reagent 1714a,15 furnished vinylstannane 18, which we
employed in a Stille coupling reaction16 with vinyl iodide
1917,18 to provide 20 after ketalization under standard
conditions. LiAlH4 reduction then gave 16 in nearly quantita-
tive yield.
Scheme 4a
The synthesis of 4-chloro-3-methylcyclobutenone, the
vinylketene precursor required for the key benzannulation
step, is outlined in Scheme 6. Reaction of monochloro-
Scheme 6
a Key: (a) 1.3 equiv of t-BuMe2SiCl, 1.4 equiv of Et3N, 0.04
equiv of DMAP, CH2Cl2, rt, 2.5 h, 98%; (b) 2.5 equiv of 13, 2.5
equiv of n-BuLi, -78 °C, 90 min; then 2.5 equiv of 1-pentynyl-
copper, 5.0 equiv of HMPT, -50 °C, 3 h; then 2.5 equiv of
BF3‚Et2O, 1.0 equiv of 9, -78 °C to rt, THF, 14 h, 75-78%; (c)
1.2 equiv of TBAF, DMF, 0 °C, 3.5 h, 83-90%; (d) 0.2 equiv of
p-TsOH‚H2O, 6.0 equiv of CaSO4, 5:1 cyclohexane-HOCH2CH2OH,
rt, 3.5 h, 76%. b Reactions performed beginning with racemic 9.
ketene19 with ethoxyacetylene furnished the desired cyclo-
adduct (21), but subsequent addition of CH3Li and hydrolysis
under standard acidic conditions produced a complex mixture
of products. Conversion of 21 to 4 was ultimately realized
via a modified protocol in which the CH3Li adduct is first
acylated, after which hydrolysis is conducted under mild
alkaline conditions.20
Our initial studies of the key aromatic annulation step
focused on the reaction of 4 and other cyclobutenones with
methoxyacetylene derivatives. Although the desired benz-
annulation product was obtained in good yield, cleavage of
the resultant aryl methyl ether to reveal the desired resorcinol
failed to take place under a variety of conditions.21 Attention
was then turned to the application of various acetal and silyl
ether derivatives, but these approaches were frustrated by
our inability to develop efficient synthetic routes to the
requisite alkyne annulation components. Success was ulti-
mately realized through the application of benzyloxyalkyne
25. Initially we had avoided the use of benzyloxyacetylenes
as annulation components due to their propensity to undergo
[3,3] sigmatropic rearrangement on mild heating.22 On further
consideration, however, we felt that these alkynyl ethers
(14, ca. 85:15 mixture of C-2 epimers) to n-Bu4NF in
dimethylformamide resulted in desilylation with concomitant
equilibration at C-2 to afford 15 and its epimer in a ratio of
93:7. Protection of the ketone carbonyl group with ethylene
glycol under standard conditions was complicated by com-
peting substitution reactions at the dienyl side chain but was
eventually achieved in good yield via the indicated protocol.
An alternative route to key intermediate 16, outlined in
Scheme 5, employs bis(tributylstannyl)ethylene14 as a syn-
Scheme 5
(15) Me3SiCl was used to promote this reaction. For a discussion, see:
Frantz, D. E.; Singleton, D. A. J. Am. Chem. Soc. 2000, 122, 3288 and
references therein.
(16) Reviewed in: Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React.
1997, 50, 1.
(17) Previous synthesis: Chen, S. H.; Horvath, R. F.; Joglar, J.; Fisher,
M. J.; Danishefsky, S. J. J. Org. Chem. 1991, 56, 5834.
(18) We prepared 19 by a modification of the method previously
employed by Ohba et al. for the corresponding ethyl ester (Ohba, M.;
Kawase, N.; Fujii, T. J. Am. Chem. Soc. 1996, 118, 8250). Attempts to
achieve Stille coupling to allylic alcohol derivatives (both vinyl bromides
and iodides) were unsatisfactory under a variety of conditions.
(19) Reviewed in: (a) Brady, W. T. Tetrahedron 1981, 37, 2949. (b)
Tidwell, T. Ketenes; Wiley & Sons: New York, 1995; pp 336-348.
(20) For previous examples of the hydrolysis of vinylogous hemiketals
under alkaline conditions, see: (a) Corey, E. J.; Danheiser, R. L.;
Chandrasekaran, S.; Siret, P.; Keck, G. E.; Gras, J.-L. J. Am. Chem. Soc.
1978, 100, 8031. (b) Liebeskind, L. S.; Wirtz, K. R. J. Org. Chem. 1990,
55, 5350.
thetic linchpin for the assembly of the sesquiterpenyl section
of ascochlorin. Conjugate addition of the mixed cuprate
(21) Reactions with basic and nucleophilic reagents were too sluggish
to be useful, and exposure to acidic (and Lewis acidic) conditions resulted
in cyclization to form chromanes.
(14) (a) Corey, E. J.; Wollenberg, R. H. J. Am. Chem. Soc. 1974, 96,
5581. (b) Renaldo, A. F.; Labadie, J. W.; Stille, J. K. In Organic Syntheses;
Wiley & Sons: New York, 1993; Collect. Vol. VIII, pp 268-274.
(22) (a) Wunderli, A.; Zsindely, J.; Hansen, H. J.; Schmid, H. Chimia
1972, 26, 643. (b) Katzenellenbogen, J. A.; Utawanit, T. Tetrahedron Lett.
1975, 38, 3275 and references therein.
Org. Lett., Vol. 2, No. 21, 2000
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