Angewandte
Chemie
Table 2: Optimization of the allylsilane annulation with alkylidene
product [5; for structure see Eq. (1)] is determined based on
control of the b-silyl-stabilized carbocation intermediate
3.[9,10] Selective formation of 4, resulting from rearrangement
of the b-silyl carbocation intermediate, is a critical component
of the successful development of this methodology. Our initial
studies with chiral tin(IV),[11] copper(II),[7] and scandium-
(III)[5a,12] complexes afforded only low selectivity and/or low
reactivity for the synthesis of 4a (entries 1–4).[13]
oxindoles.[a,b]
To identify a more effective catalyst, we investigated
scandium(III)/pybox complexes with NaBArF [BArF = B-
(3,5-C6H3(CF3)2)4] (Table 1, entries 5–9).[14]
A significant
activating effect was observed for both ScCl3- and Sc(OTf)3-
derived complexes, thus affording 4a[15] with high yield and up
to 97:3 enantioselectivity (entries 5 and 6). Using other
counterions such as NaSbF6 and KPF6, or additives such as
TMSCl, did not enhance reactivity (see Table S1 in the
Supporting Information). The amount of NaBArF was also
observed to have a significant effect on the enantioselectivity
where increasing the NaBArF from 5 to 50 mol% lowered the
rate of the reaction and afforded racemic 4a (Table 1,
entry 7). It was also observed that the indapybox ligand
plays a critical role in diastereocontrol. In the absence of
ligand, the annulation proceeded with low diastereoselectivity
(entry 8). Evaluation of various ligands showed that (R,S)-
indapybox (L2) affords the highest diastereo- and enantiose-
lectivity (Table S1).
The primary activating effect of NaBArF is attributed to
the formation of a cationic scandium complex.[12] Formation
of a cationic Sc(OTf)2BArF·(R,S)-indapybox complex is
supported by isolation of NaOTf from the precipitate (63%
yield based on FAAS and 19F NMR analysis).[16] The erosion
of enantioselectivity with increasing amounts of NaBArF may
be due to generation of Sc(BArF)3 or Sc(BArF)2X species.
However, investigation of a preformed Sc(BArF)3 species did
not show comparable erosion (Table 1, entry 9).[17] Analysis of
the Sc(OTf)2BArF·(R,S)-indapybox complex using 1H, 19F,
and 45Sc NMR spectroscopy indicates that formation of
a dynamic catalyst complex is rapid and reversible on the
NMR time scale. Based on literature precedent for carbocat-
ion stabilization, we also hypothesize that NaBArF can play
a secondary role to facilitate formation of the transient b-silyl
carbocation (3).[18]
[a] Reaction conditions: See Table 1, entry 5 (10 mol%). Yield of isolated
product. [b] Diastereomeric and enantiomeric ratios determined as in
Table 1. [c] Using 20 mol% catalyst. [d] Reaction run for 4 days using
20 mol% catalyst with 20 mol% TfOH. [e] Yield over two steps (see
Table S7).[20] Thermal ellipsoids shown at 50% probability.
The scandium(III)/pybox/NaBArF system is also effective
for the catalytic enantioselective 1,4-conjugate addition of
allyltrimethylsilane (2b) to afford the allylation product 5
[Eq. (1)]. Even when using a small silyl group such as TMS,
these reaction conditions still afford 4b, which suggests that
reaction conditions using NaBArF suppress silyl elimination
and/or promote 1,2-silyl migration.
With this optimal catalyst system, we demonstrated that
the spirocyclopentane annulation proceeds with excellent
yields, and diastereo- and enantioselectivity for a variety of
alkylidene oxindole substrates (Table 2). Various ester (1c–g)
and nitrile (1h) substrates proceed efficiently. The phenyl-
substituted alkylidene 1i required higher catalyst loading and
extended reaction times, thus affording the spirocycle 4i with
high diastereoselectivity and moderate enantioselectivity.
Chelating oxindoles containing urea and Cbz groups (1j and
1k) also afford the products 4j and 4k, respectively, in
excellent yield and enantioselectivity.[19]
The NH spirooxindoles, such as 4l and 4m, can be
accessed by simple deprotection of the N-acyl oxindoles with
KHCO3 and H2O2 in high yield (80–88% yield over two
steps). The silyl-substituted spirooxindoles can be oxidized
Angew. Chem. Int. Ed. 2014, 53, 9462 –9465
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