Exo-selective asymmetric inverse-electron demand hetero-diels-alder reaction catalyzed by Cu(II)-hydroxy oxazoline ligands

Article abstract of DOI:10.1055/s-0030-1260780

Cu(II) complexes of hydroxy oxazolines derived from (+)-(S)-ketopinic acid catalyze the asymmetric hetero-Diels-Alder cycloaddition of enol ethers and ,-unsaturated -keto esters. The reaction takes place with unprecedented exo selectivity providing 2,4-trans-disubstituted chiral 2,3-dihydropyrans with up to 88% ee. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260780

1592
LETTER
Exo-Selective Asymmetric Inverse-Electron Demand Hetero-Diels–Alder
Reaction Catalyzed by Cu(II)–Hydroxy Oxazoline Ligands
E
xo
-
Selective Asym
n
metric
H
ete
d
r
o-Diels–A
l
r
der Reac
e
tion a Barba, Santiago Barroso, Gonzalo Blay,* Luz Cardona, Martina Melegari, José R. Pedro*
Departament de Química Orgànica, Facultat de Química, Universitat de València, 46100 Burjassot (València), Spain
Fax +34(963)544328; E-mail: gonzalo.blay@uv.es; E-mail: jose.r.pedro@uv.es
Received 30 March 2011
On the other hand, the development of new chiral mole-
Abstract: Cu(II) complexes of hydroxy oxazolines derived from
(+)-(S)-ketopinic acid catalyze the asymmetric hetero-Diels–Alder
cycloaddition of enol ethers and b,g-unsaturated a-keto esters. The
reaction takes place with unprecedented exo selectivity providing
cules that can be used as ligands in asymmetric Lewis acid
catalyzed reactions constitutes an area of intense research.
We have previously developed hydroxy oxazoline ligands
2,4-trans-disubstituted chiral 2,3-dihydropyrans with up to 88% ee. derived from (+)-(S)-ketopinic acid and amino alcohols.
The copper(II) complexes of these ligands were good cat-
alysts for the asymmetric Diels–Alder reaction.12 As a
continuation of our research on asymmetric cycloaddition
reactions,13 we report here the first example of asymmet-
ric inverse-electron demand HDA reaction between vinyl
ethers and b,g-unsaturated a-keto esters which takes place
with exo diastereoselectivity, by using these ligands and
copper(II) salts.
Key words: asymmetric catalysis, cycloaddition, copper, acetals,
heterocycles
The tetrahydropyran and dihydropyran moieties are
present in a large number of natural products and bioac-
tive compounds.1 Compounds having these structural sub-
units also serve as versatile and important building blocks
in organic synthesis.2 Inverse-electron demand hetero-
Diels–Alder (HDA) reactions between p-electron-defi-
cient oxadienes (a,b-unsaturated ketones) and electron-
rich dienophiles is one of the most straightforward proce-
dures to prepare 2,3-dihydropyrans (Scheme 1). This re-
action has been thoroughly studied over the past decades,3
and the development of some asymmetric versions has
been achieved by using different chiral Lewis acids.4 Af-
ter the initial studies by Tietze5 and Wada6 with Ti(IV)
catalysts, an important breakthrough was the use of BOX-
Cu(II) complexes as catalysts in the HDA reactions of vi-
nyl ethers with a,b-unsaturated acyl phosphonates and
a,b-unsaturated acyl esters described by the groups of
Evans7 and Jørgensen,8 respectively.9 Our group has also
used this catalytic system in an asymmetric inverse-elec-
tron demand HDA reaction with 2-alkenoyl pyridine N-
oxides as oxadienes.10 In all these cases the corresponding
2,4-cis-disubstituted adducts, resulting from the endo ap-
proach between the alkene and the oxadiene were ob-
tained as the major diastereomers, with good enantiomeric
excesses. However, to the best of our knowledge, an
asymmetric inverse-electron demand HDA reaction pro-
viding the enantioenriched 2,4-trans-disubstituted ad-
ducts (exo approach) has not been reported.11
MsCl, Et3N,
1. SOCl2, reflux
CH2Cl2
O
O
NH2
HO
or Mo(VI),
toluene, reflux
NH
HO
HO2C
2.
O
Et3N, CH2Cl2, 0 °C
LiAlH4⋅2THF,
toluene, –10 °C
OH
or NaBH4, CeCl3,
MeOH, –10 °C
O
O
O
N
N
OH
OH
OH
O
N
O
3
N
O
N
1
2
Ph
R1O
O
X
R1O
O
X
O
X
R1O
OH
OH
OH
+
+
O
N
O
O
N
N
R2
R2
5
6
4
R2
exo
endo
Ph
Scheme 1 Inverse-electron demand hetero-Diels–Alder reaction
SYNLETT 2011, No. 11, pp 1592–1596
Advanced online publication: 10.06.2011
DOI: 10.1055/s-0030-1260780; Art ID: B06711ST
x
x
.x
x
.2
0
1
1
Scheme 2 Hydroxy oxazoline ligands derived from (+)-(S)-keto-
pinic acid used in this study: synthesis and structures
© Georg Thieme Verlag Stuttgart · New York

LETTER
Exo-Selective Asymmetric Hetero-Diels–Alder Reaction
1593
With ligands 1–6 in hand, we studied the reaction between
ethyl vinyl ether (7a) and (E)-ethyl 2-oxo-4-phenylbut-3-
enoate (8a) to optimize the conditions (Scheme 3). The re-
sults are gathered in Table 1.
Table 1 Reaction between Ethyl Vinyl Ether (7a) and (E)-Ethyl 2-
Oxo-4-phenylbut-3-enoate (8a); Screening of Ligands and Solvents
Entry
1
L
1
2
3
4
5
6
5
5
5
5
5
5
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Time (h) Yield (%)a 9aa/10aab ee (%)c
1.5
2
83
89
91
92
90
91
90
90
92
95
86
89
80:20
74:26
86:14
89:11
100:0
81:19
10:90
71:29
70:30
90:10
67:33
76:24
-54:13
-47:50
-49:23
+30:50
+52:nd
+38:10
+10:8
Following our previous studies on the Diels–Alder reac-
tion, a first screening of the prepared ligands 1–6 was car-
ried out using copper(II) triflate as Lewis acid, in
dichloromethane at 0 °C. Under these conditions, all
ligands favored the formation of the 2,4-trans-disubstitut-
ed adduct 9aa. This was determined from the coupling
constants for the H(2) signal in the 1H NMR spectrum of
9aa, which appeared at d = 5.25 as a triplet (t, J = 2.4 Hz)
indicating the pseudoequatorial orientation of this proton
as expected for the trans diastereomer, while in the cis di-
astereomer 10aa, the signal for this proton appeared at d =
5.16 as a doublet of doublets (dd, J = 8.1, 2.7 Hz) as it has
been observed with other 2,4-cis-disubstituted 3,4-dihy-
dropyrans, in which this proton is oriented in a pseudoax-
ial position. On the other hand, the major enantiomer
obtained for the7,8 exo adduct depended exclusively on the
stereochemistry of the stereogenic center at the oxazoline
ring. Thus, oxazolines 1–3, prepared from (S)-amino alco-
hols, gave the levorotatory product (–)-(2R,4S)-9aa, and
oxazolines 4–6, prepared from (R)-amino alcohols gave
the enantiomeric dextrorotatory product (+)-(2S,4R)-9aa.
This inversion was not always observed with the minor
diastereomer 10aa. Ligand 5 gave the best overall results
in terms of diastereo- and enantioselectivity (entry 5).
When Zn(II) instead of Cu(II) was used, an inversion of
the diastereoselectivity was observed, the 2,4-cis adduct
10aa (endo approach) being favored, although with low
ee. Decreasing the temperature to –20 °C improved the ee
values, although the diastereoselectivity was decreased.
We then tested different solvents and with EtOAc we
could obtain the highest ee value, still maintaining the
diastereoselectivity in a reasonable 76:24 ratio, favoring
the exo-adduct 9aa (entry 12).
2
3
3
4
2
5
1.5
4
6
7d
8e
9
16
3
+64:59
+73:50
+50:22
+62:66
+81:19
1.5
10
11
12
toluene
hexane
EtOAc
16
3
3
a Isolated yield (9aa + 10aa).
b Determined by 1H NMR.
c Determined by HPLC on chiral stationary phases. For 9aa (only) (+)
refers to the (2S,4R)-enantiomer and (-) to the (2R,4S)-enantiomer.
d Zn(OTf)2 was used.
e Reaction was carried out at –20 °C.
The synthesis of ligands 1–6 was carried out according to
our previous procedure,12 which is outlined in Scheme 2.
Thus, (S)-ketopinic acid chloride was condensed with the
appropriate amino alcohol to give a hydroxy amide, which
was then cyclized to the oxazoline. This step was carried
out with mesyl chloride–Et3N for hydroxy amides derived
from primary alcohols, and by dehydration with
(NH4)6Mo7O24·4H2O in toluene at reflux temperature14 for
hydroxy amides derived from secondary alcohols. Final-
ly, reduction of the ketone carbonyl group at C(2) of the
norbornane skeleton provided compounds 1–6 bearing an
exo C(2)-OH group as the major products. These ligands
were prepared to study the effect of different substituents
on the oxazoline ring. Ligands 1–3 derived all from (S)-
amino alcohols with different substituents; an aliphatic
isopropyl group for 1, an aromatic phenyl group for 2, and
a conformationally restricted indane ring for 3. Ligands
4–6 are the corresponding diastereomers derived from the
(R)-amino alcohols.
With these optimized conditions we studied the scope of
the reaction. First, we tested the reaction of ethyl vinyl
ether (7a) with different b,g-unsaturated a-keto esters 8
(Scheme 4, Table 2).
The alkoxy group OR2 of the ester showed some influence
on the stereoselectivity of the reaction (entries 1–3), the
best result being obtained with a medium-sized ethoxy
group. The R1 group on the g carbon was also amenable to
variation. Diastereoselectivities in the range of 63:37 to
78:22 were obtained, favoring the formation of the 2,4-
trans-diastereomer 9 (exo approach) in all the cases. High
enantioselectivities, near or above 85% ee, were obtained
O
1
2
EtO
O
6
CO2Et
EtO
O
CO2Et
O
L (0.1 equiv)
EtO
OEt
Cu(OTf)2 (0.1 equiv)
+
3
5
+
4
0 °C, solvent
Ph
Ph
Ph
7a
8a
9aa
(2,4-trans,exo)
10aa
(2,4-cis,endo)
Scheme 3 HDA reaction between ethyl vinyl ether (7a) and (E)-ethyl 2-oxo-4-phenylbut-3-enoate (8a)
Synlett 2011, No. 11, 1592–1596 © Thieme Stuttgart · New York

1594
A. Barba et al.
LETTER
O
CO2R2
EtO
O
CO2R2
EtO
O
O
EtO
OR2
5 (0.1 equiv)
Cu(OTf)2 (0.1 equiv)
+
+
0 °C, EtOAc
R1
R1
R1
7a
8a–i
9aa–ai
10aa–ai
(exo)
(endo)
Scheme 4 HDA reaction between ethyl vinyl ether (7a) and b,g-unsaturated a-keto esters 8 catalyzed by the 5-Cu(OTf)2 complex
when R1 was an aromatic ring, regardless of the electron- To determine the absolute stereochemistry of the major
withdrawing (entries 4 and 5) or electron-donating (entry exo adducts 9 resulting from this HDA reaction, com-
6) properties of the substituent, or when R1 was a hetero- pound (+)-9aa (Table 2, entry 1) was converted into
aromatic ring (entries 7 and 8). However, when R1 was an butenolide 11 following a four-steps sequence involving
aliphatic methyl group, we observed a serious decrease in ozonolysis of the double bond and reductive treatment of
the ee of the resulting product (entry 9).
the ozonide, hydrolysis of the acetal and oxidation of the
resulting lactol (Scheme 6).7d In this way, the known
butenolide15 (S)-(+)-11 was obtained which allowed us to
assign the absolute stereochemistry of compound (+)-9aa
as (2S,4R). For the rest of the major exo-adducts 9
(Tables 2 and 3) it was assigned as (2S,4R) on the assump-
tion of a uniform mechanistic pathway.16
Table 2 Reaction between Ethyl Vinyl Ether (7a) and b,g-Unsatur-
ated a-Keto Esters 8 Catalyzed by the 5-Cu(OTf)2 Complex
Entry R1
R2
Time 9–10 Yield 9/10b ee
(h)
(%)a
89
87
83
98
84
88
87
84
87
(%)c
76:24 81:19
72:28 74:14
80:20 62:3
76:24 88:2
73:27 85:30
63:37 88:nd
75:25 87:25
78:22 84:25
72:28 45:16
1
2
3
4
5
6
7
8
9
Ph
Et
3
aa
ab
ac
ad
ae
af
In summary, we have described a new catalytic enantiose-
lective hetero-Diels–Alder reaction between vinyl ethers
and b,g-unsaturated a-keto esters which is catalyzed by
new copper(II) complexes of ketopinic acid based hy-
droxy oxazoline ligands.17 The reaction provides 2,4-
trans-disubstituted chiral dihydropyrans with up to 88%
ee. To the best of our knowledge, this is the first example
Ph
Me
i-Pr
Et
3
Ph
3
4-NO2C6H4
4-BrC6H4
4-MeOC6H4
2-furyl
2-thiophenyl
Me
3
Et
3
Et
3
Table 3 Reaction between Different Dienophiles 7 and b,g-Unsat-
urated a-Keto Ester 8a Catalyzed by the 5-Cu(OTf)2 Complex
Et
3
ag
ah
ai
Entry R3
R4
Time 9–10 Yield 9/10b ee
Et
3
(h)
(%)a
96 90:10 75:nd
60 2:98 nd:32
44 13:87 2:37
(%)c
Et
3
1
2
3
OEt
Me
H
3
ba
ca
da
a Isolated yield (9 + 10).
b Determined by 1H NMR.
c Determined by HPLC on chiral stationary phases.
SEt
24
24
2-pyrrolidone
H
a Isolated yield (9 + 10).
Finally we examined the influence of the dienophile
(Scheme 5, Table 3). With 1,1-disubstituted vinyl ether
7b (R3 = EtO, R4 = Me) the reaction proceeded with good
yield, high diastereoselectivity (exo/endo = 90:10) and
fair enantioselectivity, providing the major exo adduct
9ba with 75% ee. However, when the dienophile was a vi-
nyl thioether or an enamine, the HDA reaction took place
more slowly to give the corresponding endo diastereo-
mers 10ca and 10da with low enantioselectivities (entries
2 and 3).
b Determined by 1H NMR.
c Determined by HPLC on chiral stationary phases.
O
1. O3, CH2Cl2–MeOH, –80 °C
2. NaBH4, –80 °C to r.t.
EtO
O
CO2Et
O
3. 1 M HCl, THF, reflux
4. TPAP, NMO, 4 Å MS, CH2Cl2
Ph
(S)-(+)-11
Ph
13%
(+)-9aa
Scheme 6
R4
R4
O
R3
O
CO2Et
R3
O
CO2Et
R3
R4
O
5 (0.1 equiv)
OEt
Cu(OTf)2 (0.1 equiv)
+
+
0 °C, EtOAc
Ph
Ph
Ph
7b–d
8a
9ba–da
10ba–da
(exo)
(endo)
Scheme 5 HDA reaction between dienophiles 7 and b,g-unsaturated a-keto ester 8a catalyzed by the 5-Cu(OTf)2 complex
Synlett 2011, No. 11, 1592–1596 © Thieme Stuttgart · New York

LETTER
Exo-Selective Asymmetric Hetero-Diels–Alder Reaction
1595
(10) Barroso, S.; Blay, G.; Muñoz, M. C.; Pedro, J. R. Adv. Synth.
Catal. 2009, 351, 107.
of such a catalytic enantioselective HDA reaction which
leads preferentially to the exo diastereomer.
(11) Selective endo or exo approach in the HDA reaction between
vinyl ethers and a,b-unsaturated acyl esters, has been
accomplished by using Eu or Sn Lewis acids, in a non-
asymmetric reaction, see: Martel, A.; Leconte, S.; Dujardin,
G.; Brown, E.; Maisonneuve, V.; Retoux, R. Eur. J. Org.
Chem. 2002, 514.
Acknowledgment
The authors thank the Ministerio de Ciencia e Innovación and
FEDER (CTQ2009-13083) and the Generalitat Valenciana
(ACOMP/2009/338) for financial support. S.B. thanks the Univer-
sitat de València for a pre-doctoral grant (V Segles program).
(12) Barroso, S.; Blay, G.; Cardona, L.; Pedro, J. R. Synlett 2007,
2659.
(13) (a) Barroso, S.; Blay, G.; Pedro, J. R. Org. Lett. 2007, 9,
1983. (b) Barroso, S.; Blay, G.; Al-Midfa, L.; Muñoz, M. C.;
Pedro, J. R. J. Org. Chem. 2008, 73, 6389. (c) Barroso, S.;
Blay, G.; Muñoz, M. C.; Pedro, J. R. Org. Lett. 2011, 13,
402.
References and Notes
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(16) We have not determined the absolute stereochemistry of the
minor endo-adducts 10. For a description of these adducts
see refs. 5 and 6.
(17) Synthesis of Ligand 5: A solution of (S)-(+)-ketopinic acid
(1; 1.0 g, 5.5 mmol) in SOCl2 (4.5 mL) was refluxed for 2 h
and the excess SOCl2 was removed under reduced pressure.
The residue dissolved in CH2Cl2 (3.8 mL) was added drop-
wise to a solution of (R)-2-amino-2-phenylethanol (0.76 g,
5.5 mmol) and Et3N (0.75 mL, 5.5 mmol) in CH2Cl2 (3 mL)
at 0 °C under nitrogen. After 1 h, the mixture was diluted
with EtOAc (150 mL), washed with 2 M HCl (2 × 30 mL),
sat. aq NaHCO3 (2 × 30 mL) and brine (30 mL), dried
over MgSO4 and concentrated. The crude product was
crystallized from hexane–CH2Cl2 to give 1.49 g (90%) of
hydroxy amide; mp 140–142 °C; [a]D25 –6.2 (c = 0.78,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 8.37 (d, J = 6.4 Hz,
1 H), 7.32 (m, 5 H), 5.15 (td, J = 5.4, 7.0 Hz, 1 H), 3.87 (m,
2 H), 2.81 (s, 1 H), 2.58 (m, 1 H), 2.51 (dd, J = 4.7, 8.5 Hz,
1 H), 2.17 (m, 1 H), 2.09 (t, J = 4.4 Hz, 1 H), 2.00 (d, J = 18.8
Hz, 1 H), 1.69 (ddd, J = 4.6, 9.2, 13.8 Hz, 1 H), 1.45 (m, 1
H), 1.22 (s, 3 H), 0.94 (s, 3 H). 13C NMR (75.5 MHz,
CDCl3): d = 217.3 (s), 169.8 (s), 139.0 (s), 128.7 (d), 127.6
(d), 126.5 (d), 67.1 (t), 64.5 (s), 55.7 (d), 50.3 (s), 43.6 (t),
43.2 (d), 28.4 (t), 27.7 (t), 20.8 (q), 20.3 (q). MS (FAB):
m/z (%) = 302 (100) [M+ + 1], 154 (71), 137 (58). HRMS:
m/z calcd for C18H24NO3: 302.1756; found: 302.1754.
Mesyl chloride (6.75 mmol) was added dropwise to a
solution of hydroxy amide (1.03 g, 3.4 mmol), Et3N (5.8 mL)
and diisopropylethylamine (1.2 mL) in CH2Cl2 (17 mL)
under nitrogen at 0 °C. The reaction was stirred overnight.
After this time, the reaction mixture was diluted with EtOAc
(200 mL), washed with H2O (2 × 25 mL) and brine (25 mL),
dried over MgSO4, concentrated under reduced pressure and
the product was purified by flash chromatography eluting
with hexane–EtOAc to give 0.93 g (96%) of keto-oxazoline;
mp 122–125 °C; [a]D25 +88.5 (c = 0.73, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 7.29 (m, 5 H), 5.23 (dd, J = 8.0, 10.2
Hz, 1 H), 4.67 (dd, J = 8.5, 10.1 Hz, 1 H), 4.07 (t, J = 8.1 Hz,
1 H), 2.49–2.64 (m, 2 H), 2.16 (t, J = 4.4 Hz, 1 H), 2.07 (m,
1 H), 1.98 (d, J = 18.3 Hz, 1 H), 1.84 (ddd, J = 4.7, 9.2, 13.9
Hz, 1 H), 1.43 (ddd, J = 4.0, 9.2, 12.9 Hz, 1 H), 1.19 (s, 3 H),
1.13 (s, 3 H). 13C NMR (75.5 MHz, CDCl3): d = 211.9 (s),
165.4 (s), 142.4 (s), 128.6 (d), 127.4 (d), 126.5 (d), 74.8 (t),
69.3 (d), 63.0 (s), 49.4 (s), 44.4 (d), 43.8 (t), 27.3 (t), 26.6 (t),
21.4 (q), 19.8 (q). MS (EI): m/z (%) = 283 (73) [M+], 268
(26), 255 (99), 240 (60), 214 (28), 210 (19), 165 (24), 120
(27), 104 (60), 91 (100), 77 (67), 67 (81). HRMS: m/z calcd
for C18H21NO2: 283.1572; found: 283.1571.
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4487. (c) Zhuang, W.; Thorhauge, J.; Jørgensen, K. A.
Chem. Commun. 2000, 459. (d) Audrian, H.; Jørgensen,
K. A. J. Am. Chem. Soc. 2000, 122, 11543.
(9) The HDA reaction has also been carried out with
immobilized BOX ligands, see: (a) Shin, Y. J.; Yeom, C.-E.;
Kim, M. J.; Kim, B. M. Synlett 2008, 89. (b) O’Leary, P.;
Krosveld, N. P.; De Jong, K. P.; van Koten, G.;
Klein Gebbink, R. J. M. Tetrahedron Lett. 2004, 45, 3177.
(c) Wan, Y.; McMorn, P.; Hancock, F. E.; Hutchings, G. J.
Catal. Lett. 2003, 91, 145. (d) Kurosu, M.; Porter, J. R.;
Foley, M. A. Tetrahedron Lett. 2004, 45, 145.
Synlett 2011, No. 11, 1592–1596 © Thieme Stuttgart · New York

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A. Barba et al.
LETTER
A solution of [LiAlH4·2THF] complex in toluene (1 M, 1.5
mL, 1.5 mmol) was added dropwise to a solution of keto-
oxazoline (0.47 g, 1.67 mmol) in toluene (17 mL) under
nitrogen at –40 °C. The reaction was stirred until the starting
material was consumed (TLC). The reaction mixture was
then diluted with EtOAc (150 mL), washed with brine (3 ×
10 mL), dried over MgSO4, concentrated under reduced
pressure and the product was purified by flash chromato-
graphy eluting with hexane–EtOAc to give 295 mg (62%) of
compound 5 and 71 mg (15%) of its C2-epimer. Compound
5: [a]D25 +14.3 (c = 1.02, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 7.25 (m, 5 H), 5.53 (br s, 1 H), 5.20 (dd, J = 7.7,
10.1 Hz, 1 H), 4.53 (dd, J = 8.4, 10.2 Hz, 1 H), 4.06 (dd, J =
3.5, 7.8 Hz, 1 H), 4.00 (t, J = 8.1 Hz, 1 H), 2.20 (m, 1 H),
1.83–1.96 (m, 2 H), 1.70–1.80 (m, 2 H), 1.27 (m, 1 H), 1.22
(s, 3 H), 1.14 (m, 1 H), 1.06 (s, 3 H). 13C NMR (75.5 MHz,
CDCl3): d = 170.2 (s), 142.0 (s), 128.5 (d), 127.4 (d), 126.2
(d), 77.5 (d), 73.4 (t), 68.4 (d), 53.0 (s), 49.7 (s), 45.6 (d),
39.3 (t), 30.3 (t), 27.6 (t), 21.9 (q), 20.5 (q). MS (EI) m/z (%)
= 285 (10) [M+], 270 (71), 257 (100), 242 (88), 216 (22), 202
(50), 174 (16), 151 (24), 120 (25), 104 (46), 91 (73), 77 (57).
HRMS: m/z calcd for C18H23NO2: 285.1729; found:
285.1718.
stirring for 30 min, the solution was cooled at 0 °C and ethyl
vinyl ether (7a; 75 mL, 0.75 mmol) was added. After 3 h, the
reaction mixture was filtered through a short pad of silica gel
eluting with CH2Cl2 to give 61.4 mg (89%) of compound
9aa + 10aa (Table 1, entry 12). HPLC analysis (Chiralpak
IC, 2% isopropanol–98% hexane, 1.0 mL/min): (+)-(2S,4R)-
9aa: tR = 12.2 min, (–)-(2R,4S)-9aa: tR = 17.0 min, 10aa
(enantiomer 1): tR = 27.6 min, 10aa (enantiomer 2): tR =
33.6 min. A pure sample of enantioenriched (+)-9aa was
obtained by flash column chromatography, eluting with
hexane–CH2Cl2 (1:9); [a]D25 +136 (c = 1.0, CHCl3, 81% ee).
1H NMR (300 MHz, CDCl3): d = 7.16–7.29 (m, 5 H), 6.15
(dd, J = 1.8, 2.4 Hz, 1 H), 5.25 (t, J = 2.4 Hz, 1 H), 4.21 (q,
J = 7.0 Hz, 2 H), 3.86 (dq, J = 9.9, 7.2 Hz, 1 H), 3.71 (ddd,
J = 2.4, 6.3, 11.7 Hz, 1 H), 3.61 (dq, J = 9.9, 7.2 Hz, 1 H),
2.11 (dddd, J = 12.0, 6.3, 2.1, 1.8 Hz, 1 H), 1.76 (ddd, J =
12.0, 11.7, 2.4 Hz, 1 H), 1.25 (t, J = 7.0 Hz, 3 H), 1.18 (t,
J = 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 162.9 (s),
143.4 (s), 140.8 (s), 128.7 (d), 127.6 (d), 126.8 (d), 115.3 (d),
97.1 (d), 64.2 (t), 61.1 (t), 34.9 (t), 34.0 (d), 15.1 (q), 14.2 (q).
MS (EI): m/z (%) = 276 (1.5) [M+], 230 (15), 203 (6), 157
(25), 131 (100). HRMS: m/z calcd for C16H20O4: 276.1362;
found: 276.1364. Minor diastereomer 10aa: 1H NMR (300
MHz, CDCl3): d = 7.21–7.40 (m, 5 H), 6.13 (dd, J = 1.2, 3.0
Hz, 1 H), 5.15 (dd, J = 2.4, 8.1 Hz, 1 H), 4.26 (m, 2 H), 4.03
(dq, J = 9.6, 6.9 Hz, 1 H), 3.71 (ddd, J = 3.0, 6.9, 9.6 Hz, 1
H), 3.63 (dq, J = 9.6, 6.9 Hz, 1 H), 2.30 (dddd, J = 13.5, 6.9,
2.4, 1.2 Hz, 1 H), 1.96 (ddd, J = 13.5, 9.6, 8.1 Hz, 1 H), 1.31
(t, J = 7.2 Hz, 3 H), 1.23 (t, J = 6.9 Hz, 3 H).
Experimental Procedure for the Enantioselective HDA
Reaction: Copper triflate (9.0 mg, 0.025 mmol) in a Schlenk
tube was dried at 90 ºC under vacuum for 1 h. The tube was
filled in with nitrogen and ligand 5 (7.1 mg, 0.025 mmol)
was added followed by anhyd EtOAc (0.75 mL). The
mixture was stirred for 1 h and keto ester 8a (50 mg, 0.25
mmol) dissolved in EtOAc (0.4 mL) was added. After
Synlett 2011, No. 11, 1592–1596 © Thieme Stuttgart · New York