d, 2 H, J = 8.0 Hz), 7.46 (d, 2
H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): d = 20.9, 22.1,
29.2, 33.0, 59.9, 76.7, 100.6, 125.2, 127.3, 127.5, 127.8,
128.6, 130.2, 131.6, 136.4, 136.6, 138.6, 168.7. IR (CH2Cl2):
1097, 1383, 1417, 1638, 2850, 2954 cm–1. HRMS (EI): m/z
calcd for C23H27NO4 [M + H]+: 382.2018; found: 382.2029.
N-Methoxy-N-methyl-4-(2-nitrostyryl)benzamide (8d)
Yield 70% (E:Z = 9:1); Rf = 0.4 (hexane–EtOAc,7:3); yellow
solid, mp 60–63 °C. 1H NMR (400 MHz, CDCl3): d (E-
isomer) = 3.38 (s, 3 H), 3.58 (s, 3 H), 7.09 (d, 1 H, J = 16.0
Hz), 7.42–7.46 (m, 1 H), 7.57 (d, 2 H, J = 8.4 Hz), 7.62 (d, 1
H, J = 7.6 Hz), 7.67 (d, 1 H, J = 16.4 Hz), 7.73 (d, 2 H,
J = 8.4 Hz), 7.77 (d, 1 H, J = 7.2 Hz), 7.98–8.00 (m, 1 H); d
(Z-isomer, nonoverlapped signals) = 3.32 (s, 3 H), 3.52 (s, 3
H), 6.77 (d, 1 H, J = 12.0 Hz), 6.97 (d, 1 H, J = 12.0 Hz),
7.49 (d, 2 H, J = 8.0 Hz), 7.81 (d, 1 H, J = 8.0 Hz), 7.93 (d,
1 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): d (E-
isomer) = 33.2, 60.5, 124.4, 124.8, 126.1, 127.8, 127.9,
128.4, 132.2, 132.4, 132.7, 133.3, 138.2, 147.6, 168.8; d (Z-
isomer, nonoverlapped signals) = 60.6, 124.3, 128.2, 130.4,
131.7, 132.8. IR (CH2Cl2): 1264, 1345, 1523, 1635, 3054
cm–1. HRMS (EI): m/z calcd for C17H16N2O4 [M + H]+:
313.1188; found: 313.1194.
(8) Aldehyde 2, a crystalline solid, was conveniently prepared in
high overall yield by a literature-known, two-step synthetic
procedure, using cheap and commercially available
tris(hydroxymethyl)aminomethane (TRIS) as the starting
material. See: Ooi, H.; Ishibashi, N.; Iwabuchi, Y.; Ishihara,
J.; Hatakeyama, S. J. Org. Chem. 2004, 69, 7765.
(9) For reviews on Julia olefination, see: (a) Blakemore, P. R. J.
Chem. Soc., Perkin Trans. 1 2002, 2563. (b) Kelly, S. E.
Comp. Org. Synth. 1991, 1, 792.
(10) 4-{(Benzo[d]thiazol-2-ylsulfonyl)methyl}-N-methoxy-N-
methylbenzamide (4)
Yield 85–88%; Rf = 0.35 (hexane–ethyl acetate, 6:4);
colorless crystals, mp 142–145 °C. 1H NMR (400 MHz,
CDCl3): d = 3.32 (s, 3 H), 3.47 (s, 3 H), 4.79 (s, 2 H), 7.33
(d, 2 H, J = 8.0 Hz), 7.56–7.62 (m, 3 H), 7.63–7.69 (m, 1 H),
7.94 (d, 1 H, J = 8.0 Hz), 8.26 (d, 1 H, J = 8.0 Hz). 13C NMR
(100 MHz, CDCl3): d = 32.6, 59.7, 60.1, 121.3, 124.6, 126.8,
127.2, 127.8, 127.9, 129.8, 133.9, 136.1, 151.6, 164.1,
168.0. IR (CH2Cl2): 1152, 1332, 1469, 1639, 2929, 2972
cm–1. HRMS (EI): m/z calcd for C17H16N2O4S2 [M + H]+:
377.0630; found: 377.0618.
4-(3,4-Dimethoxystyryl)-N-methoxy-N-methyl
Benzamide (8e)
Yield 66% (E:Z = 3:1); Rf = 0.37 (hexane–EtOAc, 7:3);
yellow viscous liquid. 1H NMR (400 MHz, CDCl3): d (E-
isomer) = 3.28 (s, 3 H), 3.49 (s, 3 H), 3.82 (s, 3 H), 3.86 (s,
3 H), 6.78 (d, 1 H, J = 8.0 Hz), 6.89 (d, 1 H, J = 16.4 Hz),
6.97–6.99 (m, 2 H), 7.04 (d, 1 H, J = 16.0 Hz), 7.43 (d, 2 H,
J = 8.4 Hz), 7.62 (d, 2 H, J = 8.4 Hz); d (Z-isomer,
nonoverlapped signals) = 3.26 (s, 3 H), 3.46 (s, 3 H), 3.54 (s,
3 H), 3.77 (s, 3 H), 6.43 (d, 1 H, J = 12.4 Hz), 6.51 (d, 1 H,
J = 12.4 Hz), 6.65–6.68 (m, 2 H), 6.72–6.74 (m, 1 H), 7.24
(d, 2 H, J = 8.4 Hz), 7.47 (d, 2 H, J = 8.4 Hz).13C NMR (100
Synlett 2007, No. 18, 2841–2846 © Thieme Stuttgart · New York

LETTER
Access to Immunosuppressive Agent FTY720 and Analogues
selected compounds are given below.
2845
MHz, CDCl3): d = 33.8, 55.8, 55.9, 61.1, 108.8, 111.2,
120.3, 121.9, 125.7, 128.2, 128.5, 128.8, 130.2, 131.2,
132.3, 139.9, 149.1, 149.3, 169.5; d (Z-isomer non-
overlapped signals) = 55.5, 55.8, 60.9, 110.9, 111.7, 125.8,
127.9, 128.6, 129.4, 130.0, 140.2, 148.3, 148.4, 169.6. IR
(CH2Cl2): 1264, 1514, 1635, 3053 cm–1. HRMS (EI): m/z
calcd for C19H21NO4 [M + H]+: 328.1549; found: 328.1546.
tert-Butyl {3-[4-Methoxy(methyl)carbamoyl]styryl}-1H-
indole-1-carboxylate (8f)
(E)-tert-Butyl [5-(4-Heptanoylstyryl)-2,2-dimethyl-1,3-
dioxan-5-yl]carbamate (10b)
Yield 65%; Rf = 0.4 (hexane–EtOAc, 7:3); colorless solid,
mp 86–89 °C. 1H NMR (400 MHz, CDCl3): d = 0.89 (t, 3 H,
J = 7.2 Hz), 1.29–1.35 (m, 6 H), 1.44 (s, 9 H), 1.48 (s, 3 H),
1.49 (s, 3 H), 1.68–1.74 (m, 2 H), 2.94 (t, 2 H, J = 7.6 Hz),
3.91–4.01 (m, 4 H), 5.27 (br s, 1 H), 6.35 (d, 1 H, J = 16.4
Hz), 6.58 (d, 1 H, J = 16.4 Hz), 7.43 (d, 2 H, J = 8.0 Hz),
7.90 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): d =
14.0, 19.4, 22.5, 24.3, 27.7, 28.4, 29.0, 31.9, 38.6, 53.1, 66.1,
79.8, 98.4, 126.5, 128.5, 129.5, 131.0, 136.1, 140.9, 154.8,
200.0. IR (CHCl3): 1167, 1466, 1601, 1682, 1716, 2853,
2923 cm–1. HRMS (EI): m/z calcd for C26H40NO5 [M + H]+:
446.2906; found: 446.2899.
Yield 56% (E:Z = 3:2); Rf = 0.27 (hexane–EtOAc, 7:3); pale
yellow viscous liquid. 1H NMR (400 MHz, CDCl3): d (E-
isomer) = 1.70 (s, 9 H), 3.38 (s, 3 H), 3.58 (s, 3 H), 7.21 (d,
1 H, J = 17.2 Hz), 7.32–7.38 (m, 4 H), 7.55 (d, 2 H, J = 8.4
Hz), 7.72 (d, 2 H, J = 8.4 Hz), 7.77 (s, 1 H), 7.90 (d, 1 H,
J = 7.2 Hz), 8.20 (d, 1 H, J = 8.0 Hz); d (Z-isomer,
nonoverlapped signals) = 3.33 (s, 3 H), 3.52 (s, 3 H), 6.68–
6.75 (m, 2 H), 7.08–7.12 (m, 1 H), 7.23–7.29 (m, 2 H), 7.35
(d, 2 H, J = 8.4 Hz), 7.48 (s, 1 H), 7.56 (d, 2 H, J = 8.4 Hz),
8.11 (d, 1 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): d (E-
isomer) = 28.2, 33.8, 61.1, 84.1, 115.5, 118.7, 119.9, 121.7,
123.1, 124.5, 124.8, 125.6, 127.8, 128.5, 128.9, 132.4,
140.1, 149.5, 169.6; d (Z-isomer, nonoverlapped signals) =
83.8, 115.1, 117.0, 121.5, 122.5, 124.4, 128.3, 129.2, 130.4,
132.6, 135.2. IR (CH2Cl2): 1261, 1457, 1604, 1723, 2853,
2923, 2956 cm–1. HRMS (EI): m/z calcd for C24H26N2O4 [M
+ H]+: 407.1971; found: 407.1981.
(E)-tert-Butyl [2,2-Dimethyl-5-(4-octanoylstyryl)-1,3-
dioxan-5-yl]carbamate (10d)
Yield 75%; Rf = 0.4 (hexane–EtOAc, 7:3); colorless solid,
mp 83–86 °C. 1H NMR (400 MHz, CDCl3): d = 0.88 (t, 3 H,
J = 7.2 Hz), 1.28–1.38 (m, 8 H), 1.44 (s, 9 H), 1.47 (s, 3 H),
1.49 (s, 3 H), 1.70–1.74 (m, 2 H), 2.93 (t, 2 H, J = 7.2 Hz),
3.91–4.00 (m, 4 H), 5.25 (br s, 1 H), 6.35 (d, 1 H, J = 16.4
Hz), 6.58 (d, 1 H, J = 16.4 Hz), 7.43 (d, 2 H, J = 8.4 Hz),
7.90 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): d =
14.0, 19.5, 22.6, 24.5, 27.6, 28.4, 29.0, 29.3, 32.8, 38.6, 53.1,
66.1, 79.8, 98.4, 126.5, 128.4, 129.5, 131.0, 136.1, 140.9,
154.8, 199.9. IR (CHCl3): 1168, 1456, 1603, 1685, 1719,
2853, 2923 cm–1. HRMS (EI): m/z calcd for C27H42NO5 [M
+ H]+: 460.3063; found: 460.3076.
4-[2-(Furan-2-yl)vinyl]-N-methoxy-N-methyl
Benzamide (8g)
Yield 75% (E:Z = 5:4); Rf = 0.3 (hexane–EtOAc, 7:3);
yellow viscous liquid. 1H NMR (400 MHz, CDCl3): d (E-
isomer) = 3.26 (s, 3 H), 3.46 (s, 3 H), 6.18–6.23 (m, 1 H),
6.29–6.37 (m, 4 H), 6.85 (d, 1 H, J = 16.0 Hz), 6.94 (d, 1 H,
J = 16.4 Hz), 7.37–7.41 (m, 4 H), 7.56–7.60 (m, 3 H); d (Z-
isomer, nonoverlapped signals) = 3.27 (s, 3 H), 3.48 (s, 3 H).
13C NMR (100 MHz, CDCl3): d (E-isomer) = 33.8, 61.0,
109.5, 111.8, 118.0, 125.7, 126.0, 128.8, 132.6, 139.4,
142.5, 152.9, 169.5; d (Z-isomer, nonoverlapped signals) =
110.7, 111.3, 118.9, 126.7, 128.1, 128.3, 139.8, 141.9,
151.7, 169.7. IR (CH2Cl2): 1378, 1416, 1639, 2929 cm–1.
HRMS (EI): m/z calcd for C15H15NO3 [M + H]+: 258.1130;
found: 258.1138.
(E)-tert-Butyl [5-(4-Benzoylstyryl)-2,2-dimethyl-1,3-
dioxan-5-yl]carbamate (10e)
Yield 72%; Rf = 0.4 (hexane–EtOAc, 7:3); colorless solid,
mp 109–112 °C. 1H NMR (400 MHz, CDCl3): d = 1.45 (s, 9
H), 1.48 (s, 3 H), 1.50 (s, 3 H), 3.92–4.01 (m, 4 H), 5.24 (br
s, 1 H), 6.37 (d, 1 H, J = 16.4 Hz), 6.61 (d, 1 H, J = 16.4 Hz),
7.45–7.50 (m, 4 H), 7.57–7.59 (m, 1 H), 7.76–7.79 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 19.5, 27.7, 28.4, 53.1,
66.1, 79.8, 98.4, 126.2, 128.2, 129.5, 129.9, 130.0, 132.3,
136.5, 137.7, 140.6, 154.8, 196.1. IR (CHCl3): 1165, 1494,
1601, 1655, 1711, 2927, 2976 cm–1. HRMS (EI): m/z calcd
for C26H32NO5 [M + H]+: 438.2280; found: 438.2281.
(16) (a) Fürstner, A.; Leitner, A.; Méndez, M.; Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856. (b) Fürstner, A.; Leitner, A.
Angew. Chem. Int. Ed. 2002, 41, 609. (c) See also ref. 4c
and references cited therein.
(14) (E)-tert-Butyl (5-{4-[Methoxy(methyl)carbamoyl]sty-
ryl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamate (9)
Yield 70%; Rf = 0.35 (hexane–EtOAc, 6:4); colorless solid,
mp 115–118 °C. 1H NMR (400 MHz, CDCl3): d = 1.36 (s, 9
H), 1.38 (s, 3 H), 1.40 (s, 3 H), 3.26 (s, 3 H), 3.45 (s, 3 H),
3.82–3.92 (m, 4 H), 5.27 (br s, 1 H), 6.23 (d, 1 H, J = 16.4
Hz), 6.48 (d, 1 H, J = 16.4 Hz), 7.30 (d, 2 H, J = 8.0 Hz),
7.56 (d, 2 H, J = 8.4 Hz). 13C NMR (100 MHz, CDCl3): d =
19.6, 27.4, 28.3, 33.7, 53.0, 60.9, 66.0, 79.6, 98.3, 125.9,
128.6, 129.5, 130.0, 132.9, 138.8, 154.8, 169.4. IR (CHCl3):
1166, 1456, 1637, 1712, 2851, 2921 cm–1. HRMS (EI): m/z
calcd for C22H33N2O6 [M + H]+): 421.2339; found:
421.2348.
(15) General Procedure for the Addition of Grignard
Reagent, R1MgBr to the Weinreb Amides 9 and 14
To a stirred solution of 9 or 14 (0.7 mmol) in anhyd THF (3
mL), the appropriate solution of alkyl or arylmagnesium
bromide (4.2 mmol, 6 equiv) in anhyd THF (5 mL) was
added under inert atmosphere at –10 °C and the mixture was
stirred for 3 h between –10 °C and 0 °C. Subsequent
hydrolysis was achieved by cautious addition of sat. NH4Cl
solution. The aqueous layer was extracted with EtOAc, dried
over Na2SO4, and concentrated to furnish the crude product,
which was purified by silica gel column chromatography
using hexane–EtOAc (85:15) to afford ketones 10a–e and
15, respectively. The spectral and analytical details for
(17) Reagents and conditions: (a) PPh3 (1.2 equiv), acetone,
reflux, 6 h, 80%; (b) P(OEt)3 (1.5 equiv), toluene, 110 °C, 8
h, 60%.
{4-[Methoxy(methyl)carbamoyl]benzyl}(triphenyl)phos-
phonium Bromide (12)
Yield 80%; Rf = 0.2 (MeOH–CHCl3, 3:7); white solid. 1H
NMR (400 MHz, CDCl3): d = 3.32 (s, 3 H), 3.57 (s, 3 H),
5.06 (d, 2 H, JHP = 15.2 Hz), 7.12 (d, 2 H, J = 8.0 Hz), 7.49
(d, 2 H, J = 8.0 Hz), 7.69–7.76 (m, 12 H), 7.90–7.94 (m, 3
H). 13C NMR (100 MHz, CDCl3): d = 30.3, 30.8, 61.7, 118.5,
119.4, 129.6, 131.5, 131.8, 131.9, 132.0, 135.3, 135.5,
135.7, 136.6, 170.7. IR (CHCl3): 1165, 1368, 1645, 3026
cm–1.
Diethyl {4-[Methoxy(methyl)carbamoyl]benzyl}phos-
phonate (13)
Yield 60%; Rf = 0.1 (hexane–EtOAc, 3:7), colorless liquid.
1H NMR (400 MHz, CDCl3): d = 1.25 (t, 6 H, J = 6.8 Hz),
3.18 (d, 2 H, JHP = 22.0 Hz), 3.35 (s, 3 H), 3.55 (s, 3 H),
4.00–4.06 (m, 4 H), 7.34 (dd, 2 H, J = 2.4, 8.0 Hz), 7.65 (d,
2 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): d = 16.3,
33.6 (d, JCP = 140 Hz), 33.7, 60.9, 62.2, 128.5, 129.4, 132.5,
134.5, 169.5. IR (CHCl3): 1019, 1220, 1380, 1633, 2981
Synlett 2007, No. 18, 2841–2846 © Thieme Stuttgart · New York

2846
S. Balasubramaniam et al.
LETTER
cm–1. HRMS (EI): m/z calcd for C14H23NO5P [M + H]+:
316.1314; found: 316.1317.
1.44 (s, 3 H), 1.48 (s, 9 H), 1.98–2.02 (m, 2 H), 2.58–2.62
(m, 2 H), 3.35 (s, 3 H), 3.55 (s, 3 H), 3.69 (d, 2 H, J = 12.0
Hz), 3.90 (d, 2 H, J = 12.0 Hz), 5.01 (br s, 1 H), 7.21 (d, 2 H,
J = 8.0 Hz), 7.60 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz,
CDCl3): d = 18.9, 27.4, 28.3, 28.6, 32.3, 32.8, 50.6, 59.9,
65.2, 78.4, 97.4 126.1, 126.9, 127.5, 130.6, 143.9, 153.9,
168.8. IR (CHCl3): 1164, 1453, 1638, 1710, 2934, 2976
cm–1. HRMS (EI): m/z calcd for C22H35N2O6 [M + H]+:
423.2495; found: 423.2486.
(18) tert-Butyl (5-{4-[Methoxy(methyl)carbamoyl]styryl}2,2-
dimethyl-1,3-dioxan-5-yl)carbamate (9 + Z-isomer)
Yield 70% (Z:E = 3:1); Rf = 0.35 (hexane–EtOAc, 6:4);
colorless liquid. 1H NMR (400 MHz, CDCl3): d (Z-
isomer) = 1.32 (s, 3 H), 1.38 (s, 9 H), 1.45 (s, 3 H), 3.37 (s,
3 H), 3.56 (s, 3 H), 3.77 (d, 2 H, J = 11.6 Hz), 3.88–3.94 (m,
2 H), 5.20 (br s, 1 H), 5.65 (d, 1 H, J = 12.8 Hz), 6.68 (d, 1
H, J = 12.8 Hz), 7.30 (d, 2 H, J = 8.0 Hz), 7.64 (d, 2 H,
J = 8.0 Hz); d (E-isomer, nonoverlapped signals) = 3.35 (s,
3 H), 3.53 (s, 3 H), 3.88–3.94 (m, 4 H), 5.27 (br s, 1 H), 6.23
(d, 1 H, J = 16.4 Hz), 6.48 (d, 1 H, J = 16.4 Hz), 7.39 (d, 2
H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): d (Z-isomer) =
18.8, 19.4, 20.9, 27.6, 28.3, 33.7, 52.5, 60.9, 65.8, 79.4, 98.1,
125.9, 128.6, 129.5, 130.0, 132.9, 140.1, 154.4, 169.4; d (E-
isomer, nonoverlapped signals) = 53.0, 66.0, 98.3, 127.9,
131.5, 132.6, 138.8. IR (CHCl3): 1166, 1456, 1637, 1712,
2851, 2921 cm–1. HRMS (EI): m/z calcd for C22H33N2O6
[M + H]+: 421.2339; found: 421.2348.
(20) tert-Butyl [2,2-Dimethyl-5-(4-octanoylphenethyl)-1,3-
dioxan-5-yl]carbamate (15)
Yield 70%; Rf = 0.4 (hexane–EtOAc, 7:3); colorless solid,
mp 60–63 °C. 1H NMR (400 MHz, CDCl3): d = 0.88 (t, 3 H,
J = 6.8 Hz), 1.25–1.35 (m, 8 H), 1.42 (s, 3 H), 1.44 (s, 3 H),
1.47 (s, 9 H), 1.70–1.74 (m, 2 H), 1.99–2.11 (m, 2 H), 2.60–
2.64 (m, 2 H), 2.92 (t, 2 H, J = 7.2 Hz), 3.69 (d, 2 H, J = 12.0
Hz), 3.89 (d, 2 H, J = 12.0 Hz), 4.95 (br s, 1 H), 7.26 (d, 2 H,
J = 8.0 Hz), 7.87 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz,
CDCl3): d = 13.2, 19.0, 21.7, 23.7, 26.3, 27.6, 28.2, 28.5,
28.8, 30.8, 32.4, 37.7, 50.9, 65.5, 78.8, 97.6, 127.5, 127.7,
134.4, 146.7, 154.1, 199.3. IR (CHCl3): 1198, 1498, 1606,
1682, 1715, 2856, 2926 cm–1. HRMS (EI): m/z calcd for
C27H44NO5 [M + H]+: 462.3219; found: 462.3229.
(19) tert-Butyl (5-{4-[Methoxy(methyl)carbamoyl]pheneth-
yl}-2,2-dimethyl-1,3-diox-an-5-yl)carbamate (14)
Yield 95%; Rf = 0.35 (hexane–EtOAc, 6:4); colorless solid,
mp 89–91 °C. 1H NMR (400 MHz, CDCl3): d = 1.42 (s, 3 H),
Synlett 2007, No. 18, 2841–2846 © Thieme Stuttgart · New York

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