Zinc(II)-Catalyzed Asymmetric Diels-Alder Reaction of (E)-1-Phenyl Dienes with β,γ-Unsaturated α-Ketoesters

Article abstract of DOI:10.1021/acs.joc.8b01771

A highly regio-, diastereo-, and enantioselective Diels-Alder reaction of β,γ-unsaturated α-ketoesters with (E)-1-phenyl dienes has been accomplished by using a stable and easily available chiral N,N′-dioxide/zinc(II) complex as catalyst. Only one isomer of the corresponding cyclohexenes with three chiral centers was obtained in good to excellent yields with excellent ee values under mild reaction conditions. The configurations of the product and chiral N,N′-dioxide/zinc(II) catalyst were identified by X-ray diffraction analysis. In addition, a possible catalytic model was proposed to explain the origin of the asymmetric induction.

Full text of DOI:10.1021/acs.joc.8b01771

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Article
Zinc(II)-Catalyzed Asymmetric Diels-Alder Reaction of
(E)-1-Phenyldienes with #,#-Unsaturated #-Ketoesters
Qian Xiong, Lili Lin, Xiaohu Zhao, Jiawen Lang, Xiaohua Liu, and Xiaoming Feng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01771 • Publication Date (Web): 17 Sep 2018
Downloaded from http://pubs.acs.org on September 18, 2018
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Zinc(II)ꢀCatalyzed Asymmetric DielsꢀAlder Reaction of (E)ꢀ1ꢀPhenyldienes with
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β,γꢀUnsaturated αꢀKetoesters
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Qian Xiong, Lili Lin,* Xiaohu Zhao, Jiawen Lang, Xiaohua Liu, and Xiaoming Feng*
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Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu, 610064, People’s Republic of China
Fax: (+86) 28ꢀ8541ꢀ8249; eꢀmail: lililin@scu.edu.cn; xmfeng@scu.edu.cn
ABSTRACT: A highly regioꢀ, diastereoꢀ and enantioseletive DielsꢀAlder reaction of β,γꢀunsaturated
αꢀketoesters with (E)ꢀ1ꢀphenyldienes has been accomplished by using a stable and easily available
chiral N,N′ꢀdioxide/zinc(II) complex as catalyst. Only one isomer of the corresponding cyclohexenes
with three chiral centers were obtained in good to excellent yields with excellent ee values under mild
reaction conditions. The configurations of the product and chiral N,N′ꢀdioxide/zinc(II) catalyst were
identified by Xꢀray diffraction analysis. Besides, a possible catalytic model was proposed to explain the
origin of the asymmetric induction.
INTRODUCTION
There is no doubt that DielsꢀAlder reaction1 is one of the most efficient methods to construct
cyclohexenes. The hypothetical natural DielsꢀAlder adducts2 kuwanons I, J, brosimone B and
sanggenons C, O (Scheme 1, aꢀe) are isolated from the cultivated mulberry tree and other moraceous
plants, which exhibit potential biological activities including anticancer, antiꢀHIV.3 Liu’s group
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developed a cascade strategy via goldꢀcatalyzed isomerization of unactivated allenes into 1,3ꢀdienes
and the following cycloaddition with the reactive alkenes to synthesize substituted cyclohexenes.4a For
the asymmetric synthesis, Lei’s group4c developed a chiral VANOL/boron complexꢀcatalysed
asymmetric DielsꢀAlder reaction of (E)ꢀ1ꢀphenyldienes with 2′ꢀhydroxychalcone derivatives, and
applied it in the enantioselective synthesis of kuwanons I, J and brosimone B. J. A. Porco Jr’s group
also used an B(OPh)3/BINOL complexꢀpromoted enantioselective DielsꢀAlder reaction of
(E)ꢀ1ꢀphenyldiene derivatives with 2′ꢀhydroxychalcones as a key step to synthesize the optically pure
natural sanggenons.4f Considering the usefulness of DielsꢀAlder reaction about (E)ꢀ1ꢀphenylꢀ3ꢀmethyl
dienes, developing new catalytic systems to synthesize these cyclohexenes with three chiral centers is
still meaningful.
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Carbonyl compounds coordinate with Lewis acid catalyst generally in a monodentate manner or a
bidentate manner. The monodentate coordination is flexible and can lead to different selectivity under
different conditions.5b Comparatively, the bidentate coordination is more rigid, which makes it easier to
control the reaction selectivity.5a Chiral N,N′ꢀdioxide6 developed by our group can coordinate with
various metal salts to catalyze asymmetric reactions. Meanwhile, zinc(II) salts feature advantages in
economic efficiency, abundance and environmentꢀfriendly.7 Herein, we report our achievements in
developing a N,N′ꢀdioxide/Zn(II) complex as catalyst to catalyze the asymmetric DielsꢀAlder reaction
of (E)ꢀ1ꢀphenyldienes with β,γꢀunsaturated αꢀketoesters8 under mild reaction conditions.
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Scheme 1. Natural products and reactions of (E)ꢀ1ꢀphenyldienes.
RESULTS AND DISCUSSION
Initially,
the
reaction
of
β,γꢀunsaturated
αꢀketoester
(1a)
and
(E)ꢀ(3ꢀmethylbutaꢀ1,3ꢀdienꢀ1ꢀyl)benzene (2a) was employed as the model reaction to optimize the
reaction conditions (Table 1). Firstly, no reaction occurred in the absence of metal no matter with or
without ligand. Then, various metal salts complexing with chiral N,N'ꢀdioxide ligand LꢀPrPr2 were
o
investigated in CH2Cl2 at 35 C. Both the DielsꢀAlder product and heteroꢀDielsꢀAlder product were
detected (Table 1, entries 3ꢀ5).[9,10] When Mg(OTf)2 was applied, a mixture of DielsꢀAlder product 3aa
and heteroꢀDielsꢀAlder product 4aa was obtained in 37% total yield with poor regioselectivity (Table 1,
entry 3). Both of Ni(OTf)2 and Zn(OTf)2 could improve the ratio of 3aa to 4aa (entries 4ꢀ5), and
Zn(OTf)2 showed higher ee value. Subsequently, various N,N′ꢀdioxide ligands with different chiral
backbones and steric hindrance on aniline were examined (entries 5ꢀ8). It was found that Lꢀpipecolic
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acid derived LꢀPiPr2 was superior to LꢀPrPr2 and LꢀRaPr2 (entry 7 vs entries 5ꢀ6). LꢀPiPr3 could
increase the yield and keep the enantioselectivity (entry 8). When CHCl2CHCl2 was used as solvent
and adjusting the ratio of 1a and 2a to 1:2, only DielsꢀAlder product was obtained in 97% yield with 98%
ee (entry 9). The catalyst loading could be decreased to 5 mol%, and still excellent yield and ee were
obtained (entry 10). So, the optimal reaction condition were established as 1a/2a (1:2),
Zn(OTf)2/LꢀPiPr3 (1:1, 5 mol%) in CHCl2CHCl2 at 35 oC for 24 h.
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Table 1 Optimization of the reaction conditions
ee (%)c
Entrya Ligand
Metal
Yield (%)b 3aa/4aac
3aa 4aa
1
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2
ꢀ
LꢀPrPr2
LꢀPrPr2
LꢀPrPr2
LꢀPrPr2
ꢀ
ꢀ
3
Mg(OTf)2 37
35:65
92:8
82:18
93:7
98:2
98:2
>99:1
50
45
67
55
80
80
98
82
ꢀ
4
Ni(OTf)2
Zn(OTf)2
61
56
49
51
63
97
5
15
ꢀ
6
LꢀRaPr2 Zn(OTf)2
7
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
ꢀ
LꢀPiPr2
LꢀPiPr3
LꢀPiPr3
8
ꢀ
9d,e
ꢀ
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10d,e,f
Zn(OTf)2
94
>99:1
94
ꢀ
LꢀPiPr3
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8
a Unless otherwise noted, all reaction were carried out with 1a (0.10
mmol), 2a (0.10 mmol), metal/ligand (1:1, 10 mol%) in CH2Cl2 (1.0
mL) at 35 oC. b total Isolated yield of 3aa and 4aa. 4aa can not be
isolated and detected separately. c Determined by chiral HPLC analysis.
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d
e
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CHCl2CHCl2 was used. 0.20 mmol 2a was used. used 5 mol%
catalyst.
Under the optimized reaction conditions, the substrate scope was then investigated. Firstly, a wide
range of β,γꢀunsaturated αꢀketoesters were evaluated (Table 2). The different ester groups have little
effect on the yields but have some effects on the ee values (entries 1ꢀ3). The ethyl R2 improved the ee
value to 99%, while the benzyl R2 decreased the ee value to 88%. The reason might be that the ester
groups are closer to the ZnII center, affecting the face selectivity of the reaction. The β,γꢀunsaturated
αꢀketoesters with either electronꢀwithdrawing or electronꢀdonating substituents on phenyl R1 group
mostly could transformed to the corresponding products in excellent yields and enantioselectivities
(entries 4ꢀ14). Exceptly, 2ꢀmethoxyl product 3ea was obtained in lower yield, which might be caused
by both the electronic nature and steric encumbrance between the catalyst and the substrate (entry 5).
To our delight, condensedꢀring, cinnamyl and heteroꢀaromatic β,γꢀunsaturated αꢀketoesters 1oꢀq were
also well tolerated in the catalytic system, giving the corresponding products in 78ꢀ98% yields with
97ꢀ99% ee (entries 15ꢀ17). Notably, the γꢀalkylꢀsubstituted β,γꢀunsaturated αꢀketoester 1r also
proceeded well, and the desired product 3ra was obtained in 93% yield with 99% ee (entry 18). R1
group show obvious difference on the yields, which might be caused by it’s influence on the LOMO
energy.
Table 2 Substrate scope of the β,γꢀunsaturated αꢀketoesters
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Entrya
1
R1
R2
Yield (%)b
ee (%)c
Ph
Me
Et
94 (3aa)
96 (3ba)
99 (3ca)
98 (3da)
64 (3ea)
90 (3fa)
95 (3ga)
97 (3ha)
99 (3ia)
80 (3ja)
81 (3ka)
93 (3la)
93 (3ma)
95 (3na)
78 (3oa)
98 (3pa)
93 (3qa)
93 (3ra)
94 (1R, 2S, 3R)
99 (1R, 2S, 3R)
88 (1R, 2S, 3R)
99 (1R, 2S, 3R)
99 (1R, 2S, 3R)
97 (1R, 2S, 3R)
99 (1R, 2S, 3R)
99 (1R, 2S, 3R)
98 (1R, 2S, 3R)
99 (1R, 2S, 3R)
99 (1R, 2S, 3R)
99 (1R, 2S, 3R)
99 (1R, 2S, 3R)
99 (1R, 2S, 3R)
99 (1R, 2S, 3R)
98 (1R, 2S, 3R)
97 (1R, 2S, 3R)
99
2
Ph
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3
Ph
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4
3ꢀMeC6H4
2ꢀMeOC6H4
3ꢀMeOC6H4
4ꢀMeOC6H4
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4ꢀPhC6H4
2ꢀFC6H4
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4ꢀFC6H4
3ꢀClC6H4
2,6ꢀCl2C6H3
4ꢀBrC6H4
2ꢀNaphthyl
Ph
3ꢀThienyl
Cyclohexyl
a Unless otherwise noted, the reaction was carried out with 1 (0.10
mmol), 2a (0.20 mmol), Zn(OTf)2/LꢀPiPr3 (1:1,
5
mol%) in
b
c
CHCl2CHCl2 (1.0 mL) for 24 h. r.r. = regio ratio. Isolated yield.
Determined by chiral HPLC analysis.
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Subsequently, the scope of (E)ꢀ1ꢀphenyldienes was investigated by reacting with β,γꢀunsaturated
αꢀketoester (1a) (Table 2). The substituent R4 at different positions of the phenyl group had little
influence on the yield and selectivity (entries 1ꢀ6). The R3 turned into the ethyl substitution, giving the
corresponding compound 3ag in 99% yield with 93% ee (entry 7). However, if R3 was H or phenyl
substituent, the reaction didn’t occur (Table 3, entries 8ꢀ9). For diene 2h without the methyl group, the
high HOMO energy might prevent the occurrence of the reaction. Meanwhile, the larger steric
hindrance between the catalyst might make it difficult for diene 2i to enter the catalytic active center of
the model. So, appropriate steric and electrical properties on the 3ꢀposition of diene were critical for the
reaction activity. When (E)ꢀ1ꢀphenyldienes (2f) reacted with other β,γꢀunsaturated αꢀketoesters (1d and
1n), the corresponding compounds were obtained with little influence on the yield and selectivity
(entries 10ꢀ11). The absolute configuration of 3ad was determined to be (1R, 2S, 3R) by Xꢀray
crystallographic analysis,11 and the others were assigned to be the same by comparing the Cotton effect
of the CD spectra with that of 3ad (for details, see the ESI).
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Table 3 Substrate scope of the (E)ꢀ1ꢀphenyldienes a
Entrya
R3
R4
Yield (%)b
94 (3aa)
87 (3ab)
90 (3ac)
98 (3ad)
91 (3ae)
94 (3af)
ee (%)c
1
2
3
4
5
6
Me
Me
Me
Me
Me
Me
Ph
94 (1R, 2S, 3R)
99 (1R, 2S, 3R)
99 (1R, 2S, 3R)
91 (1R, 2S, 3R)
99 (1R, 2S, 3R)
97 (1R, 2S, 3R)
2ꢀClC6H4
3ꢀFC6H4
4ꢀFC6H4
3ꢀMeOC6H4
4ꢀMeOC6H4
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Et
Ph
99 (3ag)
93 (1R, 2S, 3R)
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8
8
H
Ph
NR (3ah)
NR (3ai)
94 (3aj)
97 (3ak)
ꢀ
9
Ph
Me
Me
Ph
ꢀ
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10d
11e
4ꢀMeOC6H4
4ꢀMeOC6H4
94 (1R, 2S, 3R)
94 (1R, 2S, 3R)
a Unless otherwise noted, the reaction was carried out with 1a (0.10
mmol), 2 (0.20 mmol), Zn(OTf)2/LꢀPiPr3 (1:1, 5 mol%) in
CHCl2CHCl2 (1.0 mL) for 24 h. r.r. = regio ratio. b Isolated yield. c
d
Determined by chiral HPLC analysis. NR = no reaction. 1d was
used. e 1n was used.
To show the synthetic utility of the current catalytic system, a gramꢀscale synthesis is of 3na was
carried out under the optimized reaction condition. As shown in the Scheme 2, in the presence of 5 mol%
of LꢀPiPr3ꢀZn(OTf)2 complex, 3.0 mmol of 1n reacted well with 6.0 mmol of 2a, and 1.194 g (96%
yield) 3na was obtained with 97% ee.
Scheme 2 Scaleꢀup version of the reaction.
To explore the mechanism of the reaction, the single crystal of the catalyst was tried to be prepared.
After lots of attempts, the crystal was obtained at the condition of LꢀPiPr3, Zn(BF4)2•6H2O and
pyridine in a 1:1:2 ratio in THF and nꢀhexane, which showed four oxygens of the N,N′ꢀdioxide LꢀPiPr3,
one oxygen of H2O and one nitrogen of pyridine coordinate to the ZnII center to form an octahedral
geometry.12 HRMS analysis was also carried out. The spectrum of a mixture of LꢀPiPr3 and Zn(OTf)2
in a 1:1 ratio in CHCl2CHCl2 displayed an ion at m/z 945.4326 (m/z calcd for [LꢀPiPr3 + Zn2+ + OTfꢀ]+:
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945.4360), which suggested that the ligand coordinated with the metal in a 1:1 ratio. In the spectrum of
5
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a mixture of LꢀPiPr3, Zn(OTf)2 and 1a in a ratio 1:1:1 in CHCl2CHCl2, the signal of [LꢀPiPr3 + Zn2+
+
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8
9
OTfꢀ + 1a]+ at m/z 1135.4985 (m/z calcd 1135.4980) was observed, which suggested that the
LꢀPiPr3ꢀZn(OTf)2 complex coordinated with 1a in a 1:1 ratio. Besides, Operando IR experiments of 1e
and 2a suggested that the reaction proceeded through a concerted pathway since the amount of product
increased with the consumption of starting materials and no intermediates were observed.
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Scheme 3 Proposed transitionꢀstate model for the reaction.
On the basis of above analysis and the determination of the absolute configuration of the products,
a possible transitionꢀstate model was proposed. As shown in Scheme 3, four oxygens of the
N,N′ꢀdioxide LꢀPiPr3 and the two oxygens of β,γꢀunsaturated αꢀketoester 1 coordinate to the ZnII
center, forming an octahedral complex. At the same time, the coordination could decrease the LUMO
energy of β,γꢀunsaturated αꢀketoester 1 and promote the DielsꢀAlder reaction. Since the Si face of the
β,γꢀunsaturated αꢀketoester 1 is shielded by the neighboring amide group of the ligand, hence, the
(E)ꢀ1ꢀphenyldienes attack from the Re face of the β,γꢀunsaturated αꢀketoester 1 through a concerted
pathway to form the (1R, 2S, 3R)ꢀconfigured product 3.
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In summary, a highly regioselective, diastereoseletive and enantioseletive DielsꢀAlder reaction of
(E)ꢀ1ꢀphenyldienes with β,γꢀunsaturated αꢀketoesters is realized in the presence of a chiral
N,N′ꢀdioxideꢀZnII complex. A wide range of cyclohexenes were obtained in excellent yields with
excellent ee values. Furthermore, a possible transition model was proposed to explain the origin of
chirality.
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EXPERIMENTAL SECTION
General remarks:
Reactions were carried out using commercial available reagents in ovenꢀdried apparatus. CH2Cl2 was dried over powdered
K2CO3 and distilled over CaH2 just before use. CHCl2CHCl2 was dried and distilled over CaH2. 1H NMR spectra were recorded
at 400 MHz. The chemical shifts were recorded in ppm relative to tetramethylsilane and with the solvent resonance as the
internal standard. Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet,
dd = doublet of doublets), coupling constants (Hz), integration. 13C NMR data were collected at 100 MHz with complete proton
decoupling. Chemical shifts were reported in ppm from the tetramethylsilane with the solvent resonance as internal standard.
Metal catalysts obtained from commercial sources were used without further purification. Enantiomeric excesses were
determined by chiral HPLC analysis on Daicel Chiralcel IA/IB/IC/ID/IE/OXꢀH in comparison with the authentic racemates.
Optical rotations were reported as follows: [α] Tλ = (c: g/100 mL, in CH2Cl2, D: 589 nm). HRMS was recorded on a commercial
apparatus (ESI Source, TOF).
General procedure for the synthesises of dienes
General procedure: To a solution of methyltriphenylphosphonium bromide (8.0 g, 22.0 mmol) in THF (50 mL), was added NaH
(1.0 g, 22.0 mmol). The mixture was stirred for 1 hour at 60 °C. The ketone (20.0 mmol) was then added and the solution was
stirred at 60 °C until the reaction is completed by GC analysis or by TLC. The solvent was removed under reduced pressure and
the crude diene was purified by flash chromatography (petroleum ether: 100%) on silica gel or by distillation.
General procedure for the synthesis of racemic products
General procedure: To an ovenꢀdried tube was added Zn(OTf)2 (0.005 mmol, 5 mol%), racemic PiPr2 (0.005 mmol, 5 mol %),
β,γꢀunsaturated αꢀketoester 1a (0.10 mmol), (E)ꢀ(3ꢀmethylbutaꢀ1,3ꢀdienꢀ1ꢀyl)benzene 2a (0.20 mmol) and CH2Cl2 (1.0 mL). The
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reaction was stirred at 0 or 35 C, and then crude product was directly purified by flash chromatography on silica gel column
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Typical procedure for the asymmetric reaction
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General procedure: To an ovenꢀdried tube was added Zn(OTf)2 (0.005 mmol, 5 mol%), LꢀPiPr3 (0.005 mmol, 5 mol %). After
nitrogen replacement, β,γꢀunsaturated αꢀketoester 1a (0.10 mmol) and Cl2CHCHCl2 (1.0 mL) were added under nitrogen
atmosphere. The mixture was stirred in Cl2CHCHCl2 (1.0 mL) at 35 °C for 0.5 h. Subsequently,
(E)ꢀ(3ꢀmethylbutaꢀ1,3ꢀdienꢀ1ꢀyl)benzene 2a (0.20 mmol) was added. The reaction was stirred at the same temperature for 24 h,
and then crude product was directly purified by flash chromatography on silica gel column (eluent: petroleum ether/ethyl acetate
= 9/1) to afford the desired product 3aa (94% yield, 94% ee and >19:1 d.r.).
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀoxoacetate (3aa)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 31.4 mg, 94% yield, 94% ee; [α]21
=
D
ꢀ215.2 (c = 0.62 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 7.37 min, tR (major) = 7.74 min. 1H NMR (400 MHz, CDCl3) δ = 7.27 – 7.12 (m, 8H), 7.09 –
7.02 (m, 2H), 5.62 – 5.49 (m, 1H), 4.23 (dd, J = 11.2, 6.0 Hz, 1H), 4.15 – 4.06 (m, 1H), 3.68 (s, 3H), 3.36 (td, J = 10.6, 6.0 Hz,
1H), 2.46 (dd, J = 18.0, 6.0 Hz, 1H), 2.28 – 2.15 (m, 1H), 1.83 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 194.1, 161.3,
144.6, 140.1, 134.9, 129.5, 128.6, 128.4, 127.5, 127.4, 126.5, 122.1, 52.9, 52.5, 43.7, 38.9, 37.0, 23.4. HRMS (ESIꢀTOF) calcd
for C22H22O3Na+ ([M+Na+]) = 357.1461, Found 357.1466.
Ethyl 2ꢀ((1'R,2'S,3'R)ꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀoxoacetate （3ba）
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 33.4 mg, 96% yield, 99% ee; [α]21
=
D
ꢀ181.1 (c = 0.58 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 7.02 min, tR (major) = 7.66 min. 1H NMR (400 MHz, CDCl3) δ = 7.27 – 7.12 (m, 8H), 7.10 –
7.03 (m, 2H), 5.60 – 5.50 (m, 1H), 4.22 (dd, J = 11.2, 6.0 Hz, 1H), 4.18 – 4.04 (m, 3H), 3.36 (td, J = 10.6, 6.0 Hz, 1H), 2.46 (dd,
J = 18.0, 6.0 Hz, 1H), 2.21 (dd, J = 17.6, 9.6 Hz, 1H), 1.83 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
= 194.4, 160.9, 144.7, 140.2, 134.7, 129.5, 128.6, 128.4, 127.6, 127.3, 126.5, 122.2, 62.3, 52.4, 43.7, 38.9, 37.0, 23.4, 14.0.
HRMS (ESIꢀTOF) calcd for C23H24O3Na+ ([M+Na+]) = 371.1618, Found 371.1621.
Benzyl 2ꢀ((1'R,2'S,3'R)ꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀoxoacetate (3ca)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 40.1 mg, 99% yield, 88% ee; [α]21
=
D
ꢀ181.1 (c = 0.76 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 11.04 min, tR (major) = 11.56 min. 1H NMR (400 MHz, CDCl3) δ = 7.39 – 7.28 (m, 5H), 7.23
– 7.11 (m, 8H), 7.00 – 6.92 (m, 2H), 5.57 – 5.47 (m, 1H), 5.20 – 5.12 (m, 1H), 5.09 – 4.99 (m, 1H), 4.22 (dd, J = 11.2, 6.0 Hz,
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1H), 4.11 – 4.03 (m, 1H), 3.34 (td, J = 10.8, 6.0 Hz, 1H), 2.44 (dd, J = 18.0, 6.0 Hz, 1H), 2.19 (dd, J = 18.0, 10.4 Hz, 1H), 1.81 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 194.0, 160.6, 144.6, 140.1, 134.7, 129.4, 128.8, 128.7, 128.6, 128.4, 127.5, 127.3,
126.5, 122.1, 67.7, 52.5, 43.7, 38.9, 36.9, 23.4. HRMS (ESIꢀTOF) calcd for C28H26O3Na+ ([M+Na+]) = 433.1774, Found
433.1776.
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Methyl 2ꢀ((1'R,2'S,3'R)ꢀ3'',5'ꢀdimethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀoxoacetate
(3da)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 34.1 mg, 98% yield, 99% ee; [α]21
=
D
ꢀ201.9 (c = 0.59 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 6.64 min, tR (major) = 7.13 min. 1H NMR (400 MHz, CDCl3) δ = 7.28 – 7.19 (m, 3H), 7.13 –
7.04 (m, 3H), 7.01 – 6.91 (m, 3H), 5.61 – 5.49 (m, 1H), 4.23 (dd, J = 11.2, 6.0 Hz, 1H), 4.10 – 4.05(4.14, 1H), 3.69 (s, 3H), 3.36
– 3.28 (m, 1H), 2.45 (dd, J = 18.0, 6.0 Hz, 1H), 2.29 – 2.15 (m, 4H), 1.82 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 194.1,
161.3, 144.5, 140.2, 138.1, 134.8, 129.5, 128.6, 128.5, 128.4, 127.3, 124.3, 122.1, 52.9, 52.5, 43.8, 39.1, 36.9, 23.4, 21.5. HRMS
(ESIꢀTOF) calcd for C23H24O3Na+ ([M+Na+]) = 371.1618, Found 371.1620.
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ2''ꢀmethoxyꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3ea)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 23.3 mg, 64% yield, 99% ee; [α]21
=
D
ꢀ163.4 (c = 0.41 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), ,tR (minor) = 8.94 min, tR (major) = 10.67 min. 1H NMR (400 MHz, CDCl3) δ = 7.27 – 7.17 (m, 3H), 7.14
– 7.03 (m, 4H), 6.87 – 6.76 (m, 2H), 5.58 – 5.50 (m, 1H), 4.42 (dd, J = 10.4, 6.0 Hz, 1H), 4.10 – 4.03 (m, 1H), 3.78 (s, 3H), 3.73
– 3.64 (m, 4H), 2.49 – 2.42 (m, 1H), 2.21 (dd, J = 17.6, 9.6 Hz, 1H), 1.83 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 194.5,
161.5, 157.1, 140.4, 135.3, 132.4, 129.5, 128.3, 128.2, 127.4, 127.2, 122.1, 120.9, 111.1, 55.6, 52.7, 51.2, 43.7, 36.8, 23.4.
HRMS (ESIꢀTOF) calcd for C23H24O4Na+ ([M+Na+]) = 387.1567, Found 387.1570.
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ3''ꢀmethoxyꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3fa)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 32.4 mg, 90% yield, 97% ee; [α]21
=
D
ꢀ197.6 (c = 0.50 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =20/80,
1.0 mL/min, λ = 254 nm), tR (minor) = 6.09 min, tR (major) = 7.06 min. 1H NMR (400 MHz, CDCl3) δ = 7.24 (m, 3H), 7.13 (t, J
= 7.9 Hz, 1H), 7.09 – 7.03 (m, 2H), 6.76 (d, J = 7.6 Hz, 1H), 6.74 – 6.70 (m, 1H), 6.70 – 6.64 (m, 1H), 5.59 – 5.50 (m, 1H), 4.23
(dd, J = 11.2, 6.0 Hz, 1H), 4.14 – 4.05 (m, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.33 (td, J = 10.6, 6.0 Hz, 1H), 2.52 – 2.42 (m, 1H),
2.62 – 2.16 (m, 1H), 1.83 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 194.0, 161.3, 159.8, 146.3, 140.1, 134.8, 129.6, 129.5,
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128.4, 127.4, 122.1, 119.8, 113.4, 111.8, 55.2, 52.9, 52.4, 43.7, 38.9, 37.0, 23.4. HRMS (ESIꢀTOF) calcd for C23H24O4Na+
([M+Na+]) = 387.1567, Found 387.1574.
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Methyl 2ꢀ((1'R,2'S,3'R)ꢀ4''ꢀmethoxyꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3ga)
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Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 34.6 mg, 95% yield, 99% ee; [α]21
=
D
ꢀ198.0 (c = 0.51 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =20/80,
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1.0 mL/min, λ = 254 nm), tR (minor) = 6.41 min, tR (major) = 7.26 min. H NMR (400 MHz, CDCl3) δ = 7.28 – 7.17 (m, 3H),
7.13 – 7.02 (m, 4H), 6.81 – 6.71(m, 2H), 5.61 – 5.48 (m, 1H), 4.17 (dd, J = 11.2, 6.0 Hz, 1H), 4.11 – 4.03 (m, 1H), 3.73 (s, 3H),
3.68 (s, 3H), 3.31 (td, J = 10.6, 6.0 Hz, 1H), 2.44 (dd, J = 18.2, 6.0 Hz, 1H), 2.19 (dd, J = 18.4, 10.4 Hz, 1H), 1.83 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ = 194.3, 161.3, 158.1, 140.2, 136.6, 134.9, 129.5, 128.5, 128.4, 127.3, 122.1, 114.0, 55.3,
52.9, 43.8, 39.0, 36.1, 23.4. HRMS (ESIꢀTOF) calcd for C23H24O4Na+ ([M+Na+]) = 387.1567, Found 387.1564.
Methyl 2ꢀ((1R,2S,3R)ꢀ3ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ5ꢀmethylꢀ1,2,3,4ꢀtetrahydroꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ
2ꢀoxoacetate (3ha)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 36.7 mg, 97% yield, 99% ee; [α]21
=
D
ꢀ176.7 (c = 0.63 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =20/80,
1.0 mL/min, λ = 254 nm), tR (minor) = 7.44 min, tR (major) = 8.53 min. 1H NMR (400 MHz, CDCl3) δ = 7.26 (m, 2H), 7.21 (m,
1H), 7.09 – 7.00 (m, 2H), 6.72 – 6.59 (m, 3H), 5.87 (s, 2H), 5.59 – 5.48 (m, 1H), 4.15 (dd, J = 11.2, 6.0 Hz, 1H), 5.59 – 5.48 (m,
1H), 3.71 (s, 3H), 3.27 (td, J = 10.6, 6.0 Hz, 1H), 2.44 (dd, J = 18.2, 6.0 Hz, 1H), 2.17 (dd, J = 18.4, 10.4 Hz, 1H), 1.82 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ = 194.1, 161.2, 147.7, 146.0, 140.1, 138.5, 134.7, 129.5, 128.4, 127.4, 122.1, 120.6, 108.4,
107.9, 100.9, 52.9, 52.8, 43.8, 39.1, 36.7, 23.3. HRMS (ESIꢀTOF) calcd for C23H22O5Na+ ([M+Na+]) = 401.1359, Found
401.1369.
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1'':4'',1'''ꢀquaterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3ia)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford white solid; m.p. 48ꢀ52 oC; 40.6 mg, 99% yield, 98%
ee; [α]21 = ꢀ193.9 (c = 0.62 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/
D
nꢀhexane =5/95, 1.0 mL/min, λ = 254 nm), tR (minor) = 11.03 min, tR (major) = 12.67 min. 1H NMR (400 MHz, CDCl3) δ = 7.56
– 7.50 (m, 2H), 7.47 – 7.43 (m, 2H), 7.42 – 7.37 (m, 2H), 7.32 – 7.21 (m, 6H), 7.11 – 7.01 (m, 2H), 5.63 – 5.49 (m, 1H), 4.28 (dd,
J = 11.2, 6.0 Hz, 1H), 4.18 – 4.09 (m, 1H), 3.70 (s, 3H), 3.40 (td, J = 10.4, 6.0 Hz, 1H), 2.50 (dd, J = 18.2, 6.0 Hz, 1H), 2.25 (dd,
J = 18.4, 10.4 Hz, 1H), 1.84 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 194.1, 161.2, 143.7, 141.0, 140.1, 139.4, 134.8,
129.5, 128.8, 128.4, 128.0, 127.4, 127.2, 127.1, 122.1, 52.9, 52.5, 43.8, 38.9, 36.6, 23.4. HRMS (ESIꢀTOF) calcd for
C28H26O3Na+ ([M+Na+]) = 433.1774, Found 433.1778.
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Methyl 2ꢀ((1'R,2'S,3'R)ꢀ2''ꢀfluoroꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3ja)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 34.8 mg, 80% yield, 99% ee; [α]21
=
8
D
9
ꢀ179.8 (c = 0.50 in CH2Cl2); the ee was determined by UPC2 Phenomenex analysis using a chiral OJH column (methanol/ CO2
=10/90, 1.0 mL/min, λ = 254 nm) tR (minor) = 5.92 min, tR (major) = 7.17 min. 1H NMR (400 MHz, CDCl3) δ = 7.29 – 7.19 (m,
3H), 7.15 – 7.03 (m, 4H), 7.02 – 6.90 (m, 2H), 5.62 – 5.47 (m, 1H), 4.34 (dd, J = 11.2, 6.0 Hz, 1H), 4.21 – 4.11 (m, 1H), 3.72 (s,
3H), 3.65 (td, J = 10.8, 6.0 Hz, 1H), 2.47 (dd, J = 18.0, 6.0 Hz, 1H), 2.24 (dd, J = 18.0, 10.4 Hz, 1H), 1.83 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ = 193.9, 161.2, 160.8 (d, J = 246.1), 139.9, 134.7, 131.1 (d, J = 13.9), 129.4, 128.8 (d, J = 4.9), 128.5,
128.0 (d, J = 8.5), 127.5, 124.4 (d, J = 3.3), 122.2, 115.8 (d, J = 22.8), 52.9, 51.4, 43.8, 37.3, 31.1, 23.3. 19F NMR (376 MHz,
CDCl3) δ = ꢀ117.86. HRMS (ESIꢀTOF) calcd for C22H21FO3Na+ ([M+Na+]) = 375.1367, Found 375.1365.
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Methyl 2ꢀ((1'R,2'S,3'R)ꢀ4''ꢀfluoroꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3ka)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 28.5 mg, 81% yield, 99% ee; [α]21
=
D
ꢀ186.0 (c = 0.48 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 6.85 min, tR (major) = 7.43 min. 1H NMR (400 MHz, CDCl3) δ = 7.28 – 7.24 (m, 2H), 7.22
(m, 1H), 7.13 (m, 2H), 7.07 – 7.01 (m, 2H), 6.90 (m, 2H), 5.59 – 5.51 (m, 1H), 4.19 (dd, J = 11.2, 6.0 Hz, 1H), 4.14 – 4.07 (m,
1H), 3.71 (s, 3H), 3.38 – 3.30 (m, 1H), 2.44 (dd, J = 18.0, 6.0 Hz, 1H), 2.24 – 2.13 (m, 1H), 1.83 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ = 194.0, 161.5 (d, J = 245.2), 161.2, 140.2 (d, J = 3.1), 140.0, 134.7, 129.5, 129.0 (d, J = 7.9), 128.5, 127.4,
122.2, 115.4 (d, J = 21.2), 53.0, 52.7, 43.8, 39.0, 36.3, 23.4. 19F NMR (376 MHz, CDCl3) δ = ꢀ116.73. HRMS (ESIꢀTOF) calcd
for C22H21FO3Na+ ([M+Na+]) = 375.1367, Found 375.1367.
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ3''ꢀchloroꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3la)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 34.2 mg, 93% yield, 99% ee; [α]21
=
D
ꢀ194.8 (c = 0.50 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 7.00 min, tR (major) = 7.23 min. 1H NMR (400 MHz, CDCl3) δ = 7.29 – 7.21 (m, 3H), 7.18 –
7.16 (m, 1H), 7.15 – 7.08 (m, 2H), 7.08 – 7.01 (m, 3H), 5.59 – 5.51 (m, 1H), 4.21 (dd, J = 11.2, 6.0 Hz, 1H), 4.17 – 4.09 (m, 1H),
3.73 (s, 3H), 3.62 – 3.29 (m, 1H), 2.45 (dd, J = 18.0, 6.0 Hz, 1H), 2.19 (dd, J = 18.0, 10.4 Hz, 1H), 1.83 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ = 193.8, 161.2, 146.8, 139.8, 134.5, 134.4, 129.9, 129.4, 128.5, 127.8, 127.5, 126.8, 125.7, 122.2, 53.0, 52.4,
43.7, 38.8, 36.8, 23.3. HRMS (ESIꢀTOF) calcd for C22H2135ClO3Na+ ([M+Na+]) = 391.1071, Found 391.1074. HRMS (ESIꢀTOF)
calcd for C22H2137ClO3Na+ ([M+Na+]) = 393.1042, Found 393.1065.
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Methyl 2ꢀ((1'R,2'S,3'R)ꢀ2'',6''ꢀdichloroꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3ma)
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Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 37.5 mg, 93% yield, 99% ee; [α]21
=
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ꢀ111.4 (c = 0.68 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 6.79 min, tR (major) = 7.00 min. 1H NMR (400 MHz, CDCl3) δ = 7.29 –7.19 (m, 4H), 7.13 –
7.03 (m, 3H), 6.97 (t, J = 8.0 Hz, 1H), 5.64 – 5.52 (m, 1H), 5.09 (dd, J = 11.6, 5.2 Hz, 1H), 4.42 – 4.26 (m, 2H), 3.83 (s, 3H),
2.72 – 2.56 (m, 1H), 2.24 (dd, J = 17.6, 5.6 Hz, 1H), 1.85 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 193.0, 160.9, 139.4,
137.9, 137.4, 134.9, 133.5, 129.9, 129.5, 128.7, 128.4, 127.9, 127.5, 122.6, 53.0, 51.1, 44.7, 34.1, 33.6, 23.3. HRMS (ESIꢀTOF)
calcd for C22H2035Cl2O3Na+ ([M+Na+]) = 425.0682, Found 425.0690. HRMS (ESIꢀTOF) calcd for C22H2035Cl37ClO3Na+ ([M+Na+])
= 427.0652, Found 427.0669.
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Methyl 2ꢀ((1'R,2'S,3'R)ꢀ4''ꢀbromoꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3na)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford white solid; m.p. 38ꢀ42 oC; 39.2 mg, 95% yield, 99%
ee; [α]21 = ꢀ181.5 (c = 0.69 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/
D
nꢀhexane =5/95, 1.0 mL/min, λ = 254 nm) tR (minor) = 7.17 min, tR (major) = 7.90 min. 1H NMR (400 MHz, CDCl3) δ = 7.38 –
7.31 (m, 2H), 7.24 (m, 3H), 7.11 – 7.00 (m, 4H), 5.63 – 5.47 (m, 1H), 4.19 (dd, J = 11.2, 6.0 Hz, 1H), 4.16 – 4.06 (m, 1H), 3.71
(s, 1H), 3.35 – 3.27 (m, 1H), 2.43 (dd, J = 18.0, 6.0 Hz, 1H), 2.23 – 2.11 (m, 1H), 1.83 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ = 193.9, 161.2, 143.7, 139.9, 134.5, 131.7, 129.4, 128.5, 127.5, 122.2, 120.2, 53.0, 52.5, 43.7, 38.8, 36.5, 23.3. HRMS
(ESIꢀTOF) calcd for C22H2179BrO3Na+ ([M+Na+]) = 435.0566, Found 435.0575. HRMS (ESIꢀTOF) calcd for C22H2181BrO3Na+
([M+Na+]) = 437.0546, Found 437.0562.
Methyl 2ꢀ((1R,2S,3R)ꢀ5ꢀmethylꢀ3ꢀ(naphthalenꢀ2ꢀyl)ꢀ1,2,3,4ꢀtetrahydroꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ2ꢀ
oxoacetate (3oa)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford white solid; m.p. 44ꢀ46 oC; 30.0 mg, 78% yield, 99%
ee; [α]21 = ꢀ176.7 (c = 0.58 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/
D
nꢀhexane =10/90, 1.0 mL/min, λ = 254 nm), tR (minor) = 6.84 min, tR (major) = 8.02 min. 1H NMR (400 MHz, CDCl3) δ = 7.79 –
7.69 (m, 3H), 7.62 (s, 1H), 7.44 – 7.37 (m, 2H), 7.33 (dd, J = 8.4, 1.6 Hz, 1H), 7.30 – 7.20 (m, 3H), 7.13 – 7.05 (m, 2H), 5.64 –
5.52 (m, 1H), 4.36 (dd, J = 11.2, 6.0 Hz, 1H), 4.20 – 4.08 (m, 1H), 3.65 (s, 3H), 3.53 (td, J = 10.4, 6.0 Hz, 1H), 2.53 (dd, J = 18.0,
6.0 Hz, 1H), 2.32 (dd, J = 17.2, 9.6 Hz, 1H), 1.85 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 194.0, 161.2, 142.0, 140.1,
134.8, 133.6, 132.4, 129.5, 128.5, 128.3, 127.8, 127.7, 127.4, 126.2, 126.1, 126.0, 125.5, 122.2, 52.9, 52.6, 43.8, 38.9, 37.1, 23.4.
HRMS (ESIꢀTOF) calcd for C26H24O3Na+ ([M+Na+]) = 407.1618, Found 407.1624.
Methyl 2ꢀ((1R,2S,3S)ꢀ5ꢀmethylꢀ3ꢀ((E)ꢀstyryl)ꢀ1,2,3,4ꢀtetrahydroꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ2ꢀ
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oxoacetate (3pa)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 35.3 mg, 98% yield, 98% ee; [α]21
=
D
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ꢀ247.1 (c = 0.61 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 8.15 min, tR (major) = 8.92 min. 1H NMR (400 MHz, CDCl3) δ = 7.30 – 7.15 (m, 8H), 7.09 –
7.00 (m, 2H), 6.43 (d, J = 15.9 Hz, 1H), 6.01 (dd, J = 16.0, 8.0 Hz, 1H), 5.57 – 5.44 (m, 1H), 4.10 – 4.00 (m, 1H), 3.83 (dd, J =
10.4, 6.4 Hz, 1H), 3.71 (s, 3H), 3.09 – 2.95 (m, 1H), 2.38 (dd, J = 17.6, 5.6 Hz, 1H), 2.09 (dd, J = 17.2, 9.6 Hz, 1H), 1.83 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ = 194.3, 161.4, 140.3, 137.3, 134.0, 131.9, 131.3, 129.4, 128.6, 128.4, 127.3, 126.2, 122.0,
52.9, 52.3, 43.2, 35.5, 34.1, 23.6. HRMS (ESIꢀTOF) calcd for C24H24O3Na+ ([M+Na+]) = 383.1618, Found 383.1627.
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Methyl 2ꢀ((1R,2S,3S)ꢀ5ꢀmethylꢀ3ꢀ(thiophenꢀ3ꢀyl)ꢀ1,2,3,4ꢀtetrahydroꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ2ꢀoxoacetate
(3qa)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 32.0 mg, 94% yield, 97% ee; [α]21
=
D
ꢀ237.1 (c = 0.46 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 8.74 min, tR (major) = 9.32 min. 1H NMR (400 MHz, CDCl3) δ = 7.28 – 7.23 (m, 2H), 7.23 –
7.16 (m, 2H), 7.08 – 7.02 (m, 2H), 6.99 – 6.90 (m, 2H), 5.58 – 5.48 (m, 1H), 4.12 (dd, J = 10.8, 6.0 Hz, 1H), 4.08 – 3.99 (m, 1H),
3.68 (s, 3H), 3.53 (td, J = 10.0, 6.0 Hz, 1H), 2.50 (dd, J = 18.0, 6.0 Hz, 1H), 2.22 (dd, J = 18.0, 10.0 Hz, 1H), 1.83 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ = 194.2, 161.3, 145.2, 140.2, 134.5, 129.5, 128.4, 127.3, 127.0, 125.7, 122.0, 120.8, 53.0,
43.6, 38.1, 32.5, 23.4. HRMS (ESIꢀTOF) calcd for C20H20SO3Na+ ([M+Na+]) = 363.1025, Found 363.1024.
Methyl 2ꢀ(3ꢀcyclohexylꢀ5ꢀmethylꢀ1,2,3,4ꢀtetrahydroꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ2ꢀoxoacetate (3ra)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 32.0 mg, 94% yield, 99% ee; [α]21
=
D
ꢀ214.9 (c = 0.45 in CH2Cl2).; the ee was determined by UPC2 Phenomenex analysis using a chiral OJH column (methanol/ CO2
=10/90, 1.0 mL/min, λ = 254 nm), tR (major) = 4.41 min, tR (minor) = 5.42 min. 1H NMR (400 MHz, CDCl3) δ = 7.28 – 7.16 (m,
3H), 7.11 – 6.91 (m, 2H), 5.58 – 5.40 (m, 1H), 3.95 – 3.85 (m, 2H), 3.80 (s, 3H), 2.16 – 2.05 (m, 2H), 1.94 (dd, J = 18.8, 11.2 Hz,
1H), 1.80 (s, 3H), 1.75 – 1.66 (m, 2H), 1.66 – 1.57 (m, 2H), 1.48 – 1.35 (m, 2H), 1.22 – 0.97 (m, 5H). 13C{1H} NMR (101 MHz,
CDCl3) δ = 194.9, 161.9, 140.4, 134.9, 129.6, 128.2, 127.1, 121.7, 53.0, 49.7, 43.2, 37.5, 34.9, 31.4, 29.6, 27.0, 26.9, 26.8, 26.5,
23.8. HRMS (ESIꢀTOF) calcd for C22H28O3Na+ ([M+Na+]) = 363.1931, Found 363.1931.
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ2ꢀchloroꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3ab)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 32.1 mg, 87% yield, 99% ee; [α]21
=
D
ꢀ115.1 (c = 0.61 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 7.91 min, tR (major) = 8.74 min. 1H NMR (400 MHz, CDCl3) δ = 7.37 – 7.34 (m, 1H), 7.27 –
7.12 (m, 8H), 5.53 – 5.43 (m, 1H), 4.57 (dd, J = 10.8, 5.6 Hz, 1H), 4.46 – 4.36 (m, 1H), 3.69 (s, 3H), 3.29 (td, J = 10.2, 6.0 Hz,
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1H), 2.49 (dd, J = 18.2, 6.0 Hz, 1H), 2.32 – 2.21 (m, 1H), 1.85 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 193.2, 160.9,
143.9, 137.5, 135.5, 134.4, 131.7, 129.5, 128.7, 128.5, 127.6, 126.7, 121.6, 53.0, 50.0, 39.3, 38.5, 37.9, 23.4. HRMS (ESIꢀTOF)
calcd for C22H2135ClO3Na+ ([M+Na+]) = 391.1071, Found 391.1070. HRMS (ESIꢀTOF) calcd for C22H2137ClO3Na+ ([M+Na+]) =
393.1042, Found 393.1050.
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Methyl 2ꢀ((1'R,2'S,3'R)ꢀ3ꢀfluoroꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3ac)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 31.7 mg, 90% yield, 98% ee; [α]21
=
D
ꢀ221.9 (c = 0.60 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 6.93 min, tR (major) = 7.54 min. 1H NMR (400 MHz, CDCl3) δ = 7.25 – 7.12 (m, 6H), 6.93 –
6.86 (m, 1H), 6.85 – 6.75 (m, 2H), 5.58 – 5.45 (m, 1H), 4.22 (dd, J = 11.2, 6.0 Hz, 1H), 4.14 – 4.06 (m, 1H), 3.70 (s, 3H), 3.32
(td, J = 10.8, 6.0 Hz, 1H), 2.46 (dd, J = 18.2, 6.0 Hz, 1H), 2.28 – 2.17 (m, 1H), 1.83 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ = 193.9, 162.8 (d, J = 246.9), 161.3, 144.3, 142.9 (d, J = 6.7), 135.4, 129.8 (d, J = 8.4), 128.7, 127.5, 126.6, 125.2 (d, J = 2.8),
121.5, 116.5 (d, J = 21.6), 114.3 (d, J = 21.2), 53.0, 52.4, 43.4, 38.8, 36.9, 23.3. 19F NMR (376 MHz, CDCl3) δ = ꢀ112.86. HRMS
(ESIꢀTOF) calcd for C22H21FO3Na+ ([M+Na+]) = 375.1367, Found 375.1366.
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ4ꢀfluoroꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3ad)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford white solid; m.p. 86ꢀ90 oC; 34.5 mg, 98% yield, 91%
ee; [α]21 = ꢀ182.6 (c = 0.62 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/
D
nꢀhexane =5/95, 1.0 mL/min, λ = 254 nm), tR (minor) = 6.99 min, tR (major) = 7.46 min. 1H NMR (400 MHz, CDCl3) δ = 7.25 –
7.20 (m, 2H), 7.16 (m, 3H), 7.03 (m, 2H), 6.94 (m, 2H), 5.58 – 5.46 (m, 1H), 4.21 (dd, J = 11.2, 6.0 Hz, 1H), 4.12 – 4.04 (m, 1H),
3.70 (m, 3H), 3.34 – 3.26 (m, 1H), 2.45 (dd, J = 18.0, 6.0 Hz, 1H), 2.27 – 2.15 (m, 1H), 1.83 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ = 194.2, 162.1 (d, J = 246.7), 161.3, 144.3, 135.8 (d, J = 3.2), 135.0, 131.0 (d, J = 8.1), 128.7, 127.5, 126.6, 122.0,
115.2 (d, J = 21.4), 52.9, 52.5, 43.0, 38.9, 37.0, 23.3. 19F NMR (376 MHz, CDCl3) δ = ꢀ115.53. HRMS (ESIꢀTOF) calcd for
C22H21FO3Na+ ([M+Na+]) = 375.1367, Found 375.1363.
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ3ꢀmethoxyꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3ae)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 33.1 mg, 91% yield, 99% ee; [α]21
=
D
ꢀ230.0 (c = 0.56 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 9.65 min, tR (major) = 12.16 min. 1H NMR (400 MHz, CDCl3) δ = 7.25 – 7.10 (m, 6H), 6.77 –
6.70 (m, 1H), 6.67 – 6.58 (m, 2H), 5.59 – 5.48 (m, 1H), 4.22 (dd, J = 11.2, 6.0 Hz, 1H), 4.12 – 4.05 (m, 1H), 3.76 (s, 3H), 3.70 (s,
3H), 3.36 (td, J = 10.8, 6.0 Hz, 1H), 2.45 (dd, J = 18.4, 6.0 Hz, 1H), 2.20 (dd, J = 18.0, 10.4 Hz, 1H), 1.82 (s, 3H). 13C{1H}
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NMR (101 MHz, CDCl3) δ = 193.9, 161.3, 159.5, 144.6, 141.8, 134.8, 129.4, 128.6, 127.5, 126.5, 122.0, 121.9, 115.8, 112.1,
55.2, 52.8, 52.4, 43.7, 38.9, 37.0, 23.4. HRMS (ESIꢀTOF) calcd for C23H24O4Na+ ([M+Na+]) = 387.1567, Found 387.1568.
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oxoacetate (3af)
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Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford colorless oil; 34.2 mg, 94% yield, 97% ee; [α]21
=
D
ꢀ235.9 (c = 0.57 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 6.63 min, tR (major) = 7.25 min. 1H NMR (400 MHz, CDCl3) δ = 7.25 – 7.10 (m, 5H), 7.01 –
6.93 (m, 2H), 6.84 – 6.73 (m, 2H), 5.62 – 5.44 (m, 1H), 4.22 (dd, J = 11.2, 6.0 Hz, 1H), 4.12 – 4.04 (m, 1H), 3.76 (s, 3H), 3.71 (s,
3H), 3.33 (td, J = 10.8, 6.0 Hz, 1H), 2.44 (dd, J = 18.0, 6.0 Hz, 1H), 2.20 (dd, J = 18.0, 10.4 Hz, 1H), 1.82 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ = 194.2, 161.3, 158.8, 144.7, 134.4, 132.0, 130.5, 128.6, 127.5, 126.5, 122.5, 113.8, 55.3, 52.9, 52.6,
43.0, 39.1, 36.9, 23.3. HRMS (ESIꢀTOF) calcd for C23H24O4Na+ ([M+Na+]) = 387.1567, Found 387.1566.
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ5'ꢀethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀoxoacetate (3ag)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford olorless oil; 34.5 mg, 99% yield, 94% ee; [α]21
=
D
ꢀ174.0 (c = 0.39 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =5/95, 1.0
mL/min, λ = 254 nm), tR (minor) = 11.27 min, tR (major) = 8.10 min. 1H NMR (400 MHz, CDCl3) δ = 7.26 – 7.11 (m, 8H), 7.09
– 7.02 (m, 2H), 5.63 – 5.48 (m, 1H), 4.25 (dd, J = 11.2, 6.0 Hz, 1H), 4.17 – 4.09 (m, 1H), 3.69 (s, 3H), 3.38 – 3.29 (m, 1H), 2.48
(dd, J = 18.0, 6.0 Hz, 1H), 2.23 (dd, J = 18.0, 10.4 Hz, 1H), 2.17 – 2.08 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ = 194.2, 161.3, 158.8, 144.7, 134.4, 132.0, 130.5, 128.6, 127.5, 126.5, 122.5, 113.8, 55.3, 52.9, 52.6, 43.0, 39.1,
36.9, 23.3. HRMS (ESIꢀTOF) calcd for C23H24O3Na+ ([M+Na+]) = 371.1618, Found 371.1621.
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ4ꢀmethoxyꢀ3'',5'ꢀdimethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ2ꢀ
oxoacetate (3aj)
Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford olorless oil; 35.4 mg, 94% yield, 94% ee; [α]25
=
D
ꢀ209.3 (c = 0.52 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =20/80,
1.0 mL/min, λ = 254 nm), tR (minor) = 5.95 min, tR (major) = 6.59 min. 1H NMR (400 MHz, CDCl3) δ = 7.08 – 6.94 (m, 6H),
6.81– 6.78 (m, 2H), 5.54 – 5.50 (m, 1H), 4.18 (dd, J = 11.2, 5.6 Hz, 1H), 4.10 – 4.03 (m, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.34 –
3.25 (m, 1H), 2.46 – 2.35 (m, 1H), 2.25 (s, 3H), 2.12 –2.13 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ = 194.2, 161.3, 158.8,
141.6, 135.9, 134.5, 132.1, 130.5, 129.3, 127.4, 122.5, 113.8, 55.3, 52.8, 43.0, 39.2, 36.5, 23.3, 21.1. HRMS (ESIꢀTOF) calcd for
C24H26O4Na+ ([M+Na+]) = 401.1723, Found 401.1715.
Methyl 2ꢀ((1'R,2'S,3'R)ꢀ4''ꢀbromoꢀ4ꢀmethoxyꢀ5'ꢀmethylꢀ1',2',3',4'ꢀtetrahydroꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)
ꢀ2ꢀoxoacetate (3ak)
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Purified by flash chromatography (petroleum ether: EtOAc = 9:1) to afford olorless oil; 42.7 mg, 97% yield, 94% ee; [α]21
=
D
ꢀ189.2 (c = 0.65 in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2ꢀpropanol/ nꢀhexane =20/80,
1.0 mL/min, λ = 254 nm), tR (minor) = 6.15 min, tR (major) = 6.86 min. 1H NMR (400 MHz, CDCl3) δ = 7.37 – 7.30 (m, 2H),
7.09 – 7.03 (m, 2H), 7.00 – 6.92 (m, 2H), 6.83 – 6.74 (m, 2H), 5.57 – 5.48 (m, 1H), 4.18 (dd, J = 11.2, 5.6 Hz, 1H), 4.13 – 4.06
(m, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.34 – 3.23 (m, 1H), 2.47 – 2.37 (m, 1H), 2.20 – 2.11 (m, 1H), 1.82 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ = 193.9, 161.2, 158.9, 143.7, 134.2, 131.8, 131.7, 130.4, 129.4, 122.6, 120.2, 113.8, 55.3, 53.0, 52.6, 42.9,
38.9, 36.5, 23.3. HRMS (ESIꢀTOF) calcd for C23H2379BrO4Na+ ([M+Na+]) = 465.0672, Found 465.0678. C23H2381BrO4Na+
([M+Na+]) = 467.0651, Found 467.0659.
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Supporting Information
ESIꢀMS analysis, operando IR experiments, Xꢀray crystallography data for compound 3ad and compound [LꢀPiPr3 + Zn2+ + H2O
+ Pyridine]2+, full optimization details, 1H and 13C NMR spectra, HPLC and CD spectra are available. This material is available
free of charge via the Internet at http://pubs.acs.org
ACKNOWLEDGMENTS
We appreciate the National Natural Science Foundation of China (Nos. 21572136 and 21432006) for financial support.
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(10) See the ESI of 1H NMR spectra of DA and HDA product and HPLC.
(11) CCDC 1581047 (3ad) contains the supplementary crystallographic data for this paper. These data are provided free of
charge by The Cambridge Crystallographic Data Centre.
(12) CCDC 1839343 ([LꢀPiPr3 + Zn2+ + H2O + Pyridine]2+) contains the supplementary crystallographic data for this paper.
These data are provided free of charge by The Cambridge Crystallographic Data Centre.
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