Scheme 3. Synthesis of 3,1,1-OPP (26)
Scheme 4. Synthesis of 2,2,1,1-OPP (28), 2,1,2-OPP (33), and
2,2,2-OPP (34)
the standard chlorination/pyrophosphorylation proce-
dure produced the corresponding diphosphates 19 and
20 in good yields.
then applied to 27 to yield 2,2,1,1-OPP (28) in a 72% yield
(Scheme 4).
We had targeted three frame-shifted FPP compounds
that have the same overall length as FPP: 1,3,1-OPP, 3,1,1-
OPP, and 2,1,2-OPP. With 1,3,1-OPP (12) prepared, we
next turned our focus to the synthesis of 3,1,1-OPP (26),
which would require an alternative approach (Scheme 3).
This synthesis began with propargyl alcohol 21, the pre-
cursor to the central isoprene unit of 26. Following the
iodination of 21, we performed Negishi’s ZACA reaction15
to produce the iodo-alcohol 22 in a 52% yield. We then
planned to install the terminal isoprene using the vinyl
Grignard reagent 23.16 Coupling of the alkyl iodide of 22
with the vinyl Grignard reagent 23 in the presence of CuI
produced 24 in a 55% yield. The geranyl analog 24 was
then subjected to the same synthetic methodology devel-
oped for the synthesis of 19 and 20 (Scheme 2) for the
production of 3,1,1-OPP (26). CoreyꢀKim bromination17
of 24, displacement of the resulting allylic bromide with the
vinyl lithium derivative of 12, and deprotection afforded
alcohol 25 in a 46% yield. Conversion to the diphosphate
was achieved as previously described, resulting in the syn-
thesis of 3,1,1-OPP (26).
In addition to preparing molecules of similar length to
FPP, we also targeted a molecule more similar to geranyl-
geranyl diphosphate (GGPP) in length. This molecule
(2,2,1,1-OPP (28), Scheme 4) is only one CH2 unit shorter
than GGPP. To synthesize 2,2,1,1-OPP we started with
farnesyl bromide, then performed our two-step vinyl
lithium coupling/deprotection sequence (as in Scheme 2).
This generated the precursor alcohol (27) of 2,2,1,1-OPP
in a 54% yield (Scheme 4). The standard CoreyꢀKim
chlorination/Poulter diphosphorylation procedure18 was
The last two compounds targeted for synthesis were two
FPP analogs containing nonallylic diphosphates (2,1,2-
OPP (33) and 2,2,2-OPP (34), Scheme 4). These molecules
were hypothesized to behave as nonsubstrates due to the
significantly decreased leaving group ability of homoallylic
diphosphate, which should not allow the prenylation of
cysteine found on the CaaX sequence of FTase substrates.
Homofarnesol (32) was previously synthesized,12 but not
converted into the corresponding diphosphate. Following
Kocienski’s procedure,12 we synthesized 32 in good yield
from iodide 30. The diphosphorylation procedure devel-
oped by Davisson et al.18 was used to successfully synthe-
size homofarnesyl diphosphate (34, Scheme 4) in excellent
yield. The WenkertꢀKocienski homologation protocol
allowed for the elongation of geranyl bromide 29 to
alcohol 31, the precursor to 2,1,2-OPP (33).
Preliminary evaluation of the eight frame-shifted FPP
analogs versus mammalian FTase7,10 revealed that four of
the analogues are substrates (11, 12, 26, 28) and four of the
analogues are not accepted as substrates (19, 20, 33, 35)
(Figure 1). A preliminary inhibitory potency assay with the
four nonsubstrates revealed that homofarnesyl dipho-
sphate (34) was the only analog with an apparent IC50
below 1 μM, although an inseparable ammonium p-tolue-
nesulfonate contaminant prevented the determination of
an IC50 value. Analogs 19, 20, and 33 all exhibit very poor
binding to FTase, demonstrating that modest changes to
the FPP isoprenoid motif can lead to significant changes in
binding. A more detailed evaluation of the four substrates
provided further surprising effects of subtle structural
changes in the isoprenoid moiety. For example, the con-
formationally restricted1E,4E-pentadiene structural motif
found in the “tail” of 11, 12, and 20 appears to translate
(15) Rand, C. L.; Vanhorn, D. E.; Moore, M. W.; Negishi, E. J. Org.
Chem. 1981, 46, 4093–4096.
(16) Derguiniboumechal, F.; Linstrumelle, G. Tetrahedron Lett.
1976, 3225–3226.
(17) Corey, E. J.; Takeda, M.; Kim, C. U. Tetrahedron Lett. 1972,
4339–4342.
(18) Davisson, V. J.; Woodside, A. B.; Neal, T. R.; Stremler, K. E.;
Muehlbacher, M.; Poulter, C. D. J. Org. Chem. 1986, 51, 4768–4779.
Org. Lett., Vol. XX, No. XX, XXXX
C