Catalytic enantioselective carboannulation with allylsilanes

Article abstract of DOI:10.1002/anie.201403607

The first catalytic asymmetric carboannulation with allylsilanes is presented. The enantioselective [3+2] annulation is catalyzed using a scandium(III)/indapybox complex with tetrakis-[3,5-bis(trifluoromethyl)phenyl]- borate (BArF) to enhance catalytic activity and control stereoselectivity. Functionalized cyclopentanes containing a quaternary carbon center are derived from alkylidene oxindole, coumarin, and malonate substrates with high stereoselectivity. The enantioselective 1,4-conjugate addition and enantioselective lactone formation (by trapping of the β-silyl carbocation) is also described. It's a trap: The catalytic asymmetric carboannulation of alkylidene oxindole, coumarin, and malonate substrates with allylsilanes in the presence of a Sc^III/BArF/indapybox catalyst affords functionalized cyclopentanes containing a quaternary carbon center with high stereoselectivity. Enantioselective allylation and asymmetric lactone formation by trapping of the β-silyl carbocation are also presented.

Full text of DOI:10.1002/anie.201403607

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Angewandte
Communications
DOI: 10.1002/anie.201403607
Synthetic Methods
Catalytic Enantioselective Carboannulation with Allylsilanes**
Nicolas R. Ball-Jones, Joseph J. Badillo, Ngon T. Tran, and Annaliese K. Franz*
Abstract: The first catalytic asymmetric carboannulation with
allylsilanes is presented. The enantioselective [3+2] annulation
is catalyzed using a scandium(III)/indapybox complex with
tetrakis-[3,5-bis(trifluoromethyl)phenyl]-borate (BArF) to
enhance catalytic activity and control stereoselectivity. Func-
tionalized cyclopentanes containing a quaternary carbon
center are derived from alkylidene oxindole, coumarin, and
malonate substrates with high stereoselectivity. The enantiose-
lective 1,4-conjugate addition and enantioselective lactone
formation (by trapping of the b-silyl carbocation) is also
described.
L
ewis acid catalyzed conjugate addition and cyclization
reactions of unsaturated carbonyl compounds are important
routes for the synthesis of complex heterocycles and carbo-
cycles. Despite significant advances in asymmetric cataly-
sis,[1,2] many conjugate addition and cyclization reactions
using unsaturated carbonyl compounds still lack catalytic
asymmetric variants. First reported by Knçlker et al. in
1990,[3] the cyclopentane annulation of air- and moisture-
stable allylsilane nucleophiles with unsaturated carbonyl
compounds is a transformation where a catalytic asymmetric
variant has eluded development.[4–6] The challenge associated
with controlling additions to unsaturated carbonyl com-
pounds is highlighted by the fact that only one method has
been reported for a catalytic enantioselective conjugate
addition reaction using allylsilanes (Scheme 1A).[7] Herein,
we report the first catalytic asymmetric annulation of
allylsilanes with unsaturated carbonyl compounds (Scheme
1B) to access cyclopentanes possessing up to three stereo-
centers, including a quaternary carbon spirocenter.
Scheme 1. Catalytic asymmetric additions of allylsilanes to a,b-unsatu-
rated carbonyl compounds. BArF=tetrakis-[3,5-bis(trifluoromethyl)-
phenyl]borate.
Table 1: Optimization of the allylsilane annulation with alkylidene
oxindoles.[a]
The reaction of the alkylidene oxindole 1a with allylsilane
2a[8] offers a platform to study the reactivity and selectivity
for the annulation reaction (Table 1). The selective formation
of a cyclic product (4) or an allylation (Hosomi–Sakurai)
Entry Conditions
Yield [%][b] d.r.[c]
e.r.[d]
1
2
SnCl4/(S)-binol (20 mol%), 24 h
Cu(OTf)2/(S)-PhBox/NaBArF
(10 mol%), 168 h
75[c] 50:50[e] 70:30
<5
n.d.
n.d.
[*] N. R. Ball-Jones, Dr. J. J. Badillo, N. T. Tran, Prof. A. K. Franz
Department of Chemistry, University of California
One Shields Avenue, Davis, CA 95616 (USA)
E-mail: akfranz@ucdavis.edu
3
4
5
6
7
8
9
ScCl3/L2/NaSbF6 (10 mol%), 72 h <5
n.d.
n.d.
n.d.
n.d.
97:3
92:8
56:44
–
ScCl3/L2/NaSbF6, TMSCl[f]
ScCl3/L2/NaBArF
<10[c]
99
99:1
95:5
95:5
65:35
95:5
Homepage: http://chemgroups.ucdavis.edu/~franz/
Sc(OTf)3/L2/NaBArF
ScCl3/L2 with 50 mol% NaBArF
ScCl3/NaBArF
94
[**] We thank Prof. Dean Tantillo (UCD) and Dr. Gonzalo Jimꢀnez-Osꢀs
(UCLA) for helpful discussions, and Prof. Mark Mascal and Dr.
Gorkem Gunbas (UCD) for a generous donation of NaBArF. This
research is supported by donors of the American Chemical Society
Petroleum Research Fund and NIH/NIGMS (P41-GM0089153).
A.K.F. acknowledges the 3M Corporation for a Nontenured Faculty
Award, N.R.B.-J. and N.T.T. acknowledge the Department of
Education for a GAANN fellowship, J.J.B. acknowledges the NSF for
a graduate research fellowship, and N.T.T. acknowledges UC Davis
for a Bradford Borge Chemistry Fellowship.
73
95[c]
99[c]
Sc(BArF)3/L2 (20 mol%)
84:16
[a] All reactions performed under argon with 3.0 equiv of allylsilane in
a 1:1.1:1 ratio of [ScCl3(thf)3], (R,S)-indapybox, and NaBArF for 1 h at
a 5 mol% catalyst loading (unless otherwise noted). [b] Yield of isolated
product. [c] Determined using 1H NMR spectroscopy. [d] Determined
using chiral-phase HPLC. [e] Allylation product 5 was also observed.
[f] Used 3 equiv of TMSCl. binol=2,2’-dihydroxy-1,1’-binaphthyl,
M.S.=molecular sieves, Tf=trifluoromethanesulfonyl, thf=tetrahydro-
furan, TMS=trimethylsilyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403607.
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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
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Table 3: Formation of the lactone 8 f by trapping of a b-silyl carbocation.
also be accessed with high diastereoselectivity [Eq. (3)].
While oxindole derivatives are highly enantioselective, mal-
onate and coumarin derivatives eluded asymmetric induction.
In summary, we have developed the first catalytic
asymmetric [3+2] annulation of unsaturated carbonyl com-
pounds with allylsilanes, thus giving spirocyclopentane core
structures in high yields, and diastereo- and enantioselectiv-
ities. Significant ligand and counterion effects are observed to
control the path of the transient b-silyl carbocation (annula-
tion versus allylation versus lactone), as well as the diastereo-
and enantioselectivity. The annulation methodology can be
applied to malonate- and coumarin-derived electrophiles with
high yields and diastereoselectivities. More detailed mecha-
nistic and computational studies are underway to elucidate
the factors controlling the stereoselectivity.
X
Ratio (8 f/4 f)[a]
Yield [%][b]
d.r.[c]
e.r.[d]
OTf
Cl
63:37
19:81
53
18
44:17:19:20
21:47:23:9
85:15
94:6
[a] Based on mass recovery. [b] Yield of isolated product. [c] Determined
using 1H NMR spectroscopy. [d] Determined using chiral-phase HPLC.
Thermal ellipsoids shown at 30% probability.
Received: March 23, 2014
Published online: July 13, 2014
using modified Tamao–Fleming conditions to generate hy-
droxy-substituted spirooxindoles (6n) with retention of
stereochemistry.[21]
Keywords: allylic compounds · asymmetric catalysis ·
.
conjugate addition · cyclization · scandium
Rate enhancement observed with the ester-substituted
alkylidene 1d compared to that of the phenyl-substituted
alkylidene 1i (45 min versus 4 d) suggests that the reaction is
promoted by coordination of the proximal ester group with
the transient b-silyl carbocation (e.g. 7; Table 3). Using the
tert-butyl-substituted oxindole 1 f leads to trapping of the
transient b-silyl carbocation and isolation of the lactone
8 f.[15,22] The yield of 8 f is influenced by the use of chloride
versus triflate salt (53 versus 18% yield, Table 3), which is
attributed to Lewis acid initiated deprotection of the tert-
butyl ester. The reaction of 1 f using excess NaBArF
(60 mol%) promotes allylation with 95% conversion (in
48 h).
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2012, 51, 989; b) During review of this manuscript, the first
catalytic asymmetric allylsilane [4+2] annulation with b,g-
unsaturated a-ketoesters was reported. See: Y. Matsumura, T.
Suzuki, A. Sakakura, K. Ishihara, Angew. Chem. 2014, 126, 6245;
Angew. Chem. Int. Ed. 2014, 53, 6131.
The enhanced catalytic activity with NaBArF and the
reactivity trends observed with alkylidene oxindoles translate
to the malonate- and coumarin-derived electrophiles 9 and 11,
respectively, which broadens access to functionalized carbo-
cycles containing a quaternary carbon center [Eqs. (2) and
[6] Allylsilane precursors have been used to generate trimethylene-
methane nucleophiles. See: B. M. Trost, N. Cramer, S. M.
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(3); DMBS = dimethylbenzhydrylsilane, TBAF = tetra-n-
butylammonium fluoride, THF = tetrahydrofuran].[23] Allyl-
silane annulation followed by oxidation afforded the carbo-
cycle 10 in high diastereoselectivity, but with low enantiose-
lectivity [Eq. (2)]. The cyclopentane 11, a carbocycle not
previously accessed using [3+2] annulation methodology, can
[11] M. E. Kieffer, L. M. Repka, S. E. Reisman, J. Am. Chem. Soc.
2012, 134, 5131.
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ineffective as catalysts. See Tables S1–S4 in the Supporting
Information.
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[15] The structure and absolute stereochemistry of 4m was assigned
based on X-ray crystallography (anomalous dispersion method).
The relative stereochemistry of 8 f was assigned by X-ray
analysis. Absolute stereochemistry of 8 f was assigned by analogy
to the structure of 4m. CCDC 958776 (4m) and 961076 (8 f)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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carbocations, see: a) J. B. Lambert, Y. Zhao, H. Wu, J. Org.
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carbocation isolation, see: b) S. R. Bahr, P. Boudjouk, J. Org.
Chem. 1992, 57, 5545.
[19] A chelating electrophile is required for enantiocontrol: The N-
methyl substrate 4o afforded racemic product in 60% con-
version.
[20] See Table S7 for details of deprotection conditions.
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[23] The relative stereochemistry of 10 and 12 was assigned by
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