References
For recent reviews of polyamine
analogues and conjugates, see:
1a
Karigiannis G.
Papaioannou D.
Eur. J. Org. Chem.
2000,
1841
1b
Kuksa V.
Buchan R.
Synthesis
2000,
1189
2a Squalamine
(3) is currently undergoing phase II clinical trials
for cancer treatment: Moore KS.
Wehrli S.
Roder H.
Rogers M.
Forrest JN.
McCrimmon D.
Zasloff M.
Proc.
Natl. Acad. Sci. U.S.A.
1993,
90:
1354
2b For a recent report, see: Williams JI.
Weitman S.
Gonzalez CM.
Jundt CH.
Marty J.
Stringer SD.
Holroyd KJ.
McLane MP.
Chen Q.
Zasloff M.
Von Hoff DD.
Clinical
Cancer Research
2001,
7:
724 ;
and references cited therein
3
Eldefrawi AT.
Eldefrawi ME.
Konno K.
Mansour NA.
Nakanishi K.
Oltz E.
Usherwood PN.
Proc.
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1988,
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Solid-phase synthesis of polyamine
skeletons:
4a
Manov N.
Bienz S.
Tetrahedron
2001,
57:
7893
4b
Renault J.
Lebranchu M.
Lecat A.
Uriac P.
Tetrahedron Lett.
2001,
42:
6655
4c
Sukhdev M.
Carmen L.
Dan K.
Timothy C.
Dennis GH.
J.
Org. Chem.
2001,
66:
874
4d
Chhabra SR.
Khan AN.
Bycroft BW.
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2000,
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4e
Chhabra SR.
Khan AN.
Bycroft BW.
Tetrahedron Lett.
2000,
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1095
4f
Hone ND.
Payne LJ.
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Carrington S.
Renault J.
Tomasi S.
Corbel JC.
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Dooley NC.
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5b
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Kan T.
Fukuyama T.
Chem. Pharm.
Bull.
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6a For
a review of Ns chemistry, see: Kan T.
Fukuyama T.
J. Syn. Org. Chem., Jpn.
2001,
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779
6b
Fukuyama T.
Jow C.-K.
Cheung M.
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6c
Fukuyama T.
Cheung M.
Jow C.-K.
Hidai Y.
Kan T.
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38:
5831
6d
Fukuyama T.
Cheung M.
Kan T.
Synlett
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1301
6e
Fujiwara A.
Kan T.
Fukuyama T.
Synlett
2000,
1667
6f Kurosawa, W.; Kan, T.;
Fukuyama, T. Org. Synth.,
in press.
7 For an alkylation of sulfonamides
with alkyl halides on the solid-support, see: Dankwardt SM.
Smith DB.
Porco JA.
Nguyen CH.
Synlett
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854
8 The sulfonamide 8 was
readily prepared from 1,3-diaminopropane, see ref.
[5b]
9
Piek T.
Hue B.
Biochem. Physiol.
1989,
93C:
403
For recent syntheses of philanthotoxin-343,
see:
10a
Stromgaard K.
Andersen K.
Ruhland T.
Krogsgaard-Larsen P.
Jaroszewski JW.
Synthesis
2001,
877
10b
Stromgaard K.
Brier TJ.
Andersen K.
Mellor IR.
Saghyan A.
Tikhonov D.
Usherwood PNR.
Krogsgaard-Larsen P.
Jaroszewski JW.
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10c
Chhabra SR.
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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,
CH2Cl2 (93%);(ii) Ac2O,
pyridine (quant.);(iii) TFA, CH2Cl2;(iv) butyryl
chloride, Et3N, CH2Cl2 (88%,
2 steps).
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)-(-)-α-methylbenzylamine
gave a single isomer. However, treatment of DCC with corresponding
carboxylic acid of 11 and (S)-(-)-α-methylbenzylamine
gave a 1:1 mixture of the diastereomers.
13
Miller SC.
Scanlan TS.
J. Am. Chem. Soc.
1997,
119:
2301
14 The resin 5 could
be recycled by treatment with SOCl2/CH2Cl2 (1:9)
after cleavage of the substrates.
For a review of alkylation of Ns-amide
under Mitsunobu reaction on the solid-support, see:
15a
Bennet WD.
Combinatorial Chemistry,
A Practical Approach
Fenniri H.
Oxford
University Press Inc.;
New York:
2000.
p.169
15b For a recent report, see: Russell DV.
Robert HEH.
Org. Lett.
2001,
3:
3931 ; detailed references are cited in ref.10a
16
Synthetic Procedure
for the Polymer Bound Spermine
(10).
To a suspension of the freshly prepared resin 5 (1.40
g, 0.90 mmol/g) and 1,3-diaminopropane (0.60 mL, 7.20 mmol)
in anhyd CH2Cl2 (12.5 mL) was added i-Pr2NEt (1.20 mL, 6.87 mmol)
at r.t. under an argon atmosphere. After shaking for 16 h, the resin
was filtered, washed with 10% H2O 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 (1.71 g) and 2-nitrobenzenesulfonyl
chloride (1.80 g, 8.12 mmol) in anhyd CH2Cl2 (12.5
mL) was added 2,4,6-collidine (2.00 mL, 15.2 mmol) at r.t. under
an argon atmosphere. After shaking for 16 h, the resin was filtered,
washed with 10% H2O in THF, THF, and ether,
and then dried in vacuo 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, 25.3 mmol) in DMF (10.0 mL) was
added K2CO3 (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 10% H2O
in THF, THF, and ether, and then dried in vacuo 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 K2CO3 (1.75 g, 12.7 mmol) at 60 °C. After
stirring for 16 h, the mixture was then cooled to r.t. Then the
resin was filtered, washed with 10% H2O in THF, 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 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 CH2Cl2 (2.5
mL) was added TFA (10 µL, 0.130 mmol) at r.t. After shaking
for 5 min, the resin was filtered and washed with MeOH:CH2Cl2 (1:2).
The combined washings were evaporated with benzene and dried in
vacuo to provide N
1-Alloc-N
4,N
8-di-Ns-spermine
(23.5 mg, 91% from 5) as the TFA
salt. 1H NMR (400 MHz, DMSO-d
6): δ = 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 H, m), 7.19 (1 H, m), 7.78-8.00 (10 H, m). 13C
NMR (100 MHz, DMSO-d
6): δ = 24.8,
25.0, 28.4, 36.5, 37.7, 44.7, 45.2, 46.8, 47.1, 64.2, 116.9, 124.3,
124.4, 129.6, 129.6, 131.6, 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 (C26H37N6O10S2,
MH+). To a suspension of the resin 9 (220 mg) and Pd(PPh3)4 (100
mg, 0.087 mmol) in 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% H2O
in THF, THF, and ether, and then dried in vacuo for 8 h to give
the resin 10 (217 mg).
17
Synthetic Procedure
for Philanthotoxin-343
(4). To a suspension
of the resin 10 (217 mg) in CH2Cl2 (2.5
mL) was added 11 (168 mg, 0.405 mmol) at
r.t. After shaking for 2 d, the resin was filtered, washed with
10% H2O in THF, THF, 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 K2CO3 (60 mg, 0.434 mmol)
at r.t. After shaking for 16 h, the resin was filtered, washed with
10% H2O in 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 µL, 0.426
mmol) in DMF (1.0 mL) was added DBU (60 µL, 0.402 mmol)
at r.t. After shaking for 6 h, the resin was filtered, washed with 10% H2O
in THF, THF, and ether, and then dried in vacuo for 3 h to give
the resin (41 mg). To a mixture of the resulting resin in CH2Cl2 (2.5
mL) was added TFA (30 µL, 0.389 mmol) at r.t. After shaking
for 5 min, the resin was filtered and washed with MeOH:CH2Cl2 (1:2).
The combined washings were evaporated with benzene and dried in
vacuo to provide Philanthotoxin-343(4)
(18.0 mg, 75% from 5) as the TFA
salt. [α]D +5.1 (c 0.14, CH3OH). 1H
NMR (400 MHz, CD3OD): δ = 0.77 (3 H,
t, J = 7.5
Hz), 1.46 (2 H, q, 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, J = 8.5 Hz). 13C
NMR (100 MHz, D2O): δ = 13.4, 19.7,
23.6, 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, 1133,
1202, 1433, 1517, 1678, 2965 cm-1.
MS: m/z = 436 (MH+);
HR MS: Found 436.3264 (MH+). Calcd 436.3288 (C23H42O3N5,
MH+).
