Lewis Acid Promoted Trapping of Chiral Aza-enolates

Article abstract of DOI:10.1055/s-0037-1611657

We present a study on sequential conjugate addition of Grignard reagents to alkenyl-heteroarenes followed by trapping of the resulting enolates, yielding moderate to good diastereoselectivities. Contrary to conventional wisdom, one-pot conjugate addition/trapping using two reactive Michael acceptors in combination with Grignard reagents can proceed via conjugate addition to the least reactive Michael acceptor. This unusual chemoselectivity is triggered by the presence of a Lewis acid, reverting the usual reactivity order of Michael acceptors.

Full text of DOI:10.1055/s-0037-1611657

SYNTHESIS
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Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
F. Lanza et al.
Paper
Synthesis
Lewis Acid Promoted Trapping of Chiral Aza-enolates
Francesco Lanza
Ph2
P
Juana M. Pérez
CuBr
P
Alk
*
Ravindra P. Jumde
Syuzanna R. Harutyunyan*
Fe
Cy2
AlkMgBr
Het
0
0
0
0-
0
0
0
3-2
4
1
1-1
2
5
0
Het
*
+
R
R
BF3·OEt2
DCM, –78 °C, 3 h
Electrophile
E*
Stratingh Institute for Chemistry, Rijksuniversiteit Groningen,
Nijenborgh 4, 9747 AG, Groningen, The Netherlands
s.harutyunyan@rug.nl
one-pot reaction
3 chiral centers, dr up to 6:1
Electrophile: a,b-unsaturated esters, ketones
Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
Received: 07.12.2018
Accepted after revision: 17.12.2018
Published online: 29.01.2019
tion before the reaction is quenched. During this investiga-
tion we encountered the formation of an unknown side
product in some specific reactions. Isolation and full char-
acterization of the latter led us to identify it as compound
2a, resulting from the trapping of aza-enolate 1a′ by anoth-
er molecule of substrate 1a (Scheme 1). Hereafter, the pro-
cess leading to the formation of compound 2a will be re-
ferred to as ‘auto-trapping’. Remarkably, compound 2a was
formed as a single diastereoisomer with high enantioselec-
tivity (97% ee), despite the presence of three stereocenters.
This unexpected reactivity and diastereoselectivity
prompted us to investigate alkenyl-heteroarenes in a tan-
dem conjugate addition/enolate trapping reaction se-
quence, aiming to access chiral heteroarenes with both α-
and β-stereocenters, as is commonly encountered in bio-
active compounds.
DOI: 10.1055/s-0037-1611657; Art ID: ss-2018-z0823-op
License terms:
Abstract We present a study on sequential conjugate addition of
Grignard reagents to alkenyl-heteroarenes followed by trapping of the
resulting enolates, yielding moderate to good diastereoselectivities.
Contrary to conventional wisdom, one-pot conjugate addition/trapping
using two reactive Michael acceptors in combination with Grignard re-
agents can proceed via conjugate addition to the least reactive Michael
acceptor. This unusual chemoselectivity is triggered by the presence of
a Lewis acid, reverting the usual reactivity order of Michael acceptors.
Key words aza-enolate trapping, copper catalyst, Lewis acid, conju-
gate addition, one-pot reaction
The construction of molecular scaffolds with multiple
stereocenters has always been a major challenge in organic
chemistry. One of the possible approaches to address this
challenge is through conjugate additions of organometallics
to afford metal enolates that can be trapped with electro-
philes, thus generating two or more stereocenters. The
presence of multiple stereocenters makes controlling their
absolute and relative configurations a difficult task. Meth-
ods employing compounds that can undergo intramolecular
trapping1 or cyclic substrates2–4 have emerged as principal
strategies to harness the diastereoselectivity of the process.
Moreover, regardless of the cyclic or acyclic substrate em-
ployed, addition of co-solvents and/or additives is often re-
quired to increase the reactivity of the corresponding eno-
lates and to further improve the outcomes of the processes.5
We recently reported the highly enantioselective catalytic
transformation of a wide range of β-substituted conjugated
alkenyl-N-heteroaromatics into their corresponding chiral
alkylated products via Lewis acid activation in combination
with highly reactive Grignard reagents and a chiral copper
catalyst.6 Aza-enolates are the products of this transforma-
To study the reactivity of the resulting aza-enolate
towards trapping with electrophiles, the conjugate addition
of EtMgBr to (E)-2-styrylbenzo[d]oxazole (1b) in DCM at
–78 °C in the presence of BF3·Et2O as a Lewis acid was
selected as model reaction (Scheme 2). In the presence of
chiral catalyst Cu-L1, the conjugate addition step typically
proceeded with 97% enantioselectivity and full conversion
into the addition product. To ensure the completion of the
addition reaction, the electrophile was added 3 hours after
the start of the reaction at the same temperature, followed
by warming to room temperature (R.T.) and further stirring
for several hours.
Initial attempts to trap the aza-enolate formed upon
conjugate addition using MeI (3a) and BnBr (3b) as electro-
philes resulted in recovery of only conjugate addition prod-
uct 5. Significant conversion towards trapping product 4
was observed when more reactive benzaldehyde (3c) (30%)
and ethyl crotonate (2d) (54%) were used as electrophiles.
Remarkably, in both cases, only two diastereoisomers were
detected in the crude NMR spectra, in 2:1 and 1:1 ratios, re-
spectively (Scheme 2).
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

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F. Lanza et al.
Paper
Synthesis
O
Ph
P
N
X
Cy
Cu-L1 (5 mol%)
BF3·OEt2
Ph
N
O
P
MgBr
N
O
N
Fe
*
*
*
Cy
+
+
Et2O, –78 °C
O
Ph
(Rc,Sp)-L1
Ph
1a
1a'
X = BF3 or MgBr
2a
Scheme 1 Auto-trapping of 1a upon conjugate addition of PhMgBr
1) Cu-L1 (5 mol%)
EtMgBr (1.5 equiv)
BF3·OEt2 (1.2 equiv)
DCM, –78 °C, 3 h
E
N
N
N
O
+
O
O
Ph
Ph
Ph
2) E+ (3a–d) (2 equiv)
R.T.
–78 °C
1b
4a–d
5
E+ = MeI
BnBr
3a
3b
3c
Conversion 4a = 0%
Conversion 4b = 0%
Conversion 4c = 30%, dr = 2:1
Conversion 4d = 54%, dr = 1:1
5 = 99%
5 = 99%
5 = 70%
5 = 46%
PhCHO
CH3CH=CHCOOCH2CH3 3d
Scheme 2 Sequential Asymmetric Conjugate Addition (ACA)/enolate trapping of 1b with alkylating agents
In an attempt to improve the stereoselectivity, the reac-
tion using ethyl crotonate (3d) as the electrophile was per-
formed while keeping the temperature constant at –78 °C,
also after the addition of the electrophile. This was indeed
beneficial, with the diastereoisomeric ratio (dr) increasing
from 1:1 to 6:1 without any significant loss in terms of con-
version. With these reaction conditions in hand, we decided
to study the influence of the addition of compound 3d at
different reaction times (Table 1).
We found that the timing for the addition of the electro-
phile was important for the trapping efficiency. Increasing
the time gap between conjugate addition and addition of
the electrophile from 3 to 16 hours led to a significant de-
crease in the amount of enolate-trapped product (Table 1,
entries 1 and 2). In trapping reactions of reactive enolates
with reactive electrophiles it is common to add the electro-
phile in excess and only when the corresponding enolate
has been formed. It is never added to the reaction mixture
before the actual conjugate addition is complete, in order to
avoid an obvious side reaction derived from the addition of
the organometallic to an electrophile instead of the sub-
strate. In our particular case, crotonate 3d is expected to be
more reactive towards Grignard addition than the alkenyl-
heteroarene substrate 1b. Furthermore, it is known that the
same catalytic system (Cu-L1) in combination with Gri-
gnard reagents is the system of choice for catalytic asym-
metric additions to crotonates.7 Therefore, addition of cro-
tonate 3d to the reaction mixture from the start (or in other
Table 1 Addition of the Electrophile at Different Reaction Timesa
1) Cu-L1 (5 mol%)
EtMgBr (1.5 equiv)
BF3·OEt2 (1.2 equiv)
O
H
OEt
N
O
N
O
DCM, –78 °C
H
N
O
+
O
2)
Ph
Ph
Ph
H
EtO
1b
3d
4d
5
Entry
Time gap
3d:4b
dr
1
2
16 h
3 h
40:60
50:50
2:1
6:1
a Reaction performed using compound 1b (1 equiv), CuBr·SMe2 (5 mol%), L1 (6 mol%), EtMgBr (1.5 equiv), BF3·OEt2 (1.2 equiv), and 3d (4 equiv) in DCM
(1 mL/mmol) at –78 °C, 3 h after addition of the electrophile.
b Determined via NMR spectroscopy.
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F. Lanza et al.
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Synthesis
Cu-L1 (5 mol%)
EtMgBr (1.5 equiv)
BF3·OEt2 (1.2 equiv)
DCM, –78 °C, 3 h
O
H
OEt
+
N
N
O
H
N
O
O
O
Ph
Ph
Ph
H
EtO
4d
5
1b
3d
(4 equiv)
Conversion = 88%, yield = 68%
ee = 97%, dr = 6:1
Conversion = 10%
Scheme 3 One pot ACA/enolate trapping of 1b with ethyl crotonate (3d)
words, a one-pot reaction) prior to addition of the Grignard
reagent is rather counterintuitive and would be expected to
fail. However, based on our previous observations of ‘auto-
trapped’ products, we decided to perform the reaction in
this way. Remarkably, introducing the electrophile 3d at the
beginning of the reaction prior to addition of the Grignard
reagent provided the aza-enolate trapping product 4d as
the main product, with only small amounts of conjugate
addition product 4 and no traces of conjugate addition of
the Grignard reagent to crotonate 3d, despite it being pres-
ent in excess (4 equiv) at the beginning of the reaction
(Scheme 3).
In order to explain these results, we hypothesize that
the presence of the Lewis acid is essential for this observed
chemoselectivity. We believe that BF3·OEt2 binds selectively
to the more basic substrate, namely alkenyl-heteroarene 1b,
thus transforming it into a more reactive Michael acceptor
than crotonate 3d. This hypothesis is supported by NMR ex-
periments which indeed show full binding of BF3·OEt2 to 1b,
whilst in the case of 3d the equilibrium was shifted towards
the non-bound state (see the Supporting Information,
Figure S1). Upon addition of EtMgBr to the alkenyl-
heteroarene two possible enolate species can be formed,
namely a boron-aza-enolate8 and a magnesium-aza-eno-
late.9
Table 2 Optimization of the Concentration of Electrophile 3da
Cu-L1 (5 mol%)
EtMgBr (1.5 equiv)
BF3·OEt2 (1.2 equiv)
N
O
DCM, –78 °C
O
N
4d
+
5
+
3d (x equiv)
Ph
Ph
O
Ph
N
1b
2b
Equiv of 3d
4d (%)b
5 (%)b
2b (%)b
1.2
2.0
2.5
4.0
10
18
73
88
54
60
15
10
36
22
12
traces
a Reaction carried out using compound 1b (1 equiv), CuBr·SMe2 (5 mol%),
L1 (6 mol%), EtMgBr (1.5 equiv), and BF3·OEt2 (1.2 equiv) in DCM (1
mL/mmol) at –78 °C, 3 h.
b Determined via NMR spectroscopic analysis.
served. When BCl3 and BBr3 were used as Lewis acids, com-
pounds 6 and 7, derived from N-acylation of the conjugate
addition product 5, were formed predominantly (Figure 1).
In our hypothesis, one of the two possible enolate spe-
cies is the kinetic, highly reactive enolate, that is replaced
over time by the less reactive thermodynamic enolate.
Unfortunately, we were not able to confirm this by NMR. In
this scenario, the immediate availability of 3d would favor
the trapping of the most reactive enolate, while delayed ad-
dition of 3d to the reaction mixture should result in a lower
conversion, as shown in Table 1.
O
O
N
Ph
N
O
O
Ph
6
7
Figure 1 N-Acylation products 6 and 7
Next, we studied the effect of the concentration of 3d
(Table 2). From the data obtained, it is clear that a large ex-
cess of ester 3d is required in order to achieve higher con-
version toward the trapping product. Interestingly, the
auto-trapping product 2b becomes more prominent when
the amount of 3d drops below 4 equivalents.
Looking more carefully at the reaction promoted by
BF3·OEt2, we noticed that compounds 6 and 7 were also
formed under these reaction conditions, but in lower
amounts (ca. 5%). From this short screening of Lewis acids,
BF3·OEt2 emerged as the optimum choice for this transfor-
mation.
We have also looked into the effect of various Lewis ac-
ids on the course of the reaction. Trimethylsilyl triflate
(TMSOTf) failed in promoting not only the enolate trapping
but also the conjugate addition to 1b, with the conjugate
addition to ethyl crotonate (3d) being the only pathway ob-
With optimized conditions in hand, the reaction was
tested using different carbonyl electrophiles (Table 3).
Among all the Michael acceptors tested, only ester 3d and
ethyl cinnamate (3e) furnished the desired enolate-trap-
ping products in moderate yields and high enantioselectivi-
ties. β,β-Substituted Michael acceptor 3f was not suitable
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Table 3 Scope of the Reaction Using Different Electrophilesa
Cu-L1 (5 mol%)
EtMgBr (1.5 equiv)
BF3·OEt2 (1.2 equiv)
H
E
N
O
N
O
N
+
Ph
Ph
O
Ph
H
3 (4 equiv), DCM, –78 °C, 3 h
Et
Et
5
4
1b
Entry
1
Electrophile
3
4:5b
Yield (%)c drb
ee (%)d Entry
Electrophile
3
4:5b
Yield (%)c drb
ee (%)d
–
O
O
O
3d
88:10
68
49
–
6:1
97
91
–
6e
7e
8e
9
3i
–
–
–
–
–
–
–
OEt
3d
3i
O
O
2
3
3e
3f
76:24
0:100
2.5:1:1
–
3j
–
–
–
–
Ph
OEt
3j
3e
O
O
O
3k
OEt
3f
3k
O
4
3g
3h
27:30
–
n.d.
–
2.8:1
–
n.d.
–
3l
100:0
40
52
3:1:1f
1.7:1f
97
97
NMe2
Ph
3l
3g
O
O
5e
10
3m
100:0
OMe
3h
3m
a Reaction carried out using compound 1b (1 equiv), CuBr·SMe2 (5 mol%), L1 (6 mol%), EtMgBr (1.5 equiv), BF3·OEt2 (1.2 equiv), and Michael acceptor (4 equiv) in
DCM (1 mL/mmol) at –78 °C, 3 h.
b Determined via NMR spectroscopy.
c Yields of isolated diastereoisomeric mixtures; n.d. = not determined.
d Determined via HPLC analysis.
e Unreacted benzoxazole 1b recovered. Only the products of conjugate addition to 3h–k were observed.
f All four possible diastereoisomers are formed.
for this transformation (entry 3), while N,N-dimethyl cro-
tonamide (3g) showed some reactivity but with a lower
conversion than its ester analogue 3d (compare entries 1
and 4). In the presence of more reactive Michael acceptors
such as methyl acrylate (3h), lactone 3i, and enones 3j and
3k, conjugate addition to the latters became the predomi-
nant process (entries 5–8), with 1b recovered at the end of
the reaction. To our delight, two very reactive aromatic (3l)
and aliphatic (3m) ketones (entries 9 and 10), that are com-
mon substrates for alkylations with Grignard reagents and
that can also be catalyzed by the same Cu-based catalytic
system,10 also proved to be suitable electrophiles for our
trapping protocol, providing the corresponding α-tertiary
alcohols in moderate yields, albeit with a drop in the dia-
stereoselectivities.
These results provide us with a rough idea on the reac-
tivity of the Lewis activated compound 1b, placing it be-
tween a ketone and an ester in a hypothetical reactivity
scale (Figure 2).
To conclude our investigation, we studied the influence
of the nature of the alkenyl-heteroarenes on the efficiency
of the trapping process (Table 4). The results shown in Table
4 indicate that the process is strongly substrate dependent,
with only benzoxazoles and analogous compounds under-
going the enolate trapping (entries 1–3 and 5). Pyridine 1f
displayed a lower reactivity with only 36% conversion
toward 4r (entry 6), while substrate 1g yielded a complex
reaction mixture (entry 7). Other substrates containing
quinoline, pyrimidine or triazine moieties, unfortunately
did not afford any trapping product (entries 8–12). How-
ever, it is worth noting that in all these cases the addition of
EtMgBr proceeded towards the heteroarene substrate in the
presence of the more reactive crotonate 3d.
BF3
N
O
O
O
>
N
O
>
>
R
R1
RO
R2 = alkyl, aryl
R2
Ph
Ph
R1 = alkyl
Figure 2 Hypothetical reactivity scale of Michael acceptors
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Table 4 Scope of the Reaction Using Different Heterocyclesa
O
R
Cu-L1 (5 mol%)
EtMgBr (1.5 equiv)
BF3·OEt2 (1.2 equiv)
H
OEt
O
H
Het
+
Het
1
+
DCM, –78 °C, 3 h
R
OEt
H
3d
Et
5
Et
4
Entry Substrate
4
4:5b
Yield (%)c dr (%)b
ee (%)d Entry Substrate
4
4:5b
Yield (%)c dr (%)b ee (%)d
F
F
N
O
F
N
1
4d
88:10
68
6:1
97
7
4s
–
–
–
–
Ph
Ph
1b
1g
N
O
2
3
4n
4o
4p
4q
76:24
60:40
0:100
100:0
53
58
–
3:1
3:1
–
79
94
–
8
9
4t
–
–
–
–
–
–
–
–
–
–
–
–
–
–
N
1h
Ph
1a
1c
1d
N
S
4u
4v
4x
Ph
N
N
Ph
Pr
1i
N
S
4
10
11
0:100
5
1j
Ph
N
N
5
n.d.
4.4:3.6:1.1f n.d.
0:100
0:100
N
O
Ph
N
5
1e
1k
OMe
N
N
6e
4r
36:64
–
3:1
n.d.
12
4y
–
–
–
Ph
MeO
N
1f
5
1I
a Reaction carried out using substrate 1 (1 equiv), CuBr·SMe2 (5 mol%), L1 (6 mol%), EtMgBr (1.5 equiv), BF3·OEt2 (1.2 equiv), and ethyl crotonate (3d) (4 equiv) in
DCM (1 mL/mmol) at –78 °C, 3 h; the absolute configuration is established based on the X-ray crystal structure of product 4o.
b Determined via NMR spectroscopy.
c Yields of isolated products; n.d. = not determined.
d Determined via HPLC analysis.
e 3.0 equivalents of TMSOTf and 10% of Cu-L1 were used.
f Determined via GC-MS.
In conclusion, a one-pot procedure for the conjugate ad-
dition of alkenyl-heteroarenes with subsequent trapping of
the resulting aza-enolate with Michael acceptors has been
explored. The process shows high stereoselectivity, but the
high specificity for oxazole and benzoxazole derivatives, as
well as for α,β-unsaturated esters, limits the scope of its ap-
plication. Interestingly, the superior affinity of BF3·OEt2 to-
wards the more Lewis basic benzoxazole resulted in a dras-
tic change in reactivity order, allowing the conjugate addi-
tion to the latter to occur in the presence of commonly
more electrophilic esters, thus facilitating one-pot conju-
gate addition/trapping reactions with alkenyl-hetero-
arenes.
solvents were freshly collected from a solvent purification system
prior to use. All reactions using oxygen- and/or moisture-sensitive
materials were carried out with anhydrous solvents (vide infra) under
a nitrogen (dried over P2O5) atmosphere using oven-dried glassware
and standard Schlenk techniques. Grignard reagents were purchased
from Sigma-Aldrich and used as received (EtMgBr, 3 M in Et2O;
PhMgBr, 3 M in Et2O). Unless otherwise noted substrates were pre-
pared by literature methods (vide infra). Chiral ligands (RevJosiphos)
were purchased from Solvias. All reported compounds were charac-
terized by 1H and 13C NMR spectrometry and compared with litera-
ture data. All new compounds were fully characterized by 1H and 13
NMR spectrometry and HRMS techniques.
C
Reactions were monitored by 1H NMR. Purification of the products,
when necessary, was performed by flash column chromatography us-
ing Merck 60 Å 230–400 mesh silica gel. NMR data was collected on
Bruker Avance NEO 600 (1H at 600.0 MHz; 13C at 150.87 MHz),
equipped with a Prodigy Cryo-probe, Varian Inova 500 (1H at 500.0
MHz; 13C at 125.72 MHz, 19F at 470.37 MHz), equipped with an indi-
rect detection probe, and Varian VXR400 (1H at 400.0 MHz; 13C at
Unless otherwise indicated, reagents and substrates were purchased
from commercial sources and used as received. Solvents not required
to be dry were purchased as technical grade and used as received. Dry
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Paper
Synthesis
100.58 MHz, 19F at 376.29, 31P at 161.94 MHz), equipped with a 5 mm
z-gradient broadband probe, spectrometers. Chemical shifts are re-
ported in parts per million (ppm) relative to the residual solvent sig-
nal (CDCl3, 1H: 7.26 ppm; 13C: 77.16 ppm). Coupling constants are re-
ported in hertz. Multiplicities are reported with standard abbrevia-
tions (s: singlet, br s: broad singlet, d: doublet, dd: doublet of
doublets, ddd: doublet of doublet of doublets, t: triplet, td: triplet of
doublets, q: quartet, dq: doublet of quartets, quin: quintet, sext: sex-
tet, sept: septet, m: multiplet). High-resolution mass spectrometry
was performed using an LTQ Orbitrap XL apparatus with ESI ioniza-
tion. Enantiomeric excesses (ee) were determined by chiral HPLC
analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimad-
zu SPD-M10AVP diode array detector and a Waters Acquity UPC2 sys-
tem with a PDA detector and a QDA mass detector.
(E)-2-Styrylbenzoxazole (1b)
Compound 1b was prepared according to the literature proce-
dure.[11] The product was obtained as a white solid after crystalliza-
tion from MeOH. Yield = 65%. The NMR data are in agreement with
those presented in the literature.11
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 16.3 Hz, 1 H), 7.68–7.64 (m,
1 H), 7.54–7.51 (m, 2 H), 7.51–7.45 (m, 1 H), 7.39–7.25 (m, 5 H), 7.02
(d, J = 16.3 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 166.9, 153.8, 137.6, 135.3, 134.3,
129.4, 128.9, 128.5, 127.4, 126.3, 125.3, 122.9, 122.1, 121.5.
(E)-2-Styrylbenzothiazole (1c)
Compound 1c was prepared according to the literature procedure.6
The product was obtained as a white solid after crystallization from
MeOH. Yield = 46%. The NMR data are in agreement with those pre-
sented in the literature.6
Enantioselective Enolate Trapping; General Procedure A
In a heat-dried Schlenk tube equipped with a septum and a magnetic
stir bar, CuBr·SMe2 (0.05 equiv) and the ligand (Rc,Sp)-RevJosiphos
(L1) (0.06 equiv) were dissolved in DCM (1 mL/0.1 mmol of substrate)
and stirred under a nitrogen atmosphere for 15 min. The substrate
(1.0 equiv) was added in one portion. After stirring for 5 min at room
temperature, the mixture was cooled to –78 °C and BF3·OEt2 (1.2
equiv) was added. After 5 min, the trapping agent (4.0 equiv) was
added followed by EtMgBr (1.5 equiv). After stirring at –78 °C for 3 h,
the reaction was quenched with MeOH (1 mL) followed by saturated
aqueous NH4Cl solution (1 mL) and warmed to R.T. The reaction mix-
ture was extracted with DCM (3 × 10 mL). The combined organic
phases were dried over MgSO4, filtered and the solvents removed on a
rotary evaporator. The oily crude residue was purified by flash
column chromatography using a mixture of pentane and EtOAc as
eluent.
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.2 Hz, 1 H), 7.87 (d, J = 7.7
Hz, 1 H), 7.62–7.57 (m, 2 H), 7.54 (d, J = 16.2 Hz, 1 H), 7.48 (ddd, J =
8.3, 7.2, 1.3 Hz, 1 H), 7.45–7.34 (m, 5 H).
13C NMR (101 MHz, CDCl3): δ = 137.7, 129.4, 128.9, 127.4, 126.3,
125.3, 122.9, 122.1, 121.5.
(E)-2-(Pent-1-en-1-yl)benzothiazole (1d)
Compound 1d was prepared according to the literature procedure.6
The product was obtained as an orange-yellow solid after silica gel
flash column chromatography (pentane/EtOAc, 95:5, v/v). Yield = 71%.
The NMR data are in agreement with those presented in the litera-
ture.6
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 8.1 Hz, 1 H), 7.75 (d, J = 9.3
Hz, 1 H), 7.39 (td, J = 8.3, 7.2, 1.3 Hz, 1 H), 7.32–7.24 (m, 1 H), 6.80–
6.63 (m, 2 H), 2.28–2.13 (m, 2 H), 1.52 (sext, J = 7.4 Hz, 2 H), 0.95 (t, J =
7.4 Hz, 3 H).
Racemic Enolate Trapping; General Procedure B
In a heat-dried Schlenk tube equipped with a septum and a magnetic
stir bar, CuBr·SMe2 (0.05 equiv) and the ligand (±)-BINAP (0.06 equiv)
were dissolved in DCM (1 mL/0.1 mmol of substrate) and stirred un-
der a nitrogen atmosphere for 15 min. The substrate (1.0 equiv) was
added in one portion. After stirring for 5 min at room temperature,
the mixture was cooled to –78 °C and BF3·OEt2 (1.2 equiv) was added.
After 5 min, the trapping agent (4.0 equiv) was added followed by
EtMgBr (1.5 equiv). After stirring at –78 °C for 3 h, the reaction was
quenched with MeOH (1 mL) followed by saturated aqueous NH4Cl
solution (1 mL) and warmed to R.T. The reaction mixture was extract-
ed with DCM (3 × 10 mL). The combined organic phases were dried
over MgSO4, filtered and the solvents removed on a rotary evaporator.
The oily crude residue was purified by flash column chromatography
using a mixture of pentane and EtOAc as eluent.
13C NMR (101 MHz, CDCl3): δ = 167.3, 153.5, 141.7, 133.9, 125.9,
124.9, 124.6, 122.6, 121.2, 34.8, 21.6, 13.6.
(E)-4,5-Diphenyl-2-(prop-1-en-1-yl)oxazole (1e)
Compound 1e was prepared according to the literature procedure.6
The product was obtained as a pale yellow solid after silica gel flash
column chromatography (pentane/EtOAc, 95:5, v/v). Yield = 66%. The
NMR data are in agreement with those presented in the literature.6
1H NMR (400 MHz, CDCl3): δ = 7.81–7.67 (m, 2 H), 7.67–7.56 (m, 2 H),
7.49–7.21 (m, 6 H), 6.85 (dq, J = 15.8, 6.9 Hz, 1 H), 6.41 (d, J = 15.8 Hz,
1 H), 1.96 (dd, J = 6.9, 1.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.8, 144.6, 136.1, 135.4, 132.6,
129.0, 128.6, 128.5, 128.4, 128.1, 128.0, 126.5, 117.8, 18.6.
(E)-2-(Prop-1-en-1-yl)benzoxazole (1a)
Compound 1a was prepared according to the literature procedure.6
The product was obtained as a pale yellow solid after silica gel column
chromatography (pentane/EtOAc, 95:5, v/v). Yield = 78%. The NMR
data are in agreement with those presented in the literature.6
1H NMR (400 MHz, CDCl3): δ = 7.75–7.59 (m, 1 H), 7.55–7.40 (m, 1 H),
7.35–7.20 (m, 2 H), 7.04 (dq, J = 15.9, 6.9 Hz, 1 H), 6.46 (dq, J = 15.9,
1.8 Hz, 1 H), 2.02 (dd, J = 6.9, 1.8 Hz, 3 H).
(E)-4-Styrylpyridine (1f)
To a heated solution of DMF, KOH (60 °C) and γ-picoline (50 mmol, 1
equiv) was added dropwise benzaldehyde (25 mmol, 0.5 equiv). The
reaction mixture was heated to 160 °C. After 16 h, the mixture was
cooled to room temperature and diluted with H2O. The mixture was
extracted with DCM (3 × 20 mL). The combined organic phase was
washed with H2O (6 × 15 mL), dried over MgSO4 and the volatiles re-
moved under reduced pressure. The residue was purified by flash
chromatography (pentane/EtOAc, 80:20) to afford pure product 1f as
a white solid. Yield = 63%. The NMR data are in agreement with those
presented in the literature.12
13C NMR (101 MHz, CDCl3): δ = 162.3, 150.1, 141.9, 139.0, 124.7,
124.2, 119.7, 118.2, 110.1, 18.7.
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1H NMR (400 MHz, CDCl3): δ = 8.58 (d, J = 5.1 Hz, 2 H), 7.55 (d, J = 7.0
Hz, 2 H), 7.44–7.34 (m, 5 H), 7.31 (d, J = 16.0 Hz, 1 H), 7.02 (d, J = 16.3
Hz, 1 H).
(E)-2-(Oct-1-en-1-yl)pyrimidine (1k)
Compound 1k was prepared according to the literature procedure.13
The product was obtained as a colorless oil after silica gel flash
column chromatography (pentane/EtOAc, 95:5, v/v).
13C NMR (101 MHz, CDCl3): δ = 150.3, 144.8, 136.3, 133.3, 129.0,
1H NMR (400 MHz, CDCl3): δ = 8.65 (d, J = 4.9 Hz, 2 H), 7.17 (dt, J =
15.6, 7.0 Hz, 1 H), 7.05 (t, J = 4.9 Hz, 1 H), 6.55 (dt, J = 15.6, 1.5 Hz, 1 H),
2.30 (qd, J = 7.2, 1.6 Hz, 2 H), 1.57–1.44 (m, 2 H), 1.42–1.20 (m, 6 H),
0.93–0.79 (m, 3 H).
128.9, 127.2, 126.1, 121.0.
HRMS (ESI+): m/z [M + H]+ calcd for C13H12N: 182.09643; found:
182.09655.
(E)-2-(3-Phenylprop-1-en-1-yl)-5-(trifluoromethyl)pyridine (1g)
13C NMR (101 MHz, CDCl3): δ = 164.8, 156.9, 142.5, 129.4, 118.3, 32.7,
Compound 1g was prepared according to the literature procedure.6
The product was obtained as a pale yellow liquid after silica gel flash
column chromatography (pentane/EtOAc, 95:5, v/v). Yield = 50%.
31.7, 28.9, 28.6, 22.6, 14.1.
(E)-2,4-Dimethoxy-6-(oct-1-en-1-yl)-1,3,5-triazine (1l)
Compound 1l was prepared according to the literature procedure.13
The product was obtained as a colorless oil after silica gel flash
column chromatography (pentane/EtOAc, 95:5, v/v).
1H NMR (400 MHz, CDCl3): δ = 8.84 (s, 1 H), 7.85 (dd, J = 8.3, 2.2 Hz, 1
H), 7.53–7.27 (m, 5 H), 7.24 (q, J = 7.3, 1 H), 6.57 (d, J = 15.9 Hz, 1 H),
6.43 (dt, J = 15.7, 6.9 Hz, 1 H), 3.82 (d, J = 6.9 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 7.36 (dt, J = 15.5, 7.0 Hz, 1 H), 6.27 (d,
J = 15.5 Hz, 1 H), 3.98 (s, 6 H), 2.29–2.18 (m, 2 H), 1.45 (quin, J = 7.2
Hz, 2 H), 1.35–1.15 (m, 6 H), 0.87–0.76 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 164.4, 146.5 (q, J = 3.9 Hz), 137.1,
133.7 (q, J = 3.5 Hz), 132.9, 128.7, 127.6, 126.4, 126.2, 122.7, 42.0.
(E)-2-Styrylquinoline (1h)
13C NMR (101 MHz, CDCl3): δ = 174.8, 172.5, 147.7, 127.8, 54.9, 32.7,
Compound 1h was prepared according to the literature procedure.6
The product was obtained as a white solid after silica gel flash column
chromatography (pentane/EtOAc, 95:5, v/v). Yield = 91%. The NMR
data are in agreement with those presented in the literature.6
31.6, 28.9, 28.2, 22.5, 14.0.
HRMS (ESI+): m/z [M + H]+ calcd for C13H21N3O2: 252.17065; found:
252.17052.
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 8.6 Hz, 1 H), 8.09 (d, J = 9.3
Hz, 1 H), 7.78 (dd, J = 8.1, 1.4 Hz, 1 H), 7.74–7.61 (m, 5 H), 7.50 (ddd,
J = 8.1, 6.9, 1.2 Hz, 1 H), 7.45–7.36 (m, 3 H), 7.36–7.28 (m, 1 H).
(E)-4,4,5,5-Tetramethyl-2-styryl-1,3,2-dioxaborolane (8)
Compound 8 was synthesized according to the literature procedure.14
The product was isolated as a colorless oil after flash column chroma-
tography (pentane/EtOAc, 99:1, v/v). Yield = 87%.
13C NMR (101 MHz, CDCl3): δ = 156.3, 148.6, 136.9, 136.7, 134.8,
1H NMR (400 MHz, CDCl3): δ = 7.51–7.47 (m, 2 H), 7.40 (d, J = 18.5 Hz,
1 H), 7.36–7.28 (m, 3 H), 6.17 (d, J = 18.5 Hz, 1 H), 1.32 (s, 12 H).
130.1, 129.5, 129.3, 129.1, 129.0, 127.8, 127.7, 127.6, 126.5, 119.6.
(E)-2-(3-Phenylprop-1-en-1-yl)quinoline (1i)
13C NMR (101 MHz, CDCl3): δ = 152.1, 140.1, 131.5, 131.2, 129.7, 86.0,
27.5.
HRMS (ESI+): m/z [M + H]+ calcd for C14H20BO2: 231.15509; found:
231.15324.
Compound 1h was prepared according to the literature procedure.6
The product was obtained as a colorless oil after silica gel flash col-
umn chromatography (pentane/EtOAc, 95:5, v/v). Yield = 76%.
1H NMR (400 MHz, CDCl3): δ = 8.04 (dd, J = 8.1, 2.8 Hz, 2 H), 7.74 (dd,
J = 8.1, 1.4 Hz, 1 H), 7.68 (ddd, J = 8.5, 6.9, 1.5 Hz, 1 H), 7.51 (d, J = 8.6
Hz, 1 H), 7.47 (ddd, J = 8.1, 6.9, 1.2 Hz, 1 H), 7.38–7.21 (m, 5 H), 6.96
(dt, J = 15.9, 6.8 Hz, 1 H), 6.78 (dt, J = 15.8, 1.5 Hz, 1 H), 3.67 (d, J = 6.8
Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 156.0, 148.0, 139.2, 136.1, 136.0,
132.1, 129.5, 129.1, 128.8, 128.5, 127.4, 127.1, 126.3, 125.9, 118.7,
39.4.
HRMS (ESI+): m/z [M + H]+ calcd for C18H16N: 246.12790; found:
246.12773.
(E)-4,4,5,5-Tetramethyl-2-(oct-1-en-1-yl)-1,3,2-dioxaborolane (9)
Compound 9 was synthesized according to the literature procedure.14
The product was isolated as a colorless oil after flash column chroma-
tography (pentane/EtOAc, 99:1, v/v). Yield = 72%. The NMR data are in
agreement with those presented in the literature.
1H NMR (400 MHz, CDCl3): δ = 6.63 (dt, J = 18.0, 6.4 Hz, 1 H), 5.42 (dt,
J = 18.0, 1.6 Hz, 1 H), 2.19–2.06 (m, 2 H), 1.45–1.35 (m, 2 H), 1.26 (s,
18 H), 0.98–0.76 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 154.8, 82.9, 35.8, 31.7, 28.9, 28.2, 24.7,
22.6, 14.1.
(E)-2-(Oct-1-en-1-yl)quinolone (1j)
Compound 1j was prepared according to the literature procedure.6
The product was obtained as a colorless oil after silica gel flash col-
umn chromatography (pentane/EtOAc, 95:5, v/v). Yield = 91%. The
NMR data are in agreement with those presented in the literature.6
1H NMR (400 MHz, CDCl3): δ = 8.10–7.95 (m, 2 H), 7.76–7.59 (m, 2 H),
7.55–7.34 (m, 2 H), 6.90–6.76 (m, 1 H), 6.70 (d, J = 15.9 Hz, 1 H), 2.30
(q, J = 7.2 Hz, 2 H), 1.52 (quin, J = 7.3 Hz, 2 H), 1.42–1.19 (m, 6 H),
0.97–0.79 (m, 3 H).
(E)-4,4,5,5-Tetramethyl-2-(3-phenylprop-1-en-1-yl)-1,3,2-dioxa-
borolane (10)
Compound 10 was synthesized according to the literature proce-
dure.14 The product was isolated as a colorless oil after flash column
chromatography (pentane/EtOAc, 99:1, v/v). Yield = 53%.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.26 (m, 2 H), 7.23–7.15 (m, 3 H),
6.78 (dt, J = 17.8, 6.3 Hz, 1 H), 5.47 (dt, J = 17.8, 1.6 Hz, 1 H), 3.49 (dd,
J = 6.3, 1.6 Hz, 2 H), 1.26 (s, 12 H).
13C NMR (101 MHz, CDCl3): δ = 152.3, 138.9, 128.8, 128.3, 126.0, 82.9,
42.1, 24.7.
HRMS (ESI+): m/z [M + H]+ calcd for C15H22BO2: 245.17074; found:
13C NMR (101 MHz, CDCl3): δ = 156.5, 148.0, 138.0, 136.1, 131.0,
129.5, 129.1, 127.4, 127.1, 125.8, 118.7, 33.1, 31.7, 29.0, 28.9, 22.6,
14.1.
245.17078.
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(E)-N-(2-Bromophenyl)but-2-enamide (11)
(3S,4S)-3-(Benzooxazol-2-yl)-2,4-diphenylhexan-2-ol (4l)
Compound 11 was synthesized according to the literature proce-
dure.15 The product was isolated as a yellow oil after flash column
chromatography (pentane/EtOAc, 95:5, v/v). Yield = 78%. The NMR
data are in agreement with those presented in the literature.6
1H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 8.3 Hz, 1 H), 7.54 (dd, J = 8.1,
1.5 Hz, 1 H), 7.39–7.27 (m, 1 H), 7.10–6.90 (m, 2 H), 6.01 (dq, J = 15.1,
1.7 Hz, 1 H), 1.95 (dd, J = 6.9, 1.7 Hz, 3 H).
Compound 4l was synthesized following general procedure A with 1b
(0.1 mmol), BF3·OEt2 (0.12 mmol, 1.2 equiv), EtMgBr (3 M in Et2O, 0.15
mmol, 1.5 equiv), CuBr·SMe2 (0.005 mmol, 5 mol%), ligand (R,Sp)-L1
(0.006 mmol, 6 mol%), and 3l (0.4 mmol, 4 equiv) in DCM (1 mL).
Product 4l was obtained as a white solid after flash column chroma-
tography (SiO2, pentane/EtOAc, 97:3, v/v).
Yield: 14.8 mg (40%); 97% ee.
13C NMR (101 MHz, CDCl3): δ = 163.8, 142.1, 135.8, 132.2, 128.33,
128.32, 125.4, 125.0, 122.0, 17.9.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.30 (m, 3 H), 7.28–7.22 (m, 1 H),
7.20–7.08 (m, 4 H), 7.07–6.92 (m, 6 H), 4.79 (s, 1 H), 3.89 (d, J = 4.3 Hz,
1 H), 3.54–3.49 (m, 1 H), 2.19–2.02 (m, 1 H), 2.02–1.90 (m, 1 H), 1.78
(s, 3 H), 0.86 (t, J = 7.3 Hz, 3 H).
Ethyl (3S,4R,5S)-4-(Benzoxazol-2-yl)-3-methyl-5-phenylhepta-
13C NMR (101 MHz, CDCl3): δ = 166.2, 149.1, 148.4, 141.9, 140.0,
128.9, 128.0, 127.6, 126.4, 126.1, 124.5, 124.3, 123.9, 119.3, 110.0,
76.5, 54.7, 47.4, 30.0, 28.7, 12.6.
HRMS (ESI+): m/z [M + H]+ calcd for C18H26NO3: 372.1964; found:
372.1962.
noate (4d)
Compound 4d was synthesized following general procedure A with of
1b (0.1 mmol), BF3·OEt2 (0.12 mmol, 1.2 equiv), EtMgBr (3 M in Et2O,
0.15 mmol, 1.5 equiv), CuBr·SMe2 (0.005 mmol, 5 mol%), ligand
(Rc,Sp)-L1 (0.006 mmol, 6 mol%), and 3d (0.4 mmol, 4 equiv) in DCM
(1 mL). Product 4d was obtained as a pale yellow oil after flash col-
umn chromatography (SiO2, pentane/EtOAc, 97:3, v/v).
CSP-HPLC (254 nm, Chiralcel OD-H, n-heptane/iPrOH = 99:1, 40 °C,
0.5 mL/min): tR = 10.26 min (minor), tR = 17.78 min (major).
Yield: 24.8 mg (68%); 97% ee.
1H NMR (400 MHz, CDCl3): δ = 7.75 (dd, J = 6.3, 3.0 Hz, 1 H), 7.55 (dd,
J = 6.4, 2.9 Hz, 1 H), 7.41–7.32 (m, 4 H), 7.30–7.23 (m, 3 H), 4.09 (qt, J =
7.1, 3.7 Hz, 2 H), 3.57 (dd, J = 11.6, 3.6 Hz, 1 H), 3.19 (td, J = 11.0, 3.6
Hz, 1 H), 2.26–2.05 (m, 2 H), 1.93 (dd, J = 15.1, 6.5 Hz, 1 H), 1.51–1.32
(m, 2 H), 1.21 (t, J = 7.1 Hz, 3 H), 0.97 (d, J = 6.7 Hz, 3 H), 0.60 (t, J = 7.3
Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 172.4, 167.3, 150.6, 141.8, 141.3,
128.7, 128.4, 126.9, 124.7, 124.4, 120.0, 110.7, 60.4, 49.2, 48.5, 40.3,
30.8, 28.9, 14.6, 14.3, 12.0.
(4S,5S)-4-(Benzooxazol-2-yl)-3-methyl-5-phenylheptan-3-ol (4m)
Compound 4m was synthesized following general procedure A with
1b (0.1 mmol), BF3·OEt2 (0.12 mmol, 1.2 equiv), EtMgBr (3 M in Et2O,
0.15 mmol, 1.5 equiv), CuBr·SMe2 (0.005 mmol, 5 mol%), ligand
(Rc,Sp)-L1 (0.006 mmol, 6 mol%), and 3m (0.4 mmol, 4 equiv) in DCM
(1 mL). An inseparable mixture of isomers of product 4m was ob-
tained as a white solid after flash column chromatography (SiO2, pen-
tane/EtOAc, 97:3, v/v).
Yield: 16.8 mg (52%); 97% ee.
HRMS (ESI+): m/z [M + H]+ calcd for C23H28NO3: 366.20689; found:
366.20637.
Major Diastereoisomers
1H NMR (400 MHz, CDCl3): δ = 7.76–7.72 (m, 1 H), 7.55–7.50 (m, 1 H),
7.39–7.27 (m, 4 H), 7.27–7.19 (m, 3 H), 3.54 (d, J = 8.1 Hz, 1 H), 3.30
(dtd, J = 11.6, 7.8, 3.8 Hz, 1 H), 1.61–1.28 (m, 4 H), 1.19 (s, 3 H), 0.78 (t,
J = 7.5 Hz, 3 H), 0.56–0.52 (m, 3 H).
CSP-HPLC (206 nm, Chiralcel OD-H, n-heptane/iPrOH = 95:5, 40 °C,
0.5 mL/min): tR = 7.99 min (major), tR = 13.02 min (minor).
Ethyl (3S,4S,5S)-4-(Benzoxazol-2-yl)-3,5-diphenylheptanoate (4e)
Compound 4e was synthesized following general procedure A with
0.1 mmol of 1b (0.1 mmol), BF3·OEt2 (0.12 mmol, 1.2 equiv), EtMgBr
(3 M in Et2O, 0.15 mmol, 1.5 equiv), CuBr·SMe2 (0.005 mmol, 5 mol%),
ligand (R,Sp)-L1 (0.006 mmol, 6 mol%), and 3e (0.4 mmol, 4 equiv) in
DCM (1 mL). Product 4e was obtained as a pale yellow oil after flash
column chromatography (SiO2, pentane/EtOAc, 97:3, v/v).
1H NMR (400 MHz, CDCl3): δ = 7.76–7.72 (m, 1 H), 7.55–7.50 (m, 1 H),
7.39–7.27 (m, 4 H), 7.27–7.19 (m, 3 H), 3.54 (d, J = 8.1 Hz, 1 H), 3.30
(dtd, J = 11.6, 7.8, 3.8 Hz, 1 H), 1.61–1.28 (m, 4 H), 1.11 (s, 3 H), 0.78 (t,
J = 7.5 Hz, 3 H), 0.56–0.52 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 167.8, 149.9, 143.9, 140.8, 128.6,
128.4, 126.6, 124.8, 124.4, 119.8, 110.6, 75.1, 54.3, 47.2, 34.7, 27.0,
25.4, 11.9, 8.2.
Yield: 20.9 mg (49%); 91% ee.
1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 6.5 Hz, 1 H), 7.40 (t, J = 7.6
Hz, 3 H), 7.38–7.26 (m, 2 H), 7.25 (d, J = 7.3 Hz, 3 H), 7.10 (dt, J = 14.4,
7.0 Hz, 3 H), 6.65 (d, J = 7.4 Hz, 2 H), 4.00 (dddd, J = 17.8, 10.7, 7.1, 3.6
Hz, 2 H), 3.91 (dd, J = 11.2, 4.4 Hz, 1 H), 3.50 (td, J = 7.7, 4.4 Hz, 1 H),
2.99 (td, J = 10.6, 4.0 Hz, 1 H), 2.88 (dd, J = 16.0, 7.9 Hz, 1 H), 2.57 (dd,
J = 15.9, 7.8 Hz, 1 H), 1.54–1.35 (m, 2 H), 1.09 (t, J = 7.1 Hz, 3 H), 0.56
(t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.7, 166.3, 150.4, 141.8, 141.0,
139.4, 128.9, 128.8, 128.6, 127.7, 127.0, 126.8, 124.7, 124.2, 119.9,
110.5, 60.3, 49.7, 48.0, 42.4, 39.0, 28.4, 14.0, 11.5.
13C NMR (101 MHz, CDCl3): δ = 167.6, 149.8, 143.4, 140.7, 128.7,
128.5, 126.8, 124.8, 124.4, 119.8, 110.6, 75.2, 54.6, 47.2, 32.8, 27.1,
24.1, 11.9, 7.7.
Minor Diastereoisomers
1H NMR (400 MHz, CDCl3): δ = 7.59–7.49 (m, 1 H), 7.41–7.35 (m, 1 H),
7.25–7.23 (m, 2 H), 7.05–6.91 (m, 5 H), 3.42 (d, J = 5.7 Hz, 1 H), 3.39–
3.30 (m, 1 H), 2.18–2.02 (m, 1 H), 1.94–1.79 (m, 2 H), 1.79–1.63 (m, 2
H), 1.23 (s, 2 H), 1.01 (t, J = 7.5 Hz, 3 H), 0.77 (t, J = 7.3 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.59–7.49 (m, 1 H), 7.41–7.35 (m, 1 H),
7.25–7.23 (m, 2 H), 7.05–6.91 (m, 5 H), 3.40 (d, J = 5.1 Hz, 1 H), 3.39–
3.30 (m, 1 H), 2.18–2.02 (m, 1 H), 1.94–1.79 (m, 2 H), 1.79–1.63 (m, 2
H), 1.23 (s, 2 H), 0.88 (t, J = 7.5 Hz, 3 H), 0.80 (t, J = 7.4 Hz, 3 H).
HRMS (ESI+): m/z [M + H]+ calcd for C28H30NO3: 428.22202; found:
428.22157.
CSP-HPLC (233 nm, Chiralcel OD-H, n-heptane/iPrOH = 95:5, 40 °C,
0.5 mL/min): tR = 8.51 min (major), tR = 9.23 min (minor).
13C NMR (101 MHz, CDCl3): δ = 166.8, 149.7, 142.1, 140.4, 128.8,
127.7, 126.1, 124.5, 124.1, 119.6, 110.2, 74.9, 54.0, 47.5, 33.3, 29.2,
25.6, 12.5, 8.1.
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13C NMR (101 MHz, CDCl3): δ = 166.8, 149.6, 141.9, 140.3, 128.9,
127.6, 126.1, 124.5, 124.1, 119.5, 110.2, 74.8, 53.9, 47.3, 34.9, 29.8,
24.2, 12.5, 8.5.
(E)-1-{(Z)-2-[(S)-2-Phenylbutylidene]benzoxazol-3(2H)-yl}but-2-
en-1-one (6) and (E)-1-{(E)-2-[(S)-2-Phenylbutylidene]benzoxaz-
ol-3(2H)-yl}pent-2-en-1-one (7)
In a heat-dried Schlenk tube equipped with a septum and a magnetic
stir bar, CuBr·SMe2 (5 mol%; 0.05 equiv) and the ligand (Rc,Sp)-L1 (6
mol%, 0.06 equiv) were dissolved in DCM (1 mL/0.1 mmol of sub-
strate) and stirred under a nitrogen atmosphere for 15 min. Substrate
1b (0.1 mmol, 1.0 equiv) was added in one portion. After stirring for 5
min at room temperature, the mixture was cooled to –78 °C and BCl3
or BBr3 (0.12 mmol, 1.2 equiv) was added. After 5 min, compound 3d
(0.4 mmol, 4.0 equiv) was added followed by EtMgBr (0.15 mmol, 3 M
in Et2O, 1.5 equiv). After stirring at –78 °C for 3 h, the reaction was
quenched with MeOH (1 mL) followed by saturated aqueous NH4Cl
solution (1 mL) and warmed to R.T. The reaction mixture was extract-
ed with DCM (3 × 10 mL). The combined organic phases were dried
over MgSO4, filtered and the solvents removed on a rotary evaporator.
The oily crude residue was purified by flash column chromatography
using a mixture of pentane and EtOAc as eluent. Compounds 6 and 7
were obtained as inseparable mixtures of isomers in 1.85:1 ratios.
Yield = 63%; 33% ee. (Note: the ee was measured for the corresponding
1,4-addition product obtained under the same reaction conditions).
CSP-HPLC (206 nm, Chiralpak OJ-H, n-heptane/iPrOH = 99.7:0.3,
40 °C, 0.5 mL/min): tR = 17.54, 23.64 min (major), tR = 34.11, 47.07
min (minor).
Ethyl (3S,4S,5S)-4-(Benzoxazol-2-yl)-3,5-dimethylheptanoate (4n)
Compound 4n was synthesized following general procedure A with
1a (0.1 mmol), BF3·OEt2 (0.12 mmol, 1.2 equiv), EtMgBr (3 M in Et2O,
0.15 mmol, 1.5 equiv), CuBr·SMe2 (0.005 mmol, 5 mol%), ligand
(Rc,Sp)-L1 (0.006 mmol, 6 mol%), and 3d (0.4 mmol, 4 equiv) in DCM
(1 mL). Product 4n (an inseparable mixture of diastereoisomers) was
obtained as a pale yellow oil after flash column chromatography (SiO2,
pentane/EtOAc, 97:3, v/v).
Yield: 16.1 mg (53%); 79% ee.
1H NMR (400 MHz, CDCl3): δ (major diastereoisomer) = 7.72–7.67 (m,
1 H), 7.52–7.46 (m, 1 H), 7.34–7.27 (m, 2 H), 4.18–4.08 (m, 2 H), 2.90
(dd, J = 9.7, 5.4 Hz, 1 H), 2.73–2.61 (m, 1 H), 2.37 (dd, J = 15.6, 5.6 Hz, 1
H), 2.13–1.93 (m, 2 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.22–1.14 (m, 2 H), 1.03
(dd, J = 9.4, 6.7 Hz, 6 H), 0.83 (t, J = 7.4 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ (minor diastereoisomer) = 7.73–7.66 (m,
1 H), 7.53–7.45 (m, 1 H), 7.34–7.27 (m, 2 H), 4.19–4.07 (m, 2 H), 2.97
(t, J = 7.6 Hz, 1 H), 2.73–2.61 (m, 1 H), 2.44 (dd, J = 15.4, 5.2 Hz, 1 H),
2.14–1.91 (m, 2 H), 1.59–1.47 (m, 1 H), 1.37–1.24 (m, 1 H), 1.25 (t, J =
7.2 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.95 (t, J = 7.4 Hz, 3 H), 0.88 (d, J =
6.7 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 172.5, 167.6, 141.0, 136.9, 124.4,
124.1, 119.7, 110.4, 60.3, 50.1, 40.3, 34.8, 30.3, 27.1, 16.6, 15.1, 14.2,
11.1.
Compound 6
1H NMR (400 MHz, CDCl3): δ = 7.81–7.68 (m, 1 H), 7.55 (ddd, J = 8.6,
6.2, 3.8 Hz, 1 H), 7.35 (ddt, J = 7.3, 4.4, 1.6 Hz, 1 H), 7.32–7.23 (m, 3 H),
7.23–7.17 (m, 2 H), 7.12 (dq, J = 8.4, 7.0 Hz, 1 H), 6.82 (dq, J = 15.6, 6.9
Hz, 1 H), 6.06 (dq, J = 15.6, 1.6 Hz, 1 H), 4.70 (d, J = 11.1 Hz, 1 H), 3.69
(qd, J = 10.8, 3.6 Hz, 1 H), 1.73 (ddd, J = 6.9, 1.7, 0.8 Hz, 3 H), 1.68–1.56
(m, 2 H), 0.67 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 193.1, 162.8, 151.2, 145.3, 141.2,
140.7, 130.4, 128.6, 128.5, 127.0, 125.3, 124.6, 120.2, 111.0, 57.1, 48.0,
27.1, 18.5, 11.7.
HRMS (ESI+): m/z [M + H]+ calcd for C18H26NO3: 304.1907; found:
304.1911.
HRMS (ESI+): m/z [M + H]+ calcd for C21H22NO2: 320.16510; found:
320.16451.
CSP-HPLC (233 nm, Chiralcel OD-H, n-heptane/iPrOH = 99.8:0.2,
40 °C, 0.5 mL/min): tR = 21.15 min (major), tR = 27.13 min (minor).
Compound 7
1H NMR (400 MHz, CDCl3): δ = 7.55 (ddd, J = 8.6, 6.2, 3.8 Hz, 1 H),
7.41–7.32 (m, 2 H), 7.32–7.23 (m, 2 H), 7.23–7.16 (m, 2 H), 7.16–7.08
(m, 1 H), 7.06–6.99 (m, 1 H), 6.41 (dd, J = 15.6, 1.7 Hz, 1 H), 4.63 (d, J =
11.1 Hz, 1 H), 3.69 (qd, J = 10.8, 3.7 Hz, 1 H), 1.91 (ddd, J = 6.9, 1.7, 0.8
Hz, 3 H), 1.57–1.43 (m, 2 H), 0.75 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 193.7, 162.3, 150.9, 146.1, 141.2,
141.0, 130.5, 128.4, 128.3, 126.8, 124.9, 124.2, 119.9, 110.6, 57.3, 48.0,
27.5, 18.7, 12.0.
Ethyl (3S,4R,5S)-4-(Benzothiazol-2-yl)-3-methyl-5-phenylhepta-
noate (4o)
Compound 4o was synthesized following general procedure A with 1c
(0.1 mmol), BF3·OEt2 (0.12 mmol, 1.2 equiv), EtMgBr (3 M in Et2O, 0.15
mmol, 1.5 equiv), CuBr·SMe2 (0.005 mmol, 5 mol%), ligand (Rc,Sp)-L1
(0.006 mmol, 6 mol%), and 3d (0.4 mmol, 4 equiv) in DCM (1 mL).
Product 4o was obtained as a pale yellow oil after flash column chro-
matography (SiO2, pentane/EtOAc, 97:3, v/v).
Yield: 22.1 mg (58%); 94% ee.
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 8.1 Hz, 1 H), 7.89 (d, J = 7.9
Hz, 1 H), 7.49 (t, J = 7.3 Hz, 1 H), 7.44–7.33 (m, 3 H), 7.29 (d, J = 6.9 Hz,
3 H), 4.20–4.00 (m, 2 H), 3.71 (dd, J = 11.5, 3.5 Hz, 1 H), 3.12 (td, J =
10.8, 3.7 Hz, 1 H), 2.27–2.11 (m, 2 H), 1.97–1.87 (m, 1 H), 1.56–1.39
(m, 2 H), 1.31–1.17 (m, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 0.58 (t, J = 7.3 Hz,
3 H).
13C NMR (101 MHz, CDCl3): δ = 171.6, 170.6, 152.4, 141.3, 133.8,
127.7, 127.5, 125.8, 125.0, 123.9, 122.0, 120.5, 59.3, 52.3, 49.6, 39.3,
30.1, 27.7, 13.6, 13.4, 11.1.
Funding Information
Financial support from NWO (Vidi and ECHO to S.R.H.) and the Minis-
try of Education, Culture and Science (Gravity programme
024.001.035 to S.R.H.) is acknowledged. J.M.P. thanks the European
Commission for an Intra-European Marie Curie fellowship (grant
746011–ChirPyr).
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Acknowledgment
382.18413.
We also thank Solvias for a generous gift of Josiphos ligands, T.D.
Tiemerma-Wegman for HRMS support and Pieter van der Meulen for
NMR support.
CSP-HPLC (254 nm, Chiralpak AD-H, n-heptane/iPrOH = 99:1, 40 °C,
0.5 mL/min): tR = 14.79 min (minor), tR = 16.84 min (major).
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

J
F. Lanza et al.
Paper
Synthesis
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J