A Lewis acid dependent asymmetric Diels-Alder process in the cyclization of new chiral acrylamides with dienes

Article abstract of DOI:10.1039/a902535i

Diels-Alder cycloadditions of chiral acrylamides with cyclopentadiene proceed with high diastereofacial selectivity, giving either endo-R to endo-S products depending of the Lewis acid used.

Full text of DOI:10.1039/a902535i

A Lewis acid dependent asymmetric Diels–Alder process in the cyclization of
new chiral acrylamides with dienes
Doo Han Park, Sung Han Kim, Sam Min Kim, Jin Dong Kim and Yong Hae Kim*
Department of Chemistry, Korea Advanced Institute of Science & Technology, Taejon, 305-701, Korea.
E-mail: kimyh@sorak.kaist.ac.kr
Received (in Cambridge, UK) 30th March 1999, Accepted 20th April 1999
Diels–Alder cycloadditions of chiral acrylamides with cyclo-
pentadiene proceed with high diastereofacial selectivity,
giving either endo-R to endo-S products depending of the
Lewis acid used.
contrast to other general dienophiles, 1 containing a carboxylate
moiety reacts with 4 to give differently configured adducts
depending on the Lewis acids employed; in the presence of
TiCl4, Ti(OPri)4 or SnCl4, 6a was obtained as the major
diastereomer (6a:6b = endo-R:endo-S = > 99:1; entries 4–6
in Table 1), but with AlEt2Cl, ZnCl3 or BF3·Et2O the opposite
configuration of 6b was obtained (6a:6b = 1: > 99; entries
Lewis acid catalyzed addition of dienes to chiral acrylamides is
a useful reaction because it provides one of the most effective
methods for creating new chiral centers during the formation of
six-membered rings.1 Various types of chiral dienophiles such
as chiral esters,1 N-acyloxazole derivatives,2 N-acylsultams,3
acrylates4 and acrylamides5 have been developed. Metal
coordination is important for diastereofacial selectivity in the
asymmetric synthesis. Lewis acids have been used for chelate
formation in Diels–Alder cyclizations to obtain high diaster-
eofacial selectivities.1–5 In general, the S form of the chiral
dienophile (auxiliary) exclusively afford the endo-R adduct
over the endo-S one, and the R form exclusively gives the S
adduct over the endo-R one. Issues associated with this absolute
stereochemical control depending upon Lewis acids and the
structures of dienophiles provide an important challenge in the
area of practical Diels–Alder reaction designs.4a,5b
H
Lewis acid
Xc
+
+
H
COXc
O
COXc
endo-R
6a–8a
endo-S
6b–8b
1–3
4
COXc
1 Y = CO2Me
2 Y = CH2OMe
3 Y = CPh2OH
H
Xc =
+
COXc
H
Y
H
N
exo-R
6c–8c
exo-S
6d–8d
In the hope of obtaining the opposite configuration of the
endo adduct and understanding the mechanism, three different
dienophiles 1, 2 and 3 were prepared and reacted with dienes in
the presence of various Lewis acids. Here we describe the
intriguing results obtained during development of Lewis acid
dependent stereocontrol toward both endo-R and endo-S
configuration with high diastereofacial selectivity. In order to
generalize the results, the requisite dienophiles 1–3 were
synthesized from (S)-indoline-2-carboxylic acid.6 They were
purified and their optical purities ( > 99.8% ee) were determined
by HPLC (Daicel chiral OD column, PriOH–n-hexane, 5:95).
The preliminary studies involved reaction of 1–3 with 4 and 5,
as shown in Scheme 1.
5
TiCl4, Ti(OPri)4
SnCl4, ZrCl4
6a
+ 6b = 87–95%
endo R : endo S = >99 : 1
1
3
+
+
4
4
ZnCl2, AlEt2Cl
BF3•Et2O
6a
+ 6b = 83–93%
endo R : endo S = >1 : 99
TiCl4, SnCl4, ZrCl4
8a
+ 8b = 88–95%
ZnCl2, AlEtCl2, BF3•Et2O
CH2Cl2
endo R : endo S = >99 : 1
Extremely high levels of asymmetric induction can be
achieved in Diels–Alder cycloadditions of 1 or 3 with 4; in
Scheme 1
Table 1 Assymetric Diels–Alder cycloaddition with 1 and 3
Entry
Dienophile
Lewis acid
T/°C
t/h
Yield (%)a endo:exob endob ds
Config.c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1
1
1
1
1
1
3
3
3
3
3
3
3
3
3
2
2
Et2AlCl
BF3·Et2O
ZnCl2
TiCl4
Ti(OPri)4
SnCl4
—
Et2AlCl
AlCl3
BF3·Et2O
ZnCl2
TiCl4
Ti(OPri)4
SnCl4
ZrCl4
EtAlCl2
TiCl4
278
278
25
0
25
278
25
240
240
278
25
25
25
278
240
278
278
10
5
12
10
12
5
48
10
8
5
12
7
15
10
5
95
90
90
92
87
92
92
95
88
91
90
90
89
91
93
83
75
90:10
94:6
83:17
65:5
72:28
95:5
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
98:2
> 99:1
> 99:1
99:1
99:1
94:6
S
S
S
R
R
R
R
R
R
R
R
R
R
R
R
S
91:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
98:2
> 99:1
88:12
85:15
> 99:1
86:14
97:3
7
12
R
a Isolated yield. b Determined by HPLC analysis. (Chiral Column: Daicel OD). c Confirmed by [a]D of iodolactone or norbonene-2-methanol.
Chem. Commun., 1999, 963–964
963

H
O
H
O
O
O
M
OMe
Ph
Ph
In summary, asymmetric Diels–Alder cycloadditions of 1, or
3 with 4 proceed with absolutely stereocontrolled diaster-
eofacial selectivities in both endo-S and endo-R (up to > 99%
de) depending upon Lewis acids used and the structures of
chiral dienophiles.
This work was supported by the Center for Biological
Molecules, Korea Science and Engineering Foundation.
H
Me
N
N
N
O
O
M′
M′
O
Si
Si
Re
9
10
M′ = Ti, Sn, Zr, or H
Fig 1 Possible intermediates in Diels–Alder reactions.
11
M = Zn, Al, or B
Notes and references
1 For reviews, see L. A. Paquett, Asymmetric Synthesis, ed. J. D. Morrison,
Academic Press, New York, 1994, vol. 3; W. Oppolzer, Angew. Chem.,
Int. Ed. Engl., 1984, 23, 876; H. Waldmann, Synthesis, 1994, 535.
2 (a) D. A. Evans, K. T. Chapman and J. Bisaha, J. Am. Chem. Soc., 1986,
110, 1238 and references therein; (b) K. Kimura, K. Murata, K. Otsuka,
T. Shizuka, M. Maratake and T. Kunieda, Tetrahedron Lett., 1992, 33,
4461; (c) S. Castellino and W. J. Dwight, J. Am. Chem. Soc., 1993, 115,
2986; (d) S. Castellino, J. Org. Chem., 1990, 55, 5197; (e) M. R. Banks,
A. J. Blake, A. R. Brown, J. I. G. Cadosan, S. Gavr, I. Gosney, P. K. G.
Hodgson and P. Thorburn, Tetrahedron Lett., 1994, 35, 489; (f) N.
Hashimoto, T. Ishizuha and T. Kunieda, Tetrahedron Lett., 1994, 35,
721; (g) L. F. Tietze, C. Schneider and A. Montenbruck, Angew. Chem.,
Int. Ed. Engl., 1994, 33, 980.
3 W. Oppolzer, M. Wills, M. J. Kelly, M. Signer and J. Blagg, Tetrahedron
Lett., 1990, 35, 5015; W. Oppolzer, Pure Appl. Chem., 1990, 62, 1241
and references therein; W. Oppolzer, C. Chapus, G. M. Dao, D. Reichlin
and T. Godel, Tetrahedron Lett., 1982, 23, 4781; D. P. Curran, B. H. Kim,
J. Daugherty and T. A. Heffner, Tetrahedron Lett., 1988, 29, 3555; W.
Oppolzer, C. Chapuis and G. Bernardinelli, Helv. Chim. Acta, 1984, 67,
1397.
1–3 in Table 1). In the case of 2, the same trend of 7b was
observed, but in a less diastereoselective manner than for 1
(entries 16 and 17). In particular, 3 containing a diphenyl-
substituted tertiary alcohol moiety affords exceptionally high
diastereofacial selectivities (8a:8b = > 99:1, yield = > 90%;
entries 7–15) regardless of the natures of the Lewis acid. The
endo configurations were readily ascertained by iodolactoniza-
tion of 6a–8a with I2 in DMF.5b The exo compound cannot be
lactonized under the same reaction conditions. The ratio of
endo-R and endo-S was determined by HPLC with the crude
6a–8a and 6b–8b without purification.7 The absolute configura-
tion of 6a, 7b or 8a was determined by reductive cleavage of 6a
to the known norbornene-2-methanol and subsequent compar-
ison of [a]D values.8
The differently configured adducts produced can be ration-
alized by the different intermediates formed between 1–3 and
the metals of the Lewis acids. Compounds 1–3 react with 4 to
favor formation of endo-R species 6a or 8a with TiCl4,
Ti(OPri)4, SnCl4 or ZrCl4 probably via formation of seven-
membered ring chelates with the acryloyl moiety of 10 or 11
having a cisoid conformation.4a,5b Helmechen and co-workers
reported the first evidence of formation of a seven-membered
ring chelate complex.4a It is noteworthy that even in the absence
of any Lewis acid, 3 reacts with 4 to give an excellent chemical
yield (92%) and high stereofacial selectivity (endo:exo =
> 99:1, endo-R:endo-S = > 99:1; entry 9 in Table 1) at 25 °C
after a long reaction time (24 h). The results can be attributed to
the hydrogen-bond cisoid conformation intermediate 11 where
the hydrogen acts as a Lewis acid. On the other hand, 1 or 2
prefer endo-S formation 6b or 7b with ZnCl2, AlEtCl2 or
BF3·Et2O, with high diastereofacial selectivity probably result-
ing from intermediate 9, as shown in Fig. 1 In contrast to Ti or
Sn Lewis acids, relatively weaker Lewis acids such as Zn, Al, or
B may not form a seven-membered ring complex, instead
forming a weak coordination with the amide carbonyl group
(9).4a,5b In the case of Evans’ model dienophile, an a,b-
unsaturated S-oxazolidinone, the endo-R form was obtained2a
and explained by formation of a six-membered ring inter-
mediate with Et2AlCl, which was clarified by a 13C NMR
study.2c However, in contrast to a significant chemical shift
change9a in the 1–SnCl4 chelation complex 11, 13C NMR
measurement of the 1-Et2AlCl mixture did not show significant
changes in the chemical shifts for either of the amide or ester
carbonyl peaks,9b which can be explained by a weak coordina-
tion (9) between 1 and Et2AlCl. Species 1 and 3 also reacted
with less reactive acrylic diene 5 at 25 °C to result in the same
trend: for 1 with TiCl4 the ratio of endo R:endo S was 97:3,
while with EtAlCl2 the ratio was reversed to 3:97, which is
comparable to entry 1; for 3 with both TiCl4 and Et2AlCl, endo
R:endo S = 97:3 and 94:6 respectively, which is comparable
to entries 8 and 12.
4 (a) T. Poll, O. Metter and G. Helmechen, Angew. Chem., Int. Ed. Engl.,
1985, 24, 112; (b) T. Poll, G. Helmechen and B. Bauer, Tetrahedron Lett.,
1984, 25, 2191; (c) W. Choy, L. A. Reed, III and S. Masamune, J. Org.
Chem., 1983, 48, 1137; (d) W. Oppolzer, C. Chapuis, G. M. Dao, D.
Reichlin and J. T. Godel, Tetrahedron Lett., 1982, 46, 4781.
5 (a) Y. Kawanami, T. Katsuki and M. Yamaguchi, Bull. Chem. Soc. Jpn.,
1987, 60, 4190; (b) H. Waldmann, J. Org. Chem., 1988, 53, 6133,
Tetrahedron Lett., 1989, 30, 4227; (c) M. P. Buence, C. A. Cativiela and
J. A. Magorall, J. Org. Chem., 1991, 56, 6551; (d) R. K. Boeckman, Jr.,
S. G. Nelson and M. D. Gaul, J. Am. Chem. Soc., 1992, 114, 2258.
6 Y. H. Kim, D. H. Park and I. S. Byun, J. Org. Chem., 1993, 58, 4511;
Y. H. Kim, S. H. Kim and D. H. Park, Tetrahedron Lett., 1993, 34, 6063;
(c) Y. H. Kim and J. Y. Choi, Tetrahedron Lett., 1996, 37, 5543.
7 In a typical experimental, a Lewis acid (1 mmol) was added to a solution
of 1 (0.5 mmol) in CH2Cl2 (5 ml) under N2. After stirring 10 min, 4 (5
mmol) was added. The reaction mixture was stirred while following the
reaction by TLC, quenched with 1 M HCl solution, and then extracted
with CH2Cl2 three times. The organic layer was dried over anhydrous
MgSO4 and concentrated in vacuo. The endo configurations were
determined by the known iodolactonizations of 6a–8a with I2 in DMF [8a
lactone: [a]D 2110.6 (c 1.0, CHCl3)] [ref. 5(b)]. The ratio of endo-R and
endo-S was determined by HPLC analysis using a chiral column (Daicel
OD, PriOH–n-hexane 1:9).
8 J. A. Berson, A. Remanick, S. Suzuki, D. R. Warnhoff and D. Willner,
J. Am. Chem. Soc., 1961, 83, 3986; W. Krimse and R. Siegfried, J. Am.
Chem. Soc., 1983, 105, 950.
9 (a) The 13C NMR spectrum of the mixture of 6a and SnCl4 (1:1) was
taken to show the significant chemical shift changes of the acrylamide
carbonyl carbon (d 163.8) and ester carbonyl carbon (d 171.7) to d 169.6
and 175.0, respectively, which support formation of a seven-membered
ring complex between 6a and SnCl4. (b) In the case of 6a–Et2AlCl (1:2)
no significant chemical shift changes for the two carbonyl carbons could
be observed.
Communication 9/02535I
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Chem. Commun., 1999, 963–964