to frequently used R-alkynone-forming reactions. The salient
features of the reaction process are (i) both starting reactants
are easily available, (ii) considerable structural variation is
tolerated in both the nucleophilic and electrophilic reaction
components, including lactones with five-, six-, and seven-
membered rings, and (iii) the reaction procedure is opera-
tionally simple and high yielding (79-98%). As expected,7
the addition reaction could be conducted using optically
active secondary alcohols (e.g., 1d) to give optically active
adducts (3d, 3i).
Scheme 1
With the requisite collection of alkynones 3 assembled,
we proceeded with our investigation of the conversion 3 to
4 (Scheme 3).
1′ to convert lactones 2 into benzyl-protected hydroxyl
R-alkynones 3 followed by a one-pot cascade consisting of
palladium-catalyzed hydrogenation of the triple bond, hy-
droxyl group deprotection, and spirocyclization under mild
nonacidic conditions.
Scheme 3
Common synthetic routes to R-alkynones include the
coupling of acid chlorides, acid anhydrides, esters, and acyl
cyanides with either metal (e.g., Li, Mg, Cu, Cd, Si, Ag,
Zn, and Sb) acetylides or with free terminal alkynes under
palladium and/or copper catalysis.3 A few reports also exist
describing the use of lithium alkynyltrifluoroborates instead
of alkynyllithium reagents in coupling reactions with acid
anhydrides4 or esters.5 Very recently, we have shown that
lithium alkynyltrifluoroborates also mediate a rapid and
regioselective ring opening of lactones.6
Thus, the synthesis of R-alkynones 3 was achieved
according to our established protocol6 via a smooth and
regioselective acyl C-O ring cleavage of lactones treated
with alkynyltrifluoroborates 1′ readily generated in situ from
corresponding benzyl protected alkynols 1 by the addition
of stoichiometric quantities of nBuLi and BF3‚OEt2 in THF.
The scope of the reaction was established with a variety
of alkynyltrifluoroborates using seven lactone models
(Scheme 2).
In our preliminary experiments, we examined the Pd/C-
catalyzed hydrogenation of 3 in chloroform, anticipating that
a trace of HCl liberated by a partial hydrogenolysis of the
C-Cl bonds8 might promote the hydrogenolysis of benzyl
groups9 and dehydrative ketalization as well. However, the
use of CHCl3 led to disappointing results. Although the
procedure afforded the desired spiroketals 4 in moderate
yields, it did not yield reproducible results in our hands
(probably as a result of the uncontrolled activity of the Pd/C
catalyst resulting in variable amounts of HCl liberated). On
the other hand, a smooth and reproducible conversion of 3
to 4 was effected in a one-pot manner by treating 3 with
hydrogen in the presence of 10% palladium on charcoal in
EtOH or EtOAc solutions. The exploitation of these solvents
is demonstrated in the synthesis of several categories of
spiroketals (Table 1).
Scheme 2
Inspection of the data in Table 1 reveals that, from the
structural standpoint, the spirocyclization reaction proceeds
with good generality, creating [4.4], [4.5], [5.5], and [5.6]
spiroketal structures in similarly high yields (75-97%).
Several other observable trends should be mentioned: (i)
The rate of spiroketal formation follows approximately the
order [4.4] ≈ [4.5] > [5.5] > [5.6]. (ii) Where possible, the
(3) (a) Katritzky, A. R.; Lang, H. J. Org. Chem. 1995, 60, 7612-7618.
(b) Chowdhury, C.; Kundu, N. G. Tetrahedron 1999, 55, 7011-7016. (c)
Kakino, R.; Narahashi, H.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc.
Jpn. 2002, 75, 1333-1345. (d) Alonso, D. A.; Na´jera, C.; Pacheco, M. C.
J. Org. Chem. 2004, 69, 1615-1619. (e) Chen, L.; Li, Ch.-J. Org. Lett.
2004, 6, 3151-3153 and references therein.
(4) Brown, H. C.; Racherla, U. S.; Singh, S. M. Tetrahedron Lett. 1984,
25, 2411-2414.
(5) (a) Yamaguchi, M.; Shibato, K.; Fujiwara, S.; Hirao, I. Synthesis
1986, 421-422. (b) Krafft, M. E.; Bonaga, L. V. R.; Felts, A. S.; Hirosawa,
Ch.; Kerrigan, S. J. Org. Chem. 2003, 68, 6039-6042.
(6) Doubsky´, J.; Streinz, L.; Lesˇeticky´, L.; Koutek, B. Synlett 2003, 937-
942.
(7) Jacobson, R.; Taylor, R. J.; Williams, H. J.; Smith, L. R. J. Org.
Chem. 1982, 47, 3140-3142.
(8) Secrist, J. A.; Logue, M. W. J. Org. Chem. 1972, 37, 335-336.
The results shown in Scheme 2 demonstrate that this
reaction sequence constitutes a highly practical alternative
4910
Org. Lett., Vol. 6, No. 26, 2004