As the results of the Pd-catalyzed cross coupling of the
alkenylalanes formed above with 1.05 equiv of 1 run in THF
or DMF-THF (2:1) summarized in Table 1 indicate, clean
conjugated π-bonds is as many as five. These favorable
characteristics are not readily shared by widely used hydro-
metalation reactions involving Al, B, and Zr.10 These
hydrometalation reactions are generally very favorable with
simple terminal alkynes. With conjugated terminal alkynes,
however, these reactions tend to place metals at internal
carbon atoms to considerable extents.5b,10
Table 1. Pd-Catalyzed Reaction of Alkenylalanes with
(E)-1-Bromo-2-iodoethylene
Another critical finding is that â,â-disubstituted alkenyl-
alanes generated in situ by the Zr-catalyzed carboalumination
can be directly and selectively cross-coupled with the two-
and four-carbon synthons 1 and 2 under the optimized
conditions of the double metal catalysis involving Pd and
Zn reagents,4,11 permitting the desired five-carbon homolo-
gation of terminal alkynes with almost a total control of
stereo- and regiochemistry in one pot. This is, at least in
part, due to the very favorable reactivity of 1 and 2 in their
Pd-catalyzed cross coupling. Although known for more than
two decades, application of the Zr-catalyzed carboalumina-
tion to the synthesis of natural products by direct carbo-
metalation-cross coupling tandem processes has been
limited to a very small number of cases.12 In most of the
other cases, the carboalumination products have been con-
verted first to the corresponding iodides and other organic
derivatives and then used in subsequent cross coupling and
other steps after purification.13 Indeed, we have previously
reported that 5 can be cleanly converted to (E,E)-1-(4′-iodo-
3′-methyl-1′,3′-butadienyl)-2,6,6-trimethylcyclohexene in 82%
yield.13a Its reaction with the Zn derivative of 2, generated
in situ via treatment of 2 with t-BuLi (2.1 equiv) in Et2O
(-78 °C) followed by addition of dry ZnBr2 (1 equiv) in
THF (-78 °C), under conditions similar to those of step iii
in Scheme 1 provided g99% isomerically pure 6 in 92%
yield after deprotection and simple column chromatography.
Although this double functional modification, i.e., Al f I
and Br f Li f Zn, does lead to a higher yield of cross
coupling, it involves at least one more step. Overall, the one-
pot procedure is clearly the more favorable of the two.
γ-Carotene has been previously synthesized first by
Weedon14a and later by Eugster.14b In the Weedon synthesis,
the C15 + C10 + C15 building principle was applied by using
(all-E)-2,7-dimethyl-2,4,6-octatriene-1,8-dial obtainable in six
a By GLC.
and selective formation of the desired bromides is observable
only in the presence of DMF as a cosolvent. THF alone is
unsatisfactory in these reactions.
It is equally important that, throughout all of the syntheses
shown in Scheme 1, careful examination of each step by 1H
and 13C NMR spectroscopy before and after product isola-
tion-purification has clearly indicated that the extent of
formation of stereoisomers, if any, is e1-2% (S/N g 50-
100). Although the Zr-catalyzed methylalumination is known
to produce minor amounts (typically e5%) of regioisomers
containing Al in an internal position,2 the amount of any
isomeric byproduct9 after cross coupling (steps iii and vi)
or hydroxymethylation (step ix) is estimated to be e1-2%
each. This is most likely attributable to the lower reactivity
of the internally aluminated isomers relative to that of the
desired terminally aluminated isomers. No difficulty has been
encountered in obtaining any of the isolated products in
Scheme 1 in g99% isomeric purity after a simple and single
chromatographic operation (silica gel or neutral alumina).
In short, all steps are g99% stereoselective, and minor
amounts of regioisomers and other isomers can be readily
separated to give g99% isomerically pure carotenoids.
The unprecedentedly high selectivity level achieved in this
study is critically dependent on a hitherto largely unrecog-
nized ability of the Zr-catalyzed carboalumination (methyl-
alumination to be specific) to maintain (i) high product yield,
(ii) high regioselectivity of g95%, and (iii) essentially 100%
stereoselectivity even in those cases where the number of
(10) (a) Zweifel, G.; Arzoumanian, H.; Whitney, C. C. J. Am. Chem.
Soc. 1967, 89, 3652. (b) Schwartz, J.; Labinger, J. A. Angew. Chem., Int.
Ed. Engl. 1976, 15, 333. (c) Lipshutz, B. H.; Lindsley, C. J. Am. Chem.
Soc. 1997, 119, 4555. (d) Unpublished results observed by M. Hata and F.
Zeng in our laboratories.
(11) In addition to the cross coupling conditions indicated in the footnote
iii in Scheme 1, the use of 5 mol % of Cl2Pd(PPh3)2 and 10 mol % of
DIBAH in THF was comparably satisfactory.
(12) For example, a-farnesene was synthesized by Zr-catalyzed methy-
lalumination followed by Pd-catalyzed allylation in one pot [Matsushita,
H.; Negishi, E. J. Am. Chem. Soc. 1981, 103, 2882].
(13) (a) Negishi, E.; Owczarczyk, Z. Tetrahedron Lett. 1991, 32, 6683.
(b) Barrett, A. G. M.; Edmunds, J. J.; Hendrix, J. A.; Horita, K.; Parkinson,
C. J. J. Chem. Soc., Chem. Commun. 1992, 1238. (c) Rayner, C. M.; Astles,
P. C.; Paquette, L. A. J. Am. Chem. Soc. 1992, 114, 3926. (d) Torrado, A.;
Iglesias, B.; Lo´pez, S.; de Lera, A. R. Tetrahedron, 1995, 51, 2435. (e)
Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron Lett. 1996, 37,
7107. (f) Liu, F.; Negishi, E. J. Org. Chem. 1997, 62, 8591. (g) Kuramochi,
K.; Nagata, S.; Itaya, H.; Takao, K.; Kobayashi, S. Tetrahedron Lett. 1999,
40, 7371.
(9) These very minor byproducts are mostly unidentified, but the
likelihood of their being isomeric to the desired products are inferred, for
example, by their GLC analysis, when applicable.
(14) (a) Manchand, P. S.; Ru¨egg, R.; Schwieter, U.; Siddons, P. T.;
Weedon, B. C. L. J. Chem. Soc. 1965, 2019. (b) Zumbrunn, A.; Uebelhart,
P.; Eugster, C. H. HelV. Chim. Acta 1985, 68, 1519.
Org. Lett., Vol. 3, No. 5, 2001
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