R. Peters et al.
Table 2. Tandem approach featuring two consecutive Michael additions as key steps to form spirocyclic prod-
ucts 3.
adopts a chairlike conformation
(Figure 2, bottom, left), in
which the phenyl substituent
and the azlactone
N atom
adopt a trans-diaxial position.
The alternative chair conformer
with an axial azlactone carbonyl
moiety (after ring inversion) is
expected to be energetically
less-favorable due to a more
severe 1,3-diaxial interaction as
a consequence of the enhanced
steric demand of the carbonyl
group relative to the azlactone
N atom. Chairlike conformers
were also noticed for trans-3d
and -3e (Figure 2).
Entry
2
3
R1
R2
trans/cis
Yield
d.r.
ee
trans-3 [%][a]
trans-3[b]
trans-3[c]
[d]
1
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
Ph
Ph
89:11
92:8
93:7
85
89
78
43
44
23
73
82
73
78
13
52
79
–
–
–
–
–
–
95
91
96
91
63
81
2[e,f]
3[e]
4[f]
5[f]
6
4-MeO-C6H4
4-Me-C6H4
4-Br-C6H4
2-Cl-C6H4
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeO-C6H4
4-Me-C6H4
4-Br-C6H4
2-Cl-C6H4
Me
4-MeO-C6H4
4-Me-C6H4
4-Br-C6H4
2-Cl-C6H4
4-NC-C6H4
4-O2N-C6H4
2-furyl
[d]
[d]
[d]
75:25
> 100:1
62:38
83:17
91:9
88:12
>100:1
n.d.
[d]
[d]
7
8
57:43
57:43
50:50
60:40
73:27
67:33
65:35
77/>98[g]
99/93[g]
92/93[g]
81/47[g]
88/86[g]
94/91[g]
98/95[g]
9[f]
10
11[f]
12[f]
13
The absolute configuration of
the minor diastereomer of
trans-3l could also be deter-
j
k
l
j
k
l
76:24
88:12
mined
(Figure 3).[23]
The
m
m
5R,6S,10S configuration reveals
that only the configuration at
[a] Yield of the isolated product. [b] Diastereomeric ratio of two trans isomers determined by 1H NMR spec-
troscopic analysis of the isolated product. [c] Determined by HPLC analysis. [d] Only one trans diastereomer
is possible with symmetric dienone substrates 2. [e] Reaction at 558C. [f] One equivalent of the dienone was the spirocenter is inverted rela-
used. [g] ee values of the major and minor trans isomers, respectively.
tive to (5S,6S,10S)-3j. By using
an unsymmetrical dienone, the
ties with unsymmetrical dienones and the enantioselectivity
is usually high for both of them. Good yields of the trans
isomers have been obtained for unsymmetrical dienones car-
rying a s donor (entry 8), a p donor (entry 7), a s acceptor
(entries 9 and 10), or an electron-rich heterocycle (entry 13).
Moderate or poor yields were obtained for dienone sub-
strates equipped with a p acceptor (entries 11 and 12).
catalyst system used is thus not capable of setting up the
configuration of the spirocenter with a high level of stereo-
control.
The conformational behavior in solution was studied by
1H NMR spectroscopy for compounds 3. In a chairlike con-
formation of a trans-1,3-disubstituted cyclohexanone moiety
only one 1,3-trans-diaxial proton–proton coupling can be ob-
served, whereas in a twistlike conformation two of them are
present. The average coupling constants for 1,3-trans-diaxial
Stereochemistry: Compared with the major products ob-
tained from simple enones (see ref. [13]), the configuration
is surprisingly inverted at the b-positions to the keto group,
as revealed by the X-ray single-crystal structure analysis of
trans-3j (major diastereomer and enantiomer), which pos-
sesses an S,S,S configuration (Figure 2, top).[21,22] Additional
X-ray crystal structure analyses of trans-3a, trans-3d, trans-
3e, and trans-3l (major isomer) confirm the preferred trans
configuration of the cyclohexanone rings with regard to the
two dienone b-substituents (Figure 2). The S configuration
of the stereocenters in the b-position to the keto group has
also been confirmed by chemical correlation for trans-3a
(see below in the subchapter “azlactone derivatization”). A
stereochemical consequence of the symmetric constitution
of trans-3a is that the spirocenter is not a stereocenter in
that case.
3
couplings usually range from J=10 to 15 Hz, whereas the
other vicinal 3J couplings are usually between 2 to 5 Hz,
both depending on the dihedral angle.[24] It should be noted
that in NMR spectroscopic experiments, usually only the
average of these couplings can be measured for equilibrium
mixtures of conformers, meaning that “mixed” coupling con-
stants are observed. For the preference of a chairlike confor-
mation of trans-1,3-disubstituted cyclohexanones in solution,
the observed coupling constants for the vicinal couplings are
consequently lower than for the preference of a twistlike
conformation. For the proton on C10 of trans-3a (see
3
Figure 4 with R1 =R2 =Ph), J couplings of 8.5 and 5.1 Hz
3
are observed, whereas for the proton on C6 J values of 12.3
and 4.4 Hz are measured. That means there is arguably one
1,3-trans-diaxial interaction and one “mixed” coupling,
pointing to a mixture of both chair and twist conformers.
The existence of significant amounts of the twist conformer
in solution is also supported by a relatively strong nuclear
Overhauser effect (NOE) signal between the proton on C10
and the axial proton on C7, for which the distance is consid-
erably shorter in the twist conformation (2.64 ꢃ in the crys-
tal structure of trans-3a (R=Ph, twist conformer) versus
Different conformers are preferred in the solid state de-
pending on the dienone substitution patterns. In trans-3a
and the major diastereomer of trans-3j, a twist conformation
of the cyclohexanone core is found that accommodates both
aryl rings in equatorial positions.
On the contrary, the major isomer of trans-3l carrying one
phenyl group plus a para-nitro-substituted phenyl ring
8344
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 8342 – 8351