options for the increased convergence in the total synthesis
of natural products7 because of the availability of several
methods to synthesize alkyne motifs. Also, alkynes are
relatively inert towardmanyreaction conditions, making it
a safe way for higher functionality order construction.
So far, Au(I), Au(III), Pt(II), Pd(II), Ir(I), and Rh(I)
have been used for the synthesis of spiroketals from
alkynediol motifs.6,7a,8 There is still a great need for the
development of a new catalytic system to address several
issues together, viz. expensive catalysts, low yields, long
reaction times, poor regioselectivities, elevated tempera-
tures, and need of additional Bronsted acid catalysts and
additives. In our recent paper on the synthesis of the
natural product hippuristanol and its analogues,9 we have
reported the identification of Hg(OTf)2-catalyzed trans-
formation of semiprotected alkyne diol to the correspond-
ing spiroketal unit in a cascade manner. Herein, we
describe the scope and limitations of this new catalytic
system,10 addressing all of the issues mentioned above to
make it a highly generalized method.
Table 1. Hg(II)-Catalyzed Spiroketalization of Various Internal
Alkyne Diols
We began our investigations with a representative
example 1a (Table 1, entry 1). This substrate was selected
by Brabander et al.6a to compare the efficiency of several
catalysts and conditions regarding the yield, time, and
regioselectivity. We considered this a good beginning to
evaluate our catalyst system. Brabander reported that
PdCl2 and AuCl3 yielded 6-exo and 7-endo products in
an almost 2:1 ratio in 52% and 41% yields, respectively.
Other Au catalysts, which needed other additive or Bronsted
acid support, gave lower yields and regioselectivities.
Pt catalysts improved the yields and regioselectivities,
but again needed Bronsted acid catalyst for both deprotec-
tion of THP ether and spiroketalization. When we sub-
jected the same substrate to the catalytic system, 10 mol %
of Hg(OTf)2 in aqueous CH3CN at ambient temperature,
the 6-exo product 2a was formed exclusively in 90% yield
in a cascade manner. No further acid catalysts were needed
for deprotection of THP acetal or to ensure cyclization.
With this interesting result, we prepared various starting
materials and subjected to the same conditions to get
similar results which are summarized in Table 1. In entry
2, though the diol 1b has the possibilities for both 5-exo-
and 6-exo-dig cyclizations to give the corresponding 5,7-
and 6,6-spiroketals, respectively, we observed only the
later possibility to get 6,6-spiroketal 2a in 92% yield. The
same result was observed with substrate 1d (entry 4) which
gave exclusively 6-exo product 2b in 94% yield. Then we
a All the products were prepared as racemic mixture. b Isolated yields.
c General procedure A used; see the Supporting Information. d General
procedure B used; see the Supporting Information.
performed the reaction on 1c (with the reversal of protec-
tion in 1a) (entry 3) anticipating the 5-exo-dig cyclization
either in full or part, but we observed the exclusive forma-
tion of 6,6-spiroketal 2a in 90% yield. The same was
ascertained with compound 1e in entry 5 to furnish 6,6-
spiroketal 2b in 90% yield. This implies that the kinetics of
the reaction favors the 6-exo-dig cyclization rather than
6-endo- or 5-exo-dig cyclizations.
Having found a solution for the 6-exo selective hydro-
alkoxylation, we next wanted to examine the 5-endo-dig
cyclization. Thus, on exposure to the same reaction
conditions, substrates 1f and 1g produced 5,6-spiro-
ketal 2c in 92% and 90% respectively. This could be
either through 6-exo-dig or 5-endo-dig cyclizations. But
interestingly, substrates 1h and 1i gave 5,5-spiroketal
2d in 94% and 90% yields respectively implying that in
all cases from 1f to 1i the reactions might have taken
place through 5-endo-dig cyclization. Notably, the cy-
clization of substrates 1fÀi are faster than the other
examples listed above implying that the transition state
energy of 5-endo-dig cyclization is quite lower than
6-exo-dig cyclization.
(7) (a) Li, Y.; Zhou, F.; Forsyth, C. J. Angew. Chem., Int. Ed. 2007,
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(9) (a) Ravindar, K.; Reddy, M. S.; Lindqvist, L.; Pelletier, J.;
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Our next study was aimed at the evaluation of other
mercury catalysts and conditions. We selected example 1h
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