An N,N′-dioxide/In(OTf)3 catalyst for the asymmetric hetero-Diels-Alder reaction between Danishefsky's dienes and aldehydes: Application in the total synthesis of triketide

Article abstract of DOI:10.1002/anie.200704759

(Chemical Equation Presented) In-teresting catalyst: An asymmetric hetero Diels-Alder reaction between Danishefsky's dienes and various aldehydes using an N,N′-dioxide/In(OTf)₃ complex affords highly substituted chiral dihydropyranones with up

Full text of DOI:10.1002/anie.200704759

Communications
DOI: 10.1002/anie.200704759
Asymmetric Catalysis
An N,N’-Dioxide/In(OTf)3 Catalyst for the Asymmetric Hetero-Diels–
Alder Reaction Between Danishefskyꢀs Dienes and Aldehydes:
Application in the Total Synthesis of Triketide**
Zhipeng Yu, Xiaohua Liu, Zhenhua Dong, Mingsheng Xie, and Xiaoming Feng*
Table 1: The asymmetric HDA reaction of benzaldehyde with diene 1
Highly substituted dihydropyranones are key structural
elements in many bioactive natural products and important
catalyzed by N,N’-dioxide/In(OTf)3 complexes.[a]
pharmaceuticals,[1] and asymmetric hetero-Diels–Alder
(HDA) reactions between Danishefskyꢀs dienes and carbonyl
compounds have been shown to be the most powerful and
straightforward approach to these optically active dihydro-
pyranones.[2] Great effort has been devoted to this area in the
last two decades and a number of successful methods have
been reported.[2,3] Despite these excellent catalysts, however,
InIII, which is a strong activator of carbonyl compounds, has
rarely been employed as an asymmetric catalyst of these
reactions,[4] therefore the development of InIII-based catalysts
is of great potential interest. N,N’-Dioxide/metal complexes
are excellent chiral scaffolds,[5,6] especially for metals such as
indium,[4d] cadmium,[5b] copper,[5d,e] and scandium,[5c] and have
exhibited great potential in many asymmetric reactions.
Herein we present a novel and efficient chiral catalyst
system based on N,N’-dioxide/In(OTf)3 complexes and its
application in the asymmetric HDA reaction.
Our preliminary investigation revealed that treatment of
2a with diene 1 (1.5 equiv) in the presence of 5 mol% of an
aromatic amide derived N,N’-dioxide/In(OTf)3 (1:1) complex
(Table 1, entries 1–8) in THF gave compounds (2S,3S)-3a
(16–84% ee) as the major HDA product. A similar reaction in
the presence of aliphatic amide derived complexes (Table 1,
entries 9–12) showed the opposite stereoinduction and gave
(2R,3R)-3a (20–66% ee) as the major product. As for the
chiral backbone moiety, (S)-pipecolic acid derived N,N’-
dioxides (Scheme 1) were found to be superior to l-proline
derived ones (up to 84% ee; entries 1 vs. 2 and 6 vs. 8 in
Table 1). These results indicate that a three-carbon linkage is
best. Although a five-carbon linkage affords a comparable
Entry
L
x
Solvent
Yield
[%][b]
trans/cis
ee
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13[e]
14[e]
15[f]
16[f]
17[f]
18[f,g]
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L12
L8
L8
L8
L8
L8
L8
5
5
5
5
5
5
5
5
5
5
5
5
2.5
1
5
5
5
5
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
tBuOMe
m-xylene
PhOMe
PhOMe
55
64
54
48
50
61
11
54
56
37
80
73
52
<5
85
86
93
96
1:3
1:3.7
1:4.7
1:4.3
1:3.2
1:2.1
1:7.5
1:1.2
1:1.8
1:1.3
1:4.2
1:2.8
1:1.2
n.d.
28
53
52
16
47
74
77
84
20[d]
54[d]
39[d]
66[d]
84
80
96
84
97
1:6
<1:20
1:15
<1:20
98
[a] Unless otherwise noted, the reactions were performed with N,N’-
dioxide/In(OTf)3 (1:1) complexes prepared in situ at 08C for 48 h
(0.25m). TFA=Trifluoro acetic acid. [b] Yield of isolated cis isomer.
[c] Configuration of cis isomer was (2S,3S) as determined by HPLC.
[d] (2R,3R) configuration. [e] Reaction time: 72 h. [f] The catalyst was
pre-prepared (0.125m). [g] 4-Š molecular sieves were added.
[*] Z. Yu, X. Liu, Z. Dong, M. Xie, Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology (Sichuan
University), Ministry of Education, College of Chemistry, Sichuan
University
Chengdu 610064 (P.R. China)
Fax: (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
Prof. Dr. X. Feng
State Key Laboratory of OralDiseases, Sichuan University
Chengdu 610041 (P.R. China)
[**] We are gratefulto the NationalNaturalScience Foundation of China
(grant Nos. 20732003 and 20472056) for financialsupport. We asl o
thank the Sichuan University Analytical & Testing Center for
performing the NMR analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. N,N’-Dioxide ligands evaluated.
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Angew. Chem. Int. Ed. 2008, 47, 1308 –1311

Angewandte
Chemie
enantioselectivity and better diastereoselectivity, the yield of
the reaction is very poor (Table 1, entry 6 vs. entries 5 and 7).
Accordingly, the sterically hindered amide L8 was chosen as
the most promising ligand. Reducing the catalyst loading to
1 mol% produced no significant loss in ee value but the
overall yield was lower (Table 1, entries 13 and 14).
A remarkable improvement was achieved by varying the
reaction solvent. THF was used to prepare the catalyst in situ
and then replaced by a different reaction solvent.[7] Thus,
tBuOMe showed excellent enantioselectivity (up to 96% ee,
Table 1, entry 15), while m-xylene showed excellent diaste-
reoselectivity (up to 1:20; Table 1, entry 16). Anisole appears
to combine the merits of tBuOMe and m-xylene (up to
97% ee and 1:15 d.r.; Table 1, entry 17), although the best
result was obtained upon adding 4-Š molecular sieves
(Table 1, entry 18).[8]
A wide range of aromatic, aliphatic, and heterocyclic
aldehydes were investigated under the optimized conditions
and trisubstituted dihydropyranones 3 were obtained with
excellent enantioselectivity (up to 99% ee) and high diaste-
reoselectivity (Table 2, entries 1–31). Significantly, m-hydrox-
ybenzaldehyde, which has a reasonably acidic hydroxy group,
undergoes an HDA reaction to afford the product with up to
96% ee and 1:20 d.r. (Table 2, entry 23). It is noteworthy that
the system L8/In(OTf)3 leads to excellent enantioselectivities
for the HDA reactions between diene 1 and aliphatic
aldehydes (up to 98% ee; Table 2, entries 24–31), which
could allowthe preparation of various key natural-product
frameworks, especially those of beetle pheromone.[1a–c]
To extend the diene scope, our further examination of the
substrate generality focused on the HDA reaction of diene 4
and several representative aldehydes. The results in Table 3
showthat the reactions with aromatic aldehydes furnish the
dihydropyranones in more than 92% yield and up to 98% ee
in a shorter time (Table 3, entries 1–4),[3m] although the
ee values obtained with straight-chain aliphatic aldehydes
are not so good (Table 3, entries 5–7). The a-branched
aliphatic aldehyde (Table 3, entry 8) shows a high reactivity
(up to 82% yield) and good enantioselectivity (up to 92% ee),
and the HDA reaction with (E)-cinnamaldehyde gave a
quantitative yield and up to 97% ee (Table 3, entry 9).
From a practical point of view, the catalyst stability was
determined on a gram scale by mixing L8/In(OTf)3 with 4-Š
molecular sieves in THF and removing the solvent to give a
stable white solid. The activity of the catalyst was found to
remain unchanged even after more than half a year.[9]
We applied this reaction to the synthesis of triketide in an
effort to showits practical utility. [1f,g,10] Our approach involved
the addition of diene 1 to 2aa on a sub-gram scale catalyzed
Table 2: Substrate scope of the asymmetric HDA reaction with diene 1
and L8/In(OTf)3 as catalyst.[a]
Entry
R
Yield [%][b]
trans/cis
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
96 (3a)
89 (3b)
98 (3c)
80 (3d)
93 (3e)
84 (3 f)
96 (3g)
97 (3h)
33 (3i)
96 (3j)
90 (3k)
96 (3l)
83 (3m)
90 (3n)
<1:20
<1:20
<1:20
1:4[d]
98 (2S,3S)
4-ClC6H4
3-ClC6H4
2-ClC6H4
3,4-Cl2C6H3
2,4-Cl2C6H3
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-FC6H4
4-BrC6H4
3-BrC6H4
4-NO2C6H4
3-NO2C6H4
98
99
78
99
90
98
97
93
99
96
97
95
97
1:16
1:8[d]
<1:20
<1:20
n.d.
<1:20
1:16
<1:20
1:10
1:20
15
83 (3o)
1:18
98
16
17
18
19
20
21
22
23
4-MeOC6H4
1-naphthyl80 (
2-naphthyl91 (
3-PhOC6H4
4-PhC6H4
4-PhCH2C6H4
2-furyl89 (
3-HOC6H4
Et
66 (3p)
3q)
1:3
1:10
<1:20
<1:20
1:17
92
98
96
98
97
98
99
96
Table 3: Substrate generality of the asymmetric HDA reactions of diene 4
with L8/In(OTf)3 as catalyst.[a]
3r)
95 (3s)
81 (3t)
55 (3u)
3v)
96 (3w)
70 (3aa)
20 (3ab)
52 (3ac)
1:10
1:9[d]
1:20[d]
1:9
24[e]
25[e]
26[e]
98[f]
96[f]
98[f]
Entry
R
t [h]
Yield [%][b]
ee [%][c]
iBu
nBu
n.d.
1:10
1
2
3
4
5
6
7
8
Ph
30
99 (5a)
5b)
97 (5c)
99 (5d)
82 (5e)
5 f)
98
88
84
95
80
81
81
92
27[e]
58 (3ad)
1:10
98[f]
1-naphthyl30
2-ClC6H4
3-ClC6H4
Et
pentyl32
hexyl32
cyclohexyl
92 (
28[e]
29[e]
30
pentyl52 (
hexyl52 (
cyclohexyl
3ae)
3af)
33 (3ag)
1:11
1:12
n.d.
97[f] (2R,3S)
24
24
32
76 (
95 (
98[f]
98
31
92 (3ah)
1:17
98 (2R,3S)
5g)
82 (5h)
32
[a] Unless otherwise noted, all reactions were carried out with aldehyde
(0.25 mmol) and diene 1 (1.5 equiv) in PhOMe (2.0 mL) at 08C for 48 h.
The catalyst was pre-prepared in the presence of 4-Š molecular sieves.
[b] Yield of cis isomer isolated. [c] Determined by HPLC. [d] d.r.
determined by HPLC. The absolute configurations were determined by
comparison with literature data.[3l] [e] Reaction time: 60 h. [f] Determined
by GC.
9
30
99 (5i)
97
[a] Unless otherwise noted, all reactions were carried out with aldehyde
(0.25 mmol) and diene 4 (1.5 equiv) in PhOMe (2.0 mL) at 08C. The
catalyst was pre-prepared in the presence of 4-Š molecular sieves.
[b] Yield of isolated product. [c] Determined by HPLC.
Angew. Chem. Int. Ed. 2008, 47, 1308 –1311
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www.angewandte.org
1309

Communications
Keywords: aldehydes ·
.
asymmetric catalysis · cycloaddition ·
indium · nitrogen oxide
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=
to its C C double bond, in 81% yield. Similarly, products 8
and 11 can be considered as stable precursors of triketide
sugars.[10g]
In conclusion, we have developed a novel N,N’-dioxide/
In(OTf)3 catalyst that catalyzes the HDA reaction with an
extremely broad range of substrates and produces highly
substituted chiral pyranones in good yields with up to 99% ee.
The stability of the catalyst facilitates its practical usage, and
this reaction has been successfully applied on a sub-gram scale
to the synthesis of triketide. Future efforts will focus on the
application of this system to the development of an asym-
À
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synthesis.
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Experimental Section
Typical experimental procedure: The prepared catalyst (5 mol%; see
Supporting Information) was stirred in anisole (2.0 mL) in a dry
reaction tube under nitrogen. This mixture was cooled to 08C and the
aldehyde (0.25 mmol) and diene 1 (100 mL) were added. The mixture
was stirred at 08C for 48 h and then TFA (0.1 mL) was added. Work-
up was performed as described in the Supporting Information.
Received: October 15, 2007
Published online: January 4, 2008
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Angew. Chem. Int. Ed. 2008, 47, 1308 –1311
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