P. Allevi et al. / Bioorg. Med. Chem. 7 (1999) 2749±2752
2751
chlorodimethylthexylsilane (7.9 mL; 40 mmol) for 1 h at
room temperature. At this time, the mixture was poured
in ice cold water and worked up to aord the thexylsilyl
derivative 5 (10.7 g; Y 90%): mp 114±116ꢀC (needles from
moist acetone); [a]2d0 49.8 (CHCl3; c 1); 1H NMR
(CDCl3; 500 MHz): d 5.10 (1H, dd, J=11.5, 2.5 Hz, H-13),
4.91 (1H, dd, J=5.0, <1Hz, H-100), 4.41 (1H, d, J=
7.5 Hz, H-10), 4.02 (1H, dd, J=9.5, 1.5 Hz, H-3), 4.00 (1H,
dq, J=9.5, 7.5 Hz, H-500), 3.82 (1H, ddq, J=8.5, 7.0,
2.0 Hz, H-8), 3.68 (1H, d, J<1Hz, H-11), 3.57 (1H, d,
J=7.5Hz, H-5), 3.47 (1H, ddq, J=11.0, 7.0, 2.0 Hz, H-50),
3.30 (3H, s, 300-OCH3), 3.20 (1H, dd, J=10.5, 7.5 Hz, H-
20), 3.00 (1H, d, J=9.5Hz, H-400), 2.88 (1H, dq, J=9.5,
7.5 Hz, H-2), 2.67 (1H, dq, J=7.0, <1Hz, H-10), 2.43
(1H, ddd, J=12.5, 10.5, 3.0 Hz, H-30), 2.34 (1H, dd,
J=15.0, <1 Hz, H-200a), 2.28 (6H, s, N(CH3)2), 1.98 (1H,
ddq, J=7.5, 7.5, 1.5 Hz, H-4), 1.89 (1H, ddq, J=15.0,
7.5, 2.5 Hz, H-14a), 1.66±1.53 (5H, overlapping), 1.46
(3H, s, 6-CH3), 1.45 (1H, ddq, J=15.0, 11.5, 7.5 Hz, H-
14b), 1.28 (3H, d, J=7.5 Hz, 500-CH3), 1.22 (3H, s, 300-
CH3), 1.21 (3H, d, J=7.0 Hz, 50-CH3), 1.16 (3H, d,
J=7.5 Hz, 2-CH3), 1.15 (3H, d, J=7.0 Hz, 10-CH3), 1.11
(3H, s, 12-CH3), 1.09 (3H, d, J=7.5 Hz, 4-CH3), 0.99
(3H, d, J=7.0 Hz, 8-CH3), 0.88 [6H, s, SiC(CH3)2
CH(CH3)2], 0.87 (6H, d, J=4.0 Hz, SiC(CH3)2 CH
(CH3)2), 0.82 (3H, dd, J=7.5, 7.5 Hz, 15-CH3), 0.19 and
0.18 ppm (2Â3H, 2Âs, Si(CH3)2).
Synthesis of 20,400-[O-bis(trimethylsilyl)]clarithromycin
A 9-[O-(dimethylthexylsilyl)oxime] (7). The protected
oxime 6 (9.0 g; 8.66 mmol) dissolved in a solution of
THF:DMSO (180 mL; 1:1, v/v) was treated with CH3I
(1.51 mL; 24.3 mmol) and stirred for 10 min at 0±5ꢀC.
Then NaH (414 mg of a 60% dispersion; 10.35 mmol)
was added and the mixture was stirred for 1 h at the
same temperature. The mixture was then poured into ice
cold water and worked up to aord the 6-O-methyl
derivative 7 as a crude amorphous solid (8.82 g) contain-
ing some unmethylated starting material (5%; TLC
separation). The crude product 7 resisted all eorts of
crystallization and was used for the next reaction without
1
puri®cation. Its H NMR spectrum (CDCl3; 500 MHz)
showed (main compound): d 5.09 (1H, dd, J=11.0,
2.5 Hz, H-13), 4.87 (1H, dd, J=5.0, <1Hz, H-100), 4.39
(1H, d, J=7.0 Hz, H-100), 4.20 (1H, dq, J=9.5, 6.5 Hz, H-
500), 3.82 (1H, ddq, J=8.5, 7.0, 2.0 Hz, H-8), 3.77 (1H, dd,
J=9.5, 1.5 Hz, H-3), 3.76 (1H, d, J<1 Hz, H-11), 3.62
(1H, ddq, J=11.0, 6.0, 2.0 Hz, H-50), 3.59 (1H, d,
J=7.5Hz, H-5), 3.29 (3H, s, 300-OCH3), 3.14 (1H, d,
J=9.5Hz, H-400), 3.11 (1H, dd, J=10.0, 7.0 Hz, H-20),
3.02 (3H, s, 6-OCH3), 2.81 (1H, dq, J=9.5, 7.0 Hz, H-2),
2.57 (1H, dq, J=7.0, <1Hz, H-10), 2.51 (1H, ddd,
J=12.5, 10.0, 4.0 Hz, H-30), 2.33 (1H, dd, J=15.0, <1
Hz, H-200a), 2.20 (6H, s, N(CH3)2), 1.91 (1H, ddq,
J=14.0, 7.5, 2.5 Hz, H-14a), 1.81 (1H, ddq, J=7.5, 6.5,
1.5 Hz, H-4), 1.69±1.41 (6H, overlapping), 1.62 (3H, s, 6-
CH3), 1.40 (3H, s, 300-CH3), 1.20 (3H, d, J=6.5Hz, 500-
CH3), 1.16±1.11 (9H, overlapping, 2-CH3, 10-CH3, 50-
CH3), 1.15 (3H, s, 12-CH3), 1.02 (3H, d, J=6.5Hz, 4-
CH3), 0.91 (3H, d, J=7.5 Hz, 8-CH3), 0.88 (6H, s,
SiC(CH3)2CH(CH3)2), 0.85 (6H, d, J=4.5 Hz, SiC(CH3)2
CH(CH3)2), 0.82 (3H, dd, J=7.5, 7.5 Hz, 15-CH3), 0.17
and 0.16 (2Â3H, 2Âs, Si(CH3)2), 0.13 (3H, s, Si(CH3)3),
0.07ppm (3H, s, Si(CH3)3).
Elemental analysis, calculated for C45H86N2O13Si: C,
60.64; H, 9.73; N, 3.14. Found: C, 60.9; H, 9.6; N, 3.2%.
Synthesis of 20,400-[O-bis(trimethylsilyl)]erythromycin A
9-[O-(dimethylthexylsilyl)oxime] (6). The thexylsilyl deri-
vative 5 (9 g; 10mmol) dissolved in EtOAc (80 mL) was
treated with 1-trimethylsilylimidazole (3.0 mL; 20mmol)
and chlorotrimethylsilane (2.58 mL; 20 mmol) at room
temperature for 1 h. At this time, the mixture was poured
in ice cold water and worked up to aord the dimethyl-
thexylsilyltrimethylsilyl derivative 6 (9.94 g; Y 95.1%): mp
105±108ꢀC (needles from moist acetone); [a]2d0 49.2
(CHCl3; c 1); 1H NMR (CDCl3; 500 MHz): d 5.06 (1H, dd,
J=11.5, 2.5 Hz, H-13), 4.86 (1H, dd, J=5.0, <1Hz, H-
100), 4.36 (1H, d, J=7.5Hz, H-10), 4.21 (1H, dq, J=9.5,
6.5 Hz, H-500), 4.13 (1H, dd, J=9.5, 1.5 Hz, H-3), 3.83 (1H,
ddq, J=8.5, 7.5, 2.0 Hz, H-8), 3.68 (1H, d, J<1Hz, H-11),
3.60 (1H, ddq, J=11.0, 6.5, 2.0 Hz, H-50), 3.54 (1H, d,
J=8.0Hz, H-5), 3.28 (3H, s, 300-OCH3), 3.14 (1H, dd,
J=10.5, 7.5 Hz, H-20), 3.13 (1H, d, J=9.5 Hz, H-400), 2.82
(1H, dq, J=9.5, 7.0 Hz, H-2), 2.69 (1H, dq, J=7.0,
<1Hz, H-10), 2.51 (1H, ddd, J=12.5, 10.5, 4.5 Hz, H-30),
2.33 (1H, dd, J=15.0, <1Hz, H-200a), 2.20 (6H, s,
N(CH3)2), 1.94±1.86 (2H, overlapping, H-4 and H-14a),
1.67±1.42 (6H, overlapping), 1.56 (3H, s, 6-CH3), 1.42 (3H,
s, 300-CH3), 1.19 (3H, d, J=6.5 Hz, 500-CH3), 1.17±1.14
(9H, overlapping, 2-CH3, 10-CH3, 50-CH3), 1.13 (3H, s,
12-CH3), 1.06 (3H, d, J=7.5Hz, 4-CH3), 0.99 (3H, d, J=
7.5 Hz, 8-CH3), 0.88 (6H, s, SiC(CH3)2CH(CH3)2), 0.87
(6H, d, J=3.5 Hz, SiC(CH3)2CH(CH3)2), 0.83 (3H, dd, J=
7.5, 7.5 Hz, 15-CH3), 0.18 and 0.17 [2Â3H, 2Âs, Si(CH3)2],
0.12 (3H, s, Si(CH3)3), 0.09 ppm (3H, s, Si(CH3)3).
The presence of the possible 6,11-dimethylated homo-
logue and of the 11-methyl isomer could not be exclu-
ded by the analysis of the 1H NMR spectrum of 7.
However performing the methylation using 13CH3I (on
0.5 mmol scale), the 13C NMR analysis of the crude
product precluded any appreciable presence of these
compounds and indicated that 6-methylated compound
7 was more than 90% pure.
Synthesis of clarithromycin (2). To the crude 9-[O-(di-
methylthexylsilyl)oxime 7, (8.82 g), dissolved in ethanol
(30 mL) containing formic acid (0.88 mL; 23.2mmol), was
added an aqueous solution of Na2S2O5 (3.78g in 30mL)
and re¯uxed for 30min. At this time the mixture was
cooled to room temperature, diluted with water and its pH
adjusted to 11 with NaOH (2 M). The resulting suspension
was extracted with ethyl acetate, worked up and crystal-
lised from ethanol to aord clarithromycin (2) (4.32g;
66.3% yield from compound 6): mp 221±224ꢀC; [a]d20
82.6 (CHCl3; c 1) (lit.4 mp 222±225ꢀC; [a]2d0 90.4); and
the expected 1H NMR spectrum.11,12
Acknowledgements
Elemental analysis, calculated for C51H102N2O13Si3: C,
59.15; H, 9.93; N, 2.70. Found: C, 58.9; H, 9.8; N, 2.5%.
We thank Professor Riccardo Stradi for a generous gift of
erythromicyn A and the Italian Ministero dell'Universita