M. E. Fox et al. / Tetrahedron Letters 48 (2007) 945–948
Table 1. Reaction of protected glycine equivalents with 3,4-epoxy-1-butene
947
Z
Pd source
Ligand
Solvent
Ligand/Pd molar ratio
Branched 7%
trans-8%
cis-9%
COOEt
COOEt
COOEt
CN
Pd(OAc)2
Pd(OAc)2
(allylPdCl)2
(allylPdCl)2
PPh3
THF
THF
CH2Cl2
CH2Cl2
4
2
2.5
2.5
0
0
100
100
50
44
0
50
56
0
DPPE
(S,S)-5
(S,S)-5
0
0
Product ratios were determined by 1H NMR.
Ph
N
Z
Ph
N
Z
Ph
N
Ph
H
MsCl, Et3N,
CH2Cl2
Ph
Ph
NaH, THF, or
KOtBu, THF
Z
Z
N
Ph
MsO
Ph
OH
+
7a Z = COOEt
7b Z = CN
10a Z = COOEt 59% from 6a
10b Z = CN 54% from 6b
11a Z = COOEt 24% 12a Z = COOEt 23%
11b Z = CN 30% 12b Z = CN 20%
56% for mixture of 11a and 12a
HCl, H2O,
toluene
H2N
COOEt
H2N
COOMe
MeOH, K2CO3
59%
24% from a crude
mixture of 11a and 12a
1b
1c
Scheme 3. Cyclisation of branched adducts to derivatives of (1R,2S)-dehydrocoronamic acid 1.
product 7. The ratio of diastereoisomers obtained was
3:2 for both nucleophiles. However, as discussed earlier,
this ratio is not important in achieving a high enantio-
meric excess in the synthesis of dehydrocoronamic acid
by this route; it is the control over the C2 stereocentre
which is of greater significance.
tion is thus the same and the enantiomeric excess com-
pares closely to the values obtained in other reactions
of 3,4-epoxy-1-butene using ligand (S,S)-5.
Thus, we have demonstrated a concise catalytic asym-
metric synthesis of dehydrocoronamic acid ethyl ester
1b using a novel strategy. We believe that with improve-
ments to the selectivity in the cyclisation step and with
an upgrade in enantiomeric excess, for example by crys-
tallisation as a suitable salt, this route has the potential
to provide an efficient synthesis of this important
molecule.
The branched adducts 7 were cyclised to derivatives of
dehydrocoronamic acid by mesylation of the primary
alcohol followed by treatment with sodium hydride or
potassium tert-butoxide (Scheme 3). An approximately
1:1 mixture of the desired cyclopropane 11 and 2,3-
dihydroazepine 12 resulting from facile aza-Cope rear-
rangement of the opposite diastereoisomer was obtained
with both nitrile7–9 and ester substrates. The mixture
was readily separated by chromatography. The benzo-
phenone imine protecting group of 11a was cleaved by
treatment with aqueous hydrochloric acid; conditions
under which the 2,3-dihydroazepine was unaffected.
Thus, by treatment of a toluene solution of the crude
mixture of 11a and 12a with aqueous hydrochloric acid,
the resulting cyclopropyl amino ester 1b was extracted
into the aqueous phase, leaving the unreacted
dihydroazepine 12a in the organic phase. Hence, it was
possible to isolate amino ester 1b from this mixture
without recourse to chromatography. The more
demanding nitrile to ester conversion required for 11b
was not attempted. In order to determine the enantio-
meric excess, ethyl ester 1b was converted to methyl ester
1c, for which we were able to develop a chiral GC as-
say.14 Thus, the absolute stereochemistry of the major
enantiomer was shown to be (1R,2S)15 and the enantio-
meric excess to be 88%. The facial selectivity in the
palladium-catalysed asymmetric allylic alkylation reac-
Acknowledgement
We are grateful to David Baldwin for assistance with
chiral analysis.
References and notes
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Bolger, G.; Bonneau, P.; Boes, M.; Cameron, D. R.;
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reau, N.; Kawai, S. H.; Kukolj, G.; Lagace, L.; LaPlante,
S. R.; Narjes, H.; Poupart, M.-A.; Rancourt, J.; Sentjens,
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Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong,
´
C.-L.; Llinas-Brunet, M. Nature 2003, 426, 186–189.
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Duceppe, J.-S.; Simoneau, B.; Wang, X.-J.; Zhang, L.;
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Krueger, T.; Schnaubelt, J. J. Org. Chem. 2005, 70, 5869–
5879.