Total Synthesis of Mycoside B and HBAD-I
mixture was stirred at 0 °C. Then Cl3CCN (20.5 mL, 205 mmol,
7 equiv.) was added and the mixture stirred until consumption of
the starting material (1.5 h). Silica gel (ca. 500 mg) was added to
quench the reaction, and the mixture was filtered and concentrated
under reduced pressure. The product was purified by flash
chromatography to give compound 28α (11.7 g, 22.1 mmol, 75%
yield) and its anomer 28β (1.7 g, 3.2 mmol, 10.9% yield). The spec-
troscopic data are in agreement with those of previous reports for
these compounds.[30]
fied by flash chromatography to give compound 30 (3.32 g,
6.08 mmol, 87% yield) as a colorless oil. [α]2D2 = –113.6 (c = 1.0,
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 9.0 Hz, 2
1
H), 7.44–7.30 (m, 10 H), 6.83 (d, J = 9.0 Hz, 2 H), 5.52 (d, J =
1.7 Hz, 1 H), 4.92 (d, J = 10.9 Hz, 1 H), 4.81 (d, J = 11.9 Hz, 1
H), 4.75 (d, J = 11.5 Hz, 1 H), 4.68 (d, J = 10.9 Hz, 1 H), 4.20 (dt,
J = 3.1, 1.5 Hz, 1 H), 4.04 (dd, J = 9.1, 3.4 Hz, 1 H), 3.80 (dq, J
= 9.8, 6.3 Hz, 1 H), 3.55 (t, J = 9.4 Hz, 1 H), 2.73 (d, J = 1.5 Hz,
1 H), 1.29 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 155.9 (s), 138.3 (d), 138.1 (s), 137.7 (s), 128.6 (d), 128.4 (d),
128.0 (d), 127.9 (d), 127.82 (d), 127.76 (d), 118.5 (d), 97.0 (d), 84.7
(s), 79.67 (d), 79.64 (d), 75.4 (t), 72.3 (t), 68.29 (d), 68.22 (d), 17.9
(q) ppm. HRMS (ESI+): calcd. for C26H27IO5Na [M + Na]+
569.0795; found 569.0807.
1
28α: H NMR (400 MHz, CDCl3): δ = 8.67 (s, 1 H), 7.40–7.29 (m,
10 H), 6.20 (d, J = 1.9 Hz, 1 H), 5.51 (dd, J = 3.3, 2.0 Hz, 1 H),
4.95 (d, J = 10.8 Hz, 1 H), 4.75 (d, J = 11.2 Hz, 1 H), 4.66 (d, J =
10.8 Hz, 1 H), 4.60 (d, J = 11.2 Hz, 1 H), 4.02 (dd, J = 9.5, 3.4 Hz,
1 H), 3.97 (dq, J = 9.8, 6.3 Hz, 1 H), 3.55 (t, J = 9.6 Hz, 1 H), 2.21
(s, 3 H), 1.38 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 170.0 (s), 160.1 (s), 138.1 (s), 137.5 (s), 128.4 (d), 128.4
(d), 128.3 (d), 128.1 (d), 127.89 (d), 127.85 (d), 95.2 (d), 79.3 (d),
77.2 (d), 75.6 (t), 72.0 (t), 70.7 (d), 67.6 (d), 21.0 (q), 18.0 (q) ppm.
28β: 1H NMR (400 MHz, CDCl3): δ = 8.66 (s, 1 H), 7.51–7.18 (m,
10 H), 5.90 (d, J = 2.9 Hz, 2 H), 4.96 (d, J = 10.9 Hz, 1 H), 4.79
(d, J = 11.2 Hz, 1 H), 4.66 (d, J = 10.9 Hz, 1 H), 4.55 (d, J =
11.2 Hz, 1 H), 3.77 (dd, J = 8.7, 3.1 Hz, 1 H), 3.68–3.46 (m, 2 H),
2.22 (s, 3 H), 1.44 (d, J = 5.8 Hz, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 170.23 (s), 160.17 (s), 138.07 (s), 137.35 (s), 128.39 (d),
128.32 (d), 128.07 (d), 127.95 (d), 127.82 (d), 127.75 (d), 95.04 (d),
79.49 (d), 79.01 (d), 75.35 (t), 72.79 (d), 71.49 (t), 66.47 (d), 20.85
(q), 17.79 (q) ppm.
p-Iodophenyl
3,4-Di-O-benzyl-2-O-methyl-α-L-rhamnopyranoside
(3): NaH (55% dispersion in mineral oil, 527 mg, 12.1 mmol) was
added at 0 °C to a solution of 30 (3.30 g, 6.04 mmol) and methyl
iodide (1.50 mL, 24.2 mmol) in DMF (30 mL). The mixture was
stirred at 0 °C until completion (1 h), quenched with a saturated
solution of NH4Cl (20 mL), and diluted with Et2O (300 mL). The
organic layer was washed with NH4Cl (20 mL) and brine (20 mL),
dried (Na2SO4), the solvent removed under reduced pressure, and
the residue purified by flash chromatography to give compound 3
(3.20 g, 5.71 mmol, 95% yield) as a colorless oil. [α]2D2 = –101.2 (c
= 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J =
9.0 Hz, 1 H), 7.47–7.29 (m, 10 H), 6.82 (d, J = 9.0 Hz, 2 H), 5.49
(d, J = 1.9 Hz, 1 H), 4.96 (d, J = 10.8 Hz, 1 H), 4.81 (d, J =
12.5 Hz, 1 H), 4.77 (d, J = 12.5 Hz, 1 H), 4.66 (d, J = 10.8 Hz, 1
H), 4.04 (dd, J = 9.3, 3.2 Hz, 1 H), 3.73 (dq, J = 9.8, 6.3 Hz, 1 H),
3.70 (dd, J = 3.2, 2.0 Hz, 1 H), 3.60 (t, J = 9.5 Hz, 1 H), 3.58 (s, 3
H), 1.29 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 156.1 (s), 138.35 (s), 138.30 (d), 138.26 (s), 128.4 (d), 128.3,
127.9 (d), 127.8 (d), 127.73 (d), 127.66 (d), 118.5 (d), 95.5 (d), 84.7
(s), 80.2 (d), 79.5 (d), 77.8 (d), 75.5 (t), 72.5 (t), 68.8 (d), 59.6 (q),
17.9 (q) ppm. HRMS (ESI+): calcd. for C27H29IO5Na [M + Na]+
583.0952; found 583.0964.
The four compounds interconvert under these conditions and con-
verge into a single product. Similarly, both 28α and 28β can be
used in the next step to give a very similar result.
p-Iodophenyl
2-O-Acetyl-3,4-di-O-benzyl-α-L-rhamnopyranoside
(29): A solution of 28α (4.80 g, 9.04 mmol) in CH2Cl2 (15 mL) was
added to a suspension of 4-iodophenol (3.78 g, 17.2 mmol) in
CH2Cl2 (40 mL) at –45 °C. Then TMSOTf (163 μL, 0.9 mmol) was
added and the mixture stirred while slowly warming to 20 °C.
When 28α had been completely consumed (1.5 h), pyridine (1 mL)
was added to quench the reaction. The mixture was filtered and
the solvents removed under reduced pressure. The residue was di-
luted in EtOAc (300 mL) and washed with a 3 m NaOH solution
(2ϫ 30 mL), water (20 mL), NH4Cl (20 mL), and brine (20 mL).
The organic layer was dried with Na2SO4, the solvent removed un-
der reduced pressure, and the residue purified by flash chromatog-
raphy to give compound 29 (4.79 g, 90% yield) as a colorless oil.
4-[(17R,19R,24S,25R)-17,19-Dihydroxy-25-methoxy-24-methylhep-
tacos-1-ynyl]phenyl 3,4-Di-O-benzyl-2-O-methyl-α-L-rhamnopyrano-
side (31): A stock solution of the catalyst was prepared by mixing
PPh3 (7.0 mg, 26.8 μmol), CuI (10.2 mg, 53.6 μmol), and
[PdCl2(PPh3)2] (18.8 mg, 26.8 μmol) in freshly distilled Et3N
(8.9 mL) and stirring this solution at 40 °C for 15 min. Then this
stock solution (1.8 mL, equivalent loading of 5 mol-% Pd, 5 mol-
% PPh3, and 10 mol-% Cu) was added to a solution of compound
5 (58.2 mg, 128 μmol) and monosaccharide 3 (60.0 mg, 107 μmol)
in freshly distilled Et3N (0.3 mL). The mixture was then stirred at
40 °C until completion (5 h). Triethylamine was removed under a
stream of nitrogen and the residue dissolved in toluene and purified
by column chromatography to give compound 31 (86.0 mg,
97 μmol, 91% yield) as a waxy solid. [α]2D2 = –67.5 (c = 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.42 (d, J = 6.6 Hz, 2 H), 7.38–
7.27 (m, 10 H), 6.93 (d, J = 8.9 Hz, 2 H), 5.51 (d, J = 1.8 Hz, 1
H), 4.95 (d, J = 10.8 Hz, 1 H), 4.81 (d, J = 12.2 Hz, 1 H), 4.75 (d,
J = 12.5 Hz, 1 H), 4.64 (d, J = 10.8 Hz, 1 H), 4.04 (dd, J = 9.3,
3.2 Hz, 1 H), 3.93 (br. s, 2 H), 3.73 (dq, J = 9.8, 6.5 Hz, 1 H), 3.68
(dd, J = 3.2, 2.0 Hz, 1 H), 3.58 (d, J = 9.4 Hz, 1 H), 3.56 (s, 3 H),
3.34 (s, 3 H), 2.87 (ddd, J = 7.5, 5.2, 4.0 Hz, 1 H), 2.37 (t, J =
7.1 Hz, 2 H), 2.34 (s, 2 H), 1.72–1.02 (m, 39 H), 0.92 (t, J = 7.4 Hz,
3 H), 0.84 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 155.5 (s), 138.43 (s), 138.33 (s), 132.8 (d), 128.4 (d), 128.4 (d),
128.0 (d), 127.9 (d), 127.8 (d), 127.7 (d), 117.8 (s), 116.1 (d), 95.3
(d), 89.4 (s), 86.7 (d), 80.3 (d), 80.0 (s), 79.5 (d), 77.9 (d), 75.5 (t),
72.5 (t), 69.50 (d), 69.45 (d), 68.8 (d), 59.6 (q), 57.4 (q), 42.3 (t),
1
[α]2D2 = –49.6 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ =
7.58 (d, J = 8.7 Hz, 2 H), 7.42–7.29 (m, 10 H), 6.81 (d, J = 8.7 Hz,
2 H), 5.53 (m, 1 H), 5.44 (s, 1 H), 4.96 (d, J = 10.8 Hz, 1 H), 4.78
(d, J = 11.2 Hz, 1 H), 4.65 (d, J = 10.6 Hz, 1 H), 4.63 (d, J =
11.1 Hz, 1 H), 4.13 (dd, J = 9.3, 3.3 Hz, 1 H), 3.82 (dq, J = 9.8,
6.3 Hz, 1 H), 3.53 (t, J = 9.4 Hz, 1 H), 2.20 (s, 3 H), 1.31 (d, J =
6.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.3 (s), 155.7
(s), 138.4 (d), 138.2 (s), 137.8 (s), 128.4 (d), 128.4 (d), 128.0 (d),
127.9 (d), 127.8 (d), 127.7 (d), 118.6 (d), 95.8 (d), 85.1 (s), 79.8 (d),
77.6 (d), 75.5 (t), 72.0 (t), 68.66 (d), 68.67 (d) 21.0 (q), 17.94
(q) ppm. HRMS (ESI+): calcd. for C28H28IO6Na [M + Na]+
611.0910; found 611.0914.
p-Iodophenyl 3,4-Di-O-benzyl-α-L-rhamnopyranoside (30): Sodium
methoxide (188 mg, 3.48 mmol) was added to a solution of com-
pound 29 (4.1 g, 6.97 mmol) in MeOH (40 mL) and the mixture
was stirred at room temp. until completion (24 h). The resulting
solution was diluted with EtOAc (200 mL) and washed with water
(20 mL) and brine (20 mL). The organic layer was dried (Na2SO4),
the solvent removed under reduced pressure, and the residue puri-
Eur. J. Org. Chem. 2013, 4642–4654
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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