required alcohol-protected synthons,2,4a,5-7 Grignard reaction
of a long-chain protected bromo alcohol with an allylic
bromide in the presence of Li2CuCl4,8 selective alkylation
reactions of (Z)-3-hexene-1,6-diol,9 selective isomerization
of one triple bond of a diynol,10 two sequential carbocupra-
tion reactions of acetylene,11 Pd-catalyzed alkylation of a
organozinc intermediate with a iodoalkene,12 and opening
of alkenyl cyclopropenyl ketones.13 However, some of them
show low stereoselectivity and others afford low overall
yields for preparative purposes,10,13 and to our knowledge,
neither of them is convergent. Therefore, a convergent, and
stereoselective synthesis, amenable for preparative applica-
tions, is still needed. In this paper, we report a convenient
synthesis of compounds 1 and 2 that fulfills these require-
ments.
Scheme 1
Alkenol 3 was prepared by hydrogenation (Pd Lindlar/
quinoline) at -10 °C in hexane of 4-nonynol, obtained from
2-chloromethyltetrahydrofuran.14 Under these conditions,
compound 3 was obtained in >99.5% stereomeric purity and
53% overall yield after column chromatography. This
procedure was clearly superior to the elegant method of ring
opening of 3,4-dihydropyran by the Grignard reagent of
n-butyl bromide in the presence of (tpp)2NiCl2 as catalyst15
(20% yield, Z:E 96:4).
Elongation of the chain was initially tried by coupling of
the Grignard reagent of iodide 516 with tosylate 8, obtained
in turn by alkylation of THP-protected propargyl alcohol with
TBDMS-protected bromohexanol 6, in the presence of Li2-
CuCl4. The reaction failed to produce the coupling product
10 furnishing, unexpectedly but univocally, iododerivative
9 in 66% yield. To our knowledge, this type of reaction is
unprecedented and was confirmed with other model tosylates,
implying a possible nucleophilic iodide-copper species
responsible for the nucleophilic displacement of the tosylate.
Equally unsuccessful was the reaction of the organocuprate
derivative of 5 (2.2 equiv of t-BuLi/CuI in pentane/ether 3:2)
with 8, while reaction of the organozinc derivative of 5 with
9 in the presence of Me2Cu(CN)(MgCl)2 in THF:DMPU17,18
provided the expected compound 10 along with 11 in 46:54
ratio (Scheme 1). This mixture was inseparable, so an
alternative approach was undertaken.
Alkylation of sulfone-mediated carbanions has been well
documented,19,20 and accordingly, sulfone 12 was considered
a good substrate to construct the C-18 chain. Transformation
of 3 into bromide 4 was carried out through the intermediate
formation of the trifluoroacetate ester as leaving group, in a
convenient one-step process.16 We feel that our procedure
is shorter and at least as efficient as the classical mesylation/
tosylation process. Compund 4 was reacted with sodium
benzenesulfinate in DMF providing sulfone 12 in 81% yield,
along with 11% of the corresponding phenyl sulfinate ester,
after column chromatography purification. Utilization of
benzenesulfinate anion supported on Amberlyst A-26 resin
to minimize sulfinate ester formation21 or Dowex 1-X gave
in our hands inferior results (36-43% of 12 along with 18%
of phenyl sulfinate). The other synthon required was iodide
9, which was obtained by two routes: (a) selective hydrolysis
of the TBDMS group of acetylene 7 with neutral alumina22,23
(4) (a) Tumlinson, J. H.; Yonce, C. E.; Doolittle, C. E.; Heath, R. R.;
Gentry, C. R.; Mitchell, E. R. Science 1974, 185, 614. (b) Priesner, E.;
Dobler, G.; Voerman, S. Ent. Exp. Appl. 1986, 41, 313.
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(10) Abrams, S. R.; Nucciarone, D. D.; Steck, W. F. Can. J. Chem. 1983,
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(12) Ramiandrasoa, F.; Descoins, C. Synth. Commun. 1989, 19, 2703.
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(19) For a review, see: Simpkins, N. S. Sulphones in Organic Synthesis;
Pergamon Press: Oxford, 1993; Vol. 10.
(20) Olson, G. L.; Cheung, H.-C.; Morgan, K. D.; Neukom, C.; Saucy,
G. J. Org. Chem. 1976, 41, 3287.
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(22) Feixas, J.; Capdevila, A.; Camps, F.; Guerrero, A. J. Chem. Soc.,
Chem. Commun. 1992, 1451.
(16) Camps, F.; Gasol, V.; Guerrero, A. Synthesis 1987, 511.
(17) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 23, 2117.
(18) Achyatha Rao, S.; Knochel, P. J. Org. Chem. 1991, 56, 4591.
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846
Org. Lett., Vol. 1, No. 6, 1999