Enantioselective β-Protonation of Enals via a Shuttling Strategy

Article abstract of DOI:10.1021/jacs.7b02889

Remote asymmetric protonation is a longstanding challenge due to the small size of protons. Reactions involving electron-deficient olefins pose a further difficulty due to the electrophilic nature of these substrates. We report a shuttling system that delivers a proton in a highly enantioselective manner to the β-carbon of enals using a chiral N-heterocyclic carbene (NHC) catalyst. Choices of a Br?nsted base shuttle and a Br?nsted acid cocatalyst are critical for highly stereoselective β-protonation of the homoenolate intermediate and regeneration of the NHC catalyst results in functionalization of the carbonyl group. Thioesters with a β-chiral center were prepared in a redox-neutral transformation with an excellent yield and ee.

Full text of DOI:10.1021/jacs.7b02889

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Article
Enantioselective #–Protonation of Enals via a Shuttling Strategy
Jiean Chen, Yuan Pengfei, Leming Wang, and Yong Huang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 05 May 2017
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Enantioselective β–Protonation of Enals via a Shuttling Strategy
§
§
Jiean Chen, Pengfei Yuan, Leming Wang and Yong Huang*
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen
Graduate School of Peking University, Shenzhen, 518055, China
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Abstract
Remote asymmetric protonation is a longstanding challenge due to the small size
of protons. Reactions involving electronꢀdeficient olefins pose a further difficulty
due to the electrophilic nature of these substrates. We report a shuttling system
that delivers a proton in a highly enantioselective manner to the βꢀcarbon of
enals using a chiral Nꢀheterocyclic carbene (NHC) catalyst. Choices of a
Brønsted base shuttle and a Brønsted acid coꢀcatalyst are critical for highly
stereoselective βꢀprotonation of the homoenolate intermediate and regeneration
of the NHC catalyst results in functionalization of the carbonyl group. Thioesters
with a βꢀchiral center were prepared in a redoxꢀneutral transformation with
excellent yield and ee.
Introduction
Carbonyl compounds with a chiral center at the βꢀposition are important building
blocks in synthetic chemistry. These structural motifs are generally prepared by
nucleophilic addition to readily available α,βꢀunsaturated carbonyl substrates.
Representative examples include asymmetric Michael additions and hydrogenations .
Reactions of this sort are carried out using stoichiometric reductive organometallic or
organohydride species such as Zn,
Hantzsch esters
environments is often necessary. The carbonyl moiety, most commonly an aldehyde,
ketone, amide or ester, remains unchanged after the reaction. An alternative
redoxꢀneutral strategy that creates such chiral centers with concurrent transformation
of the carbonyl group is highly stepꢀ and atomꢀeconomical.
1
2
1a,1d
1b
1c
1e
1f
2aꢀf
B, Mg, Si, Al, metal hydride,
(Figures 1a, 1b). Protection against moisture and oxidative
and
2gꢀj
Nꢀheterocyclic carbenes (NHC) are versatile catalysts that deliver umpolung
activation of carbonyl groups and its conjugated double bond. The biomimetic acyl
anion mechanism via homoenolate intermediates is wellꢀestablished for concomitant
functionalization of a carbonyl group and its βꢀcarbon (Figure 1). NHCs react with
an α,βꢀunsaturated aldehyde to generate an umpolung homoenolate intermediate
which is nucleophilic at the βꢀcarbon and electrophilic at the carbonyl center. This
species can undergo double functionalization using a combination of a nucleophile
and an electrophile. To date, asymmetric transformations involving this strategy have
been applied mostly in cycloadditions (for example, the headꢀtoꢀtail cycloaddition
between a homoenolate and a dipolar reagent). In fact, a nucleophile alone can add
across the βꢀcarbon and carbonyl center of a homoenolate by providing an
electrophilic proton. However, asymmetric nonꢀcycloaddition reactions involving
3
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nucleophiles are very rare. The reason for this is the challenge which lies in the
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control of facial selectivity during protonation of the βꢀcarbon of the homoenolate.
The proton is the smallest electrophile and shielding one prochiral face is far less
effective for an incoming proton than for other electrophiles. Although asymmetric
αꢀprotonation of the NHCꢀderived acyl azolium has been reported, remote
βꢀprotonation of homoenolates remains a significant challenge. In the only report on
highly enantioselective βꢀprotonation of enals with a βꢀester directing group, Scheidt
et al. found that bulky thioureas are an effective coꢀcatalyst that enhances facial
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e,7g
shielding of the βꢀcarbon by forming hydrogen bonds with a βꢀester group.
This
method not only stabilizes the corresponding homoenolate intermediate, but also
enhances chiral communication between the NHC and the βꢀcarbon. In contrast,
βꢀalkyl enals are notorious as substrates in asymmetric βꢀprotonation.
βꢀMethylcinnamaldehyde for example, lacks a βꢀdirecting group and leads to poor
7cꢀd
selectivity (53% ee).
This type of substrate is prone to E/Z isomerization, further
complicating the stereoselectivity issue. In this paper, we report our serendipitous
discovery of a simple shuttling strategy that delivers highly enantioselective
βꢀprotonation of enals in the absence of any directing group.
Figure 1. Construction of the βꢀchiral center of carbonyl compounds.
To solve the longstanding challenge of enantioselective enal βꢀprotonation, we
initially proposed a tethered catalyst strategy. We envisioned that a Lewis acid
coꢀcatalyst might bridge chirality transfer from NHC to the distal βꢀcarbon (Figure
In this scenario, the enol functionality might serve as an internal directing
group by coordinating to a Lewis acid which, in a cyclic transition state might guide
5c,5j,9
2).
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protonation to occur from only one face. A common competing side reaction
5h,7d,10
involving homoenolate is oxidation to vinyl acyl azolium.
Tethering the enol
and thiol might not only stabilize a homoenolate intermediate, but could also
accelerate protonation by enhancing the acidity of the thiol.
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Figure 2. Original model of synergistic catalysis using NHC/Lewis acid
Results and Discussion
To test our design, we used βꢀmethyl cinnamaldehyde (1a) and 2ꢀphenylethanethiol
(2a) as model substrates. The reaction using the catalytic NHC precursor (4a) and
DABCO resulted in 53% yield and 67% ee (Table 1, entry 1). Use of 4 Å molecular
sieves slightly improved the yield. We found that introduction of various Lewis acids
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a
9d
has a strong impact on the enantioselectivity. Mg and Sc compounds gave only
marginal improvement (entries 2 and 3), and both Zn and Cu compounds resulted in
high yield and ee (entries 4 and 5). These results suggest that the selectivity of this
11
reaction is directly correlated with the sulfur binding affinity of metals. Interestingly,
the choice of base was found to be crucial for the enantioselectivity. Among the
organic bases examined, only bridgehead nitrogen bases, i.e. DABCO and
quinuclidine, delivered high ee (entries 5ꢀ9). Acyl transfer catalysts, such as DMAP,
failed to promote a faster and more selective protonation/thioesterification sequence.
This result suggests that thiols are sufficiently nucleophilic to turnover NHC catalyst
by themselves (entry 7). Poor ee was observed using DBU and Hünig's base (entries 8
and 9). Potassium carbonate did not give any desired product due to lack of a proton
source in the reaction (entry 10). The structure of the NHC precursor (4) was briefly
examined. The pentafluoroaryl substituted analogue (4b) gave poor conversion and ee,
probably due to reduced nucleophilicity of the corresponding homoenolate and a
5h,7d
competing pathway for formation of unsaturated ester (entry 11).
The reaction
proceeded poorly when methyl groups on 4a were replaced by bulky ethyl or
isopropyl groups (catalyst 4c and 4d) (entries 12 and 13). The gradual decrease of
conversion indicated that the formation of the homoenolate might be challenging in
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these cases since a large amount of start material remained. Reducing loading of
both catalysts to 5 mol% did not affect the ee (entry 14). A combination of 4a and
2
Cu(OTf) was chosen as the optimal catalyst system. Although the NHC/Cu(I) system
13
has been reported by Chi and coworkers, this work represents the first report of
NHC/Cu(II) synergistic catalysis.
a
Table 1. Optimization of Conditions
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entry NHC cat.
Lewis acid
—
base
yield (%)
53
ee (%)
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4a
4a
4a
4a
4a
DABCO
DABCO
DABCO
DABCO
DABCO
quinulidine
DMAP
67
70
74
94
95
95
52
36
15
n. d.
79
97
80
95
Mg(OTf)2
42
Sc(OTf)
2
24
Zn(OTf)
2
92
Cu(OTf)
2
2
96
4a
4a
4a
4a
4a
Cu(OTf)
81
Cu(OTf)2
65
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
2
DBU
31
DIPEA
39
1
0
K
2
CO
3
trace
59
1
1
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3
4b
4c
4d
4a
DABCO
DABCO
DABCO
DABCO
1
1
Cu(OTf)2
57
Cu(OTf)
2
2
38
d
14
Cu(OTf)
83
(
a) Reactions were performed using 0.1 mmol 1a and 0.12 mmol 2a in 1.0 mL toluene
at rt for 5 h. (b) Isolated yield. (c) Determined by chiral HPLC. (d) 5 mol% 4a and
Lewis acid.
The scope of the enal was investigated using the aforementioned reaction conditions
Figure 3). Electronꢀrich and electronꢀpoor substituents at various positions are well
(
tolerated by the βꢀaryl group (product 3aaꢀ3ja). Challenging substrates with an
orthoꢀsubstituent performed well (product 3ia for example). Substrates with a
βꢀthienyl group gave 94% yield and 98% ee. Remarkably, a basic βꢀpyridyl group did
not interfere with either Lewis acid or protonation. The dienal (1a) yielded the
βꢀprotonation product in 70% yield with 94% ee and exclusive regioselectivity
(
product 3na). Besides methyl, enals with higher order βꢀalkyl groups were equally
effective and selective (3oaꢀ3ra) but βꢀdialkyl enals failed to react under these
reaction conditions, due to unproductive homoenolate formation. Simple alkyl
mercaptans and more acidic derivatives were evaluated and afforded comparable
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yields and selectivity (Figure 3, product 3abꢀ3ae).
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Figure 3. Substrate scope of βꢀdisubstituted enals
Trifluoromethylated chiral centers are particularly attractive in medicinal chemistry
but such products are challenging in asymmetric hydrogenation and Michael addition
reactions. The orchestration of NHC/Cu(OTf) cooperative catalysis is effective for
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enantioselective βꢀprotonation of enals with a βꢀCF group. Switching from DABCO
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to quinuclidine delivers better enantioselectivity (Figure 4). The reaction exhibits a
similar substituent effect on the βꢀaryl moiety (Figure 4, product 6baꢀ6ha). Both high
yield and high ee are obtained when benzyl mercaptan and isopropyl mercaptan are
used as nucleophiles (Figure 4, product 6af, 6ag). The βꢀaryl was essential for high
enantioselectivity under the standard conditions. No reaction occurred for βꢀdialkyl
enals.
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Figure 4. Substrate scope for βꢀCF enals
During these preliminary studies, we observed an interesting experimental
phenomenon which suggests an alternative mode of asymmetric control in our
proposed NHC/Lewis acid cooperative mechanism. A mixure of Cu(OTf)
4a), quinuclidine and 4 Å molecular sieves in toluene is a bright green suspension
which changes to pale yellow immediately upon addition of mercaptan. This
observation suggests rapid formation of copper sulfide and quinuclidinium triflate
2
, precatalyst
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Figure 5a). The quinuclidinium ion is a stronger acid than mercaptan (RN —H,
pKa = 9.8 vs RS—H, pKa ≈ 15, DMSO) and may well be the actual proton source
rather than mercaptan. This hypothesis is supported by data in Table 1, where the
structure of the base is essential for enantioselectivity. If quinuclidinium triflate is the
actual proton source, there would be little interaction between copper and the
homoenolate. In other words, copper would play no part in the key protonation step.
The role of copper is to generate the quinuclidinium ion, a more effective and
selective proton source, from quinuclidine and mercaptan.
Entry 1 in Table 1 shows that the mercaptan (2a) reacts with the enal (1a) in the
absence of any Lewis acid, giving moderate ee. This indicates that mercaptan itself is
a nonꢀselective proton source. Quinuclidine did not react with the thiol due to the
large pKa gap. In order to verify this finding, we examined reactions replacing
Cu(OTf) with various Brønsted acids by forming quinuclidinium in situ (Figure 5b).
2
We were delighted to find that an acid coꢀcatalyst can effectively promote the reaction.
Weaker acids are in equilibrium with quinuclidine and the free acid acts as a parallel,
nonꢀselective proton source. In case of strong acids, nearly all protons exist in the
quinuclidinium form, which is a more reactive and selective proton source. High
enantioselectivity was obtained when strong acids (pKa < 1) were used. Identical
yield and ee were obtained using either preformed quinuclidine triflate or triflic acid.
Chiral quinuclidines, in combination with an achiral NHC (4d) were tested. Quinine
and quinidine delivered 12% and ꢀ12% ee respectively (Figure 5c). The opposite
facial preference further supports quinuclidinium as the proton source. When quinine
and quinidine were used in conjunction with chiral NHC (4a), no match/mismatch
was observed, suggesting NHC is the primary selectivity modulator and the effect of
the amine is mostly steric. Based on these results, it is evident that quinuclidine is a
unique proton shuttle. The chiral influence of NHC is well received by the bridgehead
structure of quinuclidine.
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Figure 5. A shuttling mechanism for asymmetric βꢀprotonation
The substrate scopes of enal and mercaptan were examined using the new
organocatalytic protocol. Thioesters with a βꢀchiral center were prepared in excellent
yield and with high ee (Figure 6). Heterocycles or functional groups that previously
2
were incompatible with the Cu(OTf) conditions were well tolerated. For example, a
βꢀpyrazinyl enal afforded the racemic product (3ua) in low yield using Cu(OTf)2.
Under the protonꢀshuttling conditions, 3ua was isolated in 99% yield and 81% ee. In
addition, mercaptans containing heteroatom substituents, which are poor substrates for
the NHC/Cu(II) system, participate in βꢀprotonation/thioesterification with excellent
reactivity and selectivity under the organocatalytic conditions (3ai, 3bj). Bulky
secondary alkyl mercaptans showed no attenuation of reactivity under the standard
conditions (3lh, 6al). Nꢀprotected Lꢀcysteine also functions as a valid thiol
nucleophile, the corresponding product (6mm) being obtained in 99% yield and 97:3
de. The choice of acid also impacts the ee. Phosphoric acid (PA) generally affords a
higher ee than TfOH for βꢀalkyl enals, while TfOH is more selective for βꢀCF
substrates (e.g. 3ua, racemic product using TfOH vs 81% ee using PA; 6la, 89% ee
with TfOH vs 80% ee with PA).
3
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Figure 6. Expansion of substrate scope using the protonꢀshuttling strategy
15a
15b
βꢀTrifluoromethyl and βꢀmethyl enals generated a βꢀchiral center with S and R
configuration respectively. This outcome is probably a result of the olefin geometry.
βꢀMethyl enals are formed with a trans orientation of the carbonyl and βꢀaryl groups
(E isomer), while βꢀCF enals prefer to exist with a cis alignment of the carbonyl and
3
βꢀaryl groups (E isomer). The independently prepared Z isomer of 5a was subjected to
the protonꢀshuttling reaction conditions and desired βꢀprotonation product was
obtained in 71% ee with R configuration (Figure 7). In situ olefin isomerization of
enal (5a) was examined and proton shuttling conditions do not promote E/Z
isomerization. However, this substrate suffered reversible sulfaꢀMichael addition
when treated with mercaptan and quinuclidine. Both E and Z isomers of 5a reacted
with thiol (3a) at comparable rates. When 5aꢀZ was used as the substrate, only its
corresponding E isomer remained. These data suggest βꢀprotonation of both geometric
isomers of 5a is equally efficient, and the Z form undergoes partial isomerization
before the protonation is complete, resulting in the compromised ee of product 6aa.
When racemic sulfaꢀMichael adduct (7a) was subjected to the protonꢀshuttling
conditions, product 6aaꢀS was obtained in 75% yield and 90% ee. Retro
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sulfaꢀMichael followed by enantioselective βꢀprotonation is responsible for this
outcome.
Ph
O
standard condition
CF3 O
3
+
+
R -SH
F3C
H
Ph
6aa-S, 90%, 95% ee
SR3
5
a (E/Z > 95/5)
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CF3
O
CF3
O
standard condition
3
R -SH
Ph
H
Ph
SR3
5a' (E/Z < 5/95)
6aa-R, 90%, 71% ee
3
Ph
O
3
R S CF O
Ph
O
R -SH, quinuclidine (50 mol%)
3
+
F3C
H
Ph
H
H
F3C
H
4
Å MS, PhMe
5
a (E/Z > 95/5)
7a, 42%
5a, 56% (E/Z > 95/5)
3
CF3
O
3
R S CF O
Ph
O
R -SH, quinuclidine (50 mol%)
3
+
Ph
H
Ph
F3C
H
4Å MS, PhMe
5a' (E/Z < 5/95)
7a, 39%
5a, 60% (E/Z > 95/5)
O
3
CF3
O
standard condition
R S CF3
3
+
R -SH
Ph
SR3
Ph
H
rac-7a
6aa-S, 75%, 90% ee
Figure 7. Mechanistic experiments
Facial differentiation in this transformation is most likely determined by the
homoenolate intermediate with the lowest energy. Theoretical studies by Yates et al.
suggest that Breslow enolates derived from triazolium precursors prefer to adopt the E
conformation, in which the OH group is oriented away from the two adjacent nitrogen
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atoms. A similar conclusion was obtained by minimization of the homoenolate from
catalyst 4a and enal 5a. The B3LYPꢀD3/6ꢀ311+G** program determined that the
Eꢀconformer is 3.06 kcal/mol more stable than the Zꢀconformer. One of the
orthoꢀmethyl groups on 4a shields the bottom siꢀface of homoenolateꢀE, leaving the
top reꢀface open for the bulky protonꢀshuttle (Figure 8). A similar rationale can be
made for βꢀalkyl enals.
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Figure 8. Minimized conformations of the homoenolate intermediate
Conclusion
In summary, we have discovered a highly enantioselective βꢀprotonation of enals
using mercaptans via synergistic NHC/amine/copper catalysis. The high correlation
between stereoselectivity and the sulfurphilicity of the metals led to identification of
an organocatalytic protonꢀshuttling approach for highly stereoselective protonation of
homoenolates. The combination of a bridgehead tertiary amine and a strong Brønsted
acid coꢀcatalyst was found to activate a crucial proton shuttle that delivers excellent
reactivity and enantioselectivity. This strategy might find general applications in
controlling βꢀchiral centers of carbonyl compounds.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, product characterizations and copies of all NMR spectra.
This material is available free of charge via the Interꢀnet at http://pubs.acs.org.
Author Information
Corresponding Author
huangyong@pkusz.edu.cn
Author Contributions
*
§
J. Chen and P. Yuan contributed equally.
Notes
The authors declare no competing financial interest.
Acknowledgements
This work is financially supported by the National Natural Science Foundation of
China (21572004 for Y. H. and 21602007 for J. C.), the China Postdoctoral Science
Foundation (2016M590009 for J. C), Guangdong Province Special Branch Program
2014TX01R111 for Y. H.), and Shenzhen Basic Research Program
(JCYJ20160226105602871 for Y. H.).
(
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TOC graphic
R2 OH R'
R2
chiral NHC
R1
H
N
R2
*
O
-alkyl enals
proton-shuttling strategy
SR3
chiral thioesters
O
R3
N
S
H
X
R1
R1
R
H
proton shuttle
H
up to 99% yield, 99% ee
R1 = aryl, vinyl
R2 = alkyl, CF3
synergistic process
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