Two Catalytic Methods of an Asymmetric Wittig [2,3]-Rearrangement

Article abstract of DOI:10.1021/acs.joc.6b02786

Two different approaches for asymmetric catalytic Wittig [2,3]-rearrangement were developed. Allyloxymalonate derivatives were converted into homoallyl alcohols via organocatalytic or Ca²⁺-catalyzed pathways in moderate to high enantioselectivi

Full text of DOI:10.1021/acs.joc.6b02786

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Article
Two Catalytic Methods of an Asymmetric Wittig [2,3]-Rearrangement
Maksim Ošeka, Mariliis Kimm, Ivar Jarving, Kristin Lippur, and Tõnis Kanger
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02786 • Publication Date (Web): 22 Feb 2017
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Two Catalytic Methods of an Asymmetric Wittig [2,3]-Rearrangement
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Maksim Ošeka, Mariliis Kimm, Ivar Järving, Kristin Lippur, and Tõnis Kanger*
Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15, 12618
Tallinn, Estonia
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*Corresponding author: eꢀmail: tonis.kanger@ttu.ee
Abstract: Two different approaches for asymmetric catalytic Wittig [2,3]ꢀrearrangement
were developed. Allyloxymalonate derivatives were converted into homoallyl alcohols via
organocatalytic or Ca2+ꢀcatalyzed pathways in moderate to high enantioselectivities.
Introduction
Catalytic reactions are of fundamental importance in chemistry. Both metalꢀcatalyzed and
organocatalytic reactions are widely used in asymmetric synthesis. When a catalytic reaction
is applied in a rearrangement reaction with a hundred percent atom efficiency, it leads to a
highly efficient process. In this context, the development of an asymmetric catalytic
rearrangement reaction remains challenging.
The sigmatropic Wittig [2,3]ꢀrearrangement of allyl ethers affording sterically hindered
homoallyl alcohols with a potential stereogenic center is an efficient tool for the formation of
a CꢀC bond (Scheme 1).1
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Scheme 1. Base induced Wittig [2,3]-rearrangement.
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A great deal of effort has been invested in anionꢀpromoted Wittig rearrangements. Usually
strong Lewis bases, such as BuLi or tꢀBuLi are used to generate carbanion. 2 For
enantioselective reactions, chiral ligands have been used.3
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Examples of catalytic asymmetric Wittig rearrangements remain scarce. The pioneering
organocatalytic paper in this field was published by Gaunt in 2006.4 Only one example of an
aminocatalytic asymmetric reaction was described and the obtained results remained
moderate (ee 60%). Approximately 10 years later new approaches were simultaneously
published by Denmark 5 and by us 6 . Denmark used phaseꢀtransfer catalysis for the
rearrangement of allyloxyoxindole derivatives in moderate enantioselectivities (ee up to 54%).
We used squaramideꢀcatalyzed reactions on the same substrate, affording products in high
enantiomeric purity (ee up to 97%) but the diastereoselectivity of the reaction was low (up to
2.7:1). Recently, Jacobsen et al published a conceptually new approach based on a synergistic
ionꢀbinding thiourea catalysis.7 It was shown that in the transition state of [2,3]ꢀsigmatropic
rearrangements a set of noncovalent interactions involving hydrogen bondings by thiourea
and simultaneous ionꢀbindings were responsible for the enantioselectivity of the reaction.
High yields and enantioselectivities were obtained by applying this concept to
allyloxymalonate derivatives (ee up to 93%). The following is complementary in terms of
described methods and provides new information on the asymmetric Wittig rearrangement.
Results and Discussion
Herein we present two alternative methods for a Wittig [2,3]ꢀsigmatropic rearrangement
reaction of allyloxyꢀ1,3ꢀdicarbonyl compounds (Scheme 2).
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Scheme 2. Two approaches to a Wittig [2,3]-rearrangement.
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The organocatalytic method is based on our previous experience with an asymmetric Wittig
[2,3]ꢀrearrangement of oxindole derivatives.6 An alternative method is a metalꢀcatalyzed
reaction in the presence of chiral ligands. Best to our knowledge, this is the first Lewis acid
catalyzed asymmetric Wittig [2,3]ꢀrearrangement.8 For the past ten years calcium catalytic
reactions have shown very high potency towards 1,3ꢀcarbonyl compounds. Calcium salts
combined with chiral ligands can promote high enantioselective outcomes in various
reactions.9,10,11
It is proposed that the formation of an anion in the substrate serves as a trigger for the
rearrangement reaction. Therefore cinnamyloxymalonate 1a, possessing an acidic proton, was
chosen as a model compound.
Organocatalytic Wittig [2,3]-rearrangement
The set of organocatalysts used are depicted in Figure 1. Our first choice was bifunctional
squaramide I, which showed high enantiodiscrimination in the case of allyloxyꢀoxindole
derivatives. The second group of catalysts (compounds IIꢀVII) is based on a
cyclopropenimine scaffold. These highly basic compounds are comparable to the basicity of
guanidines.12 In addition to their high Lewis basicity they are also hydrogen bond donors
(except catalysts III and VII). Monofunctional chiral guanidine VIII was the last choice.13
The results of screening experiments are presented in Table 1. Chiral squaramide I did not
show any activity towards cinnamyloxymalonate 1a even at a higher temperature and
extended reaction time (Table 1, entry 1). When highly basic cyclopropenimine II was used
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for the rearrangement, excellent reactivity and promising selectivity were achieved (Table 1,
entry 2). Lowering the temperature of the reaction increased the enantioselectivity to 50%,
while full conversion was reached with longer reaction time (Table 1, entry 3). Furthermore, a
variety of catalyst II analogues were synthesized in order to improve the enantioselectivity of
the reaction (Table 1, entries 4ꢀ8). Cyclopropenimine catalyst IIꢀVII can be very easily
prepared from aminoꢀalcohols by a twoꢀstep procedure described by the Lambert group.12 The
instability of the cyclopropenimine catalysts as free bases should be noted. However,
hydrochloric salts of the catalysts are stable at room temperature. Unfortunately, none of those
analogues gave full conversion at reasonable reaction time and the selectivity in most cases
was lower. Catalyst III and VII were exceptional with no hydrogen bond donor sites.
Although almost full conversion was obtained at room temperature in the presence of catalyst
III, the enantioselectivity of the reaction was very low (ee of 2a 8%, Table 1, entry 4).
Sterically more hindered catalyst VII was inactive, affording no conversion (Table 1, entry 8).
The reaction catalyzed by guanidine VIII gave poorer results (Table 1, entry 9). Since full
conversion is particularly important in terms of purification as compounds 1 and 2 are
chromatographically inseparable, catalyst II was chosen for further screening, despite the fact
that catalyst IV was to some extent more selective. Also, catalyst II is more stable than
catalyst IV. Next, several typical solvents for hydrogenꢀbond mediated transformations were
tested (Table 1, entries 10ꢀ13).. It is known that apolar solvents are preferred for the hydrogen
bond catalyzed reactions. Hexane was excluded because of low solubility of reactants in this
solvent. The reaction was faster in 1:1 mixture of hexane and chloroform than in CDCl3 but
the stereoselectivity was lower (Table 1, entries 3 and 10). Etheral solvents or toluene had no
advantages over chloroform (Table 1, entries 12ꢀ14). As expected, racemic product was
obtained in protonic solvent (Table 1, entry 15). The decrease of the amount of catalyst II led
to only partial conversion after two days of the reaction (Table 1, entry 16).
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Figure 1. Catalysts screened for the organocatalytic Wittig [2,3]ꢀrearrangement of
cinnamyloxymalonates.
Table 1. Catalyst screening and optimization of the organocatalytic Wittig [2,3]-
rearrangement of cinnamyloxymalonate 1aa
Conv.
Entry Catalyst
Solvent
Temp.
Time
ee (%)c
(%)b
0
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3
4
5
6
7
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
55 °C
rt
96 h
2 h
ꢀ
I
100
100
94
33
50
8
II
ꢀ20 °C
rt
18 h
2 h
II
III
IV
V
ꢀ20 °C
ꢀ20 °C
rt
23 h
18 h
18 h
97
52
ꢀ37
rac
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45
VI
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CDCl3
CDCl3
55 °C
55 °C
72 h
72 h
0
ꢀ
VII
90
ꢀ20
VIII
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9
Hexane:
10
ꢀ20 °C
5 h
100
45
II
d
CDCl3
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11
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EtOAc
toluene
THF
rt
23 h
20 h
20 h
18 h
18 h
48 he
80
83
17
28
23
31
rac
ꢀ
II
II
II
II
II
II
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
74
Et2O
78
MeOH
CDCl3
100
57
a
b
Reaction conditions: 0.1 mmol scale, 20 mol % of cat., solvent (0.5 mL). Conversion
determined by 1H NMR analysis of the crude mixture. Determined by chiral HPLC analysis
c
d
e
of the sample obtained by preparative TLC. Mixture 1:1. Reaction conditions: 0.1 mmol
scale, 10 mol % of cat., solvent (0.25 mL).
Ca2+-catalyzed Wittig [2,3]-rearrangement reaction
Next, the results of a Caꢀcatalyzed Wittig [2,3]ꢀsigmatropic rearrangement reaction of
allyloxyꢀ1,3ꢀdicarbonyl compounds will be discussed.
In a metalꢀcatalyzed reaction, several factors besides the chiral ligand (such as the source of
metal, the solvent and the additional base) influence the stereoselectivity of the rearrangement.
We limited the scope of ligands to bisoxazoline derivatives as most widely used in Ca2+ꢀ
catalysis1415 although oxazolidines and bisoxazolidines have also been used in catalysis with
other metals.16 Also, the choice of solvent was 2ꢀpropanol as we have previously shown its
superiority over other solvents for Ca2+ꢀbisoxazolineꢀcatalyzed reactions.17 (See Supporting
Information for full optimization procedures).
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Initially different calcium salts were screened in the presence or absence of imidazole as an
additional base (Table 2, entries 1ꢀ6). The addition of imidazole in a calcium chloride/L1
catalyzed reaction (Figure 2) was needed to yield higher conversion and enantioselectivity
(Table 2, entries 1ꢀ2). The reaction with calcium iodide stopped after 6 hours, within 24 hours
the reaction had not proceeded further. Calcium(II) bis(trifluoromethanesulfonimide)
(Ca(NTf2)2) proved to be the superior of the Caꢀsalts (Table 2, entry 4), giving full conversion
and enantiomeric excess of 75% in 24 hours. Next, other organic bases were evaluated (Table
2, entries 7ꢀ10), but still the addition of imidazole gave slightly higher enantioselectivity than
with the other bases. The presence of cesium carbonate gave a racemic product in 6 hours,
indicating that the inorganic base prevailed over the Caꢀcomplex (Table 2, entry 11).
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Table 2. Optimization of the reaction conditions of a Ca2+-catalyzed rearrangementa
Conv.
Entry
Caꢀsalt
Base
Time
ee (%)c
(%)b
58
92
36
99
99
99
79
97
1d
2
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CaCl2
CaCl2
−
3 d
3 d
39
49
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
Et3N
CaI2
6 he
24 h
1 h
64
Ca(NTf2)2
75
f
Ca(HFIP)2
Ca(HMDS)2
Ca(NTf2)2
Ca(NTf2)2
rac
rac
68
f
1 h
24 h
24 h
DIPEAf
70
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Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Morpholine
Pyridine
24 h
3 d
85
40
99
70
52
10
11g
Cs2CO3
6 h
rac
9
a
Reaction conditions: 1a (0.1 mmol), L1 (5 mol%), Caꢀsalt (5 mol%) and base (5 mol%) in
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b
1
2ꢀpropanol (1 mL) was stirred at 60 °C. Conversion was determined by H NMR of the
crude product. c Enantiomeric excess was determined by chiral HPLC. d Reaction was carried
e
f
out without additional base. Reaction stopped after 6 h. HFIP = hexafluoroisopropanyl,
g
HMDS = hexamethyldisilazane, DIPEA = N,Nꢀdiisopropylethylamine.
Reaction was
conducted at room temperature.
After the optimized conditions for the coordinative neutral ligand L1 were determined (Table
3, entry 1), we screened other bisoxazoline ligands (Table 3, entries 2ꢀ6). Unexpectedly, all of
the ligands were less active and produced products with either low enantioselectivity or
racemic outcome. We also assessed the complex formation by NMR and ESIꢀMS, and found
that the 1:1 complex between ligand L1 and Ca(NTf2)2 formed immediately after mixing the
two together (Figure S1 in SI), and was stable for at least up to 300 °C in ESIꢀMS (Figure S3
in SI).
Figure 2. Bisoxazoline ligands used in the current study.
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Table 3. Screening of different bisoxazoline ligandsa
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Conv.
(%)b
99
Entry Ligand Time
ee (%)c
1
2
3
4
5
6
24 h
3 d
75
L1
L2
L3
L4
L5
L6
12
−
24 h
24 h
24 h
24 h
44
ꢀ12
rac
rac
rac
29
43
54
a Reaction conditions: 1a (0.1 mmol), ligand (5 mol%), Ca(NTf2)2 (5 mol%) and imidazole (5
mol%) in 2ꢀpropanol (1 mL) were stirred at 60 °C. b Conversion was determined by 1H NMR
of the crude product. c Enantiomeric excess was determined by chiral HPLC.
Scope of two alternative methods for a Wittig [2,3] rearrangement reaction
The scope of the reaction was evaluated by studying the effects of the substituents at the
aromatic ring and at the carbonyl moiety. The two methods applied afforded comparable
results in terms of yields and enantiomeric purities (Figure 3). The main difference was in the
enantioselection. In organocatalytic reactions, the main enantiomer was in Rꢀconfiguration;
metalꢀcatalyzed reactions afforded Sꢀenantiomer as a major isomer. The absolute
configuration was determined by a comparison of the optical rotation of compound 2a with
data published by Jacobsen.7 Both methods are sensitive to steric hindrance and no products
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were formed with isopropyl or tertꢀbutyl derivatives 1b and 1c. Mixed ester 1e was
synthesized to explore the diastereoselectivity of the reaction. Unfortunately, the methods
were characterized by low or moderate diastereoselectivity (for 2e dr 1.5:1 and 3:1).
Diketones 1f and 1g were poor starting materials for the rearrangement affording product with
low yield or no conversion by Caꢀcatalyzed reactions (organocatalytic reactions were not
applied on these compounds). The organocatalytic method showed higher sensitivity towards
the steric hindrance. Previously we have found that only Eꢀisomers of phenyl substituted
allyloxy compounds were reactive in the case of organocatalytic rearrangement of oxindole
derivatives.6 The enantiomeric purity of the oꢀchlorophenyl derivative 2h was lower in the
case of the organocatalytic method compared with that obtained by metalꢀcatalysis. Metaꢀ and
paraꢀsubstitution did not affect the results substantially (compounds 2i and 2j).
Electrondonating, electron withdrawing and heteroaromatic substituents were tolerated under
the reaction conditions (2k-n). Surprisingly low enantiomeric excess was obtained with
nitrophenyl derivative 2l by the organocatalytic method. This might be due to the fact that the
nitro group is a very strong Hꢀbond acceptor and therefore the transition state could be
completely different.
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a Reaction conditions for the organocatalytic reaction A: 0.1 mmol scale, 20 mol % of cat. II,
CDCl3 (0.5 mL), ꢀ20°C, 24 h. Enantiomeric excess is determined by chiral HPLC analysis of
b
the isolated product. Reaction conditions for the Caꢀcatalyzed reaction B: 1a-n (0.1 mmol),
L1 (5 mol%), Ca(NTf2)2 (5 mol%) and imidazole (5 mol%) in 2ꢀpropanol (1 mL) were stirred
c
d
1
at 60 °C for 24 h. Isolated yield. Diastereoisomeric ratio is determined by H NMR
analysis of the crude mixture. e Reaction was stopped after 48 h. f Reaction was finished after
48 h. g Reaction was finished after 6 h.
Figure 3. Scope of the reaction (Rꢀenantiomers obtained by organocatalytic method are
depicted).
Based on the obtained results we propose transition state models for both methods.
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Figure 4. Model for the interaction of catalyst II with malonate derivative 1a to account for
the stereochemical outcome of the rearrangement.
In the organocatalytic reaction first the malonate derivative 1a is deprotonated by a strongly
basic catalyst affording an enolate anion and a cyclopropenium ion (Figure 4). It has been
shown that a weak intramolecular CH…O interaction (0.5 kcal/mol) is responsible for the
transition state organization in reactions catalyzed by chiral cyclopropenimines.18 Our results
indicate that the hydrogen bond donor capability of the catalyst is essential for achieving high
stereoselectivity. Catalysts II and III differ from each other by their hydrogen bond donating
properties. Methoxyꢀprotected catalyst III has no hydrogen bond donors, by what lowering
the stereoselectivity of the reaction drastically (compare entries 2 and 4 in Table 1). The same
observation had been made by Lambert.18 It is assumed that in the enantiodetermining
rearrangement step, the conformation of the substrate is fixed with hydrogen bonds. The
hydrogen bond between the OH group of catalyst II and the allylic oxygen promotes the
rearrangement. A similar activation model has previously been proposed for the cycloaddition
of azomethine ylides19 and for a Mannich reaction.20
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Figure 5. Model for the complexation of a Ca2+/indaꢀPybox complex with compound 1a to
account for the stereochemical outcome of the rearrangement.
Calcium2+/Pybox complexes have been previously investigated by NMR 21 and Xꢀray
crystallography22. Based on these publications, it is assumed that in the Ca2+ꢀcatalytic reaction,
the N,N,Nꢀtridentate indaꢀPybox ligand first forms a complex with Ca(NTf2)2, which is a
strong Lewis acid. Then, calcium enolate is formed with substrate 1a and the oxygen in the
allyloxy group coordinates with calcium. Finally, the second trifluoromethanesulfonimide
group is removed from calcium, giving the presented model (Figure 5).
Conclusions
We have developed two independent asymmetric catalytic methods for a Wittig [2,3]ꢀ
rearrangement. In the organocatalytic pathway, a highly basic substituted cyclopropenimine
catalyst was used. In the metalꢀcatalyzed reaction, a Ca2+/bisoxazoline complex was
employed. Our ongoing investigations are focused on mechanistic models in order to increase
so far modest selectivities.
Experimental Section
General remarks
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Full assignment of H and 13C chemical shifts is based on the 1D and 2D FT NMR spectra
measured on a 400 MHz instrument. Residual solvent signals were used (CDCl3 δ = 7.26 (1H
NMR), 77.16 (13C NMR) and CD3OD δ = 3.31 (1H NMR), 49.00 (13C NMR)) as internal
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standards. All peak assignments are confirmed by 2D experiments (1Hꢀ1H COSY, Hꢀ13C
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HMQC, Hꢀ13C HMBC). High resolution mass spectra were recorded by using an QꢀTOF
LC/MS spectrometer by using ESI ionization. Optical rotations were obtained at 20 °C in
CHCl3 and calibrated with pure solvent as a blank. Chiral HPLC was performed by using
Chiralpak ADꢀH (250 x 4.6 mm), Chiralcel OJꢀH (250 x 4.6 mm), Chiralcel ODꢀH (250 x 4.6
mm), Chiralpak ASꢀH (250 x 4.6 mm) or Lux 3u Amyloseꢀ2 (250 x 4.6 mm) columns.
Precoated silica gel 60 F254 plates were used for TLC. Column chromatography was
performed on a preparative purification system with silica gel Kieselgel 40ꢀ63 µm. The
measured melting points are uncorrected. Purchased chemicals and solvents were used as
received. DCM was distilled over phosphorous pentoxide. Petroleum ether has a boiling point
of 40ꢀ60 °C. The reactions were performed under air atmosphere without additional moisture
elimination unless stated otherwise.
Catalysts I23, VI24, and VIII25 were prepared according to literature procedures and the
analytical data matched with that of the literature. New catalysts III, IV, V and VII were
prepared according to the analogous literature procedure. 26 Catalyst II is commercially
available as an HCl salt.
Ligands L5 and L6 were purchased and used as received. Ligands L1-L4 were prepared
according to the literature procedures.27,28,29,30
Synthesis of catalysts III•HCl, IV•HCl, V•HCl , and VII
Dicyclohexylamine (6.0 equiv) was slowly added to a solution of tetrachlorocyclopropene
(1.0 equiv) in DCM (0.1 M solution). A white precipitate formed as the reaction mixture was
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stirred for a further four hours at room temperature. Next, primary amine (1.1 equiv) was
added in one portion and the reaction mixture was stirred overnight. The crude reaction
mixture was filtered through a celite plug, then washed with 1.0 M HCl (3 x), dried with
anhydrous sodium sulfate and concentrated in vacuo to yield pure cyclopropenimine
hydrochloride salt. The cyclopropenimine salt can be stored at room temperature without
noticeable decomposition.
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Free cyclopropenimine was obtained by dissolving the corresponding hydrochloride salt in
DCM and washing the solution with 1.0 M aq NaOH, drying with anhydrous sodium sulfate
and
concentrating
in
vacuo.(S)-N1,N1,N2,N2-tetracyclohexyl-3-((1-methoxy-3-
phenylpropan-2-yl)imino)cycloprop-1-ene-1,2-diamine hydrochloride salt III•HCl
The synthesis was conducted with (S)ꢀphenylalaninol methyl ether, affording compound III
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as a brown amorphous solid in 90% yield (131 mg). Optical rotation for III: [α]D –31.9 (c
0.11, CHCl3).
Spectra data for III•HCl: 1H NMR (400 MHz, CD3OD) δ 7.33 – 7.20 (m, 5H, Ar), 3.96 (ddt, J
= 9.5, 7.9, 4.6 Hz, 1H, NCH), 3.64 (dd, J = 9.5, 4.7 Hz, 1H, CH2O), 3.54 (dd, J = 9.4, 8.2 Hz,
1H, CH2O), 3.46 – 3.35 (m, 7H, CH3 and NCyH), 3.04 (dd, J = 13.9, 4.4 Hz, 1H, CH2Ph),
2.84 (dd, J = 13.9, 9.9 Hz, 1H, CH2Ph), 1.95 – 1.18 (m, 40H, CyH). 13C NMR (101 MHz,
MeOD) δ 139.1, 130.4, 129.7, 127.9, 117.7, 115.9, 76.3, 61.4, 60.4, 59.6, 38.9, 33.3, 33.2,
26.71, 26.66, 25.7.
(S)-2-((2,3-Bis(dicyclohexylamino)cycloprop-2-en-1-ylidene)amino)-3,3-dimethylbutan-
1-ol hydrochloride salt IV•HCl
The synthesis was conducted with (S)ꢀtertꢀleucinol, affording compound IV•HCl as an offꢀ
white solid in 85% yield (490 mg). Optical rotation for IV•HCl: [α]D20 –46.9 (c 0.09, CHCl3).
1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H, OH), 6.83 (d, J = 9.8 Hz, 1H, NH), 4.10 (dd, J =
11.9, 9.7 Hz, 1H, CH2OH), 3.78 (dd, J = 12.0, 4.0 Hz, 1H, CH2OH), 3.42 (td, J = 9.7, 4.0 Hz,
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1H, CHtBu), 3.32 (tt, J = 11.9, 3.4 Hz, 4H, NCyH), 2.05 – 1.10 (m, 40H, CyH), 0.94 (s, 9H,
tBu). 13C NMR (101 MHz, CDCl3) δ 119.0, 68.4, 59.7, 59.5, 34.9, 32.7, 26.9, 25.9, 25.8,
25.02, 24.99, 24.93.
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HRMS (ESI) calculated for C33H58N3O, [M + H]+: 512.4574, found 512.4569.
(1R,2R)-2-((2,3-Bis(dicyclohexylamino)cycloprop-2-en-1-ylidene)amino)cyclohexan-1-ol
hydrochloride salt V•HCl
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The synthesis was conducted with (1R,2R)ꢀ2ꢀaminocyclohexanol, affording compound
V•HCl was obtained as an offꢀwhite solid in 87% yield (475 mg). Optical rotation for V•HCl:
[α]D20 –14.8 (c 0.11, CHCl3).
1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H, OH), 7.80 (d, J = 7.5 Hz, 1H, NH), 4.20 – 3.99 (m,
1H, CyH), 3.51 – 3.22 (m, 5H, CyH), 3.15 – 2.95 (m, 1H, CyH), 2.29 – 2.02 (m, 3H, CyH),
2.00 – 1.06 (m, 44H, CyH). 13C NMR (101 MHz, CDCl3) δ 117.2, 115.0, 70.5, 63.6, 59.6,
34.00, 33.98, 32.32, 32.29, 29.0, 28.9, 25.85, 25.82, 25.79, 24.90, 24.84, 24.80, 24.7, 24.4.
HRMS (ESI) calculated for C33H56N3O, [M + H]+: 510.4418, found 510.4412.
N1,N1,N2,N2-tetracyclohexyl-3-(((R)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-
vinylquinuclidin-2-yl)methyl)imino)cycloprop-1-ene-1,2-diamine VII
The synthesis was conducted with (R)ꢀ(6ꢀmethoxyquinolinꢀ4ꢀyl)((1S,2S,4S,5R)ꢀ5ꢀ
vinylquinuclidinꢀ2ꢀyl)methanamine, affording compound VII after purification by column
chromatography on silica gel (5% NH3/MeOH in DCM), as an offꢀwhite solid in 26% yield
(75 mg). Optical rotation for VII: [α]D20 +157.1 (c 0.09, CHCl3).
1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 4.5 Hz, 1H, ArH), 8.00 (d, J = 9.2 Hz, 1H, ArH),
7.88 (s, 1H, ArH), 7.49 (d, J = 3.5 Hz, 1H, ArH), 7.38 (dd, J = 9.2, 2.6 Hz, 1H, ArH), 6.21
(ddd, J = 17.0, 10.2, 6.6 Hz, 1H, CHCH2), 6.03 (d, J = 7.4 Hz, 1H, CHN), 5.23 – 5.10 (m, 2H,
CHCH2), 4.08 (s, 3H, OCH3), 3.35 – 3.05 (m, 5H), 3.03 – 2.78 (m, 3H), 2.73 – 2.50 (m, 1H),
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2.31 (q, J = 8.0 Hz, 1H), 2.00 – 0.52 (m, 45H). C NMR (101 MHz, CDCl3) δ 158.5, 147.9,
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145.1, 140.1, 131.9, 128.3, 122.9, 115.7, 115.5, 113.8, 103.0, 58.7, 56.8, 49.2, 47.4, 39.6, 32.2,
31.9, 28.2, 25.2, 25.1, 24.6.
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HRMS (ESI) calculated for C47H68N5O, [M + H]+: 718.5418, found 718.5414.
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Synthesis of starting materials 1a-n
The synthesis of compounds 1a and 1c was described by Jacobsen.7 We used a slightly
modified procedure. The synthesis of allyloxyꢀ1,3ꢀdicarbonyl compounds 1a-n was achieved
as follows. 1,3ꢀDicarbonyl compounds were reacted with tosyl azide to produce diaza
compounds, which were subjected to rhodiumꢀcatalyzed OH insertion reaction, affording the
desired compounds 1. A general procedure for the formation of 1a is presented. In the
synthesis of 1a and 1h-n, transesterification of malonyl ester occurred, to improve the yield,
transesterification with pꢀTsOH in MeOH can be conducted. This procedure was performed
only with compound 1a.
Dimethyl 2-diazomalonate
To a solution of tosyl azide (1.735 g, 8.8 mmol) in acetonitrile (12 mL), triethylamine (1.227
ml, 8.8 mmol) and dimethyl malonate (0.916 mL, 8 mmol) was added at 0 °C. The reaction
mixture was stirred overnight at room temperature. Then, solvent was evaporated under
reduced pressure and the crude mixture purified by column chromatography on silica gel (10ꢀ
20% EtOAc in petroleum ether/DCM 3/1 mixture), affording title compound as a colourless
oil (1.227 g, 97%).
Dimethyl 2-(cinnamyloxy)malonate 1a
To a 10ꢀmL flask was added cinnamyl alcohol (322 mg, 2.4 mmol) and rhodium(II) acetate
dimer (4.4 mg, 0.01 mmol). The flask was flushed with Ar and DCM was added (5 mL).
Dimethyl 2ꢀdiazomalonate (286 mg, 2 mmol) solution in DCM (5 mL) was added over 5
minutes at 0 °C. The reaction was stirred overnight at rt. After evaporating the solvent, the
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crude mixture was purified by column chromatography on silica gel (3ꢀ10% EtOAc in
petroleum ether/DCM 3/1 mixture), affording compound 1a as a colourless oil. The impure
fractions were dried under vacuum, dissolved in MeOH (10 mL), pꢀtoluenesulfonic acid (30
mg) was added and the mixture was stirred at reflux overnight. After purification in the same
conditions, the fractions were combined, affording compound 1a as a colourless oil in 64%
total yield (336 mg).
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1H NMR (400 MHz, CDCl3) δ 7.41 – 7.37 (m, 2H, 2×ArH), 7.35 – 7.29 (m, 2H, 2×ArH), 7.29
– 7.23 (m, 1H, ArH), 6.64 (d, J = 15.9 Hz, 1H, CHAr), 6.28 (dt, J = 15.9, 6.5 Hz, 1H,
CH2CH), 4.64 (s, 1H, CH), 4.34 (dd, J = 6.5, 1.2 Hz, 2H, CH2), 3.81 (s, 6H, 2xCH3). 13C
NMR (101 MHz, CDCl3) δ 167.0, 136.1, 134.9, 128.6, 128.1, 126.7, 123.7, 77.5, 71.8, 53.0.
HRMS (ESI) calculated for C14H16NaO5, [M + Na]+: 287.0890, found 287.0879.
Diisopropyl 2-(cinnamyloxy)malonate 1b
Compound 1b was obtained as a colourless oil in 70% yield (112 mg).
1H NMR (400 MHz, CDCl3) δ 7.41 – 7.36 (m, 2H, 2×ArH), 7.35 – 7.29 (m, 2H, 2×ArH), 7.28
– 7.25 (m, 1H, ArH), 6.63 (d, J = 16.0 Hz, 1H, CHAr), 6.30 (dt, J = 15.9, 6.5 Hz, 1H,
CH2CH), 5.12 (hept, J = 6.3 Hz, 2H, CH(CH3)2), 4.52 (s, 1H, CH), 4.34 (dd, J = 6.5, 1.1 Hz,
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2H, CH2), 1.27 (d, J = 6.2 Hz, 6H, 2xCH3), 1.26 (d, J = 6.3 Hz, 6H, 2xCH3). C NMR (101
MHz, CDCl3) δ 166.3, 136.3, 134.7, 128.7, 128.2, 126.8, 124.3, 78.1, 71.7, 69.9, 21.8, 21.7.
HRMS (ESI) calculated for C18H24NaO5, [M + Na]+: 343.1516, found 343.1510.
Di-tert-butyl 2-(cinnamyloxy)malonate 1c
Compound 1c was obtained as a white solid in 62% yield (255 mg).
1H NMR (400 MHz, CDCl3) δ 7.42 – 7.36 (m, 2H, 2×ArH), 7.35 – 7.28 (m, 2H, 2×ArH), 7.28
– 7.22 (m, 1H, ArH), 6.63 (d, J = 15.9 Hz, 1H, CHAr), 6.30 (dt, J = 15.9, 6.4 Hz, 1H,
CH2CH), 4.37 (s, 1H, CH), 4.32 (dd, J = 6.4, 1.2 Hz, 2H, CH2), 1.49 (s, 18H, 2xtBu). 13C
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NMR (101 MHz, CDCl3) δ 166.0, 136.5, 134.3, 128.7, 128.1, 126.8, 124.6, 82.8, 79.0, 71.4,
28.1.
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Compound 1d was obtained as a white solid in 56% yield (170 mg), mp 65ꢀ67 °C.
1H NMR (400 MHz, CDCl3) δ 7.47 – 7.15 (m, 15H, 15xArH), 6.58 (d, J = 15.9 Hz, 1H,
CHAr), 6.26 (dt, J = 15.9, 6.5 Hz, 1H, CH2CH), 5.19 (s, 4H, CH2Ph), 4.69 (s, 1H, CH), 4.34
(dd, J = 6.5, 1.1 Hz, 2H, CH2). 13C NMR (101 MHz, CDCl3) δ 166.5, 136.2, 135.0, 128.7
(2C), 128.6, 128.5 (2C), 128.2, 126.8, 124.0, 77.7, 71.9, 67.7.
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HRMS (ESI) calculated for C26H24NaO5, [M + Na]+: 439.1516, found 439.1505.
1-Benzyl 3-methyl 2-(cinnamyloxy)malonate 1e
Compound 1e was obtained as a colourless oil in 59% yield (146 mg).
1H NMR (400 MHz, CDCl3) δ 7.41 – 7.23 (m, 10H, 10xArH), 6.60 (d, J = 15.9 Hz, 1H,
CHAr), 6.27 (dt, J = 16.0, 6.5 Hz, 1H, CH2CH), 5.26 (d, J = 12.3 Hz, 1H, CH2Ph), 5.22 (d, J
= 12.2 Hz, 1H, CH2Ph), 4.66 (s, 1H, CH), 4.33 (dd, J = 6.5, 1.0 Hz, 2H, CH2), 3.76 (s, 3H,
CH3). 13C NMR (101 MHz, CDCl3) δ 167.0, 166.6, 136.2, 135.0, 128.73 (2C), 128.67, 128.4,
128.3, 126.8 (2C), 123.9, 77.7, 71.9, 67.7, 53.0.
HRMS (ESI) calculated for C20H21O5, [M + H]+: 341.1384, found 341.1379.
3-(Cinnamyloxy)pentane-2,4-dione 1f
Compound 1f was obtained in 3 hours at 5 °C, as a pale yellow oil, which solidifies in the
freezer, in 62% yield (227 mg).
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Spectra data for symmetric enol: H NMR (400 MHz, CDCl3) δ 14.38 (s, 1H, OH), 7.44 –
7.39 (m, 2H, 2xArH), 7.37 – 7.31 (m, 2H, 2xArH), 7.30 – 7.26 (m, 1H, ArH), 6.68 (d, J =
15.9 Hz, 1H, CHAr), 6.36 (dt, J = 15.9, 6.1 Hz, 1H, CH2CH), 4.31 (dd, J = 6.1, 1.3 Hz, 2H,
CH2), 2.20 (s, 6H, 2xCH3). 13C NMR (101 MHz, CDCl3) δ 186.5, 136.4, 135.7, 133.6, 128.8,
128.3, 126.7, 124.3, 75.3, 21.0.
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HRMS (ESI) calculated for C14H16NaO3, [M + Na]+: 255.0992, found 255.0986.
2-(Cinnamyloxy)-1,3-diphenylpropane-1,3-dione 1g
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Compound 1g was obtained as a yellow amorphous solid in 27% yield (87 mg).
1H NMR (400 MHz, CDCl3) δ 8.01 – 7.92 (m, 2H, 2xArH), 7.58 – 7.49 (m, 1H, ArH), 7.47 –
7.28 (m, 12H, 12xArH), 6.59 (d, J = 15.9 Hz, 1H, CHAr), 6.23 (dt, J = 15.9, 6.4 Hz, 1H,
CH2CH), 5.66 (s, 1H, CH), 4.83 (dt, J = 6.4, 1.4 Hz, 2H, CH2). 13C NMR (101 MHz, CDCl3)
δ 193.3, 168.8, 135.8, 134.6, 133.7, 133.0, 130.8, 129.7, 129.1, 129.0, 128.9, 128.7, 128.4,
128.2, 126.8, 122.7, 66.4, 60.7.
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HRMS (ESI) calculated for C24H20NaO3, [M + Na]+: 379.1305, found 379.1280.
Dimethyl (E)-2-((3-(2-chlorophenyl)allyl)oxy)malonate 1h
Compound 1h was obtained as a white solid in 34% yield (91 mg), mp 53ꢀ55 °C.
1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.3, 2.2 Hz, 1H, ArH), 7.35 (dd, J = 7.5, 1.8 Hz,
1H, ArH), 7.25 – 7.15 (m, 2H, 2xArH), 7.02 (d, J = 15.9 Hz, 1H, CHAr), 6.28 (dt, J = 15.9,
6.4 Hz, 1H, CH2CH), 4.65 (s, 1H, CH), 4.38 (dd, J = 6.4, 1.1 Hz, 2H, CH2), 3.82 (s, 6H,
2xCH3). 13C NMR (101 MHz, CDCl3) δ 167.1, 134.4, 133.4, 130.9, 129.9, 129.3, 127.2, 127.0,
126.9, 77.7, 71.9, 53.1.
HRMS (ESI) calculated for C14H15ClNaO5, [M + Na]+: 321.0500, found 321.0488.
Dimethyl (E)-2-((3-(3-chlorophenyl)allyl)oxy)malonate 1i
Compound 1i was obtained as a colourless oil in 53% yield (149 mg).
1H NMR (400 MHz, CDCl3) δ 7.38 – 7.35 (m, 1H, ArH), 7.29 – 7.20 (m, 3H, 3xArH), 6.59 (d,
J = 15.9 Hz, 1H, CHAr), 6.30 (dt, J = 15.9, 6.3 Hz, 1H, CH2CH), 4.62 (s, 1H, CH), 4.33 (dd,
J = 6.3, 1.2 Hz, 2H, CH2), 3.82 (s, 6H, 2xCH3). 13C NMR (101 MHz, CDCl3) δ 167.0, 138.1,
134.7, 133.2, 130.0, 128.2, 126.8, 125.6, 124.9, 77.8, 71.6, 53.1.
HRMS (ESI) calculated for C14H16ClO5, [M + H]+: 299.0681, found 299.0675.
Dimethyl (E)-2-((3-(4-chlorophenyl)allyl)oxy)malonate 1j
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Compound 1j was obtained as a white amorphous solid in 56% yield (159 mg).
1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.5 Hz, 2H, 2xArH), 7.28 (d, J = 8.8 Hz, 2H,
2xArH), 6.59 (d, J = 16.0 Hz, 1H, CHAr), 6.26 (dt, J = 15.9, 6.4 Hz, 1H, CH2CH), 4.62 (s, 1H,
CH), 4.32 (dd, J = 6.4, 1.1 Hz, 2H, CH2), 3.81 (s, 6H, 2xCH3). 13C NMR (101 MHz, CDCl3) δ
167.0, 134.7, 133.9, 133.5, 128.9, 128.0, 124.6, 77.8, 71.8, 53.1.
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HRMS (ESI) calculated for C14H15ClNaO5, [M + Na]+: 321.0500, found 321.0487.
Dimethyl (E)-2-((3-(4-methoxyphenyl)allyl)oxy)malonate 1k
Compound 1k was obtained as a colourless oil in 63% yield (166 mg).
1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.7 Hz, 2H, 2xArH), 6.85 (d, J = 8.7 Hz, 2H,
2xArH), 6.57 (d, J = 15.9 Hz, 1H, CHAr), 6.14 (dt, J = 15.9, 6.7 Hz, 1H, CH2CH), 4.63 (s, 1H,
CH), 4.31 (dd, J = 6.7, 1.0 Hz, 2H, CH3), 3.81 (s, 3H, OCH3), 3.80 (s, 6H, 2xCH3). 13C NMR
(101 MHz, CDCl3) δ 167.2, 159.8, 134.9, 128.9, 128.1, 121.5, 114.1, 77.4, 72.2, 55.4, 53.1.
HRMS (ESI) calculated for C15H18NaO6, [M + Na]+: 317.0996, found 317.0981.
Dimethyl (E)-2-((3-(4-nitrophenyl)allyl)oxy)malonate 1l
Compound 1l was obtained as a yellow solid in 46% yield (147 mg), mp 58ꢀ60 °C.
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.7 Hz, 2H, 2xArH), 7.52 (d, J = 8.8 Hz, 2H,
2xArH), 6.74 (d, J = 16.0 Hz, 1H, CHAr), 6.47 (dt, J = 16.0, 5.9 Hz, 1H, CH2CH), 4.63 (s, 1H,
CH), 4.38 (dd, J = 5.9, 1.4 Hz, 2H, CH2), 3.83 (s, 6H, 2xCH3). 13C NMR (CDCl3, 101 MHz) δ
166.8, 147.4, 142.7, 131.6, 129.1, 127.3, 124.2, 78.2, 71.3, 53.2.
HRMS (ESI) calculated for C14H15NNaO7, [M + Na]+: 332.0741, found 332.0732.
Dimethyl (E)-2-((3-(naphthalen-2-yl)allyl)oxy)malonate 1m
Compound 1m was obtained as a pale yellow oil in 33% yield (97 mg).
1H NMR (400 MHz, CDCl3) δ 7.83 – 7.77 (m, 3H, 3xArH), 7.75 (s, 1H, ArH), 7.60 (dd, J =
8.6, 1.7 Hz, 1H, ArH), 7.50 – 7.42 (m, 2H, 2xArH), 6.80 (d, J = 15.9 Hz, 1H, CH), 6.41 (dt, J
= 15.9, 6.5 Hz, 1H, CH2CH), 4.67 (s, 1H, CH), 4.39 (dd, J = 6.5, 1.2 Hz, 2H, CH2), 3.82 (s,
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6H, 2xCH3). C NMR (101 MHz, CDCl3) δ 167.2, 135.1, 133.7, 133.6, 133.4, 128.4, 128.2,
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127.8, 127.1, 126.5, 126.3, 124.3, 123.6, 77.7, 72.1, 53.1.
HRMS (ESI) calculated for C18H18NaO5, [M + Na]+: 337.1046, found 337.1040.
Dimethyl (E)-2-((3-(thiophen-2-yl)allyl)oxy)malonate 1n
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Compound 1n was obtained as a yellow oil in 38% yield (102 mg).
1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 4.9 Hz, 1H, ArH), 7.07 – 6.87 (m, 2H, 2xArH),
6.76 (d, J = 15.7 Hz, 1H, CHAr), 6.10 (dt, J = 15.7, 6.5 Hz, 1H, CH2CH), 4.62 (s, 1H, CH),
4.29 (dd, J = 6.5, 1.2 Hz, 2H, CH2), 3.81 (s, 6H, 2xCH3). 13C NMR (101 MHz, CDCl3) δ
167.1, 141.2, 128.1, 127.5, 126.7, 125.2, 123.3, 77.6, 71.6, 53.1.
HRMS (ESI) calculated for C12H14NaO5S, [M + Na]+: 293.0454, found 293.0447.
General procedure for organocatalytic Wittig [2,3] rearrangement of allyloxy-1,3-
dicarbonyl compounds 1 (Method A)
A solution of allyloxyꢀ1,3ꢀdicarbonyl compound 1 (0.1 mmol) in CDCl3 (0.25 mL) was added
to a cooled solution of catalyst II (20 mol%) in CDCl3 (0.25 mL). The reaction mixture was
stirred at ꢀ20 °C for 24 hours. Upon completion of the reaction, the crude mixture was directly
purified by flash chromatography on silica gel (0ꢀ10% EtOAc in petroleum ether/DCM 3/1
mixture), affording the desired product 2. The enantioselectivity of the isolated product was
determined by HPLC analysis, providing the product in (R)ꢀconfiguration.
General procedure for Ca-catalyzed asymmetric Wittig [2,3] rearrangement of allyloxy
1,3-dicarbonyl compounds 1 (Method B)
To a solution of allyloxy 1,3ꢀdicarbonyl compound 1 (0.1 mmol) in 2ꢀpropanol (1 mL),
Ca(NTf2)2 (0.005 mmol), ligand L1 (0.005 mmol) and imidazole (0.005 mmol) were added.
The reaction mixture was stirred at 60 °C. Then, the solvent was evaporated and the residue
was purified by flash chromatography on silica gel (0ꢀ10% EtOAc in petroleum ether/DCM
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3/1 mixture), affording the desired product 2. The enantioselectivity of the isolated product
was determined by HPLC analysis, providing the product in (S)ꢀconfiguration.
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Dimethyl (R)-2-hydroxy-2-(1-phenylallyl)malonate 2a
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Compound 2a was obtained as a white solid, for method A in 87% yield (23 mg) and for
method B in 67% yield (18 mg), mp 86ꢀ88 °C. The enantioselectivity was determined by
chiral HPLC analysis (Chiralpak ADꢀH, hexane:2ꢀpropanol = 90:10, flow rate = 1.0 mL/min,
25 °C, λ = 210 nm), (R)-2a 10.7 min and (S)-2a 9.6 min, enantiomeric excess for compound
2a for method A was 50% and for method B was 75%. Optical rotation for (R)-2a (ee 50%):
[α]D20 –28.8 (c 0.11, CHCl3). Analytic data were in agreement with the literature data.7
1H NMR (400 MHz, CDCl3) δ 7.40 – 7.35 (m, 2H, ArH), 7.31 – 7.20 (m, 3H, ArH), 6.18 (ddd,
J = 17.1, 10.1, 9.1 Hz, 1H, CHCH2), 5.23 – 5.13 (m, 2H, CH2), 4.33 (d, J = 9.0 Hz, 1H,
CHAr), 3.92 (s, 1H, OH), 3.84 (s, 3H, CH3), 3.61 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3)
δ 170.0, 169.8, 138.1, 135.6, 129.3, 128.4, 127.5, 118.4, 82.7, 54.7, 53.8, 53.5.
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HRMS (ESI) for C14H16NaO5, calculated for [M + Na]+: 287.0890, found: 287.0889.
Dibenzyl (R)-2-hydroxy-2-(1-phenylallyl)malonate 2d
Compound 2d was obtained as a colorless oil, for method A in 75% yield (29 mg) and for
method B in 88% yield (36 mg). The enantioselectivity was determined by chiral HPLC
analysis (Chiralpak ADꢀH, hexane:2ꢀpropanol = 90:10, flow rate = 1.0 mL/min, 25 °C, λ =
210 nm), (R)-2d 31.1 min and (S)-2d 25.3 min, enantiomeric excess for compound 2d for
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method A was 0% and for method B was 85%. Optical rotation for (S)-2d (ee 85%): [α]D
15.6 (c 0.15, CHCl3).
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1H NMR (400 MHz, CDCl3) δ 7.38 – 7.27 (m, 10H, ArH), 7.24 – 7.19 (m, 3H, ArH), 7.17 –
7.09 (m, 2H, ArH), 6.16 (ddd, J = 17.0, 10.3, 8.9 Hz, 1H, CHCH2), 5.22 (s, 2H, CH2Ar), 5.12
– 5.03 (m, 2H, CHCH2), 4.98 (d, J = 12.2 Hz, 1H, CH2Ar), 4.93 (d, J = 12.2 Hz, 1H, CH2Ar),
4.34 (d, J = 8.8 Hz, 1H, CHAr), 3.98 (s, 1H, OH). 13C NMR (101 MHz, CDCl3) δ 169.4,
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169.1, 138.1, 135.6, 134.9, 134.6, 129.4, 128.73 (2C), 128.68, 128.63, 128.61, 128.5, 128.4,
127.4, 118.4, 82.6, 68.6, 68.4, 54.4.
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HRMS (ESI) for C26H24NaO5, calculated for [M + Na]+: 439.1516, found: 439.1519.
1-Benzyl 3-methyl 2-hydroxy-2-((R)-1-phenylallyl)malonate 2e
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Compound 2e was obtained as a colorless oil, for method A in 73% yield (24 mg) and for
method B in 68% yield (23 mg).
NMR data for the main diastereoisomer. 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.19 (m, 10H,
ArH), 6.22 – 6.09 (m, 1H, CHCH2), 5.26 (s, 2H, CH2Ar), 5.10 – 5.04 (m, 2H, CHCH2), 4.33
(d, J = 8.9 Hz, 1H, CHAr), 3.93 (s, 1H, OH), 3.56 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3)
δ 169.7, 169.4, 138.2, 135.4, 135.0, 129.4, 128.8, 128.7, 128.6, 128.4, 127.5, 118.5, 82.6, 68.5,
54.5, 53.4.
HRMS (ESI) for C20H20NaO5, calculated for [M + Na]+: 363.1203, found: 363.1193.
3-Hydroxy-3-(1-phenylallyl)pentane-2,4-dione 2f
Compound 2f was obtained as a yellow oil, for method B in 48% yield (11 mg). The
enantioselectivity was determined by chiral HPLC analysis (Chiralpak ADꢀH, hexane:2ꢀ
propanol = 95:5, flow rate = 1.0 mL/min, 25 °C, λ = 230 nm), major enantiomer 6.0 min,
minor enantiomer 5.3 min, enantiomeric excess for compound 2f for method B was 32%.
Optical rotation for 2f (ee 32%): [α]D20 +2.7 (c 0.099, CHCl3).
1H NMR (400 MHz, CDCl3) δ 7.38 – 7.31 (m, 2H, ArH), 7.31 – 7.18 (m, 3H, ArH), 6.02 (ddd,
J = 17.1, 10.2, 9.1 Hz, 1H, CHCH2), 5.16 – 5.09 (m, 2H, CH2), 4.95 (s, 1H, OH), 4.35 (d, J =
9.1 Hz, 1H, CHAr), 2.34 (s, 3H, CH3), 1.99 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ
206.9, 206.8, 138.1, 135.5, 129.1, 128.6, 127.5, 118.2, 94.0, 55.7, 26.4, 26.1.
HRMS (ESI) for C14H16NaO3, calculated for [M + Na]+: 255.0992, found: 255.0987.
Dimethyl (R)-2-(1-(2-chlorophenyl)allyl)-2-hydroxymalonate 2h
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Compound 2h was obtained as a white solid, for method A in 71% yield (20 mg) and for
method B in 57% yield (17 mg), mp 35ꢀ37 °C. The enantioselectivity was determined by
chiral HPLC analysis (Chiralpak ADꢀH, hexane:2ꢀpropanol = 99:1, flow rate = 1.0 mL/min,
25 °C, λ = 210 nm), (R)-2h 35.3 min and (S)-2h 39.6 min, enantiomeric excess for compound
2h for method A was 19% and for method B was 57%. Optical rotation for (R)-2h (ee 19%):
[α]D20 –17.0 (c 0.11, CHCl3).
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1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 7.8, 1.8 Hz, 1H, ArH), 7.35 (dd, J = 7.8, 1.5 Hz,
1H, ArH), 7.21 (td, J = 7.6, 1.5 Hz, 1H, ArH), 7.15 (td, J = 7.6, 1.8 Hz, 1H, ArH), 6.00 (ddd,
J = 16.9, 10.4, 8.4 Hz, 1H, CHCH2), 5.20 – 5.16 (m, 1H, CH2), 5.15 (d, J = 0.9 Hz, 1H, CH2),
5.06 (d, J = 8.4 Hz, 1H, CHAr), 4.05 (d, J = 0.9 Hz, 1H, OH), 3.87 (s, 3H, CH3), 3.58 (s, 3H,
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CH3). C NMR (101 MHz, CDCl3) δ 170.0, 169.7, 136.1, 134.8, 134.2, 130.3, 129.7, 128.5,
127.1, 118.9, 82.3, 54.0, 53.5, 49.0.
HRMS (ESI) for C14H15ClNaO5, calculated for [M + Na]+: 321.0500, found: 321.0487.
Dimethyl (R)-2-(1-(3-chlorophenyl)allyl)-2-hydroxymalonate 2i
Compound 2i was obtained as a white solid, for method A in 72% yield (21 mg) and for
method B in 97% yield (29 mg), mp 43ꢀ45 °C. The enantioselectivity was determined by
chiral HPLC analysis (Chiralpak ADꢀH, hexane:2ꢀpropanol = 90:10, flow rate = 1.0 mL/min,
25 °C, λ = 210 nm), (R)-2i 9.6 min and (S)-2i 8.5 min, enantiomeric excess for compound 2i
for method A was 50% and for method B was 70%. Optical rotation for (R)-2i (ee 50%):
[α]D20 –28.0 (c 0.07, CHCl3).
1H NMR (400 MHz, CDCl3) δ 7.41 – 7.35 (m, 1H, ArH), 7.30 – 7.24 (m, 1H, ArH), 7.23 –
7.18 (m, 2H, ArH), 6.16 – 6.06 (m, 1H, CHCH2), 5.22 – 5.18 (m, 1H, CH2), 5.16 (s, 1H, CH2),
4.30 (d, J = 8.9 Hz, 1H, CHAr), 3.94 (s, 1H, OH), 3.84 (s, 3H, CH3), 3.64 (s, 3H, CH3). 13C
NMR (101 MHz, CDCl3) δ 169.8, 169.5, 140.2, 135.0, 134.1, 129.63, 129.60, 127.7, 127.6,
119.0, 82.5, 54.2, 53.9, 53.6.
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HRMS (ESI) for C14H16ClO5, calculated for [M + H]+: 299.0681, found: 299.0670.
Dimethyl (R)-2-(1-(4-chlorophenyl)allyl)-2-hydroxymalonate 2j
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Compound 2j was obtained as a white solid, for method A in 59% yield (17 mg) and for
method B in 67% yield (20 mg), mp 47ꢀ49 °C. The enantioselectivity was determined by
chiral HPLC analysis (Chiralpak ADꢀH, hexane:2ꢀpropanol = 95:5, flow rate = 1.0 mL/min,
25 °C, λ = 210 nm), (R)-2j 16.9 min and (S)-2j 15.2 min, enantiomeric excess for compound
2j for method A was 50% and for method B was 58%. Optical rotation for (R)-2j (ee 50%):
[α]D20 –27.2 (c 0.09, CHCl3).
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1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.5 Hz, 2H, ArH), 7.25 (d, J = 8.7 Hz, 2H, ArH),
6.11 (ddd, J = 17.5, 9.8, 8.9 Hz, 1H, CHCH2), 5.20 – 5.16 (m, 1H, CH2), 5.16 – 5.13 (m, 1H,
CH2), 4.31 (d, J = 8.8 Hz, 1H, CHAr), 3.94 (s, 1H, OH), 3.84 (s, 3H, CH3), 3.63 (s, 3H, CH3).
13C NMR (101 MHz, CDCl3) δ 169.9, 169.5, 136.7, 135.2, 133.4, 130.8, 128.6, 118.7, 82.5,
53.91, 53.89, 53.6.
HRMS (ESI) for C14H15ClNaO5, calculated for [M + Na]+: 321.0500, found: 321.0491.
Dimethyl (R)-2-hydroxy-2-(1-(4-methoxyphenyl)allyl)malonate 2k
Compound 2k was obtained as a white solid, for method A in 62% yield (17 mg) and for
method B in 35% yield (10 mg), mp 74ꢀ76 °C. The enantioselectivity was determined by
chiral HPLC analysis (Chiralpak ADꢀH, hexane:EtOH = 95:5, flow rate = 1.0 mL/min, 25 °C,
λ = 254 nm), (R)-2k 39.0 min and (S)-2k 21.8 min, enantiomeric excess for compound 2k for
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24.9 (c 0.09, CHCl3).
1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz, 2H, ArH), 6.81 (d, J = 8.7 Hz, 2H, ArH),
6.15 (ddd, J = 17.1, 10.2, 8.8 Hz, 1H, CHCH2), 5.22 – 5.11 (m, 2H, CH2), 4.28 (d, J = 8.8 Hz,
1H, CHAr), 3.90 (s, 1H, OH), 3.83 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.62 (s, 3H, CH3). 13C
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NMR (101 MHz, CDCl3) δ 170.0, 169.8, 158.9, 135.8, 130.4, 130.1, 118.1, 113.8, 82.8, 55.3,
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Dimethyl (R)-2-hydroxy-2-(1-(4-nitrophenyl)allyl)malonate 2l
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Compound 2l was obtained as a yellow solid, for method A in 56% yield (16 mg) and for
method B in 77% yield (24 mg), mp 99ꢀ101 °C. The enantioselectivity was determined by
chiral HPLC analysis (Chiralpak ADꢀH, hexane:2ꢀpropanol = 90:10, flow rate = 1.0 mL/min,
25 °C, λ = 210 nm), (R)-2l 23.8 min and (S)-2l 19.5 min, enantiomeric excess for compound
2l for method A was 9% and for method B was 35%. Optical rotation for (R)-2l (ee 9%):
[α]D20 –10.9 (c 0.13, CHCl3).
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.6 Hz, 2H, ArH), 7.59 (d, J = 8.7 Hz, 2H, ArH),
6.11 (dt, J = 18.1, 9.2 Hz, 1H, CHCH2), 5.22 (s, 1H, CH2), 5.19 (d, J = 6.6 Hz, 1H, CH2), 4.44
(d, J = 8.9 Hz, 1H, CHAr), 4.02 (s, 1H, OH), 3.86 (s, 3H, CH3), 3.63 (s, 3H, CH3). 13C NMR
(101 MHz, CDCl3) δ 169.7, 169.2, 147.3, 145.9, 134.4, 130.4, 123.5, 119.7, 82.2, 54.11,
54.07, 53.7.
HRMS (ESI) for C14H16NO7, calculated for [M + H]+: 310.0921, found: 310.0910.
Dimethyl (R)-2-hydroxy-2-(1-(naphthalen-2-yl)allyl)malonate 2m
Compound 2m was obtained as a white solid, for method A in 80% yield (25 mg) and for
method B in 77% yield (24 mg), mp 89ꢀ91 °C. The enantioselectivity was determined by
chiral HPLC analysis (Chiralpak ADꢀH, hexane:2ꢀpropanol = 90:10, flow rate = 1.0 mL/min,
25 °C, λ = 210 nm), (R)-2m 24.9 min and (S)-2m 14.7 min, enantiomeric excess for
compound 2m for method A was 59% and for method B was 63%. Optical rotation for (R)-
2m (ee 59%): [α]D20 –48.9 (c 0.06, CHCl3).
1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H, ArH), 7.83 – 7.74 (m, 3H, ArH), 7.53 (dd, J = 8.5,
1.6 Hz, 1H, ArH), 7.48 – 7.42 (m, 2H, ArH), 6.28 (ddd, J = 17.1, 10.2, 8.9 Hz, 1H, CHCH2),
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5.26 – 5.17 (m, 2H, CH2), 4.52 (d, J = 8.8 Hz, 1H, CHAr), 4.00 (s, 1H, OH), 3.87 (s, 3H,
CH3), 3.58 (s, 3H, CH3). 13C NMR (CDCl3, 101 MHz) δ 170.0, 169.7, 135.7, 135.6, 133.5,
132.8, 128.3, 128.1, 128.0, 127.7, 127.5, 126.05, 125.97, 118.6, 82.9, 54.8, 53.8, 53.5.
HRMS (ESI) for C18H18NaO5, calculated for [M + Na]+: 337.1046, found: 337.1039.
Dimethyl (S)-2-hydroxy-2-(1-(thiophen-2-yl)allyl)malonate 2n
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Compound 2n was obtained as a white solid, for method A in 84% yield (22 mg) and for
method B in 78% yield (21 mg), mp 54ꢀ56 °C. The enantioselectivity was determined by
chiral HPLC analysis (Chiralpak ADꢀH, hexane:2ꢀpropanol = 90:10, flow rate = 1.0 mL/min,
25 °C, λ = 210 nm), (R)-2n 12.7 min and (S)-2n 11.7 min, enantiomeric excess for compound
2n for method A was 42% and for method B was 63%. Optical rotation for (R)-2n (ee 42%):
[α]D20 –35.5 (c 0.09, CHCl3).
1H NMR (400 MHz, CDCl3) δ 7.19 (ddd, J = 5.1, 1.2, 0.5 Hz, 1H, ArH), 6.99 (ddd, J = 3.5,
1.2, 0.5 Hz, 1H, ArH), 6.93 (dd, J = 5.1, 3.5 Hz, 1H, ArH), 6.09 (ddd, J = 17.0, 10.1, 8.9 Hz,
1H, CHCH2), 5.22 (ddd, J = 17.0, 1.4, 0.9 Hz, 1H, CH2), 5.17 (ddd, J = 10.1, 1.5, 0.6 Hz, 1H,
CH2), 4.67 (d, J = 8.9 Hz, 1H, CHAr), 3.99 (d, J = 0.8 Hz, 1H, OH), 3.83 (s, 3H, CH3), 3.70 (s,
3H, CH3). 13C NMR (101 MHz, CDCl3) δ 169.6, 169.5, 139.6, 135.3, 126.6, 126.5, 125.2,
118.7, 82.4, 53.79, 53.75, 50.5.
HRMS (ESI) for C12H14NaO5S, calculated for [M + Na]+: 293.0454, found: 293.0446.
AUTHOR INFORMATION
Corresponding Author*
Eꢀmail: tonis.kanger@ttu.ee
Notes
The authors declare no competing financial interest.
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The Journal of Organic Chemistry
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Acknowledgments
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The authors thank the Estonian Ministry of Education and Research (Grant Nos. IUT 19ꢀ32,
IUT 19ꢀ9 and PUT 1468) and the Centre of Excellence in Molecular Cell Engineering (2014ꢀ
2020.4.01.15ꢀ0013) for financial support.
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Supporting Information
1H and 13C NMR spectra, HPLC data, additional optimization data of Caꢀcatalyzed reaction,
NMR and HRMS study of Ca complex. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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