noester 9 was reacted with DEAD and triphenylphosphine
in benzene under high dilution conditions to produce the
cyclic phosphonates 10a and 10b in 82% yield as a 5:1
mixture of diastereomers.6
Scheme 1
In addition to the two 14-membered ring diastereomers
10a and 10b, a cyclic dimer side product 11 was isolated as
rod-shaped crystals on purification of 10a and 10b. The
structure of dimer 11 was determined by single-crystal X-ray
diffraction (Figure 1).7 Dimer 11, a centrosymmetric 28-
Figure 1. Stereoview of an ORTEP representation of dimer 11
showing 33% probability ellipsoids. Hydrogen atoms have been
given arbitrary thermal parameters for clarity.
membered ring compound with two parallel chains bridged
at both ends by the phosphonate group, contains four
stereogenic centers with R*R* stereochemistry on one bridge
and the mirror image S*S* stereochemistry at the opposite
then reduced using H2 and 10% Pd/C in EtOAc to give the
saturated diphenyl phosphonate 7 in 99% yield. Phosphonate
7 was subsequently reacted with p-toluenesulfonic acid to
liberate the secondary hydroxyl of compound 8 in 86% yield.
Phosphonic acid monoester 9 was produced in 76% yield
by base hydrolysis of 8 in refluxing potassium hydroxide/
THF.
(6) Selected data for compounds are as follows. 10a: Rf ) 0.71 (silica
gel, petroleum ether/ethyl acetate 1:1); FTIR (neat) 2927, 2859, 1593, 1490,
1
1458, 1380, 1253, 1210, 1163, 1071, 991, 920, 766 cm-1; H NMR (400
MHz, CDCl3) δ 7.05-7.38 (m, 5H), 4.75 (m, 1H), 1.24-1.88 (m, 22H),
1.22 (d, J ) 6.3 Hz, 3H); 31P NMR (81 MHz, CDCl3) δ 29.6; HRMS calcd
for C19H31O3P 338.2011, found 338.2002. Anal. Calcd for C19H31O3P: C,
67.42; H, 9.24. Found: C, 67.20; H, 9.20. 10b: mp 97-99 °C.; Rf ) 0.57
(silica gel, petroleum ether/ethyl acetate 1:1); FTIR (CDCl3) 2932, 2860,
1593, 1492, 1456, 1223, 1011 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.05-
7.38 (m, 5H), 4.65 (m, 1H), 1.93 (m, 2H), 1.20-1.73 (m, 20H), 1.43 (d, J
) 6.2 Hz, 3H); 31P NMR (81 MHz, CDCl3) δ 27.8; HRMS calcd for
C19H31O3P 338.2011, found 338.2009. Anal. Calcd for C19H31O3P: C, 67.42;
H, 9.24. Found: C, 67.15; H, 9.39. 11: mp 103-105 °C; Rf ) 0.62 (silica
gel, petroleum ether/ethyl acetate 1:1); FTIR (CDCl3) 2930, 2856, 1593,
The key step5 in the synthesis of the macrocyclic phos-
phonate 10 was the cyclization of 9 to give the 14-membered
ring phosphonate 10. The hydroxy phosphonic acid mo-
(5) To a stirred solution of compound 9 (125 mg, 0.351 mmol) in 150
mL of dry PhH at room temperature under N2 was added Ph3P (368 mg,
1.40 mmol), followed by DEAD (221 µL, 1.40 mmol). After 2 h, the solvent
was removed under reduced pressure, and the resulting crude mixture was
purified by flash chromatography using 2:1 hexane and ethyl acetate to
afford the separated diastereomers, 10a and 10b, in a 5:1 ratio based on
recovered yields and a combined yield of 82%. In addition, 6 mg of dimer
11 was isolated as a colorless, crystalline solid.
1491, 1229, 1012 cm-1 1H NMR (400 MHz, CDCl3) δ 7.10-7.33 (m,
;
10H), 4.66 (m, 2H), 1.84 (m, 4H), 1.68 (m, 4H), 1.56 (m, 4H), 1.20-1.45
(m, 40H), 1.15 (d, J ) 6.2 Hz, 6H); 31P NMR (81 MHz, CDCl3) δ 29.0;
HRMS calcd for C38H62O6P2 676.4022, found 676.4002. Anal. Calcd for
C38H62O6P2: C, 67.42; H, 9.24. Found: C, 67.51; H, 9.28.
(7) Crystal data for 11: C38H62O6P2; monoclinic; P21/n; a ) 7.841(1)
Å; b ) 5.664(2) Å; c ) 43.378(1) Å; â ) 90.259(8)°; V ) 1926.4(5) Å3;
Z ) 2; colorless; T ) 294 K; R ) 0.030; GOF ) 2.27.
644
Org. Lett., Vol. 3, No. 5, 2001