C O M M U N I C A T I O N S
at -78 °C with 1 equiv of n-BuLi in THF (to form the lithium
alkoxide) and further dropwise addition (titration) of a blue solution
of Li in EtNH2 until a faint blue end point was reached. Extractive
isolation and flash chromatography on silica gel provided pure (95%
by GC analysis) 6 in 96% yield.
All-E geranylgeraniol was prepared from E-geranial dimethyl-
acetal and silane 2 under the same conditions used for 6 (Scheme
1) (95% purity by GC analysis) with essentially identical yields.
Similarly prepared by the method exemplified in Scheme 1 was
all-E hexaprenol (farnesylfarnesol) from E,E-farnesal dimethylacetal
(3) and allylic silane 7.11 All-E hexaprenol was also made from
geranylgeranial dimethylacetal (produced by the method for 3) and
allylic silane 2. Finally, all-E heptaprenol was obtained from 7 and
geranylgeranial dimethylacetal by a sequence completely parallel
to that outlined in Scheme 1. These results confirm the generality,
efficacy, and utility of the new oligoprenol synthesis.
chromatography on silica gel. This reaction opens a route for the
synthesis of oligoprenols containing a single defined Z-olefinic unit,
when combined with the selective deoxygenation methodology
shown in Scheme 1. The highly selective formation of a new
Z-olefinic unit in the thermal coupling reaction, which is potentially
more widely applicable in the synthesis of isoprenoids, is readily
understood in terms of a sterically favored six-membered cyclic
transition state of the metalloene type. A full discussion of this
thermal Z-selective coupling process and its utility in synthesis will
be presented elsewhere.
In summary, we have described a remarkably simple solution to
the classic unsolved problem of constructing all-E oligoprenols by
multiprenyl fragment coupling via a cationic pathway analogous
to the biosynthetic prenylation process. The success of this process
depended not only on the crucial coupling step but also on the
development of (1) an efficient synthesis of allylic secondary silanes
such as 2 and 7, (2) stereocontrolled synthesis of E-oligoprenal
acetals such as 3, and (3) selective allylic demethoxylation such as
5 f 6.
In contrast to the successful synthesis of the series of all-E prenols
from tetra to hepta members using the acetal coupling method,
exemplified by 2 + 3 f 4 in Scheme 1, the use of a free aldehyde
for coupling to the allylsilane component 2 or 7 fails due to the
intervention of a different reaction pathway. Thus, the reaction of
E-geranial with 2 and BF3‚Et2O in CH2Cl2 at -78 °C produces the
tetrahydrofuran derivative 8 in good yield. In this case the cationic
Supporting Information Available: Experimental procedures for
the compounds described along with NMR, IR, and mass spectral data
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Rowland, R. L.; Latimer, P. H.; Giles, J. A. J. Am. Chem. Soc. 1956,
78, 4680. (b) Erickson, R. E.; Shunk, C. H.; Trenner, N. R.; Arison, B.
H.; Folkers, K. J. Am. Chem. Soc. 1959, 81, 4999.
(2) See: ComprehensiVe Natural Products Chemistry; Pergamon-Elsevier
Science: New York, 1998; Vol. 2.
(3) Ourisson, G.; Nakatani, Y. Curr. Biol. 1994, 1, 11.
(4) (a) Cane, D. E. Chem. ReV. 1990, 90, 1089. (b) Poulter, C. D.; Rilling,
H. C. Acc. Chem. Res. 1978, 11, 307.
(5) Biellmann, J. F.; Ducep, J. B. Tetrahedron Lett. 1969, 3707.
(6) (a) Altman, L. J.; Ash, L.; Kowerski, R. C.; Epstein, W. W.; Larsen, B.
R.; Rilling, H. C.; Muscio, F.; Gregonis, D. E. J. Am. Chem. Soc. 1972,
94, 3257. (b) Altman, L. J.; Ash, L.; Marson, S. Synthesis 1974, 129. (c)
Kondo, K.; Matsumoto, M. Tetrahedron Lett. 1976, 391. (d) Masaki, Y.;
Hashimoto, K.; Kaji, K. Tetrahedron Lett. 1978, 5123. (e) Sato, K.; Inoue,
S.; Onishi, A.; Uchida, N.; Minowa, N. J. Chem. Soc., Perkin Trans. 1
1981, 761.
(7) Additional steps are required to complete the synthesis of oligoprenols
by the Biellmann-Ducep method, the E-selectivity of which appears to
be approximately 87%.6a Yields in the coupling step of 50-75% have
been reported.6
(8) Fairlamb, I. J. S.; Dickinson, J. M.; Pegg, M. Tetrahedron Lett. 2001, 42,
2205.
(9) Me3SiLi was prepared as a red-brown solution by the reaction of Me3-
SiSiMe3 in 4:1 THF-HMPA with 1 equiv of MeLi at -7 °C for 15 min;
see: Still, W. C. J. Org. Chem. 1976, 41, 3064. This reagent was added
to a solution of ICuP(OMe)3 in THF at -78 °C to give after 15 min the
reagent Me3SiCuP(OMe)3 as a dark-brown solution.
(10) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron 1998, 54, 15,679. Repeated
attempts to prepare 3 by the method described yielded only ca. 1:1 mixtures
of E and Z acetals.
(11) The allylic silane 7 was synthesized from the TBS ether of E,E-farnesol
by an analogous process to that used for 2.
(12) Substrate 9 was synthesized from the reaction of the mesylate of 1 with
Me3SnCuP(OMe)3.
intermediate generated by C-C coupling of the geranial-BF3
complex and silane 2 undergoes silyl migration and ring closure
rather than desilylation. Nor does the use of E-geranial, BF3‚Et2O,
and the trimethyltin substrate 912 (CH2Cl2, -78 °C) lead to efficient
formation of an oligoprenol derivative. Instead, mixtures of the
desired SE2′ and the undesired SE2 (primary-secondary) coupling
products result. Another noteworthy result is the highly stereo-
selective thermal reaction of E-geranial and 9 (neat, 90 °C, 48 h)
that produces the E,Z,E-alcohol 10 in 63% isolated yield after flash
JA0127537
9
J. AM. CHEM. SOC. VOL. 124, NO. 11, 2002 2431