Asymmetric iminium ion catalysis: An efficient enantioselective synthesis of pyranonaphthoquinones and β-lapachones

Article abstract of DOI:10.1002/anie.200705110

(Chemical Equation Presented) An addition-cyclization reaction cascade triggeredby an organocatalyst was used for the enantioselective preparation of a series of biologically active 1,2- and 1,4-pyranonaphthoquinones from aliphatic andaromatic α,β-unsaturated aldehydes and2-hydroxy-1-4- naphthoquinone. A trimethylsilyl-protected diarylprolinol serves as the Lewis base organocatalyst.

Full text of DOI:10.1002/anie.200705110

Communications
DOI: 10.1002/anie.200705110
Organocatalysis
Asymmetric Iminium Ion Catalysis: An Efficient Enantioselective
Synthesis of Pyranonaphthoquinones and b-Lapachones**
Magnus Rueping,* Erli Sugiono, and Estíbaliz Merino
Naphthoquinones are common in the plant kingdom. As a
result of their molecular structure they exhibit redox proper-
ties that influence various regulatory cellular processes. Their
cytotoxic activity is a result of the quinone core structure,
which is an important pharmacophore.[1] Furthermore, a
number of naturally occurring 1,4- and 1,2-naphthoquinones
are associated with diverse biological activities[2] and are
components of antibacterial, fungicidal, antimalarial, anti-
parasitic, and antitumoral agents.[3] Based on their biological
and structural properties, the 1,2- and 1,4-naphthoquinones
are considered privileged structures in medicinal chemistry.
Following previous studies on the activation of aldimines
and carbonyl functionalities with chiral Brønsted acids,[4] we
decided to examine an enantioselective Brønsted acid cata-
lyzed synthesis of 1,2-pyranonaphthoquinones starting from
hydroxynaphthoquinone and a,b-unsaturated aldehydes
[Eq. (1)]. However, in initial experiments we did not obtain
satisfactory results with regard to reactivity and selectivity.
aldehyde 2a could be carried out in the presence of diaryl-
prolinol ethers[7] 4a and 4b in DMSO to give the correspond-
ing 1,2-pyranonaphthoquinone 3a in good yields and excel-
lent enantioselectivities (Table 1, entries 1 and 2).[8] This new
Table 1: Solvent survey of the diarylprolinol ether catalyzed enantio-
selective synthesis of 1,4-naphthoquinones.[a]
Entry[b]
T [8C]
Catalyst
Solvent
Yield [%][d]
ee [%][e]
1
2
3
4
5
RT
RT
0
0
0
4a
4b
4a
4a
4a
4a
4a
4b
4a
4b
DMSO
DMSO
Et2O
86
78
48
24
71
54
76
77
34
69
82
98
90
85
90
66
92
99
92
98
Bu2O
CH2Cl2
toluene
CH2Cl2
CH2Cl2
toluene
toluene
6
0
7[c]
8[c]
9
À20
À20
À20
À20
10[c]
[a] TMS=trimethylsilyl. [b] Reactions were performed with hydroxyqui-
none 1,aldehyde 2a (1.5 equiv) and 20 mol% 4 for 20 h. [c] 40 h.
[d] Yield of isolated product after column chromatography. [e] Enantio-
meric excess was determined by HPLC.
Therefore, we decided to investigate an alternative
reaction with a chiral secondary amine as the organocatalyst.
In contrast to primary amines previously employed, which are
known to lead to the condensation product,[5] we assumed that
it should be feasible to activate a,b-unsaturated aldehydes 2
using secondary amines through the formation of an inter-
mediary iminium ion.[6] The subsequent 1,4-addition reaction
to 2-hydroxy-1,4-naphthoquinone 1, followed by an acetali-
zation should give the corresponding enantiomerically
enriched 1,4-pyranonaphthoquinones 3. The initial experi-
ments showed that the reaction of 1 with the a,b-unsaturated
asymmetric addition–cyclization cascade[9] can also be per-
formed in other solvents, whereby the best enantioselectiv-
ities (up to 99% ee) and yields were obtained with dichloro-
methane as the solvent in combination with catalyst 4b
(Table 1, entry 8).
Further reaction optimization focused on the solvent
concentration and catalyst loading of 4a and 4b (Table 2).
While lower catalyst loadings resulted in slightly reduced
enantioselectivities, the variation of the concentration did not
have any significant influence (Table 2, entries 1–5). Again
catalyst 4b gave the best results when the reaction was carried
out in dichloromethane (0.2m 1, 0.2m 2a) (Table 2, entries 6–
8).
[*] Prof. Dr. M. Rueping,Dr. E. Sugiono,Dr. E. Merino
Degussa Endowed Professorship
Institute for Organic Chemistry and Chemical Biology
Johann Wolfgang Goethe-University Frankfurt am Main
Max-von-Laue Strasse 7,60438 Frankfurt am Main (Germany)
Fax: (+49)69-798-29248
Using the optimized reaction conditions we investigated
the scope of the diarylprolinol ether catalyzed enantioselec-
tive addition–cyclization reaction cascade using various a,b-
unsaturated aldehydes 2 (Table 3). In general, aliphatic
(Table 3, entries 1–6) as well as aromatic (Table 3, entries 7–
15) a,b-unsaturated aldehydes could be employed success-
fully in this new transformation, and a diverse set of 1,4-
E-mail: M.rueping@chemie.uni-frankfurt.de
[**] The authors acknowledge Degussa GmbH and the DFG (Priority
Programme Organocatalysis) for financial support as well the
Ministerio de Educacion y Ciencia,Spain,for a stipend given to E.M.
and Dr. M. Bolte for the X-ray crystal structure analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
3046
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Chemie
Table 2: Effect of catalyst loading and concentration of 1.
Table 4: Transformation of 1,4-naphthoquinones to 1,2-naphthoqui-
nones.
Entry[a]
Catalyst (mol%)
Concentration
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4a (5)
0.2m
0.2m
0.1m
0.2m
0.3m
0.2m
0.2m
0.2m
47
76
53
76
69
40
41
77
87
88
90
92
91
99
99
99
4a (10)
4a (20)
4a (20)
4a (20)
4b (5)
5b
5c
5d
5e
5 f
5g
5h
5j
4b (10)
4b (20)
[a] Reactions were performed with hydroxyquinone 1 and aldehyde 2a
(1.5 equiv). [b] Yield of isolated product after column chromatography.
[c] Enantiomeric excess was determined by HPLC using a Chiralpak AD-
H column.
Table 3: Scope of the diarylprolinol-catalyzed addition–cyclization cas-
cade reaction.
5m
5n
Entry[a]
Product
R
T [8C]
Yield [%][e]
ee [%][f]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3a[b]
3b
3c
3d
3e
CH(CH3)2
C2H5
À20
À20
À20
À20
À20
À20
À20
RT
RT
RT
RT
RT
77
55
75
52
46
43
56
50
57
84
57
49
82
87
51
99
98
99
98
98
99
91
99
99
99
96
95
90
92
93
C3H7
C4H9
C7H15
C10H21
3 f
3g
Ph
3h[c]
3h[d]
3i[d]
3j[d]
3k[d]
3l
2-ClC6H4
2-ClC6H4
2-BrC6H4
2-CH3C6H4
2-CF3C6H4
3-BrC6H4
4-BrC6H4
4-CH3OC6H4
transformed to further interesting derivatives. For instance,
oxidation of 3a with PCC provides the corresponding lactone
6a, which again can be isolated without loss of enantiopurity
(Scheme 1).[10]
With regard to the mechanism, we assume that the
reaction of the diphenylprolinol ether 4 with the a,b-
unsaturated aldehyde 2 results in the intermediary iminium
ion A (Scheme 2). Subsequent 1,4-addition to 2-hydroxy-1,4-
naphthoquinone (1) followed by an isomerization gives rise to
adduct B, which after hydrolysis and acetylization yields the
desired 1,4-naphthoquinone 3 with regeneration of the
catalyst.
0
0
0
3m
3n
[a] Reactions were performed with hydroxyquinone 1,aldehyde
2
(1.3 equiv),and 20 mol% 4b for 3 d. [b] 40 h. [c] 24 h. [d] Performed
with 20 mol% 4a at RT for 24 h. [e] Yield of isolated product after column
chromatography. [f] Enantiomeric excess was determined by HPLC on a
chiral stationary phase.
pyranonaphthoquinones 3a–n was isolated in good yields and
with excellent enantioselectivities (90–99% ee).
Having developed an efficient and highly enantioselective
method for the synthesis of 1,4-pyranonaphthoquinones 3, we
decided to transform the new products to the desired
biologically active 1,2-pyranonaphthoquinones 5 (Table 4).
It was thereby shown that application of sodium borohydride
and concentrated hydrochloric or sulfuric acid resulted in the
corresponding b-lapachone derivatives 5 without loss of
enantiopurity.[10] The 1,4-naphthoquinone 3 can also be
Scheme 1. Oxidation of 1,4-pyranonaphthoquinone 3a. PCC=pyridi-
nium chlorochromate.
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Communications
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Figure 1. X-ray crystal structures of 1,4-naphthoquinone 3j and 1,2-
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Received: November 5, 2007
Published online: March 10, 2008
Keywords: iminium ions · lapachones · Lewis base catalysis ·
.
naphthoquinones · organocatalysis
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Chemie
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[10] A detailed description is given in the Supporting Information.
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