Catalytic asymmetric Diels-Alder reactions of α-thioacrylates for the preparation of norbornenone

Article abstract of DOI:10.1039/a805366i

Cu^II-bisoxazoline complexes catalyse the asymmetric Diels-Alder cycloaddition of α-thioacrylates with cyclopentadiene to give the cycloadducts in up to 92% yield, 88% de and > 95% ee for the endo product; deprotection gives good yields of (1S,4S)-norbornenone with high enantioselectivity.

Full text of DOI:10.1039/a805366i

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Catalytic asymmetric Diels–Alder reactions of a-thioacrylates for the
preparation of norbornenone
Varinder K. Aggarwal,*a† Emma S. Anderson,a D. Elfyn Jones,a Kerstin B. Obiereya and Robert Gilesb
a Department of Chemistry, University of Sheffield, Sheffield, UK S3 7HF
b SmithKline Beecham, Old Powder Mills, Tonbridge, Kent, UK TN11 9AN
CuII–bisoxazoline complexes catalyse the asymmetric Diels–
Alder cycloaddition of a-thioacrylates with cyclopentadiene
to give the cycloadducts in up to 92% yield, 88% de and
> 95% ee for the endo product; deprotection gives good
yields of (1S,4S)-norbornenone with high enantioselectiv-
ity.
substituent. Higher selectivity was obtained with phenylthio-
compared to methylthio-acrylates (entries 1 and 3) and higher
selectivity was obtained with small or moderately sized ester
substituents [Me, Et, Pri > > But (entries 2, 3, 6, 8 and 9)]. The
But ester was much less reactive than the other esters and the
reaction had to be conducted at 0 °C (entry 8). This presumably
was the cause of the reduction in enantioselectivity. Higher
selectivity was obtained at lower temperature (compare entries
3 and 4) and the use of cationic complexes16 led to high
reactivity even at 278 °C (entries 5 and 7) and high exo/endo
selectivity as well as high enantioselectivity. The optimum
reagents and conditions required ethyl a-phenylthioacrylate as
dienophile, the cationic phenyl-substituted bisoxazoline–cop-
The catalytic asymmetric Diels–Alder reaction has been an area
of considerable interest over the last two decades and a large
number of metals, ligands and dienophiles have been studied.1–4
The most successful systems have common features associated
with them: a bidentate ligand which complexes to the metal and
a dienophile which acts as a two point binder to the ligand–
metal complex.5–7 Two point binding of both the ligand to the
metal and dienophile to the complex results in limiting the
number of accessible conformations of the dienophile bound to
the Lewis acid and can result in high enantioselectivity.
We have been interested in developing ketene equivalents for
Diels–Alder reactions8 and have therefore sought dienophiles
that could be easily converted to carbonyl compounds. To
achieve good levels of enantioselectivity we also needed
dienophiles that could act as two point binders to appropriate
metals. a-Thioacrylates seemed ideal for our purpose as it was
known that a-methylthioacrylates underwent Diels–Alder reac-
tions with cyclopentadiene, for example, and that the adducts
could be readily converted into norbornenones.9–11 Such
dienophiles may also act as two point binders to appropriate
metals through carbonyl and sulfur coordination. We therefore
prepared a range of a-thioacrylates.12 We chose copper as the
metal due to its known propensity to bind to both the sulfide and
ester moieties and as ligands we chose bisoxazolines13,14 due to
the success of copper–bisoxazoline complexes in Diels–Alder
reactions.15–25
O
O
catalyst 8
R′S
SR′
OR
OR
SR'
O
OR
1 R = Et, R′ =Me
2 R = Me, R′ = Ph
3 R = Et, R′ = Ph
4 R = Pri, R′ = Ph
5 R = But, R′ = Ph
6 R =CH2CF3, R′ = Ph
O
2 +
2 Y –
H3C CH3
H3C CH3
CuY2
O
O
O
O
N
N
N
N
Diels–Alder reactions were conducted between cyclopenta-
diene and the various acrylates26 using the copper bisoxazoline
complex 827 (Scheme 1) and the results are shown in Table 1.
It was found that the selectivity of the Diels–Alder reaction
was highly dependent on the nature of the ester and thio
Cu
Ph
Ph
Ph
Ph
7
8
Scheme 1
Table 1 Diels–Alder reactions of a-thioacrylates with cyclopentadiene catalysed by Cu–bisoxazoline complexes
Dienophile
Entry
R
RA
Catalysta
t/h
T/°C
Yield (%)
exo:endob
Eec (%)
1
2
3
4
5
6
7
8
9
1
2
3
3
3
4
4
5
6
Et
Me
Et
Et
Et
Pri
Pri
But
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuBr2/AgSbF6
Cu(OTf)2
CuBr2/AgSbF6
Cu(OTf)2
6
6
6
9
1
4
2.5
5.5
1.5
240
240
240
278
278
240
278
0
53
44
50
76
92
70
90
91
92
1:2.4
1:3.7
1:4
40
84
80
> 95
> 95
85
81
26
1:7
d
d
d
1:15
1:2.3
1:5
1:2.5
1:13
CF3CH2 Ph
CuBr2/AgSbF6
278
> 95
a 20 mol% Cu(OTf)2, 30 mol% bisoxazoline 7, 1 equiv. dienophile and 4 equiv. cylopentadiene. b Determined by NMR integration of crude reaction mixtures.
c Determined by NMR integration in the presence of Pirkle’s reagent, (R)-(2)-2,2,2-trifluoro-1-(9-anthryl)ethanol. d 10 mol% of CuBr2/AgSbF6, 10 mol%
bisoxazoline 7, 1 equiv. dienophile and 4 equiv. cylopentadiene.
Chem. Commun., 1998
1985

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We thank the EPSRC and SB for a CASE award (E. A.), the
European Union and Sheffield University for additional
support. We thank Ian Davies (Merck) for valuable discus-
sions.
i
iii
SPh
OEt
SPh
OH
70%
88%
O
O
O
9
10
11
88% ee
Notes and References
>95% ee
15:1 (endo : exo )
15:1 (endo : exo )
27:1 (endo : exo )
ii
† E-mail: v.aggarwal@sheffield.ac.uk
Scheme 2 Reagents and conditions: i, KOH, BuiOH, H2O; ii, recrystallisa-
tion (light petroleum); iii, (PhO)2P(O)N3, Et3N, MeCN, H2O
1 W. Oppolzer, Angew. Chem., Int. Ed. Engl., 1984, 23, 876.
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6 E. J. Corey, D. BarnesSeeman and T. W. Lee, Tetrahedron Lett., 1997,
38, 1699.
per complex, and reaction at 278 °C in CH2Cl2 (entry 5); under
these conditions good diastereoselectivity and essentially
complete enantioselectivity was observed.
Conversion of the a-phenylthio ester to a carbonyl group was
initially problematic. Hydrolysis of the ester to the acid
occurred efficiently but attempts to convert the a-phenylthio
acid 10 to the carbonyl group using NCS was unsuccessful. This
reagent had previously been used to convert an a-methylthio
acid to a carbonyl group.9 We were eventually successful using
a different strategy: instead of activating the sulfide we
activated the acid and reacted the a-phenylthio acid with
diphenylphosphoryl azide28 and obtained the corresponding
ketone 11 directly in high yield and with 88% ee29 (Scheme 2).
The lower enantioselectivity observed for 11 is due to the
presence of the exo isomer in 10.
7 E. J. Corey, D. BarnesSeeman and T. W. Lee, Tetrahedron Lett., 1997,
38, 4351.
8 V. K. Aggarwal, J. Drabowicz, R. S. Grainger, Z. Gultekin, M.
Lightowler and P. L. Spargo, J. Org. Chem., 1995, 60, 4962.
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10 J. L. Boucher and L. Stella, Tetrahedron, 1988, 44, 3595.
11 J. L. Boucher and L. Stella, Tetrahedron, 1988, 44, 3607.
12 J. Durman, J. I. Grayson, P. G. Hunt and S. Warren, J. Chem. Soc.,
Perkin Trans. 1, 1986, 1939.
13 A. Pfaltz, Acc. Chem. Res., 1993, 26, 339.
14 A. V. Bedekar, E. B. Koroleva and P. G. Andersson, J. Org. Chem.,
1997, 62, 2518.
A transition state involving bidentate binding of the dieno-
phile via sulfur and the carbonyl oxygen to a square planar CuII
complex15,16,21,23,24,30,31 may be used to rationalise the enantio-
and diastereo-selectivities. However, the high enantioselectivity
observed is perhaps surprising as the alkene of the dienophile
lies close to the C2 axis of the metal catalyst where it encounters
the minimum steric influence from the phenyl groups of the
oxazoline moiety. Indeed, all successful dienophile–metal–
oxazoline combinations place the alkene moiety directly over
one of the oxazoline substituents where it has maximum
influence on the enantioselectivity of the reaction.32 In our case
we believe that the substituent on sulfur plays a major role in
controlling enantioselectivity. We believe there is very high
diastereoselectivity in formation of the dieneophile–metal–
oxazoline complex (only one of the two enantiotopic lone pairs
binds to the copper) and it is the orientation of the sulfur
substituent which controls the facial attack on the dienophile
(Fig. 1). This substituent is forced below the plane of the
complex and when this group is large it effectively blocks the Si
face of the dienophile and therefore forces the diene onto the Re
face. From analysis of molecular models, the opposite enantio-
mer would be expected if the dienophile was bound to Cu in a
tetrahedral arrangement. This provides further circumstantial
evidence for a square planar complex.
15 D. A. Evans, S. J. Miller and T. Lectka, J. Am. Chem. Soc., 1993, 115,
6460.
16 D. A. Evans, J. A. Murry, P. Vonmatt, R. D. Norcross and S. J. Miller,
Angew. Chem., Int. Ed. Engl., 1995, 34, 798.
17 D. A. Evans, M. C. Kozlowski and J. S. Tedrow, Tetrahedron Lett.,
1996, 37, 7481.
18 D. A. Evans and D. M. Barnes, Tetrahedron Lett., 1997, 38, 57.
19 D. A. Evans and J. S. Johnson, J. Org. Chem., 1997, 62, 786.
20 D. A. Evans, E. A. Shaughnessy and D. M. Barnes, Tetrahedron Lett.,
1997, 38, 3193.
21 I. W. Davies, C. H. Senanayake, R. D. Larsen, T. R. Verhoeven and
P. J. Reider, Tetrahedron Lett., 1996, 37, 1725.
22 I. W. Davies, L. Gerena, L. Castonguay, C. H. Senanayake, R. D.
Larsen, T. R. Verhoeven and P. J. Reider, Chem. Commun., 1996,
1753.
23 I. W. Davies, L. Gerena, D. W. Cai, R. D. Larsen, T. R. Verhoeven and
P. J. Reider, Tetrahedron Lett., 1997, 38, 1145.
24 M. Johannsen and K. A. Jorgensen, J. Org. Chem., 1995, 60, 5757.
25 M. Johannsen, S. Yao and K. A. Jorgensen, Chem. Commun., 1997,
2169.
26 The acrylates were prepared from the corresponding sulfoxides by a
Pummerer reaction. See: J. Durman, J. I. Grayson, P. G. Hunt and S.
Warren, J. Chem. Soc., Perkin Trans. 1, 1986, 1939; H. J. Monteiro and
A. L. Gemal, Synthesis, 1975, 437.
27 The catalyst formed from the phenyl-substituted bisoaxazoline with
Cu(OTf)2 was found to be much more reactive at room temperature than
catalysts incorporating Bui-, Bn- or But-substituted bisoxazolines which
required up to eight days to go to completion. Studies were therefore
concentrated on the phenyl-substituted bisoaxazoline.
28 K. Ninomiya, T. Shioiri and S. Yamada, Tetrahedron, 1974, 30,
2151.
29 Chiral GC analysis of (±)-9 was carried out on a Chiral cyclodextrin a
column (30 m, 0.25 mm i.d.), using hydrogen as the carrier gas at 16 psi,
70 °C isothermal, flame ionisation detection. (1R,4R)-(+)-9 had a
retention time of 10.50 min while (1S,4S)-(2)-9 had a retention time of
10.04 min. From GC analysis, (1S,4S)-(2)-9 was obtained with 88%
ee.
H
Me
O
N
O
OEt
Cu
Ph
Me
N
S
•
Ph
•
O
Ph
H
30 D. A. Evans, M. C. Kozlowski, C. S. Burgey and D. W. C. MacMillan,
J. Am. Chem. Soc., 1997, 119, 7893.
Fig. 1 The dienophile–metal–oxazoline complex
31 Jorgensen has suggested that reactions occur via square planar and
tetrahedral Cu complexes depending on the substitution of the oxazoline
(ref. 24).
32 For an exception, see: Y. Honda, T. Date, H. Hiramatsu and M.
Yamauchi, Chem. Commun., 1997, 1411. They carried out a cycloaddi-
tion between a benzoylacrylate and cyclopentadiene using MgI2–
bisoxazoline complex. No comment was made on the origin of the
enantioselectivity.
The size of the ester group of the dienophile is critical; an
excessively bulky group may prevent the essential two-point
binding, as seems to be the case with tert-butyl. Equally, the
substituent on sulfur of the dienophile is also critical. Although
the same discrimination between the lone pairs on sulfur may be
observed with the S-methyl substituted dienophile, the methyl
group is not sufficiently sterically hindering to effectively block
the Si face to approach of the diene component, resulting in
significantly reduced enantioselectivity in this case.
Received in Liverpool, UK, 10th July 1998; 8/05366I
1986
Chem. Commun., 1998