Artigo Enol Oxidação

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N-Heterocyclic Carbene/Lewis Acid Catalyzed
Enantioselective Aerobic Annulation of alpha,beta-
Unsaturated Aldehydes with 1,3-Dicarbonyl Compounds
Danbo Xie, Dan Shen, Qiliang Chen, Jiaqi Zhou, Xiaofei Zeng, and Guofu Zhong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01152 • Publication Date (Web): 23 Jun 2016
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Page 1 of 15 The Journal of Organic Chemistry
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4 N-Heterocyclic Carbene/Lewis Acid Catalyzed
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Enantioselective Aerobic Annulation of α,β-Unsaturated
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11 Aldehydes with 1,3-Dicarbonyl Compounds
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14 Danbo Xie, Dan Shen, Qiliang Chen, Jiaqi Zhou, Xiaofei Zeng,* and Guofu Zhong*
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17 College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou
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19 310036, China.
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22 E-mail: [email protected] ; [email protected]
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35 Abstract: A novel and efficient aerobic asymmetric cyclization reaction of cinnamaldehydes and
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37 1,3-dicarbonyl compounds through oxidative NHC-catalysis has been developed, and allows the
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synthesis of a wide range of enantiomeric enriched dihydropyranone derivatives in good yields
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42 with good to excellent enantioselectivities. Various α,β-unsaturated aldehydes with aliphatic and
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44 aromatic substitution groups and 1,3-dicarbonyl compounds were well tolerated. The air was
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directly used as the oxidant, which make this asymmetric cyclization reaction in highly efficient,
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49 cheap and green manner.
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52 Over the past two decades, N-Heterocyclic carbene (NHC) catalysis has emerged as a
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54 powerful and useful methodology in organic synthesis by providing an assortment of new
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56 scaffolds as well as enantiomerically enriched compounds.1 In this synthetic strategy, aldehydes
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and their derivatives are activated by NHCs a through the formation of acyl anion equivalent b
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60 1
ACS Paragon Plus Environment
The Journal of Organic Chemistry Page 2 of 15
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and b’ (so called Breslow intermediate2), which can react as enolate or homoenolate with various
4
5 electrophiles to undergo the nucleophilic addition process (Scheme 1). With this unique
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7 chemistry termed umpolung, dozens of reactivity manifolds have been developed across a range
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9 of reaction subtypes for the formation of C-C, C-N and C-O bonds and corresponding
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compounds with significantly importance.
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13 While the activation modes of NHC catalysis have been well established, chemists realized that
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15 the Breslow intermediate could be readily oxidized by mild inorganic and organic oxidants to
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17 acylazolium ion species c and c’, which could undergo subsequent esterification reaction through
18 O acylation with different O nucleophiles.3 Moreover, the oxidative generated α,β-unsaturated
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20 acylazolium intermediate c could serve as unique and efficient Michael acceptors. which has
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22 been succefully employed in the 1,4-addition by reacting with soft carbon nucleophiles. In this
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24 strategy the intermediate c is typically generated from the nucleophilic addition of NHC with
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α,β-unsaturated acyl fluoride,4 esters,5 acids6 or anhydrides7, the internal redox reaction
27 generated ynals8, or enals in the presence of the high cost 3,3',5,5'-tetra-tert-
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29 butyldiphenoquinone9 (DPQ, $125/50mg from Sigmaaldrich Pte. Ltd.) as external oxidant. which
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31 is greatly limited the large scale synthesis.
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33 Scheme 1. Activation of carbonyl compounds through enolate/homoenolate and oxidative
34 acylazolium salt intermediates in NHC catalysis
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36 O O OH
OH
37 N
N R H R H R N
38 R
N N umplong N N umplong N N
39
40 b' a b
41 [O] [O]
42
43 O
O O
44 1 N
45 R
N R 1 OH R OR R
O
46 Michael N N
N N R 2 NH 2
R NHR1 acceptor
47 c' c
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49 The incorporation of atmosphere molecular oxygen (O2) into an organic oxidation
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51 reaction offers one of the most ideal processes in organic synthesis.10 The activation of O2
52 by NHC catalysts was succeeded by several research groups in NHC-catalyzed oxidation
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54 of aldehydes, the corresponding carboxylic acids11 and esters12 could be obtained in
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56 moderate to good yields. In these approaches, the Breslow intermediates generated from
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58 aldehydes and NHC catalyst could be oxidized to acylazolium ions by O2, which can
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60 2
1
2
3
undergo the next O-acylation reactions. We therefore envisioned that this chemistry could
4
5 be more attractive if O2 could be directly used as oxidant in NHC-catalyzed
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7 enantioselective reactions. However, to the best of our knowledge, there is no successful
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9 example concerning an NHC-catalyzed asymmetric reaction with O2 as oxidant. Given
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the fact that, 3,4-dihydro-α-pyranones are important intermediate for the construction of
12 pyridones, γ-lactones, benzenoid derivatives etc.,13 some successful examples in the
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14 synthesis of 3,4-dihydro-α-pyranones were reported by several groups.14 To make the
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16 synthesis of this kind of compounds in a more efficient and green manner, we decided to
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18 contribute a catalytically asymmetric synthesis of 3,4-dihydro-α-pyranones through a
19 chiral NHC-catalyzed reaction of cinnamaldehyde with 1,3-dicarbonyl compounds by
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21 using air as the oxidant.
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25 Table 1. Reaction condition optimizationa
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35 entry NHC base solvent additives yield (%)b ee (%)c
36 1 A DABCO THF — 80 60
37 2 A DABCO THF LiCld 79 87
38 3 A DABCO THF LiCle 80 89
39 4 A DABCO THF LiClf 82 94
40 5 A DABCO THF LiClg 81 91
41 6 B DABCO THF LiCl f 65 77
42 7 C DABCO THF LiCl f 75 85
43 8 D DABCO THF LiCl f 82 62
44 9 A DABCO THF LiOTf 70 80
45 10 A DABCO THF LiBF3 78 85
46 11 A DABCO THF Sc(OTf)3 N.R. —
47 12 A K2CO3 THF LiCl f 65 83
48 13 A Cs2CO3 THF LiCl f 78 89
49 14 A DMAP THF LiCl f 65 89
50 15 A DABCO Tol LiCl f 80 92
51 16 A DABCO DCM LiCl f 27 91
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60 3
1
2
3
a
4 General conditions: 1a (0.2 mmol), 2a (0.1 mmol), A (0.02 mmol), solvent
5 (1 mL), 14h. b Yields of isolated products based on 2a. c Enantiomeric excess
6 of 3a, determined by HPLC on a chiral stationary phase; absolute
7 configuration of the major enantiomer was assigned based on optical rotation
8 of 3a (see the Supporting Information). d 0.1 mmol LiCl. e LiCl (0.1 mmol)
9 and 3Å M.S. powder (20 mg). f LiCl (0.1 mmol) and 4Å M.S. powder (20
10 mg). g LiCl (0.1 mmol) and 5Å M.S. powder (20 mg).
11
12
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14 As a starting point, we examined the reaction of cinnamaldehyde (1a, 2.0 equiv.) with
15 acetylacetone (2a, 1.0 equiv.) in the presence of NHC catalyst A (20 mol%) and DABCO (1.5
16
17 equiv.) in THF under air without any external oxidant. To our delight, the reaction proceeded
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19 well and the desired dihydropyranone 3a was obtained with 80% yield and 60% ee, the cinnamic
20
21 acid 4a was found to be the side product. Next, we started to optimize the reaction conditions. It
22
23
was reported that Lewis acids can be good cooperative catalyst in NHC catalysis due to the
24 complexation of the O-atom of the acylazolium ion with the metal cation, which should lower
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26 the LUMO hence activate the Michael acceptor.15 Therefore, a series of Lewis acids were tested
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28 in this reaction, and LiCl was found to be the best, the ee value of 3a could be improved to 87%.
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30 (Table 1, entries 2, 9-11; LiBr, Mg(OTf)2, MgI2 et. al. see the Supporting Information) A slight
31 increase of the ee value was achieved when molecular sieves (M.S.) were used, and 4Å M.S.
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33 exhibited most superiority (3a: 82% yield and 94% ee). (Table 1, entries 3-5) Catalyst A remains
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35 the best catalyst among several catalysts that were studied under this condition. (Table 1, entries
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37 5-8) After further screening of bases and solvents in the reaction, (Table 1, entries 12-16) the
38
best results could be achieved in the presence of catalyst A (20 mmol%), LiCl (1.0 equiv.) and
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40 4Å M.S. (20 mg) in THF under air at r.t..
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42 With the optimal reaction conditions in hand, we started to explore the substrate scope through
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44 the variation of enals. A range of enals were examined and found to react well with
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46
acetylacetone in this study. (Table 2, products 3a-j) The ones that bearing electron-withdrawing
47 and electron-donating groups on the para- and ortho- positions can provide the corresponding
48
49 dihydropyraones (3b-3g) in good yields (64-81%) and with good to excellent enantioselectivities
50
51 (85-94% ee). When the (E)-3-(furan-2-yl)acrylaldehyde was used, the product 3h was afforded
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53 in 73% yield and with slightly lower enantioselectivity (87% ee). Surprisingly, the β-alkyl
54 substituted aldehydes in this aerobic annulation reaction also worked well with good yields and
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60 4
1
2
3
relatively lower ee values (3i: 71% yield and 77% ee; 3j: 71% yield and 80% ee), which were
4
5 usually difficult to succeed in such kind of NHC-catalyzed oxidative asymmetric reaction.
6
7 Table 2. The exploration of substrate scopea
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38 Further investigation of different 1,3-dicarbonyls were also conducted, the heptane-3,5-
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40 dione could offer the product 3m in high yield (74%) and ee (90%); unfortunately, the 1-
41 phenylbutane-1,3-dione only gave 3k in 69% ee probably due to the steric reason. We
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43 found that β-keto esters are also good nucleophiles for this NHC-catalyzed aerobic
44
45 oxidative annulation reaction (3l and 3n-q). All β-keto esters used can offer the desired
46
47 products in good yields (65-81%) and excellent enantioselectivities (89-92%); however, a
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noticeable steric effect of the ester groups on these substrates was not observed in this
49
50 reaction.
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52 The suggested catalytic cycle is depicted below (Scheme 2). First, the enaminol II could be
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54 generated through the reaction of carbene I and enal 1a. Next, in the presence of O2, the
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enaminol II will be oxidized to α,β-unsaturated acyl triazolium species III, which could act as
57 good Michael acceptor; further formation of the product 3a and liberation of the carbene catalyst
58
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60 5
1
2
3
I are similar to the literature reported by Studer and co-workers. We suppose that, in this aerobic
4
5 oxidative strategy, a hydroperoxide anion will be gernerated in the oxidation process, which will
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7 greatly facilitate the formation of the side product cinnamic acid 4. Indeed, we observed the
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9 cinnamic acid as main side product in this reaction.
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11 Scheme 2. The proposed catalytic cycle
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To verify our hypothesis, some control experiments were conducted. When the reaction
33 of cinnamaldehyde 1a and acetylacetone 2a in the presence of A was carried out under N2
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35 without any external oxidant, nearly no reaction happened; when O2 gas was used instead
36
37 of N2, the reaction went smoothly and afforded the desired product 3a in 77% yield,
38 18
39 however, the ee value dropped to 58% (Scheme 3, exp. 1). An O isotope labeling
40 experiment of NHC-catalyzed oxidation of cinnamaldehyde was also taken out by using
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18
42 O2 as the oxidant, and the product yielded in 85% was found to be cinnamic-18O acid
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44 (Scheme 3, exp. 2). This implied that O2 can successfully promote the oxidation of
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46 homoenolate II to the α,β-unsaturated acyl triazolium intermediate III, which facilitated
47
the consequence Michael addition reaction with 1,3-dicarbonyl compounds. Next,
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49 hydrogen peroxide was used as oxidant instead of O2 under N2 atmosphere in the
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51 cyclization reaction; we found that only trace amount of desired 3a was detected, and the
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53 side product cinnamic acid 4 was isolated in 83% yield (Scheme 3, exp. 3), which
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55
indicated that the hydroperoxide anion generated facilitated the formation of cinnamic
56 acid.
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60 6
1
2
3
Scheme 3. Control experiments
4 O
5 1) A
CHO O O DABCO O
6
+ THF, RT
7 R
O
8 1a 2a 3a
9 1) N2 , 24 h, no reaction
2) O2 , 4 h, yield: 77%, 58% ee
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11 2) A
CHO CO18OH
DABCO
12
18
13 THF, O2 , RT
1a 4h 4: 85% yield
14
15 A, LiCl
O
16 3) DABCO
CHO O
O O H2 O2
17 + + cinnamic acid
O
18 THF, N 2, RT
4h
19 1a 2a 3a: trace 4: 83% yield
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21
22 Conclusions
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24 In conclusion, we have developed an aerobic asymmetric annulation reaction of
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26 cinnamaldehydes and 1,3-dicarbonyl compounds through oxidative NHC-catalysis, the desired
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28 dihydropyranones were obtained in good yields and good to excellent enantioselectivities. The
29 air was directly used as the oxidant, which make this asymmetric annulation reaction in highly
30
31 efficient, cheap and green manner. We expect air to offer alternative, concise and low cost
32
33 strategy for oxidative NHC-catalysis.
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35 ■ EXPERIMENTAL SECTION
36
37 Analytical thin layer chromatography (TLC) was performed using precoated silica gel plate (0.2
38
39 mm thickness). Further visualization was possible by staining with basic solution of potassium
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41 permanganate or acidic solution of ceric molybdate. Proton nuclear magnetic resonance spectra
42
(1H NMR) were recorded by using CDCl3 as solvent. Chemical shifts for 1H NMR spectra are
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44 reported as δ in units of parts per million (ppm) downfield from SiMe4 (0.0) and relative to the
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46 signal of chloroform-d (7.26, singlet). Multiplicities were given as: s (singlet), d (doublet), t
47
48 (triplet), dd (doublets of doublet) or m (multiplets). The number of protons (n) for a given
49
50
resonance is indicated by nH. Coupling constants are reported as a J value in Hz. Carbon nuclear
51 magnetic resonance spectra (13C NMR) are reported as δ in units of parts per million (ppm)
52
53 downfield from SiMe4 (0.0) and relative to the signal of chloroform-d (77.0, triplet).
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55 Enantiomeric excesses were determined by high performance liquid chromatography (HPLC)
56
57 analysis on a chiral stationary phase. Optical rotations were measured in CHCl3 with a 10 cm cell
58
59
60 7
1
2
3
(c given in g/100 mL). Absolute configuration of the products was determined by comparing the
4
5 optical rotation with the known compounds. High resolution mass spectrometry (HRMS) was
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7 recorded on QTOF perimer for ESI+. The NHC-catalysts were prepared according to the
8
9 literatures reported.16 Enals which are not commercially available were prepared following the
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11
literatures procedures.17 The racemic products used to determine the ee values were synthesized
12 by using cis-mixture catalyst as racemic catalyst to generate racemic products. It was prepared
13
14 by mixing the following two catalysts in 1:1 ration.
15
16 General procedure for the synthesis of 3: To an oven dried 5 mL vial was added aldehyde (1, 0.4
17
18 mmol, 2.0 equiv.), 1,3-dicarbonyl compounds (2, 0.2 mmol, 1.0 equiv.) and NHC-catalyst A
19 (0.04 mmol, 0.2 equiv.) in 1 mL solvent, followed by addition of base and additive, the resulting
20
21 reaction mixture was stirred under air at rt. After the reaction was complete, (monitored by TLC)
22
23 water was added to the vial, extracted with dichloromethane, dried over anhydrous Na2SO4,
24
25 filtered, and concentrated under reduced pressure. The resulting residue was purified by flash
26
27
chromatography (EtOAc/hexane) to provide 3.
28 (R)-5-Acetyl-6-methyl-4-phenyl-3,4-dihydro-2H-pyran-2-one (3a). Reaction time: 14 h.
29
30 Colourless oil, yield: 19 mg (82%); [α]D20 = -116.4 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3)
31
32 δ 7.34 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 4.14 (d, J = 6.7 Hz,
33
34 1H), 2.97 (dd, J = 15.7, 7.2 Hz, 1H), 2.84 (dd, J = 15.7, 2.5 Hz, 1H), 2.43 (s, 3H), 2.12 (s, 3H);
35 13
C NMR (125 MHz, CDCl3) δ 197.9, 165.5, 160.2, 139.8, 129.5, 128.0, 126.7, 117.4, 38.9, 37.2,
36
37 29.8, 19.1; HRMS (ESI) calcd for C14H14O3 (M+H)+: 231.1016, Found: 231.1043; 94% ee as
38
39 determined by HPLC (Chiralcel IB, 80:20 hexanes/i-PrOH, 1 mL/min), tr (major) = 9.5 min, tr
40
41 (minor) = 8.2 min.
42
43
(R)-5-Acetyl-4-(4-methoxyphenyl)-6-methyl-3,4-dihydro-2H-pyran-2-one (3b). Reaction
44 time: 14 h. Yellow solid, yield: 21 mg (81%); mp: 92.1-93.5 oC; [α]D20 = -91.0 (c 0.7, CHCl3); 1H
45
46 NMR (500 MHz, CDCl3) δ 7.06 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.09 (d, J = 5.9 Hz,
47
48 1H), 3.78 (s, 3H), 2.93 (dd, J = 15.6, 7.1 Hz, 1H), 2.80 (dd, J = 15.6, 1.6 Hz, 1H), 2.41 (s, 3H),
49 13
50 2.12 (s, 3H); C NMR (125 MHz, CDCl3) δ 198.0, 165.7, 160.0, 159.2, 131.6, 127.8, 117.6,
51 114.8, 55.3, 38.1, 37.4, 29.6, 19.0; HRMS(ESI) calcd for C15H16O4 (M+H)+: 261.1121, Found:
52
53 261.1130; 85% ee as determined by HPLC (Chiralcel IB, 85:15 hexanes/i-PrOH, 1 mL/min), tr
54
55 (major) = 12.6 min, tr (minor) = 11.6 min.
56
57
58
59
60 8
1
2
3
(R)-5-Acetyl-4-(4-fluorophenyl)-6-methyl-3,4-dihydro-2H-pyran-2-one (3c). Reaction time:
4
5 18 h.Yellow solid, yield: 18 mg (73%); mp: 111.8-112.6 oC; [α]D20 = -72.0 (c 0.6, CHCl3); 1H
6
7 NMR (500 MHz, CDCl3) δ 7.12 (dd, J = 8.7, 5.2 Hz, 2H), 7.03 (t, J = 8.6 Hz, 2H), 4.16 (d, J =
8
9 6.2 Hz, 1H), 2.95 (dd, J = 15.7, 7.2 Hz, 1H), 2.81 (dd, J = 15.7, 2.5 Hz, 1H), 2.43 (d, J = 0.8 Hz,
10 13
11
3H), 2.14 (s, 3H); C NMR (125 MHz, CDCl3) δ 197.6, 165.4, 162.5 (d, 1JC-F = 246.8 Hz),
12 160.4, 135.4, 128.4 (d, 3JC-F = 8.7 Hz), 117.5, 116.5 (d, 2JC-F = 21.3 Hz), 38.1, 37.2, 29.8,
13
14 19.1; HRMS (ESI) calcd for C14H13 FO3 (M+H)+: 249.0921, Found: 249.0920; 91% ee as
15
17
18 (minor) = 10.4 min
19
(R)-5-Acetyl-4-(4-chlorophenyl)-6-methyl-3,4-dihydro-2H-pyran-2-one (3d). Reaction time:
20
21 14 h. Yellow oil, yield: 17 mg (64%); [α]D20 = -21.5 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3)
22
23 δ 7.31 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 4.15 (d, J = 6.6 Hz, 1H), 2.96 (dd, J = 15.7,
24 13
25 7.3 Hz, 1H), 2.80 (dd, J = 15.7, 2.5 Hz, 1H), 2.43 (d, J = 0.8 Hz, 3H), 2.14 (s, 3H); C NMR
26
27
(125 MHz, CDCl3) δ 197.4, 165.3, 160.6, 138.2, 133.8, 129.6, 128.1, 117.2, 38.1, 36.9, 29.8,
28 19.2; HRMS (ESI) calcd for C14H13ClO3 (M+H)+: 265.0626, Found: 265.0536; 94% ee as
29
31
32 (minor) = 23.5 min.
33
34 (R)-5-Acetyl-6-methyl-4-(4-nitrophenyl)-3,4-dihydro-2H-pyran-2-one (3e). Reaction time:
36
37 δ 8.20 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 4.34 (d, J = 6.7 Hz, 1H), 3.02 (dd, J = 15.9,
38
13
39 7.5 Hz, 1H), 2.85 (dd, J = 15.9, 2.3 Hz, 1H), 2.47 (s, 3H), 2.21 (s, 3H); C NMR (125 MHz,
40
41 CDCl3) δ 196.6, 164.7, 161.2, 147.6, 147.3, 127.8, 124.6, 117.2, 38.3, 36.3, 30.2, 19.5; HRMS
42
43
(ESI) calcd for C14H13NO5 (M+H)+: 276.0866, Found: 276.0877; 90% ee as determined by
44 HPLC (Chiralcel AD, 90:10 hexanes/i-PrOH, 1 mL/min), tr (major) = 26.9 min, tr (minor) = 29.2
45
46 min.
47
48 (R)-5-Acetyl-4-(2-methoxyphenyl)-6-methyl-3,4-dihydro-2H-pyran-2-one (3f). Reaction
49 o
50 time: 14 h. White solid, yield: 21 mg (80%); mp: 90.5-92.0 C; [α]D20 = -35.6 (c 0.8, CHCl3); 1H
51 NMR (500 MHz, CDCl3) δ 7.26 (td, J = 8.1, 1.7 Hz, 1H), 6.97 (dd, J = 7.4, 1.5 Hz, 1H), 6.89 (dd,
52
53 J = 11.5, 4.3 Hz, 2H), 4.54–4.46 (m, 1H), 3.86 (s, 3H), 2.91–2.82 (m, 2H), 2.42 (d, J = 0.9 Hz,
54
55 3H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 198.3, 166.2, 160.4, 156.5, 129.1, 127.2,127.1,
56
57 121.1, 116.4, 110.9, 55.2, 35.0, 32.9, 29.3, 19.0; HRMS (ESI) calcd for C15H16O4 (M+H)+:
58
59
60 9
1
2
3
261.1120, Found: 261.1109; 93% ee as determined by HPLC (Chiralcel AD, 98:2 hexanes/i-
4
5 PrOH, 1 mL/min), tr (major) = 18.5 min, tr (minor) = 21.1 min.
6
7 (R)-5-Acetyl-6-methyl-4-(2-nitrophenyl)-3,4-dihydro-2H-pyran-2-one (3g). Reaction time:
8
10
11
δ 7.99 (dd, J = 8.1, 1.2 Hz, 1H), 7.60–7.56 (m, 1H), 7.48 (td, J = 8.1, 1.3 Hz, 1H), 7.22 (dd, J =
12 7.8, 1.2 Hz, 1H), 4.86 (d, J = 6.7 Hz, 1H), 3.07 (dd, J = 16.1, 7.7 Hz, 1H), 3.00 (dd, J = 16.1, 2.4
13
13
14 Hz, 1H), 2.48 (d, J = 0.9 Hz, 3H), 2.09 (s, 3H); C NMR (125 MHz, CDCl3) δ 196.7, 165.0,
15
16 162.0, 148.7, 134.3, 134.1, 129.1, 128.2, 125.7, 116.4, 35.8, 34.2, 29.7, 19.3; HRMS (ESI) calcd
17
18 for C14H13NO5 (M+H)+: 276.0866, Found: 276.0866; 92% ee as determined by HPLC (Chiralcel
19
AD, 95:5 hexanes/i-PrOH, 1 mL/min), tr (major) = 18.7 min, tr (minor) = 20.6 min.
20
21 (S)-5-Acetyl-4-(furan-2-yl)-6-methyl-3,4-dihydro-2H-pyran-2-one (3h). Reaction time: 14h.
22
23 Yellow oil, yield: 16 mg (73%); [α]D20 = -35.7 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3) δ
24
25 7.34 (d, J = 1.2 Hz, 1H), 6.28 (dd, J = 3.2, 1.9 Hz, 1H), 6.09 (d, J = 3.2 Hz, 1H), 4.26 (d, J = 6.6
26
27
Hz, 1H), 3.04 (dd, J = 15.9, 2.1 Hz, 1H), 2.84 (dd, J = 15.9, 6.8 Hz, 1H), 2.37 (s, 3H), 2.31 (s,
28 3H); 13C NMR (125 MHz, CDCl3) δ 197.1, 165.5, 161.0, 152.5, 142.8, 115.7, 110.4, 106.6, 33.8,
29
30 32.3, 29.8, 19.4; HRMS (ESI) calcd for C12H12O4 (M+H)+: 221.0808, Found: 221.0834; 87% ee
31
32 as determined by HPLC (Chiralcel IB, 90:10 hexanes/i-PrOH, 1 mL/min), tr (major) = 11.0 min,
33
34 tr (minor) = 9.4 min.
35 (S)-5-Acetyl-6-methyl-4-propyl-3,4-dihydro-2H-pyran-2-one (3i). Reaction time: 14 h.
36
38
39 2.98–2.90 (m, 1H), 2.73 (dd, J = 15.9, 1.9 Hz, 1H), 2.59 (dd, J = 15.9, 6.4 Hz, 1H), 2.35 (s, 3H),
40 13
41 2.27 (s, 3H), 1.53–1.39 (m, 2H), 1.33 (dd, J = 8.1, 4.2 Hz, 2H), 0.91 (t, J = 7.0 Hz, 3H); C
42
43
NMR (125 MHz, CDCl3) δ 197.7, 167.0, 158.8, 120.4, 35.6, 33.1, 32.1, 30.2, 19.8, 19.3, 13.8;
44 HRMS (ESI) calcd for C11H16O3 (M+Na)+: 219.0992, Found: 219.0990; 77% ee as determined
45
46 by HPLC (Chiralcel IB, 90:10 hexanes/i-PrOH, 1 mL/min), tr (major) = 8.0 min, tr (minor) = 7.5
47
48 min.
49
50 (S)-5-Acetyl-6-methyl-4-pentyl-3,4-dihydro-2H-pyran-2-one (3j). Reaction time: 14 h.
51 Yellow oil, yield: 16 mg (71%); [α]D20 = -2.1 (c 0.7, CHCl3); 1
H NMR (500 MHz, CDCl3) δ
52
53 2.95–2.87 (m, 1H), 2.73 (dd, J = 15.9, 1.8 Hz, 1H), 2.58 (dd, J = 15.9, 6.4 Hz, 1H), 2.35 (s, 3H),
54
55 2.27 (s, 3H), 1.30 (m, 8H), 0.87 (t, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 197.8, 167.02,
56
57 158.7, 120.4, 33.4, 33.1, 32.3, 31.5, 30.2, 26.2, 22.4, 19.3, 13.9; HRMS (ESI) calcd for C13H20O3
58
59
60 10
1
2
3
(M+H)+: 225.1485, Found: 225.1480; 80% ee as determined by HPLC (Chiralcel IB, 95:5
4
5 hexanes/i-PrOH, 1 mL/min), tr (major) = 8.6 min, tr (minor) = 8.2 min.
6
7 (R)-5-Acetyl-4,6-diphenyl-3,4-dihydro-2H-pyran-2-one (3k). Reaction time: 14 h.
8 o
9 Colourless oil, yield: 20 mg (69%); mp: 76.5-77.6 C; [α]D20 = 1
-1.8 (c 0.8, CHCl3); H NMR (500
10
11
MHz, CDCl3) δ 7.58–7.53 (m, 2H), 7.46–7.43 (m, 1H), 7.32 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.3
12 Hz, 3H), 7.15–7.11 (m, 1H), 7.08–7.04 (m, 2H), 4.24 (dd, J = 7.1, 3.1 Hz, 1H), 2.99 (dd, J = 16.0,
13
13
14 7.6 Hz, 1H), 2.86 (dd, J = 16.0, 3.6 Hz, 1H), 1.83 (d, J = 1.0 Hz, 3H). C NMR (125 MHz,
15
16 CDCl3) δ 195.8, 166.5, 154.7, 140.0, 138.4, 133.1, 129.1, 128.8, 128.7, 127.6, 126.8, 117.8, 39.5,
17
18 36.2, 19.0; HRMS (ESI) calcd for C19H16O3 (M+H)+: 293.1172, Found: 293.1146; 74% ee as
19
determined by HPLC (Chiralcel IB, 90:10 hexanes/i-PrOH, 1 mL/min), tr (major) = 10.4 min, tr
20
21 (minor) = 9.6 min.
22
23 Ethyl (R)-6-ethyl-2-oxo-4-phenyl-3,4-dihydro-2H-pyran-5-carboxylate (3l). Reaction time:
24
26
27
δ 7.29 (t, J = 7.4 Hz, 2H), 7.23 (dd, J = 10.5, 4.2 Hz, 1H), 7.13 (d, J = 7.3 Hz, 2H), 4.27–4.22 (m,
28 1H), 4.12 (q, J = 7.1 Hz, 2H), 2.92 (ddd, J = 13.7, 12.1, 7.5 Hz, 2H), 2.87 – 2.77 (m, 2H), 1.27 (t,
29
13
30 J = 7.5 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); C NMR (125 MHz, CDCl3) δ 166.3, 165.9, 165.8,
31
32 140.6, 129.0, 127.4, 126.5, 109.3, 60.8, 37.8, 36.4, 25.4, 14.0, 11.7; HRMS (ESI) calcd for
33
34 C16H18O4 (M+H)+: 275.1278 , Found: 275.1265; 92% ee as determined by HPLC (Chiralcel IB,
35 95:5 hexanes/i-PrOH, 1 mL/min), tr (major) = 6.9 min, tr (minor) = 6.1 min.
36
37 (R)-6-Ethyl-4-phenyl-5-propionyl-3,4-dihydro-2H-pyran-2-one (3m). Reaction time: 14 h.
38
40
41 7.34 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 7.3 Hz, 2H), 4.11 (dd, J = 7.1, 2.8
42
43
Hz, 1H), 2.95 (dd, J = 15.7, 7.2 Hz, 1H), 2.81 (dd, J = 15.7, 3.0 Hz, 1H), 2.73 (qd, J = 13.8, 7.1
44 Hz, 2H), 2.49 (dq, J = 17.8, 7.2 Hz, 1H), 2.23 (dq, J = 17.8, 7.2 Hz, 1H), 1.28 (t, J = 7.4 Hz, 3H),
45
46 0.94 (t, J = 7.2 Hz, 3H).13C NMR (126 MHz, CDCl3) 13
C NMR (125 MHz, CDCl3) δ 201.1,
47
48 165.9, 163.7, 139.7, 129.5, 127.9, 126.7, 116.5, 38.7, 37.4, 34.7, 25. 3, 11.9, 7.9; HRMS (ESI)
49
50 calcd for C16H18O3 (M+H)+: 259.1329, Found: 259.1298; 90% ee as determined by HPLC
51 (Chiralcel IB, 80:20 hexanes/i-PrOH, 1 mL/min), tr (major) = 6.5 min, tr (minor) = 5.5 min.
52
53 Methyl (R)-6-methyl-2-oxo-4-phenyl-3,4-dihydro-2H-pyran-5-carboxylate (3n). Reaction
54
55 time: 14 h. Yellow oil, yield: 20 mg (81%); [α]D20 = -46.0 (c 0.8, CHCl3); 1H NMR (500 MHz,
56
57 CDCl3) δ 7.30 (t, J = 7.4 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 7.3 Hz, 2H), 4.26 (d, J =
58
59
60 11
1
2
3
7.2 Hz, 1H), 3.68 (s, 3H), 2.94 (dd, J = 15.8, 7.5 Hz, 1H), 2.83 (dd, J = 15.8, 2.1 Hz, 1H), 2.48 (s,
4
5 3H). 13C NMR (125 MHz, CDCl3) δ 166.4, 166.0, 161.7, 140.4, 129.1, 127.5, 126.6, 109.7, 51.9,
6
7 37.8, 36.5, 18.9; HRMS (ESI) calcd for C14H14O4 (M+H)+: 247.0965, Found: 247.0932; 90% ee
8
9 as determined by HPLC (Chiralcel IB, 80:20 hexanes/i-PrOH, 1 mL/min), tr (major) = 8.8 min, tr
10
11
(minor) = 6.3 min.
12 Ethyl (R)-6-methyl-2-oxo-4-phenyl-3,4-dihydro-2H-pyran-5-carboxylate (3o). Reaction
13
14 time: 14 h. Yellow oil, yield: 20 mg (77%); mp: 78.2-79.5 oC; [α]D20 = -115.0 (c 0.8, CHCl3); 1H
15
16 NMR (500 MHz, CDCl3) δ 7.29 (dd, J = 10.1, 4.6 Hz, 2H), 7.26–7.23 (m, 1H), 7.15–7.12 (m,
17
18 2H), 4.25 (d, J = 7.4 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.94 (dd, J = 15.9, 7.6 Hz, 1H), 2.82 (dd,
19 13
J = 15.9, 2.3 Hz, 1H), 2.47 (d, J = 0.8 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). C NMR (125 MHz,
20
21 CDCl3) δ 166.0, 165.9, 161.2, 140.6, 129.0, 127.4, 126.6, 110.0, 60.8, 37.8, 36.3, 18.8, 14.0;
22
23 HRMS (ESI) calcd for C15H16O4 (M+H)+: 261.1121 , Found: 261.1121; 90% ee as determined by
24
25 HPLC (Chiralcel IB, 80:20 hexanes/i-PrOH, 1 mL/min), tr (major) = 9.1 min, tr (minor) = 6.5
26
27
min.
28 Isopropyl (R)-6-methyl-2-oxo-4-phenyl-3,4-dihydro-2H-pyran-5-carboxylate (3p).
29
30 Reaction time: 14 h. Yellow oil, yield: 19 mg (69%); [α]D20 1
= -135.0 (c 0.5, CHCl3); H NMR
31
32 (500 MHz, CDCl3) δ 7.31–7.27 (m, 2H), 7.25–7.21 (m, 1H), 7.15–7.11 (m, 2H), 4.98 (dt, J =
33
34 12.5, 6.2 Hz, 1H), 4.23 (d, J = 6.7 Hz, 1H), 2.95 (dd, J = 15.9, 7.7 Hz, 1H), 2.82 (dd, J = 15.9,
35 2.5 Hz, 1H), 2.46 (d, J = 0.9 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.06 (d, J = 6.2 Hz, 3H);13C
36
37 NMR (125 MHz, CDCl3) δ 166.2, 165.4, 160.9, 140.8, 128.9, 127.4, 126.6, 110.3, 68.4, 37.9,
38
39 36.3, 21.9, 21.5, 18.8; HRMS (ESI) calcd for C16H18O4 (M+H)+: 275.1278, Found: 275.1258;
40
41 90% ee as determined by HPLC (Chiralcel IB, 95:5 hexanes/i-PrOH, 1 mL/min), tr (major) = 8.2
42
43
min, tr (minor) = 6.4 min.
44 Benzyl (R)-6-methyl-2-oxo-4-phenyl-3,4-dihydro-2H-pyran-5-carboxylate (3q). Reaction
45
46 time: 14 h. Yellow oil, yield: 22 mg (65%); [α]D20 = -56.4 (c 0.5, CHCl3); 1H NMR (500 MHz,
47
48 CDCl3) δ 7.31 (dd, J = 25.2, 17.2 Hz, 6H), 7.12 (t, J = 7.2 Hz, 4H), 5.11 (q, J = 12.5 Hz, 2H),
49
50 4.27 (d, J = 7.4 Hz, 1H), 2.95 (dd, J = 15.9, 7.7 Hz, 1H), 2.82 (d, J = 15.8 Hz, 1H), 2.49 (s, 3H);
51 13
C NMR (125 MHz, CDCl3) δ 165.9, 165.7, 162.0, 140.5, 135.6, 129.1, 128.5, 128.2, 127.9,
52
53 127.6, 126.6, 109.6, 66.6, 37.9, 36.4, 18.9; HRMS (ESI) calcd for C20H18O4 (M+H)+: 323.1278,
54
55 Found: 323.1269; 89% ee as determined by HPLC (Chiralcel IB, 95:5 hexanes/i-PrOH, 1
56
57 mL/min), tr (major) = 14.8 min, tr (minor) = 11.0 min.
58
59
60 12
1
2
3
4
5 ■ASSOCIATED CONTENT
6
7 Supporting Information
8
9
10 The Supporting Information is available free of charge on the ACS Publications website at DOI:
11
12 10.1021/acs.joc.
13
14 Copies of 1H, 13C NMR and chiral HPLC spectra for compounds 3a-q and MS spectra of 4 (PDF)
15
16
17 ■AUTHOR INFORMATION
18
19
Corresponding Author
20
21
22 *E-mail: [email protected]; [email protected]
23
24 Notes
25
26
27
The authors declare no competing financial interest.
28
29 ■ACKNOWLEDGMENTS
30
31
32 This paper is dedicated to professor Dieter Enders on the occasion of his 70th birthday.
33 We gratefully acknowledge the Natural Science Foundation of China (No. 21373073), the
34
35 Young National Natural Science Foundation of China (No. 21302033), the PCSIRT (IRT
36
37 1231) and Hangzhou Normal University for financial support. G.Z. appreciated a
38
39 Qianjiang Scholar from Zhejiang Province in China.
40
41
42
43 ■REFERENCES
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60 15

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The Journal of Organic Chemistry is published by the American Chemical Society.

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