our more recent discovery that 1-hydrazinodienes are ame-
nable to chiral catalyst-controlled, enantioface-selective
Diels–Alder cycloadditions, as well as the cycloaddition be-
havior of new 1-hydrazinodienes for use in chemical synthe-
sis.[10]
mize nonbonded interactions between the Lewis acid-acti-
vated carbonyl and the substituents attached to the hydra-
zine moiety of the diene.[13]
Having identified the (S,S)-(À)-2,2’-isopropylidene-bis(4-
tert-butyl-2-oxazoline) chiral ligand and the hexafluoroan-
timonate counter ion as key components of an effective
chiral catalyst, we examined a variety of b-substituted N-
acryloyl oxazolidinones in asymmetric Diels–Alder reactions
with 1-hydrazinodiene 5 (Table 2).
In our effort to merge electron-deficient dienophiles with
1-hydrazinodiene 5 with high margins of stereoselectivity,
we discovered that the chiral copper(II) bis(oxazoline) cata-
lysts of Evans and co-workers[11] mediate efficient, regiose-
lective, and highly stereoselective Diels–Alder reactions of
N-acryloyl oxazolidinones with diene 5. Unions of 1-hydrazi-
nodiene 5 with N-acryloyl oxazolidinone 11a were best ach-
ieved in methylene chloride at room temperature in the
presence of 4 ꢂ molecular sieves and 10 mol% of the fresh-
ly prepared copper(II) bis(oxazoline) catalyst. In all cases,
exo cycloadduct 13a was produced as the major diastereo-
isomer with varying levels of enantioselectivity. The results
summarized in Table 1, reveal the impact of the identity of
the group R on the chiral bis(oxazoline) ligand and the
counterion on Diels–Alder diastereo- and enantioselectivity.
The tert-butyl bis(oxazoline) ligand afforded excellent levels
of diastereo- and enantioselectivities. While the chloride salt
of the copper(II) bis(oxazoline) catalyst was unreactive, the
hexafluoroantimonate and triflate salts displayed excellent
reactivities. The good-to-excellent exo diastereoselectivities
exhibited in these reactions are consistent with our prior ob-
servations on the stereochemical outcomes of 1-hydrazino-
diene cycloadditions to Ca-unsubstituted dienophiles.[6,12]
Our hypothesis is that dienophiles lacking a-substitution
should undergo exo selective Diels–Alder reactions to mini-
Table 2. Chiral catalyst-controlled, asymmetric Diels–Alder cycloaddi-
tions of diene 5 to b-substituted N-acryloyl oxazolidinones 11a–l.[a]
Product
R
Yield
[%][b]
Reaction
time [h]
e.r.[c]
13a
13b
13c
13d
13e
13 f
13g
13h
13i
H
CH3
CH2CH3
CH2CH2CH3
CH
Ph
pCH3Ph
pClPh
pBrPh
pCF3Ph
CH=CHCH3
CO2CH2CH3
84
79
74
75
65
66
65
64
54
60
54
83
3
4
6
49:1
99:1
24:1
99:1
99:1
49:1
32:1
21:1
21:1
21:1
21:1
49:1
12
24
6
12
12
12
12
18
3
ACHTUGNTERN(NUNG CH3)2
13j
13k
13l
Table 1. Chiral copper(II) bis(oxazoline)-catalyzed Diels–Alder cycload-
ditions of diene 5 with N-acryloyl oxazolidinone 11a.[a]
[a] Reactions were carried out with diene 5 (0.25 mmol), dienophile 11
(0.375 mmol), copper(II) bis(oxazoline) catalyst 14 (0.025 mmol), pow-
dered 4 ꢂ molecular sieves (ms; 37.5 mg), and CH2Cl2 (521 mL)at room
temperature. [b] Isolated yield after purification by silica gel column
chromatography. [c] Enantiomer ratios are reported for the major exo
diastereoisomer and were determined by chiral high-performance liquid
chromatography or supercritical fluid chromatography. Alloc: allyloxy
carbonyl; d.r.: diastereomer ratio; e.r.: enantiomer ratio.
Although there was some variation in reaction times, all
of the unions leading to exo cycloadducts 13a–l displayed
diastereomer ratios of greater than 20:1 and enantiomer
ratios ranging from 21–99:1. Evansꢀs copper(II) catalyst 14
is clearly capable of mediating cycloadditions of diverse, b-
substituted N-acryloyl oxazolidinones to diene 5 with high
margins of stereoselectivity.
Entry
R
X
Conversion
[%][b]
d.r.[b]
e.r.[c]
1
2
3
4
5
6
iPr
Ph
Bn
tBu
tBu
tBu
SbF6
SbF6
SbF6
SbF6
OTf
Cl
100
100
100
100
100
0
10.2:1
7.7:1
8.5:1
>20:1
>20:1
n.d.
6:1
4:1
6:1
49:1
28:1
n.d.
To further increase the scope of this chemistry, we lever-
aged our previously described method[6] to achieve syntheses
of an expanded set of hydrazinodienes with diverse substitu-
tion patterns. Thus, from simple a,b-unsaturated aldehydes
and monoallyloxycarbonyl (Alloc) hydrazine, 1-hydrazino-
dienes 15–18 (Table 3) were synthesized in three steps[14]
and employed in asymmetric Diels–Alder reactions with
a,b-unsaturated imides 11a, 11b, 11 f, and 11l.
[a] Reactions were carried out with diene 5 (0.125 mmol), dienophile 11a
(0.188 mmol), copper(II) bis(oxazoline) catalyst 12 (0.0125 mmol), pow-
dered 4 ꢂ molecular sieves (ms; 19 mg), and CH2Cl2 (250 mL) at room
temperature for 3 h. [b] Conversion and d.r. were determined by analyses
of the crude reaction mixtures by 1H NMR spectroscopy. [c] Enantiomer
ratios are reported for the major exo diastereoisomer and were deter-
mined by chiral high-performance liquid chromatography on a Chiralcel
OD column. Alloc: allyloxy carbonyl; d.r.: diastereomer ratio; e.r.: enan-
tiomer ratio; n.d.: not determined.
11132
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 11131 – 11134