LETTER
Synthesis of the Resorcylic Lactone-Based Kinase Inhibitor L-783277
1503
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Institute for Biomedical Research in Basel, Switzerland, for provi-
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ding us with a sample of natural L-783277 (1).
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5a
References and Notes
Figure 3
(1) Selected references: (a) Roberts, P. J.; Cer, C. J. Oncogene
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(2) (a) Quintas-Cardama, A.; Kantarjian, H.; Cortes, J. Nature
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(b) Perez-Soler, R. Clin. Cancer Res. 2007, 13, 4589;
erlotinib. (c) Faivre, S.; Demetri, G.; Sargent, W.; Raymond,
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(d) Moen, M. D.; McKeage, K.; Plosker, G. L.; Siddiqui, M.
A. A.; Berman, E.; Gambacorti-Passerini, C.; Goldman, J.
H.; Hochhaus, A.; Larson, R. A.; Rosti, G.; Simonsson, B.
Drugs 2007, 67, 299; imatinib. (e) Ono, M.; Kuwano, M.
Clin. Cancer Res. 2006, 12, 7242; gefitinib, erlotinib.
(f) Ma, W. W.; Jimeno, A. Drugs Today 2007, 43, 659;
druginfo/fda-temsirolimus. (g) Lackey, K. E. Curr. Top.
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C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R. A.;
Schwartz, B.; Simantov, R.; Kelley, S. Nature Rev. Drug
Discov. 2006, 5, 835.
(16) For a related sequence, see: Toba, T.; Murata, K.;
Yamamura, T.; Miyake, S.; Annoura, H. Tetrahedron Lett.
2005, 46, 5043.
(17) (a) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem.
1976, 41, 1485. (b) Sharpless, K. B.; Young, M. W. J. Org.
Chem. 1975, 40, 947.
(18) The use of the 2-TMS-ethyl ester group for protection of the
resorcylic acid carboxylate has also been reported recently
by Winssinger and co-workers as part of their synthesis of
radicicol A.12 As indicated in the text, the identification of
this carboxylate protecting group as the one most suitable for
our synthesis of L-783277 (1) occurred completely
independent of Winssinger’s work.
(19) Preparation and Analytical Data of Compounds 2 and 1
Macrocyclization
To a solution of 16 (minor isomer; 10 mg, 0.021 mmol) in
abs. toluene (3 mL) were added Ph3P (11 mg, 0.043 mmol)
and DIAD (9 mL, 9 mg, 0.043 mmol) and the reaction
mixture was stirred at r.t. for 25 min. Filtration through
Celite followed by evaporation of the filtrate and
purification of the residue by flash chromatography (SiO2
15–40 mm, Merck; hexane–EtOAc, 10:1 to 5:1) gave 7 mg
(74%) of pure macrocycle.
(3) Vieth, M.; Sutherland, J. J.; Robertson, D. H.; Campbell, R.
M. Drug Discov. Today 2005, 10, 839.
(4) For a recent review on the chemistry and biology of
resorcylic lactones, see: Winssinger, N.; Barluenga, S.
Chem. Commun. 2007, 22.
[a]20D +15.3 (c 0.533, MeOH). 1H NMR (400 MHz, CDCl3):
d = 1.24–1.28 (m, 4 H), 1.36 (s, 3 H), 1.47 (d, J = 6.5 Hz, 3
H), 1.53 (s, 3 H), 2.21–2.36 (m, 2 H), 2.40–2.47 (m, 1 H),
3.20–3.27 (m, 1 H), 3.35 (s, 3 H), 3.80 (s, 3 H), 4.08 (q,
J = 7.0 Hz, 1 H), 4.39 (d, J = 7.0 Hz, 1 H), 4.43–4.45 (m, 1
H), 4.53–4.65 (dd, J = 7.0 Hz, 2 H), 5.59–5.62 (m, 1 H),
5.92–6.09 (m, 2 H), 6.27 (d, J = 2.6 Hz, 1 H), 6.35 (d, J = 2.6
Hz, 1 H), 11.85 (s, 1 H). 13C NMR (100.6 MHz, CDCl3):
d = 17.98, 22.80, 24.64, 26.89, 29.89, 30.80, 36.29, 55.46,
55.65, 67.30, 71.03, 76.85, 79.12, 92.54, 99.29, 105.67,
107.76, 110.83, 127.35, 129.71, 147.57, 164.15, 165.55,
171.30. IR (film): n = 3734, 2934, 2361, 2341, 1732, 1645,
1614, 1456, 1375, 1255, 1210, 1159, 1094, 1032, 669 cm–1.
ESI-HRMS: m/z calcd for [M + Na]: 473.21459; found:
473.21438.
(5) (a) Nair, M. S. R.; Carey, S. T. Tetrahedron Lett. 1980, 21,
2011. (b) Nair, M. S. R.; Carey, S. T.; James, J. C.
Tetrahedron 1981, 37, 2445. (c) Agatsuma, T.; Takahashi,
A.; Kabuto, C.; Nozoe, S. Chem. Pharm. Bull. 1993, 41, 373.
(6) Ellestad, G. A.; Lovell, F. M.; Perkinson, N. A.; Hargreaves,
R. T.; McGahren, W. J. J. Org. Chem. 1978, 43, 2339.
(7) Kastelic, T.; Schnyder, J.; Leutwiler, A.; Traber, R.; Streit,
B.; Niggli, H.; MacKenzie, A.; Cheneval, D. Cytokine 1996,
8, 751.
(8) Zhao, A.; Lee, S. H.; Mojena, M.; Jenkins, R. G.; Patrick, D.
R.; Huber, H. E.; Goetz, M. A.; Hensens, O. D.; Zink, D. L.;
Vilella, D.; Dombrowski, A. W.; Lingham, R. B.; Huang, L.
J. Antibiotics 1999, 52, 1086.
Compound 2
To a solution of the above macrocycle (115 mg, 0.256
mmol) in abs. MeOH (8.5 mL, 0.03 M) were added 247 mg
(0.767 mmol) of sulfonic acid resin (Novabiochem, 3.1
mmol/g). After refluxing the mixture for 4.5 h the resin was
removed by filtration, washed with MeOH, and the
combined filtrates were evaporated in vacuo. Purification of
the residue by flash chromatography (EtOAc–MeOH 50:1 to
30:1 to 10:1) gave 43 mg (46%) of the minor isomer of 2 as
a colorless solid.
(9) Schirmer, A.; Kennedy, J.; Murli, S.; Reid, R.; Santi, D. V.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 4234.
(10) (a) Sellès, P.; Lett, R. Tetrahedron Lett. 2002, 43, 4621.
(b) Sellès, P.; Lett, R. Tetrahedron Lett. 2002, 43, 4627.
(11) Tsuji, J.; Shimizu, I.; Minami, I. Chem. Lett. 1984, 1017.
(12) Dakas, P.-Y.; Barluenga, S.; Totzke, F.; Zirrgiebel, U.;
Winssinger, N. Angew. Chem. Int. Ed. 2007, 46, 6899.
(13) For a review on asymmetric dihydroxylation reactions, see:
Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, B. K.
Chem. Rev. 1994, 94, 2483.
(14) The ee for the dihydroxylation product 5 was determined by
chiral HPLC on a Chiralpak AD-H column after conversion
into the acetonide 5a (Figure 3) – no clean separation of
enantiomers could be accomplished with 5. cis-Olefins are
known to give generally lower ee in AD-mix-mediated
dihydroxylations than the corresponding trans-isomers.13
(15) O-Isopropylidene-D-erythrono-1,4-lactone (6) is
commercially available from FLUKA.
[a]20D +30.26 (c 0.542, MeOH). 1H NMR (400 MHz,
DMSO-d6): d = 1.14–1.17 (m, 1 H), 1.34 (d, J = 6.4 Hz, 3
H), 1.43–1.51 (m, 1 H), 1.72–1.78 (m, 2 H), 2.10–2.17 (m, 1
H), 2.44–2.59 (m, 2 H), 2.82–2.90 (m, 1 H), 3.29 (s, 1 H),
3.32 (br s, 1 H), 3.70 (s, 3 H), 4.17 (d, J = 7.2 Hz, 1 H), 4.31
(d, J = 3.9 Hz, 1 H), 4.44–4.47 (m, 1 H), 4.49–4.50 (m, 1 H),
5.22–5.28 (m, 1 H), 5.43 (dt, J = 8.9 Hz, 1 H), 5.55 (dt,
J = 11.2 Hz, 1 H), 6.23 (d, J = 2.3 Hz, 1 H), 6.30 (d, J = 2.1
Hz, 1 H), 12.14 (s, 1 H). 13C NMR (100.6 MHz, DMSO-d6):
d = 18.00, 23.30, 29.15, 29.91, 31.91, 54.98, 67.36, 67.97,
69.42, 79.98, 98.59, 104.10, 114.90, 122.74, 133.20, 156.78,
160.86, 168.22. IR (film): n = 3436, 2940, 2360, 2341, 1636,
Synlett 2008, No. 10, 1500–1504 © Thieme Stuttgart · New York