The effect of pressure on the diastereoselectivity of the reaction of prenal with monoalkyl ylidenemalonates catalysed by homochiral secondary amines

Article abstract of DOI:10.1070/MC2001v011n05ABEH001502

The dienamine-mediated formation of 6-substituted cyclohexa-1,3-dienes from the title reactants catalysed by either (S)- or (R)-prolinol at 8 kbar proceeds with different net enantioselectivities depending on the structure of RCH=C(CO₂H)CO₂Alk to give a product with the same configuration as that obtained at atmospheric pressure (if R = Me₂C=CH) or with a configuration opposite to the latter (if R = Ph); by contrast, with both dienophiles the sense of enantioselectivity does not change with pressure when (S)-α,α-diphenyl-2-pyrrolidinemethanol is used as the catalyst.

Full text of DOI:10.1070/MC2001v011n05ABEH001502

,
2001, 11(5), 174–175
The effect of pressure on the diastereoselectivity of the reaction of prenal with
monoalkyl ylidenemalonates catalysed by homochiral secondary amines
Edward P. Serebryakov,* Albert G. Nigmatov and Mikhail A. Shcherbakov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328; e-mail: ser@cacr.ioc.ac.ru
1
0.1070/MC2001v011n05ABEH001502
The dienamine-mediated formation of 6-substituted cyclohexa-1,3-dienes from the title reactants catalysed by either (S)- or (R)-
prolinol at 8 kbar proceeds with different net enantioselectivities depending on the structure of RCH=C(CO H)CO Alk to give a
2
2
product with the same configuration as that obtained at atmospheric pressure (if R = Me C=CH) or with a configuration opposite
2
to the latter (if R = Ph); by contrast, with both dienophiles the sense of enantioselectivity does not change with pressure when
(
S)-α ,α -diphenyl-2-pyrrolidinemethanol is used as the catalyst.
Recently, the catalytic synthesis of optically active cyclohexa-
1
,3-dienes from β -branched α ,β -alkenals and various monoalkyl
Process (1):
Me
1
ylidenemalonates was described, and factors affecting the ap-
parent (net) enantioselectivity of this process were studied. The
reaction mechanism (Scheme 1) involves the transient forma-
tion of a dienamine followed by two consecutive, inherently
diastereoselective reactions. One of them, intermolecular [4+2]
CO H
2
2
O
cat.
1
–3
*
CO Me
2
1
2
O
OMe
4
cycloaddition, is strongly accelerated by pressure, whereas the
3
other is believed to proceed via a six-membered transition state,5
which can also be affected by pressure.
Process (2):
Me
Since the net enantioselectivity of cyclohexadiene formation
1
,2
diminishes with temperature, we used a high-pressure tech-
nique as an alternative to heating for accelerating the process
without damaging the ee of its products. Scheme 2 demon-
strates two examples examined.
CO H
2
cat.
1
+
*
CO Et
Ph
2
4
The experiments were performed in dry toluene at 20±2 °C
O
OEt
†
both under normal pressure (~1 bar) and at 8 kbar. Enantiopure
5
(
(
S)-α ,α -diphenyl-2-pyrrolidinemethanol 6, (S)-prolinol 7 and
R)-prolinol ent-7 (0.1 equiv. each) were used as catalysts. The
OH
Ph
OH
OH
results are shown in Table 1.
N
H
N
H
N
H
Table 1 indicates that the application of a high pressure results
in diminished chemical yields of target products 3 and 5. How-
ever, with all three catalysts, prolonged exposures of process
Ph
6
7
ent-7
(
2) to high pressure markedly increased the ee of ester 5 (cf.
Scheme 2
runs 2.2–2.3, 2.5–2.6, 2.8–2.9); this trend can be useful from
the preparative standpoint.
In process (1), the sense of its net enantioselectivity is not
altered by a high pressure. The ee of ester (S)-3 slightly dimin-
ishes when catalyst 6 is used, whereas a relatively high increase
in ee is observed if this process is catalysed by 7 or ent-7.
†
2
Experiments at 1 bar were carried out as described earlier, however,
dry toluene was used instead of benzene. Acid esters 2 (mp 84 °C) and 4
mp 95 °C) were prepared as Z isomers of ~100% geometrical purity ( H
1
(
13
and C NMR data) according to refs. 2 and 6, respectively. Experiments
at 8 kbar were performed using a termostatted Barostat HP unit in 2 ml
Teflon ampoules. The ampoules were filled at 0–5 °C first with dieno-
philes 2 or 4 (0.4–0.5 mmol) in 0.5 ml of PhMe and then with solutions
of enal 1 (0.4–0.5 mmol) and a chiral amine (0.04–0.05 mmol) in toluene
to the total volume of 2 ml. The time span between the application of the
pressure and the attainment of a steady state was ~10 min. At both pres-
sures, the work-up of the reaction mixture included its concentration in
vacuo, the extraction of an oily residue with pentane, and the fractiona-
tion of the pentane-extracted solute by column chromatography (SiO2).
The purity of the products was controlled by TLC on Silufol plates
hexane–AcOEt, 6:1; R 0.55 for 3 and 0.45 for 5) and by H NMR
spectroscopy (Bruker AM-300 instrument, in d -benzene). Enantiomer
ratios (er) and the values of ee in scalemic 3 and 5 were determined by
R1
R1
RR* NH
R2
R2
+
H O (1)
2
O
NRR*
A
B
R1
CO H
R3
2
R2
R3
1
(
f
CO Alk
2
6
C
B
(2)
NRR*
correlating the [a] of a specimen with the ratio of peak areas belonging
D
AlkO C
O
to R and S antipodes in the 1H NMR spectrum recorded in the presence
2
O
of (S)- or (R)-BINOL (for details, see refs. 1, 2). For the enantiomers of 3,
this correlation was linear in the whole range of ee (from ~0 to ~100%).
In the case of 5, this correlation was also linear up to the largest ee
attainable at atmospheric pressure (32%); further estimates of ee were
made using [a]D alone on the assumption that the linearity still holds.
H
D
R1
R2
For (S)-5 and (R)-5 with 100% ee, an extrapolation gave |[a] | = 186°.
D
(3)
D
+ CO2 + HNRR*
CO Alk
All [ ] (measured in benzene at 20±4 °C) and the corresponding
a
D
R3
enantiomer ratios and ee given in Table 1 are the mean values of three
significantly close results. Material balances for processes (1) and (2) at
both pressures revealed methyl 5-methylhexa-3,5-dienoate (from 2) or ethyl
cinnamate (from 4) as main low-molecular-weight by-products (up to 3%
at 1 bar and below 1.5% at 8 kbar), and polar polymers (Rf < 0.05), which
2
E
R1 ¹ H
6
are insoluble in pentane (up to 35% at normal pressure and up to 50% at
Scheme 1
8
kbar in the case of dienophile 4).
–
174 –

,
2001, 11(5), 174–175
Table 1 The effect of pressure on the chemical yields and net enantio-
selectivities of processes (1) and (2) in the presence of amines 6, 7 and ent-7
in dry toluene at 20±2 °C.
s-cis2
Me
H
6
X = Ph COH
2
N
X
H
7 X = CH2OH
Yield
[a]b
R:S
ratio
Run
Amine P/bar
t/h
ee (%)
a
D
(
%)
Process (1): 1 + 2 ® 3
s-cis1
Me
H
X
1.1
1.2
1.3
1.4
1.5
1.6
6
6
7
7
1.0
8000
1.0
8000
1.0
8000
360
72
120
96
120
72
39
27
52
18
54
35
+296°
+238°
+53°
+76°
–41°
<2:98
10:90
41:59
37:63
57:43
64:36
> 96
80
18
26
14
N
H
ent-7
ent-7
–82°
28
F
O
Me
Me
H
HO
Process (2): 1 + 4 ® 5
OMe
2
2
2
2
2
2
2
2
2
2
.1a
.1b
.2
.3
.4
.5
.6
.7
.8
6
6
6
6
7
7
7
1.0
1.0
360
20
48
240
360
24
336
120
24
0
7
5
6
20
6
6.5
14
3.5
7
—
—
H
O
c
c
c
d
+53°
+71°
+167°
–14.5°
+34°
+60°
+17°
34:66
31:69
5:95
54.5:45.5
41:59
36:64
45:55
32
38
90
9
18
28
10
14
40
d
8000
8000
1.0
8000
8000
1.0
d
d
H
G
OEt
d
d
O
O
d
d
d
H H
ent-7
ent-7
ent-7
8000
8000
–12.5° 53:47
–74° 70:30
HO
.9
168
Figure 1
a
b
c
Isolated yield. Measured at 20±4 °C in dry benzene (c 1.0). At 50 °C,
d
because at 20 °C process (2) is not observed. For a specimen with ee ~100%,
it was extrapolated that |[a] | = 186°.
1
D
We thank Dr. M. I. Struchkova and Mr. A. V. Ignatenko
(N. D. Zelinsky Institute of Organic Chemistry, Moscow) for
their help in determining the ee of the products by the H NMR–
chiral solvating agent technique, and to Professor V. M. Zhulin
and Dr. I. V. Zavarzin for their kind permission to use their high-
pressure equipment. This work was supported by the Russian
Foundation for Basic Research (grant nos. 96-03-33396 and 99-
03-32992) and by INTAS (grant no. 96-1109).
The application of a high pressure to process (2) led to some-
what puzzling results. First, at 8 kbar, amine 7 catalysed the
formation of dextrotatory ester (S)-5, while under atmospheric
pressure it favoured the formation of levorotatory (R)-5. As the
complement to this reversal, instead of (S)-5, which was obtained
at 1 bar using ent-7 as the catalyst, (R)-5 was isolated when a
mixture of 1, 4 and ent-7 was exposed to 8 kbar. With both
catalysts, the reversal of net enantioselectivity increased at pro-
longed exposures to a high pressure. Second, while process (1)
catalysed by bulky amine 6 at 8 kbar afforded a specimen of (S)-3
with a lower ee than that attained at 1 bar, a specimen of (S)-5,
which was isolated when process (2) was catalysed by 6 at 8 kbar,
had a higher ee than that of an analogous specimen of (S)-5
obtained at 1 bar.
1
References
1
A. G. Nigmatov and E. P. Serebryakov, Izv. Akad. Nauk, Ser. Khim.,
996, 663 (Russ. Chem. Bull., 1996, 45, 623).
E. P. Serebryakov, A. G. Nigmatov, M. A. Shcherbakov and M. I. Struchkova,
Izv. Akad. Nauk, Ser. Khim., 1998, 84 (Russ. Chem. Bull., 1998, 47, 82).
3 A. G. Nigmatov and E. P. Serebryakov, Izv. Akad. Nauk SSSR, Ser.
Khim., 1991, 1079 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1991, 40,
1
2
Different patterns of the net enantioselectivity of processes (1)
and (2) under high pressure imply that the preferred transition
states of their pivotal steps are different. This difference may
originate from different diastereofacial selectivities with which
each of the two reactive conformations of transient dienamines
9
61).
4
(a) G. Jenner, in Organic High Pressure Chemistry, ed. W. J. leNoble,
Elsevier, Amsterdam, 1988, pp. 143–203; (b) R. van Eldik, T. Asano and
W. J. leNoble, Chem. Rev., 1989, 89, 549; (c) G. Jenner, Tetrahedron,
997, 53, 2669; (d) M. Ciobanu and K. Matsumoto, Liebigs Ann. Chem.,
997, 623; (e) L. F. Tietze, M. Henrich, A. Niklaus and M. Bubak,
1
1
1
2
(
e.g., s-cis -8a,b and s-cis -8a,b generated from enal 1 and
amines 6 or 7) approaches – in both endo and exo modes – the
preferred conformations of dienophiles 2 or 4 (F and G, respec-
Chem. Eur. J., 1999, 5, 297.
5 (a) C. Mannich and E. Ganz, Ber., 1922, 55, 3504; (b) N. Campbell and
R. S. MacPherson, J. Chem. Soc., Perkin Trans. 1, 1974, 43.
2
tively, as determined using the PC MODEL program ) (Figure 1).
Note that, by contrast with pressure-assisted asymmetric Diels–
Alder reactions of achiral 1,3-dienes with homochiral dieno-
philes,4 analogous pressure-assisted processes involving con-
formationally flexible homochiral dienamines and achiral dieno-
philes rarely occur in high-pressure organic chemistry.
6 A. G. Nigmatov, I. N. Kornilova and E. P. Serebryakov, Izv. Akad. Nauk,
Ser. Khim., 1996, 154 (Russ. Chem. Bull., 1996, 45, 144).
(c)
Received: 13th July 2001; Com. 01/1828
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