Catalytic asymmetric aza Diels-Alder reactions of hydrazones using a chiral zirconium catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.01.111

Catalytic asymmetric aza Diels-Alder reactions of acylhydrazones with Danishefsky's dienes have been developed. A chiral zirconium complex derived from zirconium propoxide and 3,3′,6,6′-I₄BINOL was found to be effective in this reaction, and th

Full text of DOI:10.1016/j.tetlet.2005.01.111

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1803–1806
Catalytic asymmetric aza Diels–Alder reactions
of hydrazones using a chiral zirconium catalyst
*
ꢀ
Yasuhiro Yamashita, Yumiko Mizuki and Shu Kobayashi
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 29 December 2004; revised 21January 2005; accepted 24 January 2005
Dedicated to Professor Iwao Ojima on the occasion of his 60th birthday
Abstract—Catalytic asymmetric aza Diels–Alder reactions of acylhydrazones with Danishefskyꢀs dienes have been developed. A chi-
ral zirconium complex derived from zirconium propoxide and 3,30,6,60-I4BINOL was found to be effective in this reaction, and the
desired optically active 2,3-dihydro-4-pyridone derivatives were obtained with high enantioselectivities. Asymmetric formal synthe-
sis of a natural product, coniine, was conducted using this catalytic asymmetric reaction as a key step.
Ó 2005 Published by Elsevier Ltd.
Development of efficient methods for constructing nitro-
gen-containing heterocycles is among the most impor-
tant tasks in organic synthesis as well as medicinal
chemistry, because the heterocycles are key building
blocks for the preparation of biologically important
alkaloids, peptides, and aza sugars, etc. Aza Diels–Alder
reactions of imines with activated dienes, such as 1-alk-
oxy-3-siloxy-1,3-butadienes and its derivatives (Dani-
shefskyꢀs dienes),1 opened an efficient way to
whereas aza Diels–Alder reaction of a,b-unsaturated
hydrazones as dienes with olefins has been investigated,6
the reactions of hydrazones as dienophiles with dienes,
to the best of our knowledge, have never been reported
regardless of its potential usefulness. In particular, such
reactions would provide powerful methods when the N–
N bonds of the products are cleaved under reductive
conditions to afford N-unprotected piperidine deriva-
tives. In this letter, we describe catalytic asymmetric
aza Diels–Alder reactions of hydrazones with Danishef-
skyꢀs dienes using a chiral zirconium catalyst.
functionalized
piperidines,
2,3-dihydro-4-pyridone
derivatives.2 Recently, catalytic asymmetric versions of
the aza Diels–Alder reactions have been explored, and
high enantioselectivities were attained in some cases.3,4
However, substrate generality of the reactions is still
limited, especially in the reactions of unstable imines
derived from aliphatic aldehydes.4
In a preliminary investigation, we examined the aza
Diels–Alder reaction of benzoylhydrazone 1a derived
from 3-phenylpropionaldehyde with 1-methoxy-3-tri-
methylsilyloxy-1,3-butadiene 2a in the presence of
an achiral Lewis acid. It was found that boron
trifluorideÆdiethyl ether (BF3ÆOEt2) was an effective pro-
moter for this reaction, affording the desired product 3a
in high yield (Scheme 1).7
Acylhydrazones are stable imine equivalents, those
derived from aromatic, a,b-unsaturated, and even ali-
phatic aldehydes are stable crystals easy to handle at
room temperature. We have already reported that ben-
zoylhydrazones reacted with several nucleophiles, such
as silicon enolates and allylating agents, etc., in the pres-
ence of a catalytic amount of a Lewis acid to afford the
corresponding adducts in high yields.5 However,
Encouraged by this result, we decided to develop asym-
metric aza Diels–Alder reactions of hydrazones with
Danishefskyꢀs dienes using a chiral Lewis acid catalyst.
We have already investigated catalytic asymmetric
reactions of benzoylhydrazones and found that chiral
zirconium Lewis acids were effective for achieving high
enantioselectivity.8 First, a chiral zirconium catalyst
prepared from zirconium propoxide–propanol com-
plex and 3,30,6,60-tetraiodo-1,10-binaphthalen-2,20-diol
Keywords: Zirconium; Lewis acid; Asymmetric; Hydrazone; Aza
Diels–Alder reaction.
*
Corresponding author. Tel.: +81358411094; fax: +8135684 0634;
e-mail: skobayas@mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.01.111

1804
Y. Yamashita et al. / Tetrahedron Letters 46 (2005) 1803–1806
Ph
O
N
H
BF3•OEt2
(1.1 eq.)
N
Ph
OSiMe3
HN
N
+
O
OMe
CH2Cl2, –45 o
30 min
C
Ph
H
Ph
O
(1.5 eq.)
2a
1a
3a
81%
Scheme 1.
(3,30,6,60-I4BINOL) was tested. The catalyst was previ-
ously shown to be effective for asymmetric [3+2] cyclo-
addition of hydrazones with olefins.8b,c In the reaction
of 1a with 2a in toluene at 0°C, the desired product 3a
was obtained with high enantioselectivity but in low
yield in the presence of 20mol% of the catalyst (Table
1, entry 1). During this reaction there formed methanol,
which was generated by decomposition of the intermedi-
ate with free propanol and was supposed to prevent the
reaction by affecting the catalyst structure (an exchange
of the propoxy group for the methoxy group). We then
employed diene 2b containing a tert-butyloxy group in-
stead of the methoxy group, and found that the yield of
the reaction was slightly improved to 35% with keeping
high enantioselectivity (entry 2). The effect of substitu-
ents on the benzoyl moiety of the hydrazone was also
examined; however, both electron-donating (MeO) and
electron-withdrawing groups (Cl, CF3) had no good
effect on the yield (entries 3–5).
THF, and DME as co-solvents of TBME. The yields
reached up to 81% with maintaining the enantioselectivi-
ties (entries 8–11). In this reaction system, the catalyst
loading was reduced to 10mol% without significant loss
of the yield and enantioselectivity (entry 12).
Other substrates were then subjected to this reaction
(Table 3). The hydrazone derived from n-butanaldehyde
also gave the desired product in good yield with high
enantioselectivity (entry 2). On the other hand, the
hydrazones derived from b- and a-branched aldehydes,
Table 2. Asymmetric aza Diels–Alder reactions of benzoylhydrazone
1a with diene 2ba
Entry
Solvent
Yield (%)
ee (%)
1Toluene
2
35
93
10
39
Toluene/CH2CI2 (2/1)
Toluene/tBuOMe (2/1)
tBuOMe
85
92
92
93
3
4
57
56
Next, we searched for a suitable solvent for this reaction
(Table 2). At first, mixed solvent systems with toluene
were examined, and slight improvement of the yield
was observed in a toluene–tert-butyl methyl ether
(TBME) system (entry 3).9 Further increase of the yield
was observed when TBME was used as the sole solvent
(entry 4). Cyclopentyl methyl ether (CPME) was also
gave a better yield than other ether-type solvents, Et2O
5
CPMEb
6
iPr2O
1
28
6
7
Et2O
88
88
88
92
91
91
8
tBuOMe/CH3CN (2/1)
tBuOMe/THF (2/1)
tBuOMe/DME (2/1)
tBuOMe/DME (4/1)
tBuOMe/DME (4/1)
76
81
9
10
11
12c
73
78
70
i
a The reactions were performed at 0°C for 18h in the presence of the
zirconium catalyst (20mol%).
b Cyclopentyl methyl ether.
c Using Zr catalyst (10mol%) at À10°C for 48h.
and Pr2O (entries 5–7). These results showed that the
solvent polarity was a key factor for improving the yield.
We then investigated further addition of aprotic polar
solvents to the reaction system. We employed CH3CN,
Table 1. Asymmetric aza Diels–Alder reactions of benzoylhydrazones 1 with diene 2 in the presence of a chiral zirconium complex
X
I
I
X
H
OH
Zr(OPr)4-PrOH (20 mol%)
(R)-3,3',6,6'-I4BINOL (24 mol%)
H
N
N
N
OSiMe3
N
OH
I
+
O
Toluene, 0 oC, 18 h
O
O
OR
Ph
H
I
(R)-3,3',6,6'-I4BINOL
Ph
1
2
3
1a: X=H
1b: X=CF3
1c: X=Cl
2a: R=Me
2b: R=tBu
1d: X=OMe
Entry
1
2
Yield (%)
ee (%)
93
1
2
3
4
5
1a
1a
1b
1c
1d
2a
2b
2b
2b
2b
1
35
1
9
7
22
<10
85
–

Y. Yamashita et al. / Tetrahedron Letters 46 (2005) 1803–1806
1805
Table 3. Substrate generality
Zr(OPr)4-PrOH (10 mol%)
H
N
H
N
OSiMe3
(R)-3,3',6,6'-I4BINOL (12 mol%)
tBuOMe/DME (4/1), - 10 oC, 48 h
N
N
+
OtBu
O
O
R
O
R
H
1
2b
3
Entry
R
Yield (%)
ee (%)
1
2
(1a)
(1e)
70
70
91
93
Ph
3
4
(1f)
31
50a
92
91
5
6
44
50a
89
95
(1g)
t
a Using Zr catalyst (20mol%) in BuOMe.
3-methylbutanaldehyde and cyclohexancarboxyalde-
hyde, showed lower reactivity, albeit with high enantio-
selectivities (entries 3–6). From those results, it
turned out that the present chiral zirconium catalyst sys-
tem worked well in the reactions of hydrazones derived
from various aliphatic aldehydes. This is a significant
advantage of the catalytic asymmetric aza Diels–Alder
reactions, because most reactions so far reported pro-
vided [4+2] products derived from aromatic or a,b-
unsaturated imines or surrogates.4 In the present system,
hydrazones derived from benzaldehyde and a,b-unsatu-
rated aldehydes were also tested; however, the reaction
proceeded sluggishly, presumably due to high stability
of the conjugated hydrazones.
2b (132mg, 0.61mmol) was added using TBME
(0.2mL) and DME (0.2mL). The mixture was stirred
for 48 h at the same temperature and was quenched with
saturated aqueous NaHCO3. The organic layer was sepa-
rated, and the aqueous layer was extracted with dichlo-
romethane. The organic layers were combined and dried
over anhydrous Na2SO4. After filtration and concentra-
tion under reduced pressure, the crude mixture was puri-
fied by silica gel column chromatography to afford the
desired product 3a (92mg, 70% yield). The enantiomeric
excess was determined by HPLC analysis using Daicel
CHIRALPAK AD (91% ee).
The reaction was applied to the synthesis of a natural
compound, coniine, which was isolated from the pitcher
plant, Sarracenia flava.10 The aza Diels–Alder product
3e was hydrogenated in the presence of Pd/C to afford
compound 4. Its carbonyl group was then protected
with 1,2-ethanedithiol, and the N–N bond was cleaved
with SmI2.11 After the Boc protection of the nitrogen
atom, the dithioacetal moiety was cleaved by Raney
Ni to afford Boc-protected coniine 7 in good yield. All
physical data of synthetic 7 were completely consistent
with the reported data of Boc-protected (S)-(+)-coni-
An experimental procedure is described for the reaction
of 1a with 2b (Table 2, entry 12): under argon atmo-
sphere, to
a
suspension of (R)-3,30,6,60-I4BINOL
(39mg, 0.049mmol) in TBME (0.2mL) was added a zir-
conium propoxide-propanol complex (17 mg, 77% pur-
ity, 0.041mmol) in TBME (0.2mL) at room
temperature, and the mixture was stirred for 3h. The zir-
conium catalyst solution was transferred into the flask in
which hydrazone 1a (103mg, 0.41mmol) was placed,
and the zirconium flask was rinsed with TBME
(0.2mL). The whole was cooled at À10°C, and diene
23
23
D
ine (½aŠ ¼ þ35:3 ðc 1:45; CHCl3Þ; lit.10c
,
½aŠ
¼
þ33:5 ðc D0:43; CHCl3Þ) (Scheme 2).
H
N
H
H
N
N
HSCH2CH2SH
BF3•OEt2
N
N
N
Pd-C, H2
MeOH, rt
S
O
O
O
O
O
CH2Cl2, MS 5A, rt
S
5
4
3e (93% ee)
84%
79 %
Boc
Boc
N
HN
N
(Boc)2O
S
SmI2-THF
Raney Ni
TFA
CH3CN, 50 o
C
MeOH, - 78 o
C
EtOH, reflux
S
6
7
(S)-(+)-Coniine
88%
75%
[a]D23=+35.3
(c 1.45, CHCl3)
Scheme 2. Formal synthesis of (S)-(+)-coniine.

1806
Y. Yamashita et al. / Tetrahedron Letters 46 (2005) 1803–1806
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Chem. Soc. 2004, 126, 456.
In conclusion, we have developed catalytic asymmetric
aza Diels–Alder reactions of hydrazones with Danishef-
skyꢀs dienes. A chiral zirconium complex was found to
be effective in this reaction, and the desired optically ac-
tive 2,3-dihydro-4-pyridone derivatives were obtained
with high enantioselectivities. Choice of solvents was
an important factor for the reactivity, and better reactiv-
ity was obtained in mixed solvent systems containing
aprotic polar solvents. Asymmetric formal synthesis of
coniine was conducted, and Boc-protected (S)-(+)-coni-
ine was obtained in good yield. Further application of
this aza Diels–Alder reaction to the synthesis of biologi-
cally interesting compounds is under investigation.
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Acknowledgements
7. We found that lanthanide triflates also mediated the
reactions of acylhydrazones with dienes. Oyamada. H.;
Kobayashi, S., unpublished result.
This work was partially supported by CREST, SORST,
and ERATO, Japan Science and Technology Corpora-
tion (JST), and a Grant-in-aid for Scientific Research
from Japan Society of the Promotion of Science.
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