SCHEME 6. Synthesis of Protected Galbonolide B 18
The macrocycle obtained from acetal cleavage of 18 had
identical spectral data in every respect to that published. In
addition, X-ray analysis confirmed the structure of galbonolide
B 1.
In summary, we report an efficient total synthesis of the
antifungal agent galbonolide B 1.
SCHEME 7. Synthesis of Galbonolide B 1
with 2-propenylmagnesium bromide gave the enone 1113 in high
(99%) yield. A borane mediated reduction of the enone 11 under
the conditions reported by Berenguer et al.14 gave the homochiral
allylic alcohol 12. The allylic alcohol 12 was coupled with the
carboxylate 1315 to afford the ester 14 (Scheme 4).
Experimental Section
(2S,4S)-4-((2E,7E)-(4S,9S)-2,4,8-Trimethyl-6-methylene-9-tri-
ethylsilanyloxy-undeca-2,7-dienyl)-2-(2,4,6-trimethyl-phenyl)-
1,3-dioxolane-4-carboxylic Acid (15) and (2S,4R)-4-((2E,7E)-
(4S,9S)-2,4,8-Trimethyl-6-methylene-9-triethylsilanyloxy-undeca-
2,7-dienyl)-2-(2,4,6-trimethyl-phenyl)-1,3-dioxolane-4-car-
With the ester 14 in hand, experiments were conducted to
induce an ester enolate rearrangement such that the diol present
at C4 of galbonolide B 1 could be introduced in one synthetic
operation. It was eventually found that when the ester 14 was
treated with LDA in the presence of trimethylsilyl chloride and
hexamethylphosphoric triamide in THF at -100 °C,16 the
desired rearrangement took place to afford the carboxylic acids
15 and 15′ in 75% yield and a 1:1 ratio. Carboxylic acid 15
and its C2 epimer, 15′, were separated by flash column
chromatography. Methylation of the carboxylic acid 15 with
trimethylsilyldiazomethane17 followed by removal of the silicon
protecting group and acetylation gave the ester 16 (Scheme 5).
Treatment of the ester 16 with lithium hexamethyldisilazide
in boiling THF afforded the macrocycle 17 in 32% yield
(Scheme 6).
Stereoselective methylation at C2 was achieved with potas-
sium tertiary butoxide and iodomethane using the procedure of
Tse et al.4 Inversion of the methyl group at C2 was achieved
using potassium tertiary butoxide followed by careful addition
of acetic acid to afford the macrocyclic lactone 18 in 47% yield.
The macrocyclic lactone 18 was converted into galbonolide B
using aqueous acetic acid (91%, Scheme 7).
i
boxylic Acid (15′). To a solution of Pr2NH (230 µL, 2.70 mmol)
in THF (9 mL) at 0 °C was added BuLi (1.15 mL, 2.70 mmol,
n
2.35 M in hexanes) and stirred for 10 min. The yellow solution
was cooled to -100 °C, and HMPA (2 mL) was added. A mixture
of TMSCl (454 µL, 3.59 mmol) and Et3N (250 µL, 1.80 mmol) in
THF (1 mL) was filtered and added to the reaction mixture at -100
°C quickly followed by the dropwise addition of ester 14 (530 mg,
0.90 mmol) in THF (6 mL). The resultant pale yellow solution was
stirred for 1 h at -100 °C and then allowed to warm slowly to
room temperature before being warmed to 40 °C for 10 h. The
reaction mixture was cooled to room temperature and quenched
with a saturated aqueous solution of NH4Cl (20 mL), and the phases
separated. The aqueous phase was extracted with CH2Cl2 (3 × 50
mL), and the combined organic extracts were washed brine (20
mL). The organic phase was then dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography, eluting with a gradient
of 60% Et2O/petrol to 100% Et2O, to afford the title compound 15
as a yellow gum (209 mg, 39%) and 15′ as a yellow gum (190 mg,
36%).
TLC, (90% diethyl ether/petrol) (15) Rf ) 0.53; (15′) Rf ) 0.38;
ν
max (film/cm-1) 2956 (s), 2876 (s), 1725 (m), 1613 (w), 1454 (m),
1376 (w), 1249 (m), 1067 (s), 1006 (m), 965 (w), 848 (s), 743
(m); δH (300 MHz, C6D6) (15) 7.25 (1H, bs), 6.68 (2H, s), 6.21
(1H, s), 5.81 (1H, s), 5.17 (1H, d, J ) 9.1 Hz), 5.07 (1H, s), 4.97
(1H, s), 4.64 (1H, d, JAX ) 8.7 Hz), 3.93 (1H, t, J ) 6.2 Hz), 3.69
(1H, d, J ) 8.7 Hz), 2.71-2.47 (3H, m), 2.45 (6H, s), 2.23-2.13
(1H, m), 2.07-1.99 (1H, m), 2.06 (3H, s), 1.80 (3H, s), 1.78 (3H,
s), 1.65-1.54 (2H, m), 1.01 (9H, t, J ) 7.9 Hz), 0.97 (3H, d, J )
9.1 Hz), 0.88 (3H, t, J ) 7.2 Hz), 0.62 (6H, q, J ) 7.9 Hz); (15′)
10.11 (1H, bs), 6.68 (2H, s), 6.45 (1H, s), 5.79 (1H, s), 5.24 (1H,
d, J ) 8.8 Hz), 5.04 (1H, s), 4.93 (1H, s), 4.35 (1H, d, JAX ) 8.3
Hz), 3.92 (1H, t, J ) 6.2 Hz), 3.85 (1H, d, JAX ) 8.3 Hz), 2.71
(1H, d, JAB ) 13.8 Hz), 2.65-2.54 (1H, m), 2.54-2.48 (1H, m),
(11) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22 (39), 3815.
(b) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1 (7), 351.
(12) Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123 (15),
3611.
(13) Schmid, C. R.; Glasebrook, A. L.; Misner, J. W.; Stephenson, G.
A. Bioorg. Med. Chem. Lett. 1999, 9 (8), 1137.
(14) Berenguer, R.; Garcia, J.; Vilarrasa, J. Tetrahedron: Asymmetry
1994, 5 (2), 165.
(15) Powell, N. A.; Roush, W. R. Org. Lett. 2001, (3), 453.
(16) Ireland, R. E.; Norbeck, D. W. J. Am. Chem. Soc. 1985, 107 (11),
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J. Org. Chem, Vol. 72, No. 24, 2007 9389