Enantioselective Construction of Quaternary Carbon Stereocenter via Palladium-Catalyzed Asymmetric Allylic Alkylation of Lactones

Article abstract of DOI:10.1055/s-0035-1561574

An efficient and practical method for the synthesis of α,α-disubstituted six-membered lactones was developed. Enantioselective construction of quaternary carbon centers by utilizing Pd-catalyzed asymmetric allylic alkylation proved its feasibility.

Full text of DOI:10.1055/s-0035-1561574

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 1568–1572
paper
1568
X.-H. Li et al.
Paper
Synthesis
Enantioselective Construction of Quaternary Carbon Stereocenter
via Palladium-Catalyzed Asymmetric Allylic Alkylation of Lactones
Xiao-Hui Lia
O
O
Shi-Li Wana
Di Chena
O
O
[Pd(C3H5)Cl]2 (2.5 mol%)
R1
L2 (5 mol%)
R2
Qing Rong Liua
Chang-Hua Dinga
Ping Fang*a
+
R1
LDA, LiCl, THF, –78 °C
R2
OCO2Me
67–98% yields
54–93% ee
Xue-Long Hou*a,b
PAr2
PAr2
R1 = alkyl, Ph
R2 = H, Ph, 2 furyl
10 examples
a State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
b Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China
xlhou@sioc.ac.cn
Ar = 3,5-xylyl
Received: 30.12.2015
Accepted after revision: 01.02.2016
Published online: 07.03.2016
dro-2H-pyran-2-one 3a, in 79% yield with 77% ee (Table 1,
entry 1). Encouraged by this result, influences of the reac-
tion parameters were investigated (Table 1).
DOI: 10.1055/s-0035-1561574; Art ID: ss-2015-z0746-op
The screening of base showed that both yield and ee val-
ue significantly decreased when NaHMDS or KHMDS was
the base (Table 1, entries 2, 3). The enantioselectivity was
improved when LDA was used as base (entry 4 vs. entry 1).
Thus, the effect of solvents was explored with LDA as base.
It can be seen that THF gave the better results (entry 4)
among the various solvents screened, including THF, Et2O,
methyl tert-butyl ether (MTBE), toluene, and CH2Cl2 (en-
tries 4–8). The effect of additives was also studied (entries
9–15). Both yield and ee value decreased in the absence of
LiCl (entry 9 vs. entry 4). In the presence of 2 equivalents of
LiCl as additive, the yield increased with comparable ee val-
ue (entry 10 vs. entry 4). The yield decreased and the ee
value remained the same if CuCl was the additive (entry 11
vs. entry 4). With Lewis base additive such as TMEDA or
HMPA, inferior results were obtained (entries 12, 13).
Mixed additives such as TMEDA and LiCl or HMPA and LiCl
gave superior yields while the ee values were lower than
that with LiCl as the only additive (entries 14, 15 vs. entry
4). Based upon these results, a series of chiral ligands (Fig-
ure 1) with different electronic and steric factors were
screened in THF with LDA as base and LiCl as additive (en-
tries 16–25). When L2 with much more steric hindrance on
P atom was used, both yield and enantioselectivity in-
creased further (entry 16 vs. entry 4) while the reactions
using ligands L3–L9 with a biphenylene backbone afforded
the product in good yields but with varied lower ee values
(entries 17–23). It seems that the ligand L3 has bigger dihe-
dral angle than that of ligand L1 and the ee value was lower
Abstract An efficient and practical method for the synthesis of α,α-
disubstituted six-membered lactones was developed. Enantioselective
construction of quaternary carbon centers by utilizing Pd-catalyzed
asymmetric allylic alkylation proved its feasibility.
Key words palladium, allylic alkylation, asymmetric catalysis, lac-
tones, quaternary carbon
The palladium-catalyzed asymmetric allylic alkylation
(AAA) is among the most useful protocols for enantioselec-
tive construction of carbon–carbon and carbon–heteroat-
om bonds.1 Different kinds of ‘hard’ carbanions have been
used as nucleophile successfully.2,3 In spite of the fact that
the esters are very useful class of compounds in organic
synthesis,4 only a few reports appeared with the use of es-
ters as the precursor of nucleophile in this reaction2j–k,3e
and only one example was involved in the construction of
α-chiral quaternary center with modest enantioselectivi-
ty.2k In the course of the research on the palladium-cata-
lyzed AAA during recent years,3,5 we have successfully de-
veloped many different types of enolates as nucleophile.3 In
this paper, we would like to report our further studies using
α-substituted lactones as pre-nucleophile to construct chi-
ral quaternary center by Pd-catalyzed AAA. Initially, the re-
action of 3-benzyltetrahydro-2H-pyran-2-one (1a) and allyl
methyl carbonate (2a) was carried out in the presence of
catalytic amounts of [Pd(C3H5)Cl]2 and (R)-BINAP, using
LiHMDS as base and LiCl as additive in THF at –78 °C. The
reaction afforded the product, 2,2-disubstituted tetrahy-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1568–1572

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Synthesis
Table 1 Optimization of Parameters for the Reaction of 1a with 2aa
enantioselectivity (entry 24). By using Trost’s ligand L11,
the reaction could provide only in low yield with moderate
enantioselectivity (entry 25).
O
O
Ph
Under the optimized conditions, the substrate scope
was explored and the results are summarized in Table 2.
Generally the reactions proceeded smoothly for all α-sub-
stituted six-membered lactones to produce the correspond-
ing lactones with α-chiral quaternary carbon in 67–98%
yields with 54–94% ee, in spite of the substituent at α-posi-
tion of carbonyl being benzyl (Table 2, entry 1), alkyl (en-
tries 2–4), or phenyl (entry 5). The reaction was also suit-
able for 3-methylchroman-2-one (1f) (entry 6). With allyl
substrate 2b, it also afforded the corresponding products 3g
and 3j with excellent ee values (entries 7, 10). Only reac-
tions using 1e with a phenyl as substituent at α-position
delivered the products 3h and 3i with moderate ee values
(entries 8, 9).
O
[Pd(C3H5)Cl]2 (2.5 mol%)
ligand (5 mol%)
1a
Ph
+
O
base, additive, solvent,
–78 °C
OCO2Me
3a
2a
Entry L*
Base
LiHMDS
Solvent
THF
Additive
Yield (%)b ee (%)c
1
2
L1
LiCl
79
15
trace
78
63
69
32
NPe
68
86
69
49
23
86
85
83
82
84
79
91
89
82
82
46
18
77
–6d
–
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
NaHMDS THF
LiCl
3
KHMDS
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
THF
THF
Et2O
MTBE
toluene
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
LiCl
4
LiCl
85
50
40
37
–
5
LiCl
6
LiCl
7
LiCl
Table 2 Substrate Scope for Pd-Catalyzed AAAa
8
LiCl
O
O
9
none
LiClf
62
87
85
77
51
80
67
90
57
68
81
78
69
80
81
11
67
R1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
[Pd(C3H5)Cl]2 (2.5 mol%)
O
O
1
CuCl
TMEDA
HMPA
TMEDA + LiCl
HMPA + LiCl
LiCl
L2 (5 mol%)
R2
+
LDA, LiCl, THF, –78 °C
R2
OCO2Me
R1
3
2a R2 = H
2b R2 = Ph
2c R2 = 2-furyl
O
O
1a R1 = Bn
1b R1 = Et
1c R1 = i-Bu
1d R1 = Me
1e R1 = Ph
O
O
LiCl
R1
Me
LiCl
1a–e
1f
LiCl
Entry
1
2
Product
Yield (%)b
ee (%)c
LiCl
LiCl
1
2
1a
1b
1c
1d
1e
1f
2a
3a
3b
3c
3d
3e
3f
83
79
82
89
80
98
78
90
88
67
90
89
75
92
48
94
87
54
59
93
LiCl
2a
2a
2a
2a
2a
2b
2b
2c
2b
LiCl
3
LiCl
4
LiCl
5
a Reactions were carried out at –78 °C, molar ratio of
6
1a/2a/[Pd(C3H5)Cl]2/L/base/additive = 100:120:2.5:5:120:100.
b Isolated yields of 3a is based on 1a.
c Determined by chiral HPLC.
7
1a
1e
1e
1d
3g
3h
3i
8
d The reversed sequence of peaks by HPLC.
e NP: No product.
9
f Two equivalents of LiCl were used as additive.
10
3j
a Reactions were carried out at –78 °C, molar ratio of
1/2/[Pd(C3H5)Cl]2/L2/Base/Additive = 100:120:2.5:5:120:100.
in the reaction with L3 as ligand than that using L1 (entry
17 vs. entry 4). The same trend was observed also in the re-
actions with ligand L7 and L9; ligand L7 with bigger dihe-
dral angle than that of ligand L9, afforded the product with
lower ee value (entry 21 vs. entry 23). By using ligand L10,
the reaction could proceed only in moderate yield with low
b Isolated yields of 3 are based on 1.
c Determined by chiral HPLC or GC.
The absolute configuration of 3a was determined as R
by comparing the sign of the optical rotation of the product
with that reported in the literature.6
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Synthesis
O
O
O
F
F
O
O
O
O
PAr2
PAr2
PPh2
PPh2
O
O
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
F
F
O
O
O
L1, Ar = Ph
L2, Ar = 3,5-xylyl
L3
L4
L5
L6
Cl
O
O
O
O
O
MeO
MeO
PPh2
PPh2
O
PPh2
PPh2
MeO
MeO
PPh2
PPh2
PAr2
PAr2
NH
PPh2
HN
Ph2P
O
O
Cl
L7
L8
L9
L10
Ar = 4-MeO-3,5-(t-Bu)2C6H2
L11
Figure 1 The structure of ligands L1–L11
In summary, we have realized the Pd-catalyzed asym-
metric allylic alkylation of α-substituted six-membered
lactones with allyl methyl carbonates in good yields with
good enantioselectivities. The chiral quaternary carbon
center has also been constructed successfully during the re-
action. Further investigations to extend the reaction scope
and applications in organic synthesis are in progress.
HPLC: Chiralpak AD-H; hexane–i-PrOH (95:5), flow rate
mL/min, 230 nm, tR = 11.5 min, 12.3 min; ee = 90%.
= 0.7
IR (film): 2963 (w), 1718 (m), 1454 (w), 1260 (m), 1098 (s), 1018 (s),
798 (s), 703 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 1.38–1.47 (m, 1 H), 1.64–1.73 (m, 1 H),
1.79–1.82 (m, 2 H), 2.18 (dd, J = 13.2, 8.4 Hz, 1 H), 2.60 (d, J = 13.2 Hz,
1 H), 2.68 (dd, J = 13.2, 6.4 Hz, 1 H), 3.30 (d, J = 13.2 Hz, 1 H), 3.90–3.95
(m, 1 H), 4.11–4.17 (m, 1 H), 5.12–5.19 (m, 2 H), 5.75–5.85 (m, 1 H),
7.17–7.31 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 21.0, 27.8, 45.0, 45.5, 47.5, 70.05,
119.4, 126.8, 128.3, 130.3, 133.1, 137.0, 175.2.
HRMS: m/z [M + H]+ calcd for C15H19O2: 231.1385; found: 231.1383.
All the experiments were carried out in flame-dried glassware under
a dry argon atmosphere. The solvents were purified and dried over
appropriate drying agents and distilled under argon prior to use. 1H
NMR and 13C NMR spectra were recorded in CDCl3 using TMS as inter-
nal standard on a Bruker Avance 300 MHz, 400 MHz, or 600 MHz
spectrometers at r.t. HRMS analyses were carried out using the Fin-
nigan MAT 8430 spectrometer.
3-Allyl-3-ethyltetrahydro-2H-pyran-2-one (3b)
Yield: 26.5 mg (79%); slightly yellow oil; [α]D26 +3.0 (c = 0.95 in CHCl3).
Chiral GC: RESTEK Rt-βDEXcst column, 30 m × 0.25 mm × 0.12 μm
[carrier gas: N2, injector temperature: 250 °C, split ratio: 30, constant
column flow: 10 psi, column temperature 60 °C (5 min), 60–150 °C (2
°C/min), 150 °C (5 min), 150–180 °C (3 °C/min), FID detector tempera-
ture: 250 °C], tR = 56.0 min, 56.4 min; ee = 89%.
The synthesis of 3-substituted tetrahydro-2H-pyran-2-ones 1a–e is
provided in the Supporting Information.
α,α-Disubstituted Esters 3; General Procedure
α-Substituted ester 1 (0.2 mmol), LiCl (8.4 mg, 0.2 mmol), and THF
(1.0 mL) were added to a dry Schlenk tube. LDA (1.0 M in THF, 0.24
mL, 0.24 mmol) was then added dropwise and the contents were
stirred for 0.5 h at –78 °C. In a separate flask, [Pd(C3H5)Cl]2 (1.8 mg,
0.005 mmol) and ligand L2 (7.3 mg, 0.01 mmol) were dissolved in
THF (1.0 mL) and stirred at r.t. for 0.5 h, which was then added to the
above enolate solution at –78 °C, followed by the addition of respec-
tive allyl methyl carbonate 2 (28 mg, 0.2 mmol). The resulting mix-
ture was stirred at –78 °C. After completion (monitored by TLC), the
reaction mixture was quenched by sat. aq NH4Cl and extracted with
Et2O (3 × 5 mL). The combined organic layers were dried (Na2SO4) and
the solvent was removed under reduced pressure. The residue was
purified by column chromatography (silica gel, PE–EtOAc, 10:1) to af-
ford the desired product.
IR (film): 2962 (w), 2927 (w), 1729 (m), 1462 (w), 1260 (s), 1092 (s),
1019 (s), 798 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 7.6 Hz, 3 H), 1.52–1.61 (m, 1
H), 1.77–1.88 (m, 5 H), 2.20 (dd, J = 13.6, 5.6 Hz, 1 H), 2.54 (dd, J =
13.6, 8.4 Hz, 1 H), 4.29–4.32 (m, 2 H), 5.10–5.14 (m, 2 H), 5.71–5.82
(m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 8.7, 21.2, 28.6, 32.2, 43.6, 46.2, 70.1,
118.9, 133.5, 175.4.
HRMS: m/z [M + H]+ calcd for C10H17O2: 169.1229; found: 169.1225.
3-Allyl-3-isobutyltetrahydro-2H-pyran-2-one (3c)
Yield: 32.1 mg (82%); slightly yellow oil; [α]D26 +7.1 (c = 0.85 in CHCl3).
Chiral GC: VARIAN CHIRASIL- DEXCB column, 30 m × 0.25 mm × 0.12
μm [carrier gas: N2, injector temperature: 250 °C, split ratio: 30, con-
stant column flow: 10 psi, column temperature 60 °C (5 min), 60–150
°C (2 °C/min), 150 °C (2 min), 150–180 °C (3 °C/min), FID detector
temperature: 250 °C], tR = 47.6 min, 47.9 min; ee = 75%.
3-Allyl-3-benzyltetrahydro-2H-pyran-2-one (3a)
26
Yield: 38.2 mg (83%); slightly yellow oil; [α]D +13.2 (c = 0.94 in
CHCl3).
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IR (film): 2956 (m), 2927 (w), 2871 (w), 1723 (s), 1396 (w), 1240 (m),
1135 (s), 917 cm–1 (w).
IR (film): 2959 (m), 1719 (s), 1451 (m), 1263 (m), 1115 (s), 972 (m),
801 (m), 700 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 0.90 (d, J = 6.4 Hz, 3 H), 0.93 (d, J = 6.4
Hz, 3 H), 1.41–1.47 (m, 1 H), 1.73–1.93 (m, 6 H), 2.18 (dd, J = 13.6, 8.0
Hz, 1 H), 2.52 (dd, J = 13.6, 6.4 Hz, 1 H), 4.32–4.35 (m, 2 H), 5.09–5.15
(m, 2 H), 5.71–5.81 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.0, 23.3, 24.6, 24.8, 28.5, 45.1, 45.4,
47.6, 70.1, 119.1, 133.4, 175.8.
1H NMR (400 MHz, CDCl3): δ = 1.45–1.49 (m, 1 H), 1.65–1.69 (m, 1 H),
1.84–1.87 (m, 2 H), 2.31–2.37 (m, 1 H), 2.68 (d, J = 13.2 Hz, 1 H), 2.86–
2.92 (m, 1 H), 3.32 (d, J = 13.6 Hz, 1 H), 3.92–3.94 (m, 1 H), 4.10–4.14
(m, 1 H), 6.18–6.21 (m, 1 H), 6.47 (d, J = 15.6 Hz, 1 H), 7.19–7.35 (m,
10 H).
13C NMR (100 MHz, CDCl3): δ = 21.2, 28.0, 44.4, 45.8, 48.1, 70.2, 124.7,
126.2, 126.9, 127.5, 128.4, 128.6, 130.4, 134.3, 136.9, 137.0, 175.5.
HRMS: m/z [M + NH4]+ calcd for C21H26NO2: 324.1958; found:
HRMS: m/z [M + H]+ calcd for C12H21O2: 197.1542; found: 197.1540.
324.1961.
3-Allyl-3-methyltetrahydro-2H-pyran-2-one (3d)
Yield: 27.4 mg (89%); colorless oil; [α]D26 +3.3 (c = 1.00 in CHCl3).
3-Cinnamyl-3-phenyltetrahydro-2H-pyran-2-one (3h)
Yield: 52.6 mg (90%); colorless oil; [α]D26 +85.8 (c = 0.98 in CHCl3).
Chiral GC: VARIAN CHIRASIL-DEXCB column, 30 m × 0.25 mm × 0.12
μm [carrier gas: N2, injector temperature: 250 °C, split ratio: 30, con-
stant column flow: 10 psi, column temperature 60 °C (5 min), 60–150
°C (3 °C/min), 150 °C (5 min), 150–180 °C (3 °C/min), FID detector
temperature: 250 °C], tR = 31.2 min, 31.5 min; ee = 92%.
HPLC: Chiralpak PC-2; hexane–i-PrOH (60/40), flow rate
mL/min, 230 nm, tR = 16.1 min, 17.1 min; ee = 54%.
= 0.5
IR (film): 2964 (m), 1714 (m), 1448 (w), 1262 (s), 1094 (s), 1023 (s),
802 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 1.02–1.89 (m, 2 H), 2.03–2.12 (m, 1 H),
2.44–2.50 (m, 1 H), 2.63–2.69 (m, 1 H), 2.90–2.96 (m, 1 H), 3.97–4.00
(m, 1 H), 4.16–4.20 (m, 1 H), 6.06–6.10 (m, 1 H), 6.36 (d, J = 16.0 Hz, 1
H), 7.19–7.31 (m, 10 H).
HPLC: Chiralpak AD-H; i-PrOH–hexane (3:97), flow rate: 0.7 mL/min,
214 nm, tR (minor) = 12.8 min, tR (major) = 13.5 min; ee = 91%.
1H NMR (400 MHz, CDCl3): δ = 1.30 (s, 3 H), 1.57–1.66 (m, 1 H), 1.84–
1.97 (m, 3 H), 2.20 (dd, J = 13.6, 8.0 Hz, 1 H), 2.54 (dd, J = 13.2, 6.8 Hz,
1 H), 4.25–4.39 (m, 2 H), 5.10–5.16 (m, 2 H), 5.70–5.81 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.6, 26.3, 31.6, 42.2, 44.5, 70.4, 102.5,
13C NMR (100 MHz, CDCl3): δ = 19.4, 27.9, 45.2, 51.7, 67.9, 125.4,
119.1, 133.2, 176.1.
126.0, 126.2, 127.3, 127.4, 128.5, 129.0, 133.9, 137.2, 140.4, 174.3.
HRMS: m/z [M + NH4]+ calcd for C20H24NO2: 310.1802; found:
310.1805.
3-Allyl-3-phenyltetrahydro-2H-pyran-2-one (3e)
Yield: 34.6 mg (80%); colorless oil; [α]D26 +81.4 (c = 0.99 in CHCl3).
(E)-3-[3-(Furan-2-yl)allyl]-3-phenyltetrahydro-2H-pyran-2-one
(3i)
HPLC: Chiralpak OJ-H; hexane–i-PrOH (90/10), flow rate
mL/min, 214 nm, tR = 18.3 min, 20.0 min; ee = 48%.
= 0.7
26
Yield: 49.6 mg (88%); slightly yellow oil; [α]D +62.2 (c = 0.99 in
IR (film): 2963 (w), 1729 (s), 1446 (w), 1261 (m), 1151 (m), 1094 (s),
798 (m), 701 cm–1 (m).
CHCl3).
HPLC: Chiralpak PC-2; hexane–i-PrOH (60/40), flow rate
mL/min, 230 nm, tR = 12.9 min, 14.1 min; ee = 59%.
= 0.5
1H NMR (400 MHz, CDCl3): δ = 1.69–1.88 (m, 1 H), 1.93–2.01 (m, 1 H),
2.33–2.39 (m, 1 H), 2.47 (dd, J = 13.6, 7.6 Hz, 1 H), 2.69 (dd, J = 13.6,
6.8 Hz, 1 H), 3.90–3.96 (m, 1 H), 4.09–4.15 (m, 1 H), 4.94–5.00 (m, 2
H), 5.54–5.65 (m, 1 H), 7.19–7.31 (m, 5 H).
IR (film): 2963 (m), 2906 (s), 1411 (s), 1259 (m), 1081 (s), 1014 (s),
794 (s), 701 cm–1 (m).
13C NMR (100 MHz, CDCl3): δ = 19.4, 27.9, 45.9, 51.1, 67.8, 118.8,
126.0, 127.3, 128.8, 133.7, 140.4, 174.2.
HRMS: m/z [M + H]+ calcd for C14H17O2: 217.1229; found: 217.1228.
1H NMR (400 MHz, CDCl3): δ = 1.80–1.92 (m, 2 H), 2.06–2.11 (m, 2 H),
2.44–2.50 (m, 1 H), 2.63 (dd, J = 14.0, 7.2 Hz, 1 H), 2.63 (dd, J = 14.0,
8.4 Hz, 1 H), 3.97–4.00 (m, 1 H), 4.16–4.23 (m, 1 H), 5.99–6.05 (m, 1
H), 6.13–6.21 (m, 2 H), 6.32–6.34 (m, 1 H), 7.29–7.40 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 19.5, 27.9, 45.0, 51.7, 67.9, 106.9,
111.1, 122.4, 124.1, 126.0, 127.4, 129.0, 140.3, 141.6, 152.7, 174.2.
HRMS: m/z [M + NH4]+ calcd for C18H22NO3: 300.1594; found:
3-Allyl-3-methylchroman-2-one (3f)
26
Yield: 39.6 mg (98%); slightly yellow oil; [α]D –6.9 (c = 0.05 in
CHCl3).
300.1596.
HPLC: Chiralpak OJ-H; hexane–i-PrOH (95/5), flow rate = 0.5 mL/min,
214 nm, tR = 13.4 min, 14.5 min; ee = 94%.
3-Cinnamyl-3-methyltetrahydro-2H-pyran-2-one (3j)
Yield: 30.8 mg (67%); colorless oil; [α]D26 +0.58 (c = 1.07 in CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.26 (s, 3 H), 2.28–2.40 (m, 2 H), 2.75
(d, J = 16.0 Hz, 1 H), 2.91 (d, J = 16.0 Hz, 1 H), 5.03 (d, J = 16.8 Hz, 1 H),
5.14 (d, J = 10.4 Hz, 1 H), 5.73–5.84 (m, 1 H), 7.01 (d, J = 8.0 Hz, 1 H),
7.07 (d, J = 7.2 Hz, 1 H), 7.14 (d, J = 6.4 Hz, 1 H), 7.23–7.27 (m, 1 H).
HPLC: Chiralpak AD-H; i-PrOH–hexane (5:95); flow rate: 0.7 mL/min,
214 nm, tR = 15.7 min, 17.7 min; ee = 93%.
13C NMR (100 MHz, CDCl3): δ = 22.2, 35.4, 40.4, 40.8, 116.0, 119.6,
121.6, 124.3, 128.1, 128.5, 132.2, 151.2, 172.6.
HPLC: Chiralpak PC-2; hexane–i-PrOH (60/40), flow rate
mL/min, 230 nm, tR = 15.7 min, 17.7 min.
= 0.5
IR (film): 2962 (m), 1725 (w), 1258 (s), 1076 (s), 1011 (s), 789 cm–1
(m).
1H NMR (400 MHz, CDCl3): δ = 1.35 (s, 3 H), 1.64–1.68 (m, 1 H), 1.87–
1.99 (m, 3 H), 2.36 (dd, J = 14.0, 7.2 Hz, 1 H), 2.74 (dd, J = 13.6, 8.4 Hz,
1 H), 4.28–4.36 (m, 2 H), 6.15–6.18 (m, 1 H), 6.46 (d, J = 16.0 Hz, 1 H),
7.22–7.35 (m, 5 H).
3-Benzyl-3-cinnamyltetrahydro-2H-pyran-2-one (3g)
Yield: 47.7 mg (78%); colorless oil; [α]D26 –5.2 (c = 0.97 in CHCl3).
HPLC: Chiralpak PA-2; hexane–i-PrOH (95/5), flow rate = 0.7 mL/min,
214 nm, tR = 42.2 min, 46.3 min; ee = 87%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1568–1572

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X.-H. Li et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 20.6, 26.5, 31.8, 42.8, 43.8, 70.5, 124.9,
126.2, 127.4, 128.5, 134.1, 137.1, 176.2.
HRMS: m/z [M + H]+ calcd for C15H19O2: 231.1380; found: 231.1385.
(i) Trost, B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2009, 131,
12056. (j) Meletis, P.; Patil, M.; Thiel, W.; Frank, W.; Braun, M.
Chem. Eur. J. 2011, 17, 11243. (k) Moorlag, H.; de Vries, J. G.;
Kaptein, B.; Schoemaker, H. E.; Kamphuis, J.; Kellogg, R. M. Rec.
Trav. Chim. Pays-Bas 1992, 111, 129. (l) Nemoto, T.; Tsuruda, K.;
Yoshida, M.; Kono, M.; Hamada, Y. Synthesis 2015, 47, 3914.
(m) Asad, S. A.; Mahmun Hossain, M. Synthesis 2016, 48, 200.
(3) (a) Yan, X. X.; Liang, C. G.; Zhang, Y.; Hong, W.; Cao, B. X.; Dai, L.-
X.; Hou, X.-L. Angew. Chem. Int. Ed. 2005, 44, 6544. (b) Zheng,
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Acknowledgment
This research was financially supported by National Natural Science
Foundation of China (21421091, 21272251, 21302205), the NSFC and
the Research Grants Council of Hong Kong Joint Research Scheme
(21361162001), Chinese Academy of Sciences, Technology Commis-
sion of Shanghai Municipality, and Croucher Foundation of Hong
Kong.
Supporting Information
(4) For reviews, see: (a) Pielartzik, H.; Irmisch-Pielartzik, B.; Eicher,
T. In Houben-Weyl, 4th ed., Vol. E5; Falbe, J., Ed.; Thieme: Stutt-
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561574.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1568–1572