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Synlett 2006(18): 2929-2934  
DOI: 10.1055/s-2006-947328
LETTER
© Georg Thieme Verlag Stuttgart · New York

Application of the Heck Reaction in the Synthesis of Macrocycles Derived from Amino Alcohols

Susan E. Gibson*a, Cristina Leccia, Andrew J. P. Whiteb
a Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AY, UK
Fax: +44(207)5945804; e-Mail: s.gibson@imperial.ac.uk;
b Department of Chemical Crystallography, Imperial College London, South Kensington Campus, London SW7 2AY, UK
Further Information

Publication History

Received 22 February 2006
Publication Date:
04 August 2006 (online)

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Abstract

A double Heck reaction is the key step in a straightforward and versatile synthesis of nitrogen-rich macrocycles, including one which X-ray crystallography has revealed forms a tube-like structure.

Key words

amino alcohols - asymmetric synthesis - Heck reaction - macrocycles - palladium

    References and Notes

  • For recent reviews on macrocyclic chemistry, see:
  • 1a Arico F. Chang T. Cantrill SJ. Khan SI. Stoddart JF. Chem. Eur. J.  2005,  11:  4655 
    CrossrefGoogle Scholar
  • 1b Bowman-James K. Acc. Chem. Res.  2005,  38:  671 
    CrossrefGoogle Scholar
  • 1c Schalley CA. Wielandt T. Brüggemann J. Vögtle F. Top. Curr. Chem.  2004,  248:  141 
    CrossrefGoogle Scholar
  • 1d Wessjohann LA. Ruijter E. Top. Curr. Chem.  2005,  243:  137 
    CrossrefGoogle Scholar
  • 1e Botta B. Cassani M. D’Acquarica I. Misiti D. Subissati D. Delle Monache G. Curr. Org. Chem.  2005,  9:  337 
    CrossrefGoogle Scholar
  • For recent reviews on the synthetic challenges represented by macrocycles, see:
  • 1f Blankenstein J. Zhu JP. Eur. J. Org. Chem.  2005,  1949 
    CrossrefGoogle Scholar
  • 1g Bonaga LVR. Zhang HC. Moretto AF. Ye H. Gauthier DA. Li J. Leo GC. Maryanoff BE. J. Am. Chem. Soc.  2005,  127:  3473 
    CrossrefGoogle Scholar
  • 1h Beletskaya IP. Bessmertnykh AG. Averin AD. Denat F. Guilard R. Eur. J. Org. Chem.  2005,  281 
    CrossrefGoogle Scholar
  • 1i Schalley CA. Reckien W. Peyerimhoff S. Baytekin B. Vögtle F. Chem. Eur. J.  2004,  10:  4777 
    CrossrefGoogle Scholar
  • 1j Barrett AGM. Hennessy AJ. Le Vezouet R. Procopiou PA. Seale PW. Stefaniak S. Upton RJ. White AJP. Williams DJ. J. Org. Chem.  2004,  69:  1028 
    CrossrefGoogle Scholar
  • 2 For a review of applications of non-peptidic macrocycles derived from amino acids, see: Gibson SE. Lecci C. Angew. Chem. Int. Ed.  2005,  45:  1364 
    Google Scholar
  • 3a For a synthesis of K-13 analogues, see: Cristau P. Vors JP. Zhu J. Org. Lett.  2003,  5:  5575 
    CrossrefGoogle Scholar
  • 3b For a synthesis of K-13, see: Boger DL. Yohannes D. J. Org. Chem.  1989,  54:  2498 
    CrossrefGoogle Scholar
  • 3c For fermentation, isolation and biological properties, see: Kase H. Kaneko M. Yamada K. J. Antibiotics  1987,  40:  450 
    CrossrefGoogle Scholar
  • 4a Tabudravu JN. Morris LA. Milne BF. Jaspars M. Org. Biomol. Chem.  2005,  3:  745 
    Google Scholar
  • 4b Wintjens R. Liévin J. Rooman M. Buisine E. J. Mol. Biol.  2000,  302:  395 
    Google Scholar
  • 4c Cioca DP. Kitano K. Cell. Mol. Life Sci.  2002,  59:  1377 
    Google Scholar
  • 4d Bubb MR. Spector I. Beyer BB. Fosen KM. J. Biol. Chem.  2000,  275:  5163 
    Google Scholar
  • 4e For a total synthesis of jaspamide, see: Yoshiro H. Katsuyuki Y. Takefumi M. Heterocycles  1994,  39:  603 
    Google Scholar
  • 5 Ranganathan D. Samant MP. Nagaraj R. Bikshapathy E. Tetrahedron Lett.  2002,  43:  5145 
    CrossrefGoogle Scholar
  • 6a Becerril J. Burguete MI. Escuder B. Luis SV. Miravet JF. Querol M. Chem. Commun.  2002,  738 
    CrossrefGoogle Scholar
  • 6b Becerril J. Burguete MI. Escuder B. Galindo F. Gavara R. Miravet JF. Luis SV. Peris G. Chem. Eur. J.  2004,  10:  3879 
    CrossrefGoogle Scholar
  • 6c Becerril J. Escuder B. Miravet JF. Gavara R. Luis SV. Eur. J. Org. Chem.  2005,  481 
    CrossrefGoogle Scholar
  • 7 Dowden J. Edwards PD. Flack SS. Kilburn JD. Chem. Eur. J.  1999,  5:  79 
    Google Scholar
  • 8 Ranganathan D. Thomas A. Haridas V. Kurur S. Madhusudanan KP. Roy R. Kunwar AC. Sarma AVS. Vairamani M. Sarma KD. J. Org. Chem.  1999,  64:  3620 
    CrossrefGoogle Scholar
  • 9a Gibson SE. Middleton RJ. J. Chem. Soc., Chem. Commun.  1995,  1743 
    CrossrefGoogle Scholar
  • 9b Gibson SE. Guillo N. Tozer MJ. Chem. Commun.  1997,  637 
    CrossrefGoogle Scholar
  • 9c Gibson SE. Guillo N. Middleton RJ. Thuilliez A. Tozer MJ. J. Chem. Soc., Perkin. Trans. 1  1997,  447 
    CrossrefGoogle Scholar
  • 9d Gibson SE. Guillo N. Jones JO. Buck IM. Kalindjian SB. Roberts S. Tozer MJ. Eur. J. Med. Chem.  2002,  37:  379 
    CrossrefGoogle Scholar
  • 9e Gibson SE. Jones JO. Kalindjian SB. Knight JD. Steed JW. Tozer MJ. Chem. Commun.  2002,  1938 
    CrossrefGoogle Scholar
  • 9f Gibson SE. Jones JO. Kalindjian SB. Knight JD. Mainolfi N. Rudd M. Steed JW. Tozer MJ. Wright PT. Tetrahedron  2004,  60:  6945 
    CrossrefGoogle Scholar
  • 10a Gibson SE. Mainolfi N. Kalindjian SB. Wright PT. Chem. Commun.  2003,  1568 
    Google Scholar
  • 10b Gibson SE. Mainolfi N. Kalindjian SB. Wright PT. White AJP. Chem. Eur. J.  2005,  11:  69 
    Google Scholar
  • 11 Tan DS. Foley MA. Stockwell BR. Shair MD. Schreiber SL. J. Am. Chem. Soc.  1999,  121:  9073 
    CrossrefGoogle Scholar
  • 12 Meyers AI. Dickman DA. Bailey TR. J. Am. Chem. Soc.  1985,  107:  7974 
    CrossrefGoogle Scholar
  • 13 Stork G. Niu D. Fujimoto A. Koft ER. Balkovec JM. Tata JR. Dake GR. J. Am. Chem. Soc.  2001,  123:  3239 
    CrossrefGoogle Scholar
  • 14 Reddy PG. Pratap TV. Kumar GDK. Mohanty SK. Baskaran S. Eur. J. Org. Chem.  2002,  3740 
    CrossrefGoogle Scholar
  • 15 Hanessian S. Zhan L. Bovey R. Saavedra OM. Juillerat-Jeanneret L. J. Med. Chem.  2003,  46:  3600 
    CrossrefGoogle Scholar
  • 17 Wallén EAA. Christiaans JAM. Saario SM. Forsberg MM. Venäläinen JI. Paso HM. Männisto PT. Gynther J. Bioorg. Med. Chem.  2002,  10:  2199 
    CrossrefGoogle Scholar
  • 18 Iwao M. Mahalanabis KK. Watanabe M. De Silva SO. Snieckus V. Tetrahedron  1983,  39:  1955 
    Google Scholar
16

Representative Heck Reaction:
Palladium(II) acetate (0.010 g, 0.043 mmol), NaHCO3 (0.091 g, 1.08 mmol) and tetra-n-butyl ammonium chloride (0.120 g, 0.43 mmol) were added in one portion to a stirred solution of alkene 16 (0.200 g, 0.43 mmol) in dry DMF (20 mL) and the resulting mixture was heated up to 110 °C and stirred for 16 h. After cooling, the product mixture was filtered over a short pad of Celite® and concentrated in vacuo. Purification of the crude product by flash column chromatography (SiO2; hexane-EtOAc, 10:0 to 4:6) afforded 10 as a colorless crystalline solid (0.045 g, 31%). R f = 0.21 (SiO2; hexane-EtOAc, 5:5); mp 252-256 °C; [α]D 20 -177.0 [c 0. 11 (g/dL) in CH2Cl2]. IR (CH2Cl2): 3387 (N-H), 1664 (C=O), 1499 (C=C) cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.01 (d, J = 6.7 Hz, 3 H, CH 3CHCH3), 1.20 (d, J = 6.7 Hz, 3 H, CH 3CHCH3), 2.07-2.14 (m, 1 H, CH3CHCH3), 2.34-2.39 (m, 1 H, NCHCH2), 2.79-2.85 (m, 1 H, CHHNHCO), 3.62 (d, J = 13.2 Hz, 1 H, ArCHHNH), 3.64 (d, J = 12.8 Hz, 1 H, ArCHHNH), 3.73 (d, J = 13.2 Hz, 1 H, ArCHHNH), 3.75 (m, 1 H, CHHNHCO), 4.03 (d, J = 12.8 Hz, 1 H, ArCHHNH), 5.82 (d, J = 8.0 Hz, 1 H, NHCO), 5.91 (d, J = 15.6 Hz, 1 H, NHCOCH=CHAr), 6.98 (d, J = 8.0 Hz, 2 H, ArH 2,6), 7.33 (d, J = 15.6 Hz, 1 H, NHCOCH=CHAr), 7.36-7.38 and 7.43-7.47 (m, 5 H, NCH2PhH), 7.41 (d, J = 8.0 Hz, 2 H, ArH 3,5) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.2 (CH3CHCH3), 23.2 (CH3CHCH3), 28.8 (CH3 CHCH3), 38.2 (CH2NHCO), 52.2 and 54.7 (ArCH2NH and PhCH2NH), 63.6 (NCHCH2), 120.8 (NHCOCH=CHAr), 127.4 (C PhH), 127.9 (C Ar3,5H), 128.7 and 129.6 (C PhH), 129.7 (C Ar2,6H), 134.1 (C ArCH=CH), 139.0 (NHCOCH=CHAr), 140.3 and 141.9 (C ArCH2N and C PhCH2N), 164.9 (NHCO) ppm. MS (FAB/+): m/z (%): 669 (55) [M + H+], 334 (5) [M+/2]. HRMS (FAB/+): m/z calcd for C44H53N4O2: 669.4169; found: 669.4185 [M + H+]. Anal. Calcd (%) for C44H52N4O2 (668.41): C, 79.00; H, 7.84; N, 8.38. Found: C, 78.94; H, 7.79; N, 8.28.

19

Crystal Data for 21.
C30H36N4O2·0.5H2O, M = 493.64, monoclinic, P21 (no. 4), a = 11.5469 (5), b = 17.6488 (8), c = 13.8139 (6) Å, β = 107.469 (4)°, V = 2685.3 (2) Å3, Z = 4 (two independent molecules), D c = 1.221 g cm-3, µ(Cu-Kα) = 0.622 mm-1, T = 173 K, colorless blocks, Oxford Diffraction Xcalibur PX Ultra diffractometer; 9511 independent measured reflections, F 2 refinement, R1 = 0.033, wR2 = 0.079, 8661 independent observed absorption-corrected reflections [|F o| > 4σ(|F o|), 2θmax = 142°], 688 parameters. The absolute structure of 21 was determined by a combination of R-factor tests [R1+ = 0.0326, R1- = 0.0327] and by use of the Flack parameter [x + = +0.07 (13), x - = +0.93 (13)]. The included water molecule is disordered over two positions, and though the hydrogen atoms for the major (ca. 83%) occupancy site were located from a ΔF map, this disorder means that they must be treated with caution. Additionally, the presence of more than one site for the water oxygen atom means that the hydrogen bonds involving this included water can only be taken as indicative. Whilst it is clear that the N(7) proton hydrogen bonds to, and that the O(8′) carbonyl oxygen accepts a hydrogen bond from, a water molecule in this area, exactly what the distances are, and whether both bonds are ever present at the same time, are unknown. CCDC 290796.

20

The most obvious conformational difference between macrocycles A and B is the orientation of the two five-membered C4N rings with respect to the macrocycle, and this difference can be described by considering the C( macro)-N-C-C( macro) torsion angles about the common bond between the C4N ring and the macrocycle. For molecule A these torsion angles are ca. -72° and -122° at N(1) and N(18), respectively, whilst for molecule B the corresponding angles are ca. -148° and -136°, respectively.

21

These aryl-alkenyl-amide ‘sides’ are noticeably non-planar, the constituent C9NO atoms being coplanar to within only ca. 0.28 and 0.13 Å for the N(7) and N(24) units in molecule A, and ca. 0.22 and 0.29 Å for the corresponding units in molecule B.

22

The water molecule is disordered over two positions, the major (ca. 83%) occupancy orientation being shown in Figure [3] and used for the hydrogen bonding geometries.