Amino Acid Salt Catalyzed Asymmetric Synthesis of 1,2-Diols with A Quaternary Carbon Center

Article abstract of DOI:10.1055/s-0035-1560179

Enantioenriched 1,2-diols with a quaternary carbon center have great potential in the preparation of natural and biologically active compounds, but remain challenging synthetic targets which demand for both good diastereo- and enantioselectivity. As part

Full text of DOI:10.1055/s-0035-1560179

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2442–2446
letter
2442
Q. Wu et al.
Letter
Synlett
Amino Acid Salt Catalyzed Asymmetric Synthesis of 1,2-Diols with
A Quaternary Carbon Center
Quanquan Wu
Shulei Liu
O
X
CO2
N
Fangyuan Wang
Qingqing Li
Kangli Cheng
Juan Li
H
O
HO
HO
Ar
O
(20 mol%)
OR
+
OH
Ar
OR
conditions
O
O
Jun Jiang*
X = H, 55% yield, 36% ee
X = K, up to 79% yield
45:1 dr, 92% ee
College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou, Zhejiang Province 325035, P. R. of China
junjiang@wzu.edu.cn
Received: 09.06.2015
Accepted after revision: 23.07.2015
Published online: 01.09.2015
unique catalytic activity of amino acid salts in the asym-
metric synthesis of phaitanthrin A, a new type of indolo-
quinazoline alkaloid bearing a quaternary alcohol moiety.6c
Inspired by this result, we became interested in the possi-
bility of amino acid salt catalyzed enantioselective con-
struction of 1,2-diols with a quaternary carbon center from
hydroxyacetone, not only because of their synthetic poten-
tial in the preparation of natural and biologically active
compounds, but also because they are challenging synthetic
targets which demand for both good diastereo- and enanti-
oselectivity. Despite the great successes in direct asymmet-
ric aldol reactions of hydroxyacetone that have been made
in the last decades,7 aldol acceptors are mainly limited to al-
dehydes, while only few examples employed 2,2,2-trifluo-
roacetophenone,8a,b isatin,8b and β,γ-unsaturated α-keto
esters8c as electrophiles under organocatalysis conditions.
In these reports, the quaternary 1,2-diols were obtained in
moderate to good enantioselectivities of up to 90% enantio-
meric excess by the promotion of different amino acid de-
rived amides. Given the importance of chiral quaternary
1,2-diol derivatives and the limited methods for their
preparation, efficient synthesis of such molecules is still
highly sought. Herein, we wish to report an amino acid salt
catalyzed direct aldol reaction between hydroxyacetone
and α-keto esters, which afforded the 1,2-diols with a qua-
ternary carbon center in high diastereo- and enantioselec-
tivities.
DOI: 10.1055/s-0035-1560179; Art ID: st-2015-w0427-l
Abstract Enantioenriched 1,2-diols with a quaternary carbon center
have great potential in the preparation of natural and biologically active
compounds, but remain challenging synthetic targets which demand
for both good diastereo- and enantioselectivity. As part of our continu-
ous effort to explore the unique catalytic activities of amino acid salts in
the asymmetric synthesis, herein, we wish to report an amino acid salt
catalyzed direct aldol reaction between hydroxyacetone and α-keto
esters, which afforded the 1,2-diols with a quaternary carbon center in
high diastereo- and enantioselectivities.
Key words 1,2-diols, quaternary carbon center, amino acid salts,
asymmetric catalysis
Catalytic asymmetric reactions represent one of the
most important methods to obtain enantioenriched organic
molecules and thus received widespread attention over the
last few decades. In this context, great efforts have been de-
voted to develop efficient chiral catalysts with high enan-
tiocontrol; however, the preparation of these catalysts al-
ways required multistep synthesis or expensive starting
materials, both of which obviously hindered the application
of the catalysts. Thus, developing easily prepared, cost-ef-
fective catalysts with high activities is always in high de-
mand. The large amount of natural amino acids existing in
living organisms allows for the rapid development of chiral
ligands,1a,b chiral auxiliaries,1a,c as well as organocatalysts2
in asymmetric catalysis; in contrast, the amino acid metal
salts, which can be easily prepared via neutralization reac-
tion, were much less studied as chiral catalysts though the
limited examples have already revealed their catalytic po-
tential in asymmetric aldol reaction,3 Michael addition4 and
cyanosilylation,5 etc. As our continuous effort to develop
asymmetric transformations for the creation of quaternary
stereogenic centers,6 our recent research demonstrated the
Initially, potassium salts of different amino acids were
employed for the asymmetric aldol reaction between hy-
droxyacetone (2) and methyl benzoylformate (3a). As
shown in Table 1, the structure of the amino acid (Figure 1)
obviously has an influence on the catalytic activity. For ex-
ample, (S)-indoline-2-carboxylic acid, (S)-piperidine-2-car-
boxylic acid, (S)-serine-, and (S)-cysteine-derived potassi-
um salts showed very low catalytic abilities (Table 1, entries
6, 7, 9, 10), while potassium (S)-prolinate was proved to be
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2442–2446

2443
Q. Wu et al.
Letter
Synlett
NH2
CO2K
NH2
CO2K
CO2K
NH2
CO2K
NH2
1a
1b
1f
1c
1d
CO2K
NH2
CO2K
CO2K
N
H
CO2K
CO2K
N
N
H
H
N
H
1e
1i
1g
1h
NH2
NH2
S
S
HS
HO
CO2K
CO2K
CO2K
NH2
N
1j
1k
H
1l
N
PhCO2H⋅H2N
22 mol% + 20 mol%
MeO
CO2
N
CO2H
CO2X
N
2X'
H
N
H
H
1n
1q, X' = Ca
1r, X' = Ba
1o, X = Li
1p, X = Na
1m
N
Figure 1 Catalysts used in this work
the best choice of catalyst, affording the desired 1,2-diol
product with good yield, diastereo- and enantioselectivity
(Table 1, entry 8, 71%, 6:1 dr, 71% ee).
also tested, all of which afforded the desired 1,2-diol prod-
ucts with high diastereo- and enantioselectivities (Table 3,
entries 6–14, 12:1 to 45:1 dr, 87–92% ee). Notably, α-keto
esters containing heteroaromatic rings were also good elec-
trophiles in this aldol reaction, yielded the major diastereo-
mers with good yields and optical purities (Table 3, entries
13 and 14). The stereochemistry of the major diastereomer
of 4j was confirmed by X-ray analysis to have the R,R con-
figuration (Figure 2, for details, please see the Supporting
Information).
In contrast, when (S)-proline was employed as the cata-
lyst, much lower yield and enantioselectivity of the prod-
ucts were observed (Table 1, entry 13). Besides, a chiral pri-
mary amine–Brønsted acid mixture 1n, which was proved
to be the efficient catalytic system in asymmetric aldol re-
action between protected hydroxyacetone and β,γ-unsatu-
rated α-keto esters8d was also tested; however, only disap-
pointing results were obtained (Table 1, entry 14). Subse-
quently, an investigation of the effects of cation species was
carried out, revealing the fact that changing the potassium
ion to other cation species did not lead to an increase in en-
antioselectivity (Table 1, entries 15–18).
Having identified the best catalyst, we next focused on
the evaluation of different reaction conditions. In the pres-
ence of 20 mol% 1h, the reaction between methyl benzoyl-
formate (3a) and five equivalents of hydroxyacetone (2)
proceeded smoothly in various solvents; however, DMF was
found to be superior to other solvents in terms of enantio-
selectivity (Table 2, entries 1–7). Finally, the best compro-
mise between conversion and enantioselectivity was
reached when the reaction was carried out at –10 °C (Table
2, entry 8).
To demonstrate the generality of the protocol, a variety
of α-keto esters were employed as acceptors under optimal
reaction conditions.9 Among different esters, the tert-butyl
ester offered the best yield, diastereo- and enantioselectivi-
ty (Table 3, entry 5), while methyl, ethyl, isopropyl, and
benzyl esters can also participate well in this transforma-
tion with good diastereo- and enantioselectivities (Table 3,
entries 1–4). Subsequently, different tert-butyl esters were
Figure 2 X-ray structure of 4j
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2442–2446

2444
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Letter
Synlett
Table 1 Effects of Catalysts on the Reaction of Hydroxyacetone (2)
and Methyl Benzoylformate (3a)a
Table 2 Optimizing the Reaction Conditionsa
O
O
O
HO
HO
O
cat. 1h
(20 mol%)
O
O
cat. 1
(20 mol%)
HO
O
O
OH +
O
O
HO
O
solvent
r.t., 24 h
OH
+
O
O
MeCN
r.t., 24 h
2
3a
4a
O
2
3a
4a
Entry
Solvent
Yield (%)b
drc
7:1
ee (%)d
Entry
Catalyst
Yield (%)b
drc
ee (%)d
1
CHCl3
THF
65
72
51
60
64
66
73
77
69
60
76
73
80
64
70
74
88
89
1
2
1a
1b
1c
1d
1e
1f
69
3:1
3:1
3:1
–
49
18
29
–
2
3:1
5:1
3:1
7:1
6:1
5:1
10:1
7:1
55
3
DMSO
DMF
3
59
4
4
–
5
toluene
EtOAc
5
71
4:1
–
48
–
6
6
trace
trace
71
7
benzonitrile
DMF
8e
9f
7
1g
1h
1i
–
–
8
6:1
–
71
–
DMF
a Unless otherwise noted, the reaction was carried out with 0.2 mmol meth-
yl benzoylformate (3a), 1 mmol hydroxyacetone (2), and 20 mol% 1h in 0.5
mL solvent at r.t. for 24 h.
9
trace
trace
66
10
11
12
13
14
15
16
17e
18e
1j
–
–
b Isolated yield of the main diastereomer.
1k
1l
3:1
2:1
4:1
2:1
6:1
6:1
6:1
3:1
28
9
c The diastereomeric ratios were determined by NMR analysis.
d Determined by chiral HPLC.
62
e The reaction was carried out at –10 °C.
1m
1n
1o
1p
1q
1r
55
36
3
f The reaction was carried out at –20 °C for 36 h.
12
In accounting for the obtained good yields, diastereo-
71
67
71
54
53
and enantioselectivities, a possible dual activation mecha-
nism of this aldol reaction is proposed. First, hydroxyace-
tone (2) was converted into an enamine in the presence of
catalyst 1h (Scheme 2, TS-1), the hydrogen bond formed
within the enamine enhanced the nucleophilic ability of
hydroxyacetone; meanwhile, the carbonyl of α-keto ester
was efficiently activated by hydrogen bonding as well as
chelating with potassium ion of the catalyst (TS-2); the
subsequent nucleophilic attack of enamine to the carbonyl
group of α-keto ester from Re face led to the aldol adducts 4
with 2R,3R configuration in high diastereo- and enantiose-
lectivities.
In conclusion, we have developed an efficient asymmet-
ric direct aldol reaction between hydroxyacetone and α-
keto esters, in which the simple amino acid salt potassium
(S)-prolinate exhibited outstanding catalytic ability and af-
forded a variety of 1,2-diols with a quaternary carbon cen-
ter in high diastereo- and enantioselectivities. Further ex-
plorations of the utilities of natural amino acid salts in new
asymmetric transformations are continued in our laborato-
ry.
57
41
25
a Unless otherwise noted, the reaction was carried out with 0.2 mmol
methyl benzoylformate (3a), 1 mmol hydroxyacetone (2), and 20 mol% of
catalyst in 0.5 mL MeCN at r.t. for 24 h.
b Isolated yield of the main diastereomer.
c The diastereomeric ratios were determined by NMR analysis.
d Determined by chiral HPLC.
e Conditions: 10 mol% of catalyst were used.
To explore the role of the hydroxyl group of hydroxyace-
tone in the present transformation, methoxyacetone was
employed as nucleophile under optimal conditions
(Scheme 1). The low reactivity of methoxyacetone exhibit-
ed in this aldol reaction reveals the fact that the hydroxyl
group of hydroxyacetone is critical to the success of nucleo-
philic attack in the promotion of amino acid salts.
O
O
O
1h (20 mol%)
no reaction
+
O
Acknowledgment
O
DMF, –10 °C
3e
We are grateful for financial support from NSFC (21472141) and Zhe-
jiang Provincial Natural Science Foundation of China (LY13B020008).
Scheme 1 Amino acid salt catalyzed aldol reaction by employing me-
thoxyacetone as nucleophile
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2442–2446

2445
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Letter
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Table 3 Amino Acid Salt Catalyzed Asymmetric Aldol Reaction be-
tween Hydroxyacetone and Different α-Keto Estersa
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560179.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
O
O
O
HO
HO
Ar
1h (20 mol%)
OR
Ar
+
OH
References and Notes
OR
DMF, –10 °C
O
(1) (a) Blaser, H. U. Chem. Rev. 1992, 92, 935. For a review on amino
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Wittmann, S.; Reiser, O. Chem. Eur. J. 2011, 17, 11024. For amino
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Yamamoto, H. Chem. Commun. 2009, 5412.
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2005, 127, 12224.
O
2
3
4
Entry
Ar
Ph
R
Time (h) Yield (%)b dr (%)c
ee (%)d
1
2
Me
18
16
16
16
16
72
90
16
16
16
16
16
16
16
4a 77
4b 66
4c 73
4d 70
4e 77
4f 77
4g 62
4h, 73
4i 69
10:1
10:1
15:1
10:1
25:1
25:1
25:1
16:1
13:1
12:1
12:1
20:1
45:1
20:1
88
90
90
89
92
90
89
92
91
91
91
92
87
90
Ph
Ph
Ph
Ph
Et
3
i-Pr
4
Bn
5
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
6
4-MeC6H4
7
4-MeOC6H4
4-FC6H4
8
9
4-ClC6H4
4-BrC6H4
4-IC6H4
10
11
12
13
14
4j 66
4k 56
4l 79
β-naphthyl
2-thienyl
2-furyl
4m 78
4n 69
a Unless otherwise noted, the reaction was carried out with 0.2 mmol α-
keto ester 3, 1 mmol hydroxyacetone (2) and 20 mol% 1h in 0.5 mL dry
DMF at –10 °C.
b Isolated yield of the main diastereomer.
c The diastereomeric ratios were determined by NMR analysis.
d Determined by chiral HPLC.
O
OH
2
O
(6) (a) Liu, H.; Wu, H.; Luo, Z.; Shen, J.; Kang, G.; Liu, B.; Wan, Z.;
Jiang, J. Chem. Eur. J. 2012, 18, 11899. (b) Kang, G.; Wu, Q.; Liu,
M.; Xu, Q.; Chen, Z.; Chen, W.; Luo, Y.; Ye, W.; Jiang, J.; Wu, H.
Adv. Synth. Catal. 2013, 355, 315. (c) Kang, G.; Luo, Z.; Liu, C.;
Gao, H.; Wu, Q.; Wu, H.; Jiang, J. Org. Lett. 2013, 15, 4738.
(7) For selected examples, see: (a) Notz, W.; List, B. J. Am. Chem. Soc.
2000, 122, 7386. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F.
III. J. Am. Chem. Soc. 2001, 123, 5260. (c) Tang, Z.; Yang, Z. H.;
Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. Org. Lett. 2004, 6,
2285. (d) Chen, X. H.; Luo, S. W.; Tang, Z.; Cun, L. F.; Mi, A. Q.;
Jiang, Y. Z.; Gong, L. Z. Chem. Eur. J. 2007, 13, 689. (e) Xu, X. Y.;
Wang, Y. Z.; Gong, L. Z. Org. Lett. 2007, 9, 4247. (f) Ramasastry,
S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F. III. J. Am. Chem. Soc.
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J. Am. Chem. Soc. 2007, 129, 3074. (h) Luo, S.; Xu, H.; Zhang, L.;
Li, J.; Cheng, J.-P. Org. Lett. 2008, 10, 653. (i) Wu, X. Y.; Ma, Z. X.;
Ye, Z. Q.; Qian, S.; Zhao, G. Adv. Synth. Catal. 2009, 351, 158.
(j) Li, J.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2009, 74, 1747.
(k) Popik, O.; Pasternak-Suder, M.; Leśniak, K.; Jawiczuk, M.;
Górecki, M.; Frelek, J.; Mlynarski, J. J. Org. Chem. 2014, 79, 5728.
O–
H
K+
N
CO2K
N
H
O
TS-1
1h
O
O
OR
Ar
OH
OH
O
O
3
RO2C
O– K+
4
N
Ar
O
O
H
CO2R
TS-2
Scheme 2 Proposed mechanism of amino acid salt catalyzed asym-
metric aldol reaction between hydroxyacetone and α-keto esters
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2442–2446

2446
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(8) (a) Kokotos, C. G. J. Org. Chem. 2012, 77, 1131. (b) Tanimura, Y.;
Yasunaga, K.; Ishimaru, K. Tetrahedron 2014, 70, 2816. (c) Guo,
W.; Wei, J.; Liu, Y.; Li, C. Tetrahedron 2014, 70, 6561. For selected
example of asymmetric aldol reaction between protected
hydroxyacetone and β,γ-unsaturated α-keto esters, see: (d) Liu,
C.; Dou, X.; Lu, Y. Org. Lett. 2011, 13, 5248.
(9) General Experimental Procedures for the Synthesis of 4
α-Keto esters 3 (0.2 mmol), catalyst 1h (20 mol%), and dry DMF
(0.5 mL) were added to a tube. The mixture was stirred at –10 °C
for 10 min, then hydroxyacetone (2, 1 mmol) was added drop-
wise, and the resulting mixture was stirred at this temperature
for specific time until the reaction was completed. The reaction
mixture was purified through flash column chromatography on
a silica gel (eluent: PE–EtOAc = 10:1 to 5:1) to yield the target-
ing products.
Data of Compound 4e
C
15H20O5, 43.3 mg, 77% yield, white solid, 92% ee, 25:1 dr;
[α]D21 –0.8 (c 0.33 in CH2Cl2). HPLC: DAICEL CHIRALCEL AD-H,
2-PrOH–n-hexane= 15:85, flow rate = 1.0 mL/min, λ = 254 nm,
tR (minor) = 8.8 min; tR (major) = 10.6 min. 1HNMR (500 MHz,
CDCl3): δ = 7.80–7.82 (m, 2 H), 7.40–7.43 (m, 2 H), 7.34–7.37
(m, 1 H), 4.88 (d, J = 5 Hz, 1 H), 4.08–4.10 (m, 2 H), 1.58 (s, 3 H),
1.50 (s, 9 H). 13CNMR (126 MHz, CDCl3): δ = 27.8, 27.9, 80.2,
81.9, 84.4, 126.3, 128.4, 128.5, 137.9, 171.4, 205.2. IR (KBr): γ =
3497, 2974, 2352, 1716, 1252, 1162, 844, 751, 735, 700, 650
cm–1
[C15H20NaO5]+: 303.1208; found: 303.1217.
.
HRMS (Micromass GCT–MS ESI): m/z calcd for
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2442–2446