Highly Versatile Synthesis of Polyamines by Ns-strategy on a Novel Trityl Chloride Resin

Abstract

A solid-phase synthesis of polyamines on 4-alkoxytrityl chloride resin 5 is described. By alkylation of nitrobenzenesulfon­amide 8 with alkyl halide 7 prepared from the resin 5, spermine bound resin 10 was efficiently synthesized. Condensation of 10 and tyrosine derivative followed by deprotection and cleavage from the resin afforded highly pure philanthotoxin-343 (4).

polyamines - solid-phase synthesis - 2-nitrobenzenesulfonamide - 4-alkoxytrityl chloride resin - philanthotoxin-343

References

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<A NAME="RU00802ST-1A">1a</A> Karigiannis G. Papaioannou D. Eur. J. Org. Chem.  2000,  1841 

<A NAME="RU00802ST-1B">1b</A> Kuksa V. Buchan R. Synthesis  2000,  1189 

<A NAME="RU00802ST-2A">2a</A> 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 

<A NAME="RU00802ST-2B">2b</A> 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

<A NAME="RU00802ST-3">3</A> Eldefrawi AT. Eldefrawi ME. Konno K. Mansour NA. Nakanishi K. Oltz E. Usherwood PN. Proc. Natl. Acad. Sci. U.S.A.  1988,  85:  4910 

Solid-phase synthesis of polyamine skeletons:

<A NAME="RU00802ST-4A">4a</A> Manov N. Bienz S. Tetrahedron  2001,  57:  7893 

<A NAME="RU00802ST-4B">4b</A> Renault J. Lebranchu M. Lecat A. Uriac P. Tetrahedron Lett.  2001,  42:  6655 

<A NAME="RU00802ST-4C">4c</A> Sukhdev M. Carmen L. Dan K. Timothy C. Dennis GH. J. Org. Chem.  2001,  66:  874 

<A NAME="RU00802ST-4D">4d</A> Chhabra SR. Khan AN. Bycroft BW. Tetrahedron Lett.  2000,  41:  1099 

<A NAME="RU00802ST-4E">4e</A> Chhabra SR. Khan AN. Bycroft BW. Tetrahedron Lett.  2000,  41:  1095 

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<A NAME="RU00802ST-4G">4g</A> Carrington S. Renault J. Tomasi S. Corbel JC. Uriac P. Blagbrough IS. Chem. Commun.  1999,  1341 

<A NAME="RU00802ST-4H">4h</A> Dooley NC. Ostresh JM. Houghten RA. Bioorg. Med. Chem. Lett.  1998,  2273 

<A NAME="RU00802ST-5A">5a</A> Hidai Y. Kan T. Fukuyama T. Tetrahedron Lett.  1999,  40:  4711 

<A NAME="RU00802ST-5B">5b</A> Hidai Y. Kan T. Fukuyama T. Chem. Pharm. Bull.  2000,  48:  1570 

<A NAME="RU00802ST-6A">6a</A> For a review of Ns chemistry, see: Kan T. Fukuyama T. J. Syn. Org. Chem., Jpn.  2001,  59:  779 

<A NAME="RU00802ST-6B">6b</A> Fukuyama T. Jow C.-K. Cheung M. Tetrahedron Lett.  1995,  36:  6373 

<A NAME="RU00802ST-6C">6c</A> Fukuyama T. Cheung M. Jow C.-K. Hidai Y. Kan T. Tetrahedron Lett.  1997,  38:  5831 

<A NAME="RU00802ST-6D">6d</A> Fukuyama T. Cheung M. Kan T. Synlett  1999,  1301 

<A NAME="RU00802ST-6E">6e</A> Fujiwara A. Kan T. Fukuyama T. Synlett  2000,  1667 

<A NAME="RU00802ST-6F">6f</A>

Kurosawa, W.; Kan, T.; Fukuyama, T. Org. Synth., in press.

<A NAME="RU00802ST-7">7</A> For an alkylation of sulfonamides with alkyl halides on the solid-support, see: Dankwardt SM. Smith DB. Porco JA. Nguyen CH. Synlett  1997,  854 

<A NAME="RU00802ST-8">8</A>

The sulfonamide 8 was readily prepared from 1,3-diaminopropane, see ref. [5b]

<A NAME="RU00802ST-9">9</A> Piek T. Hue B. Biochem. Physiol.  1989,  93C:  403 

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<A NAME="RU00802ST-10A">10a</A> Stromgaard K. Andersen K. Ruhland T. Krogsgaard-Larsen P. Jaroszewski JW. Synthesis  2001,  877 

<A NAME="RU00802ST-10B">10b</A> Stromgaard K. Brier TJ. Andersen K. Mellor IR. Saghyan A. Tikhonov D. Usherwood PNR. Krogsgaard-Larsen P. Jaroszewski JW. J. Med. Chem.  2000,  43:  4526 

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<A NAME="RU00802ST-11">11</A>

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).

<A NAME="RU00802ST-12">12</A>

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.

<A NAME="RU00802ST-13">13</A> Miller SC. Scanlan TS. J. Am. Chem. Soc.  1997,  119:  2301 

<A NAME="RU00802ST-14">14</A>

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:

<A NAME="RU00802ST-15A">15a</A> Bennet WD. Combinatorial Chemistry, A Practical Approach   Fenniri H. Oxford University Press Inc.; New York: 2000.  p.169 

<A NAME="RU00802ST-15B">15b</A> For a recent report, see: Russell DV. Robert HEH. Org. Lett.  2001,  3:  3931 ; detailed references are cited in ref.^10a

<A NAME="RU00802ST-16">16</A>

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).

<A NAME="RU00802ST-17">17</A>

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⁺).