Biomimetic catalytic enantioselective decarboxylative aldol reaction of β-ketoacids with trifluoromethyl ketones

Article abstract of DOI:10.1039/c2cc30949a

We disclose an organocatalyzed enantioselective decarboxylative ketone aldol reaction of β-ketoacids with trifluoromethyl ketones in the presence of biscinchona alkaloid (DHQD)₂AQN, affording chiral tertiary alcohols in up to 98% yield and 90% ee. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc30949a

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COMMUNICATION
Biomimetic catalytic enantioselective decarboxylative aldol reaction
of b-ketoacids with trifluoromethyl ketoneswz
Yan Zheng, Heng-Ying Xiong, Jing Nie, Ming-Qing Hua and Jun-An Ma*
Received 9th February 2012, Accepted 9th March 2012
DOI: 10.1039/c2cc30949a
We disclose an organocatalyzed enantioselective decarboxylative
mild conditions. Furthermore, our preliminary investigation into
the mechanism of this transformation suggests a stepwise process
involving nucleophilic addition of b-ketoacid to the trifluoromethyl
ketone followed by a subsequent decarboxylation reaction.
In an initial investigation, we conducted the decarboxylative
aldol reaction of 3-oxo-3-phenylpropanoic acid 1a with 2,2,2-
trifluoroacetophenone 2a by employing triethylamine as an
organocatalyst to afford the desired product 3a in 48% isolated
ketone aldol reaction of b-ketoacids with trifluoromethyl ketones in
the presence of biscinchona alkaloid (DHQD) AQN, affording
2
chiral tertiary alcohols in up to 98% yield and 90% ee.
Nature uses enzymatic activation of malonic acid half thioesters
(MAHTs) via decarboxylative transformation for the biosynthesis
of polyketides and fatty acids. Aspiring to imitate this biocatalytic
1
9
yield. In addition, a significant amount of acetophenone,
process, organic chemists have succeeded in developing a host of
asymmetric catalytic systems to demonstrate the synthetic useful-
ness of deployment of direct decarboxylative additions in enantio-
generated through decarboxylative protonation of 1a, was
recovered in this case. Therefore, we tried slow addition of
2.0 equiv. of 1a to a mixture of the catalyst and 2a. As expected,
the yield was improved to 98% even in the presence of catalytic
triethylamine (20 mol%). Next, a series of natural chiral
cinchona alkaloids and commercially available biscinchona
2–5
selective carbon–carbon bond-forming reactions.
Nearly all
such studies have focused on the two-carbon extension asymmetric
transformations of thioester enolates and their equivalents. In
sharp contrast, the biomimicry of b-ketoacid decarboxylation for
the asymmetric introduction of synthetically useful keto-carbonyl
groups remains largely untapped. The lack of progress may be
attributed to the unimolecular decomposition of b-ketoacids and
the difficulty of stereochemical control as compared to thioester
enolates and ester enolates. One example of asymmetric decarboxy-
lative reaction of b-ketoacids came from Evans and co-workers,
who reported a nickel-catalyzed addition of b-ketoacids to
alkaloids were tested (Fig. 1). It was found that (DHQD)
was the most promising catalyst for the model reaction
Table 1, entry 7), whereas all the other chiral bases tested
2
AQN
(
resulted in low enantioselectivities (entries 1–6 and 8). In
addition, the solvent was found to have an important effect
on the reactivity (entries 9–12). Among the solvents tested, THF
was found to be the best with respect to catalytic activity
and asymmetric induction. Substantial decrease in reaction
temperature revealed that the enantioselectivity can be signifi-
cantly improved from 63% ee (entry 7) to 85% and 90% ee
6
nitroalkenes to afford the enantiomerically enriched adducts.
Mahrwald and Rohr described an asymmetric decarboxylative
aldol reaction of b-ketoacids, but the use of chiral aldehydes is a
prerequisite for asymmetric induction. Accordingly, the direct
7
catalytic enantioselective decarboxylative ketone aldol reaction of
b-ketoacids for the synthesis of chiral tertiary alcohols has not
been reported so far, and thus remains an important challenge.
8
Asymmetric organocatalysis, where small organic molecules
catalyze the reactions without the presence of any metal, has
become an attractive strategy in organic synthesis. Herein we
report details of our discovery of the first enantioselective
decarboxylative ketone aldol reaction of b-ketoacids catalyzed
in the absence of metal ions. We found that the cinchona
alkaloid-derived organocatalysts promote the decarboxylative
aldol reactions of b-ketoacids with trifluoromethyl ketones under
Department of Chemistry, Tianjin University, Tianjin 300072, China.
E-mail: majun_an68@tju.edu.cn; Fax: +86-22-2740-3475
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
Fig. 1 Cinchona alkaloids tested in the decarboxylative aldol reaction
of b-ketoacid 1a with trifluoroacetophenone 2a.
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc30949a
4
308 Chem. Commun., 2012, 48, 4308–4310
This journal is c The Royal Society of Chemistry 2012

a
Table 1 Optimization of conditions for the decarboxylative aldol
reaction
Table 2 Scope of the enantioselective decarboxylative aldol reaction
a
b
c
Entry
1
Product
Yield (%)
ee (%)
Temp (1C)/ Yield ee
b
c
Entry Catalyst (mol%)
Solvent Time (h)
(%)
(%)
3a
3b
3c
96
90
82
80
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
Quinine (20)
THF
THF
THF
THF
THF
0/12
0/12
0/12
0/12
0/12
0/12
0/12
0/12
88
88
87
86
88
73
95
96
46
25
0
6 (+)
01 4 (ꢀ)
Quinidine (20)
Cinchonine (20)
Cinchonidine (20)
6 (+)
38 (ꢀ)
8 (ꢀ)
63 (ꢀ)
36 (+)
23 (ꢀ)
15 (ꢀ)
0
2
3
4
5
6
97
93
94
86
63
(DHQD)
(DHQD)
(DHQD)
2
2
2
PYR (20)
PHAL (20) THF
AQN (20) THF
(DHQ) AQN (20)
2
THF
(DHQD)
(DHQD)
(DHQD)
(DHQD)
(DHQD)
(DHQD)
(DHQD)
(DHQD)
2
2
2
2
2
2
2
2
AQN (20) toluene 0/12
AQN (20) Et
0
1
2
3
4
5
6
2
O
0/12
0/12
AQN (20) CH
AQN (20) CH
AQN (20) THF
AQN (20) THF
AQN (20) THF
AQN (10) THF
2 2
Cl
3
CN 0/12
0
0
3d
3e
3f
76
80
72
ꢀ20/24
ꢀ40/28
ꢀ60/48
ꢀ20/48
97
96
53
88
85 (ꢀ)
90 (ꢀ)
90 (ꢀ)
87 (ꢀ)
a
The reaction was carried out with b-ketoacid 1a (0.2 mmol) and
trifluoromethyl ketone 2a (0.1 mmol) in THF (0.6 mL). Isolated
b
c
yield. Enantiomeric excess was determined by chiral HPLC analysis.
(
entries 13 and 14). Further changes in reaction temperature
and the amount of catalyst did not have any significant effect on
the enantioselectivity; however, reduced yields were observed,
even with prolonged reaction times (entries 15 and 16).
7
8
9
3g
3h
3i
80
72
60
74
75
85
With the optimized reaction conditions in hand, the scope of
this organocatalytic enantioselective decarboxylative aldol reaction
was examined by varying both b-ketoacids and trifluoromethyl
ketones. The results are summarized in Table 2. Most of the
trifluoromethylated tertiary alcohols were obtained in high yields
with the range of 64–90% ee (entries 1–5 and 10–14). However, by
contrast, the substituent at the 2-position of the aryl rings has a
little effect on the reactivity. These reactants gave the aldol
products in moderate to good yields (entries 6–9, 15, and 16).
When 1,1,1-trifluoroacetone was employed, the desired
product was also obtained in 94% yield with 64% ee
1
1
1
0
1
2
3j
85
98
97
65
65
64
3k
3l
1
0
(
entry 17). It is noteworthy that the reaction worked well with
1,1,1-trifluoro-4-phenylbut-3-yn-2-one to give the 1,2-adduct
in high yield and moderate enantioselectivity (entry 18).
In addition, we investigated the decarboxylative aldol reaction
of alkyl-substituted b-ketoacids including 3-oxobutanoic acid,
3-oxopentanoic acid, and 3-cyclopropyl-3-oxopropanoic acid
with 2,2,2-trifluoroacetophenone 2a. These substrates were found
to be unsuitable for this asymmetric transformation and no
desired products were observed.
13
3m
3n
95
92
78
72
An organocatalytic decarboxylative aldol experiment on a
mmol scale of 2a was also carried out with 1a, and the
1
1
1
4
5
6
2
condensation product 3a was obtained with excellent optical
purity after single recrystallization from CH Cl /hexane
2
2
3o
3p
60
60
60
62
(Scheme 1). Furthermore, the organocatalyst was recovered
in almost quantitative yield and reused without any loss of
1
1
reactivity and enantioselectivity. In addition, the absolute
configuration of 3a was determined to be R by comparison
with the sign of optical rotation of the deprotected compound
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4308–4310 4309

Table 2 (continued )
Entry Product
salt to trifluoromethyl ketones gave the addition intermediate,
followed by the decarboxylation to afford the desired aldol
product (Fig. 2b).
b
c
Yield (%)
ee (%)
In conclusion, we have successfully developed the first
organocatalyzed enantioselective decarboxylative ketone
aldol reaction of b-ketoacids with trifluoromethyl ketones by
employing chiral cinchona alkaloids as efficient catalysts. A
series of chiral trifluoromethyl-substituted tertiary alcohols
were obtained in good to high yields (60–98%) and enantio-
selectivities (60–90% ee). Further investigations to understand
the mechanism and to improve the enantioselectivity are
underway.
1
7
3q
3r
94
64
18
98
61
a
The reaction was carried out with b-ketoacid 1a (0.2 mmol) and
trifluoromethyl ketone 2a (0.1 mmol) in THF (0.6 mL), using 20%
b
c
(DHQD)
excess was determined by chiral HPLC analysis.
2
AQN at ꢀ40 1C for 28 h. Isolated yield. Enantiomeric
This work was supported financially by the National
Natural Science Foundation of China (NSFC) (No. 20972110
and 20902067).
Notes and references
1
2
3
J. Staunton and K. J. Weissman, Nat. Prod. Rep., 2001, 18, 380.
For a review, see: Y. Pan and C.-H. Tan, Synthesis, 2011, 2044.
For the catalytic enantioselective decarboxylative aldol reactions
of MAHTs and their equivalents, see: (a) S. Orlandi, M. Benaglia
and F. Cozzi, Tetrahedron Lett., 2004, 45, 1747; (b) D. Magdziak,
G. Lalic, H. M. Lee, K. C. Fortner, A. D. Aloise and M. D. Shair,
J. Am. Chem. Soc., 2005, 127, 7284; (c) K. C. Fortner and
M. D. Shair, J. Am. Chem. Soc., 2007, 129, 1032;
(
d) D. J. Schipper, S. Rousseaux and K. Fagnou, Angew. Chem.,
Int. Ed., 2009, 48, 8343; (e) J. Baudoux, P. Lefebvre, R. Legay,
M.-C. Lasne and J. Rouden, Green Chem., 2010, 12, 252;
Scheme 1 Scaled-up version of the decarboxylative aldol reaction,
(
f) N. Hara, S. Nakamura, Y. Funahashi and N. Shibata, Adv.
and further transformation.
Synth. Catal., 2011, 353, 2976; (g) X.-J. Li, H.-Y. Xiong,
M.-Q. Hua, J. Nie, Y. Zheng and J.-A. Ma, Tetrahedron Lett.,
2
012, 53, 2117.
4
5
For the catalytic enantioselective decarboxylative Mannich reac-
tions of MAHTs and their equivalents, see: (a) A. Ricci,
D. Pettersen, L. Bernardi, F. Fini, M. Fochi, R. P. Herrera and
V. Sgarzani, Adv. Synth. Catal., 2007, 349, 1037; (b) L. Yin,
M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 9610;
(c) Y. Pan, C. W. Kee, Z. Jiang, T. Ma, Y. Zhao, Y. Yang, H. Xue
and C.-H. Tan, Chem.–Eur. J., 2011, 30, 8363.
For the catalytic enantioselective decarboxylative Michael addition
reactions of MAHTs and their equivalents, see: (a) J. Lubkoll and
H. Wennemers, Angew. Chem., Int. Ed., 2007, 46, 6841;
(
b) M. Furutachi, S. Mouri, S. Matsunaga and M. Shibasaki,
Chem.–Asian J., 2010, 15, 2351; (c) H. Y. Bae, S. Some, J. H. Lee,
J.-Y. Kim, M. J. Song, S. Lee, Y. J. Zhang and C. E. Song,
Adv. Synth. Catal., 2011, 353, 3196.
6 D. A. Evans, S. Mito and D. Seidel, J. Am. Chem. Soc., 2007,
129, 11583.
1
9
Fig. 2 (a) F NMR monitoring of the reaction mixture of b-ketoacid
a, trifluoromethyl ketone 2a, and NEt in THF-d as a function of time
1
3
8
7
8
K. Rohr and R. Mahrwald, Org. Lett., 2011, 13, 1878.
For selected reviews, see: (a) B. List, Tetrahedron, 2002, 58, 5573;
at 0 1C; (b) proposed mechanism for the organocatalytic decarboxylative
aldol reaction of b-ketoacids with trifluoromethyl ketones.
(
b) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004,
1
0
43, 5138; (c) W. Notz, F. Tanaka and C. F. Barbas III., Acc. Chem.
Res., 2004, 37, 580; (d) Asymmetric Organocatalysis, ed.
A. Berkessel and H. Grcger, Wiley-VCH, New York, 2005;
(e) Enantioselective Organocatalysis, ed. P. I. Dalko, Wiley-VCH,
Weinheim, 2007; (f) S. Mukherjee, J. W. Yang, S. Hoffmann and
B. List, Chem. Rev., 2007, 107, 5471.
For the achiral decarboxylative aldol reactions with metal catalysts
and organocatalysts, see: (a) M. Stiles, D. Wolf and G. V. Hudson,
¨
J. Am. Chem. Soc., 1959, 81, 628; (b) H. Brunner, J. Muller and
reported in the literature. Further reduction of enantio-
enriched 3a in the presence of NaBH gave trifluoromethylated
4
diols 4 and 5 (1 : 1 dr), which were easily isolated through
silica gel column chromatography in 98% yield with excellent
enantiomeric purities (98% ee).
9
1
9
It was noteworthy that F NMR analysis of the reaction
progress between 1a and 2a with triethylamine in THF-d8
revealed the appearance of a new peak (at ꢀ85.05 ppm) that
J. Spitzer, Monatsh. Chem., 1996, 127, 845; (c) T. Kourouli,
P. Kefalas, N. Ragoussis and V. Ragoussis, J. Org. Chem., 2002,
1
2
was tentatively assigned as the reaction intermediate (A).
6
7, 4615; (d) G. Lalic, A. D. Aloise and M. D. Shair, J. Am. Chem.
With the disappearance of this intermediate A and the reactant
Soc., 2003, 125, 2852; (e) N. Blaquiere, D. G. Shore, S. Rousseaux
and K. Fagnou, J. Org. Chem., 2009, 74, 6190.
0 Z.-J. Liu, Y.-Q. Mei and J.-T. Liu, Tetrahedron, 2007, 63, 855.
1 The recycling and reuse of (DHQD)AQN in the model reaction:
product 3a was obtained in 97% yield with 89% ee.
2
a (ꢀ72.35 ppm) from the catalytic system, the aldol product
a (at ꢀ80.95 ppm) was formed (Fig. 2a). Based on these
1
1
3
preliminary results, a stepwise process could be involved in the
catalytic cycle, in which nucleophilic addition of the ketoacid
12 All attempts to isolate this postulated intermediate failed.
4
310 Chem. Commun., 2012, 48, 4308–4310
This journal is c The Royal Society of Chemistry 2012