Iridium-Catalyzed Enantioselective Allylic Substitution of Aliphatic Esters with Silyl Ketene Acetals as the Ester Enolates

Article abstract of DOI:10.1002/anie.201704354

Enantioselective allylic substitution with enolates derived from aliphatic esters under mild conditions remains challenging. Herein we report iridium-catalyzed enantioselective allylation reactions of silyl ketene acetals, the silicon enolates of esters, to form products containing a quaternary carbon atom at the nucleophile moiety and a tertiary carbon atom at the electrophile moiety. Under relatively neutral conditions, the allylated aliphatic esters were obtained with excellent regioselectivity and enantioselectivity. These products were readily converted into primary alcohols, carboxylic acids, amides, isocyanates, and carbamates, as well as tetrahydrofuran and γ-butyrolactone derivatives, without erosion of enantiomeric purity.

Full text of DOI:10.1002/anie.201704354

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Accepted Article
Title: Iridium-Catalyzed Enantioselective Allylic Substitutions of
Aliphatic Esters via Silyl Ketene Acetals
Authors: Xingyu Jiang and John F. Hartwig
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704354
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10.1002/anie.201704354
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Iridium-Catalyzed Enantioselective Allylic Substitutions of
Aliphatic Esters via Silyl Ketene Acetals
Xingyu Jiang and John F. Hartwig*
Abstract: Enantioselective allylic substitutions with enolates derived
from aliphatic esters under mild conditions remain challenging.
Herein we report iridium-catalyzed enantioselective allylations of silyl
ketene acetals, the silicon enolates of esters, to form products
containing a quaternary carbon at the nucleophile moiety and a
tertiary carbon at the electrophile moiety. Under relatively neutral
conditions, the allylated aliphatic esters were obtained with excellent
regioselectivity and enantioselectivity. These products were readily
converted to primary alcohols, carboxylic acids, amides, isocyanates,
and carbamates, as well as tetrahydrofuran (THF) and γ-
butyrolactone derivatives, without erosion of enantiomeric purity.
enantioenriched α-allyl esters containing a quaternary α-carbon
and a tertiary β-stereocenters are inaccessible by asymmetric
Michael additions or asymmetric hydrogenations of the α,β-
unsaturated esters. Furthermore, the enantioselective allylations
of stabilized malonate-type nucleophiles followed by
fragmentation (desulfonylation and decarboxylation) would not
afford these highly substituted products.[12]
Catalytic asymmetric allylic substitutions with enolates
form C–C bonds reliably with high enantioselectivity.[1] Such
reactions with enolates derived from ketones and aldehydes
form products bearing α-stereogenic centers[2], β-stereogenic
centers[3], or both[4]. These reactions of stabilized enolates
generated from carboxylic acid derivatives containing proximal
electron-withdrawing groups (such as acyl, carboxyalkyl, nitro or
cyano groups),[5] heteroatom functionalities[6], or aromatic
substituents[7] also occur. However, analogous transformations
of the unstabilized enolates derived from aliphatic esters are
rare. Reported enantioselective examples are limited to
palladium-catalyzed reactions of lactones or ester equivalents
with symmetrical allylic electrophiles, and one recently reported
example of a ruthenium-catalyzed process.[8-9]
The low acidity of the α hydrogens of the aliphatic esters
and the instability of the ester-derived enolates make allylation
of ester enolates challenging. Stoichiometric strong bases are
required to form the enolates in situ without self-condensation,
substrates that bear base-sensitive functionalities (for example,
acetoxyl group) are not tolerated, and Claisen condensation
between the ester products and the enolates can lead to side
products. Finally, cyclopropanation has been shown to compete
with the allylation process when palladium catalysts are used.[10]
To develop a general method for the enantioselective
allylation of aliphatic esters under mild conditions, we envisioned
that silyl ketene acetals, the silicon enolates of esters, could be
employed as the nucleophiles because they are significantly less
basic than the alkali metal enolates formed in situ by
deprotonation. Iridium complexes [Ir] (Scheme 1) developed in
our group could catalyze this proposed transformation because
they enable enantioselective allylic substitution reactions with
various nucleophiles under relatively neutral conditions, without
competing formation of cyclopropanes.[11]
Scheme 1. Iridium-catalyzed enantioselective allylic substitution reactions with
silyl ketene acetals.
Herein we report enantioselective allylations of silyl ketene
acetals catalyzed by a metallocyclic iridium complex (Scheme 1)
to form the allylated aliphatic esters with high regio- and
enantioselectivity under mild conditions. Due to the versatility of
the ester functionality in organic synthesis, these products are
readily transformed to primary alcohols, carboxylic acids, amides,
isocyanates, carbamates, tetrahydrofuran (THF) derivatives and
γ-butyrolactone derivatives without erosion of enantiomeric purity.
We began our studies on enantioselective allylic
substitutions of aliphatic silyl ketene acetals by examining the
reactions between cinnamyl methyl carbonate and ketene acetal
2a in the presence of a series of metallacyclic iridium complexes
containing a series of aryl substituents on the ligands (Table 1,
entry 1–4). A catalytic amount of tetrabutylammonium acetate
(nBu4NOAc) was added to activate the silicon enolate because
our previous studies demonstrated that carboxylates could
activate silyl enol ethers in related iridium-catalyzed allylation
reactions.[3f, 13] The reaction conducted with iridium catalyst [Ir]-2
bearing two 2-anisyl substituents on the ligand gave the ester
product 3aa in 50% yield with >20:1 branched/linear selectivity
and 98% ee. The yield was modest because side product sp
(33%) was formed from competitive nucleophilic acyl substitution
of 2a with the carbonyl group of cinnamyl methyl carbonate. To
suppress the formation of sp, we studied reactions of allylic
esters containing the 2,2,2-trichloroethyl carbonate (OTroc) and
the t-butyl carbonate (OBoc) groups that are more hindered than
the methyl carbonate. Reaction of the 2,2,2-trichloroethyl
carbonate gave 3aa in a low yield of 16% and sp in 20% yield
(entry 5), as well as an additional product in 54% yield from the
allylation of 2,2,2-trichloroethoxide generated from oxidative
addition of the carbonate and decarboxylation of the resulting
anion. However, reaction of the t-butyl carbonate formed 3aa as
a single product in 97% yield with 98% ee (entry 6).
The allylation of silyl ketene acetals containing gem-dialkyl
groups would be particularly valuable because the resulting
[*]
X. Jiang, Prof. J. F. Hartwig
Department of Chemistry, University of California
Berkeley, CA 94720 (USA)
E-mail: jhartwig@berkeley.edu
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1: Evaluation of reaction conditions for the Ir-catalyzed allylation.[a]
Table 2: Iridium-catalyzed allylations of silyl ketene acetals: scope of the allyl
benzoates.[a]
[a] Reaction conditions: 1 (0.20 mmol, 1.0 equiv), 2a (1.5 equiv), [Ir] (3 mol%),
additive (3 mol%), THF (0.4 mL), r.t., 12 h. The absolute configuration of 3aa
was assigned by analogy. [b] The branched/linear selectivities were
determined by 1H NMR analysis of the crude mixtures. [c] Determined by 1H
NMR analysis of the crude mixtures with mesitylene as an internal standard.
The yields within parentheses are that of the branched isomer and the linear
isomer isolated. [d] Determined by chiral supercritical fluid chromatography
(SFC) analysis of the branched isomer. [e] 0.5 equiv of nBu4NOAc was added.
n.d. = not determined.
[a] Condition A: [Ir]-2 (3 mol%), nBu4NOBz (3 mol%), THF (0.5 M); condition
B: [Ir]-2 (4 mol%), nBu4NOBz (4 mol%), THF (0.25 M); condition C: [Ir]-2 (3
mol%), nBu4NOBz (3 mol%), THF (0.5 M), then another batch of [Ir]-2 (3
mol%), nBu4NOBz (3 mol%) and THF were added after 12 h. The absolute
configurations were assigned by analogy. [b] The enantiomeric excesses were
determined after further transformations of the products. See SI for details.
the aryl rings all afforded the corresponding products in ≥84%
yield with >99% ee. Benzoate 1d bearing a base-sensitive
acetoxy substituent at the para-position of the phenyl ring
underwent allylation cleanly to give 3da in 87% yield with >99%
ee, highlighting the mild conditions of these reactions. In general,
the reactions of electron-deficient cinnamyl benzoates required a
higher catalyst loading of 4 mol % (condition B for 3ea–3ga) or 6
mol % (condition C for 3ha, 3ia), instead of 3 mol % (condition A
for 3aa–3ca), to reach full conversion of the allyl benzoate.
This reaction also occurred with allyl benzoates bearing
heteroaryl, naphthyl, and alkenyl substituents. Allyl benzoates
containing pyridyl (1j), furyl (1k), thienyl (1l), thiazolyl (1m),
naphthyl (1n), and 6-methoxy naphthyl (1o) groups underwent
the allylations to form products 3ja–3oa in ≥83% yield with ≥98%
ee. Sorbyl benzoate 1p reacted with silyl ketene acetal 2l to give
the allylation product 3pl in 52% yield with 98% ee.
Table 3 shows the scope of silyl ketene acetals that
underwent the allylation process. Silyl ketene acetals generated
from methyl (2a), ethyl (2b), isopropyl (2c) and phenyl (2e)
isobutyrate reacted to form products 3aa, 3ab, 3cc, and 3ce in
≥79% yield with >99% ee. The reactivity of the silyl ketene acetal
derived from t-butyl isobutyrate (2d) was lower, and 3cd was
obtained in 38% yield with 39% of 1c unconverted. Silyl ketene
Further investigation of the effect of leaving groups included
reactions of the ethyl phosphate, acetate, pivalate and benzoate
derivatives of cinnamyl alcohol (entry 7–10). The reaction of
cinnamyl benzoate 1a (entry 10) delivered 3aa in almost
quantitative (96%) yield with excellent ee (>99%). However, a
small amount of cinnamyl acetate (<5%) was observed,
presumably from reaction of the allyl iridium intermediate and
nBu4NOAc.[11d] This hypothesis was supported by the result of
the reaction conducted with 0.5 equiv of nBu4NOAc (entry 11),
which gave 3aa in a lower yield of 68% and cinnamyl acetate in
26% yield, which was higher than that from the reaction with 3
mol % of nBu4NOAc in entry 10. To avoid the formation of
cinnamyl acetate, tetrabutylammonium benzoate (nBu4NOBz)
n
was used instead of Bu4NOAc as the carboxylate additive, and
this reaction occurred to afford 3aa in quantitative yield with
>99% ee (entry 12). The reaction with cinnamyl t-butyl carbonate
occurred similarly to give 3aa in 94% yield with 98% ee (entry
13). No reaction occurred in the absence of a carboxylate
additive (entry 14) or with the TBS analog of 2a.
Table 2 shows the scope of allyl benzoates that underwent
the allylation process. The reactions with various cinnamyl
benzoates bearing electron-neutral (3aa, 3ba), electron-donating
(3ca, 3da), and electron-withdrawing (3ea–3ia) substituents on
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acetal 2f derived from (-)-nopol that bears a chiral hydrocarbon
motif also reacted to give 3cf in 93% yield with >20:1 dr.
For example, 3oa was readily converted to the primary alcohol
4a and carboxylic acid 4c without erosion of ee after reduction
and hydrolysis, respectively. The acid 4c was further
transformed into the enantioenriched amide 4e, isocyanate 4f,
and carbamate 4g. The terminal alkene functionality was also
derivatized. An intramolecular hydroalkoxylation of the olefin
moiety on alcohol 4a occurred with silver triflate[14] as the
catalyst, giving enantioenriched tetrahydrofuran derivatives 4b
and 4b’. Although the diastereoselectivity was low (1.1:1), each
diastereomer was isolated in pure form with >99% ee.
Carboxylic acid 4c underwent iodolactonization[15] to afford
lactone 4d in 84% yield as a single isomer with >99% ee.
In addition to the silyl ketene acetals derived from
isobutyrates, gem-diethyl silyl ketene acetal 2g reacted to afford
3cg in 96% yield with >99% ee. Exocyclic gem-dialkyl silyl
ketene acetals bearing exocyclic double bonds on 4- (2h), 5- (2i,
2n),6- (2j) and 7-membered (2k) rings all reacted with benzoate
1c to give products 3ch–3ck, and 3cn in ≥96 yields with ≥99%
Table 3: Iridium-catalyzed allylations of silyl ketene acetals: scope of the silyl
ketene acetals.[a]
Finally, to extend the scope of this allylation method to
form α-allyl carboxylic acids directly, the silyl-protected enolate
of isobutyric acid (2o) was tested (eq 1). The reaction between
1o and 2o formed carboxylic acid 4c in 80% yield with >97% ee.
R
OTMS
OTMS
R
OBz
COOH
1o
R =
MeO
(eq 1)
[Ir]-2, nBu4NOBz
condition B
4c
80%, 97% ee
2o
In summary, we have developed enantioselective allylic
substitutions with aliphatic silyl ketene acetals catalyzed by a
metallacyclic iridium complex. These reactions are rare
allylations of enolates derived from aliphatic esters that occur in
high enantioselectivity under mild conditions. The use of silyl
ketene acetals avoids the use of strong bases, leading to high
functional-group tolerance; a catalytic amount of carboxylate
additive (nBu4NOBz) induced reactivity, presumably by activating
the silyl ketene acetals. The allylated esters were obtained with
excellent regio- and enantioselectivity and were readily
converted to the primary alcohols, carboxylic acids, amides,
isocyanates, carbamates, THF derivatives and γ-butyrolactone
derivatives with preservation of enantiomeric purity. Studies to
achieve the regio-, diastereo- and enantioselective allylations of
unsymmetrical aliphatic acid and their derivatives are ongoing in
our laboratories.[16–17]
[a] Condition A: [Ir]-2 (3 mol%), nBu4NOBz (3 mol%), THF (0.5 M); condition
B: [Ir]-2 (4 mol%), nBu4NOBz (4 mol%), THF (0.25 M). The absolute
configurations were assigned by analogy. [b] The enantiomeric excess was
determined after further transformation of the product. [c] NMR yield.
Acknowledgements
ee. Exocyclic silyl ketene acetals containing oxygen atoms or a
difluoromethylene unit on the ring structure reacted similarly to
give the products (3cl, 3cm) in ≥93% yield with >99% ee.
To illustrate the synthetic utility of this allylation reaction,
various transformations of allylation product 3oa were conducted.
We thank the NIH-NIGMS (GM-55382) for financial support. Zhe
Ji is thanked for assistance on X-ray crystallographic analysis.
Scheme 2. Derivatizations. Steps: a) LiAlH4 (1.5 equiv), THF, 0 oC to r.t.; b) AgOTf (10 mol%), DCE, 80 oC; c) NaOH (4.0 equiv, 2 M aq), MeOH, 80 oC; d) I2 (1.3
equiv), NaHCO3 (1.4 equiv), KI (1.3 equiv), MeCN/H2O (1:1), 0 oC to r.t.; e) SOCl2 (5.0 equiv), PhH, 80 oC then BnNH2 (2.0 equiv), DMAP (20 mol%), Et3N (2.0
equiv), DCE, 80 oC; f) diphenylphosphoryl azide (1.05 equiv), Et3N (1.7 equiv), DCE, 80 oC; g) BnOH (4.0 equiv) added to the mixture after step f, 80 oC.
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10.1002/anie.201704354
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Keywords: alkylation • asymmetrical catalysis •
enantioselectivity • esters • iridium
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R
OBz
OTMS
O
R
O
92%, 1.9:1 dr,
>99% ee for
each diastereomer
1o
O
[Ir]-2, nBu4NOBz
condition B
[17] We also tested monosubstituted silyl ketene acetals for this allylaiton
reaction. The reaction of 1o with the silyl ketene acetal of γ-
butyrolactone gave the product in 25% yield with 1.4:1 dr. The bis-
allylation product was formed in 30% yield, which presumably resulted
from the enolization of the product followed by a second allylation.
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R
O
OTMS
R
OBz
1o
bis-allylation
product
+
O
O
[Ir]-2, nBu4NOBz
condition B
30%
25%, 1.4:1 dr
However, the reaction with the silyl ketene acetal of methyl propionate
gave no bis-allylation product. This lack of reaction is presumably
because acyclic esters are less acidic and less prone to enolize than
[7]
[8]
For selected recent pulications, see: a) B. M. Trost, J. T. Masters, A. C.
Burns, Angew. Chem. Int. Ed. 2013, 52, 2260; b) K. J. Schwarz, J. L.
Amos, J. C. Klein, D. T. Do, T. N. Snaddon, J. Am. Chem. Soc. 2016,
138, 5214; c) K. Balaraman, C. Wolf, Angew. Chem. Int. Ed. 2017, 56,
1390; d) X. Jiang, J. J. Beiger, J. F. Hartwig, J. Am. Chem. Soc. 2017,
139, 87.
lactones under the reaction condition.
R
OTMS
R
OBz
COOMe
1o
no
OMe
bis-allylation
product
[Ir]-2, nBu4NOBz
condition B
73%, 1.2:1 dr
For related Pd-catalyzed reactions with symmetrical electrophiles, see:
a) I. Alvarado-Beltrán, E. Maerten, R. A. Toscano, J. G. López-Cortés,
E:Z = 4:1
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10.1002/anie.201704354
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Xingyu Jiang and John F. Hartwig*
Page No. – Page No.
Iridium-Catalyzed Enantioselective
Allylic Substitutions of Aliphatic
Esters via Silyl Ketene Acetals
Enantioselective allylic substitutions with enolates derived from aliphatic esters
under mild conditions remain challenging. Herein we report iridium-catalyzed
enantioselective allylations of silyl ketene acetals, the silicon enolates of esters, to
form products containing a quaternary carbon at the nucleophile moiety and a
tertiary carbon at the electrophile moiety. Under relatively neutral conditions, the
allylated aliphatic esters were obtained with excellent regioselectivity and
enantioselectivity. These products were readily converted to primary alcohols,
carboxylic acids, amides, isocyanates, and carbamates, as well as tetrahydrofuran
(THF) and γ-butyrolactone derivatives, without erosion of enantiomeric purity.
This article is protected by copyright. All rights reserved.