Platinum(II) chloride-catalyzed stereoselective domino enyne isomerization/diels-alder reaction

Article abstract of DOI:10.1021/jo1014068

Chiral 1,6-enynes were prepared via Ir-catalyzed allylic substitutions. Their platinum(II) chloride-catalyzed domino enyne isomerization/Diels-Alder reaction provided stereoselective access to complex heterocycles. Very high diastereoselectivity was induc

Full text of DOI:10.1021/jo1014068

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one pot, not a domino manner,3a i.e. by addition of the
Platinum(II) Chloride-Catalyzed Stereoselective
Domino Enyne Isomerization/Diels-Alder Reaction
dienophile after complete formation of the diene. Domino
sequences were accomplished by Bentz and Laschat3b for
Diels-Alder reactions at room temperature in the presence
of stoichiometric amounts of BCl3. We wondered whether
the domino sequence could be accomplished for thermal
Diels-Alder reactions, which would often require tempera-
tures not tolerated by Grubbs-type catalysts. We have now
found that this is possible with platinum(II) chloride as a
thermally stable catalyst. Thermal Diels-Alder reactions
could be carried out at 110 °C (refluxing toluene) with a high
degree of diastereoselectivity. In addition, we herein describe
the synthesis of a new class of chiral, 5-substituted enynes
that allows diastereoselective Diels-Alder reactions to give
complex tricyclic heterocycles of potential interest for medic-
inal chemistry.
Mathias Schelwies, Andreas Farwick, Frank Rominger, and
€
Gunter Helmchen*
€
Organisch-Chemisches Institut der Universitat Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
g.helmchen@oci.uni-heidelberg.de
Received July 26, 2010
In the exploratory work, the chiral 1,6-enynes 3a4 and 3b
were chosen as substrates. These compounds were prepared
from cinnamyl methyl carbonate (1) with high enantiomeric
purity (97.5-98.5% ee) by asymmetric Ir-catalyzed allylic
substitution and subsequent alkylation with propargyl bro-
mide (Scheme 2).5 Then catalysts for the enyne isomerization
were screened using 3a as substrate (Table 1).
Chiral 1,6-enynes were prepared via Ir-catalyzed allylic
substitutions. Their platinum(II) chloride-catalyzed
domino enyne isomerization/Diels-Alder reaction pro-
vided stereoselective access to complex heterocycles. Very
high diastereoselectivity was induced by a chirality center
of the enyne.
Despite phenomenologically similar reactivity toward 1,6-
enynes, the catalysts differ in substrate specificity, reaction
mechanism, and required reaction conditions.1b The Grubbs
catalysts I and II did not lead to complete conversion of
enyne 3a to diene 4. This has previously been observed for
other monosubstituted alkynes.6 Better results were ob-
9
tained with PtCl2,7 FeCl3,8 and [Au(PPh3)Cl]/AgSbF6 as
Isomerization reactions of 1,6-enynes, readily inducible by
transition metal complexes, offer access to a broad range of
dienes.1 The reaction course varies with the transition metal
catalyst and the substituents of the 1,6-enyne. Our objective
was a chemoselective enyne isomerization leading to a 1,3-diene
in the presence of a dienophile in order to achieve a stereo-
selective Diels-Alder reaction in domino2 fashion (Scheme 1).
catalysts. The catalyst Ph3PAuCl/AgSbF6, displaying the
highest activity, was not compatible with dienophiles at high
temperatures, i.e. product mixtures were formed. As best
suited catalyst, PtCl2 was identified, which induced high
yields and is thermally stable as is necessary for most
Diels-Alder reactions. This catalyst had already found
application as an enyne isomerization catalyst in total
synthesis.7,10
SCHEME 1. Domino Enyne Isomerization/Diels-Alder Reaction
For the domino reaction to yield cycloadducts 5, a solu-
tion of the enyne, a dienophile and PtCl2 in toluene was
heated at reflux (Table 2). A single diastereoisomer was
obtained in all cases. HPLC analysis of the crude products
showed complete conservation of enantiomeric purity.
(4) Schelwies, M.; Moser, R.; Dempwolff, A. L.; Rominger, F.; Helmchen,
G. Chem.;Eur. J. 2009, 15, 10888–10900.
(5) (a) Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem., Int. Ed.
Consecutive sequences of enyne metathesis, using Grubbs-
type catalysts, and Diels-Alder reaction have been
^
controlled diastereoselective reactions in a sequential
€
2004, 43, 4595–4597. (b) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwies,
M.; Weihofen, R. Chem. Commun. 2007, 675–691. (c) Streiff, S.; Welter, C.;
Schelwies, M.; Lipowsky, G.; Miller, N.; Helmchen, G. Chem. Commun.
2005, 2957–2959.
(6) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
6082–6083.
3
reported. Genet et al. accomplished interesting substrate-
(1) (a) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215–236. (b) Lee,
S. I.; Chatani, N. Chem. Commun. 2008, 371–384. (c) Diver, S. T.; Giessert,
A. J. Chem. Rev. 2004, 104, 1317–1382.
(7) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organometallics
1996, 15, 901–903.
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(8) Nieto-Oberhuber, C.; Munoz, M. P.; Lopez, S.; Jimenez-Nunez, E.;
Nevado, C.; Herrero-Gomez, E.; Raducan, M.; Echavarren, A. M. Chem.;
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(3) (a) Desroy, N.; Robert-Peillard, F.; Toueg, J.; Henaut, C.; Duboc, R.;
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Rager, M.-N.; Savignac, M.; Genet, J.-P. Synthesis 2004, 2665–2672.
Eur. J. 2006, 12, 1677–1693.
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(b) Bentz, D.; Laschat, S. Synthesis 2000, 1766–1773. (c) Rosillo, M.;
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(9) Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado, C.;
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DOI: 10.1021/jo1014068
r
Published on Web 10/19/2010
J. Org. Chem. 2010, 75, 7917–7919 7917
2010 American Chemical Society

Schelwies et al.
JOCNote
SCHEME 2. Ir-Catalyzed Allylic Substitution-Propargylation Sequence
TABLE 1. Catalyst Screening for the Enyne Isomerization of 3a
TABLE 2. Platium(II) Chloride-Catalyzed Domino Enyne Isomeriza-
tion/Diels-Alder Reaction
temp.
(°C)
conversion/
time
yield
(%)
entrya
catalyst
solvent
CH2Cl2
1
2
3
4
Grubbs0 I
Grubbs0 II CH2Cl2
rflx
rflx
80
14%,b 2 d
33%,b 2 d
full,c 3 h
PtCl2
toluene
90
74
Ph3PAuCl/ CH2Cl2
AgSbF6
FeCl3
rt
full,c <1 h
5
toluene
80
incomplete,c 26 h
66
aAll reactions were carried out under an argon atmosphere on a
0.5 mmol scale. bDetermined by GC. cDetermined by TLC.
Isolated yields were good with N-phenylmaleimide and
tetracyanoethylene as dienophiles and moderate other-
wise. Considering the complexity of this multistep transfor-
mation, even yields on the order of 40% are satisfactory.
The relative configurations of the products were deter-
mined for 5a, 5d, and 5e by crystal structure analyses.11
Accordingly, the Diels-Alder reaction proceeded via endo
addition at the less hindered face of the diene moiety (Figure 1).
FIGURE 1. Endo [4πs þ 2πs] transition state.
In conclusion, we are reporting a PtCl2-catalyzed domino
enyne isomerization/Diels-Alder reaction that offers access
to highly enantioenriched complex heterocycles.
Experimental Section
General Procedure for the PtCl2-Catalyzed Enyne Isomeriza-
tion Diels-Alder Reaction: (-)-Dimethyl (3aR,8R,8aR,8bS)-
1,3-Dioxo-2,8-diphenyl-2,3,3a,4,6,8,8a,8b-octahydrocyclopenta-
[e]isoindole-7,7(1H) Dicarboxylate (5a). A solution of (-)-(R)-3a
(97.5%ee, 286 mg, 1.0 mmol) and N-phenylmaleimide (346 mg,
aThe yield of 5a upon use of isolated, pure 4 was 69%.
2.0 mmol) in toluene (2 mL) was treated with PtCl2 (13.3 mg,
50 μmol), and the resulting solution was heated at reflux until
after 2 h TLC control [petroleum ether/ethyl acetate, 3:1, Rf(3a) =
0.37, Rf(5a) = 0.10, KMnO4] indicated complete consumption of 3a.
The reaction mixture was filtered through Celite, and this was
washed with CH2Cl2 (50 mL). The solvent was removed, and the
(11) CCDC-756790 (5a), CCDC-765791 (5d), and CCDC-765792 (5e)
contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
7918 J. Org. Chem. Vol. 75, No. 22, 2010

Schelwies et al.
JOCNote
residue was subjected to flash chromatography on silica gel (30 g,
petroleum ether/ethyl acetate, 3:1) to yield 5a as a slightly yellow
foam, which was dissolved in hot ethanol (10 mL). Upon cooling to
room temperature, crystallization occurred. After washing of the
crystals with cold n-hexane (-)-(3aR,8R,8aR,8bS)-5a (283 mg,
62%) was obtained as colorless and analytically pure needles
(mp 165-167 °C). The structure of the compound was confirmed
(3 s), 171.1 (s), 171.4 (s), 176.7, 178.9 (2 s); HR-MS (EI) m/z calcd
for C27H25NO6 [Mþ] 459.1683, found 459.1661; elemental analysis
calcd for C27H25NO6 C 70.58 H 5.48 N 3.05, found C 70.66 H 5.51
N 3.07.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (SFB 623), the Studienstiftung des deutschen
Volkes (scholarship to M.S.), and the Fonds der Chemischen
Industrie for financial support. We thank Olena Tverskoy for
experimental assistance.
20
by X-ray crystal structure analysis. [R]D = -148, (c = 0.42,
MeOH, 97.5% ee according to starting material); 1H NMR
(CDCl3, 300.13 MHz) δ = 2.32-2.43 (m, 1 H), 2.70-2.80 (m,
1 H), 2.89 (dd, J = 15.5 Hz, J = 7.1 Hz, 1 H), 3.11-3.29 (m, 4 H),
3.47, 3.66 (2 s, 6 H), 4.74 (d, J = 11.9 Hz, 1 H), 5.81-5.86 (m, 1 H),
7.17-7.42 (m, 10 H); 13C NMR (CDCl3, 75.48 MHz) δ = 22.6 (t),
40.1 (t), 40.5, 41.1, 44.7 (3 d), 50.8 (d), 52.1, 52.5 (2 q), 64.2 (s),
117.1 (d), 126.6, 127.7, 128.2, 128.8, 129.2 (5 d), 132.0, 137.5, 142.2
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds and
crystallographic information for 5a, 5d, and 5e. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 22, 2010 7919