Asymmetric synthesis of allenyl oxindoles and spirooxindoles by a catalytic enantioselective saucy-marbet claisen rearrangement

Article abstract of DOI:10.1002/anie.201107417

Saucy selection: The first catalytic, enantioselective Saucy-Marbet Claisen rearrangement has been achieved. Palladium(II) (R)-binap or tBuphox catalysts L*Pd(SbF₆)₂ were employed to generate allenyl oxindoles or spirolactones bearin

Full text of DOI:10.1002/anie.201107417

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DOI: 10.1002/anie.201107417
Asymmetric Catalysis
Asymmetric Synthesis of Allenyl Oxindoles and Spirooxindoles by
a Catalytic Enantioselective Saucy–Marbet Claisen Rearrangement**
Trung Cao, Joshua Deitch, Elizabeth C. Linton, and Marisa C. Kozlowski*
The development of catalytic enantioselective Claisen re-
arrangement reactions is a longstanding challenge in organic
synthesis.[1] In the more than 100 years since the reaction was
discovered, only five highly enantioselective catalytic versions
of this concerted rearrangement have been reported; these
reactions rely on either Lewis acids,[2,3] hydrogen-bonding
catalysts[4] or chiral N-heterocyclic carbenes.[5] A related
asymmetric transformation via a p-allyl intermediate has also
been reported.[6] Furthermore, enantioselective catalysis in
the rearrangements of alkynyl vinyl ethers has not been
described, even though auxiliary-controlled diastereoselec-
tive versions are documented.[7] In asymmetric catalysis, such
a reaction presents a distinct set of challenges, since the
alkyne sp centers distort the transition-state geometries and
the cylindrically symmetric alkyne provides no opportunity
for facial discrimination. In addition, the allenyl products of
such a rearrangement are poised to undergo tandem reactions
to rapidly generate complex structures. Herein we present the
first catalytic asymmetric Saucy–Marbet Claisen rearrange-
ment, namely the transformation of propargyl ethers to
provide b-substituted allenyl carbonyls (Scheme 1).[8] The
reaction gives rise to two classes of chiral oxindoles contain-
ing newly formed quaternary centers: allenyl compounds and
spirocylic lactones through a tandem rearrangement.
To start, we employed propargyl-substituted indoles 3,
which were readily obtained from 1 and 2 (Scheme 1).[9] The
oxindole products 4 of the subsequent Saucy–Marbet Claisen
rearrangement are central building blocks for the construc-
tion of indole alkaloids[10] and are attractive platforms for
pharmaceutical agents.[11] For these reasons, the development
of catalytic asymmetric methods for their generation has been
the subject of much research.[3,12,13] In particular, the forma-
tion of enantiopure oxindoles with allenyl substitution at C3
has not yet been reported.
Evaluation of 3a with representative hydrogen bonding
and Lewis acid catalysts[14] revealed that the rearrangement
readily occurred. However, when we began testing Pd
complexes,[3] we were disappointed with the poor selectivity
(Table 1, entries 1–3) seen with the methyl ester 3a–c using
Table 1: (tBuphox)Pd(SbF6)2-catalyzed Saucy–Marbet rearrangement
(Scheme 1).[a]
Entry
3
R1 R2
cat. T [8C]
[mol%]
t
Yield [%] ee [%]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
Me
Me Me
Me Ph
Me o-Tol
Me o-BrC6H4
Me 1-Nap
Me o-MeO C6H4
Me TMS
H
20
20
5
5
5
5
5
20
20
20
0
0
0
10 min 100[b]
15 min 100[b]
14
45
78
98
96
98
98
14
45
70
8 h
96
95
93
95
90
ꢀ15 8 h
ꢀ15 8 h
ꢀ15 8 h
ꢀ15 8 h
0
0
90 min 15
9
Me tBu
2 days 100[b]
10[c]
j
Me MIDA-B[d]
45 2 days
60
[a] Reaction conditions: (tBuphox)*Pd(SbF6)2 (0.025m), CH2Cl2.
[b] Conversion [%]. [c] 1:5:5 MeCN/C6H5Cl/CH2Cl2. [d] MIDA boronate;
see reference [13]. Nap=naphthyl, TMS=trimethylsilyl, MIDA=N-
methyliminodiacetic acid.
Scheme 1. Saucy–Marbet Claisen rearrangement. NCS=N-chloro-
succinimide, MIDA=N-methyliminodiacetic acid, TMS=trimethylsilyl,
TES=triethylsilyl, TBS=tert-butylsilyl, TIPS=triisopropylsilyl.
catalysts based on the tBuphox ligand (Scheme 2). Not
unexpectedly, the alkyne geometry significantly alters the
topology of the rearrangement transition state (Scheme 3).
Closer inspection of proposed stereochemical models
revealed that the ester group, which undergoes a gearing
effect from the catalyst, would interact with larger alkyne
terminal substituents to destabilize the less-favorable reaction
[*] T. Cao, J. Deitch, Dr. E. C. Linton, Prof. M. C. Kozlowski
Department of Chemistry
Penn Merck High Throughput Experimentation Laboratory
University of Pennsylvania, Philadelphia, PA 19104-6323 (USA)
E-mail: marisa@sas.upenn.edu
[**] Financial support was provided by the NSF (CHE-0911713) and
NIH (RO1GM087605). Partial instrumentation support was pro-
vided by the NIH for MS (1S10RR023444) and NMR
(1S10RR022442) and by the NSF for an X-ray diffractometer (CHE-
0840438). The invaluable assistance of Dr. Patrick Carroll in
obtaining the crystal structures is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107417.
Scheme 2. Bidentate ligands used.
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ophos complexes gave poor selectivity (Table 2, entry 6).
Hypothesizing that trace fluoride may arise from the difluor-
ophos, we returned to binap (Table 2, entry 7), which proved
effective. Unfortunately, with 20 mol% of the Pd complex
(entry 8), the enantioselectivity suffered even after optimiza-
tion of the solvent. The use of larger silyl groups, such as
triethylsilyl (TES) or tert-butylsilyl (TBS), allowed the
selectivity to be retained even under catalytic conditions
(entries 9 and 10). Good to excellent enantioselectivities were
obtained in the rearrangement of a range of different indole
cores, producing the TES- or TBS-substituted allenes
(entries 9–15) with as little as 5 mol% catalyst (entry 12).
The absolute configurations of the products were established
through X-ray crystallography and are in accord with the
proposed stereochemical models (Scheme 3; see also the
Supporting Information).
Scheme 3. Stereochemical model of the rearrangement.
pathway. In line with this hypothesis, very high levels of
enantioselection (96–98% ee) were observed with alkynes
having ortho-substituted aryl groups at R2, along with rapid
conversions (8 h at ꢀ158C) at 5 mol% catalyst loading
(Table 1, entries 4–7). However, alkynes with larger groups,
such as trimethylsilyl (TMS), tert-butyl, or N-methyliminodi-
acetic acid (MIDA) boronate,[15] were less successful
(entries 8–10).
In attempting to use catalytic amounts of the palladium
complex with much larger triisopropylsilyl (TIPS) substrates,
higher temperatures (408C vs. RT) were required, which also
caused the formation of spirocyclic lactone 9q along with
allene 4q (Table 3, entry 1 and Scheme 4). Hypothesizing that
trace water together with the Pd catalyst hydrated allene 4 to
form intermediate ketone A (Scheme 4), we tried adding
Owing to the poor results with non-aryl alkynes, addi-
tional ligands (6–8, Scheme 2) were examined. A stereo-
chemical model with binap (see Supporting Information)
revealed the potential for good stereodifferentiation, which
was borne out with the larger tert-butyl-substituted substrate
(Table 2, entry 3), but not the smaller congeners (entries 1
and 2). Screening of other metal catalysts demonstrated that
only the palladium complexes possessed an adequate combi-
nation of reactivity and selectivity (see Supporting Informa-
tion). Further optimization around the binap ligand frame-
work proved that difluorophos was the most effective,
providing tert-butyl-substituted allene 4i with 90% yield
and 86% ee (Table 2, entry 4 vs. entries 3 and 5). Surprisingly,
use of the TMS-substituted alkyne with the optimal difluor-
Table 3: Tandem rearrangement–spirocyclization (Scheme 4).[a]
Entry
3
R1
R2
R3
t
Solvent[b] Yield [%] ee [%]
[days]
4
9
4
9
1
q
q
q
q
q
r
Me
Me
Me
Me
Me
Et
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
H
H
H
H
H
H
H
H
4.5
10
10
4.5
4.5
4
4
4
6
5
A
A
A
A
C
C
C
C
B
A
C
B
B
23 62
80
61
89 90
82
89
2[c]
3[c,d]
4[e]
55
94
5[f]
78[g]
90
90
87
92
96
91
92
92
6[f]
95
90
95
93
81
90
82
95
7[f]
s
t
CH2CF3 TIPS
Bn
Et
Et
Et
8[f]
TIPS
9[f]
u
v
w
x
l
TIPS 7-Me
TIPS 5-OMe
TIPS 7-OMe
TIPS 5-Br
10[f]
11[f]
12[f]
13[f,h]
6
6
5
Et
Me
TBS
H
86
Table 2: Substrate scope in the oxindole rearrangement (Scheme 1).[a]
[a] Reaction conditions: (binap)Pd(SbF6)2 (0.025m, 20 mol%), 408C.
[b] Solvents: A) CH2Cl2, B) 1:1 C6H5Cl/C6H5CH3, C) C6H5Cl. [c] 30 mol%
L*Pd(SbF6)2, 2,4,6-tris-tert-butylpyridine (10 mol%). [d] Ligand 7b used.
[e] 30 mol% L*Pd(SbF6)2, (tmeda)Zn(SbF6)2 (10 mol%). [f] 5–10 mol%
H2O added. [g] Performed with 0.5 mmol substrate. [h] Reaction con-
ducted at RT. TIPS=triisopropylsilyl, TBS=tert-butylsilyl.
Entry
L
3
R1 R2
R3
cat.
t
Yield [%] ee [%]
[mol%]
1
2
3
4
5
6
7
8
6
6
6
7a
8
7a
6
6
6
6
a
b
i
i
i
h
h
h
k
l
m
m
n
o
p
Me
H
H
H
H
H
H
H
H
H
H
H
20 10 min
20 30 min
20 2 days
100 10 h
100 10 h
100 10 h
100 4 h
20 4 days
20 6 days
20 5 days
20 5 days
100
100
40
90
90
95
90
100
78
90
8
4
Me Me
Me tBu
Me tBu
Me tBu
Me TMS
Me TMS
Me TMS
Me TES
Me TBS
Et TBS 7-Me
Et TBS 7-Me
Et TBS 5-OMe
Et TBS 7-OMe
Et TBS 5-Br
76
86
83
44
77
60
90
89
90
90
93
93
90
9
10
11
12
13
14
15
6
6
6
6
87
76
82
91
5
10 days
20 5 days
20 6 days
20 6 days
6
85
[a] Reaction conditions: L*Pd(SbF6)2 (0.025m), CH2Cl2 at 08C. With TES,
TBS substrates: 1:1 C6H5Cl/C6H5CH3 at RT. TMS=trimethylsilyl,
TES=triethylsilyl, TBS=tert-butylsilyl.
Scheme 4. Tandem formation of a spirocyclic oxindole.
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2,4,6-tris-tert-butylpyridine. In accord with this premise, the
additive suppressed formation of the spirocyclic lactone and
cleanly produced the allene with up to 89% ee (Table 3,
entries 2 and 3) using the segphos ligand (7b). Alternatively,
(tmeda)Zn(SbF6)2 was found to selectively absorb water,
improving selectivity to 94% ee (entry 4; tmeda = tetra-
methylethylenediamine). Notably, the allene and spirolactone
products were quite stable; for example, stirring with
0.25 equiv of trifluoroacetic acid in CH2Cl2 overnight at
ambient temperature caused no decomposition.
The potential clinical significance of spirocyclic oxin-
doles[16] has led to a demand for efficient methods for their
enantioselective synthesis.[17,18] Apart from their presence in
a large number of biologically active natural products,[19] their
topology allows functionalization of all four faces of a tetra-
hedron centered on the spirocyclic center, creating an ideal
environment for structural diversity. For these reasons, the
tandem formation of spirocyclic lactone 9 warranted further
study. Isolation of TES-substituted allene 4k (90% ee) and
TIPS-substituted 4q (89% ee) followed by resubjection to the
reaction conditions resulted in conversion to 9k (90% ee) and
9q (89% ee), respectively. Furthermore, the
a-silylketone A (Scheme 4) from the TBS-substituted alkyne
3m was isolated and found to cyclize to the spirocyclic lactone
in the presence of the palladium catalyst. From these results,
we propose a mechanism involving palladium-catalyzed
allene hydration to form A followed by palladium-catalyzed
cyclization (Scheme 4). Consistent with this mechanism,
addition of a small amount of water (5–10 mol%) provided
spirolactone products 9 in one step with high efficiency
(Table 3, entries 5–13). This class of compounds is particularly
difficult to prepare, with only two examples reported[9,20] for
the synthesis of the racemic, saturated versions of these
spirooxindoles. With our method, substrates with different
esters or indole substituents were well-tolerated, providing
the spirooxindoles with good yields and enantioselectivities
(Table 3, entries 5–13). Reactions conducted on a larger scale
also proceeded well (Table 3, entry 5). A key component of
this mechanism is stabilization of the carbocationic inter-
mediate B through the b-silyl effect;[21] indeed, non-silyl
substrates reluctantly formed the spirolactone, resulting in
a mixture of rearrangement product 4 and intermediate A.
Further study of the mechanism of the formation of allene
4 from 3 was undertaken by reacting two different substrates
in the same flask (Scheme 5). The lack of any crossover of the
alkyne portion points to a concerted Saucy–Marbet Claisen
rearrangement rather than a stepwise ionic mechanism.
Scheme 6. Transformations of the allenyl oxindoles. TBAF=tetra-
butylammonium fluoride, M.S.=molecular sieves.
The allenyl products 4 of the Saucy–Marbet Claisen
rearrangement were found to be useful substrates for
a number of transformations (Scheme 6), in addition to the
formation of the spirolactone (see above). For example,
protodesilation of 4k readily provided the simplest congener
4a, which was not directly accessible with high selectivity by
the rearrangement (see entry 1 in Tables 1 and 2). Hydration
of the allene also readily occurred with Hg(O2CCF3)2
providing a-silyl ketone 10, which could be further induced
to undergo a Brook rearrangement to provide silyl enol ether
11.
In summary, the first catalytic, enantioselective Claisen
rearrangement utilizing alkynyl substrates has been devel-
oped. This concerted Saucy–Marbet Claisen rearrangement
constitutes a mild entry to a range of allenyl oxindoles bearing
a quaternary stereocenter. Furthermore, tandem reactions of
silyl-substituted substrates permit the rapid assembly of
complex spiroooxindoles, an important class of biologically
active structures, in one operation. Moreover, this discovery
provides promise for the general use of alkynyl vinyl ethers in
catalytic, asymmetric rearrangement reactions, providing an
alternative route to valuable allenes.
Experimental Section
(R)-Ethyl 3-(1-(tert-butyldimethylsilyl)propa-1,2-dien-1-yl)-5-meth-
oxy-2-oxoindoline-3-carboxylate (4n): A solution of 3n (19.4 mg,
0.05 mmol) in toluene (1 mL) was added to a solution of the Pd[(R)-
binap](SbF6)2 complex (12 mg, 0.01 mmol, 20 mol%) in C6H5Cl
(1 mL) at ambient temperature. The resulting solution was stirred
in the absence of light at room temperature until the starting material
was completely consumed, as determined by TLC. Filtration through
a plug of SiO2 (5 mm ꢀ 2 cm) with diethyl ether, concentration of the
filtrate, and purification by column chromatography using 50%
diethyl ether/hexanes afforded 4n as a white solid in 82% yield: mp
23
136–1378C; ½aꢁD ¼ + 158.18 (c = 0.17, 93% ee, CH2Cl2). 1H NMR
(500 MHz, CDCl3): d = 7.92 (bs, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.79–
6.74 (m, 2H), 4.60 (d, J = 11.5 Hz, 1H), 4.41 (d, J = 11.5 Hz, 1H), 4.22
(qd, J = 7.5, 11.0 Hz, 1H), 4.13 (qd, J = 7.5, 11.0 Hz, 1H), 3.78 (s, 3H),
1.23 (t, J = 7.5 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 3H), 0.10 ppm (s, 3H);
13C NMR (125 MHz, CDCl3): d = 212.5, 174.8, 168.8, 155.7, 134.3,
129.7, 114.5, 113.2, 110.2, 100.2, 93.6, 74.1, 62.4, 56.1, 27.6, 19.4, 14.2,
ꢀ4.0, ꢀ4.2 ppm; IR (film) n˜ = 3252, 2958, 2858, 1931, 1746, 1622, 1468,
1259, 1089, 1027 cmꢀ1
; HRMS (ES) m/z = 386.1788 calcd for
C21H28NO4Si [MꢀH]ꢀ, found 386.1776; CSP HPLC (Chiralpak IA,
Scheme 5. Crossover mechanism experiment.
1 mLminꢀ1, 95:5 hexanes/iPrOH) tR(1) = 14.0 min, tR(2) = 21.6 min.
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Qiu, S. Shangary, W. Gao, D. Qin, J. Stuckey, K. Krajewski, P. P.
Received: October 20, 2011
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Published online: January 27, 2012
Keywords: allenyl silanes · asymmetric catalysis ·
.
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