Organocatalytic asymmetric biomimetic transamination of α-keto acetals to chiral α-amino acetals

Article abstract of DOI:10.1039/c3ra42906g

This paper describes a chiral base-catalyzed asymmetric biomimetic transamination of α-keto acetals. A wide variety of α-amino acetals containing various functional groups can be synthesized in 50-85% yield and 82-86% ee.

Full text of DOI:10.1039/c3ra42906g

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Organocatalytic asymmetric biomimetic
transamination of a-keto acetals to chiral a-amino
acetals†
Cite this: RSC Adv., 2014, 4, 2389
a
a
a
ab
Received 12th June 2013
Accepted 7th November 2013
*
Hongjie Pan, Ying Xie, Mao Liu and Yian Shi
DOI: 10.1039/c3ra42906g
www.rsc.org/advances
This paper describes a chiral base-catalyzed asymmetric biomimetic
transamination of a-keto acetals. A wide variety of a-amino acetals
containing various functional groups can be synthesized in 50–85%
yield and 82–86% ee.
Chiral amines are important functional moieties present in
many natural products and pharmaceuticals, and are useful
building blocks in organic synthesis. Various effective methods
have been developed for synthesis of optically active amines.1–3
Asymmetric transamination of ketones presents a straightfor-
ward approach to chiral amines. Great success has been ach-
ieved in biocatalytic transamination.4 Asymmetric biomimetic
transamination has also received considerable attention.5–12
Thus far, the substrates are generally limited to a-keto esters
and a-triuoromethyl ketimines. The isomerization of ketimine
to aldimine is greatly facilitated by the ester and triuoromethyl
groups. Asymmetric transamination of ketones with less
activating groups is highly desirable but still presents a formi-
dable challenge.12
Fig. 1 Selected examples of catalyst examined.
Earlier, we reported an efficient chiral base-catalyzed
biomimetic transamination of a-keto esters to a-amino esters
with o-ClPhCH2NH2 in high ee’s (Scheme 1).8a Recently, we have
Table 1 Studies on catalysts, solvents and acetal groupsa
Entry Catalyst
4
Solvent
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C5
C5
C5
C5
C5
C5
C5
4a, R ¼ Et
4a, R ¼ Et
4a, R ¼ Et
4a, R ¼ Et
4a, R ¼ Et
4a, R ¼ Et
4a, R ¼ Et
4a, R ¼ Et
4a, R ¼ Et
4b, R ¼ Me
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
Cyclohexane 35
ClCH2CH2Cl 12
MeCN
59
13
35
60
65
47
85
14
75
85
85
85
85
55
82
82
76
77
Scheme 1 Chiral base-catalyzed biomimetic transamination.
9
26
69
38
46
aBeijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
10
11
12
Toluene
4c, R ¼ nBu Toluene
4d, R ¼ iBu
Toluene
bDepartment of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
a
All reactions were carried out with a-keto acetals 4 (0.50 mmol),
o-HOPhCH2NH2 (5) (0.75 mmol), and catalyst (0.10 mmol) in solvent
USA. E-mail: yian@lamar.colostate.edu; Fax: +1-970-4911801; Tel: +1-970-4917424
b
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, HPLC data for determination of enantiomeric excesses, and
NMR spectra. See DOI: 10.1039/c3ra42906g
(2.5 mL) at reux for 72 h. Isolated yield based on a-keto acetals 4.
c
The ee’s were determined by chiral HPLC (Chiralpak AD-H column)
aer the amino acetals were converted into their N-benzoyl derivatives.
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Table 2 Catalytic asymmetric transamination of a-keto acetalsa
Entry
1
a-Amino acetalb (6)
Yieldc (%)
eed (%)
85
Scheme 2
65
shown that less activated aromatic ketones can be trans-
aminated with o-HOPhCH2NH2 to form chiral amines with up
to 85% ee.13 In efforts to further expand the substrate scope, we
have explored transamination of a-keto acetals to form optically
active a-amino acetals, which are synthetically useful
compounds.14,15 Herein, we wish to report our preliminary
results on this subject.
6a
6e
6f
2
3
4
85
61
81
84
83
84
Initial studies were carried out with 1,1-diethoxy-heptan-2-
one (4a) as substrate, o-HOPhCH2NH2 (5) as nitrogen donor,
and quinine derivatives (C1–C5) (Fig. 1) as catalysts in reuxing
toluene (Table 1, entries 1–5). Catalyst C5 gave the best result
overall (65% yield and 85% ee) (Table 1, entry 5). Among the
solvents examined (Table 1, entries 5–9), toluene was found to
be optimal. The acetal group has some impact on the enantio-
selectivity (Table 1, entires 5, 10, 11, and 12). The ethyl acetal
gave higher ee than the methyl, n-butyl, and i-butyl acetals.
The asymmetric transamination process can be extended to
a wide variety of a-keto acetals, giving the corresponding
a-amino acetals in 50–85% yield and 82–86% ee (Table 2). The
side chains of amino acetals can contain saturated (Table 2,
entry 1) or unsaturated aliphatic group (Table 2, entry 2),
heteroatoms like O and S (Table 2, entries 3 and 4), and various
aromatic groups (Table 2, entries 5–14). The absolute congu-
ration of 6h was determined by comparing the optical rotation
with the corresponding compound prepared from commercially
available (S)-7 by Swern oxidation,16 the acetal formation,16 and
debenzylation (Scheme 2).17 Alternatively, the absolute cong-
uration of (S)-phenylalaninal diethylacetal (6h) was determined
by converting it into (S)-phenylalanine hydrochloride (13) via
benzoyl protection, deprotection of ethoxy,18 Jones oxidation,19
and deprotection of benzoyl8c,20 as outlined in Scheme 3. A
possible transamination mechanism of a-keto acetals to
a-amino acetals is proposed in Scheme 4.8,11f,13
6g
5
6
7
8
6h, X ¼ H
59
50
54
72
83
82
84
86
6i, X ¼ m-Cl
6j, X ¼ m-Me
6k, X ¼ p-Me
9
6l, X ¼ H
79
66
60
70
84
84
83
85
10
11
12
6m, X ¼ o-F
6n, X ¼ m-Cl
6o, X ¼ p-Cl
13
73
66
82
82
6p
6q
14
a
All reactions were carried out with a-keto acetals 4 (0.50 mmol), o-
HOPhCH2NH2 (5) (0.75 mmol), and catalyst C5 (0.10 mmol) in
b
reuxing toluene (2.5 mL) for 72 h. For entry 5, the absolute
conguration (S) was determined by comparing the optical rotation
with the corresponding amino acetal derived from commercially
available (S)-7 (Scheme 2). The absolute congurations of remaining
c
amino acetals were tentatively proposed by analogy. Isolated yield
d
based on a-keto acetal 4. The ee’s were determined by chiral HPLC
(Chiralpak AD-H column) aer the amino acetals were converted into
their N-benzoyl derivatives.
Scheme 3
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In summary, we have shown that a-keto acetals can be effi-
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82–86% ee with o-HOPhCH2NH2 as nitrogen donor and hydro-
quinine derivative C5 as catalyst. Optically active a-amino
acetals are synthetically useful compounds. The current studies
extend the biomimetic transamination to another class of
carbonyl compounds and further demonstrate its potential for
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Acknowledgements
The authors gratefully acknowledge the National Basic Research
Program of China (973 program, 2010CB833300) and the
Chinese Academy of Sciences for the nancial support.
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