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Synlett 2008(10): 1500-1504  
DOI: 10.1055/s-2008-1078406
LETTER
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of the Resorcylic Lactone-Based Kinase Inhibitor L-783277

Tatjana Hofmann, Karl-Heinz Altmann*
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Hönggerberg HCI E 111, HCI H 405, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland
Fax: +41(44)6331369; e-Mail: karl-heinz.altmann@pharma.ethz.ch;
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Publication History

Received 10 March 2008
Publication Date:
16 May 2008 (online)

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Abstract

The total synthesis of the natural product L-783277 (1) has been accomplished based on the convergent assembly of building blocks 9, 10, and 14. Key steps are the Suzuki coupling of olefin 11 and aromatic building block 14, the Mitsunobu-based macrolactonization of seco acid 16, and the allylic oxidation of the macrocyclic triol 2 with polymer-bound IBX. Only one of the two C6′-stereoisomers of 2 provided L-783277 (1) with high selectivity.

Key words

kinase inhibitor - L-783277 - natural products - resorcylic lactone - stereoselectivity - total synthesis

    References and Notes

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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

Figure 3

15

O-Isopropylidene-d-erythrono-1,4-lactone (6) is commercially available from FLUKA.

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 µL, 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 µm, Merck; hexane-EtOAc, 10:1 to 5:1) gave 7 mg (74%) of pure macrocycle.
[α]20 D +15.3 (c 0.533, MeOH). 1H NMR (400 MHz, CDCl3): δ = 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): δ = 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): ν = 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.
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.
[α]20 D +30.26 (c 0.542, MeOH). 1H NMR (400 MHz, DMSO-d 6): δ = 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-d 6): δ = 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): ν = 3436, 2940, 2360, 2341, 1636, 1609, 1262, 1204, 1160, 1118, 1082, 1028, 991, 812 cm-1. HRMS (EI): m/z calcd for [M + Na]: 389.15707; found: 389.15719.
L-783277 (1)
A solution of 2 (11.1 mg, 0.030 mmol) in anhyd CH2Cl2 (3.5 mL, 7.4 mM) was treated with 73 mg (0.081 mol) of commercially available IBX resin (Novabiochem, 1.1 mmol/g). The progress of the reaction was monitored by TLC every 15 min and workup was initiated upon complete consumption of starting material (75 min). The resin was removed by filtration, washed several times with CH2Cl2, and the combined filtrates were evaporated in vacuo. Purification of the residue by flash chromatography in EtOAc-MeOH (20:1) gave 10.3 mg of 1 (93%, 91% purity). This material contained 8% of a second mono-oxidized product (according to MS analysis). Purification by preparative HPLC gave 5.54 mg (50%) of 1 with >95% purity. 1H NMR (500 MHz, DMSO-d 6): δ = 1.23 (m, 1 H), 1.32 (d, J = 6.2 Hz, 3 H), 1.36-1.40 (m, 2 H), 1.56-1.60 (m, 1 H), 2.37-2.43 (m, 1 H), 2.61-2.67 (m, 2 H), 3.01-3.08 (m, 1 H), 3.73 (s, 3 H), 3.74-3.75 (m, 1 H), 4.29-4.31 (m, 1 H), 4.69 (d, J = 6.6 Hz, 1 H), 4.88 (d, J = 4.9 Hz, 1 H), 5.28-5.32 (m, 1 H), 6.20-6.25 (m, 1 H), 6.28 (d, J = 2.4 Hz, 1 H), 6.30 (d, J = 2.4 Hz, 1 H), 6.50 (dd, J = 11.8 Hz, 1 H). 13C NMR (125.4 MHz, DMSO-d6): δ = 19.94, 26.85, 30.94, 34.34, 35.73, 55.24, 71.19, 72.35, 81.36, 98.79, 106.90, 108.47, 127.26, 143.03, 145.06, 161.64, 162.56, 169.73, 201.74. HRMS (EI): m/z calcd for [M + H]: 366.1673; found: 366.1675.

21

Interestingly, no differences in oxidation selectivity between C6′-isomers appear to be operative in the case of radicicol A, for which Winssinger and co-workers have reported a >90% yield for the polymer-bound IBX-mediated oxidation of the C6′-isomeric mixture of triol precursors corresponding to 2.12