can be coupled with a wide variety of organotin,3a organo-
boron,5d and organocopper reagents.15 Thus this route may
also be of more general interest, in that it should be applicable
to the stereoselective synthesis of a broad range of trisub-
stituted allylic alcohols.
is clear that this enzyme can be utilized to attach the
unnatural Z,E- and E,Z-farnesyl moieties to cysteine residues
in peptides and proteins that are normally modified with the
natural E,E-farnesyl chain.19
Acknowledgment. This research was supported by NIH
Grants CA-67292 and CA-78819 to R.A.G. R.A.G. was also
the recipient of an American Cancer Society Junior Faculty
Research Award (JFRA-609). J.T.E. was supported in part
by the WSU MBRS program (GM-08167). We thank Dr.
Mohamad Ksebati (Department of Chemistry, WSU) for
performing the NMR-based stereochemical comparison of
4 and 10.
The biological results, in particular the ability of Z,E-FPP
and E,Z-FPP to act as effective mFTase substrates, are quite
surprising. This is particularly true because the E,E-isomer
of R-hydroxyfarnesyl phosphonate is a very potent mFTase
inhibitor, while the Z,E-isomer is a very poor inhibitor.16
Perhaps the hydroxyphosphonates bind to mFTase in a
different manner than the FPP analogues. The results seen
with the three FPP isomers also appear surprising in view
of the exceptionally low Kd for FPP binding to mFTase (∼2
nM)10b along with the restrictive farnesyl binding site evident
from recent crystallographic structures.17 However, previous
studies have indicated that several other structurally diverse
FPP analogues can bind tightly to FTase, and a subset of
these can act as alternative substrates.18 Whatever the reason
for the observed relaxed substrate specificity of mFTase, it
OL990714I
(m, 2H), 2.56 (app t, 2H), 3.43 (s, 2H), 4.19 (q, 2H), 5.08 (m, 2H). 13C
NMR: δ 14.8 (O-CH2CH3), 18.4 (CH3 at C11), 22.6 (C5), 24.0 (CH3 at
C7), 26.4 (C12), 27.3 (C10), 32.6 (C9), 44.0 (C4), 50.1 (C2), 62.1 (O-CH2-
CH3), 123.6 (C6), 124.8 (C10), 132.4, 137.5, 167.9, 203.3.9 Ethyl 3-(Tri-
fluoromethylsulfonyloxy)-7,11-dimethyldodeca-2(E),6(Z),10-trienoate (14).
To a solution of 10 (867 mg, 3.26 mmol) in DMF (8.0 mL, HPLC grade,
used as obtained) at -60 °C was added potassium bis(trimethylsilyl)amide
(0.5 M in toluene; 7.7 mL, 3.85 mmol). After 2 h, 2-[N,N-bis(trifluoro-
methylsulfonyl)amino]-5-chloropyridine (1.39 g, 3.54 mmol) in ∼5 mL of
DMF was added to the resulting enolate solution, and stirring was continued
at ca. -60 °C for 3.5 h. The reaction was then taken up in 30 mL of ether,
washed with 10% aqueous citric acid (2 × 20 mL), and water (20 mL).
The organic layer was dried over MgSO4 and concentrated. Flash chroma-
tography (20:1 hexane/EtOAc) afforded 797 mg (60%) of triflate 14. None
of the isomeric triflate 11 was observed by proton NMR. 1H NMR: δ 1.28
(t, 3H), 1.60 (s, 3H), 1.69 (app s, 6H), 2.04 (app s, 4H), 2.30 (m, 2H), 2.91
(t, 2H), 4.20 (q, 2H), 5.11 (m, 3H), 5.93 (s, 1H). Note the characteristic
strong deshielding of the C4-CH2 signal (δ 2.91) by the ester carbonyl (C4-
CH2 signal for triflate 11: δ 2.39). Ethyl 3,7,11-Trimethyldodeca-2(Z),
6(Z),10-trienoate (15). Triflate 14 (580 mg, 1.46 mmol), Pd(PhCN)2Cl2
(28 mg, 0.073 mmol), AsPh3 (45 mg, 0.146 mmol), and CuI (28 mg, 0.146
mmol) were dissolved in 1.8 mL of N-methylpyrrolidone (NMP; 99.5%,
anhydrous). This solution was heated to ∼100 °C, and tetramethyltin (0.40
mL, 1.91 mmol. CAUTION: poisonous and volatile) was added. After 15
h, the reaction was cooled, taken up in 100 mL of EtOAc, and washed
with aqueous KF (3 × 30 mL). The aqueous layer was back-extracted with
EtOAc (2 × 15 mL), and the combined organic layers were dried (MgSO4)
and concentrated. Flash chromatography (hexane/EtOAc 20:1) afforded 15
(15) (a) Reference 3b. (b) Zahn, T. J.; Ksebati, M. B.; Gibbs, R. A.
Tetrahedron Lett. 1998, 39, 3991-3994. Zahn, T. J.; Gibbs, R. A.,
unpublished results. (c) For the copper-catalyzed coupling of organozinc
reagents with 5, see: Lipshutz B. H., Vivian R. W. Tetrahedron Lett. 1999,
40, 2871-2874.
(16) (a) Hohl, R. J.; Lewis, K.; Cermak, D. M.; Wiemer, D. F. Lipids
1998, 33, 39-46. (b) Note also that with the prenyltransferase FPP synthase,
neryl diphosphate, the 2-Z-isomer of the natural substrate geranyl diphos-
phate is not a substrate: Popjak, G.; Holloway, P. W.; Bond, R. P. M.;
Roberts, M. Biochem. J. 1969, 111, 333-343.
(17) (a) Park, H.; Boduluri, S.; Moomaw, J.; Casey, P.; Beese, L. Science
1997, 275, 1800-1804. (b) Strickland, C. L.; Windsor, W. T.; Syto, R.;
Wang, L.; Bond, R.; Wu, Z.; Schwartz, J.; Le, H. V.; Beese, L. S.; Weber,
P. C. Biochemistry 1998, 37, 16601-16611 and references therein.
(18) See, for example: (a) McGeady, P.; Kuroda, S.; Shimizu, K.; Takai,
Y.; Gelb, M. H. J. Biol. Chem. 1995, 270, 26347-26351. (b) Edelstein, R.
L.; Distefano, M. D. Biochem. Biophys. Res. Commun. 1997, 235, 377-
382. (c) References 3a and 3b.
(19) All reported compounds were chromatographically homogeneous
and exhibited appropriate NMR spectra. Representative procedures for the
syntheses of 10, 14, and 15 are given below. Ethyl 7,11-Dimethyl-3-
oxododeca-6(Z),10-dienoate (10). Monosodium ethyl acetoacetate (4.26
g, 28.0 mmol) in 56.0 mL of THF (distilled from Na/benzophenone) was
cooled to 0 °C and treated with butyllithium (2.0 M in hexane, 14.7 mL,
29.4 mmol). After 20 min, neryl bromide (3.03 g, 14.0 mmol) was added
to the resulting dianion. After 30 min at 0 °C, the reaction was quenched
(∼10 mL of 10% aqueous citric acid) and extracted with ether (3 × 50
mL). The organic layers were combined, washed with saturated NaCl (2 ×
30 mL), and dried (MgSO4). Flash chromatography (hexane/EtOAc 9:1)
afforded 2.50 g (67%) of 10. 1H NMR: δ 1.28 (t, 3H), 1.61 (s, 3H, CH3 at
C11), 1.69 (app s, 6H, CH3 at C7 and C12-CH3), 2.04 (narrow m, 4H), 2.30
1
(248 mg, 64%). H NMR: δ 1.28 (t, 3H), 1.61 (s, 3H), 1.68 (s, 6H), 1.88
(s, 3H), 2.04 (m, 4H), 2.15 (m, 2H), 2.63 (t, 2H, C4-CH2), 4.12 (q, 2H),
5.16 (m, 2H), 5.65 (s, 1H). The identity, and in particular the stereochem-
istry, of this ester was confirmed by the similarity of the methyl peaks in
its 1H NMR spectrum to that of (Z,Z)-methyl farnesoate.7b Moreover,
reduction of 15 afforded (Z,Z)-farnesol 16 with an 1H NMR spectrum
identical to that previously reported.7a GC-MS analysis of a sample of 16
indicated that it contained 98% (Z,Z)-farnesol, 2% (E,Z)-farnesol, and none
of the other two geometric isomers.
(20) Pompliano, D. L.; Rands, E.; Schaber, M. D.; Mosser, S. D.;
Anthony, N. J.; Gibbs, J. B. Biochemistry 1992, 31, 3800-3807.
630
Org. Lett., Vol. 1, No. 4, 1999