New bifunctional substrates for copper-catalyzed asymmetric conjugate addition reactions with trialkylaluminium

Article abstract of DOI:10.1002/ejoc.200900662

Trialfylaluminium reagents have been found to undergo a copper-catalyzed asymmetric conjugate addition (ACA) reaction with oxabicyclo[2.2.1]hepta-2,5- diene-2,3-dicarboxylates with the simultaneous creation of two stereocenters. Different types of ligands

Full text of DOI:10.1002/ejoc.200900662

FULL PAPER
DOI: 10.1002/ejoc.200900662
New Bifunctional Substrates for Copper-Catalyzed Asymmetric Conjugate
Addition Reactions with Trialkylaluminium
Chehla Ladjel,[a] Nicolas Fuchs,[a] Jinkai Zhao,[a] Gérald Bernardinelli,[a] and
Alexandre Alexakis*[a]
Keywords: Conjugation / Copper / P ligands / Aluminium / Oxygen heterocycles
Trialkylaluminium reagents have been found to undergo a
copper-catalyzed asymmetric conjugate addition (ACA) re- the development of this copper-catalyzed ACA methodology,
action with oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxyl- which affords an all-carbon quaternary center with unsubsti-
ates with the simultaneous creation of two stereocenters. Dif- tuted and substituted oxacyclic Michael acceptors. The study
of the nucleophile. Herein we report the results obtained in
ferent types of ligands were tested, and chiral phosphoramid-
ite ligands allowed the reaction to proceed with good yields
and good to excellent enantioselectivity. The syn substitution
product observed by X-ray analysis suggests an exo attack
was completed by mechanistic investigations performed to
elucidate the original reaction pathway.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
experiments in the presence of isopropyl iodide as a radical
probe.[6] Two thirds of the resulting adducts were the iso-
propyl adduct, instead of the ethyl adduct (Scheme 1).
Introduction
The asymmetric conjugate addition (ACA) reaction is
nowadays a mature methodology.[1] In particular, the rho-
dium-[1c] and copper-catalyzed ACA reactions are very ef-
ficient with both cyclic and acyclic Michael acceptors and
either Zn, Al, or Mg organometallic reagents.[2] However,
there are still some aspects that need to be clarified, for
example, difunctionalized substrates have scarcely been
studied. Although geminally difunctionalized substrates,
such as alkylidenemalonates, afford good yields and
enantioselectivities,[3] there is only a single example of the
reaction of an alkene with the electron-withdrawing groups
at both ends of the double bond, for example, fumarates or
related substrates.[4]
Fumarates are excellent substrates for Diels–Alder reac-
tions. It was expected that they would be particularly suit-
able for copper-catalyzed ACA reactions. Indeed, when di-
ethyl fumarate (1) was treated with diethylzinc with just Cu-
(OTf)2 as the catalyst for racemate formation, a quantitative
yield was obtained at –40 °C in toluene. When the reaction
was tested with a chiral phosphoramidite ligand (see Fig-
ure 1), the reaction was slower, and the best enantio-
selectivity (33% ee) was obtained with L6. As we suspected
a competitive radical achiral pathway,[5] we repeated these
Figure 1. Chiral ligands L1–L9.
[a] Université de Genève, Département de Chimie Organique,
30 Quai Ernest Ansermet, 1211 Genève 4, Switzerland
Fax: +41-22-379-6522
E-mail: Alexandre.Alexakis@unige.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900662.
Scheme 1. Addition of diethylzinc to diethyl malonate: radical
pathway.
Eur. J. Org. Chem. 2009, 4949–4955
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C. Ladjel, N. Fuchs, J. Zhao, G. Bernardinelli, A. Alexakis
FULL PAPER
The same reaction with diethyl maleate gave similar re- gate addition could be hydrogenated with loss of the
sults, but it was a much slower reaction in which the (Z) endo/exo notion. However, here again no conjugate ad-
double bond was isomerized to an (E) double bond, as de- dition took place at all.
tected by GC–MS analysis.[7]
As fumarate-type substrates were not as reactive as ex-
pected, we turned our attention to more strained com-
pounds in the hope of higher reactivity. Norbornadiene-
type substrates offer such an opportunity. Substrate 2 was
easily synthesized by Diels–Alder reaction of cyclopentadi-
ene and dimethyl acetylenedicarboxylate, and was submit-
ted to our previously described reaction conditions in the
presence of diethylzinc and a copper catalyst.[8] However,
only the reduced product was obtained, probably through
a single-electron transfer (SET) process. To overcome this
problem, alkylaluminium reagents were used instead of or-
ganozinc reagents. R3Al reagents have been used in our
group to overcome the steric hindrance in multisubstituted
substrates by Lewis acid activation.[9] The copper-catalyzed
Scheme 3. Conjugate addition to hydrogenated norbornadiene sub-
strates.
As the endo/exo attack of the nucleophile could not be
controlled by steric hindrance, we thought that coordina-
tion effects could be more effective. If the bridging methyl-
ene group could be replaced by an oxygen atom, we could
expect an efficient coordination to Al, which would favor
an exo approach of the nucleophile (Figure 2).
1,4-addition of trimethylaluminium to substrate
2
(Scheme 2) proceeded with complete conversion to afford 3
as a mixture of isomers as a result of the nonselective
endo/exo attack of the nucleophile followed by a nonselec-
tive protonation.
Figure 2. Coordination of Al to an oxanorbornadiene substrate.
Scheme 2. Addition of trimethylaluminium to 2.
Results and Discussion
The same experiment was repeated in the presence of
6 equiv. of isopropyl iodide to determine whether the reac-
To the best of our knowledge, the asymmetric conjugate
tion proceeded by a radical pathway. The absence of the addition reaction with oxygen-bridged substrates has not
isopropyl adduct confirmed a non-radical pathway. A reac- been reported previously. However, some examples of the
tion under similar conditions without the copper/ligand asymmetric copper-catalyzed ring-opening of oxabicy-
system did not lead to the product, and the starting mate- clo[2.2.1]alkenes, leading to an anti stereoselectivity as a re-
rial was recovered, which shows that the catalyst was sult of endo attack of the nucleophile, have been re-
needed. Note that this reaction afforded an all-carbon qua- ported.[11] Mechanistically, these results represent an anti
ternary center, a synthetic challenge in ACA.[10]
γ-allylic substitution of the heterobicyclic alkene, which is
To increase the steric bias between the endo and exo face, typical in organocopper chemistry.[12] Most other transi-
2 was partially hydrogenated to 4 with the Pd/Lindlar cata- tion-metal-catalyzed reactions afford the syn substitution
lyst. The two axial hydrogen atoms should prevent an endo product.[13]
attack of the nucleophile. However, no reaction took place
Substrate 7a was easily prepared by a Diels–Alder reac-
when the addition reaction was performed (Scheme 3). It tion between furan and dimethyl acetylenedicarboxylate,
seems that a partial release of the ring-strain in 4 could and was submitted to our ACA standard reaction condi-
explain such a lack of reactivity. Another way to overcome tions (Scheme 4). The reaction afforded, after quenching
the problem of selectivity between the endo/exo faces was with an acidic aqueous solution, a single product 8a, which
to test a slightly different substrate such as 5 (Scheme 3). In is a result of the conjugate addition of a methyl group fol-
this case, the potential adduct 6 obtained after the conju- lowed by opening of the oxacycle.
Scheme 4. ACA reaction of oxygen-bridged substrate 7a.
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Copper-Catalyzed Asymmetric Conjugate Addition Reactions
The syn relationship of the incoming methyl group and complete conversion but to an enantiomeric excess of 48%.
the hydroxy moiety corresponds to our anticipated coordi- Replacing the phenyl group with a 2-naphthyl group on the
nation of the oxygen bridge and Me3Al. This product 8a amine part of the ligand (L7) increased this enantiomeric
cannot arise from an allylic substitution mechanism be- excess to 93%. Other types of ligands were also tested in
cause the stereochemical relationship should be opposite.[12] this reaction, for example, the Simplephos ligand L9,[14]
Neither was any product arising from attack on the least- which has already been reported in the copper-catalyzed
substituted double bond detected. Additional proof was asymmetric conjugate addition of triethylaluminium to cy-
sought by performing the reaction with substrate 9 clohexenone, and the phosphite ligand L8 described by
(Scheme 5), which lacks the double bond between the two Chan and co-workers.[15] However, the desired product 8a
ester functionalities. No reaction took place at all.
was obtained with enantiomeric excesses of only 19 and
31%, respectively.
Table 2. Optimisation of the ligand with the Cu(CH3CN)4BF4 cata-
lyst.
Entry
Ligand
Conversion [%][a]
ee [%][b]
Scheme 5. Addition of AlMe3 to substrate 9.
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L6Ј
L7
L8
L9
99
73
91
98
99
98
99
99
99
99
73
6
In an effort to optimize this reaction, several copper salts
and ligands were tested for the asymmetric addition of tri-
methylaluminium to substrate 7a. First the reaction was
performed with different copper salts in the presence of chi-
ral phosphoramidite ligand L1 (Table 1). Diethyl ether was
used as the solvent at –45 °C, which is the optimum tem-
perature for this reaction. Although the ACA reaction
could be performed in THF, in some cases this solvent did
not lead to complete conversion at this temperature, and the
enantioselectivity was lower. Although the use of copper(I)
chloride or bromide (Entries 1 and 2) allowed complete
conversion of 7a to 8a in 30 min, the enantiomeric excesses
were less than 60%. The use of copper(II) acetate or triflate
(Entries 3 and 4) led to 70% ee, with the best enantiomeric
excess of 73% being obtained in the presence of 2 mol-% of
Cu(CH3CN)4BF4.
45
53
11
90
48
93
31
19
10
[a] Determined by GC–MS analysis. [b] Determined by GC chiral
analysis.
These optimized reaction conditions were then applied to
different oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate
substrates 7 to establish the scope of this methodology; the
results are summarized in Table 3. Several esters were tested
with trimethylaluminium as nucleophile. The best enantio-
meric excesses were obtained with methyl ester 7a (Entry 1)
and ethyl ester 7b (Entry 2), which gave 93 and 96% ee,
respectively, and isolated yields of 95 and 81%. Although
the reaction performed with triethylaluminium allowed the
products 8e and 8h to be obtained in yields of up to 90%,
the enantiomeric excesses were lower than those obtained
with trimethylaluminium. The addition of triisobutylalu-
minium to 7a enabled the isolation of 8g in 73% yield but
with a disappointing 60% ee. Commercially available
Al(nPr)3 and Al(nBu)3 were also used in this methodology,
giving good yields and moderate enantioselectivities (En-
tries 6 and 7).
Table 1. Optimisation of the copper catalyst with L1.
Entry
Copper salt
Conversion [%][a]
ee [%][b]
1
2
3
4
5
6
7
CuCl
CuBr
Cu(OAc)2·H2O
Cu(OTf)2
CuTC
Cu(CH3CN)4BF4
Cu(CH3CN)4PF6
99
99
99
99
98
99
99
56
59
71
70
70
73
71
[a] Determined by GC–MS analysis. [b] Determined by chiral GC
analysis.
The product 8a had to be derivatized with a heavy atom
The previously described reaction conditions were then to determine its absolute stereochemistry. The correspond-
used with different ligands to increase the enantioselectivity ing p-chlorobenzoate 10 could be formed, but the crystals
(Table 2). Different phosphoramidite ligands were tested were not suitable for X-ray analysis. Finally, a Diels–Alder
(Entries 1–10) in a 2:4 copper/ligand ratio (other ratios did reaction of 10 to form 4H-1,2,4-triazole-3,5-dione 11 al-
not give better results). These experiments demonstrated lowed us to obtain this information (Figure 3). The struc-
that substitution at the ortho position of the biphenol group ture clearly shows the syn relative stereochemistry between
(L1 vs. L3) led to a decrease in the enantioselectivity. The the hydroxy and methyl groups.
presence of a methoxy group on the amine part of the li-
Other similar substrates were also tested. Thus, 7a was
gand also led to a decrease in the enantioselectivity (L1 vs. partially hydrogenated to 12 with the H2/Pd Lindlar cata-
L5). When binaphthol ligands were used (L6/L6Ј) a match/ lyst. However, as for 4, no subsequent ACA reaction took
mismatch effect was observed: The (R,SS) diastereoisomer place (Scheme 6). This result again stresses the importance
afforded 90% ee, whereas the (S,SS) diastereoisomer led to of ring-strain in these substrates.
Eur. J. Org. Chem. 2009, 4949–4955
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C. Ladjel, N. Fuchs, J. Zhao, G. Bernardinelli, A. Alexakis
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Table 3. Scope of the reaction.
Entries
R
Substrate
RЈ
Product, yield [%] ee [%][a]
1
2
3
Me
Et
7a
7b
7c
7a
7a
7a
7a
7b
Me
Me
Me
Et
nPr
nBu
iBu
Et
8a, 95
8b, 81
8c, 73
8d, 90
8e, 82
8f, 79
8g, 73
8h, 92
93 (SS)
96 (SS)
67 (SS)
73 (SS)
55 (RR)
74 (RR)
60 (RR)
68 (SS)
iPr
Me
Me
Me
Me
Et
4
5[b]
6[b]
7[b]
8
Figure 4. ORTEP diagram of compound 14.[16]
The application of the ACA methodology to the corre-
sponding monosubstituted substrate was more problematic.
The substrate 15 (Scheme 8), synthesized by a Diels–Alder
reaction, presents one stereogenic center, so the only way to
obtain an enantiomerically enriched reaction product was
by kinetic resolution of the racemic mixture. Unfortunately,
the ACA of 0.5 equiv. of trimethylaluminium to compound
15 (Scheme 8) gave only 50% conversion and a poor 29%
ee. However, the reaction was completely regioselective, the
ACA occurring at the least-substituted position.
[a] Determined by chiral GC. [b] (S,RR)-L7.
Figure 3. ORTEP diagram of compound 11.[16]
Scheme 8. ACA reaction of substrate 15.
To complete this study, the aromatic bicyclic compound
17 was tested. This substrate retains the same ring-strain,
but proved quite unreactive at –45 °C (Table 4, Entry 1).
However, complete conversion could be obtained with an
enantiomeric excess of 74% (Entry 2) by raising the tem-
perature to –10 °C. The optimum conditions for this sub-
strate were obtained when the temperature was increased to
0 °C, giving the best enantiomeric excess (Entry 3). Under
the same reaction conditions, triethylaluminium gave prod-
uct 19 in 82% yield and with a moderate 56% ee (Entry 4).
Finally, it should be mentioned that under these reaction
Scheme 6. ACA reaction of partially hydrogenated 7a.
On the other hand, the sterically more crowded substrate
13, with two Me groups at the bridgehead but with the
same ring-strain, reacted in quantitative yield and excellent
(93%) enantioselectivity (Scheme 7). Only one diastereomer
was observed. Interestingly, 14 has two adjacent quaternary
centers!
Table 4. ACA to substrate 17.
Entry
R
Temperature
Product, conversion
[%][a]
ee [%][b]
[°C]
Scheme 7. ACA reaction of 13.
1
2
3
4
Me
Me
Me
Et
–45
–10
0
0
–
18, 98
18, 98 (85)
19, 98 (82)
74
80
56
0
As this adduct was isolated as a solid, the syn relative
relationship between the hydroxy and methyl groups was
confirmed by X-ray analysis (Figure 4).
[a] Isolated yields are given in parentheses. [b] Determined by chiral
HPLC or chiral SFC.
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Copper-Catalyzed Asymmetric Conjugate Addition Reactions
Procedure for the Synthesis of the 4-Phenyl-4H-1,2,4-triazole-3,5-
dione Diels–Alder Adduct of Dimethyl 6-(4-Chlorobenzoyloxy)-1-
methylcyclohexa-2,4-diene-1,2-dicarboxylate (11): Triethylamine
(20 mL, 1.42 mmol) in dry dichloromethane (5 mL) was added to
dimethyl 6-hydroxy-1-methylcyclohexa-2,4-diene-1,2-dicarboxylate
(8a; 1.146 g, 0.65 mmol) under nitrogen. The solution was cooled
to 0 °C, and 4-chlorobenzoyl chloride (0.09 mL, 0.65 mmol) was
added dropwise over 2 min. The mixture was stirred at 0 °C for
30 min and then at reflux temperature for 5 h. The solution was
then stirred at room temperature overnight. Additional 4-chlo-
robenzoyl chloride (0.05 mL, 0.36 mmol) was then added dropwise
over 2 min, and the resulting mixture was heated at reflux 1 h. The
solution was then poured into water, and the organic layer was
separated. The aqueous layer was extracted with dichloromethane.
The combined organic layers were dried with MgSO4, and the sol-
vent was evaporated under reduced pressure to give 0.331 g of a
brown paste. The crude product was purified by flash chromatog-
raphy on silica gel (diethyl ether/pentane, 4:6) to afford 193 mg
(81% yield) of 10 (Rf = 0.35). Dimethyl 6-(4-chlorobenzoyloxy)-
1-methylcyclohexa-2,4-diene-1,2-dicarboxylate (45 mg, 0.12 mmol)
and 4-phenyl-4H-1,2,4-triazole-3,5-dione (21.6 mg, 0.12 mmol)
were dissolved in toluene. The mixture was stirred at room tem-
perature for 4 h and heated at 62 °C overnight. The product was
purified by flash chromatography on silica gel, and the white solid
was recrystallized in ethyl acetate. One suitable crystal was submit-
ted to X-ray diffraction analysis.
conditions with trimethylaluminium no addition took place
with simple oxabenzonorbornadiene (that is, without the es-
ter groups).[17]
Conclusions
We have reported herein a new class of substrates for the
copper-catalyzed asymmetric conjugate addition reaction.
The methodology allows the generation of two or more ste-
reocenters, one of which is quaternary, in one step. The re-
action gives good yields and enantiomeric excesses. We have
demonstrated that the ring-strain is necessary for the reac-
tion, and we realized control experiments to illustrate the
mechanistic pathway. Finally, the syn relative stereochemis-
try of the products indicates a conjugate addition/elimi-
nation mechanism rather than an allylic substitution.
Experimental Section
General: 1H (400 or 300 MHz) and 13C (100 or 300 MHz) NMR
spectra were recorded with a Bruker 400 FT or 300 FT NMR spec-
trometer in CDCl3. The chemical shifts (δ) are given in ppm relative
to residual CHCl3, and coupling constants are reported in Hz. The
multiplicities are indicated as follows: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt
(doublet of triplets), br. s (broad singlet). Mass spectra (MS) were
obtained by EI (70 eV) and high-resolution mass spectrometry. Op-
tical rotations were recorded with a Perkin–Elmer 241 polarimeter
at 20 °C in a 10 cm cell in CHCl3. [α]D values are given in
10–1 degcm2 g–1 (concentrations c are given as g/100 mL). IR spec-
tra were recorded neat with a Perkin–Elmer Spectrum One IR spec-
trometer. Enantiomeric excesses were determined by chiral GC
with either an HP6890 or an HP6850 apparatus with the stated
column and H2 as the vector gas. Temperature programs are de-
scribed as follows: Initial temperature [°C]–initial time [min]–tem-
perature gradient [°Cmin–1]–final temperature [°C]; retention times
(T) are given in min. Enantiomeric excesses were in some cases
determined by chiral-SFC measurements with the stated column,
except for product 18 which was analyzed by HPLC. Gradient pro-
grams are described as follows: Initial methanol concentration [%]–
initial time [min]–percent gradient of methanol (%min–1)–final
methanol concentration [%]; retention times (T) are given in min.
Flash chromatography was performed by using silica gel 60 Å. All
the reactions were performed in anhydrous solvents, dried by fil-
tration over activated alumina.
Dimethyl 6-Hydroxy-1-methylcyclohexa-2,4-diene-1,2-dicarboxylate
(8a): The title compound was prepared from dimethyl 7-oxabicyclo-
[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (7a; 0.210 g, 1.00 mmol)
according to the ACA general procedure.[18] The desired alcohol
was obtained as a yellow oil (0.214 g, 95% yield) after flash
1
chromatography (diethyl ether/pentane, 4:6). Rf = 0.60. H NMR
(300 MHz, CDCl3): δ = 6.96–6.94 (m, 1 H), 6.05–5.96 (m, 2 H),
3
5.06 (d, JH,H = 6 Hz, 1 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 1.84 (d,
3JH,H = 6 Hz, 1 H), 1.35 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 177.1, 166.8, 137.4, 133.2, 132.4, 122.7, 74.5, 52.9, 52.2, 52.2,
11.8 ppm. HRMS: calcd. for C11H14O5Na 247.0733; found
249.0726. [α]2D0 = +8.16 (c = 1.02, CHCl3). Enantiomer separation:
Hydrodex-B-6-TBDM (25 m, H2, 40 cms–1): 80–0-1–170–25; T1 =
70.9, T2 = 71.46.
Diethyl 6-Hydroxy-1-methylcyclohexa-2,4-diene-1,2-dicarboxylate
(8b): The title compound was prepared from diethyl 7-oxabicyclo-
[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (7b; 0.238 g, 1.00 mmol)
according to the ACA general procedure.[19] The desired alcohol
was obtained as a yellow oil (0.211 g, 83% yield) after flash
chromatography on silica gel (diethyl ether/pentane, 4:6). Rf = 0.65.
3
1H NMR (400 MHz, CDCl3): δ = 6.94–6.92 (d, JH,H = 5 Hz, 1
H), 6.03–5.94 (m, 1 H), 5.97–5.94 (m, 1 H), 5.04–5.02 (m, 1 H),
4.25–4.13 (m, 4 H), 1.88–1.86 (d, 3JH,H = 6 Hz, 1 H), 1.35 (s, 3 H),
1.29–1.23 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.2,
166.1, 136.4, 133.3, 131.6, 122.5, 74.3, 61.3, 60.8, 51.9, 14.2, 14.1,
General Protocol for the Copper-Catalyzed Asymmetric Conjugate
Addition of Trialkylaluminium: The copper salt (0.001 mmol) and
ligand (0.002 mmol) were suspended in dry diethyl ether (1 mL)
under nitrogen. The suspension was stirred at room temperature
for 30 min and then cooled to –45 °C. Trialkylaluminium
(1.5 mmol) was added, and then the substrate (1 mmol) in diethyl
ether (1 mL) was added dropwise. The reaction mixture was stirred
for 1 h and then warmed to room temperature. The reaction mix-
ture was cooled to 0 °C and quenched with a solution of 1  HCl
(0.5 mL). The organic phase was separated, and the aqueous phase
was extracted with diethyl ether (2 mL). The combined organic lay-
ers were dried with Na2SO4, and the solvent was evaporated under
reduced pressure. The crude product was purified by column
chromatography by using the indicated solvent.
11.5 ppm. IR (neat): ν = 3460, 2982, 1706, 1257, 1102, 1024,
˜
643 cm–1. HRMS calcd. for C13H18O5Na 277.1046; found
277.1049. [α]2D0 = +19.8 (c = 0.7, CHCl3). Enantiomer separation:
Hydrodex-B-6-TBDM (25 m, H2, 40 cms–1): 80–0-1–170–25; T1 =
77.44, T2 = 78.58.
Diisopropyl 6-Hydroxy-1-methylcyclohexa-2,4-diene-1,2-dicarboxyl-
ate (8c): The title compound was prepared from diisopropyl 7-ox-
abicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate[20] (7c; 0.266 g,
1.00 mmol) according to the ACA general procedure. The desired
alcohol was obtained as a yellow oil (0.206 g, 73% yield) after flash
chromatography on silica gel (diethyl ether/pentane, 4:6). Rf = 0.60.
Eur. J. Org. Chem. 2009, 4949–4955
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FULL PAPER
1H NMR (400 MHz, CDCl3): δ = 6.88–6.87 (d, JH,H = 5 Hz, 1
3
chromatography on silica gel (diethyl ether/pentane, 4:6). Rf = 0.59.
3
H), 6.02–5.97 (m, 1 H), 5.96–5.92 (m, 1 H), 5.10–5.01 (m, 2 H), 1H NMR (300 MHz, CDCl3): δ = 7.08 (d, JH,H = 4 Hz, 1 H),
4.99–4.97 (m, 1 H), 1.82 (d, 3JH,H = 6 Hz, 1 H), 1.34 (s, 3 H), 1.27– 6.03–5.94 (m, 2 H), 5.15 (br. s, 1 H), 3.73 (s, 6 H), 2.00–1.77 (m, 4
3
3
1.21 (m, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.5,
165.7, 135.9, 133.6, 131.1, 122.6, 74.3, 68.6, 68.3, 51.9, 21.9, 21.8,
H), 0.90 (d, JH,H = 6 Hz, 3 H), 0.82 (d, JH,H = 6 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 176.9, 167.0, 138.0, 134.0, 131.3,
21.8, 21.6, 11.6 ppm. IR (neat): ν = 3460, 2971, 1703, 1257, 1099, 122.6, 75.4, 55.0, 52.8, 52.3, 35.0, 25.7, 25.6, 24.3 ppm. IR (neat):
˜
1010, 715 cm–1. HRMS: calcd. for C15H23O5 283.1540; found ν = 3489, 2956, 1709, 1434, 1253, 1064, 727 cm–1. HRMS: calcd.
˜
283.1548. [α]2D0 = +3.89 (c = 1.5, CHCl3). Enantiomer separation:
for C14H20O5 268.1307; found 268.1310. [α]2D0 = –3.87 (c = 1.06,
40 cms–1): 80–0-1–170–25; T1 = 79.24, T2 = 79.95.
Diethyl 1-Ethyl-6-hydroxycyclohexa-2,4-diene-1,2-dicarboxylate
Hydrodex-B-6-TBDM (25 m, H2, 40 cms–1): 80–0-1–170–25; T1 = CHCl3). Enantiomer separation: Hydrodex-B-6-TBDM (25 m, H2,
78.65, T2 = 79.42.
Dimethyl 1-Ethyl-6-hydroxycyclohexa-2,4-diene-1,2-dicarboxylate
(8d): The title compound was prepared from dimethyl 7-oxabicyclo-
[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (7a; 0.210 g, 1.00 mmol)
according to the ACA general procedure.[17] The desired alcohol
was obtained as a yellow oil (0.216 g, 90% yield) after flash
chromatography on silica gel (diethyl ether/pentane, 4:6). Rf = 0.62.
(8h): The title compound was prepared from diethyl 7-oxabicyclo-
[2.2.1]hepta-2,5-diene-2,3-dicarboxylate[19] (7b; 0.238 g, 1.00 mmol)
according to the ACA general procedure. The desired alcohol was
obtained as a yellow oil (0.246 g, 92% yield) after flash chromatog-
raphy on silica gel (diethyl ether/pentane, 4:6). Rf = 0.62. 1H NMR
3
3
1H NMR (300 MHz, CDCl3): δ = 7.11 (d, JH,H = 5 Hz, 1 H),
(400 MHz, CDCl3): δ = 7.11–7.10 (d, JH,H = 5 Hz, 1 H), 5.99–
6.01–5.90 (m, 2 H), 5.18 (br. s, 1 H), 3.74 (s, 3 H), 3.73 (m, 3 H), 5.90 (m, 2 H), 5.16 (s, 1 H), 4.22–4.14 (m, 4 H), 2.23–2.14 (m, 1
3
2.25–2.12 (m, 1 H), 1.96–1.84 (m, 2 H), 0.91 (t, 3JH,H = 3 Hz, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 176.2, 166.1, 136.4, 133.3,
131.6, 122.5, 74.3, 61.3, 60.8, 51.9, 14.2, 14.1, 11.5 ppm. IR (neat):
H), 1.96–1.87 (m, 2 H), 1.29–1.23 (m, 6 H), 0.92 (t, JH,H = 7 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.1, 166.4, 137.2,
133.4, 130.4, 122.0, 74.6, 61.2, 60.7, 54.9, 20.6, 14.2, 14.1,
ν = 3471, 2975, 1699, 1255, 1095, 718 cm–1. [α]20 = +29.76 (c =
10.0 ppm. IR (neat): ν = 3479, 2980, 1704, 1249, 1028, 631 cm–1.
˜
˜
D
1.36, CHCl3). Enantiomer separation: Hydrodex-B-6-TBDM
HRMS: calcd. for C14H20O5Na 291.1202; found 291.1191. [α]2D0
=
(25 m, H2, 40 cms–1): 80–0-1–170–25; T1 = 74.73, T2 = 76.71.
+5.5 (c = 1.02, CHCl3). Enantiomer separation: Hydrodex-B-6-
TBDM (25 m, H2, 40 cms–1): 80–0-1–170–25; T1 = 82.32, T2
=
Dimethyl 6-Hydroxy-1-propylcyclohexa-2,4-diene-1,2-dicarboxylate
(8e): The title compound was prepared from dimethyl 7-oxabicyclo-
[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (7a; 0.210 g, 1.00 mmol)
according to the ACA general procedure.[18] The desired alcohol
was obtained as a yellow oil (0.208 g, 82% yield) after flash
chromatography on silica gel (diethyl ether/pentane, 4:6). Rf = 0.58.
83.86.
Dimethyl 6-Hydroxy-1,3,6-trimethylcyclohexa-2,4-diene-1,2-dicar-
boxylate (14): The title compound was prepared from dimethyl 1,4-
dimethyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate[18]
(13; 0.127 g, 0.5 mmol) according to the ACA general procedure.
The desired alcohol was obtained as a solid after flash chromatog-
3
1H NMR (400 MHz, CDCl3): δ = 7.09 (d, JH,H = 5 Hz, 1 H),
5.99–5.91 (m, 2 H), 5.17 (br. s, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), raphy on silica gel (diethyl ether/pentane, 4:6). Rf = 0.54. 1H NMR
2.07 (td, 3JH,H = 4, 3JH,H = 14 Hz, 1 H), 1.89 (br. s, 1 H), 1.84 (td,
(400 MHz, CDCl3): δ = 5.76 (q, JH,H = 9 Hz, 2 H), 3.72 (s, 3 H),
3
3JH,H = 4, JH,H = 14 Hz, 1 H), 1.54–1.45 (m, 1 H), 1.36–1.27 (m, 3.72 (s, 3 H), 2.00 (s, 3 H), 1.58 (s, 3 H), 1.18 (s, 3 H) ppm. 13C
3
1 H), 0.86 (t, JH,H = 8 Hz, 3 H) ppm. 13C NMR (100 MHz, NMR (100 MHz, CDCl3): δ = 175.4, 169.1, 137.1, 136.6, 128.0,
3
CDCl3): δ = 176.6, 166.7, 137.6, 133.6, 130.4, 122.1, 74.8, 54.6,
126.6, 75.0, 57.1, 52.13, 51.2, 24.8, 19.9, 16.5 ppm. Enantiomer sep-
aration: SFC OD-H (30 °C, 200 bar, 2 mLmin–1): 5–2–1–15; T1 =
2.25, T2 = 2.79.
52.5, 51.9, 29.8, 18.6, 15.0 ppm. IR (neat): ν = 3466, 2953, 1712,
˜
1435, 1264, 1064, 759 cm–1. HRMS: calcd. for C13H18O5Na
277.1046; found 277.1040. [α]2D0 = –5.4 (c = 1.06, CHCl3). Enantio-
mer separation: SFC OD-H (30 °C, 200 bar, 2 mLmin–1): 5–2–1–
15%; T1 = 3.85, T2 = 4.76.
Dimethyl
6-Hydroxy-1,3-dimethylcyclohexa-2,4-diene-1,2-dicarb-
oxylate (16): The title compound was prepared from dimethyl 1-
methyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate[18] (15;
0.224 g, 1.00 mmol) according to the ACA general procedure. The
desired alcohol was obtained as a yellow oil after flash chromatog-
raphy on silica gel (diethyl ether/pentane, 4:6). Rf = 0.60. 1H NMR
Dimethyl 1-Butyl-6-hydroxycyclohexa-2,4-diene-1,2-dicarboxylate
(8f): The title compound was prepared from dimethyl 7-oxabicyclo-
[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (7a; 0.210 g, 1.00 mmol)
according to the ACA general procedure.[17] The desired alcohol
was obtained as a yellow oil (0.211 g, 79% yield) after flash
chromatography on silica gel (diethyl ether/pentane, 4:6). Rf = 0.58.
3
3
(400 MHz, CDCl3): δ = 5.87 (d, JH,H = 9 Hz, 1 H), 5.82 (d, JH,H
= 9 Hz, 1 H), 4.88 (s, 1 H), 3.70 (s, 6 H) 2.08 (s, 3 H), 1.41 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 176.8, 168.1, 140.33, 134.4,
129.1, 127.3, 73.7, 53.9, 52.5, 52.3, 51.3, 20.4, 12.1 ppm. Enan-
tiomer separation: Hydrodex-B-6-TBDM (25 m, H2, 40 cms–1):
3
1H NMR (300 MHz, CDCl3): δ = 7.08 (d, JH,H = 6 Hz, 1 H),
3
6.00–5.90 (m, 2 H), 5.17 (d, JH,H = 6 Hz, 1 H), 3.74 (s, 3 H), 3.73
(s, 3 H), 2.16–2.06 (m, 1 H), 1.90–1.76 (m, 2 H), 1.29–1.18 (m, 3 50–0-1–170–25; T1 = 104.38, T2 = 106.10.
H), 0.86 (t, JH,H = 7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 176.6, 166.7, 137.6, 133.6, 130.4, 122.1, 74.7, 54.6, 52.5, 51.9,
3
Dimethyl 1,2-Dihydro-1-hydroxy-2-methylnaphthalene-2,3-dicarb-
oxylate (18): The title compound was prepared from dimethyl 1,4-
epoxy-1,4-dihydronaphthalene-2,3-dicarboxylate[21] (17; 0.130 g,
0.5 mmol) according to the ACA general procedure at 0 °C. The
desired alcohol was obtained as a solid after flash chromatography
on silica gel (diethyl ether/pentane, 4:6). Rf = 0.45. 1H NMR
27.3, 27.2, 23.7, 14.0 ppm. IR (neat): ν = 3489, 2956, 1709, 1434,
˜
1253, 1064, 727 cm–1. HRMS: calcd. for C14H20O5Na 291.1202;
found 291.1208. [α]2D0 = –29.0 (c = 0.7, CHCl3). Enantiomer separa-
tion: SFC OD-H (30 °C, 200 bar, 2 mLmin–1): 5–2–1–15; T1 = 3.87,
T2 = 4.93.
3
(400 MHz, CDCl3): δ = 7.64 (d, JH,H = 7 Hz, 1 H), 7.54 (s, 1 H),
3
Dimethyl 6-Hydroxy-1-isobutylcyclohexa-2,4-diene-1,2-dicarboxyl-
ate (8g): The title compound was prepared from dimethyl 7-oxabi-
cyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (7a; 0.210 g, 1.00
mmol) according to the ACA general procedure.[18] The desired
alcohol was obtained as a yellow oil (0.195 g, 73% yield) after flash
7.50–7.46 (m, 1 H), 7.37–7.28 (m, 1 H), 5.44 (d, JH,H = 7 Hz, 1
3
H), 3.85 (s, 6 H), 2.19 (d, JH,H = 7 Hz, 1 H), 1.28 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 176.0, 166.7, 137.4, 136.1, 133.1,
131.2, 130.2, 128.7, 128.1, 124.6, 74.6, 52.9, 52.3, 27.2, 12.9 ppm.
Enantiomer separation: HPLC Chiralpak AD (Agilent 1100 series
4954
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4949–4955

Copper-Catalyzed Asymmetric Conjugate Addition Reactions
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60 min, 254 nm): T1 = 39.34, T2 = 49.32.
Dimethyl 2-Ethyl-1,2-dihydro-1-hydroxynaphthalene-2,3-dicarboxy-
late (19): The title compound was prepared from dimethyl 1,4-ep-
oxy-1,4-dihydronaphthalene-2,3-dicarboxylate[21] (17; 0.130 g,
0.5 mmol) according to the ACA general procedure at 0 °C. The
desired alcohol was obtained as a solid after flash chromatography
on silica gel (diethyl ether/pentane, 4:6). Rf = 0.42. 1H NMR
3
(400 MHz, CDCl3): δ = 7.79 (s, 1 H), 7.59 (d, JH,H = 7 Hz, 1 H),
3
7.35–7.26 (m, 2 H), 5.54 (d, JH,H = 7 Hz, 1 H), 3.84 (s, 6 H), 2.22
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3
(br. s, 1 H), 1.83–1.65 (m, 2 H), 0.74 (t, JH,H = 7 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 176.0, 166.7, 138.0, 137.3, 131.0,
130.3, 130.0, 128.4, 127.7, 123.7, 74.8, 55.1, 52.5, 52.1, 20.9,
9.5 ppm. Enantiomer separation: SFC OJ-H (30 °C, 200 bar,
2 mLmin–1): 5–2–1–15; T1 = 6.63, T2 = 10.35.
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[16] See the Supporting Information for a full color figure.
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Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra and enantiomeric separations.
Acknowledgments
The authors thank the Swiss National Research Foundation (grant
No. 200020-113332) and COST action D40 (SER contract No.
C07.0097) for financial support as well as BASF for a generous gift
of chiral amines.
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Published Online: September 1, 2009
Eur. J. Org. Chem. 2009, 4949–4955
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4955