A designed amide as an aldol donor in the direct catalytic asymmetric aldol reaction

Article abstract of DOI:10.1002/anie.201403118

The direct catalytic asymmetric aldol reaction offers efficient access to β-hydroxy carbonyl entities. Described is a robust direct catalytic asymmetric aldol reaction of α-sulfanyl 7-azaindolinylamide, thus affording both aromatic and aliphatic β-hydroxy amides with high ee values. The design of this transformation features a cooperative interplay of a soft and a hard Lewis acid, which together facilitate the challenging chemoselective enolization by a hard Bronsted base.

Full text of DOI:10.1002/anie.201403118

Angewandte
Chemie
DOI: 10.1002/anie.201403118
Asymmetric Catalysis
A Designed Amide as an Aldol Donor in the Direct Catalytic
Asymmetric Aldol Reaction**
Karin Weidner, Naoya Kumagai,* and Masakatsu Shibasaki*
Abstract: The direct catalytic asymmetric aldol reaction offers
efficient access to b-hydroxy carbonyl entities. Described is
a robust direct catalytic asymmetric aldol reaction of a-sulfanyl
7-azaindolinylamide, thus affording both aromatic and ali-
phatic b-hydroxy amides with high ee values. The design of this
transformation features a cooperative interplay of a soft and
a hard Lewis acid, which together facilitate the challenging
chemoselective enolization by a hard Brønsted base.
inherently more acidic aldehyde acceptor in a catalytic system
is a formidable challenge. To address this issue, we designed
a new amide aldol donor to override the intrinsic low acidity
of amides so that the active enolate can be preferentially
formed. Herein we report a direct catalytic asymmetric aldol
reaction of a-sulfanyl 7-azaindolinylamide as an aldol donor,
a reaction promoted by a Ag/Li-based cooperative asymmet-
ric catalyst. This new aldol donor allows direct aldol reaction
in a highly diastereo- and enantioselective fashion without
self-condensation of the aldehydes.
We reasoned that the bidentate coordination of soft
Lewis-basic functionalities, installed at suitable positions of
an amide, to a soft Lewis-acidic metal might facilitate the
chemoselective activation over aldehydes. The thus designed
a-sulfanyl 7-azaindolinylamide (1), predominantly as the E-
amide rotamer,[15,16] would form the seven-membered che-
lated structure A with the soft Lewis acid, in which the
chelation would induce tilting the indolino group so as to
partially break the amide conjugation (Figure 1). Moreover,
T
he aldol reaction is a robust and widely used transformation
of carbonyl compounds to construct b-hydroxy carbonyl
units.[1] For the reliable coupling of aldol acceptors and aldol
donors, preactivated aldol donors, for example, metal eno-
lates or enol silyl ethers, are commonly used. Given the broad
utility of b-hydroxy carbonyl fragments in organic synthesis,
significant advances have been made to devise catalytic
stereoselective aldol reactions based on the use of preformed
enolates as aldol donors.[2,3] Since the first report of the
intermolecular direct catalytic asymmetric aldol reaction
which features in situ or direct generation of nucleophilically
active enolates,[4] direct use of aldol donors has gained
increasing attention in catalytic asymmetric aldol reac-
tions.[1,5] The bottleneck in direct aldol methodology is the
reluctance of enolate formation from aldol donors, and fairly
acidic latent enolates such as ketones and aldehydes have
been preferably adopted.[5] In this context, direct aldol
reactions using less acidic carbonyl compounds, having
a carboxylic acid oxidation state, have been much less
explored because of their reluctance to form enolates.[6–13]
Only the pioneering example of a direct catalytic asymmetric
aldol reaction using amide-based aldol donors (N-Boc amide)
has been reported with limited substrate scope and moderate
ee values.[14] Specifically, the chemoselective formation of the
active enolate of an amide aldol donor in the presence of an
Figure 1. Working hypothesis for enolate formation from a-sulfanyl 7-
azaindolinylamide (1). LA=Lewis acid.
[*] Dr. K. Weidner, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry (BIKAKEN), Tokyo
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
E-mail: mshibasa@bikaken.or.jp
À
the cyclic alignment would fix the a-C H bond of the amide
suitable for deprotonation, thus allowing enolate formation
by the action of a mild Brønsted base. We anticipated that
diminished amide conjugation and conformational restriction
would work synergistically to generate an amide-derived
enolate in the presence of a more enolizable aldehyde.[17]
Our recent development of soft Lewis acid/hard Brønsted
base cooperative catalysis[18] led us to initially screen various
cationic soft Lewis acids in combination with (R)-BINAP (4)
and the lithium salt of 2,2,5,7,8-pentamethylchromanol as
a Brønsted base (Table 1). Attempted reactions, in which
isobutyraldehyde (2a) was used as the model substrate,
Prof. Dr. M. Shibasaki
JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku
Tokyo 141-0021 (Japan)
[**] This work was financially supported by JST, ACT-C and JSPS
KAKENHI Grant Number 25713002. K.W. thanks JSPS for a post-
doctoral fellowship. Dr. H. Sato, Dr. T. Kimura, and A. Matsuzawa
are gratefully acknowledged for technical assistance in X-ray
crystallography. Dr. K. Takahara is gratefully acknowledged for ESI-
MS analysis of the catalyst solutions. We thank Dr. R. Sawa and Y.
Kubota for technical assistance in NMR spectroscopy.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403118.
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Table 1: Initial screening.[a]
complex with a silver cation without
breaking the planarity of the amide
functionality.
The substrate scope of aliphatic
aldehydes under the optimized
reaction conditions is summarized
in Table 2.[22] The present catalytic
system afforded the desired aldol
products in a highly chemoselective
manner even with a,a-nonbranched
aldehydes and no self-aldol prod-
ucts were observed (entries 2–6 and
8–11). syn-Products were obtained
preferentially with high yield and
ee value. In some cases, the addition
of 2-methylthioethanol (7) was ben-
eficial to improving stereoselectiv-
ity (entries 6, 9, and 11). The reac-
tion conditions were sufficiently
mild and 3h was obtained without
lactonization (entry 10). The pres-
ent direct aldol reaction was also
performed on gram scale (entry 6).
Next we tested whether this
catalytic system would be applica-
ble to aromatic aldehydes. The
initial attempt to conduct the reac-
tion with 2-(trifluoromethyl)benzal-
dehyde (2i) afforded a striking reac-
tion outcome, namely the diaste-
reoselectivity was switched to anti
Entry softLA
Ligand hardBB
x
Additive
(x mol%) [8C]
T
t
Yield anti/syn[b] ee [%][c]
[h] [%][b]
LiOAr1
LiOAr1
LiOAr1
LiOAr1
LiOAr1
LiOAr2
DBU
10
10
10
10
10
10
10
–
–
–
–
–
–
–
–
–
–
À40 24 82
À40 24 79
À40 24 64
À40 24 86
À60 24 72
À60 24 49
23:77
28:72
18:82
31:69
9:91
9:91
–
–
–
–
15
1
[d]
1
CuPF6
4
4
4
4
5
5
5
5
5
5
5
5
5
5
2
3
4
5
6
7
8
9
Ni(OTf)2
AgPF6
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
(Ag)
AgBF4
–
AgBF4
AgBF4
38
57
43
63
–
–
–
–
À60 24
À60 24
À60 24
À60 24
0
0
0
0
NaOAr2 10
KOAr2
AgOAr3
LiOAr2
LiOAr2
–
10
10
10[e]
11
12
13
14
10 LiOTf
10 LiOTf
10 LiOTf
À60 24 89
9:91
–
–
99
–
–
À60 24
À60 24
0
0
LiOAr2
8
LiOTf
À60 36 87
9:91
99
1
[a] 1: 1.0 mmol, 2a: 1.2 mmol. [b] Determined by H NMR analysis of the crude reaction mixture.
[c] Determined by HPLC analysis. [d] Tetrakis(acetonitrile) complex was used. [e] ÀOAr3 anion was
expected to function as base. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, Tf=trifluoromethanesulfonyl,
THF=tetrahydrofuran.
indicated that AgBF4 served as a suitable Lewis acid to afford
the corresponding syn-aldol product 3a preferentially at
À408C with moderate stereoselectivity (entries 1–4). Exten-
sive screening of ligands identified (R,R)-Ph-BPE 5 as the
preferred ligand and 3a was produced in promising stereo-
selectivity at À608C (entry 5). Fluctuating stereoselectivity
Figure 2. Structural features of the reactive amide 1 and unreactive
amide 6.
was observed as a result of the retro-aldol reaction. This was
prevented by switching to the less basic Li(OC6H4-p-OMe) to
obtain higher stereoselectivity in a reproducible manner
(entry 6). Amine bases and the sodium or potassium aryl-
oxides were ineffective, thus suggesting that the lithium cation
plays a key role in promoting the reaction (entries 7–9). This
assumption is in line with the ineffectiveness of 5/AgOAr3 as
a cooperative catalyst (entry 10).[19,20] This finding directed us
to use LiOTf as an additive, which led to an enhanced
catalytic performance and higher ee value (entry 11). Control
experiments in the absence of either the soft Lewis acid or
Brønsted base failed, thus indicating that the cooperative
effect was crucial for promoting the reaction (entries 12 and
13). The catalyst loading could be reduced to 8 mol% without
any detrimental effect (entry 14). In striking contrast, the
structurally related amide 6, derived from 2-aminopyridine,
completely failed the reaction under otherwise identical
reaction conditions despite the likely formation of the
bidentate chelation to a silver cation (Figure 2).[21] This
outcome is presumably because flexible rotation along the
selective and a nearly racemic product, 3i, was obtained
(Figure 3a). Close inspection of the reaction profile revealed
the following: 1) the reaction proceeded much faster with
aromatic aldehydes than with aliphatic aldehydes, and 2) sig-
nificant retro-aldol reaction was observed as evidenced by the
continuous decrease in stereoselectivity during the course of
the reaction (Figure 3d; time course marked with red open-
circles). To protect the product from undesired re-entry into
the catalytic cycle, we sought a simple molecule bearing
a similar functional-group array as the aldol product, which
may serve as a dummy ligand. We found that 7 fulfilled this
role. The desired aldol product 3i was obtained in anti-
selective fashion with high ee value when 7 was used in
a tenfold amount relative to the catalyst (Figure 3b,c).
Whereas 1 equivalent of 7 relative to the catalyst was
insufficient for the aromatic aldehyde to prevent the retro-
aldol reaction, it was effective for the less reactive aliphatic
aldehydes, and a marginal increase in stereoselectivity was
À
C(py) N(amide) bond allowed the formation of the chelated
2
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Table 2: syn-Selective direct catalytic asymmetric aldol reaction of 1 with
Table 3: anti-Selective direct catalytic asymmetric aldol reaction of 1 with
aromatic aldehydes.[a]
aliphatic aldehydes.[a]
Entry
R
Additive
(x mol%)
3
Yield anti/syn ee
[%][b] [%][c]
Entry
Ar
3
Yield[b]
[%]
anti/syn
ee
[%][c]
1
2
3
4
iPr (2a)
nPr (2b)
–
–
–
–
–
7
–
–
7
–
7
3a 87
3b 86
3c 83
3d 91
3e 94
3e 91
3 f 85
3g 72
3g 86
3h 86
3h 86
9:91
6:94
8:92
99
97
98
93
97
97
95
98
99
89
97
1
o-CF3C6H4 (2i)
o-CF3C6H4 (2i)
o-NO2C6H4 (2j)
o-FC6H4 (2k)
p-CF3C6H4 (2l)
p-ClC6H4 (2m)
p-IC6H4 (2n)
3i
3i
3j
3k
3l
3m
3n
3o
3p
84
75
92
76
75
86
73
65
86
>98:2
>98:2
>98:2
81:19
75:25
81:19
86:14
83:17
92:8
93
93
91
99
95
85
97
93
84
2[d]
3
n-heptyl (2c)
iBu (2d)
Ph(CH2)2 (2e)
Ph(CH2)2 (2e)
cHex (2 f)
PMBO(CH2)2 (2g)
PMBO(CH2)2 (2g)
EtO2C(CH2)2 (2h)
EtO2C(CH2)2 (2h)
14:86
11:89
10:90
9:91
17:83
11:89
16:84
9:91
4
5
6
7
8
9
5
6[d]
7
8
9
10
11
C6H5 (2o)
1-naphthyl (2p)
[a] 1: 1.0 mmol, 2a: 1.2 mmol. [b] Yield of isolated product. [c] Ee of anti-
diastereomer determined by HPLC analysis. [d] 5.0 mmol of 1 and
6.0 mmol of 2i were used.
[a] 1: 1.0 mmol, 2a: 1.2 mmol. [b] Yield of the isolated products. [c] Ee of
syn-diastereomer determined by HPLC analysis. [d] 5.0 mmol of 1 and
6.0 mmol of 2e were used.
yields and excellent ee value (entries 1–4). The exclusive
anti selectivity was observed when sterically demanding
groups were present (entries 1–3). The halogenated benz-
aldehydes 2k,m,n were also compatible in this reaction
(entries 4, 6, and 7), as well as 2o and 1-naphthaldehyde
(2p; entries 8 and 9). The reaction using 2i was performed on
a 1 g scale (entry 2).
To gain insight into the silver complex, we performed
spectroscopic analysis of the catalyst solution. Whereas
a dense white suspension was formed by mixing AgBF4/5 in
a ratio 1:1 in THF, the addition of LiOTf afforded a solution
of AgBF4/5/LiOTf = 1:1:1. ESI-MS analysis of the solution
identified [Ag/5]+, [Ag/(5)2]+, [Ag2/(5)2]2+, [Ag2/(5)2/(OTf)]+,
and minor peaks for a complex bearing three molecules of 5,
thus suggesting that LiOTf dissociated the higher-order
complexes.[23] Crystallography of a single crystal obtained
from the same solution revealed a dimeric complex of Ag2/
(5)2/(OTf)2 (8; Figure 4). The same crystal was grown from
solutions of AgBF4/5/LiOTf/7 = 1:1:1:1 and AgBF4/5/LiOTf/
1 = 1:1:1:1, which would be a major species in solution phase
as suggested by 31P NMR analysis.[23] Monomeric and dimeric
silver complexes would be in equilibrium, with a preference of
the latter, but it is unclear which of the complexes is
responsible for promoting the present reaction. In ESI-MS
analysis, the monomeric Ag/7 complex [Ag/5/7]+ was
observed.[23] This complex underlies the proposed role of 7
in preventing the undesired retro-aldol reaction.[24]
Figure 3. Initial attempt of the aldol reaction using the aromatic
aldehyde 2i and the effect of MeS(CH2)2OH (7).
The 7-azaindolinylamide moiety behaves as a Weinreb
amide to prevent overreaction owing to the six-membered
chelating structure B (Scheme 1).[25] Treatment of the unpro-
tected aldol product 3i with n-butyllithium led to the clean
formation of the corresponding ketone 9 without overreac-
tion. After protection with a TBS group, reductive desulfur-
ization proceeded smoothly with nBu3SnH/AIBN to give 11.
Treatment with DIBAL-H afforded the aldehyde 12 without
over-reduction. Reduction to the primary alcohol 13 pro-
observed (Table 2, entries 6, 9, and 11). The beneficial effect
of the additive 7 in preventing the retro-aldol reaction was
evident from the consistent ee value during the course of the
reaction (Figure 3d). The modified catalyst system was
successfully applied to aromatic aldehydes with anti diaster-
eoselectivity (Table 3).[21] Aromatic aldehydes bearing an
ortho substituent afforded the desired products with high
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Figure 4. Plausible catalytic species.
[1] Modern Aldol Reactions, Vols. 1&2 (Ed.: R. Mahrwald), Wiley-
VCH, Berlin, 2004.
[2] T. Mukaiyama, K. Narasaka, K. Banno, Chem. Lett. 1973, 1011.
[3] For recent reviews: a) G. L. Beutner, S. E. Denmark, Angew.
Chem. 2013, 125, 9256; Angew. Chem. Int. Ed. 2013, 52, 9086;
b) S. B. J. Kan, K. K.-H. Ng, I. Paterson, Angew. Chem. 2013,
125, 9267; Angew. Chem. Int. Ed. 2013, 52, 9097; c) J.-M. Matsuo,
M. Murakami, Angew. Chem. 2013, 125, 9280; Angew. Chem. Int.
Ed. 2013, 52, 9109.
[4] Y. M. A. Yamada, N. Yoshikawa, H. Sasai, M. Shibasaki, Angew.
Chem. 1997, 109, 1942; Angew. Chem. Int. Ed. Engl. 1997, 36,
1871.
[5] For reviews: a) B. Alcaide, P. Almendros, Eur. J. Org. Chem.
2002, 1595; b) W. Notz, F. Tanaka, C. F. Barbas III, Acc. Chem.
Res. 2004, 37, 580; c) S. Mukherjee, J. W. Yang, S. Hoffmann, B.
List, Chem. Rev. 2007, 107, 5471; d) B. M. Trost, C. S. Brindle,
Chem. Soc. Rev. 2010, 39, 1600.
Scheme 1. Transformation of the aldol product. a) nBuLi, THF, À788C,
1.5 h, 89%. b) TBSOTf, 2,6-lutidine, THF, RT, 24 h, 89%. c) nBu3SnH,
AIBN, benzene, reflux, 2.5 h, 97%. d) DIBAL-H, THF, À408C, 2 h,
87%. e) LiEt3BH, THF, RT, 16 h, 71%. f) nBu3Sn(allyl), AIBN, benzene,
reflux, 24 h, 85%.
[6] There are numerous examples of direct aldol reactions using
aldol donors bearing electron-withdrawing a-substituents, and
are readily enolized under mild basic conditions.
[7] Use of alkylnitrile as pronucleophile in catalytic asymmetric
aldol-type reaction: Y. Suto, R. Tsuji, M. Kanai, M. Shibasaki,
Org. Lett. 2005, 7, 3757.
[8] Use of b,g-unsaturated ester as aldol donor: A. Yamaguchi, S.
Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 10842.
[9] Use of 5H-oxazol-4-ones as aldol donors: T. Misaki, G.
Takimoto, T. Sugimura, J. Am. Chem. Soc. 2010, 132, 6286.
[10] Use of thioamides as aldol donors: M. Iwata, R. Yazaki, Y.
Suzuki, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131,
18244.
[11] Use of a-hydroxyacylpyrroles as aldol donors: B. M. Trost,
W. M. Seganish, C. K. Chung, D. Amans, Chem. Eur. J. 2012, 18,
2948.
[12] Use of a-phosphonoester by a [1,2] phosphonate phosphate
rearrangement: M. T. Corbett, D. Uraguchi, T. Ooi, J. S.
Johnson, Angew. Chem. 2012, 124, 4763; Angew. Chem. Int.
Ed. 2012, 51, 4685.
[13] An intriguing direct catalytic asymmetric aldol reaction of
thiazolidinethiones using stoichiometric amount of silylating
reagent: D. A. Evans, C. W. Downey, J. L. Hubbs, J. Am. Chem.
Soc. 2003, 125, 8706.
ceeded with LiEt3BH. Subjection of 3i to Keck allylation
conditions replaced the SMe group with an allyl group to
afford the anti-oriented 14 exclusively.[26] In contrast, 10 gave
the diastereomixture of allylated compounds under the
identical reaction conditions, thus suggesting that hydrogen
bonding played a key role in rendering the reaction highly
diastereoselective.[27]
In summary, we have developed a direct catalytic
asymmetric aldol reaction of a-sulfanyl 7-azaindolinylamide
(1). Breaking the conjugation of an amide through bidentate
chelation to a Lewis acid is proposed for the preferential
formation of the amide enolate in the presence of readily
enolizable aldehydes. Both aliphatic and aromatic aldehydes
were successfully used as aldol acceptors and divergent
diastereoselectivity was observed. Tactical use of the
dummy product 7 effectively suppressed the undesired
retro-aldol reaction. The beneficial effect of 7-azaindolinyl-
amide to prevent the overreaction with organometallic
reagents is favorable for various transformations.
Received: March 8, 2014
Revised: March 26, 2014
Published online: && &&, &&&&
[14] S. Saito, S. Kobayashi, J. Am. Chem. Soc. 2006, 128, 8704.
[15] Amides bearing an N-alkyl and an N-aryl group generally favor
the configuration with the N-aryl group at the opposite side of
the carbonyl group (Ref. [16]). A single crystal of 1 was analyzed
by X-ray crystallography and the configuration was determined
to be E. See the Supporting Information.
Keywords: aldol reaction · amides · asymmetric catalysis ·
silver · synthetic methods
[16] S. Saito, Y. Toriumi, N. Tomioka, A. Itai, J. Org. Chem. 1995, 60,
4715.
.
4
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À
[17] Conjugation of the developing carbanion with s*(C S) orbital
assistance of the hard Lewis acid lithium cation to promote the
reaction.
would be also beneficial for facilitated deprotonation.
[18] For reviews: a) M. Kanai, N. Kato, E. Ichikawa, M. Shibasaki,
Synlett 2005, 1491; b) H. Yamamoto, K. Futatsugi, Angew. Chem.
2005, 117, 1958; Angew. Chem. Int. Ed. 2005, 44, 1924; c) H.
Yamamoto, K. Futatsugi in Acid Catalysis in Modern Organic
Synthesis (Eds.: H. Yamamoto, K. Ishihara), Wiley-VCH,
Weinheim, 2008; d) D. H. Paull, C. J. Abraham, M. T. Scerba,
E. Alden-Danforth, T. Lectka, Acc. Chem. Res. 2008, 41, 655;
e) N. Kumagai, M. Shibasaki, Angew. Chem. 2011, 123, 4856;
Angew. Chem. Int. Ed. 2011, 50, 4760.
[21] A series of structurally related amides were unreactive. See
Supporting Information.
[22] Details on the determination of relative and absolute config-
uration are summarized in Supporting Information. a-(Methyl-
thio)propionamide did not serve as a pronucleophile in this
catalytic system.
[23] See the Supporting Information for spectra and further dis-
cussion.
[24] For a plausible stereochemical course, see the Supporting
Information.
[25] a) S. Nahm, S. M. Weinreb, Tetrahedron 1981, 22, 3815; b) S.
Balasubramaniam, S. Aidhen, Synthesis 2008, 3707.
[26] G. E. Keck, J. B. Yates, J. Am. Chem. Soc. 1982, 104, 5829.
[27] The mechanistic basis of apparent retention of configuration in
radical allylation is currently under investigation and mecha-
nistic proposal is to be reported in due course.
[19] AgOAr3 was prepared by following the reported procedure: A.
Jakob, H. Schmidt, B. Walfort, T. Rꢀffer, T. Haase, K. Kohse-
Hçinghaus, H. Lang, Inorg. Chim. Acta 2011, 365, 1.
[20] LiOAr3 was sufficiently basic to promote the reaction in
combination with 5/AgBF4 (10 mol%, À608C, 36 h, 76%, anti/
syn = 9/91, 73% ee), thus indicating that 5/AgOAr3 required the
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Communications
Asymmetric Catalysis
K. Weidner, N. Kumagai,*
M. Shibasaki*
&&&& — &&&&
A Designed Amide as an Aldol Donor in
the Direct Catalytic Asymmetric Aldol
Reaction
In play: Direct catalytic asymmetric aldol
reactions offer efficient access to b-
hydroxy carbonyl entities. Described is
the robust title reaction of a-sulfanyl 7-
azaindolinylamide, thus affording both
aromatic and aliphatic b-hydroxy amides
with high ee values. The transformation
features the cooperative interplay of a soft
and a hard Lewis acid.
6
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