Water enables an asymmetric cross reaction of α-keto acids with α-keto esters for the synthesis of quaternary isotetronic acids

Article abstract of DOI:10.1039/c9cc06356k

A water promoted asymmetric aldol/lactonization/enolization cascade reaction of α-keto acids and α-keto esters was developed, affording the first general protocol for the construction of chiral quaternary isotetronic acids with excellent enantioselectivity. Theoretical results indicate that intramolecular ionized enamine intermediates stabilized by water generate zwitterionic transition states in a lower activation energy and higher face selectivity, resulting in high activity and chemo- and enantioselectivity.

Full text of DOI:10.1039/c9cc06356k

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Water enables an asymmetric cross reaction of
a-keto acids with a-keto esters for the synthesis
of quaternary isotetronic acids†
Cite this: Chem. Commun., 2019,
55, 12813
Received 16th August 2019,
Accepted 30th September 2019
Ping Chen,‡a Kai Wang,‡ab Boyu Zhang,a Wengang Guo,a Yan Liu*a and Can Li
*
a
DOI: 10.1039/c9cc06356k
rsc.li/chemcomm
A water promoted asymmetric aldol/lactonization/enolization cascade
reaction of a-keto acids and a-keto esters was developed, affording
the first general protocol for the construction of chiral quaternary
isotetronic acids with excellent enantioselectivity. Theoretical results
indicate that intramolecular ionized enamine intermediates stabilized
by water generate zwitterionic transition states in a lower activation
energy and higher face selectivity, resulting in high activity and chemo-
and enantioselectivity.
Isotetronic acids are a class of butenolides prevailing in numer-
ous natural products,1 pharmaceuticals,2 flavouring agents and
perfumes.3 In particular, isotetronic acids with quaternary
carbon centers (QC-isotetronic acids) bearing an ester moiety
and an alkyl substituent exhibit excellent bioactivities.4 For
example, butyrolactone I,2b natural product isolated from
Aspergillus terreus var. africanus IFO 8835 in 1977, has been
found to be a specific inhibitor of cdk1/cyclin B and cdk2/cyclin
A, exhibiting good antiproliferative activity against colon and
pancreatic carcinoma, human lung cancer and prostatic cancer
cell lines. Aspernolide A,2c isolated from the fermentation broth
Scheme 1 (A) Representative natural QC-isotetronic acids. (B) The
reported homo reaction of a-keto esters. (C) This work: polarity effect of
water enables an asymmetric cross addition of a-keto acids to a-keto
esters by stabilizing the ionized intermediate.
of a soft coral derived fungus Aspergillus terreus in 2009, has by the enantioselective homo-aldol reaction of pyruvates with
been proved to possess mild cytotoxicity against cancer cell bisoxazoline-Cu(II) or proline) (Scheme 1B).5
lines in primary tests (Scheme 1A). Thus, the development of a
Inspired by the success of the asymmetric aldol reaction of
general and stereoselective approach for the synthesis of this a-keto acids with aldehydes,6 we envisioned that QC-isotetronic
structural motif would be greatly helpful for biological studies acids can be accessed via a cross reaction of alkyl-substituted
of this type of butenolide. However, to our knowledge, such a-keto acids 1 with a-keto esters 2. However, there has been no
a methodology has not yet been established. So far, the report on this reaction even in the racemic version, due to the
QC-isotetronic acids for bioactivity studies have mainly come fact that alkyl-substituted a-keto acids 1 and a-keto esters 2 can
from isolated natural products and homo QC-isotetronic acids in principle serve as either nucleophiles or electrophiles with
(only one chiral homo QC-isotetronic acid has been synthesized respect to their roles in the reaction (Scheme 1C).7 Therefore,
differentiating the nucleophilicity and electrophilicity8 of alkyl-
substituted a-keto acids and a-keto esters is the key to achieve
the synthesis of QC-isotetronic acids.
a State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China. E-mail: yanliu503@dicp.ac.cn,
canli@dicp.ac.cn
b University of Chinese Academy of Sciences, Beijing 100039, P. R. China
† Electronic supplementary information (ESI) available. CCDC 1816205. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c9cc06356k
‡ P. C. and K. W. contributed equally to this work.
Here we found that water collaborating with a new enamine9
catalyst can differentiate the nucleophilicities and electrophilicities
of alkyl substituted a-keto acids and a-keto esters (Scheme 1C).
This finding encouraged us to develop a new asymmetric cross-
aldol/lactonization/enolization cascade reaction, affording a wide
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Table 1 Effect of watera
the reaction parameters for synthetically useful enantioselectivity.
A series of new chiral pyrrolidine-imidazoles with different sub-
stituents at the 5- and/or N-position of the imidazole ring (B–G)
were synthesized (see the ESI†). Evaluation of this type of amine
catalyst in the reaction of 1a with 2a in water indicated that while
the chemoselectivity remains high for each catalyst, the stereo-
selectivity of product 3 relied heavily on substituents at the 5-postion
of the imidazole ring (Table 2, entries 1–5). The asymmetric reaction
catalyzed by E bearing 1-naphthyl proceeded smoothly to give the
corresponding QC-isotetronic acid with a notable improvement
of the ee value up to 70% (Table 2, entry 5). A slightly enhanced
result (73% ee) was obtained by using catalyst G with the
1-naphthylmethylene substituent on N1 of the imidazole ring
(Table 2, entry 7). The effects of the ester group (COOR) in the
a-keto ester 2 were then investigated. It was found that the steric
bulkiness of ester groups has a significant effect on the enantio-
selectivity. For example, comparative enantioselectivities could be
obtained for the reaction of 1a with 2a or 2b as an electrophile,
respectively (Table 2, entries 7 and 8). On the other hand, use of
Entry
Solvent
Conv.b (%)
3a/4b
eec (%)
1
2
3
4
5
6
7
8
9
10
CH2Cl2
H2O : CH2Cl2 = 1 : 1
H2O : CH2Cl2 = 2 : 1
H2O : CH2Cl2 = 5 : 1
8
21
28
52
64
1.5 : 1
5 : 1
6 : 1
11 : 1
415 : 1
415 : 1
Nd
Nd
Nd
Nd
32
Nd
Nd
Nd
41
H2O : CH2Cl2 = 10 : 1
H2O
DMSO
DMF
Tol
76
41
o5
o5
o5
o5
Nd
Nd
Nd
Nd
THF
a
Unless noted otherwise, reactions were performed with 1a (0.3 mmol),
2a (0.1 mmol), and A (10 mol%) in 0.5 mL solvent at rt for 3 days.
b
Determined by 1H NMR spectroscopy of the crude mixture. c Determined
by chiral HPLC analysis; Nd = not determined.
range of QC-isotetronic acids with good to excellent enantio- oxobutanoate 2c bearing a bulkier tert-butyl group on its ester
selectivities (up to 95% ee). Moreover, water as the reaction moiety led to an increase in enantioselectivity, and the corres-
medium10 was demonstrated to be crucial for increasing activity ponding cross aldol product 3c was obtained with 91% ee
and enantioselectivity. DFT calculations indicate that the high without the loss of reactivity (Table 2, entries 9 and 10).
polarity of water stabilizes intramolecular ionized enamine
Using G as the catalyst, the substrate scope was then
intermediates which generate zwitterionic transition states in investigated with respect to both a-keto acids 1 and a-keto esters
a lower activation energy and higher face selectivity, resulting in 2 (Scheme 2). Gratifyingly, all the reactions proceeded cleanly under
enhanced activity and chemo- and enantioselectivity.
optimized conditions, providing the corresponding QC-isotetronic
We chose a-keto butyric acid 1a and a-keto ester 2a as the acids 3 in good yields and high enantioselectivities. A series of
model substrates to commence our study. In view of its high
efficiency in promoting the aldol reactions of a-keto acid 1a
with aldehydes, amphiphilic proline-derived imidazole A was Table 2 Evaluation of reaction conditionsa
first tested in the cascade reaction. The reactions were conducted
at room temperature, and the results are summarized in Table 1.
The reaction catalyzed by A in dichloromethane afforded cross
QC-isotetronic acid 3a and homo QC-isotetronic acids 4 with a
ratio of about 1.5 : 1 (Table 1, entry 1), albeit plagued by a low
conversion. It was surprising to find that the potential cross- and
homo-aldol products 5 and 6, which would otherwise be generated
with a-keto acid 1a as the electrophile, could not be detected.
These results suggest that despite the higher loading of a-keto acid
1a (3 molar equiv.), a-keto ester 2a reacts as the only effective aldol
Entry
R
Product
Catalyst
Conv.b (%)
eec (%)
acceptor in this reaction under this specific catalytic system. Given
the amphiphilic nature of the secondary amine catalyst, water was
subsequently examined as the co-solvent for the reaction system.
The reaction in the CH2Cl2 :H2O = 1 : 1 mixture gave 21% conver-
sion and the desired product 3a was obtained with a significantly
enhanced chemoselectivity (3a/4 = 5/1). Further increasing the
proportion of water led to a steady improvement in both reactivity
and chemoselectivity (Table 1, entries 2–6). It was surprising to
find that 3a was found as the sole product in 76% conversion and
41% ee for the reaction carried out in pure water (Table 1, entry 6).
It is worth noting that other solvents, such as DMSO, DMF, toluene
1
Et(2a)
Et(2a)
Et(2a)
Et(2a)
Et(2a)
Et(2a)
Et(2a)
Me(2b)
tBu(2c)
tBu(2c)
tBu(2c)
3a
3a
3a
3a
3a
3a
3a
3b
3c
3c
3c
A
76
81
77
73
70
72
79
81
41
54
63
58
70
72
73
65
91
91
Nd
2
B
C
D
E
3d
4d
5d
6d
F
7d
G
G
G
G
G
8d
9d
78
90
Trace
10d,e
11e,f
a
Unless noted otherwise, reactions were performed with 1a (0.3 mmol),
and THF, could not afford the corresponding product for this 2a (0.1 mmol), and cat. (10 mol%) in 0.5 mL H2O at rt for 3 days; in all
cases 3a/4 415 : 1 as determined by crude 1H NMR analysis. Determined
b
cascade reaction (Table 1, entries 7–10).
c
by 1H NMR spectroscopy of crude mixture. Determined by chiral
d
The high chemoselectivity of the cascade reaction of 1a with
stationary phase HPLC analysis. With few drops of CH2Cl2 to dissolve
e
f
2a in water encouraged us to perform further optimizations of substrates. Reaction time: 5 days. Using CH2Cl2 as solvent.
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Scheme 3 Synthetic transformations of 3.
This result indicated that the ring of isotetronic acid possesses
good stability. Moreover, the structural motif of isotetronic acid
can also tolerate the Pd(II) catalyst, which was demonstrated by
the Suzuki coupling of 3f-TBS with phenylboronic acid, leading
to the corresponding product 8 in 71% yield and 88% ee. Chiral
QC-isotetronic acid linked to two different alkyl-substituted
groups 9 was easily obtained by treatment of 3f with LiBH4,
indicating that the present cascade reaction could be a useful
platform for the synthesis of this type of compound that was
otherwise difficult to access.
To improve our understanding of the mechanism and figure
out the role played by water in this reaction, density functional
theory (DFT) calculations for the key step-aldol reaction in
the cascade reaction were carried out (see the ESI† for more
details). Firstly, two plausible intermediates were obtained
through the full optimization of geometries, which suggested
that the intermediate with neutral form (Int-I) may dominate in
dichloromethane and the intermediate with zwitterionic form
(Int-II) may dominate in water. The corresponding transition
states from these two intermediates were calculated. It was
found that the transition state from Int-I had high activation
Scheme 2 Substrate scope. Unless noted otherwise, the reaction was
conducted with 1 (1.2 mmol), 2 (0.4 mmol) and G (10 mol%) in 2 mL H2O
(100 mL CH2Cl2 was added to dissolve the substrates) at rt for 4–5 days.
Because 3 is unstable on silica gel column chromatography, yields for all
products are based on the isolated derivatives after protection by TBS, and
ee values were determined by chiral stationary phase HPLC analysis (see
the ESI†). a Reaction performed with pyruvic acid (5 mmol), 2 (1 mmol) and
G (0.1 mmol) in H2O (2 mL) for 10 days.
tert-butyl 2-oxo-4-aryl-substituted butanoates were investigated barriers (TS-I-R, 31.1 kcal molÀ1; TS-I-S, 31.7 kcal molÀ1) and a
and the corresponding products with 62–81% yield and 89–95% relatively small energy difference (0.6 kcal molÀ1), which suggests
ee were obtained irrespective of the electronic nature or the that the asymmetric aldol reaction of 1a and 2a catalyzed by G in
substitution pattern on the phenyl rings (3c–3j). The reaction dichloromethane should have low reactivity and poor enantio-
also tolerated longer and shorter alkyl chains for the substituted selectivity. On the other hand, TS-II from the water-stabilized
a-keto esters, providing adducts 3k–n with high enantioselec- intermediate Int-II has lower activation energies (TS-II-R,
tivity. Additionally, the reaction of 1a with a-keto esters bearing 22.5 kcal molÀ1; TS-II-S, 26.8 kcal molÀ1). Moreover, Int-II prefers
a benzyl protected alcohol (2n) or a vinyl group (2p–q) also gave to attack 2a from the Re face because of the steric hindrance
excellent results. Pyruvic acid was also tolerated as a nucleophile between the ester group and imidazole ring, thus showing higher
providing QC-isotetronic acid 3r with a synthetically useful yield energy difference between TS-II-R and TS-II-S (4.3 kcal molÀ1).
but with a slightly lower ee value. However, either 3-phenylpyruvic These calculated results suggest that the asymmetric reaction of
acid or 2-oxopentanoic acid could not be successfully coupled with 1a with 2a should exhibit higher reactivity and enantioselectivity
a-keto ester 2c under standard reaction conditions probably due to in the presence of water which agrees well with the experimental
the steric hindrance (3s–t). The absolute configuration of 3f was results.
determined to be R by X-ray crystallographic analysis, and those of
other QC-isotetronic acid products were assigned by analogy.
In conclusion, we discovered that a new class of bulky
proline-imidazole amphiphilic organocatalysts collaborating
The synthetic utility of this method was demonstrated in with water shows a unique ability to differentiate the nucleo-
several efficient transformations using 3f as the starting material. philicity between enolizable a-keto acids 1 and a-keto esters 2.
The enantioenriched 3f was obtained from the gram-scale reaction This protocol allows a new asymmetric catalytic cascade reaction
using the above procedure with G as the catalyst (Scheme 3). of a-keto acids 1 with a-keto esters 2, providing a fundamentally
Treatment of 3f-TBS with Adams’ catalyst under a high pressure new approach towards chiral QC-isotetronic acids with excellent
hydrogen atmosphere, followed by the protection with the TBS ees (up to 95%). DFT calculations have revealed that compared
group, unexpectedly delivered the debrominated hydrogenation with the non-ionized transition state in dichloromethane, the
product 7 in high yield and without loss of enantiopurity. zwitterionic enamine intermediate may be formed owing to the
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This work was financially supported by the National Natural
Science Foundation of China (21871254 and 21532006), DICP
(DICP ZZBS201602) and the Strategic Priority Research Program
of the Chinese Academy of Sciences (Grant No. XDB17000000).
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Conflicts of interest
There are no conflicts to declare.
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