Catalytic asymmetric synthesis of ethyl (1R,2S)-dehydrocoronamate

Article abstract of DOI:10.1016/j.tetlet.2006.12.025

A synthesis of (1R,2S)-dehydrocoronamic acid ethyl ester was developed employing a regio- and enantioselective palladium-catalysed nucleophilic ring-opening of 3,4-epoxy-1-butene with a glycine anion equivalent as the key enantiodifferentiating step. The

Full text of DOI:10.1016/j.tetlet.2006.12.025

Tetrahedron Letters 48 (2007) 945–948
Catalytic asymmetric synthesis of ethyl
(1R,2S)-dehydrocoronamate
Martin E. Fox,a,* Ian C. Lennona and Vittorio Farinab
aDowpharma, Chirotech Technology Ltd, a subsidiary of The Dow Chemical Company,
Unit 162 Cambridge Science Park, Milton Road, Cambridge CB4 0GH, UK
bDepartment of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road,
PO Box 368, Ridgefield, CT 06877-0368, USA
Received 10 October 2006; revised 24 November 2006; accepted 7 December 2006
Available online 26 December 2006
Abstract—A synthesis of (1R,2S)-dehydrocoronamic acid ethyl ester was developed employing a regio- and enantioselective palla-
dium-catalysed nucleophilic ring-opening of 3,4-epoxy-1-butene with a glycine anion equivalent as the key enantiodifferentiating
step. The desired selectivity was achieved using Trost’s naphthyl ligand. The subsequent activation of the free hydroxyl group
and ring-closure by intramolecular SN2 reaction gave the desired amino acid ethyl ester.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The cyclopropyl amino acid (1R,2S)-dehydrocoronamic
acid (1-amino-2-vinylcyclopropane-1-carboxylic acid,
vinyl-ACCA) 1a is a component of biologically active
molecules of interest to the pharmaceutical industry,
especially hepatitis C viral NS3 protease inhibitors such
as BILN 2061 (ciluprevir) 21–3 and other representative
examples such as 34 and 44,5 (Fig. 1). Owing to the wide
occurrence of 1 as a component of this class of
compound, we were interested in developing an efficient,
scaleable asymmetric synthesis of this compound. In
addition, cyclopropyl amino acids6 in general are com-
pounds of industrial importance, so such a synthesis
could have broader industrial applicability.
A high-yielding, large-scale synthesis of racemic 1 has
been developed employing a diastereoselective SN2-SN20
dialkylation of glycine anion equivalents with 2-butene-
1,4-dielectrophiles such as trans-1,4-dibromo-2-butene
(Scheme 1).2 The single enantiomer was obtained by res-
olution. In principle, a catalytic, asymmetric synthesis
MeO
O
O
Ph
H2N
HN
O
O
OR
N
H
N
N
N
O
H
N
O
S
O
S O
N
OMe
O
N
H
O
1a R = H
O
O
H
N
1b R = Et
1c R = Me
O
N
N
O
H
N
OH
O
N
O
O
O
O
N
H
OH
NH
NH
O
MeO
Ph
O
O
BILN 2061 2
3
4
Figure 1. Hepatitis C protease inhibitors containing (1R,2S)-dehydrocoronamic acid.
Keywords: Palladium; Asymmetric catalysis; Allylic alkylation; 3,4-Epoxy-1-butene; Amino acids.
*
Corresponding author. Tel.: +44 1223 728010; fax: +44 1223 506701; e-mail: mfox@dow.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.025

946
M. E. Fox et al. / Tetrahedron Letters 48 (2007) 945–948
O
R2
N
C1-C3
disconnection
R2
N
O
R1O
X
R3
X
C1-C2
disconnection
R3
OR1
+
SN2
R2
O
1
N
3
SN2'
R3
OR1
X
2
O
R2
N
R2
N
O
C1-C2
disconnection
R1O
R3
1
2
C1-C3
disconnection
R3
X
OR1
+
O
SN2
Scheme 1. Possible orders of C–C bond forming steps in cyclopropanation of a glycine anion equivalent.
has the potential to achieve a greater overall efficiency
than a resolution-based synthesis. Therefore, we were at-
tracted to this possibility. Asymmetric palladium-cataly-
sed versions of the racemic synthesis described above
have been reported.7–9 However, these gave a low enan-
tiomeric excess, and in some cases7,8 also required the
use of a chiral auxiliary. We considered an alternative
strategy (Scheme 1) involving reversal of the order of
C–C bond-forming steps in the overall cyclopropanation
sequence such that instead of forming the C1–C3 bond
followed by C1–C2, the C1–C2 bond is formed first,
followed by C1–C3. In this analysis, the nucleophilic
addition of a glycine anion equivalent to a (3-butene-1-
ol)-2-yl electrophile is required in the first step.
equivalent, as required for the synthesis of dehydro-
coronamic acid 1.
After this enantiodifferentiating step, closure of the 3-
membered ring by intramolecular SN2 reaction would
give the desired cyclopropyl amino acid. In the intermo-
lecular C–C bond forming step, two stereogenic centres
are formed giving rise to two diastereoisomers. In the
cyclisation step, C1 will be deprotonated to give a planar
enolate intermediate, and this stereocentre will be re-
formed during the intermolecular alkylation. Thus, the
stereochemistry obtained at this centre in the asymmet-
ric allylic alkylation reaction is not critical. However,
the C2 centre is unaffected in the cyclisation reaction
and is carried through unchanged into the product.
Control over the stereochemistry of the C2 centre results
from the facial selectivity of bond-formation at C3 of
the 3,4-epoxy-1-butene in the asymmetric allylic alkyl-
ation reaction. From the literature precedent with other
nucleophiles, the (S,S)-enantiomer of ligand 5 was ex-
pected to provide the (S)-stereochemistry at this centre
as required to give (1R,2S)-dehydrocoronamic acid.
We considered that this could be achieved by palla-
dium-catalysed nucleophilic ring-opening of 3,4-epoxy-
1-butene. In this asymmetric allylic alkylation reaction,
Trost’s naphthyl ligand 5 (Fig. 2) is uniquely capa-
ble,10–12 giving exclusively the branched adduct in
80–90% enantiomeric excess with both oxygen and
nitrogen-based nucleophiles. By analogy to the previ-
ously described examples, we expected to be able to
achieve selectivity for the branched product in the
addition of carbon nucleophiles, such as a glycine anion
We examined the reaction of two protected glycine
equivalents; glycine ethyl ester benzophenone imine 6a
and 2-aminoacetonitrile benzophenone imine 6b with
3,4-epoxy-1-butene using both chiral and achiral palla-
dium catalysts. Three potential products are possible
in this reaction, the desired branched product 7 and
the trans- and cis-linear products 8 and 9. The products
obtained were strongly dependent on the ligands used
O
O
N
H
N
H
(Scheme 2, Table 1). With simple achiral ligands, we ob-
PPh2 Ph2P
13
´
tained similar results to Mazon et al., with only linear
products 8 and 9 being obtained. There was little or no
selectivity for the double bond geometry. In contrast,
Trost’s naphthyl ligand gave entirely the branched
(S,S
)-5
Figure 2. Trost’s naphthyl ligand.
Ph
N
Z
Ph
N
Z
Ph
N
Z
1% Pd
ligand
Ph
N
Z
+
+
+
Ph
Ph
Ph
OH
O
Ph
OH
OH
6a Z = COOEt
6b Z = CN
7a Z = COOEt
7b Z = CN
8a Z = COOEt
8b Z = CN
9a Z = COOEt
9b Z = CN
Scheme 2. Reaction of protected glycine equivalents with 3,4-epoxy-1-butene.

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.
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