Chiral Allenes via Alkynylogous Mukaiyama Aldol Reaction

Article abstract of DOI:10.1002/anie.201603649

Herein we describe the development of a catalytic enantioselective alkynylogous Mukaiyama aldol reaction. The reaction is catalyzed by a newly designed chiral disulfonimide and delivers chiral allenoates in high yields and with excellent regio-, diastereo

Full text of DOI:10.1002/anie.201603649

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603649
German Edition: DOI: 10.1002/ange.201603649
Organocatalysis
Chiral Allenes via Alkynylogous Mukaiyama Aldol Reaction
Aurꢀlien Tap, Aurꢀlie Blond, Vijay N. Wakchaure, and Benjamin List*
Abstract: Herein we describe the development of a catalytic
enantioselective alkynylogous Mukaiyama aldol reaction. The
reaction is catalyzed by a newly designed chiral disulfonimide
and delivers chiral allenoates in high yields and with excellent
regio-, diastereo-, and enantioselectivity. Our process tolerates
a broad range of aldehydes in combination with diverse
alkynyl-substituted ketene acetals. The reaction products can
be readily derivatized to furnish a variety of highly substituted
enantiomerically enriched building blocks.
regioisomers can be produced, the carbinol allenoate through
g-addition of the alkynyl ketene acetal, and the hydroxy
alkynoate product through a-addition. Moreover, as a result
of the generation of two stereogenic elements, four stereo-
isomers can be generated in both cases. In 2008,[11] Hammond
et al. reported a Lewis acid mediated non-enantioselective
alkynylogous Mukaiyama aldol reaction that provided a solu-
tion to the a/g-selectivity problem (Scheme 1). Depending on
Allenes are surprisingly abundant and found in hundreds of
natural products with biological activity.[1] They are also
attractive motifs for chemical synthesis owing to their unusual
properties and reactivity. As cumulated dienes, allenes often
display higher reactivity than their noncumulated analogues.
Moreover, allenes display a peculiar axial chirality charac-
terized by their elongated tetrahedral geometry. Over the past
years, the allene scaffold has been exploited in different ways
including to create versatile synthetic intermediates and
chiral ligands for asymmetric catalysis.[2,3] Despite the
demand for chiral allenes though, enantioselective methods
for their synthesis are limited. Indeed, they are most
commonly prepared by the resolution of racemic allenes
and reactions involving chirality transfer from enantiomeri-
cally enriched propargyl alcohols or amines.[4–6] More
recently, metal-catalyzed asymmetric allene syntheses have
also been reported.[7] In contrast, organocatalytic approaches
still remain underexplored and are largely limited to di- or
trisubstituted allenes.[8] A significant breakthrough in this
area was made in 2013 by Maruoka and co-workers, who
reported the asymmetric functionalization of cumulenolates
under phase-transfer catalysis. This methodology gave access
to chiral tetrasubstituted allenes through alleno-Mannich and
alkylation reactions.[9] However, the corresponding asymmet-
ric aldol reaction remained challenging. Recently, Feng and
co-workers reported a gold-catalyzed nucleophilic addition of
racemic allenoates to isatins with high diastereo- and
enantioselectivity.[10] We now report an unprecedented alky-
nylogous Mukaiyama aldol reaction, which is catalyzed by
a newly designed chiral disulfonimide and provides tetrasub-
stituted allenoates with excellent diastereo- and enantiose-
lectivity.
Scheme 1. a versus g selectivity in the alkynylogous Mukaiyama aldol
reaction. Tf=trifluoromethanesulfonyl.
the Lewis acid (LA), the reaction gave access either to the
alkyne (LA = Sc(OTf)3) or to the allene product (LA =
SiCl4). High regioselectivity but no diastereoselectivity was
observed.[11–13] On the basis of our previous studies on
silylated disulfonimide (DSI)-catalyzed Mukaiyama aldol
reactions and vinylogous and bisvinylogous variants, we
became interested in also exploring silyl alkynyl ketene
acetals as nucleophiles.[14] We hypothesized that our silylated
disulfonimide Lewis acid could potentially catalyze such an
alkynylogous aldol reaction and thus offer a regio-, diastereo-,
and enantioselective approach to the synthesis of chiral
tetrasubstituted allenes.
We began our investigations by using the silyl alkynyl
ketene acetal 2 in combination with 2-naphthaldehyde (1) as
a model electrophile (Table 1). The initial objective was to
study the regioselectivity of the transformation to give
carbinol allenoate 4. By using (R)-DSI 3a, we explored the
nature of the silicon group on the nucleophile. As expected,
a strong impact of the size of the silicon group on the
regioselectivity was observed. The TES group gave a 1:1
mixture of product 4 and hydroxy alkynoate 5. A significant
improvement was noted with the TBS group, which led to
a 9:1 ratio in favor of the allene, formed with 6:1 d.r. and
a promising enantiomeric ratio of 88:12 (Table 1, entries 1
and 2). The TIPS-substituted nucleophile led to a further
increase in regio- and diastereoselectivity but also to a lower
enantiomeric ratio (Table 1, entry 3). Several DSI catalysts
Several challenges had to be considered in the design of an
asymmetric alkynylogous Mukaiyama aldol reaction. In
addition to the enantioselectivity issue, two different
[*] Dr. A. Tap, Dr. A. Blond, Dr. V. N. Wakchaure, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603649.
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Table 1: Reaction development.[a]
was then investigated under these optimal conditions
(Table 2). When 2-naphthaldehyde was employed, the trans-
formation afforded product 6a in 85% yield with 19:1 d.r. and
98:2 e.r. after cleavage of the TBS group under acidic
conditions (Table 2, entry 1). Substrates with a naphthyl
core bearing a bromine or methoxy substituent at the 6-
position gave access to the corresponding carbinol allenoates
6b and 6c in high yields with comparable diastereo- and
enantioselectivity (Table 2, entries 2 and 3). The influence of
substitution at different positions of the phenyl group was
then studied. A meta,meta-dimethyl-substituted substrate
provided the expected product 6d in 78% yield with excellent
96:4 e.r. and 27:1 d.r. (Table 2, entry 4). Product 6e was
obtained from a para-methyl-substituted substrate with much
Table 2: Scope of the asymmetric alkynylogous Mukaiyama aldol
reaction with respect to the aldehyde substrate.[a]
Entry (R)-DSI [Si]
R1
Conv. [%][b] 4/5
d.r.[b]
e.r.[c]
1
2
3
4
5
6
7
3a
3a
3a
3b
3c
3c
3c
3c
3c
TES Et
TBS Et
TIPS Et
TBS Et
TBS Et
>95
>95
>95
>95
>95
1:1
9:1
>20:1
2:1
6:1
9:1
8:1
80 :20[d]
88 :12[d]
78 :22[e]
90 :10[d]
10:1
16:1 16:1 97.5 :2.5[d]
Entry
Product
Yield
[%][b]
d.r.[c]
e.r.[d]
TBS Me >95
9:1
>20:1 20:1
9:1 96.5 :3.5[e]
TBS iPr
TBS tBu
TBS Et
>95
<5
>95
96 :4[e]
–
1[e]
2
6a
6b
6c
85
78
92
19:1
18:1
17:1
98 :2
98 :2
97:3
8
–
–
9[f]
>20:1 19:1
98 :2[d]
[a] Reactions were carried out at room temperature on a 0.05 mmol scale
and quenched after 12 h. [b] The conversion and diastereomeric ratio
were determined by 1H NMR analysis. [c] The enantiomeric ratio was
determined by HPLC on a chiral stationary phase. [d] The enantiomeric
ratio was determined after cleavage of the silicon group with 10% HCl in
MeOH. [e] The enantiomeric ratio was determined after saponification
with LiOH in MeOH. [f] The reaction was carried out at 08C and
quenched after 24 h. TBS=tert-butyldimethylsilyl, TES=triethylsilyl,
TIPS=triisopropylsilyl.
3
4
6d
78
27:1
96 :4
5
6
6e
6 f
82
10.6 :1
3.7:1
92 :8
were then screened. The use of catalyst 3b with 3,5-
di(trifluoromethyl)benzene substitution in the 3,3’-position
of the backbone gave us a hint about the nature of the “ideal”
catalyst for this reaction, since all selectivity parameters were
increased (Table 1, entry 4).[14c] In fact, by simply modulating
the CF3 substitution on those aromatic moieties, we obtained
catalyst 3c with 2,5-di(trifluoromethyl)benzene substitution,
which afforded excellent enantioselectivity (97.5 :2.5 e.r.) and
high regio- and diasteroselectivity (16:1 ratio in both cases;
Table 1, entry 5). Variation of the ester group (R1) revealed
that the ethyl moiety represented the best compromise in
terms of diastereo- and enantioselectivity as compared to
methyl and isopropyl groups (Table 1, entries 5–7). Use of the
corresponding tert-butyl ester derived ketene acetal did not
lead to any conversion (Table 1, entry 8). Optimized condi-
tions were finally established with Et2O (see the Supporting
Information for solvent screening) at 08C. Under these
conditions, the desired allene 4 was obtained with excellent
regioselectivity (> 20:1), 19:1 d.r., and 98:2 e.r. (Table 1,
entry 9).
69[f]
75.5 :24.5
7
6g
72
7.6 :1
95 :5
8
9
6h
6i
75
15:1
96 :4
93 :7
92
12.5 :1
12.3 :1
10
6j
68[f]
92.5 :7.5
11
12
6k
6l
52
4.5 :1
–
95 :5
–
<5
[a] Reactions were carried out on a 0.15 mmol scale. All regioisomeric
ratios were above 20:1. [b] The yield was determined for the mixture of
the two diastereoisomers. [c] The diastereomeric ratio was determined
by 1H NMR analysis. [d] The enantiomeric ratio was determined by HPLC
on a chiral stationary phase. [e] The reaction was carried out on
a 1.5 mmol scale. [f] The starting material was recovered.
The scope of the enantioselective alkynylogous
Mukaiyama aldol reaction with respect to the electrophile
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Table 3: Scope of the asymmetric alkynylogous Mukaiyama aldol
reaction with respect to the nucleophile.[a]
lower diastereoselectivity and a slight decrease in enantio-
selectivity (Table 2, entry 5). In comparison, ortho substitu-
tion had a dramatic effect on both the diastereo- and enantio-
selectivity: product 6 f was isolated with 3.7:1 d.r. and
75.5 :24.5 e.r. (Table 2, entry 6). 1-Naphthaldehyde and
meta-methoxybenzaldehyde proved to be good substrates
for the reaction, which afforded 6g and 6h with enantiomeric
ratios of 95:5 and 96:4, respectively. Interestingly, para-
chloro-substitution on the starting material had no effect in
terms of diastereo- and enantioselectivity (product 6j), since
very similar results were obtained for product 6i when
benzaldehyde was used (Table 2, entry 9 vs. 10). The trans-
formation also proceeded well with a-chlorocinnamaldehyde
to give product 6k with 95:5 e.r. but with moderate yield and
diastereoselectivity. Finally, the use of aliphatic aldehydes in
this reaction is currently a challenge, and no reactivity was
observed with pivalaldehyde (Table 2, entry 12). Enolizable
aliphatic aldehydes led to the formation of the corresponding
enol silanes (see the Supporting Information). The absolute
configuration of allenoate 6j was determined to be 3R,5S by
single-crystal X-ray analysis of a derivative (see the Support-
ing Information).[15] The configurations of the other products
were assigned by analogy.
Entry
1
Product
Yield [%][b]
85
d.r.[c]
19:1
e.r.[d]
98:2
6a
6m
6n
6o
6p
2[e]
33[f]
68
5:1
13:1
20:1
11:1
93.5 :6.5
96.5 :3.5
98.5 :1.5
98.5 :1.5
3
4
68
5
50
The scope of the reaction with respect to the nucleophile
was also explored (Table 3). A terminally phenyl substituted
nucleophile, 2m, reacted with naphthaldehyde (1) in the
presence of (R)-DSI 3c (5 mol%) to give product 6m with
somewhat lower reactivity and selectivity as compared to the
methyl-substituted substrate (Table 3, entry 2 vs. 1). A sub-
strate with a longer aliphatic linear chain at the same position
was also tested, and product 6n was obtained in 68% yield
with excellent selectivity (96.5 :3.5 e.r. and 13 :1 d.r.). The R2
group was investigated next. Product 6o with an n-butyl
substituent was obtained in 68% yield with very high
diastereoselectivity (20:1 d.r.) and enantioselectivity
(98.5:1.5; Table 3, entry 4). The benzyl group proved to be
a suitable substituent as well, giving access to the tetrasub-
stituted allene 6p in a 50% yield with d.r. 11:1 and an
excellent enantiomeric ratio (98.5:1.5; Table 3, entry 5).
The significant interest in chiral allenes is based on their
ability to be readily converted into enantiomerically enriched
building blocks by chirality transfer.[16] To illustrate the utility
of our products, we prepared four different highly substituted
scaffolds from the enantiomerically and diastereomerically
enriched substrate 6a (Scheme 2). After saponification of the
ester moiety with LiOH in EtOH, the corresponding carbox-
ylic acid reacted by intramolecular lactonization in the
presence of AgNO3 (10 mol%).[11] g-Lactone 7 was obtained
in 83% yield over the two steps and with perfect retention of
the stereogenic information. The enantiomerically enriched
dihydrofuran 8 could be generated directly from allene 6a in
77% yield by the use of a catalytic amount of a gold complex
activated by silver triflate,[11] again with complete preserva-
tion of stereochemical purity. NaBH4 was used a reducing
agent for the selective formation of E olefin 9.[17] We suspect
the intermediate formation of an alkoxyborohydride species,
followed by the internal 1,4-addition of a hydride to the
Michael acceptor system. Product 9 was obtained in 44%
yield with low diastereoselectivity but with high enantiomeric
[a] Reactions were carried out on a 0.15 mmol scale. All regioisomeric
ratios were above 20:1. [b] The yield was determined for the mixture of
the two diastereoisomers. [c] The diastereomeric ratio was determined
by 1H NMR analysis. [d] The enantiomeric ratio was determined by HPLC
on a chiral stationary phase. [e] The reaction was carried out at room
temperature. [f] The starting material was recovered.
Scheme 2. Derivatization of the enantiomerically enriched carbinol
allenoate 6a.
ratios for both diastereomers. Remarkably, the methylation of
allenoate 6a with a mixture of MeLi and CuI in THF
proceeded towards the exclusive formation of the Z double
bond, and subsequent lactonization furnished product 10 in
59% yield with an excellent enantiomeric ratio for each
diastereoisomer. We assume that this process involves
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In summary, we have developed an alkynylogous
Mukaiyama aldol reaction for the synthesis of chiral, enan-
tiomerically enriched allenes. Versatile silyl alkynyl ketene
acetals in combination with precatalyst disulfonimide 3c
deliver a silylium-ion-based Lewis acid, which is able to
activate a broad range of aldehydes. Chiral tetrasubstituted
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Acknowledgements
Generous support by the Max Planck Society and the
European Research Council (Advanced Grant “High Perfor-
mance Lewis Acid Organocatalysis, HIPOCAT”) is gratefully
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Keywords: aldol reactions · allenes · disulfonimides ·
Lewis acids · organocatalysis
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Received: April 14, 2016
Published online: && &&, &&&&
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Communications
Organocatalysis
A. Tap, A. Blond, V. N. Wakchaure,
B. List*
&&&& — &&&&
Chiral Allenes via Alkynylogous
Mukaiyama Aldol Reaction
A lean machine: A chiral disulfonimide
was designed as a catalyst for an alky-
nylogous Mukaiyama aldol reaction (see
scheme). A broad range of aldehydes and
diverse alkynyl-substituted ketene acetals
underwent the transformation to deliver
chiral allenoates in high yield with excel-
lent regio-, diastereo-, and enantioselec-
tivity. The products can be readily deriv-
atized to furnish highly substituted
enantiomerically enriched building
blocks.
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