Organocatalytic 1,4-Addition Reaction of 2-Formyl(thio)esters to Vinylketones: An Efficient Access to Acyclic Chiral Building Blocks with a Quaternary Carbon Stereocenter

Article abstract of DOI:10.1002/chem.201504479

2-Formyl(thio)esters were utilized as pronucleophiles to obtain less-accessible acyclic chiral building blocks bearing versatile functional groups on a quaternary carbon atom for enantioselective 1,4-addition to vinylketones. To achieve high enantioselect

Full text of DOI:10.1002/chem.201504479

DOI: 10.1002/chem.201504479
Communication
&
Asymmetric Catalysis
Organocatalytic 1,4-Addition Reaction of 2-Formyl(thio)esters to
Vinylketones: An Efficient Access to Acyclic Chiral Building Blocks
with a Quaternary Carbon Stereocenter
Toshifumi Tatsumi, Tomonori Misaki,* and Takashi Sugimura*[a]
the construction of chiral quaternary carbon atoms.[9] The CÀC
Abstract: 2-Formyl(thio)esters were utilized as pronucleo-
philes to obtain less-accessible acyclic chiral building
blocks bearing versatile functional groups on a quaternary
carbon atom for enantioselective 1,4-addition to vinylke-
tones. To achieve high enantioselectivity in the present
1,4-addition reaction, thiourea-tertiary amines containing
a bulky chiral backbone were developed as catalysts, and
several derivatizations of the products were performed to
demonstrate the synthetic utility of the products.
bond-forming reaction products bearing versatile functional
groups on a quaternary carbon atom would be useful as chiral
building blocks, especially for the preparation of a variety of
less-accessible acyclic carbon frameworks containing a chiral
quaternary carbon atom at the center of the structure. Despite
their high possibility as useful chiral building blocks in synthet-
ic chemistry,[10] direct catalytic asymmetric preparation meth-
ods are currently limited to only one example of the insertion
reaction of diazoesters to aromatic aldehydes, yielding 2-for-
mylcarboxylates bearing an aromatic ring on a chiral quaterna-
ry a-carbon atom.[11] To the best of our knowledge, a direct
preparation method of 2-formylcarboxylic acid derivatives
bearing a,a-dialkyl substituents on a chiral quaternary a-
carbon atom has not yet been reported.[12] Here, we report an
enantioselective 1,4-addition reaction of 2-formyl(thio)esters to
vinylketones involving a quaternary carbon stereocenter con-
struction catalyzed by thiourea-tertiary amine containing
a bulky chiral backbone (Scheme 1).
Quaternary carbon stereocenters[1] are often found as partial
structures in many pharmaceuticals and biologically active nat-
ural products. However, enantioselective construction of such
stereogenic centers by efficient catalytic CÀC bond-forming re-
actions is one of the great challenges in modern organic syn-
thesis,[1d,l,2] because such construction usually involves the diffi-
cult tasks of steric recognition and/or effective activation of
sterically hindered substrates; this difficulty is especially pro-
nounced in acyclic systems.[1j,2h,i] Catalytic enantioselective CÀC
bond-forming reactions with a-substituted 1,3-dicarbonyl com-
pounds acting as pronucleophiles are regarded as an impor-
tant approach for the construction of chiral quaternary stereo-
genic centers. Among these reactions, conjugate addition reac-
tions have been widely used for CÀC bond formation, and
many types of conjugate addition reactions have been report-
ed.[3–6] Transition-metal catalyst-mediated asymmetric allylic al-
kylations[7] and phase-transfer-catalyzed asymmetric alkyla-
tions[8] have also been developed and are another powerful
potential approach for CÀC bond formation. Although cyclic
1,3-dicarbonyl compounds are mainly employed as pronucleo-
philes in most of these reports, some excellent CÀC bond-
forming reactions of acyclic 1,3-dicarbonyl compounds have
also been developed in recent years.[4,7g,8i,j] However, 2-formyl-
carboxylic acid derivatives, which are a type of 1,3-dicarbonyl
compounds, have not yet been employed as pronucleophiles
for catalytic enantioselective CÀC bond-forming reactions in
Scheme 1. Asymmetric 1,4-addition reaction of 2-formylcarboxylic acid deriv-
atives.
To realize the CÀC bond forming reaction that provides vari-
ous 2-formylcarboxylic acid derivatives including a quaternary
carbon atom, we selected vinylketones as electrophiles bearing
a changeable carbon substituent (R3) according to application.
Initially, we attempted to realize the 1,4-addition with methyl
2-formylbutanoate (2a)[13] and methyl vinyl ketone (3a) using
a catalytic amount of chiral guanidine 1a. Though the 1,4-ad-
dition proceeded smoothly, the enantioselectivity was low, as
shown in Table 1, entry 1, whereas the use of guanidine 1a as
[a] T. Tatsumi, Dr. T. Misaki, Prof. Dr. T. Sugimura
Graduate School of Material Science
University of Hyogo
3-2-1 Kohto, Kamigori, Hyogo 678-1297 (Japan)
E-mail: misaki@sci.u-hyogo.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504479.
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than that of amino acid-based catalysts 1b–d (entry 11). As
shown in entry 12, catalyst 1 f-mediated 1,4-addition using 2-
formylthioester 2c (R2 =c-Hex) instead of 2b obtained a higher
chemical yield and a slightly enhanced enantioselectivity.
Next, we investigated the substrate scope of the 1,4-addi-
tion using the newly developed thiourea-tertiary amine cata-
lyst 1 f (Table 2). Various vinylketones 3 (R3 =alkyl, aryl, and al-
kenyl) were used for the enantioselective 1,4-addition (Table 2,
entries 1–7). The electronic properties of the substituents on
the aromatic ring of arylvinylketones 3d–g has only a limited
effect on the enantioselectivities (entries 3–6). A variety of alkyl
substituents can be introduced as R1 into the 2-formylthioest-
ers 2 to obtain the desired products with equally high enantio-
selectivities (entries 8–14). The 1,4-addition of bulky 2h (R1 =
iPr) was also found to show high enantioselectivity (entry 12),
and the benzyloxy group in 2j did not affect the high enantio-
selectivity during the 1,4-addition (entry 14). It should be
noted that 1,4-addition of methyl ester 2a also showed high
enantioselectivity (entry 15).
Table 1. Evaluation of catalysts 1a–i in the 1,4-addition of 2 to 3a.[a]
Entry
2[b]
cat. 1
Time
product 4
Yield
[%]
ee
[%][c]
1
2
3
4
5
6
7
8
2a
2b
2b
2b
2a
2b
2b
2b
2b
2b
2b
2c
1a
1a
1b
1c
1c
1d
1e
1 f
1g
1h
1i
45 min
30 min
5 h
3.5 h
48 h
3.5 h
18 h
8 h
5.5 h
144 h
6.5 h
6 h
4a
4b
4b
4b
4a
4b
4b
4b
4b
4b
4b
4c
52
70
67
49
70
68
64
59
75
37[e]
70
84
33
33
74
78
76
79
91[d]
93[d]
73[d]
40[d]
66
9
10
11
12
1 f
94[d]
[a] Reactions were performed on a 0.3 mmol scale in 1.0 mL of toluene
using 2.0 equiv of 3a and 5 mol% of catalyst 1. [b] See the Supporting In-
formation for the keto enol composition. [c] Determined by chiral HPLC
analysis. [d] Opposite enantiomer was formed. [e] Low conversion yield
(56%) caused the low isolated yield.
In this 1,4-addition reaction, in addition to the face control
of the enolate anion of 2-formyl(thio)esters at the CÀC bond
forming step, the high level of geometric control at the eno-
late anion generating step is essential for achieving high enan-
a catalyst resulted in high enantioselectivity for several addi-
tion reactions of 5H-oxazol-4-ones.[14] The use of 2-formylth-
ioester 2b as a pronucleophile was not effective for enhancing
the enantioselectivity (entry 2). Although the enantioselectivity
of the 1,4-addition catalyzed by guanidine 1a was low, the re-
action rate was sufficiently high. Therefore, we then attempted
to perform the 1,4-addition using thiourea-tertiary amines[15] as
catalysts of relatively low base strength instead of guanidine
1a. We first examined the 1,4-addition using a known trypto-
phan-based thiourea-tertiary amine catalyst 1b,[15h] and ob-
Table 2. 1,4-Addition of various 2-formyl(thio)esters 2 to vinylketones 3
catalyzed by 1 f.[a]
tained the product with
a significant enantioselectivity
(entry 3). This result prompted us to enhance the enantioselec-
tivity by steric tuning of thiourea-tertiary amine catalysts. The
employment of isoleucine-based catalyst 1c bearing
a branched side chain or tert-leucine-based catalyst 1d bearing
a bulky tert-butyl group showed a slight improvement in the
enantioselectivity (entries 4 and 6). Additionally, the 1,4-addi-
tion of methyl ester 2a with catalyst 1c took a long time to
complete (entry 5). Thus, we examined the 1,4-addition using
2-formylthioester 2bwith newly prepared catalysts 1e–h bear-
ing a bulky side chain (entries 7–10). Consequently, the intro-
duction of a bulky side chain into the catalyst was effective in
enhancing the enantioselectivity, and we found that catalyst
1 f (R5 =Bn) showed a somewhat higher catalytic activity and
a slightly higher enantioselectivity than catalyst 1e (R5 =Ph)
(entries 7, 8). The urea catalyst 1g showed a relatively high cat-
alytic activity, but the enantioselectivity was decreased
(entry 9). The presence of a free hydroxy group on the side
chain of the catalyst significantly reduced the catalytic activity
and enantioselectivity (entry 10). We also examined the 1,4-ad-
dition using a bifunctional cinchona alkaloid derivative 1i as
a catalyst,[3k,8f,15b,c,e,f,h–j] but the enantioselectivity was lower
Entry
2[b]
3
Time
product 4
Yield
[%]
ee
[%][c]
1
2c
2c
2c
2c
2c
2c
2c
2d
2e
2 f
2g
2h
2i
3b
3c
3d
3e
3 f
3g
3h
3a
3a
3a
3a
3d
3a
3a
3a
23 h
18 h
2 h
3 h
3.5 h
1 h
1 h
4 h
4 h
15 h
7 h
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4a
86
67
82
81
74
76
84
73
82
88
72
72
71
82
57
92
90
95
96
92
85
92
90
91
94
91
94
92
90
90
2[d]
3
4
5[d]
6[d]
7
8
9
10
11
12[e]
13
14
15
26 h
4.5 h
7 h
2j
2a
97 h
[a] Reactions were performed on a 0.3 mmol scale in 1.0 mL of toluene
using 1.5 equiv of 3 (2.0 equiv for 3a) and 5 mol% of catalyst 1 f. [b] See
Supporting Information for the keto enol composition. [c] Determined by
chiral HPLC analysis. [d] Reactions were carried out at À408C. [e] The re-
action was carried out at room temperature with 10 mol% of catalyst 1 f.
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tioselectivity. Thus, to gain preliminary insights into the enan-
tiodiscriminating step in 1,4-addition, we confirmed geometric
controllability of catalyst 1 f at the enolate anion-generating
step by trapping the enolate anion of 2-formylthioester 2b in
the corresponding enol silyl ether 5 (Scheme 2). As a result, 1 f
loss of enantiopurity by the Horner–Wadsworth–Emmons reac-
tion.[17] The ester exchange reaction of product 4c was also
possible through the use of an acetal stereomixture to obtain
4a without any loss of the enantiopurity. Incidentally, the abso-
lute configuration of the methyl ester 4a derived from 4c was
the same as that of 4a formed by the 1,4-addition of 2a to 3a
shown in Table 2, entry 15. The intramolecular aldol condensa-
tion of 4l readily obtained cyclohexenone 7 in high yield, and
the corresponding carboxylic acid 8 was easily obtained from
7 in high yield. Compound 7 can be also converted into the
known alcohol 10 without loss of the enantiopurity by the re-
duction of thioester moiety of acetal 9 derived from 7, fol-
lowed by deprotection. The absolute configuration of obtained
10 was assigned as S by comparing its optical rotation value
with the reported value;[18] hence, the absolute configuration
of 4l was S.
In conclusion, we have developed an asymmetric 1,4-addi-
tion reaction of 2-formyl(thio)esters 2 to vinylketones 3 using
the newly developed thiourea-tertiary amine catalyst 1 f involv-
ing a quaternary carbon stereocenter construction in an acyclic
system. This reaction is the first catalytic asymmetric CÀC
bond-forming reaction of 2-formylcarboxylic acid derivatives.
The facile transformations of the products 4 demonstrate the
high potential of 4 as new synthetically useful acyclic chiral
building blocks bearing versatile functional groups on a quater-
nary carbon atom.
Scheme 2. Geometric controllability in the silylation of 2-formylthioester 2b.
mediated silylation only obtained the E isomer. Because the
use of triethylamine also obtained only the E isomer,[16] the ter-
tiary amine moiety of catalyst 1 f most likely functions as
a base to generate the E-enolate anion selectively in the pres-
ent 1,4-addition, and the high enantioselectivity is achieved by
the protonated 1 f-mediated face-selective addition of the E-
enolate anion to the vinylketone.
The utility of the products 4 bearing a chiral quaternary ste-
reogenic center was demonstrated using several transforma-
tions. As illustrated in Scheme 3, the product 4c can be con-
verted into the corresponding a,b-unsaturated ester 6 without
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Advanced Molecular Transforma-
tions by Organocatalysts” from The Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan.
Keywords: aldehydes · asymmetric catalysis · enones · Michael
addition · organocatalysis
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10: [a]2D0 À30.0 (c 1.67, CHCl3) {ref. [18], [a]D20 À26.9 (c 0.658, CHCl3, 88% ee),
absolute configuration: S}.
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Received: November 9, 2015
Published online on November 23, 2015
Chem. Eur. J. 2015, 21, 18971 – 18974
www.chemeurj.org
18974
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