Scheme 1. Concept of Dual Catalytic Gold and Organic
Phosphoric Acid Enantioselective Cyclization Cascade
Scheme 2. Proof of Principle Study in the N-Sulfonyliminium
Cyclization Cascade
TheproposedconceptisdepictedinScheme1foraninternal
alkyl sulfonamide residue possessing a terminal alkyne 1. Our
initial choice of sulfonamide over carboxylic acid amide was
influenced in part by their abundance in medicinally relevant
compounds4 and by the lack of such motifs in enantioselective
cascade processes. We envisaged a novel alkyne hydro-
amination process to form isothiazolidine-1,1-dioxide (2),
which could take place under gold(I) catalysis.5,6 Protonation
would then afford the N-sulfonyliminium intermediate 3,
which through tight ion pairing/general base catalysis with
the conjugate base of the chiral phosphoric acid would facili-
tate an enantiofacially selective cyclization, thus providing a
novel route to polycyclic isothiazolidine-1,1-dioxide moieties
of type 4 (Scheme 1).7À10 Herein we report our findings.
Proof of principle was first established after a brief
screen of metal complexes by adding [P(OPh)3]AuCl
(2 mol %) and AgOTf (2 mol %) in one portion to a mixture
of sulfonamide 5a and BPA-1A (10 mol %, Table 1) in
toluene at 50 °C (Scheme 2). The reaction furnished the
cascade products 6a and 7a (5-exo and 6-endo respectively
in 9:1 ratio) with quantitative mass return at a faster rate
than previously reported in N-acyliminium cyclization
cascades.3 Unfortunately, no enantioselectivity was wit-
nessed. However, we later confirmed that this was due to a
competing gold catalyzed background reaction;11 treat-
ment of sulfonamide 5a with [P(OPh)3]AuCl (3 mol %)
and AgOTf (3 mol %) at 60 °C in toluene afforded
cyclization products 6a and 7a in quantitative yield as a
9:1 mixture of regioisomers respectively.12 A range of
alternative alkynophilicLewisacidicmetal complexes were
screened in an attempt to slow the undesirable background
process. Pleasingly, with Echavarren’s catalyst13 (8), 6a
was afforded in 56% yield and 73% ee (Table 1, entry 4). A
brief solvent screen (Table 1, entries 4À8) identified tol-
uene as the best solvent for enantioselectivity when com-
pared with other aprotic solvents.14 To further minimize
the competitive gold catalyzed background reaction and
improve efficiency, the loading of gold catalyst 8 was
decreased to 2 mol % (Table 1, entry 9), which indeed
resulted in an increase in product enantiomeric excess.
Performing the reaction at 60 °C, rather than at 100 °C,
afforded higher yields of the desired reaction product but
with reduced enantiomeric excess (Table 1, entries 9 and 11).
However, due to the increased lifespan of the gold catalyst
under these conditions we were able to lower the gold
catalyst loading even further to 0.5À1.0 mol %, which proved
beneficial to both reaction yield and enantioselectivity
(Table 1, entries 12 and 13). A subsequent screen of chiral
BPA derivatives provided no enhancement in enantioselec-
tivity (Table 1, entries 15À17) and confirmed BPA-1A was
optimal for the enantioselective cascade process.
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With optimized conditions in hand a variety of substi-
tuted indole sulfonamide derivatives were cyclized with
good to excellent yields and enantioselectivities up to
96% ee (Figure 1). The reaction was found to tolerate
electron-withdrawing halides at various positions around
the ring (6b to 6f) and the electron-deficient 5-nitrile
derivative (6g), albeit at a slower reaction rate in the latter
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(12) Treatment of alkyne 5a with BPA-1A in refluxing toluene
resulted in no reaction and showed only pure starting material.
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