Umpolung Reactivity of Aldehydes toward Carbon Dioxide

Article abstract of DOI:10.1002/anie.201806569

Carbon dioxide is an intrinsically stable molecule. Therefore, its activation requires extra energy input in the form of reactive reagents and/or activated catalysts and, often, harsh reaction conditions. Reported here is a direct carboxylation reaction of aromatic aldehydes with carbon dioxide to afford α-keto acids as added-value products. In situ generation of a reactive cyanohydrin was the key to the successful carboxylation reaction under operationally mild reaction conditions (25–40 °C, 1 atm CO₂). The resulting α-keto acids served as a platform for α-amino acid synthesis by reductive amination reactions, illustrating the chemical synthesis of essential bioactive molecules from carbon dioxide.

Full text of DOI:10.1002/anie.201806569

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Title: Umpolung Reactivity of Aldehydes toward Carbon Dioxide
Authors: Martin Juhl and Ji-Woong Lee
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Umpolung Reactivity of Aldehydes toward Carbon Dioxide
Martin Juhl and Ji-Woong Lee*
Abstract: Carbon dioxide is an intrinsically stable molecule.
Therefore, its activation requires extra energy input in the form of
reactive reagents and/or activated catalysts and, often, harsh
reaction conditions. We report here a direct carboxylation reaction of
aromatic aldehydes with carbon dioxide, to afford -keto acids as
added-value products. In situ generation of a reactive cyanohydrin
was key to the successful carboxylation reaction under operationally
mild reaction conditions (25–40 oC, 1 atm CO2). The resulting -keto
acids served as a platform for -amino acid synthesis via reductive
amination reactions, illustrating the chemical synthesis of essential
bioactive molecules from carbon dioxide.
using CO2, the substrate scope is quite limited to activated aryl
and alkyl halides, with the aid of transition metals to generate
reactive carbon-metal bonds.[1] The lack of examples with an
unreactive substrate prompted us to set out our investigation
with electrophilic aldehydes, through an aldehyde umpolung,
mimicking the -ketol rearrangement (B, Scheme 1, bottom).[5]
Such
a reaction would represent a combination of two
electrophilic substrates—carbon dioxide and carbonyl compound
—leading to a formal C1-homologation of aldehydes. Moreover,
the carboxylation of aldehydes would provide -keto acids,
which have been utilized for chemical synthesis of
heterocycles,[6]
bio-conjugation
with
hydroxyamines,[7]
decarboxylative cross- and three-component couplings (e.g.,
Minisci reaction),[8] and biological production of -amino acids[9]
via transamination and reductive amination (Leuckart–Wallach
type).[10] In addition, the use of labeled CO2 gas (11CO2, 13CO2,
and 14CO2) would provide an easy method to access carboxylic
and amino acids with traceability in in vivo and in vitro
systems.[11] Herein, we report the successful direct carboxylation
of aromatic aldehydes by taking advantage of an in situ
generated umpoled aldehyde at 1 atm of CO2 atmosphere, as an
“artificial” CO2 fixation process.[12]
Carbon dioxide functionalization is a crucial step for autotrophic
carbon fixation, where CO2 serves as an abundant and
accessible C1-building block.[1a] To overcome its thermodynamic
stability and kinetic inertness, CO2 functionalization requires
reactive nucleophiles or strain-implemented reactants under
harsh reaction conditions.[1b-d] Therefore, carboxylation of an
unreactive carbon nucleophile with CO2 under mild reaction
conditions remains a formidable challenge.[2] In plants, this
difficulty is typically overcome by performing carbon fixation with
the aid of the Rubisco enzyme[3] (via the Calvin-Benson-
Bassham cycle), which uses ribulose 1,5-biphosphate as a
substrate (Scheme 1, top). The carboxylation occurs via the -
ketol rearrangement of the -hydroxy ketone substrate, thus
generating a transient nucleophile (A) that can react with CO2.
Scheme 2. Potential carboxylation reaction using the Breslow intermediate.
We commenced our investigation by attempting to form
Breslow intermediates of aldehyde
1 with N-heterocyclic
carbenes (NHCs) and thiamine derivatives, to promote a
nucleophilic attack onto the CO2.[13] Although Breslow’s seminal
work demonstrated that carbenes can decarboxylate pyruvate,
we expected that the reverse reaction could occur under a CO2
enriched atmosphere (Scheme 2).[14,15] Despite intensive catalyst
screening (Table S1, Scheme S2), we observed no formation of
the -keto acid (2a), but benzoic acid (4a) was found as a major
byproduct (up to 83% isolated yield).[16] It is still questionable
whether the involvement of CO2 is critical in the oxidation of
aldehydes to carboxylic acids in the presence of NHCs.[16b]
Further optimization revealed that KCN afforded moderate yields
of the desired -keto acid (46%) under 1 atm of CO2 (entry 1,
Table 1), presumably via the cyanohydrin. Interestingly, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (4 equiv.) was essential
to enhance the reaction efficiency, suggesting potential CO2-
DBU interactions (Table S4).[17] Under a nitrogen atmosphere, no
product formation was observed (entry 3, Table 1) confirming
the carboxylation pathway with CO2 in dimethylformamide (DMF)
as a solvent.[18] The use of catalytic amounts of KCN was not
satisfactory, affording 11% conversion to the product (entry 4,
Table 1). Gratifyingly, Ti(OiPr)4 was a successful choice of Lewis
acid, and finally led to a high isolated yield of the product (83%,
entry 5 in Table 1; see SI for further details).
Scheme 1. Carboxylation reactions with CO2 in: 1) Calvin-Benson-Bassham
cycle (top); and 2) aldehyde-umpolung (bottom).
The resulting C6-unit, in turn, undergoes hydrolysis (retro-
Claisen) and affords two molecules of enantiopure
phosphoglycerate for monosaccharide synthesis. The critical
carbon fixation step occurs under the influence of magnesium
Lewis acid, to promote a C-C bond formation reaction with the
CO2.[4]
Despite recent progresses in C-C bond formation reactions
[a]
M. Juhl, Dr. J.-W. Lee
Department of Chemistry, Nano-Science Center
University of Copenhagen
Universitetsparken 5, Copenhagen Ø, 2100, Denmark
E-mail: jiwoong.lee@chem.ku.dk
Supporting information for this article is given via a link at the end of
the document.
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single crystallography, unambiguously confirming our expected
reaction pathway (Scheme 3; see SI for the 13C NMR analysis of
13C-2a).[21]
Table 1. Optimization of the reaction conditions.[a]
Entry
Deviation from standard reaction conditions
Yield[b]
of 2a
1
2
2
3
4
5
None
48%
16%
16%
0%
DBU (1.5 equiv.)
DBU (6 equiv.)
No CO2 (under N2)
KCN (0.1 equiv.)
Ti(OiPr)4 (1 equiv.)
Scheme 3. Mechanistic study of the carboxylation reaction of aldehyde 1a
using 13C-labeled reagents, K13CN, and 13CO2. The structure in the box is the
X-ray single crystal structure of product 2a.
11%
90%
(83%)[c]
The postulated reaction mechanism is shown in Figure 1,
suggesting a catalytic involvement of KCN. However, 1.1
equivalents of KCN were necessary to achieve a high yield of
the product. We observed the formation of the cyanated
ketoacid (E), which could be then subjected to workup
conditions to fully access -keto acids quantitatively without
forming benzoic acid 4 (Figure 1, Tables S7–8). When the
reaction conditions were applied to an isolated cyanohydrin or a
TMS-protected cyanohydrin, the corresponding -keto acids
were obtained in 81% (2b) and 3% (2a) yields, respectively.[22]
This experiment confirms the involvement of the cyanohydrin in
the reaction, while highlighting the importance of the dynamic
nature of cyanohydrin formation in the equilibrium (See SI for
experiments with different counter-cations).[23]
[a] Reaction conditions: Aldehyde 1a (1 mmol), KCN (1.1 mmol) in DMF
(0.5 mL), 1 h at 12 oC. Then DBU (4 mmol) and DMF (0.5 mL) and
Ti(OiPr)4 were added under a CO2 atmosphere (1 atm). The reaction
mixture was stirred at 40 oC for 18 h. [b] The yield was determined by 19F
nuclear magnetic resonance (NMR) (D1; relaxation time = 2 s) of the crude
reaction mixture, and confirmed by isolating the product 2a. [c] Isolated
yield after column chromatography.
To explain the formation of benzoic acid 4a as a byproduct,
product (2a) was subjected to the optimized reaction conditions.
Although -keto acids are prone to decarboxylation reactions in
the presence of nucleophilic carbenes—such as pyruvate
decarboxylase—we observed 94% of the remaining -keto acid
(2a), and 6% of aldehyde 1a was detected (Scheme S3). This
control experiment suggests that the carboxylation reaction is in
principle reversible, but the reversibility can be minimized under
optimized reaction conditions. We also ruled out the hydrolysis
mechanism of the -keto acid to form benzoic acid 4a, which
can be explained by an oxidative reaction pathway.
After establishing the optimal reaction conditions, the
complexity of the reaction (Figure S1) prompted us to investigate
the reaction mechanism. Delany et al. presented a thorough
Figure 1. Proposed mechanism of the aldehyde carboxylation reaction to
-keto acids (2), and possible side reactions.
mechanistic
study
on
“oxygenative”
and
“oxidative”
functionalization of the Breslow intermediate, concluding that
benzoin 3a might be the responsible species for generating
various byproducts.[19] To rule out a potential oxidative reaction
mechanism—hydrolysis of cyanohydrin (C) and the subsequent
oxidation of mandelic acid (D)[20]—which could lead to the -keto
acid (Scheme 3, left side), we used 13C-labeled KCN for the
carboxylation reaction. The resulting -keto acid was free of
isotope enrichment, as revealed by the 13C NMR of both the
crude mixture and the isolated product. To verify the
carboxylation reaction with atmospheric CO2, we used
13C-labeled CO2 under otherwise identical reaction conditions.
This experiment resulted in an 83% yield of the identical product
(13C-2a), with 13C-enriched at the carboxylic acid (> 99%), with a
clear coupling (51 Hz) between 13C(=O)-13C(=O,OH). The
structure of the product (2a) was further determined by X-ray
Given that the benzoin reaction is a main reaction pathway
in the umpolung reaction of aldehydes with NHCs and cyanides,
we presumed that the formation of benzoin 3 was responsible
for the byproducts observed.[24] To verify the hypothesized
reaction mechanism, we subjected isolated benzoin 3a to
different reaction conditions (Table 2; see also Table S18, for
further details). Gratifyingly, under our optimized conditions,
formation of -keto acid 2a was observed (9%) via retro-benzoin
reaction and a subsequent carboxylation reaction, with aldehyde
(1a, retro-benzoin), benzoic acid (4a), and benzil (5a) having
also been identified as byproducts (entry 1, Table 2). The role of
CO2 in the formation of these compounds is still unclear, but we
observed a considerable conversion of benzoin 3a to benzil 5a
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(14%) using only CO2 (entry 2). The benzoin reaction is indeed
reversible in the presence of KCN (entry 3 compared with entry
7), reinforcing the positive role played by KCN in the
carboxylation reaction. Surprisingly, aldehyde 1a was observed
with only DBU (entry 4), while Ti(OiPr)4 alone afforded
exclusively the oxidized product, benzil 5a (entry 5).[25a] The
oxidation reaction prevailed because of the workup procedure,
although all reactions were carried out under strict oxygen-free
conditions.[25b,c] In the presence of CO2, the reverse benzoin
reaction was promoted, but the formation of benzoic acid was
also increased (entry 6). These control experiments once again
emphasize that a combination of the reagents—KCN (entry 7),
DBU (entry 8), and Ti(OiPr)4—in the presence of CO2 is critical
to drive the unprecedented carboxylation reaction of an
aldehyde to an -keto acid.
Grignard reaction pathway. Although aliphatic aldehydes were
also tested, the low acidity of the corresponding cyanohydrins
hampered the reaction with CO2. Severe side reactions—aldol
reaction and condensation—interfered with the carboxylation
and, as such, only trace amounts of the corresponding -keto
acids were observed.[27]
Table 2. Mechanistic study with benzoin 3a.[a]
Entry
Conditions
3a[b]
1a[b]
2a[b]
4a[b]
5a[b]
Figure 2. Substrate scope of -keto acid synthesis from aldehydes and
CO2.aReaction was performed at room temperature.
1
2
3
4
5
6
7
8
Optimized (Table 1)[c]
only CO2
57%
83%
55%
85%
94%
37%
59%
74%
6%
-
9%
10%
2%
9%
3%
-
3%
14%
1%
-
-
-
-
-
-
-
Finally, we turned our attention to providing a novel
retrosynthetic analysis of -amino acids starting from carbon
dioxide and aldehydes. Despite its abundance in prebiotic
environments, CO2 has not hitherto been suggested as a
reactant or chemical building block in the origin-of-life
hypotheses, including -amino acid synthesis. The Sutherland
scenario suggests the importance of cyanide, but disregards the
involvement of CO2 in the chemistry of the prebiotic era.[28] Our
reaction conditions, resembling the primordial soup—CO2, Lewis
acid (Ti), cyanides, and aldehydes—suggest a potential scenario
of -amino acid syntheses. The proposed reaction would
undergo reductive amination with a mild reducing reagent. To
demonstrate this hypothesis, we first performed a large-scale
carboxylation reaction (20 mmol scale, 2.48 gram of 1a)
affording a 92% conversion and 85% isolated yield of 2a, which
was purified without the need for chromatography (Scheme 4).
The corresponding methyl ester (7a) could be converted to the
-amino acid 8a with 81% yield using Na(OAc)3BH as a
reducing reagent, highlighting a new synthetic pathway towards
amino acids from CO2 and aldehydes.
only KCN
9%
5%
-
only DBU
4%
only Ti(OiPr)4
CO2/KCN
6%
22%
Trace
8%
17%
11%
5%
1%
[c]
Ti(OiPr)4/DBU/CO2
14%
7%
[c]
Ti(OiPr)4/KCN/CO2
[a] Reaction conditions: Benzoin 1a (1 mmol) was subjected to the reaction
conditions as indicated, in DMF (1 mL), for 18 h at 40 oC. [b] The yield was
determined by 19F NMR of the crude reaction mixture, and compared with
that obtained after the workup procedure. Each experiment was repeated at
least three times. [c] In the case of reactions with Ti(OiPr)4, the isopropyl
ester of the carboxylic acid (6a) was also found (entry 1: 13%; entry 7: 9%;
entry 8: 3%), but was omitted from the table for clarity. Also see Ref 19.
After establishing the efficient carboxylation strategy for
aldehyde 1a, we evaluated the applicability of the reaction
conditions to various substrates (Figure 2). Electron-rich
aldehydes (1c-e) were well tolerated under these reaction
conditions, affording -keto acids with good isolated yields under
high concentration (1 M, up to 76% yield). More importantly,
halide- (1f-j) and nitrile-containing (1l) aldehydes were smoothly
converted to the products. Generally, -keto acids are accessed
via mono-Grignard reagent addition to oxalic acid diesters, or
through the oxidation of ketones with over-stoichiometric
amounts of SeO2 or CrO3.[26] Our strategy to access -keto acids
from glyoxalates under mild reaction conditions thus circumvents
the need for experimental caution and/or additional
protection/deprotection steps, which are required when using the
In conclusion, we successfully showed a carboxylation
reaction of aldehydes using an umpolung strategy with KCN.
Overcoming the inertness of CO2, we successfully achieved a
direct carboxylation reaction of aromatic aldehydes in the
presence of DBU and Ti(OiPr)4, enabling high selectivity toward
-keto acids. Our mechanistic studies support the importance of
the retro-benzoin reaction to avoid oxidative and oxygenative
functionalization of the Breslow intermediate. Further
investigation of the newly developed reaction will be an
important step toward the expansion of CO2-functionalization
chemistry with high-utility -keto acids (Scheme 4, box). We are
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Kitamura, D. Lee, S. Hayashi, S. Tanaka, M. Yoshimura, J. Org. Chem.
2002, 67, 8685–8687; d) S. N. Mistry, N. Drinkwater, C. Ruggeri, K. K.
Sivaraman, S. Loganathan, S. Fletcher, M. Drag, A. Paiardini, V. M.
Avery, P. J. Scammells, S. McGowan, J. Med. Chem. 2014, 57, 9168–
9183.
currently utilizing this umpolung strategy toward carbon dioxide
under a chiral environment, to mimic the plants’ CBB-cycle.[29]
This will help us expand our knowledge on enzymatic
(de)carboxylation reactions[30] and CO2-chemistry in prebiotic
conditions, to further elucidate the question of the origin of life.
[11] a) H. C. Harsha, H. Molina, A. Pandey, Nat. Protoc. 2008, 3, 505; b) P.
Bjurling, Y. Watanabe, B. Langstrom, Appl. Radiat. Isotopes 1988, 39,
627–630.
[12] K. Tanaka, T. Matsui, T. Tanaka, J. Am. Chem. Soc. 1989, 111, 3765–
3767.
[13] a) R. Breslow, J. Am. Chem. Soc. 1957, 79, 1762–1763; b) R. Breslow,
J. Am. Chem. Soc. 1958, 80, 3719–3726; c) R. Kluger, Chem. Rev.
1987, 87, 863–876.
[14] a) Q. Y. Hu, R. Kluger, J. Am. Chem. Soc. 2002, 124, 14858–14859; b)
Q. Hu, R. Kluger, J. Am. Chem. Soc. 2005, 127, 12242–12243.
[15] The low diffusion barrier of CO2 precludes the C-C bond formation
reaction and conversion is negligible, see: O. M. Gonzalez-James, D. A.
Singleton, J. Am. Chem. Soc. 2010, 132, 6896–6897.
[16] a) L. Gu and Y. Zhang, J. Am. Chem. Soc. 2010, 132, 914–915; b) P.-C.
Chiang, J. W. Bode, Org. Lett. 2011, 13, 2422–2425.
Scheme 4. Large-scale carboxylation of aldehyde, and the reductive
amination reaction to access unnatural -aryl amino acid ester 8a (Ar = 4-F-
C6H4), and the utility of -keto acids.
[17] a) D. J. Heldebrant, P. G. Jessop, C. A. Thomas, C. A. Eckert, C. L.
Liotta, J. Org. Chem. 2005, 70, 5335–5338; b) C. Villiers, J.-P. Dognon,
R. Pollet, P. Thuéry, M. Ephritikhine, Angew. Chem. Int. Ed. 2010, 49,
3465–3468.
Acknowledgements
[18] The reaction is compatible in dimethyl sulfoxide (DMSO) (Table S16),
excluding the involvement of DMF as a C1 source. See examples: a) J.
Kim, J. Choi, K. Shin, S. Chang, J. Am. Chem. Soc. 2012, 134, 2528–
2531; b) A. B. Pawar, S. Chang, Chem. Commun. 2014, 50, 448–450;
c) A. Rusina, A. A. Viček, Nature 1965, 206, 295.
The generous support from the Department of Chemistry,
University of Copenhagen, and from the Novo Nordisk Fonden
(NNF17OC0027598) is gratefully acknowledged. We thank Prof.
Michael Pittelkow, Prof. Mogens Brønsted, and Prof. Morten
Meldal for sharing chemicals and analytical equipment. We also
thank our analytical departments (NMR, GC/MS, LC/MS, HRMS)
and Kristina Eriksen (X-ray analysis) for their kind support.
[19] E. G. Delany, C.-L. Fagan, S. Gundala, K. Zeitler, S. J. Connon, Chem.
Commun. 2013, 49, 6513–6515.
[20] R. Mělnický, M. Grepl, A. Lyčka, V. Bertolasi, L. Kvapil, B. Dvořáková,
P. Hradil, Synthesis 2013, 45, 2447–2457.
[21] CCDC 1856602 contains the crystallographic data for this compound
(2a). This data can be obtained free of charge from The Cambridge
Crystallographic Data Center.
Keywords: Carbon dioxide • Umpolung • -keto acids •
carboxylation • amino acids
[22] For electrochemical generation of reactive intermediates for
carboxylation, see: H. Maekawa, H. Okawara, T. Murakami,
Tetrahedron Lett. 2017, 58, 206–209.
[1]
[2]
a) T. Schwander, L. Schada von Borzyskowski, S. Burgener, N. S.
Cortina, T. J. Erb, Science 2016, 354, 900-904; b) Q. Liu, L. Wu, R.
Jackstell, M. Beller, Nat. Commun. 2015, 6, 5933; c) M. Aresta, A.
Dibenedetto, A. Angelini, Chem. Rev. 2014, 114, 1709–1742; d) V. P.
Indrakanti, J. D. Kubicki, H. H. Schobert, Energy Environ. Sci. 2009, 2,
745–758.
[23] a) Y. He, Y. Xue, J. Phys. Chem. A 2010, 114, 9222–9230; b) M. J.
White, F. J. Leeper, J. Org. Chem. 2001, 66, 5124–5131.
[24] a) V. Nair, V. Varghese, R. R. Paul, A. Jose, C. R. Sinu, R. S. Menon,
Org. Lett. 2010, 12, 2653–2655; b) B. Maji, S. Vedachalan, X. Ge, S. T.
Cai, X. W. Liu, J. Org. Chem. 2011, 76, 3016–3023; c) P. Hirapara, D.
Riemer, N. Hazra, J. Gajera, M. Finger, S. Das, Green Chem. 2017, 19,
5356–5360; d) D. M. Flanigan, F. Romanov-Michailidis, N. A. White, T.
Rovis, Chem. Rev. 2015, 115, 9307–9387. A trace amount of isopropyl
ester (6a, from Ti(OiPr)4 of benzoic acid was observed by analyzing the
crude reaction mixture by GC-MS using the standard reaction
conditions (Scheme S5).
F. Julia-Hernandez, T. Moragas, J. Cornella, R. Martin, Nature 2017,
545, 84.
[3]
[4]
N. J. Claassens, Microb. Biotechnol. 2017, 10, 31–34.
a) R. J. Spreitzer, M. E. Salvucci, Annu. Rev. Plant Biol. 2002, 53, 449–
475; b) G. H. Lorimer, Annu. Rev. Plant Physiol. 1981, 32, 349–382.
D. Seebach, Angew. Chem. Int. Ed. Engl. 1979, 18, 239–258.
S. Seo, M. C. Willis, Org. Lett. 2017, 19, 4556–4559.
[5]
[6]
[7]
[25] a) B. Lou, L. Dai, Youji Huaxue 1990, 10, 357–359; b) S. Kang, C. Joo,
S. M. Kim, H. Han and J. W. Yang, Tetrahedron Lett., 2011, 52, 502–
504; c) S. M. Kim, D. W. Kim, J. W. Yang, Org. Lett. 2014, 16, 2876-
2879.
a) J. W. Bode, Acc. Chem. Res. 2017, 50, 2104–2115; b) J. W. Bode, R.
M. Fox, K. D. Baucom, Angew. Chem. Int. Ed. 2006, 45, 1248–1252.
a) Q.-Q. Wang, K. Xu, Y.-Y. Jiang, Y.-G. Liu, B.-G. Sun, C.-C. Zeng,
Org. Lett. 2017, 19, 5517–5520; b) T. Sehl, S. Bock, L. Marx, Z.
Maugeri, L. Walter, R. Westphal, C. Vogel, U. Menyes, M. Erhardt, M.
Muller, M. Pohl, D. Rother, Green Chem. 2017, 19, 380–384; c) A.
Hossian, M. K. Manna, K. Manna, R. Jana, Org. Biomol. Chem. 2017,
15, 6592–6603; d) H. Feng, D. S. Ermolat’ev, G. Song, E. V. Van der
Eycken, J. Org. Chem. 2011, 76, 7608–7613; e) R. Chen, L. Zeng, B.
Huang, Y. Shen, S. Cui, Org. Lett. 2018, 20, 3377-3380; f) M. K. H. Doll,
J. Org. Chem. 1999, 64, 1372–1374.
[8]
[26] a) H. A. Riley, A. R. Gray, Org. Synth. 1935, 15, 67–69; b) J. Anatol, A.
Medète, Synthesis 1971, 538–539.
[27] For an enzymatic carboxylation of acetaldehyde in aqueous solution,
see: M. Miyazaki, M. Shibue, K. Ogino, H. Nakamura, H. Maeda, Chem.
Commun. 2001, 1800–1801.
[28] B. H. Patel, C. Percivalle, D. J. Ritson, C. D. Duffy, J. D. Sutherland,
Nat. Chem. 2015, 7, 301–307.
[29] a) J. Vaitla, Y. Guttormsen, J. K. Mannisto, A. Nova, T. Repo, A. Bayer,
K. H. Hopmann, ACS Catal. 2017, 7, 7231–7244; b) S. Y. Park, I. S.
Hwang, H. J. Lee, C. E. Song, Nat. Commun. 2017, 8, 14877.
[30] P. V. Attwood, Int. J. Biochem. Cell B 1995, 27, 231–249.
[9]
H. Seo, M. H. Katcher, T. F. Jamison, Nature Chem. 2017, 9, 453–456.
[10] a) R. M. Herbst, D. Rittenberg, J. Org. Chem. 1943, 8, 380–389; b) A. S.
C. Chan, C. C. Chen, Y. C. Lin, Appl. Catal. A. 1994, 119, L1–L5; c) M.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Umpolung,
trêspolung
doispolung
direct carboxylation
and
Martin Juhl and Ji-Woong Lee*
A
Page No. – Page No.
reaction of aromatic aldehydes with
carbon dioxide has been achieved
under mild conditions. Umpolung
reactivity of aldehydes was effective to
tackle the intrinsically stable CO2 in
the presence of KCN, TiIV and DBU.
The obtained -keto acids can
Umpolung Reactivity of Aldehydes
toward Carbon Dioxide
undergo
reductive
amination,
suggesting a potential scenario of
prebiotic syntheses of -amino acids
from CO2 and simple starting
materials.
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