Bioinspired Diastereoconvergent Synthesis of the Tricyclic Core of

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Bio-inspired diastereoconvergent synthesis of the tricyclic core of palodesangrens via Diels-Alder reaction, LiAlH4mediated isomerization, and acid-mediated cyclization Poramate Songthammawat, Sirilak Wangngae, Koki Matsumoto, Chuthamat Duangkamol, Somsak Ruchirawat, and Poonsakdi Ploypradith J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00668 • Publication Date (Web): 16 Apr 2018 Downloaded from http://pubs.acs.org on April 16, 2018

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The Journal of Organic Chemistry

Bio-inspired diastereoconvergent synthesis of the tricyclic core of palodesangrens via DielsAlder reaction, LiAlH4-mediated isomerization, and acid-mediated cyclization Poramate Songthammawat,† Sirilak Wangngae,‡ Koki Matsumoto,‡ Chuthamat Duangkamol,‡ Somsak Ruchirawat,†,‡,§,¶ Poonsakdi Ploypradith†,‡,§,¶* †

Program in Chemical Biology, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 54

Kamphaeng Phet 6 Road, Laksi, Bangkok, Thailand 10210 ‡

Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6

Road, Laksi, Bangkok, Thailand 10210 §

Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand

73170 ¶

Centre of Excellence on Environmental Health and Toxicology, Commission on Higher

Education (CHE), Ministry of Education, Thailand E-mail: [email protected] Abstract

The cyclohexene moiety of the tricyclic 6,7-diaryl-tetrahydro-6H-benzo[c]chromene core of palodesangrens could be assembled in a biomimetic and step-economical fashion by the DielsAlder reaction between the electron-rich (E)-1,3-butadienylarenes as the diene and the electrondeficient chalcones as the dienophile. During the reduction of ketone to the corresponding alcohol by LiAlH4, the mixture of endo and exo isomers underwent a novel diastereoconvergent LiAlH4-mediated isomerization to install the desired stereochemistry at C10a. Subsequent pyran

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ring closure under acidic conditions installed the stereochemistry at the remaining C6. Overall, the tricyclic core of palodesangrens could be prepared in 3 steps and up to 38% yield.

Introduction Palodesangrens A-E (1-5, Figure 1) are tetracyclic benzo[c]pyranochromenones isolated from the bark of Brosimum rubescens Taubert,1 a plant also commonly known as blood wood found in the Amazon and Guianas as well as in Panama and Brazilian Atlantic forest. Due to their relatively small amount from natural sources (0.0005-0.0019%), their biological activities have not been fully investigated except for their moderate antiandrogenic activity.1 Some palodesangrens were found to inhibit testosterone 5-reductase as well as the formation of 5dihydrotestosterone (DHT) binding with an androgen receptor.1 Such DHT-receptor complex has been implicated as causes of some androgen-dependent diseases such as prostatic hypertrophy, prostate cancer, male pattern baldness, and hirsutism.2 Since their isolation, palodesangrens were proposed to be the first natural Diels-Alder adducts arising biosynthetically from the [4+2]cycloaddition reactions between the corresponding prenylcoumarin (6) and chalcones (7) while other related natural Diels-Alder adducts such as kuwanons biosynthetically came from stilbenes, prenylchalcones, prenylflavonoids, or prenylbenzofurans. Recently, based on their biosynthesis, several synthetic studies and/or total syntheses of some of these natural products, except those of palodesangrens, have been reported.3-9


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Figure 1. Structures of palodesangrens (1-5), proposed biosynthetic precursors (6 and 7)

During the past few years, our research group has been involved with the generation of orthoquinone methides (o-QMs) and their [4+2]-cycloaddition reactions with various activated olefins under catalysis or mediation by Lewis/-acid (PtCl4) or Brønsted acid (p-toluenesulfonic acid immobilized on silica; PTS-Si) to furnish the corresponding 2-arylchromans as well as the tricyclic 6,7-diaryl-tetrahydro-6H-benzo[c]chromene (Scheme 1).10 With the proposed biosynthesis of palodesangrens from an aryldiene such as 6 and chalcone 7 in mind, we have now developed a biosynthesis-inspired step-economy strategy for the tricyclic core of palodesangrens.



Scheme 1. Two strategies for the synthesis of the tricyclic core of palodesangrens

In our previously developed route, the o-QM precursor 8 and electron-rich chalcone 7a bearing electron-donating group(s) as Ar1 and/or Ar2 were employed in the Pt(IV)-catalyzed inverse electron demand [4+2]-cycloaddition reaction to provide the chroman ketone 9 which subsequently underwent the Kursanov reduction to install H 7 stereoselectively and then Ru(II)catalyzed ring closing metathesis (RCM) to install the cyclohexene ring of the tricyclic core 10.10e However, the relative stereochemistry of 10 at C6-C10a, C6a-C7, and C6a-C10a did not match that of the tricyclic core 11 at those identical positions on the general structure of natural palodesangren 12. Thus, our new synthetic approach was designed to overcome this issue. Since chalcones (e.g. 7) were biosynthetically proposed to be the dienophiles for the Diels-Alder reactions, we anticipated that the trans geometry of electron-poor chalcone 7b bearing electronwithdrawing substituents as Ar1 and/or Ar2, upon its Diels-Alder reaction with the aryldiene 13, would confer the desired trans relationship between H6a and H7 in the cyclohexene ketone


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product 14.3-9 In addition, we also anticipated that the subsequent steps including the acidmediated cyclization of 14 would proceed to furnish the tricyclic product 15 with the desired stereochemistry at the remaining C6 and C10a positions (vide infra).

Results and discussion As shown retrosynthetically in Scheme 2, the coumarin moiety of palodesangrens 12 was anticipated to be installed at a late stage; the key intermediate tricyclic 6,7-diaryl-tetrahydro-6Hbenzo[c]chromene 15 would arise from the corresponding cyclohexene ketone 14 which, in turn, would be furnished by the intermolecular Diels-Alder reactions between aryldiene 13 and chalcone 7b. The diene moiety of 13 would be installed via the Claisen-Schmidt condensation of the aldehyde 16 and acetone followed by the Wittig methylenation. Chalcones 7b could be prepared straightforwardly from the corresponding acetophenone and benzaldehyde derivatives.

Scheme 2. Retrosynthetic analysis of palodesangrens

As a model, we first used 2-methoxyphenyldiene 1711a and chalcone 18 for the Diels-Alder reactions. The results were summarized in Table 1. In the absence of Lewis acid, the reaction



required either conventional or microwave heating. The best isolated yield of 19 (45%) as a 10:1 mixture of endo:exo isomers could be obtained from conventional heating at 130 °C for 48 h (entry 1).6a,7c Microwave heating gave lower yields of 19 of a similar endo:exo ratio, albeit requiring shorter reaction time (entry 2). In addition, reactions employing catalytic amount (up to 20 mol%) of Cu(OAc)2, copper-2-thiophene carboxylate (CuTC), In(OTf)3, or hydroquinone in conjunction with microwave heating either did not proceed or gave 19 in low to moderate yields (up to 41%; entries 3-15). Catalytic amount of Cu(OAc)2 in MeCN, 1,4-dioxane, or DMF as solvent with conventional heating at different temperatures gave the product only in 18-34% yields (entries 3-5). Microwave irradiation at 200 °C for the reactions using Cu(OAc) 2 as catalyst in MeCN, 1,4-dioxane, DMF, and water gave similar results, providing 19 in 27-33% yields (entries 6-9). Interestingly, using a mixed solvent system of water and 1,4-dioxane (1:1 v/v) gave better yield (40%; entry 10). When catalytic amount of CuTC was employed either in MeCN or DMF, the reactions proceeded to furnish 19 in 33-40% yields (entries 11-12). Use of catalytic amount of hydroquinone in MeCN gave the product 19 in 41% yield (entry 13); however, no reaction occurred when 1,4-dioxane was employed as solvent at different temperatures (entry 14). At 50 °C, catalytic amount of In(OTf) 3 in 1,4-dioxane gave only the decomposition of the diene 17 (entry 15). In addition, when other Lewis acids (AlCl3, Me3Al, Sc(OTf)3, PtCl4, AgOTf, and BF3·Et2O) were employed as catalyst, even at low temperatures (78 to 0 °C), only the decomposition of the diene 17 was detected.11 Thus, from this model study, conventional heating at 130 °C for 48 h using toluene as solvent was the best condition for the requisite Diels-Alder reaction.

Table 1. Optimization of reaction conditions for the Diels-Alder reactions of 17 and 18a


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a

entry solvent

additive (mol%)

temp (°C)

time (h) yield (%)b

1

PhMe

none

130c

48

45d

2

PhMe

none

150-200

0.33-1

30

3

MeCN

Cu(OAc)2 (20)

70c

18-48

18-21

4

1,4-dioxane

Cu(OAc)2 (20)

110c

48

34

5

DMF

Cu(OAc)2 (20)

150c

18

31

6

MeCN

Cu(OAc)2 (20)

200

0.33

33

7

1,4-dioxane

Cu(OAc)2 (20)

200e

0.33

32

8

DMF

Cu(OAc)2 (20)

50-200

0.33

27

9

H2O

Cu(OAc)2 (20)

200

0.33

27

10

H2O:1,4-dioxane (1:1)

Cu(OAc)2 (20)

200

0.33

40

11

MeCN

CuTC (20)

200

0.33

40

12

DMF

CuTC (20)

200

0.33

33

13

MeCN

hydroquinone (20)

200

0.33

41

14

1,4-dioxane

hydroquinone (20)

50-100

0.33

no reaction

15

1,4-dioxane

In(OTf)3 (20)

50

0.33

decomposed

Unless otherwise noted, the reactions were performed using microwave irradiation at the

specified duration (h) and temperature (°C) in sealed reaction vessels. Temperature was monitored by an external surface sensor. bYields were estimated based on 1H NMR of the crude product using 1,3,5-trimethoxybenzene as an internal standard. cConventional heating was employed. dIsolated yield. eNo reaction occurred at temperatures lower than 200 °C.



With the optimal condition, we proceeded to investigate similar reactions with other aryldienes and chalcones. Starting from 2-hydroxy-4-methoxybenzadehyde 20, the corresponding aryldienes 21a-b could be prepared smoothly in 56-67% yield over 3 steps (Scheme 3).11 A number of different chalcones were prepared accordingly from the corresponding benzaldehyde and acetophenone derivatives in good to excellent yields. It should be noted that better yields of the aldol condensation between the acetophenones 22 and hydroxybenzaldehyde derivatives 23 under basic conditions could be obtained when the hydroxy groups were protected as the corresponding MOM ethers (24 and 25).12 The MOM ethers could be readily cleaved in the subsequent step using 10% sulfuric acid in refluxing ethanol. 11 Since the ensuing Diels-Alder reactions would require the dienophiles (chalcones) to be electron-deficient, the free hydroxy groups were then converted to the corresponding acetate group (chalcones 26b-l).

Scheme 3. Synthesis of aryldienes 21a-b and chalcones 26b-l


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The aryldienes 21a-b reacted with chalcones 26b-l via the Diels-Alder reactions to provide the corresponding adducts (27a-p) in 50-89% yields as 1.1:1 to 3.3:1 (endo:exo) inseparable mixtures (Figure 2).13 Generally, the electronic nature of the chalcones as well as the presence of bromine atom on the aryldiene 21b only slightly affected the yields or the stereoselectivity of the reactions. Chalcone 18 with electronically neutral phenyl groups gave 27a in 52% yield as a 2.4:1 mixture upon reacting with 21a; 27m was obtained from 18 and 21b in similar yield (59%) and stereoselectivity (2.2:1). While keeping the aromatic ring of the ketone as 4-methoxyphenyl, we observed the effect of different positions of the acetate group of chalcones on the yields (27bd and 27e-g) but not on the stereoselectivity. When 21b was employed, 27n was obtained in yield and stereoselectivity similar to those obtained for 27g. The presence of the methylenedioxy group on the ketone of chalcones increased the stereoselectivity in 27j-k to 3.3:1. The DielsAlder adduct 27o was obtained in similar stereoselectivity when 21b was employed for the reaction albeit in lower yield (50%) when compared with those of 27j-k (62%). When the aromatic ring of the ketone contained an electron-withdrawing acetate group, the adducts (27h, 27l, and 27p) were obtained in good to excellent yields (64-89%) but only in low stereoselectivity (1.1:1 to 1.5:1).



Figure 2. Diels-Alder cycloadducts 27a-p

With the cyclohexene ketone adducts in hand, we next considered the ensuing cyclization of the chroman moiety of the tricyclic core of palodesangrens. The adduct 27a was used as a model for this cyclization. We anticipated that 27a could be directly converted to the corresponding hemiketal 28a upon treating with acids which would simultaneously mediate both the cleavage of the aromatic MOM ether and the cyclization on the ketone moiety. 14 Various Brønsted acids were screened under different conditions ((a) 0.5-0.6 equivalents of p-TsOH or p-TsOH immobilized on silica (PTS-Si) in toluene or CH2Cl2 at rt to 80 °C for 6-18 h15 and (b) 10% or 3M H2SO4 in EtOH at rt for 48 h8); however, none furnished 28a. It was noted that even under


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these acidic conditions the MOM group was not cleaved (Scheme 4). Thus, we considered reducing the ketone moiety of 27a to the corresponding alcohol which, upon subsequent acidmediated cleavage of MOM ether as well as cyclization, would furnish the desired chroman 29a. However, reducing this ketone proved to be non-trivial; NaBH4 as well as hydrosilane reduction (BF3·Et2O or TFA in conjunction with Et3SiH)16 failed to reduce the ketone completely. After some experimentation, it was found that LiAlH 4 was required for this reduction, giving the corresponding alcohol, which, upon treating with 10% H2SO4 for 48 h at rt,17 furnished the tricyclic chroman 29a as a single diastereomer but only as a minor product.18 To our delight, however, the cyclohexene ketones 27b, 27e, 27i, and 27o, upon undergoing a similar reaction sequence, smoothly provided the corresponding tricyclic chromans 29b-e, each as a single diastereomer in 59-65% yields over two steps. Relative stereochemistry at all four contiguous stereogenic centers was established spectroscopically, especially by nOe studies, and it was found to be in good accordance with that reported for naturally-occurring palodesangrens.

Scheme 4. Synthesis of tricyclic chromans 29a-e

The apparent diastereoconvergence for the final two steps of converting 27b, 27e, 27i, and 27o to the corresponding tricyclic 29b-e as single diastereomers was, to the best of our knowledge, unprecedented. A plausible mechanism to account for this observation was proposed in Scheme



5 with the following supporting evidence. If one equivalent of LiAlH4 was employed, only the corresponding phenol product was obtained from cleaving the acetate group; the ketone was left intact (A). With LiAlH4 in excess, reduction of the ketone occurred with concomitant LiAlH4mediated isomerization at C10a to generate the products with C10a cis to the adjacent C6a (B). H10a is prone to undergo such reaction because of its relatively high acidity from its allylic/benzylic electronic nature.19 In order to determine whether other basic species (i.e. ethoxide, a by-product generated from the cleavage of the acetate group by LiAlH 4) may mediate this isomerization, when compound 27a was treated with stoichiometric or excessive amount of ethoxide (from Cs2CO3 and EtOH or its sodium salt) at room temperature, no isomerization was detected. Therefore, LiAlH4 was required to mediate this isomerization. However, it remains unclear whether the reduction of the ketone preceded the isomerization or vice versa. As shown in Scheme 5, the two possible intermediates A1 and A2 would be generated from the isomerization at C10a following the cleavage of the acetate group but assumingly still retaining their ketone functional groups. The intermediate A1 would be more thermodynamically stable than A2 due to the presence of the 1,3-diaxial interaction of the aromatic rings at C7 and C10a in A2. For 27a, 27b, and 27i, the crude 1H NMR of the LiAlH4 reduction clearly showed the signal of one olefin (C10; ca. 5.50 ppm) and one set of signals of the OCH2OMe of the MOM group as a major component and further supported this uncommon LiAlH4-mediated isomerization during this step (see Supporting Information for the spectra).20 Thus, the relative stereochemistry at all three stereocenters (C6a, C7, and C10a) in the tricyclic products now matched those found in natural palodesangrens. Whether the LiAlH4 reduction of the ketone was stereoselective was irrelevant because the ensuing acid-mediated ring closure of the pyran moiety would ionize the alcohol, thereby generating the corresponding carbocation (C) for the stereoselective cyclization.


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For compound 29c, the corresponding nOe values were found for H10a and H6a (2.35% and 3.01%) as well as H7 and H6 (0.49%); this further confirmed the cis relationships between H10a and H6a as well as that between H7 and H6.

Scheme 5. A proposed plausible mechanism for the diastereoconvergent generation of 29c

Conclusion



In summary, a concise bio-inspired synthesis of the tricyclic 6,7-diaryl-tetrahydro-6Hbenzo[c]chromene core of palodesangrens has been successfully developed. The cyclohexene moiety was first constructed via the key Diels-Alder reactions between the aryldienes 21a or 21b and electron-deficient chalcones 18 or 26b-l. The required trans relationship between H6a and H7 of the tricyclic core in palodesangrens was conferred by the trans geometry of chalcones. Despite only modest stereoselectivity (1.1-10:1 endo:exo ratios) obtained from the Diels-Alder reactions for the cyclohexene adducts 19 and 27a-p, the desired cis relationship between H6a and H10a was successfully installed via the subsequent novel LiAlH4-mediated isomerization of H10a, thereby converting both endo and exo isomers, in a diastereoconvergent manner, to the endo products during this step. The ensuing acid-mediated cyclization by using 10% H2SO4 generated the carbocation which underwent the stereoselective cyclization/MOM cleavage to provide the pyran ring with the desired stereochemistry at the remaining C6 stereocenter. Thus, unlike other approaches which normally employed acid-mediated cyclization either separately on one of the two endo/exo isomers or directly on the mixture containing both endo and exo isomers of the cyclohexene ketones to form the remaining ring(s), our bio-inspired diastereoconvergent strategy for the palodesangrens employed LiAlH4 as a reagent not only to reduce the ketone to the corresponding alcohol but also, more importantly, to affect the C10a isomerization. Overall, the tricyclic core 29b-e with stereochemistry at all four contiguous stereogenic centers which matched that in natural palodesangrens could be obtained in 30-38% yield over 3 steps from appropriate chalcones and dienes.

Experimental


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General Experimental Methods. Unless otherwise noted, reactions were run in oven-dried round-bottomed flasks. For microwave reactions, sealed reaction vessels were employed and the temperature was monitored by an external surface sensor. Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl or purified by the solvent purification system while dichloromethane (CH2Cl2) was also purified by the solvent purification system prior to use. All other compounds were used as received from the suppliers; PTS-Si (p-TsOH immobilized on silica) employed in these experiments possessed the surface area of 500 m2/g as indicated by the supplier. The crude reaction mixtures were concentrated under reduced pressure by removing organic solvents on rotary evaporator. Column chromatography was performed using silica gel 60 (particle size 0.06-0.2 mm; 70-230 mesh ASTM). Analytical thin-layer chromatography (TLC) was performed with silica gel 60 F254 aluminum sheets. Chemical shifts for 1H nuclear magnetic resonance (NMR) spectra were reported in parts per million (ppm, ) downfield from tetramethylsilane. Splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br), doublet of doublet (dd), doublet of triplet (dt), and doublet of doublet of doublet (ddd). Resonances for infrared (IR) spectra were reported in wavenumbers (cm-1). Low resolution (LRMS) mass spectra were obtained either using electron ionization (EI) or time-of-flight (TOF) while high resolution (HRMS) mass spectra were obtained using time-offlight (TOF) via the atmospheric-pressure chemical ionization (APCI) or electrospray ionization (ESI). Melting points were uncorrected.

General procedure for the synthesis of aryldiene 21a-b.



Claisen–Schmidt condensation. To a stirred solution of MOM-protected benzaldehyde (1.0 equiv) and acetone (5.0 equiv) in a mixture of MeOH:H2O (1:1 v/v) (10 mL/mmol) was added NaOH (3.5 equiv) and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The product was obtained following purification by column chromatography on silica (25% EtOAc/hexane).

(E)-4-(4-Methoxy-2-(methoxymethoxy)phenyl)but-3-en-2-one (20a2). Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow oil (2.0 g, 8.47 mmol, 73 %). 1H NMR (300 MHz, CDCl3): δ 2.37 (s, 3H), 3.51 (s, 3H), 3.82 (s, 3H), 5.25 (s, 2H), 6.58 (dd, J = 8.7, 2.4 Hz, 1H), 6.67 (d, J = 16.5 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 16.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 27.1, 55.4, 56.2, 94.5, 101.0, 107.4, 116.7, 125.3, 129.2, 138.4, 157.5, 162.7, 198.9. IR (UATR): max 2956, 2839, 1665, 1591, 1503 cm-1. LRMS (EI): m/z (rel intensity) 161 (21), 175 (100), 176 (16), 191 (21), 236 (11), 237 (M+, 2). TOF-HRMS: calcd for C13H16NaO4 (M + Na+) 259.0942, found 259.0941.


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(E)-4-(5-Bromo-4-methoxy-2-(methoxymethoxy)phenyl)but-3-en-2-one (20b2). Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow solid (1.0 g, 3.17 mmol, 81%). Mp 85.5–86.5 °C. 1H NMR (300 MHz, CDCl3): δ 2.37 (s, 3H), 3.52 (s, 3H), 3.92 (s, 3H), 5.27 (s, 2H), 6.65 (d, J = 16.4 Hz, 1H), 6.79 (s, 1H), 7.73 (s, 1H), 7.77 (d, J = 16.4 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 27.7, 56.4, 95.0, 99.5, 104.3, 117.9, 126.0, 131.8, 136.7, 156.9, 158.4, 198.4. IR (UATR): max 2961, 2943, 1658, 1593, 1489 cm-1. LRMS (EI): m/z (rel intensity) 76 (15), 161 (14), 239 (20), 241 (19), 253 (100), 255 (90), 316 (M+, 12). TOF-HRMS: calcd for C13H1579BrNaO4 (M + Na+) 337.0046, found 337.0039; calcd for C13H1581BrNaO4 (M + Na+) 339.0027, found 339.0023.

Wittig methylenation. To a stirred solution of methyltriphenylphosphonium bromide (2.3 equiv) in dry THF (10 mL/1 mmol) at -78 °C under argon was added n-BuLi (2.0 equiv) and the mixture was slowly warmed up to rt at which it was stirred for 1 h. At that time, the reaction mixture was cooled to -78 °C before a solution of the MOM-protected (E)-benzylideneacetones (1.0 equiv) in THF (5 mL) was added. The reaction was then further stirred at -78 °C, slowly warmed up to room temperature at which it was stirred for 3 h. The reaction was quenched with H2O, extracted with EtOAc (3 x 10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica (20% EtOAc/hexane) to give the desired product.

(E)-4-Methoxy-2-(methoxymethoxy)-1-(3-methylbuta-1,3-dien-1-yl)benzene

(21a).

Following the General Procedure for the Wittig methylenation described above, the desired product was obtained as a colorless oil (1.4 g, 5.89 mmol, 75 %). 1H NMR (300 MHz, CDCl3): δ



1.98 (s, 3H), 3.47 (s, 3H), 3.75 (s, 3H), 5.02 (d, J = 15.6 Hz, 2H), 5.18 (s, 2H), 6.53 (dd, J = 8.7, 2.4 Hz, 1H), 6.68 (d, J = 2.4, 1H), 6.80 (d, J = 6.6 Hz, 2H), 7.43 (d, J = 8.7 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 18.8, 55.3, 56.1, 94.9, 101.7, 107.2, 116.0, 120.2, 123.0, 126.9, 130.2, 142.7, 155.6, 160.2. IR (UATR): max 2936, 2837, 1726, 1677, 1606, 1505, 1464, 1442 cm-1. LRMS (EI): m/z (rel intensity) 55 (73), 57 (100), 69 (64), 71 (54), 234 (M +, 11). TOFHRMS calcd for C14H18NaO5 (M + Na++O2) 289.1045, found 289.1046.

(E)-1-Bromo-2-methoxy-4-(methoxymethoxy)-5-(3-methylbuta-1,3-dien-1-yl)benzene (21b). Following the General Procedure for the Wittig methylenation described above, the desired product was obtained as a yellow solid (170.0 mg, 0.54 mmol, 74 %). Mp 75.3–77.5 °C °C. 1H NMR (300 MHz, CDCl3): δ 1.97 (s, 3H), 3.51 (s, 3H), 3.88 (s, 3H), 5.04 (br s, 1H), 5.09 (br s, 1H), 5.21 (s, 2H), 6.74 (s, 1H), 6.75 (s, 2H), 7.67 (s, 1H).

13

C NMR (75 MHz, CDCl3): δ 18.6,

56.2, 56.3, 95.2, 100.1, 104.2, 116.9, 121.4, 121.5, 129.9, 131.2, 142.3, 154.8, 155.7. IR (UATR): max 2944, 1595, 1489, 1382, 1288 cm-1 . LRMS (EI): m/z (rel intensity) 57 (100), 69 (84), 71 (69), 83(41), 313 (M+, 2). TOFHRMS calcd for C14H1879BrNaO3 (M + H+) 313.0434, found 313.0437; calcd for C14H1881BrNaO3 (M + H+) 315.0415, found 315.0408.

General procedure for the synthesis of chalcones 23b-l.

Claisen–Schmidt condensation. To a stirred solution of the MOM-protected acetophenone (1.0 equiv) and MOM-protected aryl aldehyde (1.0 equiv) in a mixture of MeOH:H2O (1:1 v/v) (10 mL/mmol) was added NaOH (3.5 equiv). The reaction mixture was stirred at room temperature overnight. After completion, the mixture was extracted with EtOAc (3 x 15 mL) and washed


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once with brine. After being dried over Na2SO4, the combined organic layers were evaporated under reduced pressure to give the crude product which was further purified by column chromatography using 25% EtOAc/hexane as eluent to furnish the desired product.

(E)-3-(4-(Methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I1b). Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow oil (1.2 g, 4.02 mmol, 90 %). 1H NMR (400 MHz, CDCl3): δ 3.49 (s, 3H), 3.89 (s, 3H), 5.22 (s, 2H), 6.99 (d, J = 12.0 Hz, 2H), 7.08 (d, J = 12.0 Hz, 2H), 7.45 (d, J = 20.0 Hz, 1H), 7.59 (d, J = 12.0 Hz, 2H), 7.78 (d, J = 20.0 Hz, 1H), 8.04 (d, J = 12.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 55.5, 56.2, 94.2, 113.8, 116.5, 119.9, 128.8, 130.0, 130.7, 131.3, 143.6, 159.1, 163.3, 188.7. IR (UATR): max 2902, 2935, 1656, 1597, 1508, 1422 cm-1. LRMS (EI): m/z (rel intensity) 121 (23), 135 (51), 253 (62), 267 (11), 298 (M +, 100). TOFHRMS: calcd for C18H18NaO4 (M + Na+) 321.1097, found 321.1097.

(E)-3-(2-(Methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I1c). Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow oil (1.1 g, 3.69 mmol, 78%). 1H NMR (400 MHz, CDCl3): δ 3.51 (s, 3H), 3.89 (s, 3H), 5.28 (s, 2H), 6.98 (d, J = 9.2 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 1.6, 1.2 Hz, 1H), 7.61 (d, J = 15.6 Hz, 1H), 7.68 (d, J = 6.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 16.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 55.4, 56.3,



94.6, 113.7, 114.8, 121.9, 122.5, 124.8, 128.3, 130.7, 131.3, 131.5, 139.1, 156.3, 163.3, 189.0. IR (UATR): νmax 3072, 2935, 1655, 1596, 1484, 1165, 982 cm−1. LRMS (EI): m/z (rel intensity) 77 (5), 118 (13), 135 (90), 237 (100), 298 (M+, 1).TOF-HRMS: calcd for C18H18NaO4 (M + Na+) 321.1097, found 321.1106. These spectroscopic data matched those reported previously. 21

(E)-3-(3-(Methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I1d). Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow solid (1.7 g, 5.70 mmol, 82 %). Mp 75.2–77.4 °C. 1H NMR (400 MHz, CDCl3): δ 3.51 (s, 3H), 3.89 (s,3H), 5.22 (s, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 7.5 Hz, 1H), 7.28–7.36 (m, 3H), 7.52 (d, J = 15.6 Hz, 1H), 7.76 (d, J = 15.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H).

13

C NMR (100 MHz, CDCl3): δ 55.5, 56.1, 94.5, 113.9, 115.7, 118.2, 122.2,

122.3, 129.9, 130.9, 131.1, 136.6, 143.7, 157.7, 163.5, 188.7. IR (UATR): νmax 2956, 2903, 1659, 1598, 1311, 1244 cm−1. LRMS (EI): m/z (rel intensity) 121 (59), 135 (54), 237 (36), 253 (51), 298 (M+, 100). TOF-HRMS: calcd for C18H19O4 (M + H+) 299.1278, found 299.1266.

(E)-3-(3-Methoxy-4-(methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I1e). Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow solid (800 mg, 2.44 mmol, 76 %). Mp 91.5–92.5 °C. 1

H NMR (300 MHz, CDCl3): δ 3.53 (s, 3H), 3.89 (s,3H), 3.96 (s, 3H), 5,29 (s, 2H), 6.99 (d, J =

9.0 Hz, 2H), 7.24–7.17 (m, 3H), 7.42 (d, J = 15.6 Hz, 1H), 7.76 (d, J = 15.6 Hz, 1H), 8.04 (d, J =


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9.0 Hz, 1H).13C NMR (75 MHz, CDCl3): δ 55.2, 56.7, 56.1, 94.9, 110.6, 113.5, 115.5, 119.9, 122.2, 129.1, 130.9, 130.5, 143.6, 148.3,149.5, 163.0, 188.3. IR (UATR): νmax 2936, 2939, 1655, 1598, 1507, 1464, 1420, 1338 cm−1. LRMS (EI): m/z (rel intensity) 57(19), 77(19), 135(100), 283(13), 328 (M+, 30). TOF-HRMS: calcd for C19H20NaO5 (M + Na+) 351.1197, found 351.1203.

(E)-3-(4-Methoxy-3-(methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I1f). Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow solid (996 mg, 3.03 mmol, 85 %). Mp 74.2–76.6 °C. 1

H NMR (300 MHz, CDCl3): δ 3.55 (s, 3H), 3.90 (d, J = 12.9 Hz, 6H), 5.28 (s, 2H), 6.91 (d, J =

8.4 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.28 (dd, J = 8.1, 2.1 Hz, 1H), 7.40 (d, J = 15.6 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 15.6 Hz, 1H), 8.03 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 55.5, 55.9, 56.3, 95.6, 111.7, 113.8, 115.4, 120.1, 124.3, 128.2, 130.7, 131.3, 143.9, 146.8, 151.9, 163.3, 188.7. IR (UATR): νmax 2935, 1599, 1509, 1258 cm−1. LRMS (EI): m/z (rel intensity) 121 (34), 135 (100), 283 (79), 328 (53, M+). TOF-HRMS: calcd for C19H20NaO5 (M + Na+) 351.1203, found 351.1210.

(E)-3-(3,4-Bis(methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one

(I1g).

Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow solid (920 mg, 2.57 mmol, 73 %). Mp 64.6–66.1 °C.



1

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H NMR (400 MHz, CDCl3): δ 3.53 (s, 3H), 3.56 (s, 3H), 3.89 (s, 3H), 5.29 (s, 2H), 5.30 (s, 2H),

6.99 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.28–7.25 (m, 1H), 7.42 (d, J = 15.6 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 15.6 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H).

13

C NMR (100

MHz, CDCl3): 55.4, 56.3, 95.1, 95.5, 113.7, 115.9, 116.1, 120.5, 123.8, 129.5, 130.7, 131.2, 143.7, 147.3, 149.2, 163.3, 188.7. IR (UATR): νmax 2935, 2839, 1598, 1507, 1252 cm−1. LRMS (EI): m/z (rel intensity) 267 (16), 281 (49), 282 (100), 358 (32, M+). TOF-HRMS: calcd for C20H22NaO6 (M + Na+) 381.1309, found 381.1312.

(E)-3-(3,4-Bis(methoxymethoxy)phenyl)-1-(4-(methoxymethoxy)phenyl)prop-2-en-1-one (I1h). Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow solid (694 mg, 1.94 mmol, 58 %). Mp 81.3–83.5 °C. 1H NMR (400 MHz, CDCl3): δ 3.50 (s, 3H), 3.53 (s, 3H), 3.56 (s, 3H), 5.26 (s, 2H), 5.29 (s, 2H), 5.29 (s, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.25–7.28 (m, 1H), 7.40 (d, J = 15.6 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 15.6 Hz, 1H), 8.01 (d, J = 8.8 Hz, 2H). 13

C NMR (100 MHz, CDCl3): δ 56.3, 56.3, 94.1, 95.1, 95.6, 115.8, 116.0, 116.2, 120.6, 123.9,

129.5, 130.7, 131.2, 132.2, 143.9, 147.4, 149.3, 160.9, 189.0. LRMS (EI): m/z (rel intensity) 165 (100), 251 (36), 267 (69), 312 (87), 388 (M+, 66). IR (UATR): νmax 2955, 1599, 1507, 1253, 1151, 1076 cm−1. TOF-HRMS: calcd for C21H24NaO7 (M + Na+) 411.1414, found 411.1420.


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(E)-1-(3,4-Dimethoxyphenyl)-3-(4-(methoxymethoxy)phenyl)prop-2-en-1-one

(I1i).

Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow oil (1.1 g, 3.35 mmol, 77 %). 1H NMR (400 MHz, CDCl3): δ 3.49 (s, 3H), 3.97 (s, 3H), 3.98 (s, 3H), 5.22 (s, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 15.6 Hz, 1H), 7.59 (s, 1H), 7.62 (t, J = 2.0 Hz, 2H), 7.68 (dd, J = 2.0, 1.6 Hz, 1H), 7.79 (d, J = 15.6 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 56.0, 56.1, 56.1,

94.2, 109.9, 110.8, 116.5, 119.8, 122.8, 128.8, 130.0, 131.5, 143.6, 149.2, 153.1, 159.0, 188.6. LRMS (EI): m/z (rel intensity) 151 (15), 165 (39), 182 (37), 283 (78), 328 (M+, 100). TOFHRMS: calcd for C19H20NaO5 (M + Na+) 351.1203, found 351.1215.

(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-(methoxymethoxy)phenyl)prop-2-en-1-one

(I1j).

Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow solid (996 mg, 3.19 mmol, 95 %). Mp 95.4–96.8 °C. 1

H NMR (300 MHz, CDCl3): δ 3.49 (s, 3H), 5.22 (s, 2H), 6.06 (s, 2H), 6.89 (d, J = 8.1 Hz, 1H),

7.07 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 15.6 Hz, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.64 (dd, J = 8.1, 1.5 Hz, 1H), 7.77 (d, J = 15.6 Hz, 1H).

13

C NMR (75 MHz, CDCl3): δ

56.1, 94.2, 101.8, 107.8, 108.4, 116.4, 119.8, 124.4, 128.7, 130.0, 133.1, 143.8, 148.2, 151.5, 159.1, 188.2. IR (UATR): νmax 2901, 1654, 1589, 1508, 1440, 1239, 985 cm−1. LRMS (EI): m/z (rel intensity) 84 (10), 149 (37), 174 (11), 267 (66), 312 (100, M +). TOF-HRMS: calcd for C18H16NaO5 (M + Na+) 335.0889, found 335.0893.



(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(3,4-bis(methoxymethoxy)phenyl)prop-2-en-1-one (I1k). Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow solid (996 mg, 2.68 mmol, 74 %). Mp 97.3–99.8 °C. 1

H NMR (400 MHz, CDCl3): δ 3.52 (s, 3H), 3.55 (s, 3H), 5.28 (s, 2H), 5.29 (s, 2H), 6.05 (s, 2H),

6.89 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (d, J = 15.6 Hz, 1H), 7.45 (d, J = 2 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 8.4, 1.6 Hz, 1H), 7.72 (d, J = 15.6 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 56.3, 95.1, 95.5, 101.8, 107.8, 108.4,

115.9, 116.2, 120.4, 123.8, 124.6, 129.5, 133.1, 143.9, 147.4, 148.2, 149.4, 151.6, 188.3. IR (UATR): νmax 2956, 2902, 2827, 1654, 1588, 1504, 1439 cm−1. LRMS (EI): m/z (rel intensity) 149(74), 174(27), 295(36), 296 (100), 372(M+, 37). TOF-HRMS: calcd for C20H20NaO7 (M + Na+) 395.1101, found 395.1114.

(E)-3-(2-Methoxy-4-(methoxymethoxy)phenyl)-1-(4-(methoxymethoxy)phenyl)prop-2-en-1one (I1l). Following the General Procedure for the Claisen–Schmidt condensation described above, the desired product was obtained as a yellow solid (504 mg, 1.41 mmol, 69 %). Mp 97.5– 99.1 °C. 1H NMR (300 MHz, CDCl3): δ 3.49 (s, 6H), 3.89 (s, 3H), 5.20 (s, 2H), 5.24 (s, 2H), 6.61 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.7, 2.1 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 3.3, 1H), 8.00–8.07 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 55.4, 56.1, 93.9, 94.2, 99.9, 107.8, 115.6, 117.9, 120.5, 130.9, 130.5, 132.4, 139.5, 160.1, 160.3, 160.6, 189.4. IR (UATR): νmax 2955,


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2902, 1654, 1599, 1502, 1149 cm−1. LRMS (EI): m/z (rel intensity) 135(14), 165(14), 327(100), 328(19), 358(M+, 7). TOF-HRMS: calcd for C20H22NaO6 (M + Na+) 381.1308, found 381.1300.

Deprotection of MOM ether. To a solution of MOM-protected chalcones (1.0 mmol) in ethanol (8 mL) was slowly added a solution of HCl (10% aqueous solution, 3.5 mL). The mixture was refluxed for 30 min. After cooling down to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product in good purity which was used in the next step without further purification.

(E)-3-(4-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2b). Following the General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a yellow solid (705 mg, 2.77 mmol, 89 %). Mp 158.6–160.5 °C.

1

H NMR (300

MHz, acetone-d6): δ 3.84 (s, 3H), 6.79 (d, J = 9.0 Hz, 2H), 7.01 (d, 9.0 Hz, 2H), 7.55 (d, J = 15.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 15.5 Hz, 1H), 8.04 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz, acetone-d6): δ 56.1, 114.9, 116.9, 119.4, 127.8, 131.8, 131.9, 132.3, 146.1, 161.5, 165.2, 191.1. IR (UATR): max 3158, 2935, 2129, 1642, 1599, 1578, 1556 cm-1. TOF-HRMS: calcd for C16H15O3 (M + H+) 255.1016, found 255.1010. These spectroscopic data matched those reported previously.12



(E)-3-(2-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2c). Following the General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a yellow solid (286 mg, 1.12 mmol, 70 %). Mp 148.2−149.0 °C. 1H NMR (400 MHz, acetone-d6) δ 3.91 (s, 3H), 6.94 (t, J = 7.6, 1H), 7.02 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.27–7.31 (m, 1H), 7.81 (dd, J = 7.6, 1.6 Hz, 1H), 7.91 (d, J = 16.0 Hz, 1H), 8.15 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 15.6 Hz, 1H), 9.19 (s, 1H). 13C NMR (100 MHz, acetone-d6): δ 55.1, 113.8, 116.2, 120.0, 121.5, 122.3, 128.8, 130.6, 131.4, 131.5, 138.7, 156.9, 163.4, 187.7. IR (UATR): νmax 3167, 2923, 1641, 1582, 1457, 1171, 1020 cm−1. LRMS (EI): m/z (rel intensity) 254 (M+, 6), 237 (54), 135 (100), 108 (45), 77 (15), 57 (13). TOF-HRMS: calcd for C16H14NaO3 (M + Na+) 277.0835, found 277.0844. These spectroscopic data matched those reported previously. 12

(E)-3-(3-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2d). Following the General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a pale yellow solid (1.33 g, 5.23 mmol, 96 %). Mp 150.5−152.8 °C. 1H NMR (400 MHz, acetone-d6): δ 3.92 (s, 3H), 6.95 (br d, J = 5.6 Hz, 1H), 7.09 (d, 8.0 Hz, 2H), 7.29 (d, J = 13.6 Hz, 3H), 7.69 (d, J = 15.6 Hz, 1H), 7.81 (d, J = 15.6 Hz, 1H), 8.17 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, acetone-d6): δ 55.1, 114.8, 117.3, 119.9, 121.9, 129.9, 130.7, 131.1, 136.7, 143.2, 157.8, 163.6, 187.3. IR (UATR): max 3328, 2969, 1650, 1584, 1447, 1262 cm-1. LRMS (EI): m/z (rel intensity) 71 (18), 91 (14), 135 (100), 237 (23), 254 (M +, 86). TOF-HRMS: calcd for C16H15O3 (M + H+) 255.1016, found 255.1010. These spectroscopic data are in good accordance with those reported previously. 12


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(E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2e). Following the General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a yellow oil (85.1 mg, 0.29 mmol, 98 %). 1H NMR (300 MHz, CDCl3): δ 3.86 (s, 3H), 3.91 (s, 3H), 6.35 (br s, OH), 6.93−6.97 (m, 3H), 7.11 (d, J = 1.5 Hz, 1H), 7.17−7.20 (m, 1H), 7.39 (d, J = 15.6 Hz, 1H), 7.74 (d, J = 15.6 Hz, 1H), 8.02 (d, J = 8.7 Hz, 2H). 13

C NMR (75 MHz, CDCl3): δ 55.4, 55.9, 110.0, 113.7, 114.9, 119.3, 123.1, 127.5, 130.7, 131.1,

144.4, 146.8, 148.2, 163.2. 188.8. IR (UATR): max 3371, 2937, 1596, 1508, 1252, 1166 cm-1. LRMS (EI): m/z (rel intensity) 55 (50), 57 (74), 69 (42), 149 (41), 284 (M +, 100). TOF-HRMS: calcd for C17H17O4 (M + H+) 285.1130, found 285.1121.

(E)-3-(3-Hydroxy-4-methoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2f). Following the General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a brown solid (601 mg, 2.12 mmol, 99 %). Mp 126.6−128.2 °C. 1H NMR (400 MHz, CDCl3): δ 3.92 (d, J = 0.8 Hz, 6H), 7.03 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 9.2 Hz, 2H), 7.26 (dd, J = 2.4, 2.4 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 3.2 Hz, 2H), 7.85 (s, 1H), 8.18 (d, J = 9.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 55.0, 55.4, 111.4, 113.8, 113.8, 119.6, 122.1, 128.6, 130.6, 131.4, 143.4, 146.9, 149.8, 163.4, 187.2. IR (UATR): νmax 3384, 2840, 1600, 1508, 1259, 1169, 1023 cm−1. LRMS (EI): m/z (rel intensity) 124 (24), 135 (100), 269 (54), 284 (M+, 92). TOF-HRMS: calcd for C17H17O4 (M + H+) 285.1121, found 285.1124.



Page 28 of 65

(E)-3-(3,4-Dihydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2g).

Following

the

General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a yellow solid (464 mg, 1.72 mmol, 87 %). Mp 74.2−76.6 °C. 1H NMR (400 MHz, acetone-d6): δ 3.77 (s, 3H), 6.76 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.05 (dd, J = 8.4, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 2H), 7.51 (d, J = 2.4 Hz, 2H), 8.00 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, acetone-d6): δ 55.9, 114.6, 115.6, 116.3, 119.6, 122.9, 128.4, 131.4, 132.3, 144.6, 146.3, 148.8, 164.2, 188.1. IR (UATR): νmax 3329, 29842, 1646, 1598, 1510, 1257, 1169 cm−1. LRMS (EI): m/z (rel intensity) 57 (100), 71 (82), 97 (60), 149 (56), 178 (27), 221 (16), 270 (M+, 10). TOF-HRMS: calcd for C16H15O4 (M + H+) 271.0962, found 271.0963.

(E)-3-(3,4-Dihydroxyphenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one

(I2h).

Following

the

General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a red solid (408 mg, 1.59 mmol, 98 %). Mp 189.7−191.7 °C. 1H NMR (400 MHz, acetone-d6): δ 6.77 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 2H), 7.05 (dd, J = 8.2, 2.2 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 2.4 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 8.49 (br s, 3OH).

13

C NMR (100 MHz, acetone-d6): δ 114.8, 115.3, 115.5, 118.9, 122.1, 127.6, 130.6,

130.9, 143.6, 145.4, 147.9, 161.7, 187.3. IR (UATR): max 3256, 1578, 1508, 1368, 1238 cm-1. LRMS (EI): m/z (rel intensity) 57 (100), 71 (86), 83 (71), 97 (85), 127 (32), 256 (M+, 9). TOFHRMS: calcd for C15H13O4 (M + H+) 257.0810, found 257.0808. These spectroscopic data are in good accordance with those reported previously. 12


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(E)-1-(3,4-Dimethoxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one

(I2i).

Following

the

General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a yellow solid (458 mg, 1.61 mmol, 88 %). Mp 143.0−144.1 °C. 1H NMR (400 MHz, acetone-d6): δ 3.91(s, 3H), 3.92 (s, 3H), 6.92 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 2 Hz, 1H), 6.69 (d, J = 8.8 Hz, 2H), 7.72 (s, 2H), 7.85 (dd, J = 8.4, 2.0 Hz, 1H), 9.04 (br s, 1H).

13

C NMR (100 MHz, acetone-d6): δ 55.2, 55.3, 110.6, 111.0, 115.8, 118.7, 122.8,

127.0, 130.5, 131.5, 143.3, 149.4, 153.5, 159.7, 187.2. IR (UATR): νmax 3272, 2935, 1643, 1560, 1509, 1257, 1020 cm−1. LRMS (EI): m/z (rel intensity) 57 (31), 84 (27), 149 (33), 165 (26), 253 (44), 269 (22), 284 (M+, 100). TOF-HRMS: calcd for C17H17O4 (M + H+) 285.1121, found 285.1117.

(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-hydroxyphenyl)prop-2-en-1-one (I2j). Following the General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a yellow solid (677 mg, 2.52 mmol, 99 %). Mp 161.3−163.3 °C. 1H NMR (400 MHz, acetone-d6): δ 6.15 (s, 2H), 6.93 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 6.0 Hz, 3H), 7.74 (s, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 8.94 (s, OH). 13

C NMR (100 MHz, acetone-d6): δ 102.1, 107.8, 107.8, 115.8, 124.4, 126.9, 130.6, 131.8,

133.3, 143.7, 148.4, 151.6, 159.9, 186.8. LRMS (EI): m/z (rel intensity) 57(43), 84 (100), 149



(30), 174 (24), 268 (82, M+). TOF-HRMS: calcd for C16H12NaO4 (M + Na+) 291.0628, found 291.0632. These spectroscopic data are in good accordance with those reported previously. 22

(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(3,4-dihydroxyphenyl)prop-2-en-1-one (I2k). Following the General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a yellow solid (515 mg, 1.81 mmol, 84 %). Mp 215.8−216.8 °C. 1H NMR (400 MHz, acetone-d6): δ 6.00 (s, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 8.4, 1.6 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.68 (dd, J = 1.6, 8.0 Hz, 1H), 8.26 (br s, 2H).

13

C NMR (100 MHz, acetone-d6): δ

102.1, 107.8, 107.8, 114.9, 115.5, 118.7, 122.2, 124.4, 127.6, 133.3, 144.1, 145.4, 148.0, 148.3, 151.5, 186.8. IR (UATR): νmax 3469, 3247, 1642, 1562, 1436, 1253, 1027 cm−1. LRMS (EI): m/z (rel intensity) 57 (57), 71 (40), 84 (100), 97 (28), 149 (33), 167 (12), 284 (M+, 2). TOF-HRMS: calcd for C16H13O5 (M + H+) 285.0758, found 285.0765.

(E)-3-(4-Hydroxy-2-methoxyphenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one (I2l). Following the General Procedure for the deprotection of the MOM ether described above, the desired product was obtained as a red solid (315 mg, 1.20 mmol, 96 %). Mp 175.3−177.4 °C. 1H NMR (300 MHz, acetone-d6): δ 3.92 (s, 3H), 6.53 (dd, J = 8.4, 2.1 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 6.0 Hz, 2H), 7.70 (d, 6.0 Hz, 1H), 7.74 (s, 1H), 8.04−8.10 (m, 3H), 9.13 (br s, 2OH). 13

C NMR (75 MHz, acetone-d6): δ 55.9, 99.8, 108.8, 115.9, 116.6, 119.5, 131.0, 131.5, 139.2,


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161.4, 162.1, 162.3, 188.3, 206.3. IR (UATR): max 3238, 1603, 1575, 1201, 1163 cm-1. LRMS (EI): m/z (rel intensity) 55 (24), 65 (31), 121 (38), 239 (100), 270 (M +, 7). TOF-HRMS: calcd for C16H15O4 (M + H+) 271.0965, found 271.0971. These spectroscopic data are in good accordance with those reported previously. 22

Acetylation. A solution of the chalcones (1.0 equiv) and N,N-dimethylaminopyridine (DMAP; 0.5 equiv) in dry dichloromethane (10 mL/mmol) was cooled in an ice bath for 10 min before Et3N (1.3−4.0 equiv), and AcCl (1.5−5.0 equiv) were added successively. The mixture was warmed to room temperature, at which it was stirred for 2 h. The reaction mixture was quenched with water (2 mL). The resulting mixture was extracted with DCM (3 x 10 mL), and the combined organic phases were washed with water (3 x 5 mL) and brine (1 x 5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica (25% EtOAc/hexane) to give the desired product.

(E)-4-(3-(4-Methoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl

acetate

(26b).

Following

the

General Procedure for the acetylation described above, the desired product was obtained as a pale yellow solid (627 mg, 2.12 mmol, 81 %). Mp 133.5−135.2 °C. 1H NMR (300 MHz, CDCl3): δ 2.32 (s, 3H), 3.88 (s, 3H), 6.99 (d, J = 9.0, 2H), 7.16 (d, 9.0 Hz, 2H), 7.49 (d, J = 15.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 2H), 7.78 (d, J = 15.0 Hz, 1H), 8.04 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 21.1, 55.5, 113.8, 121.9, 122.11, 129.4, 130.8, 130.9, 132.8, 142.8, 152.1, 163.4, 169.1, 188.5. IR (UATR): max 2940, 2846, 1755, 1655, 1598, 1580, 1420 cm-1. LRMS (EI): m/z (rel intensity) 135 (41), 160 (23), 253 (33), 254 (100), 296 (M +, 16). TOF-HRMS: calcd for



Page 32 of 65

C18H17O4 (M + H+) 297.1121, found 297.1122. These spectroscopic data are in good accordance with those reported previously.23

(E)-2-(3-(4-Methoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl acetate (26c). Following the General Procedure for the acetylation described above, the desired product was obtained as a yellow solid (303 mg, 1.02 mmol, 99 %). Mp 125.6−127.6 °C. 1H NMR (400 MHz, CDCl3): δ 2.37 (s, 3H), 3.87 (s, 3H), 6.98 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 15.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 16.0 Hz, 1H), 8.02 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 20.9, 29.6, 55.4, 113.8, 123.1, 123.8, 126.3, 127.4, 127.8, 130.8, 131.0, 131.4, 137.0, 149.6, 163.5, 169.2, 188.3. IR (UATR): νmax 3078, 2938, 1755, 1652, 1597, 1201, 1176, 827 cm−1. LRMS (EI): m/z (rel intensity) 108 (41), 135 (100), 221 (6), 237 (96), 254 (11), 296 (M+, 1). TOF-HRMS: calcd for C18H17O4 (M + H+) 297.1120, found 297.1121.

(E)-3-(3-(4-Methoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl

acetate

(26d).

Following

the

General Procedure for the acetylation described above, the desired product was obtained as a yellow solid (1.25 g, 4.22 mmol, 82 %). Mp 96.1−98.1 °C. 1H NMR (400 MHz, CDCl3): δ 2.33 (s, 3H), 3.88 (s, 3H), 6.98 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.43−7.38 (m, 2H), 7.48 (s, 1H), 7.52 (d, J = 15.6 Hz, 1H), 7.75 (d, J = 15.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 21.1, 55.5, 113.9, 120.9, 122.8, 123.4, 126.1, 129.9, 130.9, 136.7, 142.7, 151.1, 163.6, 169.4, 188.4. IR (UATR): νmax 2936, 1753, 1659, 1597, 1309, 1198 cm−1. LRMS (EI): m/z (rel intensity) 123 (100), 189 (18), 234 (15), 296 (M +, 3) 485 (20) 530 (18). TOFHRMS: calcd for C18H16NaO4 (M + Na+) 319.0940, found 319.0939.


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(E)-2-Methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl acetate (26e). Following the General Procedure for the acetylation described above, the desired product was obtained as a yellow solid (285 mg, 0.87 mmol, 85 %). Mp 116.1−119.2 °C. 1H NMR (300 MHz, CDCl3): δ 2.34 (s, 3H), 3.90 (s, 6H), 6.99 (d, J = 9.0 Hz, 2H), 7.09 (d, J = 8.7 Hz, 1H), 7.20 (s, 1H), 7.24 (s, 1H), 7.47 (d, J = 15.6 Hz, 1H), 7.75 (d, J = 15.6 Hz, 1H), 8.04 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 20.5, 55.3, 55.8, 111.7, 113.7, 121.1, 121.7, 123.1, 133.9, 141.3, 143.1, 151.2, 163.3, 168.6, 188.3. IR (UATR): νmax 2938, 2841, 1763, 1658, 1598, 1507, 1464, 1418 cm−1. LRMS (EI): m/z (rel intensity) 77 (25), 135 (35), 269 (16), 284 (100), 325 (M +, 5). TOF-HRMS: calcd for C19H18NaO5 (M + Na+) 349.1045, found 349.1046. These spectroscopic data are in good accordance with those reported previously. 23

(E)-2-Methoxy-5-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl acetate (26f). Following the General Procedure for the acetylation described above, the desired product was obtained as a yellow solid (746 mg, 2.29 mmol, 99 %). Mp 136.2−138.1 °C. 1H NMR (300 MHz, CDCl3): δ 2.33 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 6.95 (d, J = 9.0Hz, 3H), 7.40 (d, J = 15.6 Hz, 2H), 7.45 (dd, J = 8.7, 2.1 Hz, 2H), 7.71 (d, J = 15.6 Hz, 1H), 8.02 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 20.5, 55.3, 55.9, 112.3, 113.7, 120.4, 121.8, 128.1, 128.2, 130.6, 131.0, 139.9, 142.7, 152.8, 163.2, 168.7, 188.3. IR (UATR): νmax 2841, 1761, 1600, 1509, 1258, 1023 cm−1. LRMS (EI): m/z (rel intensity) 135 (48), 267 (17), 269 (63), 284 (100), 326 (M +, 27). TOF-HRMS: calcd for C19H19O5 (M + H+) 327.1227, found 327.1222.



(E)-4-(3-(4-Methoxyphenyl)-3-oxoprop-1-en-1-yl)-1,2-phenylene diacetate (26g). Following the General Procedure for the acetylation described above, the desired product was obtained as a white solid (530 mg, 1.49 mmol, 99 %). Mp 126.1−127.0 °C. 1H NMR (400 MHz, CDCl3): δ 2.31 (s, 3H), 2.32 (s, 3H), 3.87 (s, 3H), 6.98 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 9.2 Hz, 1H), 7.45– 7.52 (m, 3H), 7.72 (d, J = 15.6 Hz, 1H), 8.02 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 20.5, 20.5, 55.4, 113.8, 122.6, 122.7, 123.8, 126.7, 130.7, 130.8, 133.9, 141.8, 142.3, 143.4, 163.4, 167.9, 168.0, 188.1. IR (UATR): νmax 3009, 2939, 1757, 1655, 1591, 1171, 1015 cm−1. LRMS (EI): m/z (rel intensity) 354 (M+, 6), 312 (28), 270 (100), 242 (12), 160 (6), 135 (16). TOF-HRMS: calcd for C20H18NaO6 (M + Na+) 377.0992, found 377.0992.

(E)-4-(3-(4-Acetoxyphenyl)-3-oxoprop-1-en-1-yl)-1,2-phenylene diacetate (26h). Following the General Procedure for the acetylation described above, the desired product was obtained as a yellow solid (480 mg, 1.26 mmol, 89 %). Mp 146.8−148.1 °C. 1H NMR (400 MHz, CDCl3): δ 2.22 (s, 3H), 2.24 (s, 3H), 2.25 (s, 3H), 7.16 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 7.35 (d, J = 16.0 Hz, 1H), 7.39–7.43 (m, 2H), 7.66 (d, J = 16.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 20.5, 20.6, 21.1, 121.8, 122.7, 122.8, 123.9, 126.8, 130.1, 133.6, 135.4, 142.5, 142.9, 143.7, 154.2, 157.9, 168.0, 168.8, 188.7. IR (UATR): νmax 3047, 1749, 1667, 1597, 1505, 1371, 1179 cm−1. LRMS (EI): m/z (rel intensity) 228 (11), 255 (26), 256 (90), 298 (100), 382 (4, M+). calcd for C21H19O7 (M + H+) 383.1125, found 383.1137.

(E)-4-(3-(3,4-Dimethoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl acetate (26i). Following the General Procedure for the acetylation described above, the desired product was obtained as a yellow oil (443 mg, 1.36 mmol, 97 %). 1H NMR (400 MHz, CDCl3): δ 2.31 (s, 3H), 3.96 (d, J =


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3.2 Hz, 6H), 6.92 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 15.6 Hz, 1H), 7.62−7.69 (m, 4H), 7.78 (d, J = 15.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 21.0, 55.9, 109.9, 110.6, 121.6, 122.0, 122.9, 129.3, 131.1, 132.6, 142.7, 149.1, 152.0, 153.2, 169.0, 188.2. IR (UATR): νmax 2952, 2836, 1651, 1601, 1504, 1258, 1151 cm−1. LRMS (EI): m/z (rel intensity) 137 (100), 149 (26), 161 (42), 177 (41), 191 (19) 229 (14) 326 (M +, 1). TOF-HRMS: calcd for C19H18NaO5 (M + Na+) 349.1046, found 349.1055.

(E)-4-(3-(Benzo[d][1,3]dioxol-5-yl)-3-oxoprop-1-en-1-yl)phenyl acetate (26j). Following the General Procedure for the acetylation described above, the desired product was obtained as a pale yellow solid (769 mg, 2.48 mmol, 99 %). Mp 140.6−142.3 °C. 1H NMR (400 MHz, CDCl3): δ 2.32 (s, 3H), 6.06 (s, 2H), 6.89 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 15.6 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 3H), 7.77 (d, J = 15.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 21.1, 101.8, 107.9, 108.3, 121.7, 122.1, 124.6, 129.4, 132.6, 132.8, 143.0, 148.3, 151.7, 152.1, 169.1, 188.0. IR (UATR): νmax 2913, 1755, 1593, 1441, 1245, 1037, 913 cm−1. LRMS (EI): m/z (rel intensity) 149 (50), 174 (95), 268 (100), 310 (M +, 19). TOF-HRMS: calcd for C18H15O5 (M + H+) 311.0914, found 311.0913.

(E)-4-(3-(Benzo[d][1,3]dioxol-5-yl)-3-oxoprop-1-en-1-yl)-1,2-phenylene

diacetate

(26k).

Following the General Procedure for the acetylation described above, the desired product was obtained as a yellow solid (511 mg, 1.39 mmol, 84 %). Mp 141.6−143.7 °C. 1H NMR (400 MHz, CDCl3): δ 2.30 (s, 3H), 2.32 (s, 3H), 6.07 (s, 2H), 6.88 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 15.6 Hz, 1H), 7.46−7.48 (m, 2H), 7.52 (d, J = 1.6 Hz, 1H), 7.63 (dd, J = 8.0, 1.6 Hz, 1H), 7.73 (d, J = 15.6 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 20.5, 20.6, 101.8, 107.8,



108.3, 122.6, 122.7, 123.9, 124.7, 126.7, 132.6, 133.8, 142.1, 142.4, 143.5, 148.3, 151.8, 167.9, 168.0, 187.7. IR (UATR): νmax 3072, 2908, 1767, 1658, 1595, 1199, 1013 cm−1. LRMS (EI): m/z (rel intensity) 149 (6), 174 (13), 256 (8), 284 (100), 326 (24), 368 (11, M+). TOF-HRMS: calcd for C20H16NaO7 (M + Na+) 391.0788, found 391.0783.

(E)-4-(3-(4-Acetoxy-2-methoxyphenyl)acryloyl)phenyl acetate (26l). Following the General Procedure for the acetylation described above, the desired product was obtained as a yellow solid (740 mg, 2.09 mmol, 70 %). Mp 97.5−99.1 °C. 1H NMR (300 MHz, CDCl3): δ 2.32 (s, 3H), 2.34 (s, 3H), 3.90 (s, 3H), 6.71 (d, J = 2.1 Hz, 1H), 6.76 (dd, J = 8.4, 2.1 Hz, 1H), 7.23 (d, J = 6.9 Hz, 1H), 7.56 (d, J = 15.6 Hz, 1H),7.63 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 15.9 Hz, 2H), 8.05 (d, J = 6.9 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 21.0, 55.7, 105.2, 113.8, 121.5, 121.6, 122.2, 129.9, 130.0, 135.9, 139.6, 153.3, 153.8, 159.5, 168.8, 169.0, 189.6. IR (UATR): νmax 2940, 1757, 1659, 1596, 1497, 1368, 1267, 1184, 1011 cm−1. LRMS (EI): m/z (rel intensity) 121 (27), 239 (100), 281 (73), 323 (46), 354 (M+, 4). TOF-HRMS: calcd for C20H18NaO6 (M + Na+) 377.0996, found 377.0996.

General procedure for the Diels-Alder reaction of aryldiene (21a and 21b) with chalcone (26b-26l)

To a solution of aryldiene (1.0 equiv) and chalcone (0.8 equiv) in toluene (10 mL/5 mmol) was placed in a sealed tube under magnetic stirring at 130 °C for 48 h. The cooled toluene was then evaporated under reduced pressure and the crude product was chromatographically purified over silica gel (20% EtOAc/hexane) to produce the desired cycloadduct.


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(2-Methoxy-5'-methyl-1',2',3',4'-tetrahydro-[1,1':3',1''-terphenyl]-2'-yl)(phenyl)methanone (19). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a white gummy solid (195 mg, 0.51 mmol, 45 %) of a 10:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.86 (s, 3H, major), 1.81 (s, 3H, minor), 2.22−2.29 (m, 1H, major), 2.22−2.29 (m, 1H, minor), 2.41−2.47 (dd, J = 18.0, 5.6 Hz, 1H, major), 2.41−2.47 (dd, J = 18.0, 5.6 Hz, 1H, minor), 2.91 (s, 3H, major), 3.32 (td, J = 6.0 Hz, 11.0 Hz, 1H, major), 3.42 (s, 3H, minor), 3.49 (td, J = 5.2, 11.6 Hz, 1H, minor), 4.39 (dd, J = 11.6, 5.6 Hz, 1H, major), 4.49 (br s, 1H, major), 5.43 (br s, 1H, minor), 5.53 (d, J = 1.8 Hz, 1H, major), 6.45 (d, J = 8.0 Hz, 1H, minor), 6.59 (d, J = 8.0 Hz, 1H, major), 6.85−6.88 (m, 1H, minor), 6.94−7.03 (m, 2H), 7.07−7.08 (d, J = 4.8 Hz, 4H), 7.13−7.21 (m, 2H), 7.29 (dd, J = 7.6, 1.6 Hz, 1H), 7.35−7.39 (m, 2H), 7.43−7.47 (m, 1H).

13

C NMR (100 MHz, CDCl3): δ 23.1

(minor), 23.2 (major), 37.2 (major), 38.1 (minor), 38.8 (minor), 40.2 (major), 44.7 (minor), 50.5 (major), 53.5 (major), 53.6 (minor), 54.8 (minor), 109.3 (major), 110.4 (minor), 119.7 (major), 120.6 (minor), 122.6 (major), 124.8 (minor), 125.8 (major), 126.1 (minor), 127.3 (minor), 127.4 (major), 127.6 (major), 127.6 (minor), 127.9 (minor), 128.0 (major), 128.1 (major), 128.4 (major), 130.7 (major), 131.5 (minor), 131.6 (major), 132.4 (minor), 133.5 (minor), 135 (major), 138.5 (minor), 138.6 (major), 143.8 (minor), 145.2 (major), 156.9 (major), 198.9, 203.9 (minor). TOF-HRMS: calcd for C27H27O2 (M + H+) 383.2005, found 383.1995.

(4-Methoxy-2-(methoxymethoxy)-5'-methyl-1',2',3',4'-tetrahydro-[1,1':3',1''-terphenyl]-2'yl)(phenyl)methanone (27a). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a yellow oil (219 mg, 0.49 mmol, 52 %) of



a 2.4:1 inseparable mixture of endo:exo isomers. 1H NMR (300 MHz, CDCl3): δ 1.80 (s, 3H, minor), 1.85 (s, 3H, major), 2.20−2.33 (m, 1H, major), 2.20−2.33 (m, 1H, minor), 2.45 (dd, J = 18.0, 5.7 Hz, 1H, major), 2.45 (dd, J = 18.0, 5.7 Hz, 1H, minor), 2.99 (s, 3H, major),3.34 (s, 3H, minor), 3.37−3.41 (m, 1H, major), 3.37−3.41 (m, 1H, minor), 3.68 (s, 3H, minor), 3.75 (s, 3H, major), 3.88 (d, J = 6.9 Hz, 1H, major), 4.36 (dd, J = 11.1, 5.4 Hz, 1H), 4.43 (br s, 1H, major), 4.72 (d, J = 6.9 Hz, 1H, minor), 4.89 (d, J = 6.9 Hz, 1H, minor), 5.41 (br s, 1H, minor), 5.52 (d, J = 1.8 Hz, 1H, major), 6.39 (d, J = 8.4 Hz, 1H), 6.49 (dd, J = 8.4, 2.4 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.57 (s, 2H), 6.97−7.13 (m, 8H), 7.18−7.23 (m, 3H), 7.37 (t, J = 7.8 Hz, 3H), 7.46 (t, J = 7.2 Hz, 1H), 7.81(d, J = 8.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 23.0 (major), 23.1 (minor), 36.9 (major), 38.1 (major), 38.7 (minor), 39.8 (major), 44.9 (minor), 50.7 (major), 53.3 (minor), 54.1 (minor), 54.9 (major), 55.1 (minor), 55.2 (major), 55.7 (minor), 94.2 (major), 94.5 (minor), 100.4 (major), 100.7 (minor), 105.6 (major), 106.7 (minor), 121.0 (minor), 122.8 (major), 125.1 (minor), 125.7 (major), 126.1 (minor), 127.2 (major), 127.3 (major), 127.4 (major), 127.5 (major), 127.9 (major), 128.0 (major), 129.2 (minor), 131.1 (major), 131.7(minor), 131.9 (minor), 133.1 (minor), 134.5 (major), 138.5(minor), 138.7 (major), 143.4 (minor), 145.0 (major), 155.6 (minor), 156.1 (major), 159.1 (minor), 159.4 (major), 199.5 (major), 204.4 (minor). IR (UATR): νmax 2909, 2832, 1670, 1608, 1583, 1503 cm−1. LRMS (EI): m/z (rel intensity) 77 (35), 105 (100), 175 (18), 189 (35), 442 (M +, 4) .TOF-HRMS: calcd for C29H30NaO4 (M + Na+) 465.2034, found 465.2036.

4''-Methoxy-2'-(4-methoxybenzoyl)-2''-(methoxymethoxy)-5'-methyl-1',2',3',6'-tetrahydro[1,1':3',1''-terphenyl]-4-yl acetate (27b). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a white solid (290 mg, 0.55 mmol,


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63 %) of a 1.8:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.56 (s, 3H, minor), 1.79 (s, 3H, major), 2.19 (s, 3H, minor), 2.20 (s, 3H, major), 2.18−2.30 (s, 1H, major), 2.18−2.30 (s, 3H, minor), 2.32 (s, 3H, minor), 2.43 (dd, J = 24.0, 7.6 Hz, 1H, major), 2.43 (dd, J = 24.0, 7.6 Hz, 1H, minor), 3.05 (s, 3H, major), 3.31−3.40 (m, 1H, minor), 3.38 (s, 3H, minor), 3.47 (td, J = 7.2, 14.8 Hz, 1H, major), 3.69 (s, 3H, minor), 3.72 (s, 3H, minor), 3.75 (s, 3H, major), 3.84 (s, 3H, major), 3.89 (s, 3H, minor), 3.97 (d, J = 9.2 Hz, 1H, major), 4.25 (dd, J = 14.8, 7.2 Hz, 1H, major), 4.25 (dd, J = 14.8, 7.2 Hz, 1H, minor), 4.39 (br s, 1H, major), 4.57 (d, J = 9.2 Hz, 1H, major), 4.70 (d, J = 8.8 Hz, 1H, minor), 4.88 (d, J = 8.8 Hz, 1H, minor), 5.41 (br s, 1H, minor), 5.51 (d, J = 5.2 Hz, 1H, major), 6.40 (d, J = 3.2 Hz, 1H), 6.49 (dd, J = 11.6, 3.2 Hz, 1H), 6.53−6.58 (m, 3H), 6.78−6.88 (m, 5H), 6.97 (d, J = 2.8 Hz, 1H), 7.11 (d, J = 11.2 Hz, 1H), 7.14−7.25 (m, 3H), 7.50 (d, J = 20.8 Hz, 1H), 7.65 (d, J = 11.2 Hz, 1H), 7.78 (d, J = 12.0 Hz, 2H), 8.03 (d, J = 12.0 Hz, 1H).

13

C NMR (100 MHz, CDCl3): δ 21.1 (minor), 23.2

(major), 36.8 (major), 37.8 (major), 38.9 (minor), 39.7 (major), 44.3 (minor), 50.6 (minor), 55.1 (major), 55.2 (minor), 55.3 (minor), 55.4 (major), 55.9 (minor), 94.6 (major), 94.8 (minor), 100.7 (major), 100.9 (minor), 105.8 (major), 106.9 (minor), 112.9 (major), 113.3 (major), 120.9 (major), 121.1 (major), 121.4 (minor), 122.2 (minor), 123.1 (major), 125.3 (minor), 128.4 (major), 128.6 (major), 129.3 (minor), 129.4 (minor), 129.7 (major), 129.8 (major), 130.8 (minor), 131.2 (major), 131.8 (minor), 132.2 (major), 134.5 (major), 141.4 (minor), 142.8 (major), 148.6 (major), 148.9 (minor), 155.9 (minor), 156.3 (major), 159.3 (minor), 159.6 (major), 162.6 (minor), 162.7 (major), 169.3 (minor), 169.4 (major), 198.2 (major). IR (UATR): νmax 2935, 2837, 1763, 1665, 1599, 1504 cm−1. LRMS (EI): m/z (rel intensity) 135 (100), 189 (15), 234 (9), 323 (9), 485 (7), 530 (M+, 10). TOF-HRMS: calcd for C32H34NaO7 (M + Na+) 553.2196, found553.2186.



4''-Methoxy-2'-(4-methoxybenzoyl)-2''-(methoxymethoxy)-5'-methyl-1',2',3',6'-tetrahydro[1,1':3',1''-terphenyl]-2-yl acetate (27c). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a yellow solid (193 mg, 0.36 mmol, 52 %) of a 1.8:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.78 (s, 3H, minor), 1.85 (s, 3H, major), 2.16−2.30 (m, 1H, major), 2.16−2.30 (m, 1H, minor), 2.22 (s, 3H, major), 2.39−2.45 (m, 1H, major), 2.39−2.45 (m, 1H, minor), 2.41 (s, 3H, minor), 3.04 (s, 3H, major), 3.32 (s, 3H, minor), 3.55 (td, J = 6.0, 10.8 Hz, 1H, major), 3.66−3.72 (m, 1H, minor) 3.67 (s, 3H, minor), 3.68 (s, 3H, minor), 3.72 (s, 3H, major), 3.80 (s, 3H, major), 3.93 (d, J = 6.8 Hz, 1H, major), 4.19 (br s, 1H, minor), 4.26 (dd, J = 11.2, 5.2 Hz, 1H, major), 4.41 (br s, 1H, major), 4.59 (d, J = 6.8 Hz, 1H, major), 4.64 (d, J = 6.8 Hz, 1H, minor), 4.85 (d, J = 6.8 Hz, 1H, minor), 5.41 (s, 1H, minor), 5.52 (d, J = 4.0 Hz, 1H, major), 6.39 (d, J = 2.8 Hz, 1H), 6.46–6.56 (m, 3H), 6.59 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 9.2 Hz, 2H), 6.89–6.93 (m, 2H), 6.95– 6.99 (m, 1H), 7.00–7.06 (m, 1H), 7.10 (dd, J = 7.6, 1.2 Hz, 1H, major), 7.14 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 20.8 (major), 21.1 (minor), 23.0 (major), 23.1 (minor), 29.6 (minor), 30.9 (major), 36.9 (major), 38.2 (minor), 50.2 (major), 52.6 (minor), 55.1 (major), 55.2 (minor), 55.2 (major), 55.3 (major), 55.7 (minor), 94.5 (major), 94.6 (minor), 100.4 (major), 100.9 (minor), 105.6 (major), 106.8 (minor), 112.7 (minor), 113.2 (major), 121.0 (minor), 122.1 (major), 122.5 (minor), 122.8 (major), 125.1 (major), 125.2 (minor), 125.7 (minor), 125.9 (major), 126.5 (major), 126.7 (minor), 127.0 (minor), 129.2 (minor), 129.6 (major), 129.8 (minor), 130.2 (minor), 130.8 (major), 131.5 (minor), 131.8 (major), 133.2 (minor), 134.8 (major), 135.6 (minor), 136.9 (major), 148.2 (minor), 148.5 (major), 155.8 (minor), 156.4 (major), 159.2


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(minor), 159.5 (major), 162.4 (minor), 162.5 (major), 169.6 (major), 197.7 (major), 201.8 (minor). IR (UATR): νmax 2958, 2910, 1762, 1672, 1599, 1168, 1005 cm−1. LRMS (EI): m/z (rel intensity) 135 (100), 181 (12), 189 (16), 234 (11), 485 (10), 530 (M +, 8). TOF-HRMS: calcd for C32H34NaO7 (M + Na+) 553.2196, found 553.2212.

4''-Methoxy-2'-(4-methoxybenzoyl)-2''-(methoxymethoxy)-5'-methyl-1',2',3',6'-tetrahydro[1,1':3',1''-terphenyl]-3-yl acetate (27d). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a white gummy solid (445 mg, 0.83 mmol, 77 %) of a 1.8:1 inseparable mixture of endo:exo isomers.

1

H NMR (300 MHz,

CDCl3): δ 1.70 (s, 2H, minor), 1.82 (s, 3H, major), 2.20 (s, 3H, major), 2.24 (s, 3H, minor), 2.26–2.33 (m, 1H, major), 2.26–2.33 (m, 1H, minor), 2.46 (dd, J = 13.8, 4.5 Hz, 1H, major), 2.46 (dd, J = 13.8, 4.5 Hz, 1H, minor), 3.00 (s, 3H, major), 3.35 (s, 3H, minor), 3.32–3.40 (m, 1H, major), 3.43−3.50 (td, J = 3.9, 8.4 Hz, 1H, minor), 3.68 (s, 2H, minor), 3.72 (s, 2H, minor), 3.75 (s, 3H, major), 3.84 (s, 3H, minor), 3.95 (d, J = 5.1 Hz, 1H, major), 4.25 (dd, J = 8.4, 3.8 Hz, 1H, major), 4.25 (dd, J = 8.4, 3.8 Hz, 1H, minor), 4.39 (br s, 1H, minor), 4.57 (d, J = 5.1Hz, 1H, major), 4.70 (d, J = 5.1Hz, 1H, minor), 4.88 (d, J = 5.1 Hz, 1H, minor), 6.39 (d, J = 1.8Hz, 1H), 6.48 (dd, J = 6.3, 1.2 Hz, 1H), 6.53−6.58 (m, 3H), 6.71−6.77 (m, 2H), 6.85−6.89 (m, 4H), 6.95−6.99 (m, 2H), 7.04−7.11 (m, 2H), 7.24−7.26 (m, 2H), 7.14−7.17 (m, 2H), 7.78 (d, J = 8.4 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 20.6 (major), 22.8 (major), 22.9 (minor), 36.5 (minor), 37.8 (minor), 38.1 (major), 39.1 (major), 44.4 (major), 50.2 (major), 54.7 (major), 54.7 (minor), 54.8 (minor), 54.9 (major), 55.0 (major), 55.5 (minor), 94.2 (major), 94.4 (minor), 100.4 (major), 100.7(minor), 105.4 (major), 106.5 (minor), 122.6 (minor), 113.0 (minor), 118.6 (major), 118.9 (minor), 120.5 (minor), 120.7 (minor), 120.9 (major), 122.7 (major), 124.3



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(major), 124.7 (minor), 124.8 (minor), 125.0 (minor), 128.6 (major), 128.6 (major), 128.6 (minor), 129.0 (minor), 129.4 (major), 129.5 (major), 130.8 (major), 131.4 (minor), 131.6 (major), 132.7 (minor), 134.0 (major), 145.2 (major), 146.8 (major), 150.1 (major), 150.2 (minor), 155.5 (minor), 156.0, 158.9 (minor), 159.2 (major), 162.3 (major), 162.4 (minor), 168.7 (major), 168.8 (minor), 197.7 (major), 201.9 (minor). IR (UATR): νmax 2945, 2837, 1764, 1669, 1599, 1505 cm−1. TOF-HRMS: calcd for C32H34NaO7 (M + Na+) 553.2196, found 553.2198.

3,4''-Dimethoxy-2'-(4-methoxybenzoyl)-2''-(methoxymethoxy)-5'-methyl-1',2',3',6'tetrahydro-[1,1':3',1''-terphenyl]-4-yl acetate (27e). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a yellow oil (452 mg, 0.81 mmol, 51 %) of a 1.2:1 inseparable mixture of endo:exo isomers. 1H NMR (300 MHz, CDCl3) δ 1.79 (s, 3H, minor), 1.85 (s, 3H, major), 2.20 (s, 3H, major), 2.22 (s, 3H, major), 2.26−2.36 (m, 1H, major), 2.26−2.36 (m, 1H, minor), 2.45 (dd, J = 24.0, 7.6 Hz, 1H, major), 2.45 (dd, J = 24.0, 7.6 Hz, 1H, minor), 3.05 (s, 3H, major), 3.34 (s, 3H, minor), 3.40−3.51 (m, 1H, major), 3.40−3.51 (m, 1H, minor), 3.58 (s, 3H, minor), 3.60 (s, 3H, major), 3.69 (s, 3H, minor), 3.72 (s, 3H, minor), 3.75 (s, 3H, major), 3.84 (s, 3H, major), 3.97 (d, J = 9.2 Hz, 1H, major), 4.28 (dd, J = 15.2, 7.2 Hz, 1H, major), 4.28 (dd, J = 15.2, 7.2 Hz, 1H, minor), 4.41 (br s, 1H, minor), 4.58 (d, J = 8.8 Hz, 1H, major), 4.70 (d, J = 8.8 Hz, 1H, minor), 4.88 (d, J = 8.8 Hz, 1H, minor), 5.41 (br s, 1H, minor), 5.51 (br d, J = 6.0 Hz, 1H, major), 6.41 (d, J = 3.6 Hz, 1H), 6.49−6.60 (m, 5H), 6.63 (dd, J = 10.8, 2.4 Hz, 1H), 6.68−6.88 (m, 5H), 6.86 (d, J = 12.0 Hz, 2H), 7.17 (d, J = 11.2 Hz, 1H), 7.27 (d, J = 12.0 Hz, 2H), 7.81 (d, J = 12.0 Hz, 2H).

13

C NMR

(75 MHz, CDCl3): δ 20.6 (minor), 23.2 (major), 36.9 (major), 28.3 (major), 39.1 (minor), 40.1 (major), 44.9 (minor), 50.4 (major), 53.5 (minor), 55.1 (major), 55.2 (minor), 55.3 (minor), 55.4


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(major), 55.6 (major), 55.9 (minor), 94.6 (major), 94.8 (minor), 100.7 (major),100.9 (minor), 112.2 (major), 112.9 (major), 113.4 (major), 119.1 (major), 119.6 (minor), 121.3 (major), 122.2 (major), 122.3 (major), 122.9 (major), 125.2 (minor), 125.3 (major), 129.3 (minor), 129.7, 129.8 (minor), 131.2(major), 131.9 (minor), 132.2 (major), 133.3 (minor), 134.5 (major), 137.6 (major), 137.8 (minor), 142.8 (major), 144.4 (minor), 150.4 (major), 155.9 (minor), 156.4 (major), 159.3 (minor), 159.6 (major), 162.7 (major), 168.9 (minor), 169.1 (major), 198.3 (major), 202.5 (minor). IR (UATR): νmax 2937, 2837, 1763, 1670, 1599, 1505, 1464 cm−1. LRMS (EI): m/z (rel intensity) 107(5), 135(100), 202(6), 560(M +, 3) .TOF-HRMS: calcd for C33H36NaO8 (M + Na+) 583.2294, found 583.2302.

4,4''-Dimethoxy-2'-(4-methoxybenzoyl)-2''-(methoxymethoxy)-5'-methyl-1',2',3',6'tetrahydro-[1,1':3',1''-terphenyl]-3-yl acetate (27f). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a white gummy solid (210 mg, 0.37 mmol, 65 %) of a 1.9:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.78 (s, 3H, minor), 1.83 (s, 3H, major), 2.18 (s, 3H, major), 2.19 (s, 3H, minor), 2.24–2.35 (m, 1H, major), 2.24–2.35 (m, 1H, minor), 2.43 (dd, J = 13.8, 4.5 Hz, 1H, major), 2.41–2.47 (m, 1H, minor), 3.04 (s, 3H, major), 3.26–23.33 (m, 1H, major), 3.34 (s, 3H, minor) 3.40 (td, J = 3.9, 8.4 Hz, 1H, minor), 3.63 (s, 3H, minor), 3.65 (s, 3H, minor), 3.66 (s, 3H, major), 3.72 (s, 3H, major), 3.79 (s, 3H, major), 3.97 (d, J = 5.4 Hz, 1H, major), 4.18–4.22 (m, 1H, minor), 4.20 (dd, J = 8.8, 8.8 Hz, 1H, major), 4.38 (br s, 1H, major), 4.57 (d, J = 7.2 Hz, 1H, major), 4.71 (d, J =6.4 Hz, 1H, minor), 4.88 (d, J = 6.4 Hz, 1H, minor), 5.39 (br s, 1H, minor), 5.49 (br d, J = 4.0 Hz, 1H, major), 6.39 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 8.4 Hz), 6.52–6.55 (m, 2H), 6.58 (d, J = 2.0 Hz, 1H), 6.63–6.59 (m, 2H), 6.80–6.85 (m, 4H), 6.92 (td, J = 2.0, 8.4 Hz,



2H), 7.15 (d, J = 6.6 Hz, 1H), 7.27 (d, J = 6.9 Hz, 1H), 7.78 (d, J = 6.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 20.4 (major), 23.0 (minor), 36.6 (major), 37.2 (major), 38.4 (major), 39.4 (major), 43.7 (minor), 50.6 (major), 54.9 (major), 55.0 (minor), 55.1 (major), 55.1 (minor), 55.2 (major), 55.5 (major), 55.6 (minor), 55.7 (minor), 94.4 (major), 94.6 (minor), 100.5 (major), 106.7 (minor), 111.8 (major), 111.9 (minor), 112.8 (minor), 113.1 (major), 121.3 (major), 121.8 (minor), 122.0 (major), 122.8 (major), 125.1 (minor), 125.3 (major), 125.8 (minor), 129.6 (major), 129.7 (minor), 130.6 (major), 130.9 (major), 131.9 (major), 134.3 (major), 136.3 (minor), 137.8 (major), 139.0 (major), 139.2 (minor), 148.8 (major), 149.0 (minor), 155.6 (minor), 156.2 (major), 159.1 (minor), 159.4 (major), 162.4 (major), 162.5 (major), 168.5 (minor), 168.6 (major), 197.9 (major), 202.4 (minor). IR (UATR): νmax 2935, 2838, 1765, 1671, 1599, 1508 cm−1. LRMS (EI): m/z (rel intensity 135 (100), 136 (9), 189 (8), 323 (5), 560 (M +, 3). TOF-HRMS: calcd for C33H37O8 (M + H+) 561.2482, found 561.2481.

4''-Methoxy-2'-(4-methoxybenzoyl)-2''-(methoxymethoxy)-5'-methyl-1',2',3',6'-tetrahydro[1,1':3',1''-terphenyl]-3,4-diyl diacetate (27g). Following the General Procedure for the DielsAlder reaction described above, the desired product was obtained as a yellow oil (290 mg, 0.49 mmol, 70 %) of a 2:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.79 (s, 3H, minor), 1.84 (s, 3H, major), 2.17 (s, 3H, major), 2.17 (s, 3H, minor), 2.19 (s, 3H, major), 2.19 (s, 3H, minor), 2.23 (s, 3H, major), 2.23 (s, 3H, minor), 2.25–2.38 (m, 1H, major), 2.25–2.38 (m, 2H, minor) 2.46 (dd, J = 18.0, 6.0 Hz, 1H, major), 3.05 (s, 3H, major), 3.31–3.38 (m, minor), 3.36 (s, 1H, minor), 3.44 (td, J = 5.6, 11.2 Hz, 1H, major), 3.68 (s, 3H, minor) 3.71 (s, 3H, minor), 3.74 (s, 3H, major), 3.83 (s, 3H, major), 3.98 (d, J = 6.8 Hz, 1H, major), 4.20 (dd, J = 11.2, 5.6 Hz, 1H, major), 4.19–4.23 (m, 1H, minor), 4.39 (br s, 1H, major), 4.57 (d, J = 6.8


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Hz, 1H, major), 4.71 (d, J = 6.8 Hz, 1H, minor), 4.88 (d, J = 6.8 Hz, 1H, minor), 5.40 (br s, 1H, minor), 5.51 (br d, J = 4.0 Hz, 1H, major), 6.40 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 8.4, 2.4 Hz, 1H), 6.53–6.58 (m, 3H), 6.92–6.99 (m, 4H), 7.13 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.8 Hz, 2H).

13

C NMR (100 MHz, CDCl3): δ 20.5 (major), 20.6 (minor), 23.1

(majorr), 23.2 (minor), 36.7 (major), 37.8 (major), 38.3 (minor), 39.2 (major), 44.2 (major), 50.6 (major), 53.8 (minor), 55.1 (major), 55.2 (minor), 55.3 (major), 55.4 (major), 55.8 (minor), 94.4 (major), 94.7 (minor), 100.6 (major), 100.9 (minor), 105.7 (major), 106.8 (minor), 112.9 (minor), 113.3 (major), 121.2 (major), 122.6 (minor), 122.6 (major), 122.7 (minor), 122.8 (major), 122.9 (major), 125.1 (major), 125.2 (minor), 125.5 (minor), 129.2 (minor), 129.7 (major), 129.8 (minor), 131.1 (major), 131.7 (minor), 132.0 (major), 132.9 (minor), 134.3 (major), 139.8 (major), 140.1 (minor), 141.4 (major), 141.6 (minor), 142.5 (minor), 144.0 (major), 155.8 (minor), 156.2 (major), 159.2 (minor), 159.5 (major), 162.6 (minor), 162.6 (major), 167.9 (minor), 167.9 (major), 168.0 (minor), 168.1 (major), 198.0 (major), 202.3 (minor). IR (UATR): νmax 2935, 2837, 1769, 1671, 1599, 1178, 1007 cm−1. LRMS (EI): m/z (rel intensity) 135 (100), 189 (14), 234 (9), 323 (8), 543 (7), 588 (3, M+). TOF-HRMS: calcd for C34H36NaO9 (M + Na+) 611.2252, found 611.2257.

2'-(4-Acetoxybenzoyl)-4''-methoxy-2''-(methoxymethoxy)-5'-methyl-1',2',3',6'-tetrahydro[1,1':3',1''-terphenyl]-3,4-diyl diacetate (27h). Following the General Procedure for the DielsAlder reaction described above, the desired product was obtained as a white gummy solid (450 mg, 0.73 mmol, 89 %) of a 1.1:1 inseparable mixture of endo:exo isomers. 1H NMR (300 MHz, CDCl3): δ 1.79 (s, 3H, minor), 185 (s, 3H, major), 2.18 (s, 3H, major), 2.19 (s, 3H, major), 2.20 (s, 3H, minor), 2.23 (s, 3H, minor), 2.32 (s, 3H, major), 2.22−2.39 (m, 2H, minor), 2.22−2.39 (m,



1H, major), 2.46 (dd, J = 13.5, 4.2 Hz, 1H, major), 3.03 (s, 3H, major), 3.35 (s, 3H, minor), 3.31−3.38 (m, 1H, minor), 3.44 (td, J = 4.2, 8.4 Hz, 1H, major), 3.69 (s, 3H, minor), 3.76 (s, 3H, major), 3.98 (d, J = 5.1 Hz, 1H, major), 4.22 (m, 1H, minor), 4.42 (br s, 1H, major), 4.56 (d, J = 5.1 Hz, 1H, major), 4.75 (d, J = 4.8 Hz, 1H, minor), 4.88 (d, J = 4.8 Hz, 1H, minor), 6.41 (d, J = 1.8 Hz, 1H), 6.49 (dd, J = 6.3, 1.8 Hz, 1H), 6.52−6.56 (m, 2H), 6.80 (d, J = 6.6 Hz, 1H), 6.86−6.88 (m, 1H), 6.92−6.98 (m, 1H), 7.09−7.16 (m, 4H), 7.14 (d, J = 6.3 Hz, 2H), 7.83 (d, J = 6.6 Hz, 2H).

13

C NMR (75 MHz, CDCl3): δ 20.4 (major), 20.9 (minor), 23.0 (major), 23.1

(minor), 36.8 (major), 37.6 (major), 38.2 (minor), 39.1 (major), 44.3 (major), 51.1 (major), 54.6 (minor), 55.0 (major), 55.1 (minor), 55.4 (major), 55.8 (minor), 94.3 (major), 94.5 (minor), 100.5 (major), 100.8 (minor), 105.7 (major), 106.9 (minor), 121.3 (minor), 121.6 (major), 122.5 (minor), 122.6, 122.7 (minor), 122.8 (major), 124.6 (minor), 125.0 (major), 125.1 (major), 125.5 (minor), 128.8 (minor), 128.9 (major), 131.0 (major), 132.9, 134.3 (major), 136.2 (major), 139.9 (major), 140.2 (minor), 141.5 (minor), 141.5 (minor), 142.1 (minor), 143.7 (major), 153.3 (minor), 153.5 (major), 155.6 (minor), 156.0 (major), 159.3 (minor), 159.5 (major), 167.7 (minor), 167.8 (major), 167.9 (minor), 168.0 (major), 168.4 (minor), 168.7 (major), 198.2 (major), 203.1 (minor). IR (UATR): νmax 2936, 1765, 1677, 1600, 1504, 1369 cm−1. LRMS (EI): m/z (rel intensity) 121 (100), 163 (75), 189 (44), 351 (34), 616 (3, M +). TOF-HRMS: calcd for C35H36NaO10 (M + Na+) 639.2200, found 639.2200.

2'-(3,4-Dimethoxybenzoyl)-4''-methoxy-2''-(methoxymethoxy)-5'-methyl-1',2',3',6'tetrahydro-[1,1':3',1''-terphenyl]-4-yl acetate (27i). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a yellow oil (187 mg, 0.33 mmol, 57 %) of a 1.9:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz,


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CDCl3): δ 1.79 (s, 3H, minor), 1.85 (s, 3H, major), 2.18 (s, 3H, minor), 2.19 (s, 3H, major), 2.33−2.36 (m, 1H, major), 2.33−2.36 (m, 1H, minor), 2.44 (dd, J = 18.0, 5.6 Hz, 1H, major), 2.44 (dd, J = 18.0, 5.6 Hz, 1H, minor), 3.07 (s, 3H, major), 3.34 (s, 3H, minor), 3.35−3.39 (m, 1H, , minor), 3.44−3.52 (td, J = 5.2, 11.2 Hz, 1H), 3.67 (s, 3H, major), 3.73(s, 3H, minor), 3.80 (s, 6H), 3.92 (s, 3H, minor), 3.99 (d, J = 6.8 Hz, 1H, major), 4.27 (dd, J = 5.6, 5.6 Hz, 1H, major), 4.27 (dd, J = 5.6, 5.6 Hz, 1H, minor), 4.39 (br s, 1H), 4.59 (d, J = 6.8 Hz, 1H, major), 4.70 (d, J = 6.0 Hz, 1H, minor), 4.88 (d, J = 6.0 Hz, 1H, minor), 5.42 (s , 1H, minor), 5.51 (d, J = 4.4 Hz, 1H, major), 6.41(d, J = 2.4 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 6.79−6.87 (m, 5H),, 7.09−7.19 (m, 6H), 7.63 (d, J = 8.4 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 20.9 (minor), 23.1 (major), 36.8 (major), 37.7 (major), 38.8 (minor), 39.6 (minor), 44.3 (minor), 50.3 (major), 55.0 (major), 55.1 (major), 55.3 (major), 55.6 (major), 55.7 (minor), 55.8 (major), 55.9 (major), 94.5 (major), 94.7 (minor), 100.5, 100.8 (minor), 105.6 (major), 106.9 (minor), 109.4 (minor), 109.7 (major), 109.8 (major), 120.9 (major), 121.3 (minor), 121.7 (major), 122.0 (minor), 122.9 (major), 125.1 (major), 125.3 (minor), 128.3 (major), 128.4 (minor), 131.1 (major), 132.0 (minor), 132.1 (major), 134.4 (major), 141.2 (minor), 142.7 (major), 147.9 (minor), 148.5 (major), 148.6 (major), 148.8 (minor), 152.2 (major), 152.3 (major), 155.8 (minor), 156.2 (major), 159.2 (minor), 159.4 (major), 169.1 (minor), 169.3 (minor), 198.2 (major), 202.6 (minor). IR (UATR): νmax 2935, 2909, 2836, 1754, 1669, 1585 cm−1. LRMS (EI): m/z (rel intensity) 104 (10), 165 (100), 187 (3), 189 (17), 560 (M +, 7). TOF-HRMS: calcd for C33H36NaO8 (M + Na+) 583.2302, found 583.2311.

2'-(Benzo[d][1,3]dioxole-5-carbonyl)-4''-methoxy-2''-(methoxymethoxy)-5'-methyl1',2',3',6'-tetrahydro-[1,1':3',1''-terphenyl]-4-yl

acetate


(27j).

Following

the

General


Procedure for the Diels-Alder reaction described above, the desired product was obtained as a yellow oil (210 mg, 0.38 mmol, 62 %) of a 3.3:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.78 (s, 3H, minor), 1.83 (s, 3H, major), 2.18 (s, 3H, minor), 2.19 (s, 3H, major), 2.29−2.81 (m, 1H, minor), 2.22−2.46 (m, 2H, minor) 2.43 (dd, J = 18.0, 5.6 Hz, 1H, major), 3.09 (s, 3H, major), 3.25−3.35 (m, 1H, major), 3.35 (s, 3H, minor), 3.45 (td, J = 5.2, 11.2 Hz, 1H, minor), 3.68 (s, 3H, minor), 3.73 (s, 3H, major), 4.08 (d, J = 6.8 Hz, 1H, major), 4.21 (dd, J = 11.2, 5.2 Hz, 1H, major), 4.73 (br s, 1H, major), 4.08 (d, J = 6.8 Hz, 1H, major), 4.21(dd, J = 11.2, 5.2 Hz, 1H, major), 4.37 (br s, 1H, major), 4.63 (d, J = 6.8 Hz, 1H, major), 4.76 (d, J = 6.8 Hz, 1H, minor), 4.91 (d, J = 6.8 Hz, 1H, minor), 5.40 (s, 1H, minor), 5.50 (d, J = 4.4 Hz, 1H, major), 5.84 (d, J = 7.2 Hz, 2H, minor), 5.95 (d, J = 7.2 Hz, 2H), 6.44 (d, J = 7.6 Hz, 1H), 6.49 (dd, J = 2.0, 8.4 Hz, 1H), 6.54 (dd, J = 8.8, 2.4 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.78 (s, 1H), 6.82 (t, J = 8.8 Hz, 3H), 7.09 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 1.2 Hz, 1H), 7.49 (dd, J = 8.0, 1.2 Hz, 1H). NMR (100 MHz, CDCl3): δ 20.9 (minor), 23.1 (major), 36.8 (major), 37.7 (minor), 38.7 (minor), 29.6 (major), 44.3 (minor), 50.6 (major), 55.0 (major), 55.2 (major), 55.3 (major), 55.8 (minor), 94.4 (major), 94.6 (minor), 100.5(major), 100.9 (minor), 101.4 (minor), 101.5 (major), 105.6(major), 106.7 (minor), 106.9 (minor), 107.2 (minor), 107.4 (major), 120.9 (major), 120.9 (minor), 121.1(major), 122.8(major), 123.3(major), 123.8 (minor), 125.1 (minor), 128.3 (major), 128.4 (minor), 131.0 (major), 133.4 (minor), 133.8 (major), 134.4 (major), 141.1 (minor), 142.5 (major), 147.3 (minor), 147.7 (major), 148.5 (major), 148.8 (minor), 150.7 (major), 150.8 (minor), 155.7 (minor), 156.2 (major), 159.2 (minor), 159.4 (major), 169.2 (minor), 169.3 (major), 197.6 (major), 201.8 (minor). IR (UATR): νmax 2907, 1764, 1607, 1504, 1439, 1244 cm−1. LRMS (EI):


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m/z (rel intensity) 149 (100), 181 (19), 189 (31), 234 (20), 544 (M +, 9). TOF-HRMS: calcd for C32H32NaO8 (M + Na+) 567.1989, found 567.1989.

2'-(Benzo[d][1,3]dioxole-5-carbonyl)-4''-methoxy-2''-(methoxymethoxy)-5'-methyl1',2',3',6'-tetrahydro-[1,1':3',1''-terphenyl]-3,4-diyl diacetate (27k). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a yellow oil (255 mg, 0.42 mmol, 62 %) of a 3.3:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.78 (s, 3H, minor), 1.84 (s, 3H, major), 2.17(s, 3H, major), 2.17(s, 3H, minor), 2.18 (s, 3H, major), 2.18 (s, 3H, minor), 2.22–2.39 (m, 1H, major), 2.22–2.39 (m, 2H, minor), 2.45 (dd, J = 18.0, 5.6 Hz, 1H, major), 3.10 (s, 3H, major), 3.24–3.35 (m, 1H, major), 3.37 (s, 3H, minor), 3.40–3.47 (m, 1H, minor), 3.68 (s, 3H, minor), 3.73 (s, 3H, major), 4.11 (d, J = 6.8 Hz, 1H, major), 4.16 (dd, J = 11.2, 5.2 Hz, 1H, major), 4.23 (br s, 1H, minor), 4.36 (br s, 1H, major), 4.64 (d, J = 6.8 Hz, 1H, major), 4.78 (d, J = 6.8 Hz, 1H, minor), 4.92 (d, J = 6.8 Hz, 1H, minor), 5.39 (br s, 1H, minor), 5.50 (d, J = 4.0 Hz, 1H, major), 5.85 (d, J = 4.0 Hz, 1H), 5.96 (d, J = 1.6 Hz, 2H), 6.44-6.49 (m, 1H), 6.52 (dd, J = 8.4, 2.4 Hz), 6.78 (d, J = 8.0 Hz, 2H), 6.87−6.99 (m, 3H), 6.94 (d, J = 8.0Hz, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 8.4, 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 20.6 (major), 20.6 (minor), 23.2 (major), 23.2 (minor), 29.7 (minor), 36.8 (major), 38.0 (major), 38.3 (minor), 39.1 (major), 44.5 (minor), 50.9 (major), 54.1 (minor), 55.2 (major), 55.3 (minor), 55.5 (major), 55.9(minor), 94.6(major), 94.8(minor), 100.7(major), 101.1(minor), 101.5 (minor), 101.7 (major), 105.7(major), 106.8(minor), 107.1(minor), 107.3 (minor), 107.6 (major), 107.6 (major), 121.2 (major), 122.7 (minor), 122.8 (major), 122.9 (major), 122.9 (minor), 123.5 (major), 124.0 (minor), 125.1 (minor), 125.2 (major), 125.7 (minor), 131.1(major), 132.9(minor), 133.5



(minor), 133.8 (major), 134.4 (major), 140.0 (major), 140.2 (minor), 141.6 (major), 141.7 (minor), 142.4 (minor), 143.9 (major), 147.5 (minor), 147.9 (major), 150.9 (major), 151.0 (minor), 155.8 (minor), 156.3 (major), 159.4 (minor), 159.6 (major), 167.9 (minor), 168.0 (minor), 168.1 (minor), 168.2 (major), 197.6 (major), 201.9 (minor). IR (UATR): νmax 2911, 1768, 1614, 1504, 1206, 1037 cm−1. LRMS (EI): m/z (rel intensity): 149 (100, 175 (13), 190 (14), 337 (16), 603 (M+, 1). TOF-HRMS: calcd for C34H34NaO10 (M + Na+) 625.2044, found 625.2055.

4-(4''-Acetoxy-2'',4-dimethoxy-2-(methoxymethoxy)-5'-methyl-1',2',3',4'-tetrahydro[1,1':3',1''-terphenyl]-2'-carbonyl)phenyl acetate (27l). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a yellow oil (321 mg, 0.55 mmol, 67 %) of a 1.6:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.77 (s, 3H, minor), 1.84 (s, 3H, major), 2.18−2.22 (m, 6H, minor), 2.18−2.22 (m, 3H, major), 2.18−2.29 (m, 1H, major), 2.18−2.29 (m, H, minor), 2.29 (br s, 3H, major), 2.29 (br s, 3H, minor), 2.39 (dd, J = 18.0, 6.0 Hz, major), 2.29−2.42 (m, 1H, minor), 3.04 (s, 3H, major), 3.34 (s, 3H, minor), 3.61 (s, 3H, major), 3.61 (s, 3H, minor), 3.68 (s, 3H, minor), 3.72 (s, 3H, major), 3.86 (br s, 3H, minor), 4.08 (d, J = 6.8 Hz, major), 4.25 (br s, 1H, major), 4.34 (br s, 1H, major), 4.58−4.61(m, 1H, minor), 4.60 (d, J = 6.8 Hz, major, 1H), 4.77 (d, J = 6.4 Hz, 1H, minor), 4.90 (d, J = 6.4 Hz, 1H, minor), 5.38 (br s, 1H, minor), 5.50 (d, J = 3.6Hz, 1H, major), 6.42−6.55 (m, 7H), 6.82 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 9.2 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 21.0 (major), 23.3 (minor), 36.6 (major), 36.9 (minor), 49.1 (major), 55.1 (major), 55.2 (minor), 55.3 (major), 55.6 (major), 55.8 (minor), 55.9 (minor), 94.5 (major), 94.6 (minor), 100.6 (major), 100.9


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(minor), 104.7 (major), 105.3 (minor), 105.8 (major), 107.1 (minor), 113.1 (major), 113.9 (minor), 120.7 (major), 121.3 (major), 121.8 (minor), 122.9 (minor), 125.1 (minor), 125.4 (major), 128.9 (major), 129.1 (major), 130.1 (major), 131.1 (minor), 133.6 (minor), 134.8 (major), 136.4 (major), 139.7 (minor), 149.6 (major), 149.9 (minor), 153.3 (minor), 153.4 (major), 155.7 (minor), 156.1 (major), 157.6 (major), 157.8 (minor), 159.3 (minor), 159.5 (major), 168.6 (minor), 168.9 (major), 169.2 (major), 169.4 (major), 198.9 (minor), 203.5 (minor). IR (UATR): νmax 2937, 2836, 1759, 1599, 1499, 1190 cm−1. LRMS (EI): m/z (rel intensity): 121 (100), 163 (56), 234 (72), 351 (75), 543 (19), 588 (M+, 14). TOF-HRMS: calcd for C34H36NaO9 (M + Na+) 611.2251, found 611.2243.

(5-Bromo-4-methoxy-2-(methoxymethoxy)-5'-methyl-1',2',3',4'-tetrahydro-[1,1':3',1''terphenyl]-2'-yl)(phenyl)methanone (27m). Following the General Procedure for the DielsAlder reaction described above, the desired product was obtained as a yellow oil (89.5 mg, 0.17 mmol, 59 %) of a 2.2:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H, minor), 1.86 (s, 3H, major), 2.21–2.32 (m, 1H, major), 2.21–2.32 (m, 1H, minor), 2.45 (dd, J = 18.0, 5.6 Hz, 1H, major), 2.39–2.49 (m, 1H, minor), 2.99 (s, 3H, major), 3.24–3.32 (m, 1H, major), 3.32 (s, 3H, minor), 3.40–3.48 (m, 1H, major), 3.40–3.48 (m, 1H, minor), 3.69 (s, 3H, minor), 3.78 (s, 3H, major), 3.88 (d, J = 7.2 Hz, 1H, major), 4.28–4.35 (m, 1H, minor), 4.33–4.39 (m, 1H, major), 4.52 (d, J = 7.2 Hz, 1H, major), 4.66 (d, J = 7.2 Hz, 1H, minor), 4.87 (d, J = 7.2 Hz, 1H, minor), 5.38 (s, 1H, minor), 5.49 (d, J = 3.6 Hz, 1H, major), 6.41 (s, 1H, minor), 6.64 (s, 1H, major), 6.92–7.06 (m, 2H), 7.05 (s, 1H), 7.07 (d, J = 4.4 Hz, 5H), 7.12 (d, J = 7.2 Hz, 2H), 7.20–7.27 (m, 2H), 7.36 (t, J = 7.0 Hz, 3H), 7.45 (t, J = 6.6 Hz, 1H), 7.79 (d, J = 7.2 Hz, 2H).

13

C NMR (100 MHz, CDCl3): δ 23.3 (major), 23.4 (minor), 37.3 (major), 38.3



(major), 38.8 (minor), 40.1 (minor), 44.9 (major), 51.0 (major), 55.6 (major), 56.0 (minor) , 56.2 (major) , 56.3 (minor), 94.8 (major), 95.1 (minor), 99.1 (major), 99.7 (minor), 102.9 (major), 103.6 (minor), 122.2 (major), 122.8 (minor), 124.4 (minor), 126.0 (major), 126.3 (minor), 126.8 (major), 127.5 (major), 127.5 (minor), 127.7 (minor), 127.8 (minor), 128.2 (major), 128.2 (minor), 128.3 (major), 132.1 (minor), 132.2 (major), 132.5 (minor), 134.4 (major), 135.7 (major), 138.5 (minor), 139.0 (major), 143.4 (minor), 144.8 (major), 155.1 (minor), 155.2 (minor), 155.5 (major), 155.9 (major), 199.8 (minor), 203.9 (major). IR (UATR): νmax 2909, 1679, 1489, 1289, 1150, 1002, 697 cm−1. LRMS (EI): m/z (rel intensity) 105 (100), 312 (15), 371 (11), 477 (8), 520 (M+, 6). TOF-HRMS: calcd for C29H3079BrO4 (M + H+) 521.1322, found 521.1318.

5''-Bromo-4''-methoxy-2'-(4-methoxybenzoyl)-2''-(methoxymethoxy)-5'-methyl-1',2',3',6'tetrahydro-[1,1':3',1''-terphenyl]-3,4-diyl diacetate (27n). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a yellow gummy solid (261 mg, 0.39 mmol, 65 %) of a 1.6:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.79 (s, 3H, minor), 1.86 (s, 3H, major), 2.16 (s, 6H, major), 2.17 (s, 3H, minor), 2.18 (s, 3H, minor), 2.23−2.33 (m, 1H, minor), 2.23−2.33 (m, 1H, minor), 2.36−2.39 (m, 1H, minor), 2.47 (dd, J = 5.6, 18 Hz, 1H, major), 3.05 (s, 3H, major), 3.26 (dd, J = 11.2, 6.0 Hz, 1H, major), 3.33 (s, 3H, minor), 3.44 (dd, J = 11.2, 5.6 Hz, 1H, minor), 3.71 (s, 3H, major), 3.71 (s, 3H, minor), 3.78 (s, 3H, major), 3.78 (s, 3H, minor), 3.82 (s, 3H, major), 3.82 (s, 3H, minor), 3.97 (d, J = 7.2 Hz, 1H, major), 4.20 (dd, J = 11.2, 6.0 Hz, 1H, major), 4.26 (m, 1H, minor), 4.34 (br s, 1H, minor), 4.57 (d, J = 7.2 Hz, 1H, major), 4.65 (d, J = 6.8 Hz, 1H, major), 4.86 (d, J = 6.8 Hz, 1H, minor), 5.36 (br s, 1H, minor), 5.48 (br d, J = 4.0 Hz, 1H, major), 6.42


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(s, 1H), 6.57 (d, J = 8.8 Hz, 1H), 6.65 (s, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.89−6.99 (m, 4H), 7.26 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.40 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H).

13

C NMR (100 MHz,

CDCl3): δ 20.5 (major), 20.6 (minor), 23.2 (major), 23.3 (minor), 36.9 (major), 37.9 (major), 38.4 (minor), 39.3 (major), 44.1 (major), 50.7 (major), 55.3 (minor), 55.4 (major), 55.6 (major), 55.9 (minor), 56.1 (major), 56.3 (minor), 94.9 (major), 95.2 (minor), 99.2 (major), 99.7 (minor), 102.8 (major), 103.5 (minor), 113.1 (minor), 113.4 (major), 122.3 (major), 122.6 (minor), 122.8 (major), 122.9 (major), 124.4 (minor), 125.2 (major), 125.6 (minor), 125.8 (minor), 129.7 (major), 129.9 (minor), 131.4 (minor), 132.0 (major), 132.3 (minor), 134.3 (minor), 134.3 (major), 135.4 (major), 140.0 (major), 140.2 (major), 141.6 (major), 141.7 (minor), 142.4 (minor), 143.7 (major), 155.1 (minor), 155.3 (minor), 155.4 (major), 155.9 (major), 162.8 (major), 167.9 (minor), 167.9 (major), 168.0 (major). IR (UATR): νmax 2936, 1769, 1599, 1504, 1370, 1207 cm−1. LRMS (EI): m/z (rel intensity) 83 (4), 97 (4), 135 (100), 136 (10), 668 (M +, 1). TOF-HRMS: calcd for C34H3579BrNaO9 (M + Na+) 689.1356, found 689.1339.

2'-(Benzo[d][1,3]dioxole-5-carbonyl)-5''-bromo-4''-methoxy-2''-(methoxymethoxy)-5'methyl-1',2',3',6'-tetrahydro-[1,1':3',1''-terphenyl]-4-yl acetate (27o). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a yellow oil (115 mg, 0.19 mmol, 50 %) of a 3.3:1 inseparable mixture of endo:exo isomers. 1H NMR (400 MHz, CDCl3): δ 1.80 (s, 3H, minor), 1.86 (s, 3H, major), 2.23−2.34 (m, 1H, major), 2.23−2.34 (m, 2H, minor), 2.45 (dd, J = 18.4, 6.0 Hz, 1H, major), 3.11 (s, 3H, major), 3.25 (td, J = 5.6, 11.2 Hz, 1H, major), 3.37 (s, 1H, minor), 3.43 (dd, J = 11.2, 6.0 Hz, 1H, minor), 3.74 (s, 1H, minor), 3.81 (s, 3H, major), 4.07 (d, J = 7.2 Hz, 1H, major), 4.20 (dd, J = 11.2, 5.2 Hz, 1H, major), 4.32 (t, J = 5.4 Hz, 1H, major), 4.62 (d, J = 7.2 Hz, 1H, major), 4.72 (d, J = 6.8 Hz, 1H,



minor), 4.91 (d, J = 7.2 Hz, 1H, minor), 5.28 (brs, 1H, minor), 5.48 (d, J = 4.4 Hz, 1H, major), 5.88 (dd, J = 8.8, 1.2 Hz, 1H, minor), 5.99 (dd, J = 6.8, 1.2 Hz, 2H, major), 6.48 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 6.77–6.87 (m, 4H), 7.07 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 7.26 (s, 1H), 7.34 (s, 1H), 7.41 (s, 1H), 7.48 (dd, J = 8.0, 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 21.1 (minor), 23.2 (major), 23.3 (minor), 37.1 (major), 37.9 (major), 38.7 (minor), 39.8(minor), 44.3 (minor), 50.8 (major), 53.5 (minor), 55.7 (major), 56.0 (minor), 56.2 (major), 60.3 (minor), 95.0 (major), 95.2 (minor), 99.2 (major), 99.8 (minor), 101.6 (minor), 101.7 (major), 102.9 (major), 103.6 (minor), 107.1 (minor), 107.3 (minor), 107.5 (major), 107.6 (major), 121.1 (major), 121.2 (minor), 122.2 (major), 122.8 (minor), 123.4 (major), 124.0 (minor), 124.4 (minor), 128.4 (major), 128.6 (minor), 133.4 (major), 133.9 (major), 134.3 (major), 135.6 (major), 141.0 (minor), 142.3 (major), 147.6 (minor), 147.9 (major), 148.7(major), 149.0 (minor), 151.0 (major), 151.1 (minor), 155.1 (minor), 155.3 (minor), 155.4 (major), 155.9 (major), 169.3 (minor), 169.4 (major), 197.8 (major), 201.5 (minor). IR (UATR): νmax 2907, 1763, 1488, 1439, 1244, 1214, 1004, 734 cm−1. LRMS (EI): m/z (rel intensity) 149 (100), 150 (8), 201 (4), 267 (3), 623 (M+, 1). TOF-HRMS: calcd for C32H3179BrNaO8 (M + Na+) 645.1095, found 645.1088; calcd for C32H3181BrNaO8 (M + Na+) 647.1080, found 647.1079.

4-(4''-Acetoxy-5-bromo-2'',4-dimethoxy-2-(methoxymethoxy)-5'-methyl-1',2',3',4'tetrahydro-[1,1':3',1''-terphenyl]-2'-carbonyl)phenyl acetate (27p). Following the General Procedure for the Diels-Alder reaction described above, the desired product was obtained as a yellow solid (311 mg, 0.47 mmol, 64 %) of a 1.5:1 inseparable mixture of endo:exo isomers. 1H NMR (300 MHz, CDCl3): δ 1.81 (s, 3H, minor), 1.88 (s, 3H, major), 2.20 (s, 3H, minor), 2.21 (s, 3H, major), 2.24 (s, 3H, minor), 2.31 (s, 3H, major), 2.20−2.31 (m, 1H, major), 2.20−2.31 (m,


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1H, minor), 2.36−2.43 (m, 1H, major), 2.36−2.43 (m, 1H, minor), 3.05 (s, 3H, major), 3.32 (s, 3H, minor), 3.59 (s, 3H, major), 3.63(s, 3H, minor), 3.74(s, 3H, minor), 3.79 (s, 3H, major), 4.06 (d, J = 7.2Hz, 1H, major), 4.24 (br s, 1H, minor), 4.29 (br s, 1H, major), 4.58 (d, J = 7.2 Hz, 1H, major), 4.69 (d, J = 6.9 Hz, 1H, minor), 4.86 (d, J = 7.2 Hz, 1H, major), 5.34 (br s, 1H, minor), 5.48 (d, J = 3.6 Hz, 1H, major), 6.35 (br s, 1H), 6.43−6.48 (m, 2H), 6.61 (s, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.94−6.99 (m, 2H), 7.12 (d, J = 8.7 Hz, 2H), 7.26−7.29 (m, 2H), 7.43 (d, J = 17.2 Hz, 2H), 7.87 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 22.1 (major), 23.3 (minor), 36.9 (major), 37.1 (minor), 49.2 (major), 55.3 (major), 55.7 (major), 55.9 (minor), 56.1 (major), 56.2 (minor), 94.8 (major), 94.9 (minor), 99.0 (major), 99.5 (minor), 102.8 (major), 103.4 (minor), 104.7 (major), 113.1 (major), 120.8 (major), 121.4 (major), 122.1 (minor), 122.8 (major), 124.2 (minor), 126.9 (minor), 128.9 (minor), 129.0 (major), 129.9 (major), 132.3 (major), 134.4 (major), 134.8 (minor), 135.9 (major), 136.4 (minor), 149.6 (major), 149.9 (minor), 153.3 (minor), 153.5 (major), 155.0 (minor), 155.1 (minor), 155.3 (major), 155.7 (major), 157.6 (major), 157.8 (minor), 168.7 (minor), 168.9 (major), 169.3 (minor), 169.4 (major), 198.9 (major). ). IR (UATR): νmax 2907, 1763, 1488, 1439, 1244, 1214, 1004, 734 cm−1. LRMS (EI): m/z (rel intensity) 57 (31), 112 (21), 161 (37), 178 (100), 666 (M +, 1) TOF-HRMS: calcd for C34H3579BrNaO9 (M + Na+) 689.1357, found 689.1369.

General procedure for cyclization of cycloadduct (29a-29e). To a solution of cycloadduct (1.0 equiv) in dry THF (10 mL/1 mmol) under Ar at 0 °C was added lithium aluminium hydride (LiAlH4) (1.5−3.0 mmol) and the reaction mixture was stirred at this temperature for 1.5 h. The reaction mixture was quenched with H2O, extracted with EtOAc (3 x 15 mL) and washed with



brine (10 mL). The combined organic layers were dried over Na 2SO4 and concentrated under reduced pressure to give crude product which was used in the next step without further purification. To a solution of alcohol (1.0 equiv) in EtOH (220 mL/1 mmol), 10% H 2SO4 (44 mL/1mmol) aqueous solution was slowly added at room temperature and the reaction was stirred for 36 h. The reaction mixture was quenched with saturated NaHCO3, extracted with EtOAc (3 x 15 mL) and washed with brine (10 mL). The combined organic phases were dried over Na 2SO4 and concentrated under reduced pressure to give crude product. The product was obtained following chromatography on silica (EtOAc/hexane).

4-(3-Methoxy-6-(4-methoxyphenyl)-9-methyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen7-yl)phenol (29b). Following the General Procedure for the LAH reduction/acid-mediated cyclization reaction described above, the desired product was obtained as a pale yellow oil (7.1 mg, 0.02 mmol, 60 % over 2 steps) of a single diastereomer. 1H NMR (400 MHz, CDCl3): δ 1.79 (s, 3H), 2.11 (br d, J = 18.8 Hz, 1H), 2.24 (br d, J = 18.8 Hz, 1H), 2.71−2.75 (m, 1H), 2.73 (q, J = 5.2 Hz, 1H), 3.09 (br s, 1H), 3.74 (s, 3H), 3.82 (s, 3H), 4.69 (br s, OH), 4.83 (d, J = 7.6 Hz, 1H), 5.63 (br s, 1H), 6.45 (d, J = 2.8 Hz, 1H), 6.49 (dd, J = 8.4, 2.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 7.03(d, J = 8.4 Hz, 3H), 7.33 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 23.4, 31.2, 37.4, 42.9, 55.2, 55.3, 77.2, 101.2, 107.9, 114.1, 115.2, 118.0, 124.9, 127.9, 128.5, 129.7, 132.2, 132.5 137.1, 153.9, 154.6, 158.9, 159.4. IR (UATR): ν max 3393, 2911, 1613, 1511, 1443, 1245, 1159, 1032 cm−1. LRMS (EI): m/z (rel intensity) 121 (17), 131 (16), 239 (100), 240 (17), 428 (M+, 30). TOF-HRMS: calcd for C28H29O4 (M + H+) 429.2060, found 429.2062.


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2-Methoxy-4-(3-methoxy-6-(4-methoxyphenyl)-9-methyl-6a,7,8,10a-tetrahydro-6Hbenzo[c]chromen-7-yl)phenol (29c). Following the General Procedure for the LAH reduction/acid-mediated cyclization reaction described above, the desired product was obtained as a yellow oil (16 mg, 0.034 mmol, 61 % over 2 steps) of a single diastereomer. 1H NMR (300 MHz, CDCl3): δ 1.78 (s, 3H), 2.16 (br d, J = 6.0 Hz, 1H), 2.22 (br d, J = 9.2 Hz, 1H), 2.40 (dd, J = 12.3, 6.3 Hz, 1H), 2.73 (q, J = 5.7 Hz, 1H), 3.12 (br s, 1H), 3.75 (s, 3H), 3.81 (s, 3H), 3.85 (s, 3H), 4.85 (d, J = 7.2 Hz, 1H), 5.51 (s, 1H), 5.66 (br s, 1H), 6.46−6.52 (m, 2H), 6.67 (s, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H). 13

C NMR (75 MHz, CDCl3): δ 23.4, 29.7, 31.2, 38.0, 42.9, 55.3, 55.8, 77.2, 101.2, 107.7, 110.1,

114.0, 114.3, 117.9, 119.9, 124.7, 127.8, 129.6, 132.6, 136.7, 143.9, 146.3, 154.4, 158.9, 159.3. IR (UATR): νmax 3520, 2930, 1614, 1505, 1443, 1247, 1159, 1033 cm−1. LRMS (EI): m/z (rel intensity) 121 (41), 145 (38), 165 (23), 269 (100), 458 (M+, 68). TOF-HRMS: calcd for C29H30NaO5 (M + Na+) 481.1985, found 481.1979.

4-(6-(3,4-Dimethoxyphenyl)-3-methoxy-9-methyl-6a,7,8,10a-tetrahydro-6Hbenzo[c]chromen-7-yl)phenol (29d). Following the General Procedure for the LAH reduction/acid-mediated cyclization reaction described above, the desired product was obtained as a colorless oil (42 mg, 0.09 mmol, 65 % over 2 steps) of a single diastereomer. 1H NMR (400 MHz, CDCl3): δ 1.79 (s, 3H), 2.11 (br d, J = 18.8 Hz, 1H), 2.24 (br d, J = 18.8 Hz, 1H), 2.37−2.42 (m, 1H), 2.71−2.75 (m, 1H), 3.11, (br s, 1H), 3.74 (s, 3H), 3.89 (s, 6H), 4.74 (s, OH), 4.82 (d, J = 8.0 Hz, 1H), 5.62 (s, 1H), 6.46 (d, J = 2.8 Hz, 1H), 6.50 (dd, J = 8.4, 2.4 Hz, 1H), 6.75 (d, J = 8.8, 2H), 6.88 (d, J = 8.8 Hz, 1H), 6.95 (s, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.04 (s,



1H).

13

C NMR (100 MHz, CDCl3): δ 14.2, 21.1, 23.4, 31.3, 37.4, 42.9, 55.3, 55.9, 56.0, 60.5,

77.7, 101.2, 107.9, 109.7, 111.1, 115.3, 118.1, 119.6, 125.1, 128.4, 129.7, 132.2, 132.9, 136.9, 148.9, 149.3, 154.0, 154.6, 158.9. IR (UATR): νmax 3440, 2909, 2836, 1614, 1504, 1443, 1262, 1026 cm−1. LRMS (EI): m/z (rel intensity) 131 (24), 151 (19), 269 (100), 32 0(22), 458 (M +, 27). TOF-HRMS: calcd for C29H31O5 (M + H+) 459.2166, found 459.2157.

4-(6-(Benzo[d][1,3]dioxol-5-yl)-2-bromo-3-methoxy-9-methyl-6a,7,8,10a-tetrahydro-6Hbenzo[c]chromen-7-yl)phenol (29e). Following the General Procedure for the LAH reduction/acid-mediated cyclization reaction described above, the desired product was obtained as a pale yellow oil (25 mg, 0.05 mmol, 59 % over 2 steps) of a single diastereomer. 1H NMR (400 MHz, CDCl3): δ 1.79 (s, 3H), 2.27−2.30 (m, 2H), 2.33 (dd, J = 12.8, 6.0 Hz, 1H), 2.74 (q, J = 5.6 Hz, 1H), 3.09 (br s, 1H), 3.81 (s, 3H), 4.79 (d, J = 7.2 Hz, 1H), 4.79 (br s, OH), 5.61 (br s, 1H), 5.98 (d, J = 2.8 Hz, 2H), 6.47 (s, 1H), 6.77 (d, J = 8.4 Hz, 2H),, 6.81 (s, 2H), 6.87 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H).

13

C NMR (100 MHz, CDCl3): δ 23.4, 31.0, 37.5, 42.7,

56.2, 77.7, 100.7, 101.2, 102.4, 106.7, 108.3, 115.4, 119.3, 120.3, 120.4, 124.1, 128.5, 132.9, 133.0, 134.0, 136.7, 147.5, 148.1, 153.7, 154.0, 154.9. IR (UATR): νmax 3405, 2918, 1616, 1504, 1443, 1247, 1161, 1039 cm−1. LRMS (EI): m/z (rel intensity) 253 (95), 320 (17), 442 (100), 443 (25), 522 (M+1, 2). TOF-HRMS: calcd for C28H2679BrO5 (M + H+) 521.0958, found 521.0939; calcd for C28H2681BrO5 (M + H+) 523.0942, found 523.0932.

Acknowledgements


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Financial support from the Thailand Research Fund (BRG5980010 and IRN58W0005 for P.P. and the Royal Golden Jubilee PHD0042/2560 for P.S.) and Mahidol University is gratefully acknowledged.

Supporting Information: 1H and 13C NMR spectra for all new compounds

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Tummatorn, J.; Batsomboon, P.; Ruchirawat, S.; Ploypradith, P. Pt(IV)-Catalyzed Generation and [4+2]-Cycloaddition Reactions of o-Quinone Methides. Tetrahedron 2011, 67, 3904–3914. d) Tangdenpaisal, K.; Chuayboonsong, K.; Sukjarean, P.; Katesampao, V.; Noiphrom, N.; Ruchirawat, S.; Ploypradith, P. Synthesis of C4-C5 Cycloalkyl-Fused and C6-Modified Chromans via ortho-Quinone Methides. Chem. Asian J. 2015, 10, 1050–1064. e) Tangdenpaisal, K.; Chuayboonsong, K.; Ruchirawat, S.; Ploypradith, P. Divergent Strategy for the Diastereoselective Synthesis of the Tricyclic 6,7-Diaryltetrahydro-6H-benzo[c]chromene Core via Pt(IV)-Catalyzed Cycloaddition of o-Quinone Methides and Olefin Ring-Closing Metathesis. J. Org. Chem. 2017, 82, 2672–2688. 11) For examples of transition metal-catalyzed Diels−Alder reactions of related example, see a) Ballerini, E.; Minuti, L.; Piermatti, O. High-Pressure Diels−Alder Cycloadditions between Benzylideneacetones and 1,3-Butadienes: Application to the Synthesis of (R,R)(−)- and (S,S)-(+)-Δ8-Tetrahydrocannabinol. J. Org. Chem. 2010, 75, 4251–4260. b) Minuti, L.; Ballerini, E.; Barattucci, A.; Bonaccorsi, P. M.; Gioia, M. L. D.; Leggio, A.; Siciliano, C.; Temperini, A. A Unified Strategy for the Synthesis of Three Conicol Marine Natural Products. Tetrahedron. 2015, 71, 3253–3262. 12) Hofmann, E.; Webster, J.; Do, T.; Kline, R.; Snider, L.; Hauser, Q.; Higginbottom, G.; Campbell, A.; Ma, L.; Paula, S. Hydroxylated Chalcones with Dual Properties: Xanthine Oxidase Inhibitors and Radical Scavengers. Bioorg. Med. Chem. 2016, 24, 578–587. 13) Similar endo:exo selectivity for this type of thermal Diels−Alder reactions was also observed and previously reported. The endo and exo isomers were assigned based on comparison of spectroscopic data, especially the two distinct olefinic protons at C10, with


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other cyclohexene adducts which were reported and characterized previously. See references 6-8 for more detail. 14) This type of consideration and strategy proved to be successful for the synthesis of kuwanol A. See reference 8c for more detail. 15) Ploypradith, P.; Cheryklin, P.; Niyomtham, N.; Bertoni, D.R.; Ruchirawat, S. SolidSupported Acids as Mild and Versatile Reagents for the Deprotection of Aromatic Ethers Org. Lett. 2007, 9, 2637–2640. 16) a)

Pri-Bar,

I.;

Buchman,

O.

Homogeneous,

Palladium-Catalyzed,

Selective

Hydrogenolysis of Organohalides. J. Org. Chem. 1986, 51, 734–736. b) Orfanopoulos, M.; Smonou, I. Selective Reduction of Diaryl or Aryl Alkyl Alcohols in the Presence of Primary Hydroxyl or Ester Groups by Etherated Boron Trifluoride-Triethylsilane System. Synth. Commun. 1988, 18, 833–839. c) Tagat, J. R.; Guzi, T. J.; Labroli, M.; Poker, C.; Xiao, Y.; Kerekes, A. D.; Yu, T.; Paliwal, S.; Tsui, H.-C.; Shih, N.-Y.; McCombie, S. W.; Madison, V. S.; Lesburg, C. A.; Duca, J. S. WO2006098961: Fused Thieno [2,3-b] Pyridine and Thiazolo [5,4-b] Pyridine Compounds for Inhibiting KSP Kinesin Activity, 2006. d) Larson, G. L.; Fry, J. L. Ionic and Organometallic-Catalyzed Organosilane Reductions. Org. React.2008, 1–737. 17) Incomplete consumption of the alcohol was observed with shorter reaction time. 18) Unfortunately, 29a was obtained with inseparable impurities; thus, its exact yield was not determined while its spectroscopic characterization was not carried out. However, some of the peaks on the 1H NMR ( 4.80 (d, J = 7.4 Hz, 1H), 3.80 (br s, 1H), 5.43 (s, 1H), and 1.79 (s, 3H)) and 13C NMR ( 77.5) are sufficiently indicative of the presence of a single diastereomer of the tricyclic product; its relative stereochemistry at C6 was assigned to be



Page 64 of 65

trans to C6a on the basis of the coupling constant (7.4 Hz) of H 6 at 4.80. See Supporting Information (pp. S67) for a listing of some peaks for the spectral comparison among compounds 29a-e and a more detailed discussion. The exact identity of the major unknown by-product(s) from the acid-mediated cyclization of 27a remains unclear and has not been clearly determined. This type of unknown by-product(s) was not observed for the acid-mediated cyclization for 27b, 27e, 27i, and 27o; presumably, the electrondonating group(s) on the aromatic ring of the benzyl alcohol moiety of these substrates, especially on the position para to the benzylic position, could provide stabilization for the corresponding carbocations to preferably undergo the desired cyclization to furnish the products 29b-e. 19) In our previous study on the tricyclic system, it was also found that H10a was prone to isomerization under different reaction conditions including the hydrosilane reduction (BF3·Et2O and Et3SiH) as well as Cs2CO3 and MeOH. See reference 10e. For other basemediated benzylic/allylic isomerizations, see a) Srebnik, M.; Lander, N.; Mechoulam, R. Base-Catalysed

Double-Bond

Isomerizations

of

Cannabinoids:

Structural

and

Stereochemical Aspects. J. Chem. Soc., Perkin Trans. 1 1984, 2881–2886. b) Hartung, C. G.; Breindl, C.; Tillack, A.; Beller, M. A Base-Catalyzed Domino-Isomerization– Hydroamination Reaction—A New Synthetic Route to Amphetamines. Tetrahedron 2000, 56, 5157–5162. c) Johnston, A. J. S.; McLaughlin, M. G.; Reid, J. P.; Cook, M. J. NaH Mediated Isomerisation–Allylation Reaction of 1,3-Substituted Propenols. Org. Biomol. Chem. 2013, 11, 7662–7666. d) Martinez-Erro, S.; Sanz-Marco, A.; Gómez, A. B.; Vázquez-Romero, A.; Ahlquist, M. S. G.; Martin-Matute, B. Base-Catalyzed Stereospecific Isomerization of Electron-Deficient Allylic Alcohols and Ethers through


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Ion-Pairing. J. Am. Chem. Soc. 2016, 138, 13408–13414. e) Suchand, B.; Satyanarayana, G. KOtBu‐Mediated Domino Isomerization and Functionalization of Aromatic Allylic Alcohols. Eur. J. Org. Chem. 2017, 26, 3886–3895. For propagylic/benzylic isomerization, see Masters, K-S.; Wallesch, M.; Bräse, S. ortho-Bromo(propa-1,2-dien-1yl)arenes: Substrates for Domino Reactions. J. Org. Chem. 2011, 76, 9060–9067. 20) There are other peaks on the crude

1

H NMR which may belong to the other

atropisomer(s) of the same product with identical relative stereochemistry at C6, C6a, C7, and C10a. For more detail on the discussion of atropisomerism of similar types of compounds, see reference 6b. Attempts to purify the alcohol products for full characterization were not successful as they led to substantial decomposition. An additional example of this LiAlH4-mediated isomerization was also provided in the Supporting Information; the 1H NMR clearly indicated the presence of a single isomer (pp. S57-S58). See also spectra of LiAlH 4 reactions of 27a, 27b, and 27i (Supporting Information pp. S55-S60). 21) Rensburg, H. V.; Heerden, P. S. V.; Ferreira, D.

J. Enantioselective Synthesis of

Flavonoids. Part 3.1 trans- and cis-Flavan-3-ol Methyl Ether Acetates. Chem. Soc., Perkin Trans. 1, 1997, 22, 3327–3338. 22) Lee, E.; Jang, I.; Shin, M. J.; Cho, H. J.; Kim, J.; Eom, J. E.; Kwon, Y.; Na, Y. Chalcones as Novel Non-peptidic μ-Calpain Inhibitors. Bull. Korean Chem. Soc., 2011, 32, 3459– 3464. 23) Wu, J. Z.; Cheng, C. C.; Shen, L. L.; Wang, Z. K.; Wu, S. B.; Li, W. L.; Chen, S. H.; Zhou, R. P.; Qiu, P. H. Synthetic Chalcones with Potent Antioxidant Ability on H2O2-Induced Apoptosis in PC12 Cells. Int. J. Mol. Sci. 2014, 15, 18525−18539.


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