Enantioselective Cyano-Alkoxycarbonylation of α-Oxoesters Promoted by Br?nsted Acid-Lewis Base Cooperative Catalysts

Article abstract of DOI:10.1021/acs.orglett.5b03093

The highly enantioselective cyano-alkoxycarbonylation of α-oxoesters with alkyl cyanoformates is promoted by a new chiral Br?nsted acid-Lewis base cooperative organocatalyst. The present catalysis can be performed at room temperature under nitrogen or air.

Full text of DOI:10.1021/acs.orglett.5b03093

Letter
pubs.acs.org/OrgLett
Enantioselective Cyano-Alkoxycarbonylation of α‑Oxoesters
Promoted by Brønsted Acid−Lewis Base Cooperative Catalysts
Kazuaki Ishihara* and Yoshihiro Ogura
Graduate School of Engineering, Nagoya University, B2-3(611), Furo-cho, Chikusa, Nagoya 464-8603, Japan
S
* Supporting Information
ABSTRACT: The highly enantioselective cyano-alkoxycarbo-
nylation of α-oxoesters with alkyl cyanoformates is promoted
by a new chiral Brønsted acid−Lewis base cooperative
organocatalyst. The present catalysis can be performed at
room temperature under nitrogen or air.
Scheme 1. Our Previous Work
ptically active cyanohydrins serve as highly versatile
Osynthetic building blocks in biologically active compounds.
However, cyanohydrins are not very stable and readily
decompose under basic conditions. In particular, it is difficult
to develop the catalytic enantioselective addition of cyanides to
ketones due to the rapid reversibility of the reaction. Thus,
procedures that allow for direct access to O-protected non-
racemic cyanohydrins are needed to avoid the reversibility of the
cyanide addition and a decrease in enantioselectivity.1
Enantioselective cyano-alkoxycarbonylation is one of the most
powerful methods for preparing O-protected non-racemic
cyanohydrins because alkyl cyanoformate is an easy-to-handle
and user-friendly cyanide source.2−8 There have been numerous
successful examples of the catalytic cyano-alkoxycarbonylation
reaction of aldehydes since the report by Shibasaki et al. in
2002.2,3 In sharp contrast, there are a few examples of the use of
ketones.4,5,7 The first success with unconjugated ketones was
achieved by Deng et al. in 2001.4 They used modified cinchona
alkaloids as chiral Lewis base catalysts. In 2014, we developed the
enantioselective cyano-alkoxycarbonylation of isatins catalyzed
by chiral β-aminothiourea 1 as an acid−base cooperative catalyst
(Figure 1 and Scheme 1).5 As shown in Scheme 1, catalyst 1
initially activates ethyl cyanoformate as an ammonium
cyanohydrinate intermediate, which reacts with N-protected
isatins to generate a diastereomeric mixture of 5 and 6. The first
step is in equilibrium. The subsequent alkoxycarbonylation is the
rate-determining step, and the final product is obtained with high
enantioselectivity through dynamic kinetic resolution of
deprotonated cyanohydrin. Mechanistic studies by Deng et al.4
also support this proposed mechanism.
Tertiary cyanohydrin derivatives derived from α-oxoesters are
very valuable as optically active compounds with a multi-
functionalized carbon center. To the best of our knowledge,
three successful examples have been reported. In 2004, Johnson
et al. reported tandem enantioselective cyanation/Brook
rearrangement/C-acylation reactions of benzoylsilanes catalyzed
by a chiral (salen)aluminum complex to give α-aryl-α-cyano-α-
silyloxyacetates.6 The enantioselectivity was good to moderate,
and aliphatic acylsilanes were unreactive. In 2009, Moberg et al.
Received: October 26, 2015
Figure 1. Brønsted acid−Lewis base cooperative organocatalysts.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03093
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Organic Letters
Letter
reported the first enantioselective cyano-acetylation of α-
oxoesters catalyzed by cinchonidine.7 The substrate was limited
to alkyl 2-oxo-2-phenylacetates, and the reaction temperature
had to be lowered to −40 or −78 °C to induce higher
enantioselectivity. In 2010, Ohkuma et al. reported the highly
catalytic enantioselective cyanosilylation of α-oxoesters by using
a [Ru(phgly)2(binap)]−PhOLi system.8 The substrate scope
was extended to aryl-, heteroaryl-, alkenyl-, and alkylacetates.
However, the reaction temperature had to be lowered to −50 or
−60 °C. Thus, more efficient methods are needed for the
enantioselective synthesis of O-protected cyanohydrins derived
from α-oxoesters.9 Here we report the highly enantioselective
cyano-alkoxycarbonylation of α-oxoesters with alkyl cyanofor-
mates catalyzed by a new chiral Brønsted acid−Lewis base
cooperative catalyst 4 at room temperature.
ee) was observed (entry 14). p-Methoxybenzyl (PMB) ester 7e
could also be used (entry 11).
To investigate the substrate scope, several 9-anthrathenyl-
methyl 2-oxoacetates (10) and 4-methoxybenzyl 2-oxoacetates
(12) were examined in the cyano-ethoxycarbonylation under the
optimized conditions (Table 2). A series of 2-aromatic, α,β-
unsaturated, and aliphatic-group-substituted 2-oxoacetates were
converted into the desired products with good to high
enantioselectivity.12
a
Table 2. Substrate Scope
First, 1 was examined as a catalyst for the enantioselective
cyano-ethoxycarbonylation of methyl 2-oxo-2-phenylacetate
(7a) with ethyl cyanoformate in distilled chloroform,10 based
on our previous results.5 The addition of 50 mol % of methanol
was slightly effective for improving the catalytic activity. The
desired product 8a was obtained in quantitative yield with 67%
ee. Structurally simpler catalyst 2 gave the same results as with 1
(Table 1, entry 2). Catalyst 3 gave higher enantioselectivity than
b
c
entry
2-oxoacetate (R4)
10a (p-MeC6H4)
product, yield (%)
ee (%)
1
2
3
4
5
11a, 96
11b, 76
11c, 89
11d, 80
11e, 88
11f, 66
11g, 74
11h, 87
11i, 75
13a, 93
13b, 90
97
97
98
98
98
97
99
97
97
73
80
10b (p-ClC6H4)
10c (p-BrC6H4)
10d (4-(MeO)C6H4)
10e ((3,4-(CH2O2)C6H3)
10f ((E)-PhCHCH)
10g ((E)-p-BrC6H4CHCH)
10h ((E)-m-BrC6H4CHCH)
10i ((E)-p-CF3C6H4CHCH)
12a (i-Bu)
d
6
d
a
7
Table 1. Screening of the Reaction Conditions
d
8
d
9
10
11
12b (PhCH2CH2)
a
Unless otherwise noted, the reaction of 10 or 12 (0.2 mmol) with
bc
,
cd
,
entry
7 (R3)
cat.
8, yield (%)
ee (%)
ethyl cyanoformate (2.0 equiv) was carried out in the presence of
methanol (50 mol %) and catalyst (10 mol %) in distilled chloroform
e
1
7a (Me)
7a (Me)
7a (Me)
7a (Me)
7a (Me)
7a (Me)
7a (Me)
7b (Et)
1
8a, >99 [99]
8a, [83]
8a, >99 [93]
8a, [92]
8a, [90]
8a, 98 [93]
9a, 91
67 [61]
[61]
67 [67]
[77]
[79]
79 [79]
81
b
c
2
3
4
5
6
2
(0.4 mL) at room temperature for 12 h. Isolated yield. Determined
d
by chiral HPLC. Reaction was carried out in chloroform (0.6 mL) at
3
room temperature for 48 h.
4a
4b
4c
4c
4c
4c
4c
4c
4c
4c
4c
The present organocatalysis proceeded smoothly in commer-
cially available chloroform10 even under air (eq 1). The addition
of methanol was not required because 0.5−1.0% ethanol was
included as stabilizer in commercially available chloroform.
fh
7 ,
g
8
8b, 88
79
g
9
7c (i-Pr)
8c, 89
71
g
g
10
11
12 ,
7d (CH2Ph)
8d, 95
82
7e (PMB)
8e, 81
89
fgh
,
7e (PMB)
9b, 98
89
g
13
7f (CH2C6H4(NO2)-p)
7g (CH2-anthathenyl-9)
8f, 72
84
g
14
8g, 98
97
a
Unless otherwise noted, the reaction of 7 (0.2 mmol) with ethyl
cyanoformate (2.0 equiv) was carried out in the presence of methanol
(50 mol %) and catalyst (10 mol %) in distilled chloroform (0.2 mL)
The absolute configuration of product 9a was determined by
transformation to known compound 15 and comparison of their
specific rotations, as shown in Scheme 2. It was quite difficult to
obtain cyano-alkoxycarbonated products chemoselectively.
Fortunately, we found that the chemoselective hydrolysis of 9a
promoted by Parkins catalyst13 and subsequent deprotection of
the alloc group gave 15 in high yield. The authentic sample of
(R)-15 was synthesized from (R)-16, which was prepared by a
known method.8,14 Thus, the absolute configuration of 9a was
determined to be (S). Notably, chemoselective hydrolysis of (R)-
16 gave (R)-17 in low yield because of the instability of the
silyloxy moiety of 16.
To demonstrate the synthetic utility of cyano-alkoxycarbo-
nated products, we converted primary amide 18 derived from 9b
to 4-methoxybenzyl (S)-2,4-dioxo-5-phenyloxazolidine-5-car-
boxylate (19) in high yield in two steps (Scheme 3). The
skeletons analogous to 19 are included in vinclozoline as a
b
c
at room temperature for 12 h. Isolated yield. Results without
d
methanol are shown in brackets. Determined by chiral HPLC.
e
f
Reaction time was 6 h. Reaction was carried out using allyl
g
h
cyanoformate for 24 h. Distilled chloroform (0.4 mL) was used.
1 and 2 (entry 3). Interestingly, β-aminosquaramide 411 was
superior to β-aminothiourea 3 with respect to enantioselectivity
(entry 4). Allyl cyanoformate could also be used in place of
ethoxycarbonylcyanide (entry 7).
Next, the effect of an alkoxy moiety (R3) of 7 was explored
(entries 6, 8−11, 13, and 14). When 9-anthrathenylmethyl ester
7g was used as a substrate, the highest enantioselectivity (97%
B
DOI: 10.1021/acs.orglett.5b03093
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Organic Letters
Letter
Scheme 2. Determination of the Absolute Configuration of 9a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03093.
Experimental details and characterization data for the
starting material and products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ishihara@cc.nagoya-u.ac.jp.
Notes
The authors declare no competing financial interest.
fungicide with antiandrogenic properties, paramethadione as
anticonvulsant, etc.
ACKNOWLEDGMENTS
■
Financial support was provided in part by JSPS KAKENHI Grant
Number 15H05755 and Program for Leading Graduate Schools
“IGER program in Green Natural Sciences”, MEXT, Japan. Y.O.
is grateful for a JSPS Research Fellowship for Young Scientists.
Scheme 3. Chemoselective Transformation from 8e to 19
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Organic Letters
Letter
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(17) Although the present kinetic studies (see the Supporting
Information) and the previous reports support our proposed
mechanism,4,5 we cannot exclude the possibility that asymmetric
induction arises solely from the first cyanation step.
(18) Cyanohydrins were not observed during the present cyano-
alkoxycarbonylation. This suggests that the cyanohydrinated oxyanion
intermediates were highly unstable.
(19) The enantioselectivity in the reaction of aliphatic-group-
substituted 2-oxoacetates 12a and 12b (entries 10 and 11, Table 2)
was slightly lower than that of 2-oxo-2-phenylacetate 7e (entry 11, Table
1). In the reaction of aliphatic substrates, the equilibrium between
diastereomeric intermediates 20 and 21 might not be high enough for
high enantioselectivity to be induced in the next step.
D
DOI: 10.1021/acs.orglett.5b03093
Org. Lett. XXXX, XXX, XXX−XXX