Bifunctional Iminophosphorane Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α-Substituted Acrylate Esters

Article abstract of DOI:10.1021/jacs.5b10226

The highly enantioselective sulfa-Michael addition of alkyl thiols to unactivated α-substituted acrylate esters catalyzed by a bifunctional iminophosphorane organocatalyst under mild conditions is described. The strong Br?nsted basicity of the iminophosphorane moiety of the catalyst provides the necessary activation of the alkyl thiol pro-nucleophile, while the two tert-leucine residues flanking a central thiourea hydrogen-bond donor facilitate high enantiofacial selectivity in the protonation of the transient enolate intermediate. The reaction is broad in scope with respect to the alkyl thiol, the ester moiety, and the α-substituent of the α,β-unsaturated ester, affords sulfa-Michael adducts in excellent yields (up to >99%) and enantioselectivities (up to 96% ee), and is amenable to decagram scale-up using catalyst loadings as low as 0.05 mol %.

Full text of DOI:10.1021/jacs.5b10226

Communication
pubs.acs.org/JACS
Bifunctional Iminophosphorane Catalyzed Enantioselective Sulfa-
Michael Addition to Unactivated α‑Substituted Acrylate Esters
Alistair J. M. Farley,§ Christopher Sandford,§ and Darren J. Dixon*
The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
Stetter reaction, and examples under Brønsted base catalysis have
yet to be reported.6
ABSTRACT: The highly enantioselective sulfa-Michael
addition of alkyl thiols to unactivated α-substituted
acrylate esters catalyzed by a bifunctional iminophosphor-
ane organocatalyst under mild conditions is described. The
strong Brønsted basicity of the iminophosphorane moiety
of the catalyst provides the necessary activation of the alkyl
thiol pro-nucleophile, while the two tert-leucine residues
flanking a central thiourea hydrogen-bond donor facilitate
high enantiofacial selectivity in the protonation of the
transient enolate intermediate. The reaction is broad in
scope with respect to the alkyl thiol, the ester moiety, and
the α-substituent of the α,β-unsaturated ester, affords sulfa-
Michael adducts in excellent yields (up to >99%) and
enantioselectivities (up to 96% ee), and is amenable to
decagram scale-up using catalyst loadings as low as 0.05
mol %.
An effective approach to overcoming low inherent reagent
electrophilicity in Brønsted base catalyzed addition reactions of
pronucleophiles is to raise the Brønsted basicity of the catalyst.7
Under a fast acid/base proton transfer regime, augmented
Brønsted basicity in the catalyst increases the concentration of
the nucleophilic conjugate base and, as a consequence, the rate of
the bimolecular addition step. To this end, we recently developed
a new family of modular bifunctional iminophosphorane (BIMP)
superbase organocatalysts for the first general enantioselective
organocatalytic nitro-Mannich reaction to unactivated keti-
mines;8 a reaction where an organosuperbase was essential for
reactivity.9 In the same vein, we postulated that the poor
reactivity of unactivated methacrylate esters toward nucleophilic
addition may be overcome using our BIMP organosuperbase
family (Scheme 1). We chose the SMA addition of alkyl thiols as
Scheme 1. Proposed BIMP Catalyzed Enantioselective Sulfa-
Michael Addition to Methyl Methacrylate
he Michael addition of a carbon-centered (C−H) or
Theteroatom-centered (X−H) acid to a conjugated electron-
deficient alkene is a fundamental reaction in organic chemistry
that allows the direct and efficient construction of C−C or C−X
bonds with perfect atom economy.1 In this union, the creation of
stereogenic centers, either directly at the β-carbon or indirectly
through protonation at the α-carbon, is common and controlling
the enantioselectivity with both metal-rich and metal-free
catalysts has been the subject of intense research activity over
the decades.2 Recently, much activity has focused on organo-
catalytic methods,3 and enantioselective additions of a wide
range of pro-nucleophiles under iminium, enamine, or tertiary
amine Brønsted base/H-bond donor catalysis to various
conjugated electron deficient acceptors including enals, enones,
nitroolefins, and other reactive Michael acceptors have been
successfully achieved.3g,h
To date, however, one class of Michael acceptor, α,β-
unsaturated esters substituted with alkyl or aryl groups at either
the α- or β-position, has remained a persistent challenge in
enantioselective organocatalysis due to their low inherent
electrophilicity4 and low propensity for catalyst activation.
Both subclasses are problematic in their own way, and each
one requires a solution. In this paper, we chose to tackle α-
substituted acrylate esters.5 Our primary aim was to realize
reactivity and enantiocontrol with substrates possessing simple
alkyl groups at the α-position. To the best of our knowledge,
organocatalytic enantioselective Michael additions to methacry-
late esters has been limited to NHC catalysis of aldehydes in the
this is an important reaction for the asymmetric construction of
chiral sulfides,10,11 and no catalytic enantioselective version to
unactivated α-substituted acrylate esters under metal-free
catalysis has previously been reported.6b Related literature
examples have employed activated derivatives including
imides11f,o and oxazolidinones10h,11m,q,r as the Michael acceptor
or possess activating α-substituents.11b,d,g,q Additionally the use
of simple aliphatic thiols11h,k,n,o,q,u (pKa(DMSO) = 17)12 in
organocatalytic asymmetric sulfa-Michael additions is much
more challenging than the use of more acidic thiol pro-
Received: September 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b10226
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Journal of the American Chemical Society
Communication
nucleophiles such as aryl thiols or thiocarboxylic acids.11 Our
hope was that the strong Brønsted basicity of the BIMP would
surmount the low inherent electrophilicity of the Michael
acceptor by increasing the concentration of the thiol conjugate
base. Following C−S bond formation, selective enantiofacial
protonation of the transient enolate intermediate would deliver
the enantioenriched Michael adduct and release the catalyst back
into the cycle (Scheme 1).
1-Propanethiol was chosen to test reactivity in a model
reaction using the inexpensive feedstock chemical methyl
methacrylate (2a) as the Michael acceptor. A promising
reactivity profile was initially established using 10 mol % of our
previously reported first generation tert-leucine derived BIMP
catalyst 1a derived from triphenylphosphine (Figure 1 and Table
reactivity, and good levels of enantiocontrol were also witnessed;
adduct 4a was afforded in quantitative yield and with 72% ee
(Table 1, entry 2). Poor reactivity was observed with less basic
BIMP catalyst 1c (Table 1, entry 3), and a drop in
enantioselectivity was witnessed using tributylphosphine derived
BIMP 1d (Table 1, entry 4).
Simple modification of the thiourea hydrogen-bond donor
group of the first generation BIMP organocatalysts led to no
improvement in the level of enantiocontrol (Table 1, entries 5−
7, and Supporting Information), and accordingly alternative
second generation BIMP organocatalyst designs were consid-
ered. Drawing inspiration from the cyclohexanediamine-derived
H-bond donor organocatalysts pioneered by Jacobsen14 and
Takemoto15 and their co-workers, we synthesized the corre-
sponding BIMPs 1h and 1i and assessed them in the model
reaction (Table 1, entries 8 and 9). Although catalytically active,
both afforded 4a with low levels of enantiocontrol, and we
postulated that the trans-1,2-diaminocyclohexane motif was
having a detrimental effect on the enantioselectivity. This was
confirmed when hybrid catalyst 1j, arising from a fusion of the
amide/thiourea unit of 1h with the tert-leucine residue of our
original BIMP catalysts 1a−g, was synthesized; we were
delighted to observe enhanced enantioselectivity (76% ee,
entry 10), while maintaining the excellent reactivity.
Further elaboration of this second generation BIMP catalyst
design revealed that both stereocenters were contributing to
enantiocontrol in the formation of 4a. When the diastereomeric
catalyst 1k was tried, the enantioselectivity was reduced to 29%
ee (Table 1, entry 11), while maintaining the same absolute
configuration, indicating that the stereogenic center of the
amide/thiourea unit was less influential on enantiofacial control
than the stereogenic center proximal to the iminophosphorane.
Fine-tuning of the amide moiety of the catalyst16 revealed 1m,
which afforded 4a in 87% ee (Table 1, entry 13). A
reoptimization of the reaction conditions to 0.05 M in diethyl
ether resulted in a marked improvement in the enantioselectivity
to 94% ee while maintaining near quantitative yields (Table 1,
entries 14 and 15 and Supporting Information).
Figure 1. Bifunctional iminophosphorane (BIMP) organocatalysts
screened for performance in the sulfa-Michael addition reaction. PMP =
p-methoxyphenyl.
1, entry 1).13 After just 3 h at rt, 49% yield of product 4a was
afforded with an encouraging ee of 66%. However, switching to
the analogous but more basic catalyst 1b derived from tris(p-
methoxyphenyl)phosphine gave rise to a significant boost in
Table 1. Catalyst Screen in the Sulfa-Michael Addition of 1-
a
Propanethiol to Methyl Methacrylate
With optimized reaction conditions established, we inves-
tigated the scope of the transformation (Table 2). An initial
screen using 1-propanethiol showed good performance across a
range of small, medium, and large ester types (89−96% ee,
entries 1−6), although the more sterically bulky esters (e.g., R1 =
t-Bu, entry 6) substantially retarded the reaction rate. Subsequent
scope with respect to the thiol was investigated using methyl
methacrylate and minimal variation to the high enantioselectivity
was observed irrespective of alkyl chain length, branching in the
α- or β-positions, or cyclic substituents (Table 2, entries 7−
12).17
Next, variation of the α-substituent of α-substituted α,β-
unsaturated methyl or phenyl esters (2g−r) was studied using 1-
propanethiol as the S-centered nucleophile (Table 3). Using
methyl ester Michael acceptors, the reaction performed well with
substituted α-methyl substituents possessing electron with-
drawing groups such as vinyl, ester, or phenyl moieties or with
an α-phenyl substituent (83−93% ee, Table 3, entries 1−4).
With alkyl substituted methyl substituents or branched
substituents at the α-position, it was advantageous to use the
slightly more active phenyl ester to compensate for the reduction
in reaction rate while maintaining high levels of enantiocontrol
(85−92% ee, Table 3, entries 6−9). Pleasingly, in addition to the
phenyl substituted substrate 2j, the reaction was also applicable
b
c
entry
catalyst
yield (%)
ee (%)
1
2
3
4
5
1a
1b
1c
1d
1e
1f
49
>99
9
66
72
68
35
57
37
4
91
>99
57
d
6
7
1g
1h
1i
40
8
91
9
9
40
6
10
11
12
13
1j
97
76
29
84
87
89
94
1k
1l
91
>99
>99
86
1m
1m
1m
e
14
f
15
97
a
Reactions were carried out with 0.20 mmol of 3a and 1.0 mmol of 2a.
Isolated yield. Enantiomeric excess (ee) determined by HPLC
analysis on a chiral stationary phase. Catalyst 1f used at 5 mol %.
Reaction performed in 0.5 M Et2O. Reaction conducted in 4.0 mL of
b
c
d
e
f
Et2O at rt using 5 mol % 1m and quenched after 24 h.
B
DOI: 10.1021/jacs.5b10226
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Journal of the American Chemical Society
Communication
Table 2. Scope with Respect to the Ester Group and Thiol
Pro-nucleophiles
Scheme 2. Decagram Scale Sulfa-Michael Addition and
a
a
Subsequent Derivatization
b
c
entry
1
R1
R2
product
yield (%)
ee (%)
Me (2a)
Ph (2b)
Et (2c)
n-Pr (3a)
n-Pr (3a)
n-Pr (3a)
n-Pr (3a)
n-Pr (3a)
n-Pr (3a)
n-Pent (3b)
i-Pent (3c)
i-Pr (3d)
c-Hex (3e)
Bn (3f)
4a
4b
4c
4d
4e
4f
97
>99
87
94
95
92
89
93
96
93
92
92
90
90
89
d
2
3
d
4
Bn (2d)
i-Pr (2e)
t-Bu (2f)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
78
5
71
a
Reagents and conditions: (a) catalyst 1m (0.05 mol %), MTBE, 55
°C, 24 h; (b) H2O2/TFA, rt, 4 h, >99% yield, 89% ee; (c) LiOH,
THF/H2O, rt, 2 h, 82% yield, 86% ee; (d) DIBAL-H, THF, −78 °C, 1
h, 64% yield, 90% ee; (e) benzylamine (3 equiv), neat, 0 °C, 12 h, 99%
yield, 89% ee; (f) allylamine (3 equiv), neat, 0 °C, 2 h, 99% yield, 91%
ee.
e
6
36
7
4g
4h
4i
>99
86
8
9
>99
81
10
11
12
4j
4k
4l
85
PMB (3g)
89
a
Reactions were carried out with 0.20 mmol of thiol (3) and 1.0 mmol
b
c
demonstrate the synthetic utility of the β-mercapto ester
products 4 resulting from the reaction, 4b was subsequently
oxidized to the sulfone 5a, hydrolyzed to the acid 5b, reduced to
the alcohol 5c, and converted quantitatively to amides 5d and 5e
by direct aminolysis with benzylamine and allylamine,
respectively.
of methacrylate ester (2). Isolated yield. Determined by HPLC or
GC analysis on a chiral stationary phase. Reaction performed with
0.40 mmol of 2. Reaction quenched after 48 h.
d
e
Table 3. Scope with Respect to the α-Substituent on the
Michael Acceptor
a
In summary, the first highly enantioselective organocatalytic
SMA of alkyl thiol pro-nucleophiles to unactivated α-substituted
acrylate esters has been developed. Good levels of reactivity, and
excellent enantioselectivities were achieved across a diverse range
of alkyl thiols and unactivated α-substituted acrylate esters using
a new second generation bifunctional iminophosphorane
(BIMP) superbase organocatalyst. The ability of BIMP organo-
catalysts to enable unactivated α-substituted acrylate esters to
undergo asymmetric conjugate additions is, we believe, a
significant advancement in the field, and further work to uncover
the breadth of their use is ongoing in our laboratories and will be
disclosed in due course.
b
c
entry
R1
R3
allyl (2g)
product yield (%) ee (%)
1
2
Me
Me
Me
Me
Me
Ph
4m
4n
94
85
99
84
47
85
98
93
96
94
89
98
93
90
86
83
92
92
88
85
90
86
94
84
CH2CO2Me (2h)
Bn (2i)
d
e
3
4o
4p
4q
4r
4
Ph (2j)
d
5
Et (2k)
6
7
8
9
Et (2l)
Ph
i-Pr (2m)
4s
Ph
c-Hex (2n)
4t
Ph
c-Pent (2o)
4-OMe(C6H4) (2p)
2-OMe(C6H4) (2q)
2-NO2(C6H4) (2r)
4u
4v
4w
4x
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b10226.
■
f
10
Me
Me
Me
S
11
12
a
Reactions were carried out with 0.20 mmol of 3a and 0.40 mmol of 2.
Isolated yield. Determined by HPLC analysis on a chiral stationary
phase. Reaction quenched after 48 h. Absolute configuration of 4o
determined by chemical correlation (see Supporting Information).
Experimental details and characterization data (PDF)
b
c
d
e
AUTHOR INFORMATION
Corresponding Author
*darren.dixon@chem.ox.ac.uk
■
f
Compound 2p (0.20 mmol) was used.
Author Contributions
to electron rich and deficient aryl substituents (84−94% ee,
entries 10−12).
§A.J.M.F. and C.S. contributed equally.
Notes
Although our methodological study was routinely carried out
at 5 mol % catalyst loading, all indications suggested that our
optimal BIMP catalyst 1m was highly active in the SMA and that
the loadings could be significantly reduced.18 Indeed, in the
reaction of 2b with 3a, after re-optimization of the reaction
parameters, we were delighted to find the catalyst loading of 1m
could be readily reduced down to 0.05 mol % while performing
the reaction on a 100 mmol scale (Scheme 2). Near full
conversion was achieved after 24 h using only ∼40 mg of in situ
generated 1m whereupon the reaction was quenched, a crude ee
of 90% was measured, and the product was purified by distillation
to afford 4b in 84.5% isolated yield with no loss in ee. To
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the EPSRC (Studentship and
Doctoral Training Grant [EP/M50659X/1] to A.J.M.F.),
AstraZeneca (Studentship to A.J.M.F.), and the SCI (Post-
graduate Scholarship to A.J.M.F.).
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Journal of the American Chemical Society
Communication
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DOI: 10.1021/jacs.5b10226
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