Synthesis of the C7-C23 Fragment Related to Iriomoteolide-1a via B-Alkyl Suzuki-Miyaura Cross-Coupling and Indium-Mediated Aldehyde Allylation

Abstract

Synthesis of the C7-C23 fragment and its 18R,19S-dia­stereomer of iriomoteolide-1a has been accomplished from the C7-C12 allyl bromide, the C13-C16 vinyl iodide, and the C17-C23 alkyl iodide fragments. These fragments were assembled first by the B-alkyl Suzuki-Miyaura cross-coupling to give the C13-C23 intermediate. The latter, after being transformed into the C13 aldehyde, was coupled to the C7-C12 allyl bromide in the presence of indium powder in THF-H₂O (1:1) at 70 ˚C to the fully functionalized C7-C23 fragment with orthogonal protecting groups at C19 (PMB ether), and C9, C14, and C22 (TBS, TES, and TBS ethers, respectively). Formation of the characteristic six-membered C9/C13-hemiacetal ring has been demonstrated after global desilylation using pyridine-buffered HF.

allylation - B-alkyl Suzuki-Miyaura cross-coupling - ­indium - iriomoteolide - macrolide

References and Notes

For isolation and structures of iriomoteolide-1a, -1b, and -1c, see:

1a Tsuda M. Oguchi K. Iwamoto R. Okamoto Y. Kobayashi J. Fukushi E. Kawabata J. Ozawa T. Masuda A. Kitaya Y. Omasa K. J. Org. Chem.  2007,  72:  4469 

1b Tsuda T. Oguchi K. Iwamoto R. Okamoto Y. Fukushi E. Kawabata J. Ozawa T. Masuda A. J. Nat. Prod.  2007,  70:  1661 

After submission of this communication, the proposed structure of iriomoteolide-1a was confirmed incorrect via total synthesis, see:

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7 Full characterization data are found in Supporting Information

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11

Due to the volatile nature of the aldehyde obtained from alcohol 11, lower yields for the Takai olefination were noted in the scale-up synthesis.

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14

Procedure for the Synthesis of Alkene 19 A flame-dried 50 mL two-neck flask was charged with the alkyl iodide 18 (680.0 mg, 1.31 mmol). The loaded flask was evacuated and backfilled with nitrogen for five times. A solution of 9-MeO-BBN (1 M in hexanes, 5.0 mL, 5.00 mmol) and dry Et₂O (12.0 mL) were then added successively at ambient temperature (about 18 ˚C). The resultant colorless solution was cooled to -78 ˚C and kept at the same temperature for 5 min. A solution of t-BuLi (1.6 M in heptane, 2.0 mL, 3.20 mmol) was rapidly added in one portion at -78 ˚C. The resultant yellow suspension was stirred for 10 min at the same temperature. Dry THF (12.0 mL) was added and the mixture turned clear. After stirring for an additional 10 min, the cold bath was removed followed by stirring at ambient temperature for 1.5 h to give a pale yellow homogeneous solution of the B-alkyl boronate.
A separate 50 mL two-neck flask was charged with
PdCl₂ (dppf)˙CH₂Cl₂ (40.0 mg, 4.9×10^-² mmol), AsPh₃ (44.0 mg, 0.14 mmol), and Cs₂CO₃ (1.04 g, 3.2 mmol). The loaded flask was evacuated and backfilled with nitrogen for five times. A solution of the vinyl iodide 5 (360.0 mg, 0.79 mmol) in degassed DMF (12.0 mL) was added through a syringe followed by adding degassed H₂O (0.36 mL, 20 mmol). Some blocky solid in the resultant yellow suspension was crushed with ultrasonication. After stirring at ambient temperature for 5 min, the above solution of the B-alkyl boronate was added via a syringe followed by stirring for another 4 h at ambient temperature. The reaction was quenched with sat. aq NH₄Cl solution. The resultant mixture was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine, dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, first with PE and then with 2% EtOAc in PE) to afford the coupling product 19 (485.0 mg, 85%).
Characterization Data for Alkene 19
Colorless oil. [α]_D ^²0 -18.1 (c 2.50, CHCl₃). R _f  = 0.21 (100% PE). ^¹H NMR (400 MHz, CDCl₃): δ = 7.25 (d, J = 7.6 Hz, 2 H), 6.86 (d, J = 7.6 Hz, 2 H), 5.60 (dt, J = 16.0, 6.4 Hz, 1 H), 5.51 (d, J = 16.0 Hz, 1 H), 4.50 and 4.32 (ABq, J = 11.2 Hz, 2 H), 3.80 (s, 3 H), 3.73-3.64 (m, 1 H), 3.41-3.34 (m, 1 H), 3.37 (s, 2 H), 2.10-1.80 (m, 3 H), 1.71-1.60 (m, 1 H), 1.51 (br dd, J = 12.8, 10.8 Hz, 1 H), 1.28 (s, 3 H), 1.20 (br dd, J = 12.8, 12.0 Hz, 1 H), 1.07 (d, J = 6.0 Hz, 3 H), 1.00-0.90 (m, 18 H), 0.88 (br s, 12 H), 0.78 (d, J = 6.4 Hz, 3 H), 0.58 (q, J = 8.0 Hz, 12 H), 0.02 (br s, 6 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.0, 136.7, 131.3, 129.2 (2×), 127.5, 113.6 (2×), 79.7, 75.6, 72.7, 71.4, 70.7, 55.3, 36.3, 36.0, 35.3, 33.6, 25.9 (3×), 24.5, 20.9, 18.1, 14.1, 13.1, 7.1 (3×), 6.8 (3×), 6.7 (3×), 4.4 (3×), -4.3, -4.8. HRMS (+ESI): m/z [M + Na⁺] calcd for C₄₀H₇₈O₅Si₃Na: 745.5049; found: 745.5013.

15

Procedure for the Synthesis of Ketone 22a A mixture of the allyl bromide 4 (63.0 mg, 0.20 mmol), the aldehyde 20 (100.0 mg, 0.16 mmol), and indium powder (24.0 mg, 0.20 mmol) in THF-H₂O (1:1, 0.4 mL) was stirred at 70 ˚C for 16 h in a sealed pressurized vial. After cooling to r.t., the reaction mixture was diluted with 10% aq NaHCO₃ (2 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with brine, dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 9% EtOAc in hexane) to provide the alcohol 21a (79.0 mg, 57%) along with the diol 21b (24.2 mg, 20%).
To a suspension of the alcohol 21a (69.0 mg, 8.1×10^-² mmol) and solid NaHCO₃ (68.0 mg, 0.81 mmol) in CH₂Cl₂ (1 mL) cooled at 0 ˚C was added Dess-Martin periodinane (0.3 M in CH₂Cl₂, 0.83 mL, 0.25 mmol) followed by stirring at 25 ˚C for 2 h. The reaction was quenched by adding sat. aq Na₂S₂O₃ and sat. aq. NaHCO₃. The resultant mixture was extracted with EtOAc (3 × 5 mL), and the combined organic layer was washed with brine, dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 9% EtOAc in hexane) to provide the ketone 22a (42.0 mg, 61%).
Characterization Data for Ketone 22a Colorless oil. [α]_D ^²0 +16.4 (c 1.13, CHCl₃). IR (film): 2956, 1722, 1514, 1465, 1251, 1083 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.24 (d, J = 8.8 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2 H), 5.87-5.68 (m, 2 H), 5.44 (d, J = 15.2 Hz, 1 H), 5.07-4.99 (m, 2 H), 4.96 (s, 1 H), 4.83 (s, 1 H), 4.48 and 4.33 (ABq, J = 11.2 Hz, 2 H), 3.82-3.75 (m, 1 H), 3.80 (s, 3 H), 3.71-3.64 (m, 1 H), 3.43 and 3.38 (ABq, J = 18.0 Hz, 2 H), 3.36-3.31 (m, 1 H), 2.30-1.49 (m, 10 H), 1.44 (s, 3 H), 1.18 (br dd, J = 12.4, 11.6 Hz, 1 H), 1.07 (d, J = 6.0 Hz, 3 H), 0.97 (t, J = 8.4 Hz, 9 H), 0.87-0.84 (m, 21 H), 0.78 (d, J = 6.4 Hz, 3 H), 0.68-0.60 (m, 6 H), 0.05-0.01 (m, 12 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 210.2, 159.0, 140.8, 135.1, 133.9, 131.2, 130.3, 129.2 (2×), 117.0, 116.5, 113.7 (2×), 82.4, 79.9, 72.6, 71.0, 70.8, 55.3, 43.7, 43.5, 41.8, 36.1 (2×), 35.4, 33.7, 25.9 (6×), 24.4, 20.8, 18.1, 18.1, 14.2, 13.4, 7.1 (3×), 6.6 (3×),
-4.3, -4.5 (2×), -4.8. HRMS (+ESI): m/z [M + Na⁺] calcd for C₄₈H₈₈O₆Si₃Na: 867.5781; found: 867.5781.

16

Procedure for the Synthesis of Hemiacetal 23 To a solution of the ketone 22a (7.8 mg, 9.2×10^-³ mmol) in dry THF (1.0 mL) was added pyridine-buffered HF (0.15 mL, prepared from 0.5 mL of HF˙pyridine, 0.7 mL of pyridine, and 1.6 mL of THF) at r.t. After stirring at the same temperature for 1 h, no reaction had taken place according to TLC analysis. Additional HF˙pyridine (0.25 mL) was added followed by stirring at r.t. for 23 h. The reaction was quenched by adding sat. aq NaHCO₃. The mixture was extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with brine, dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 33% EtOAc in hexane) to give the hemiacetal 23 (2.3 mg, 50%) along with the hydroxy ketone 22b (0.6 mg, 9%).
Characterization Data for Hemiacetal 23
Pale yellow oil. [α]_D ^²0 -17.6 (c 0.23, CHCl₃). IR (film): 3459, 2924, 1613, 1514, 1264, 1035 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.25 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 5.88-5.70 (m, 3 H), 5.11-5.03 (m, 2 H), 4.87 (d, J = 2.0 Hz, 1 H), 4.83 (d, J = 2.0 Hz, 1 H), 4.53 and 4.32 (ABq, J = 11.0 Hz, 2 H), 3.95-3.84 (m, 1 H), 3.80 (s, 3 H), 3.79-3.70 (m, 1 H), 3.42-3.33 (m, 1 H), 3.03 (d, J = 1.6 Hz, 1 H), 2.40 (s, 1 H), 2.36-2.20 (m, 4 H), 2.17-1.84 (m, 5 H), 1.71-1.50 (m, 2 H), 1.35-1.17 (m, 2 H), 1.31 (s, 3 H), 1.12 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.5 Hz, 3 H), 0.83 (d, J = 7.0 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.2, 141.5, 134.4, 133.9, 129.5 (2×), 129.3, 117.2, 113.8 (3×), 111.3, 99.2, 80.3, 77.1, 70.8, 70.7, 70.5, 55.3, 40.2, 39.3, 37.8, 36.7, 36.5, 34.9, 32.5, 21.0, 19.6, 14.5, 13.7. MS (+TOF LD): m/z (%) = 525 (100) [M + Na⁺], 467 (55) [M⁺ - H₂O - OH]. HRMS (+TOF CI): m/z [M⁺ - H₂O - OH] calcd for C₃₀H₄₃O₄ ⁺: 467.3161; found: 467.3158.

17

Characterization Data for Hemiacetal 27 Pale yellow oil. [α]_D ^²0 -2.3 (c 0.28, CHCl₃). IR (film): 3445, 2967, 2919, 1613, 1513, 1248, 1036 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.25 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 5.85-5.70 (m, 3 H), 5.12-5.03 (m, 2 H), 4.87 (s, 1 H), 4.83 (s, 1 H), 4.47 and 4.38 (ABq, J = 11.5 Hz, 2 H), 3.95-3.85 (m, 1 H), 3.80 (s, 3 H), 3.74-3.66 (m, 1 H), 3.42-3.35 (m, 1 H), 3.09 (s, 1 H), 2.45 (br s, 1 H), 2.35-2.14 (m, 5 H), 2.07-1.93 (m, 3 H), 1.90 (dd, J = 12.5, 12.5 Hz, 1 H), 1.75-1.60 (m, 2 H), 1.45-1.32 (m, 2 H), 1.29 (s, 3 H), 1.09 (d, J = 7.0 Hz, 3 H), 0.90 (d, J = 6.5 Hz, 3 H), 0.88 (d, J = 7.0 Hz, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 159.3, 141.6, 134.4, 133.8, 129.5 (2×), 129.3, 117.1, 113.9, 113.9 (2×), 111.2, 99.2, 80.0, 77.1, 70.7, 70.6, 70.0, 55.3, 40.2, 39.4, 37.9, 36.0, 36.0, 35.0, 32.7, 21.1, 20.1, 14.8, 14.6. HRMS (+TOF EI): m/z [M⁺] calcd for C₃₀H₄₆O₆ ⁺: 502.3294; found: 502.3316.