1
340
T. Kan et al.
LETTER
(
(
5) (a) Hidai, Y.; Kan, T.; Fukuyama, T. Tetrahedron Lett. 1999,
0, 4711. (b) Hidai, Y.; Kan, T.; Fukuyama, T. Chem.
25.3 mmol) in DMF (10.0 mL) was added K CO (1.80 g,
13.0 mmol) at 60 °C. After stirring for 16 h, the mixture was
then cooled to r.t. Then the resin was filtered, washed with
2
3
4
Pharm. Bull. 2000, 48, 1570.
6) (a) For a review of Ns chemistry, see: Kan, T.; Fukuyama, T.
J. Syn. Org. Chem., Jpn. 2001, 59, 779. (b) Fukuyama, T.;
Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373.
10% H O in THF, THF, and ether, and then dried in vacuo
2
for 8 h to give the resin 7 (1.43 g). To a suspension of the
above resin 7 (1.26 g) and 8 (1.30 g, 3.79 mmol) in DMF
(10.0 mL) was added K CO (1.75 g, 12.7 mmol) at 60 °C.
(
c) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan,
2
3
T. Tetrahedron Lett. 1997, 38, 5831. (d) Fukuyama, T.;
Cheung, M.; Kan, T. Synlett 1999, 1301. (e) Fujiwara, A.;
Kan, T.; Fukuyama, T. Synlett 2000, 1667. (f) Kurosawa,
W.; Kan, T.; Fukuyama, T. Org. Synth., in press.
After stirring for 16 h, the mixture was then cooled to r.t.
Then the resin was filtered, washed with 10% H O in THF,
2
THF, and ether, and then dried in vacuo for 4 h to give the
resin 9 (1.36 g). Confirmation of the structure of the
(
7) For an alkylation of sulfonamides with alkyl halides on the
solid-support, see: Dankwardt, S. M.; Smith, D. B.; Porco, J.
A.; Nguyen, C. H. Synlett 1997, 854.
spermine skeleton of 9 was performed by following acidic
cleavage from the resin. To a mixture of the resulting resin 9
(60.0 mg) in CH Cl (2.5 mL) was added TFA (10 L, 0.130
2
2
(
8) The sulfonamide 8 was readily prepared from 1,3-
diaminopropane, see ref.
9) Piek, T.; Hue, B. Biochem. Physiol. 1989, 93C, 403.
mmol) at r.t. After shaking for 5 min, the resin was filtered
and washed with MeOH:CH Cl (1:2). The combined
5
b
2
2
(
washings were evaporated with benzene and dried in vacuo
1
4
8
(
10) For recent syntheses of philanthotoxin-343, see:
a) Stromgaard, K.; Andersen, K.; Ruhland, T.; Krogsgaard-
Larsen, P.; Jaroszewski, J. W. Synthesis 2001, 877.
b) Stromgaard, K.; Brier, T. J.; Andersen, K.; Mellor, I. R.;
to provide N -Alloc-N ,N -di-Ns-spermine (23.5 mg, 91%
1
(
from 5) as the TFA salt. H NMR (400 MHz, DMSO-d ):
6
= 1.23 (2 H, m), 1.36 (2 H, m), 1.56 (2 H, m), 1.78 (2 H, m),
2.72 (2 H, m), 2.90 (2 H, m), 3.15–3.32 (8 H, m), 4.44 (2 H,
d, J = 6.0 Hz), 5.19 (2 H, dd, J = 10.8 Hz, 16.8 Hz), 5.89 (1
(
Saghyan, A.; Tikhonov, D.; Usherwood, P. N. R.;
Krogsgaard-Larsen, P.; Jaroszewski, J. W. J. Med. Chem.
1
3
H, m), 7.19 (1 H, m), 7.78–8.00 (10 H, m). C NMR (100
2000, 43, 4526. (c) Chhabra, S. R.; Khan, A. N.; Bycroft, B.
MHz, DMSO-d ): = 24.8, 25.0, 28.4, 36.5, 37.7, 44.7, 45.2,
6
W. Tetrahedron Lett. 2000, 41, 1099.
46.8, 47.1, 64.2, 116.9, 124.3, 124.4, 129.6, 129.6, 131.6,
(
(
11) N-Butyryl-O-acetyl-L-tyrosine-p-nitrophenyl ester 11 was
prepared from N-Boc-L-tyrosine in four steps: (i)p-
nitrophenol, WSCD HCl, CH Cl (93%);(ii) Ac O, pyridine
131.7, 132.4, 132.5, 133.8, 134.5, 134.6, 147.5. MS: m/z =
+
+
657 (MH ); HR MS: Found 657.2032 (MH ). Calcd
+
657.2013 (C H N O S , MH ). To a suspension of the
2
2
2
26 37
6
10 2
(
quant.);(iii) TFA, CH Cl ;(iv) butyryl chloride, Et N,
resin 9 (220 mg) and Pd(PPh ) (100 mg, 0.087 mmol) in
2
2
3
3 4
CH Cl (88%, 2 steps).
anhyd DMF or THF (2.5 mL) was added pyrrolidine (0.25
mL, 3.02 mmol) at r.t. under an argon atmosphere. After
shaking for 16 h, the resin was filtered, washed with 10%
2
2
12) While amide formation of N-acyl-amino acids is often
accompanied in racemization, no appreciable racemization
took place during the condensation of p-nitrophenyl ester 11
with primary amine as demonstrated in the following
experiments. Condensation reaction with 11 and (S)-(–)- -
methylbenzylamine gave a single isomer. However,
treatment of DCC with corresponding carboxylic acid of 11
and (S)-(–)- -methylbenzylamine gave a 1:1 mixture of the
diastereomers.
H O in THF, THF, and ether, and then dried in vacuo for 8 h
2
to give the resin 10 (217 mg).
(17) Synthetic Procedure for Philanthotoxin-343 (4). To a
suspension of the resin 10 (217 mg) in CH Cl (2.5 mL) was
2
2
added 11 (168 mg, 0.405 mmol) at r.t. After shaking for 2 d,
the resin was filtered, washed with 10% H O in THF, THF,
2
and ether, and then dried in vacuo for 4 h to give the resin 12
(316 mg). To a suspension of 12 (64 mg) in MeOH (1.0 mL)
was added K CO (60 mg, 0.434 mmol) at r.t. After shaking
(
(
(
13) Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1997, 119,
2301.
2
3
14) The resin 5 could be recycled by treatment with SOCl2/
for 16 h, the resin was filtered, washed with 10% H O in
2
CH Cl (1:9) after cleavage of the substrates.
THF, THF, and ether, and then dried in vacuo for 4 h to
afford the resin (60 mg). To a suspension of the above resin
(50 mg) and 2-mercaptoethanol (30 L, 0.426 mmol) in
DMF (1.0 mL) was added DBU (60 L, 0.402 mmol) at r.t.
After shaking for 6 h, the resin was filtered, washed with
2
2
15) For a review of alkylation of Ns-amide under Mitsunobu
reaction on the solid-support, see: (a) Bennet, W. D.
Combinatorial Chemistry, A Practical Approach; Fenniri,
H., Ed.; Oxford University Press Inc.: New York, 2000,
169. (b) For a recent report, see: Russell, D. V.; Robert, H.
10% H O in THF, THF, and ether, and then dried in vacuo
2
E. H. Org. Lett. 2001, 3, 3931; detailed references are cited
for 3 h to give the resin (41 mg). To a mixture of the resulting
resin in CH Cl (2.5 mL) was added TFA (30 L, 0.389
in ref.1
16) Synthetic Procedure for the Polymer Bound Spermine
10). To a suspension of the freshly prepared resin 5 (1.40 g,
.90 mmol/g) and 1,3-diaminopropane (0.60 mL, 7.20
mmol) in anhyd CH Cl (12.5 mL) was added i-Pr NEt (1.20
0a
.
2
2
(
mmol) at r.t. After shaking for 5 min, the resin was filtered
and washed with MeOH:CH Cl (1:2). The combined
(
0
2
2
washings were evaporated with benzene and dried in vacuo
to provide Philanthotoxin-343(4) (18.0 mg, 75% from 5) as
2
2
2
1
mL, 6.87 mmol) at r.t. under an argon atmosphere. After
shaking for 16 h, the resin was filtered, washed with 10%
the TFA salt. [ ] +5.1 (c 0.14, CH OH). H NMR (400
D
3
MHz, CD OD): = 0.77 (3 H, t, J = 7.5 Hz), 1.46 (2 H, q,
3
H O in THF, THF, and ether, and then dried in vacuo for 8 h
to give the resin (1.71 g). To a suspension of the above resin
J = 7.5 Hz), 1.70 (6 H, m), 1.99 (2 H, t, J = 8.0 Hz), 2.09 (2
H, dt, J = 7.5 Hz, J = 2.0 Hz), 2.75–3.21 (14 H, m), 4.28 (1
H, t, J = 7.6 Hz), 6.61 (2 H, d, J = 8.5 Hz), 6.95 (2 H, d,
2
(1.71 g) and 2-nitrobenzenesulfonyl chloride (1.80 g, 8.12
1
3
mmol) in anhyd CH Cl (12.5 mL) was added 2,4,6-collidine
J = 8.5 Hz). C NMR (100 MHz, D O): = 13.4, 19.7, 23.6,
2
2
2
(
2.00 mL, 15.2 mmol) at r.t. under an argon atmosphere.
After shaking for 16 h, the resin was filtered, washed with
0% H O in THF, THF, and ether, and then dried in vacuo
24.5, 26.1, 36.7, 36.9, 37.3, 38.0, 45.3, 45.7, 45.8, 47.8, 56.6,
116.3, 129.0, 131.3, 155.3, 174.7, 178.0. IR: 722, 799, 837,
–
1
1
1133, 1202, 1433, 1517, 1678, 2965 cm . MS: m/z = 436
2
+
+
for 7 h to give the resin 6 (1.86 g). To a suspension of the
above resin 6 (1.38 g) and 1,4-dibromobutane (3.00 mL,
(MH ); HR MS: Found 436.3264 (MH ). Calcd 436.3288
+
(C H O N , MH ).
2
3
42
3
5
Synlett 2002, No. 8, 1338–1340 ISSN 0936-5214 © Thieme Stuttgart · New York