Discovery of Novel Cinnamide Fungicidal Leads with Optical Hydroxyl Side Chain.

In order to overcome the resistance of phytopathogens to commercial fungicides, a series of optical 2-methyl-2,3-diol-5-pentyl-based cinnamamide derivatives were rationally designed, synthesized, characterized, and evaluated for their in vitro and in vivo fungicidal activities. The bioassay results indicated that the EC50 (concentration for 50% of maximal effect) values of (R)-11f, (R)-11m, (S)-11m and (R)-11n were 0.16, 0.28, 0.41 and 0.47 µg/mL in the in vitro evaluation against Sclerotinia sclerotiorum, respectively, while compounds (R)- and (S)-11i, (R)- and (S)-11j exhibited excellent in vivo fungicidal activity against Pseudoperonspera cubensis with inhibition rates of 100% at 400 μg/mL. These findings supported the idea that optical 2-methyl-2,3-diol-5-pentyl-containing cinnamamides (R)- and (S)-11i, (R)- and (S)-11j with 2-chloro-4-trifluoromethyl aniline and 2-(4-chlorophenyl) aniline showed excellent in vivo fungicidal activity against S. sclerotiorum and P. cubensis and were promising fungicide candidates.

1. Introduction

Dimethomorph, flumorph and pyrimorph are widely used excellent amide fungicides in agriculture fields (Scheme 1). However, resistance of phytopathogens to them has developed due to their wide application and their similar structures [1,2,3,4,5,6,7]. The resistance mechanisms have been confirmed to relate with point mutation in cellulose synthase 3 (CesA3) [1,4]. In order to overcome this problem, some works addressing this issue have been published, and several compounds had good fungicidal activities against the tested phytopathogens [8,9,10], but all of these molecules retained two (hetero)aryl groups such as benzene, pyridine and isothiazole. For example, isothiamorph was found to exhibit excellent in vivo fungicidal activity against Pseudoperonspera cubensis with both fungicidal activity and systemic acquired resistance [10]. In practice, how to find the novel chemical structures to overcome resistances is difficult and a challenge for agricultural chemists, and the costs of developments are high. To address this issue, our initial strategy was to replace one of the aryl groups in the molecules of dimethomorph, flumorph and pyrimorph with non-aryl groups, and change the morpholine motif into the other amines. However, we faced the question of how to find a suitable functional group.

Scheme 1

The structures of cinnamide fungicides commercially available and isothiamorph.

3,7-Dimethyl-7-hydroxy-2-octen-6-olide 1 (Scheme 2) is a naturally occurring seven-membered lactone that was isolated from the honeybee fungal entomopathogen Ascosphaera apis, as well as the fruit of plant Litsea cubeba in Tibet, and it exhibited good antifungal and antioxidant activities [11,12]. As reported in the literature, the lactone motif plays an important role in the chemical communication between wide varieties of organisms [13], and this class of naturally occurring lactones was confirmed to have a wide range of biological properties such as antifungal, antimicrobial, and phytotoxic activities as well as cytotoxicity against human tumor cells [14,15,16,17]. We paid attention to the total synthesis of natural products with seven-membered lactone moieties and their biological activities in previous papers [18,19,20,21,22]; the synthesis and biological activity evaluation of the racemic 3,7-dimethyl-7-hydroxy-2-octen-6-olide (1), 3,7-dimethyl-2,6- octadien-1,6-olide, 3-aryl-7-methyl-7-hydroxy-2-octen-6-olide, and their 3-(2-hydroxy- propan-2-yl)-4,5-dihydrobenzo[c]oxepin-1-(3H)-one analogues were carried out in our laboratory [18,19,20,21,22].

Scheme 2

3-Aryl analogues of naturally occurring 1 significantly improved fungicidal activity.

Among them, 3-phenyl-7-methyl-7-hydroxy-2-octen-6-olide (2) was found to exhibit more excellent fungicidal activities against several phytopathogens than naturally occurring 3,7-dimethyl-7-hydroxy-2-octen-6-olide (1) and the other derivatives, which indicated that the C3-aryl significantly improved the fungicidal activities of this type of seven-membered lactone (Scheme 2) [22]. The four isomers of 6,7-dihydroxy-3,7- dimethyloct-2-enoic acid (3) were also synthesized, and we found that the chiral acid (, )-isomer-3 was a good lead compound with excellent in vivo antifungal activities against several plant pathogens in our previous report (Scheme 3) [23]. In the other aspect, (/)-3,7-dimethylocta-2,6-dienamides (4), their 6,7-epoxy analogues (5) and optical (6 or 6)-3,7-dimethyl-6,7-dihydroxyoct-2-enamides (6) were found to exhibit in vitro and in vivo fungicidal activities against several phytopathogens in our previous reports (Scheme 3), but the 6,7-epoxy analogues (5) decreased the fungicidal activities in comparison with the amides 4 and 6 [24,25].

Scheme 3

The structures of 6,7-dihydroxy-3,7-dimethyloct-2-enoic acids and amides with fungicidal activity.

Considering the above results, our strategy was that one type of novel amide (11a–11p) was designed when CH3 of amides 6 was replaced with the aryl groups, or one aryl of dimethomorph, flumorph and pyrimorph was replaced with the optical hydroxyl side chain in -3 (Scheme 4).

Scheme 4

The design strategy of 6,7-dihydroxy-3-aryl-7-methyloct-2-enamides.

These structures were different from the dimethomorph, flumorph and pyrimorph, as they could not only improve the in vitro and in vivo fungicidal activities against phytopathogens, but also could overcome the resistance issue. The synthetic route is shown in Scheme 5, and the fungicidal activity evaluation is reported in this article.

Scheme 5

The synthetic route of optical 6,7-dihydroxy-3-aryl-7-methyloct-2-enamides 11a–11p.

2. Results and Discussion

2.1. Chemistry

As indicated in a previous report, lactone 2 was designed [26]. The lactone 2 and analogues were synthesized and evaluated for their fungicidal activities [22]. It was found that ()-2 was the most active compound with EC50 values in the range of 0.2–13.5 µg/mL against the tested phytopathgens, better than its ()-isomer and racemic mixture. The scanning electron microscope (SEM) and transmission electron microscope (TEM) observations indicated that compounds ()-2 had a significant impact on the structure and function of the hyphal cell wall of S. sclerotiorum mycelium [22]. With comparison of those data with that of naturally occurring ()-1, it was found that the C3-aryl significantly improved the fungicidal activities of this type of seven-membered lactone [22]. The amides 4, 5, and 6 having C3-CH3 were also synthesized and evaluated for their fungicidal activities. Some of them exhibited in vitro fungicidal activities against the tested phytopathogens, but were much weaker than those of ()-1, pyrimorph and dimethomorph, while several compounds showed in vivo fungicidal activities against P. cubensis and Erysiphe graminis, but which were also weaker than that of the chiral acid (, )-2 and (, )-2 [24,25]. Therefore, we attempted to replace the C3-CH3 with similar aryl groups as in the previous report [22], and hope to improve the in vitro and in vivo fungicidal activities; thus, the amides 11a–11p were designed, synthesized and evaluated for their fungicidal activities in this article.

The olefin acids 7 and 8a–8d were prepared following the procedures in the previous report [26]. The olefin acids 8a–8d could easily react with morpholine and (4-(tert-butyl) phenyl)methanamine using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and N-hydroxybenzotrizole (HOBT) as the catalysts to provide the amides 10a–10h, but the 2-chloro-4-(trifluoromethyl)aniline and 2-(4-chlorophenyl) aniline could not take part in the reaction because of the weak nucleophilic reactivity and hindrance. Then, the olefin acid 7 was initially transferred into acid chloride, and the acid chloride reacted smoothly with 2-chloro-4-(trifluoromethyl)aniline and 2-(4-chloro phenyl)aniline to afford the amides 9a and 9b. The amides 9a and 9b took part in the stereoselective Mizoroki–Heck arylation with 4-(tert-butyl)iodobenzene, 4-phenyl-iodobenzene, 1-iodonaphthalene and 2-iodonaphthalene to give the amides 10i–10p according to the protocol in the previous report [26]. Finally, we carried out the regioselective Sharpless asymmetric dihydroxylation of the amides 10a–10h at remote C=C double bond with AD-mix-β and AD-mix-α to produce the chiral amides ()- and ()-11a–11p in 75–98% high yields and 90.4–99.4% high ee values as in the previous paper [21,22,23].

2.2. The In Vitro and In Vivo Fungicidal Activities

After completion of synthesis, the in vitro and in vivo fungicidal activities of compounds 11a–11p were evaluated, as shown in Table 1, Table 2 and Table 3. The data in Table 1 indicate that all of compounds (()-11a–11p and ()-11a–11p) with dihydroxyl had weak fungicidal activities against A. solani, P. capsici, B. cinerea and R. solani, while some of them (eg. ()-11f and ()-11n) had excellent fungicidal activities against S. sclerotiorum. The EC50 values of these compounds having strong fungicidal activities against S. sclerotiorum were determined and provided in Table 2. These data indicated that ()- and ()-11a, 11c, 11e and 11g almost lost their fungicidal activities against S. sclerotiorum after dihydroxylation, however ()- and ()-11b, ()- and ()-11f, and ()-11h had good fungicidal activities with EC50 values of 0.16–67.8 µg/mL against S. sclerotiorum after dihydroxylation. These compounds (()- and ()-11m, 11n, 11o) with 2-chloro-4-trifluoromethylaniline and 2-(4-chlorophenyl)aniline exhibited excellent fungicidal activities against S. sclerotiorum with EC50 values of 0.28–11.4 µg/mL, which indicated that the dihydroxyl groups significantly improved their in vitro fungicidal activities. To our surprise, compounds ()- and ()-11e (1 + 2 = morpholino) had very weak in vitro fungicidal activities against five phytopathagens, so we primarily deduced that the α-naphthyl group had a bigger hindrance than the 4-tert-butyl-phenyl, 4-phenyl-phenyl and β-naphthyl group, as they cannot enter the active site of the target. All the data in Table 2 showed that the -configuration is much better than the -configuration for in vitro fungicidal activities; the chiral amides have much better in vitro fungicidal activities than the seven-membered lactones such as 2, ()- and ()-2 [22]. Among these compounds, the EC50 values of ()-11f, ()-11m, ()-11m and ()-11n were 0.16, 0.28, 0.41 and 0.47 µg/mL against S. sclerotiorum, respectively. They exhibited the best in vitro fungicidal activities in comparison with the chiral lactone lead ()-2, ()-2 [ and the chiral amides 6 [25].

Table 1

The in vitro fungicidal activities of compounds 11a–11p (inhibition rate %, 50 µg/mL, p < 0.05).

Compds.	R1, R2	A. solani	P. capsici	S. sclerotiorum	B. cinerea	R. solani
(R)-11a	Morpholino	15.6 ± 1.5	16.9 ± 2.5	46.3 ± 2.6	15.6 ± 1.0	5.6 ± 1.1
(S)-11a	Morpholino	16.1 ± 1.2	16.9 ± 1.8	37.5 ± 2.2	21.9 ± 1.2	6.3 ± 1.0
(R)-11b	H, 4-t-ButC6H4CH2	41.7 ± 2.0	33.8 ± 2.2	81.3 ± 3.5	36.9 ± 2.1	18.1 ± 2.2
(S)-11b	H, 4-t-ButC6H4CH2	54.4 ± 1.8	36.3 ± 2.5	78.1 ± 2.8	41.3 ± 2.5	19.4 ± 1.9
(R)-11c	Morpholino	31.7 ± 1.6	29.3 ± 1.6	27.5 ± 1.6	21.3 ± 1.8	20.9 ± 1.8
(S)-11c	Morpholino	32.3 ± 1.8	83.4 ± 1.8	23.8 ± 2.1	21.3 ± 1.5	18.0 ± 1.4
(R)-11d	H, 4-t-ButC6H4CH2	3.0 ± 1.0	7.0 ± 1.2	41.9 ± 1.9	9.4 ± 1.1	19.8 ± 1.8
(S)-11d	H, 4-t-ButC6H4CH2	2.4 ± 1.0	27.4 ± 1.5	16.3 ± 1.4	38.1 ± 2.5	50.3 ± 2.6
(R)-11e	Morpholino	0 ± 0.0	5.1 ± 1.0	0 ± 0.0	6.3 ± 1.0	13.5 ± 1.8
(S)-11e	Morpholino	10.8 ± 1.6	4.5 ± 1.1	0 ± 0.0	0 ± 0.0	11.8 ± 1.6
(R)-11f	H, 4-t-ButC6H4CH2	17.6 ± 1.8	30.6 ± 2.5	90.0 ± 2.4	28.1 ± 1.8	29.9 ± 1.9
(S)-11f	H, 4-t-ButC6H4CH2	40.7 ± 2.5	30.6 ± 1.7	78.8 ± 1.8	26.3 ± 2.2	29.3 ± 2.1
(R)-11g	Morpholino	34.7 ± 2.8	10.2 ± 2.8	16.9 ± 1.2	0 ± 0.0	15.9 ± 1.6
(S)-11g	Morpholino	41.4 ± 1.9	15.3 ± 1.6	46.9 ± 2.1	0 ± 0.0	15.7 ± 1.4
(R)-11h	H, 4-t-ButC6H4CH2	38.4 ± 3.5	21.0 ± 2.3	81.3 ± 3.0	23.8 ± 1.9	19.7 ± 2.0
(S)-11h	H, 4-t-ButC6H4CH2	56.7 ± 3.8	17.2 ± 2.9	42.5 ± 1.6	11.3 ± 1.8	27.7 ± 2.2
(R)-11i	H, 2-Cl-4-CF3C6H4	40.0 ± 2.7	23.8 ± 3.4	77.5 ± 2.4	33.1 ± 2.1	23.1 ± 1.8
(S)-11i	H, 2-Cl-4-CF3C6H4	31.1 ± 1.9	25.0 ± 1.5	75.0 ± 2.1	33.8 ± 3.0	16.9 ± 1.6
(R)-11j	H, 2-(4-Cl-C6H4)C6H4	46.7 ± 2.5	16.3 ± 1.8	74.4 ± 3.5	36.3 ± 2.6	6.3 ± 1.1
(S)-11j	H, 2-(4-Cl-C6H4)C6H4	47.2 ± 3.0	17.5 ± 1.6	65.6 ± 2.8	38.8 ± 2.9	20.0 ± 0.8
(R)-11k	H, 2-Cl-4-CF3C6H4	34.0 ± 2.4	7.0 ± 1.2	46.3 ± 1.9	19.4 ± 3.0	27.2 ± 1.4
(S)-11k	H, 2-Cl-4-CF3C6H4	32.7 ± 1.8	7.0 ± 1.4	31.3 ± 1.4	10.0 ± 1.6	41.3 ± 2.3
(R)-11l	H, 2-(4-Cl-C6H4)C6H4	2.4 ± 1.0	0.6 ± 0.5	32.5 ± 2.1	24.4 ± 1.8	24.8 ± 1.7
(S)-11l	H, 2-(4-Cl-C6H4)C6H4	5.5 ± 1.1	1.9 ± 0.8	27.5 ± 1.3	18.8 ± 2.0	19.3 ± 1.3
(R)-11m	H, 2-Cl-4-CF3C6H4	47.5 ± 3.6	36.3 ± 3.2	85.6 ± 1.0	17.5 ± 1.9	46.9 ± 2.4
(S)-11m	H, 2-Cl-4-CF3C6H4	45.1 ± 2.8	29.3 ± 2.5	81.9 ± 2.4	31.3 ± 2.2	32.7 ± 1.8
(R)-11n	H, 2-(4-Cl-C6H4)C6H4	31.6 ± 2.6	24.2 ± 3.0	91.9 ± 1.2	20.6 ± 1.8	23.7 ± 2.1
(S)-11n	H, 2-(4-Cl-C6H4)C6H4	37.1 ± 3.8	24.8 ± 2.7	66.3 ± 1.8	0 ± 0.0	24.3 ± 1.9
(R)-11o	H, 2-Cl-4-CF3C6H4	52.4 ± 4.0	24.8 ± 1.8	87.5 ± 2.3	30.6 ± 2.1	49.7 ± 2.8
(S)-11o	H, 2-Cl-4-CF3C6H4	49.9 ± 3.5	29.9 ± 2.5	85.6 ± 1.5	33.8 ± 2.7	37.8 ± 2.6
(R)-11p	H, 2-(4-Cl-C6H4)C6H4	17.7 ± 2.4	23.5 ± 1.6	70.6 ± 2.1	35.0 ± 3.4	26.5 ± 1.8
(S)-11p	H, 2-(4-Cl-C6H4)C6H4	25.5 ± 3.1	24.8 ± 2.0	49.4 ± 2.6	29.4 ± 2.2	26.0 ± 1.4
Pyrimorph		61.6 ± 3.6	100 ± 0	74.4 ± 3.0	68.1 ± 3.1	37.2 ± 2.6
Dimethomorph		14.6 ± 1.6	100 ± 0	15.0 ± 1.1	9.4 ± 1.0	20.9 ± 1.8

Table 2

The EC50 values (µg/mL) of some compounds against S. sclerotiorum in the in vitro fungicidal activities.

Compds.	EC50 (µg/mL)	Compds.	EC50 (µg/mL)	Compds.	EC50 (µg/mL)
(R)-11b	25.2	(R)-11j	58.2	(S)-11o	11.4
(S)-11b	67.8	(S)-11j	65.4	(R)-11p	13.9
(R)-11f	0.16	(R)-11m	0.28	2 [22]	5.1
(S)-11f	4.50	(S)-11m	0.41	(R)-2 [22]	2.8
(R)-11h	24.8	(R)-11n	0.47	(S)-2 [22]	10.4
(R)-11i	42.9	(S)-11n	13.5	Pyrimorph	23.0
(S)-11i	51.8	(R)-11o	5.26

Table 3

The in vivo fungicidal activities of compounds 11a–11p (efficacy%, 400 µg/mL).

Compds	P. cubensis	E. graminis	P. sorghi	C. gloeosporioides	Compds.	P. cubensis	E. graminis	P. sorghi	C. gloeosporioides
(R)-11a	0	0	0	0	(R)-11i	100/20 a/0 b/0 c	0	0	0
(S)-11a	0	0	0	0	(S)-11i	100/30/10/0	40	0	0
(R)-11b	0	0	0	0	(R)-11j	100/90/20/5	0	0	0
(S)-11b	0	0	0	0	(S)-11j	100/98/30/10	0	0	0
(R)-11c	0	0	0	0	(R)-11k	0	0	0	0
(S)-11c	0	0	0	0	(S)-11k	0	0	0	0
(R)-11d	0	0	0	0	(R)-11l	0	0	0	0
(S)-11d	0	0	0	0	(S)-11l	0	0	0	0
(R)-11e	0	0	0	0	(R)-11m	60	0	0	0
(S)-11e	0	0	0	0	(S)-11m	50	0	0	0
(R)-11f	0	0	0	0	(R)-11n	60	0	0	0
(S)-11f	0	0	0	0	(S)-11n	60	0	0	0
(R)-11g	0	0	0	0	(R)-11o	0	0	0	0
(S)-11g	0	0	0	0	(S)-11o	0	0	0	0
(R)-11h	0	0	0	0	(R)-11p	0	0	0	0
(S)-11h	0	0	0	0	(S)-11p	0	0	0	0
(Z, R)-3 [23]	100/25 a	100	60	65	Pyrimorph	100	-	-	-
(Z, S)-3 [23]	100/15 a	100	80	100	Flumorph	95	-	-	-

a: 100 µg/mL; b: 25 µg/mL; c: 6.25 µg/mL.

In order to confirm their fungicidal activities, the in vivo fungicidal activities of compounds 11a–11p were assessed, and the results are provided in Table 3. For ()- and ()-11m, 11n, they only showed 50–60% efficacy against P. cubensis, weaker than that of positive control flumorph, pyrimorph, and the lead ()-3 and ()-3. To our surprise, compounds ()- and ()-11i and 11j, with weak in vitro fungicidal activities, exhibited excellent in vivo fungicidal activities with 100% efficacies at 400 µg/mL, better than that of the positive control flumorph. They still had 20–98% efficacies when concentration decreased to 100 µg/mL, much better than the chiral acid leads ()-3 and ()-3. Notably, ()- and ()-11j remained at 5% and 10% efficacies when concentration decreased to 6.25 µg/mL. These results showed that ()- and ()- 11i, 11j, 11m and 11n were excellent lead compounds worthy of further optimization. This work is currently under way in our group.

3. Experimental Procedures

3.1. General Information

All reactions were performed with magnetic stirring. Unless otherwise stated, all reagents were purchased from commercial suppliers (Energy Chemical, Shanghai, China) and used without further purification. Organic solutions were concentrated under reduced pressure using a rotary evaporator or oil pump. Flash column chromatography was performed using Qingdao Haiyang silica gel (200–300 mesh). Melting points were measured on a Yanagimoto apparatus (Yanagimoto MFG Co., Kyoto, Japan) and are uncorrected. 1H and 13C NMR spectra were obtained on Bruker DPX 300 spectrometer (Bruker Biospin Co., Stuttgart, Germany) with CDCl3 as a solvent and TMS as an internal standard; chemical shifts were presented with δ. HR-ESI-MS spectra were analyzed on Bruker Apex II mass spectrometer (Bruker Co., Bremen, Germany). The solvents were analytical grade and newly distilled before usage. The e.e values were analyzed by an Agilent LC 1100 HPLC instrument equipped with a chiral Chiralpak AD column (250 mm × 4.6 mm), eluent: hexane/isopropanol (95:5; 90:10; 85:15), flow rate: 1.0 mL/min, UV detection wavelength: 230 nm. (See Supplementary Materials).

3.2. Synthesis of the Olefin Acids and –

The olefin acid 7 was prepared through 5-step reactions using 2-methylbut-3-en-2-ol as the starting material following the procedures. The olefin acids 8a–8d were prepared through the stereoselective Mizoroki–Heck arylation of 7 with 4-(tert-butyl)-iodobenzene, 4-phenyl-iodobenzene, 1-iodonaphthalene and 2-iodonaphthalene according to the protocol in the previous reports, and their spectral data were identical with that reported in the literature [22,26].

3.3. Synthesis of the Amides and

Synthesis of the amides 9a and 9b: The olefin acid 7 (1.0 g, 6.5 mmol) and 100 mL CH2Cl2 were added into a 250 mL single-necked flask in an ice-water bath, then we added 1 mL oxalyl dichloride and 3 drops of DMF in a stirred condition. After the bubble disappeared, we removed the ice-water bath, and reacted 1–2 h. The solvent was removed in vacuo to afford the acid chloride. The acid chloride CH2Cl2 (10 mL) solution and pyridine (1 mL) were added dropwise into the 20 mL CH2Cl2 solution of 2-chloro-4-(trifluoromethyl)- aniline (2.00 g, 10.2 mmol) or 2-(4-chlorophenyl) aniline (2.07 g, 10.2 mmol) at the ambient temperature and stirred for 8–10 h. After the reaction was completed, 30 mL water was added into the mixture, poured into the separatory funnel, shaken and separated into the organic phase. Then, the water phase was extracted with CH2Cl2 (3 × 30 mL), combined with the organic phase, and the organic phase was dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the residue was recrystallized using petroleum ether to give white solid 9a or 9b.

(E)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-7-methylocta-2,6-dienamide 9a. A white solid, yield 42%, m.p. 88–90 °C. 1H NMR (300 MHz, CDCl3) δ: 8.68 (d, J = 8.7 Hz, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.05 (dt, J = 15.2, 7.5 Hz, 1H), 6.02 (d, J = 15.2 Hz, 1H), 5.15–5.10 (m, 1H), 2.35–2.27 (m, 2H), 2.23–2.15 (m, 2H), 1.71 (s, 3H), 1.63 (s, 3H). HR-ESI-MS, m/z: C16H18ClF3NO [M+H]+, Cacld. 332.1024, Found: 332.1028.

(E)-N-(2-(4-Chlorophenyl)phenyl)-7-methylocta-2,6-dienamide 9b. A white solid, yield 45%, m.p. 105–107 °C. 1H NMR (300 MHz, CDCl3) δ: 8.34 (brs, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.42–7.30 (m, 3H), 7.24–7.11 (m, 2H), 6.99 (s, 1H), 6.90 (dt, J = 15.8, 7.5 Hz, 1H), 5.70 (d, J = 15.8 Hz, 1H), 5.12–5.06 (m, 1H), 2.35–2.28 (m, 2H), 2.23–2.15 (m, 2H), 1.68 (s, 3H), 1.59 (s, 3H). HR-ESI-MS, m/z: C21H23ClNO [M+H]+, Cacld. 340.1463, Found: 340.1461.

3.4. Synthesis of the Amides –

The general synthetic method (A): 50 mL CH2Cl2 and olefin acid 8a (686 mg, 2.4 mmol) were added into a 250 mL single-necked flask, then EDCI (652 mg, 3.4 mmol) and HOBt (458 mg, 3.4 mmol) were added into the mixture and stirred. After the mixture was clear, morpholine (0.5 mL, 5.75 mmol) was added and reacted for 10 h. Then, 30 mL water was added into the mixture, poured into the separatory funnel, shaken and separated into the organic phase. Then the water phase was extracted with CH2Cl2 (3 × 30 mL) and the organic phase was combined and dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the residue was subjected to a flash silica gel chromatography and washed with petroleum ether/EtOAc (v:v = 3:1) to give a colorless liquid 10a. Compounds 10b–10h were prepared in a similar way.

The general synthetic method (B): To add 9a (400 mg, 1.20 mmol), Pd(OAc)2 (14 mg, 0.06 mmol), P(o-MeC6H4)3 (42 mg, 0.14 mmol), 4-phenyl-iodobenzene (640 mg, 2.29 mmol), and 6 mL N(C2H5)3 into a 25 mL three-necked flask under N2 atmosphere. The mixture was stirred and heated to 110 °C for 20 h, then cooled down to the room temperature; we adjusted pH to 2 using 1M HCl solution and added 30 mL water. The water phase was extracted with EtOAc (30 mL × 3), the organic phase was combined and dried over anhydrous Na2SO4. The solvent was removed under vacuum, and the residue was subjected to a flash silica gel chromatography and washed with petroleum ether/EtOAc (v:v = 100:1) to afford a white solid 10i. Compounds 10j–10p were prepared in a similar approach.

(2E)-3-(4-tert-Butylphenyl)-7-methyl-1-morpholinoocta-2,6-dien-1-one 10a. A colorless liquid, 307 mg, yield 71%. 1H NMR (300 MHz, CDCl3) δ: 7.41–7.31 (m, 4H), 6.12 (s, 1H), 5.11 (t, J = 7.2 Hz, 1H), 3.75–3.49 (m, 8H), 2.72 (t, J = 7.8 Hz, 2H), 2.14–2.05 (m, 2H), 1.64 (s, 3H), 1.50 (s, 3H), 1.33 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 166.75, 151.05, 150.73, 137.45, 131.73, 125.86, 125.03, 123.34, 118.70, 66.53, 46.43, 41.40, 34.24, 31.15, 30.93, 27.01, 25.32, 17.33. HR-MS (ESI) m/z: Calcd. for C23H33NO2 [M+H]+, 356.2584; Found, 356.2586.

(2E)-N-(4-(tert-Butyl)benzyl)-3-(4-(tert-butylphenyl)-7-methylocta-2,6-dienamide 10b. A colorless solid, 364 mg, yield 69%, m.p. 99–100 °C. 1H NMR (300 MHz, CDCl3) δ: 7.38 (d, J = 8.4 Hz, 2H), 7.36 (s, 4H), 7.28 (d, J = 8.4 Hz, 2H), 6.02 (s, 1H), 5.97 (s, 1H), 5.17 (t, J = 7.2 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.14 (t, J = 7.8 Hz, 2H), 2.20–2.10 (m, 2H), 1.63 (s, 3H), 1.52 (s, 3H), 1.35 (s, 9H), 1.34 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 166.18, 154.46, 151.17, 150.11, 138.22, 135.19, 131.73, 127.44, 125.99, 125.27, 125.00, 123.62, 119.51, 42.90, 34.25, 34.18, 31.03, 30.96, 30.39, 27.28, 25.30, 17.36. HR-MS (ESI) m/z: Calcd. for C30H41NO [M+H]+, 432.3261; Found, 432.3255.

(2E)-3-(4-Phenylphenyl)-7-methyl-1-morpholinoocta-2,6-dien-1-one 10c. A colorless liquid, 225 mg, yield 73%. 1H NMR (300 MHz, CDCl3) δ: 7.61 (dd, J = 7.9, 2.7 Hz, 4H), 7.53–7.41 (m, 4H), 7.36 (t, J = 7.2 Hz, 1H), 6.19 (s, 1H), 5.13 (t, J = 7.0 Hz, 1H), 3.77–3.53 (m, 8H), 2.80 (t, J = 8.1 Hz, 2H), 2.08–2.17 (m, 2H), 1.65 (s, 3H), 1.51 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.59, 150.41, 140.75, 140.11, 139.38, 131.89, 128.49, 127.17, 126.81, 126.65, 123.22, 119.38, 66.57, 46.46, 41.44, 31.18, 26.94, 25.33, 17.35. HR-MS (ESI) m/z: Calcd. for C25H30NO2 [M+H]+, 376.2271; Found, 376.2270.

(2E)-N-(4-(tert-Butyl)benzyl)-3-(4-phenylphenyl)-7-methylocta-2,6-dienamide 10d. A colorless solid, 330 mg, yield 70%, m.p. 109–111 °C. 1H NMR (300 MHz, CDCl3) δ: 7.63–7.57 (m, 4H), 7.49–7.43 (m, 4H), 7.42–7.33 (m, 3H), 7.30–7.25 (m, 2H), 6.03–5.93 (m, 2H), 5.18 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 5.6 Hz, 2H), 3.17 (t, J = 7.5 Hz, 2H), 2.21–2.12 (m, 2H),1.64 (s, 3H), 1.52 (s, 3H), 1.34 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 166.00, 154.15, 150.21, 140.82, 140.16, 140.10, 135.08, 131.94, 128.50, 127.47, 127.18, 126.76, 126.66, 125.31, 123.47, 120.13, 42.96, 34.19, 31.03, 30.40, 27.18, 25.30, 17.38. HR-MS (ESI) m/z: Calcd. for C32H37NO [M+H]+, 452.2948; Found, 452.2950.

(2E)-7-Methyl-1-morpholino-3-(naphthalen-1-yl)octa-2,6-dien-1-one 10e. A colorless liquid, 265 mg, yield 62%. 1H NMR (300 MHz, CDCl3) δ: 7.99 (dd, J = 6.3, 3.5 Hz, 1H), 7.86 (dd, J = 6.3, 3.5 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.52–7.41 (m, 3H), 7.30 (dd, J = 6.9, 1.2 Hz, 1H), 6.06 (s, 1H), 5.07 (t, J = 7.2 Hz, 1H), 3.79–3.53 (m, 8H), 2.87 (t, J = 7.8 Hz, 2H), 2.10–2.04 (m, 2H), 1.60 (s, 3H), 1.40 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.09, 151.85, 139.78, 133.40, 131.80, 130.80, 128.05, 127.51, 125.76, 125.52, 125.17, 124.72, 124.63, 123.34, 122.34, 66.63, 66.50, 46.42, 41.45, 34.14, 26.47, 25.29, 17.30. HR-MS (ESI) m/z: Calcd. for C23H27NO2 [M+H]+, 350.2115; Found, 350.2118.

(2E)-N-(4-tert-Butylbenzyl)-7-methyl-3-(naphthalen-1-yl)octa-2,6-dienamide 10f. A colorless liquid, 338 mg, yield 65%. 1H NMR (300 MHz, CDCl3) δ: 7.96 (dd, J = 6.3, 3.5 Hz, 1H), 7.86 (dd, J = 6.3, 3.5 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.50–7.35 (m, 5H), 7.32–7.20 (m, 3H), 5.85 (t, J = 5.2 Hz, 1H), 5.81 (s, 1H), 5.11 (t, J = 7.2 Hz, 1H), 4.53 (d, J = 5.7 Hz, 2H), 3.20 (t, J = 7.8 Hz, 2H), 2.17–2.03 (m, 2H), 1.59 (s, 3H), 1.42 (s, 3H), 1.33 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 165.65, 155.61, 150.23, 140.41, 135.01, 133.37, 131.78, 130.57, 127.99, 127.45, 125.69, 125.49, 125.32, 124.69, 124.46, 123.52, 122.95, 42.91, 34.19, 33.44, 31.01, 26.65, 25.25, 17.28. HR-MS (ESI) m/z: Calcd. for C30H35NO [M+H]+, 426.2791; Found, 426.2788.

(2E)-7-Methyl-1-morpholino-3-(naphthalen-2-yl)octa-2,6-dien-1-one 10g. A colorless liquid, 220 mg, yield 50%. 1H NMR (300 MHz, CDCl3) δ: 7.90–7.79 (m, 4H), 7.57–7.45 (m, 3H), 6.26 (s, 1H), 5.14 (t, J = 7.2 Hz, 1H), 3.80–3.53 (m, 8H), 2.88 (t, J = 8.1 Hz, 2H), 2.17–2.08 (m, 2H), 1.65 (s, 3H), 1.47 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.61, 150.71, 137.83, 132.95, 132.81, 131.90, 127.87, 127.80, 127.26, 126.07, 125.96, 125.33, 124.21, 123.23, 119.99, 66.58, 46.48, 41.45, 31.30, 26.95, 25.34, 17.35. HR-MS (ESI) m/z: Calcd. for C23H27NO2 [M+H]+, 350.2115; Found, 350.2118.

(2E)-N-(4-tert-Butyl)benzyl-7-methyl-3-(naphthalen-2-yl)octa-2,6-dienamide 10h. A colorless liquid, 235 mg, yield 44%. 1H NMR (300 MHz, CDCl3) δ: 7.90–7.78 (m, 4H), 7.54–7.46 (m, 3H), 7.39 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 6.09 (s, 1H), 6.03 (s, 1H), 5.19 (t, J = 7.2 Hz, 1H), 4.52 (d, J = 5.6 Hz, 2H), 3.25 (t, J = 7.8 Hz, 2H), 2.21–2.12 (m, 2H), 1.63 (s, 3H), 1.49 (s, 3H), 1.34 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 166.03, 154.50, 150.19, 138.65, 135.09, 132.94, 132.89, 131.94, 127.96, 127.75, 127.48, 127.26, 126.03, 126.00, 125.56, 125.31, 124.30, 123.47, 120.77, 42.97, 34.19, 31.03, 30.50, 27.19, 25.30, 17.37. HR-MS (ESI) m/z: Calcd. for C30H35NO [M+H]+, 426.2791; Found, 426.2788.

(2E)-N-(2-Chloro-4-trifluoromethylphenyl)-3-(4-(tert-butylphenyl)-7-methylocta-2,6-dienamide 10i. A colorless liquid, 500 mg, yield 89%. 1H NMR (300 MHz, CDCl3) δ: 8.73 (d, J = 8.7 Hz, 1H), 7.83 (s, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.54 (dd, J = 8.7, 1.5 Hz, 1H), 7.43 (s, 4H), 6.11 (s, 1H), 5.19 (t, J = 7.2 Hz, 1H), 3.20 (t, J = 7.8 Hz, 2H), 2.25–2.16 (m, 2H), 1.65 (s, 3H), 1.55 (s, 3H), 1.36 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 163.99, 159.87, 152.09, 137.93, 137.85, 131.96, 126.07, 125.77 (q, J = 4.0 Hz), 125.21, 124.56 (q, J = 3.6 Hz), 123.26, 121.83, 121.26, 120.47, 118.40, 77.11, 76.68, 76.26, 34.35, 30.90, 30.70, 27.42, 25.30, 17.34. HR-MS (ESI) m/z: Calcd. for C26H29ClF3NO [M+H]+, 464.1963; Found, 464.1960.

(2E)-N-(2-(4-Chlorophenyl)phenyl)-3-(4-(tert-butyl)phenyl)-7-methylocta-2,6-dienamide 10j. A colorless liquid, 340 mg, yield 61%. 1H NMR (300 MHz, CDCl3) δ: 8.39 (s, 1H), 7.35–7.20 (m, 12H), 5.78 (s, 1H), 5.16 (t, J = 7.2 Hz, 1H), 3.14 (t, J = 7.8 Hz, 2H), 2.18–2.09 (m, 2H), 1.63 (s, 3H), 1.52 (s, 3H), 1.32 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 163.87, 157.77, 151.62, 138.21, 136.38, 134.70, 133.75, 131.66, 130.30, 129.67, 128.99, 128.39, 126.00, 125.08, 123.99, 123.52, 118.75, 34.28, 30.90, 30.55, 27.40, 25.28, 17.35. HR-MS (ESI) m/z: Calcd. for C31H34ClNO [M+H]+, 472.2402; Found, 472.2406.

(2E)-N-(2-Chloro-4-trifluoromethylphenyl)-3-(4-phenylphenyl)-7-methylocta-2,6-dienamide 10k. A colorless liquid, 309 mg, yield 53%. 1H NMR (300 MHz, CDCl3) δ: 8.75 (d, J = 8.7 Hz, 1H), 7.87 (s, 1H), 7.67–7.40 (m, 11H), 6.18 (s, 1H), 5.21 (t, J = 7.0 Hz, 1H), 3.25 (t, J = 7.8 Hz, 2H), 2.28–2.20 (m, 2H), 1.66 (s, 3H), 1.56 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 163.88, 159.46, 141.59, 139.91, 139.77, 137.78, 132.13, 128.57, 127.38, 126.95, 126.84, 126.70, 125.82 (q, J = 4.1 Hz), 124.60 (q, J =3.6 Hz), 123.13, 121.90, 120.53, 118.93, 30.71, 27.37, 25.32, 17.39. HR-MS (ESI) m/z: Calcd. for C28H25ClF3NO [M+H]+, 484.1650; Found, 484.1646.

(2E)-N-(2-(4-Chlorophenyl)phenyl)-3-(4-phenylphenyl)-7-methylocta-2,6-dienamide 10l. A colorless liquid, 348 mg, yield 60%. 1H NMR (300 MHz, CDCl3) δ: 8.39 (s, 1H), 7.64–7.56 (m, 4H), 7.49–7.20 (m, 13H), 5.85 (s, 1H), 5.18 (t, J = 7.0 Hz, 1H), 3.19 (t, J = 7.8 Hz, 2H), 2.21–2.10 (m, 2H), 1.64 (s, 3H), 1.53 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 157.38, 141.20, 140.09, 140.01, 136.38, 134.61, 133.78, 131.82, 130.31, 129.72, 129.00, 128.50, 128.40, 127.24, 126.83, 126.77, 126.67, 124.13, 123.38, 119.49, 30.55, 27.34, 25.29, 17.37. HR-MS (ESI) m/z: Calcd. for C33H30ClNO [M+H]+, 492.2089; Found, 492.2085.

(2E)-N-(2-Chloro-4-trifluoromethylphenyl)-7-methyl-3-(naphthalen-1-yl)octa-2,6-dienamide 10m. A colorless liquid, 365 mg, yield 66%. 1H NMR (300 MHz, CDCl3) δ: 8.79 (d, J = 8.7 Hz, 1H), 8.01–7.78 (m, 4H), 7.65 (s, 1H), 7.52 (m, 4H), 7.32 (d, J = 6.2 Hz, 1H), 6.04 (s, 1H), 5.13 (t, J = 7.0 Hz, 1H), 3.28 (t, J = 7.7 Hz, 2H), 2.24–2.16 (m, 2H), 1.61 (s, 3H), 1.45 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 163.60, 160.90, 140.04, 137.74, 133.44, 132.06, 130.37, 128.15, 127.98, 125.98, 125.82 (q, J = 4.0 Hz), 125.69, 125.42, 125.07, 124.70, 124.61 (q, J = 3.8 Hz), 124.40, 123.19, 122.16, 121.93, 121.25, 120.50, 76.27, 33.80, 26.71, 25.26, 17.29. HR-MS (ESI) m/z: Calcd. for C26H23ClF3NO [M-H]-, 456.1348; Found, 456.1366.

(2E)-N-(2-(4-Chlorophenyl)phenyl)-7-methyl-3-(naphthalen-1-yl)octa-2,6-dienamide 10n. A colorless liquid, 430 mg, yield 70%. 1H NMR (300 MHz, CDCl3) δ: 8.46 (d, J = 7.1 Hz, 1H), 7.92–7.78 (m, 3H), 7.51–7.39 (m, 6H), 7.35–7.29 (m, 2H), 7.21 (m, 3H), 7.11 (s, 1H), 5.70 (s, 1H), 5.10 (t, J = 7.0 Hz, 1H), 3.21 (t, J = 7.8 Hz, 2H), 2.18–2.10 (m, 2H), 1.59 (s, 3H), 1.42 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 163.80, 158.34, 140.22, 136.27, 134.59, 133.80, 133.37, 131.77, 130.44, 130.26, 129.66, 128.99, 128.44, 128.06, 127.69, 125.79, 125.58, 125.11, 124.68, 124.39, 124.12, 123.42, 122.67, 121.44, 33.54, 26.70, 25.25, 17.29. HR-MS (ESI) m/z: Calcd. for C31H28ClNO [M+H]+, 466.1932; Found, 466.1928.

(2E)-N-(2-Chloro-4-trifluoromethylphenyl)-7-methyl-3-(naphthalene-2-yl)octa-2,6-dienamide 10o. A colorless liquid, 294 mg, yield 53%. 1H NMR (300 MHz, CDCl3) δ: 8.75 (d, J = 8.8 Hz, 1H), 7.98–7.82 (m, 5H), 7.66 (s, 1H), 7.58–7.50 (m, 4H), 6.25 (s, 1H), 5.22 (t, J = 7.1 Hz, 1H), 3.27 (t, J = 7.8 Hz, 2H), 2.25–2.16 (m, 2H), 1.65 (s, 3H), 1.52 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 163.88, 159.83, 138.26, 137.78, 133.17, 132.88, 132.13, 128.07, 128.00, 127.31, 126.40, 126.26, 125.88, 125.82 (q, J = 4.1 Hz), 125.20, 124.60 (q, J = 3.5 Hz), 124.02, 123.13, 121.92, 120.55, 119.52, 30.83, 27.37, 25.30, 17.36. HR-MS (ESI) m/z: Calcd. for C26H23ClF3NO [M+H]+, 458.1493; Found, 458.1488.

(2E)-N-(2-(4-Chlorophenyl)phenyl)-7-methyl-3-(naphthalen-2-yl)octa-2,6-dienamide 10p. A colorless liquid, 424 mg, yield 69%. 1H NMR (300 MHz, CDCl3) δ: 8.40 (s, 1H), 7.84 (brs, 4H), 7.52–7.20 (m, 11H), 5.93 (s, 1H), 5.19 (t, J = 6.9 Hz, 1H), 3.27 (t, J = 7.8 Hz, 2H), 2.22–2.13 (m, 2H), 1.64 (s, 3H), 1.50 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.06, 157.75, 138.58, 136.40, 134.60, 133.78, 132.99, 132.85, 131.83, 130.31, 129.75, 129.00, 128.41, 127.99, 127.84, 127.26, 126.18, 126.14, 125.68, 124.16, 123.40, 121.82, 120.11, 30.69, 27.35, 25.30, 17.37. HR-MS (ESI) m/z: Calcd. for C31H28ClNO [M+H]+, 466.1932; Found, 466.1928.

3.5. Synthesis of the Chiral Amides –

The general synthetic method: A 50 mL round-bottomed flask equipped with a magnetic stirring bar was charged with AD-mix-β (1.4 g), water (7.5 mL) and tert-butyl alcohol (7.5 mL). The resulting mixture was stirred at room temperature to produce two clear phases. Methanesulfonamide (68 mg, 0.7 mmol) was added in one portion and the reaction mixture was stirred for 1.5 h. The reaction mixture was cooled to 0 °C. Compound 10a (356 mg, 1.0 mmol) was added at once, and the heterogeneous slurry was stirred vigorously at 0 °C for 40 h. The saturated Na2S2O3 solution (15 mL) was added at 0 °C, and the mixture was allowed to reach room temperature and stirred for 30 min. EtOAc (50 mL) and water (20 mL) were added to the reaction mixture. The organic layer was separated and the aqueous layer was re-extracted with EtOAc (50 mL×3). The combined organic phase was dried over with anhydrous Na2SO4 and the solvent was removed to give the crude product. This product was purified by flash chromatography on silica gel with petroleum ether/EtOAc (V:V = 3:1) as the eluent to give a colorless oil chiral diol amide (R)-11a 335 mg, yield 86%. In a similar way, the chiral diol amides (R)-11b-(S)-11p were prepared.

(6R,2E)-3-(4-(tert-Butylphenyl)-6,7-dihydroxy-7-methyl-1-morpholinooct-2-en-1-one (R)-11a. A colorless liquid, 335 mg, yield 86%. [α = − 77.8 (c 1.0, CHCl3), ee 95.4%. 1H NMR (300 MHz, CDCl3) δ: 7.39 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.19 (s, 1H), 3.88–3.44 (m, 9H), 3.33–3.27 (m, 1H), 3.23–3.10 (m, 1H), 2.75–2.69 (m, 1H), 1.50–1.40 (m, 2H), 1.32 (s, 9H), 1.01 (s, 3H), 0.92 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.84, 152.89, 151.69, 136.66, 126.04, 125.24, 119.38, 74.67, 71.64, 66.52, 66.37, 46.44, 41.72, 34.30, 30.90, 28.45, 26.98, 25.55, 23.01. HR-MS (ESI) m/z: Calcd. for C23H35NO4 [M+H]+, 390.2639; Found, 390.2636.

(6S,2E)-3-(4-tert-Butylphenyl)-6,7-dihydroxy-7-methyl-1-morpholinooct-2-en-1-one ()-11a. A colorless liquid, 120 mg, yield 89%. [α = +77.0 (c 0.9, CHCl3), ee 91.0%. 1H NMR (300 MHz, CDCl3) δ: 7.39 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.19 (s, 1H), 3.88–3.44 (m, 9H), 3.33–3.27 (m, 1H), 3.23–3.10 (m, 1H), 2.75–2.69 (m, 1H), 1.50–1.40 (m, 2H), 1.32 (s, 9H), 1.01 (s, 3H), 0.92 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.84, 152.89, 151.69, 136.66, 126.04, 125.24, 119.38, 74.66, 71.64, 66.52, 66.37, 46.44, 41.72, 34.30, 30.90, 28.45, 26.98, 25.55, 23.01. HR-MS (ESI) m/z: Calcd. for C23H35NO4 [M+H]+, 390.2639; Found, 390.2636.

(6R,2E)-N-(4-tert-Butylbenzyl)-3-(4-tert-butylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide (R)-11b. A colorless liquid, 105 mg, yield 78%. [α = − 93.6 (c 2.6, CHCl3), ee 97.2%. 1H NMR (300 MHz, CDCl3) δ: 7.40–7.24 (m, 8H), 6.40 (brs, 1H), 6.02 (s, 1H), 5.66 (brs, 1H), 4.47 (d, J = 5.7 Hz, 2H), 3.71–3.56 (m, 1H), 3.34 (brs, 1H), 2.98 (brs, 1H), 2.82–2.76 (m, 1H), 1.55–1.47 (m, 2H), 1.33 (s, 18H), 1.04 (s, 3H), 0.99 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.89, 155.20, 151.69, 150.24, 137.41, 134.68, 127.45, 126.06, 125.31, 125.21, 120.29, 75.06, 71.86, 43.05, 34.29, 34.19, 31.03, 30.93, 29.20, 26.43, 25.70, 23.12. HR-MS (ESI) m/z: Calcd. for C30H43NO3 [M+H]+, 466.3316; Found, 466.3315.

(6S,2E)-N-(4-tert-Butylbenzyl)-3-(4-tert-butylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11b. A colorless solid, 116 mg, yield 86%, m.p. 136–138 °C. [α = +94.0 (c 1.8, CHCl3), ee 91.4%. 1H NMR (300 MHz, CDCl3) δ: 7.40–7.24 (m, 8H), 6.09 (brs, 1H), 5.99 (s, 1H), 5.65 (d, J = 3.0 Hz, 1H), 4.48 (d, J = 5.7 Hz, 2H), 3.74–3.57 (m, 1H), 3.34 (d, J = 9.6 Hz, 1H), 2.94 (brs, 1H), 2.82–2.76 (m, 1H), 1.55–1.48 (m, 2H), 1.33 (s, 9H), 1.32 (s, 9H), 1.06 (s, 3H), 0.99 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.80, 155.52, 151.76, 150.37, 137.38, 134.57, 127.46, 126.03, 125.36, 125.23, 120.16, 74.97, 71.80, 43.11, 34.30, 34.20, 31.00, 30.91, 29.17, 26.45, 25.67, 23.06. HR-MS (ESI) m/z: Calcd. for C30H43NO3 [M+H]+, 466.3316; Found, 466.3315.

(6R,2E)-3-(4-Phenylphenyl)-6,7-dihydroxy-7-methyl-1-morpholinooct-2-en-1-one (R)-11c. A colorless solid, 115 mg, yield 84%, m.p. 135–136 °C. [α = − 54.4 (c 1.7, CHCl3), ee 95.0%. 1H NMR (300 MHz, CDCl3) δ: 7.65–7.58 (m, 4H), 7.49–7.43 (m, 4H), 7.37 (t, J = 7.2 Hz, 1H), 6.26 (s, 1H), 5.94 (d, J = 3.6 Hz, 1H), 3.85–3.50 (m, 8H), 3.35–3.15 (m, 2H), 2.93 (s, 1H), 2.80–2.70 (m, 1H), 1.55–1.49 (m, 2H), 1.03 (s, 3H), 0.94 (s, 3H).13C NMR (75 MHz, CDCl3) δ: 166.71, 152.45, 141.25, 139.84, 138.56, 128.54, 127.34, 127.00, 126.82, 126.65, 120.00, 74.72, 71.66, 66.52, 66.39, 46.48, 41.75, 28.46, 27.05, 25.64, 23.03. HR-MS (ESI) m/z: Calcd. for C25H31NO4 [M+H]+, 410.2326; Found, 410.2325.

(6S,2E)-3-(4-Phenylphenyl)-6,7-dihydroxy-7-methyl-1-morpholinooct-2-en-1-one ()-11c. A colorless solid, 116 mg, yield 85%, m.p. 134–135 °C. [α = +54.3 (c 1.3, CHCl3), ee 90.4%. 1H NMR (300 MHz, CDCl3) δ: 7.66–7.58 (m, 4H), 7.50–7.43 (m, 4H), 7.37 (t, J = 7.2 Hz, 1H), 6.26 (s, 1H), 5.94 (d, J = 3.6 Hz, 1H), 3.88–3.51 (m, 8H), 3.35–3.15 (m, 2H), 2.93 (s, 1H), 2.80–2.70 (m, 1H), 1.55–1.49 (m, 2H), 1.03 (s, 3H), 0.94 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.71, 152.46, 141.25, 139.84, 138.56, 128.54, 127.34, 127.00, 126.82, 126.65, 120.00, 74.72, 71.67, 66.52, 66.39, 46.48, 41.75, 28.45, 27.04, 25.63, 23.02. HR-MS (ESI) m/z: Calcd. for C25H31NO4 [M+H]+, 410.2326; Found, 410.2325.

(6R,2E)-N-(4-tert-Butylbenzyl)-3-(4-phenylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11d. A colorless solid, 147 mg, yield 98%, m.p. 71–73 °C. [α = −73.5 (c 1.8, CHCl3), ee 98.4%. 1H NMR (300 MHz, CDCl3) δ: 7.63–7.58 (m, 4H), 7.49–7.36 (m, 7H), 7.30–7.24 (m, 2H), 6.14 (t, J = 5.4 Hz, 1H), 6.06 (s, 1H), 5.67 (d, J = 3.0 Hz, 1H), 4.50 (d, J = 5.4 Hz, 2H), 3.84–3.62 (m, 1H), 3.37 (d, J = 10.1 Hz, 1H), 2.94 (s, 1H), 2.85–2.78 (m, 1H), 1.63–1.45 (m, 2H), 1.33 (s, 9H), 1.07 (s, 3H), 1.00 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.65, 155.05, 150.43, 141.30, 139.83, 139.28, 134.49, 128.54, 127.50, 127.33, 126.95, 126.80, 126.65, 125.38, 120.80, 74.98, 71.82, 43.17, 34.21, 31.00, 29.09, 26.47, 25.72, 23.04. HR-MS (ESI) m/z: Calcd. for C32H39NO3 [M+H]+, 486.3003; Found, 486.298.

(6S,2E)-N-(4-tert-Butylbenzyl)-3-(4-phenylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11d. A colorless solid, 148 mg, yield 98%, m.p. 148–149 °C. [α = + 75.2 (c 0.8, CHCl3), ee 96.0%. 1H NMR (300 MHz, CDCl3) δ: 7.63–7.58 (m, 4H), 7.49–7.36 (m, 7H), 7.30–7.24 (m, 2H), 6.14 (t, J = 5.4 Hz, 1H), 6.06 (s, 1H), 5.67 (d, J = 3.0 Hz, 1H), 4.50 (d, J = 5.4 Hz, 2H), 3.84–3.62 (m, 1H), 3.37 (d, J = 10.1 Hz, 1H), 2.94 (s, 1H), 2.85–2.78 (m, 1H), 1.63–1.45 (m, 2H), 1.33 (s, 9H), 1.07 (s, 3H), 1.00 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.61, 155.19, 150.47, 141.33, 139.83, 139.26, 134.45, 128.53, 127.49, 127.33, 126.96, 126.79, 126.65, 125.40, 120.74, 74.95, 71.79, 43.19, 34.21, 30.99, 29.07, 26.48, 25.71, 23.02. HR-MS (ESI) m/z: Calcd. for C32H39NO3 [M+H]+, 486.3003; Found, 486.298.

(6R,2E)-3-(Naphthalen-1-yl)-6,7-dihydroxy-7-methyl-1-morpholinooct-2-en-1-one ()-11e. A colorless liquid, 101 mg, yield 91%. [α = −67.7 (c 1.4, CHCl3), ee 97.6%. 1H NMR (300 MHz, CDCl3) δ: 8.03–7.94 (m, 1H), 7.92–7.78 (m, 2H), 7.55–7.42 (m, 3H), 7.32 (d, J = 6.9 Hz, 1H), 6.21 (s, 1H), 5.99 (d, J = 3.7 Hz, 1H), 3.85–3.59 (m, 7H), 3.52 (t, J = 4.7 Hz, 2H), 3.29 (td, J = 13.2, 4.3 Hz, 1H), 3.02 (s, 1H), 2.76 (dt, J = 13.4, 4.6 Hz, 1H), 1.86 (s, 1H), 1.50–1.27 (m, 2H), 1.02 (s, 3H), 1.02 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.38, 153.20, 138.67, 133.53, 130.47, 128.31, 128.00, 126.05, 125.71, 124.79, 124.70, 124.68, 122.84, 75.09, 71.78, 66.51, 66.32, 46.46, 41.77, 30.15, 28.48, 25.71, 22.99. HR-MS (ESI) m/z: Calcd. for C23H29NO4 [M+H]+, 384.2169; Found, 384.2168.

(6S,2E)-3-(Naphthalen-1-yl)-6,7-dihydroxy-7-methyl-1-morpholinooct-2-en-1-one ()-11e. A colorless liquid, 102 mg, yield 91%. [α=+67.9 (c 1.3, CHCl3), ee 98.0%. 1H NMR (300 MHz, CDCl3) δ: 8.04–7.94 (m, 1H), 7.91–7.80 (m, 2H), 7.54–7.45 (m, 3H), 7.32 (d, J = 6.9 Hz, 1H), 6.21 (s, 1H), 5.99 (d, J = 3.7 Hz, 1H), 3.86–3.59 (m, 7H), 3.52 (t, J = 4.8 Hz, 2H), 3.36–3.22 (m, 1H), 3.03 (s, 1H), 2.76 (dt, J = 13.2, 4.5 Hz, 1H), 1.86 (s, 1H), 1.51–1.27 (m, 2H), 1.02 (s, 3H), 1.02 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.38, 153.18, 138.66, 133.53, 130.47, 128.31, 128.00, 126.06, 125.71, 124.79, 124.70, 124.68, 122.83, 75.11, 71.82, 66.52, 66.32, 46.46, 41.78, 30.15, 28.49, 25.73, 22.99. HR-MS (ESI) m/z: Calcd. for C23H29NO4 [M+H]+, 384.2169; Found, 384.2168.

(6R,2E)-N-(4-tert-Butylbenzyl)-3-(naphthalen-1-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11f. A colorless liquid, 123 mg, yield 95%. [α = −76.2 (c 2.2, CHCl3), ee 95.6%. 1H NMR (300 MHz, CDCl3) δ: 7.95–7.77 (m, 3H), 7.537.36 (m, 5H), 7.28–7.20 (m, 3H), 6.14 (brs, 1H), 5.92 (s, 1H), 5.74 (d, J = 3.4 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.80–3.75 (m, 1H), 3.60 (d, J = 9.6 Hz, 1H), 3.03 (s, 1H), 2.80–2.70 (m, 1H), 1.50–1.35 (m, 2H), 1.33 (s, 9H), 1.05 (s, 3H), 1.04 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.39, 155.67, 150.45, 139.56, 134.41, 133.46, 130.34, 128.19, 127.91, 127.52, 125.98, 125.72, 125.39, 124.94, 124.64, 124.55, 123.80, 75.00, 71.92, 43.15, 34.21, 31.01, 29.55, 28.84, 25.79, 22.99. HR-MS (ESI) m/z: Calcd. for C30H37NO3 [M+H]+, 460.2846; Found, 460.2840.

(6S,2E)-N-(4-tert-Butylbenzyl)-3-(naphthalen-1-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11f. A colorless liquid, 120 mg, yield 93%. [α = +77.5 (c 2.1, CHCl3), ee 97.0%. 1H NMR (300 MHz, CDCl3) δ: 7.95–7.79 (m, 3H), 7.53–7.36 (m, 5H), 7.28–7.20 (m, 3H), 6.10 (brs, 1H), 5.93 (s, 1H), 5.73 (d, J = 3.4 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.80–3.75 (m, 1H), 3.60 (d, J = 9.6 Hz, 1H), 3.03 (s, 1H), 2.80–2.70 (m, 1H), 1.50–1.36 (m, 2H), 1.33 (s, 9H), 1.06 (s, 3H), 1.05 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.38, 155.68, 150.45, 139.56, 134.40, 133.46, 130.34, 128.19, 127.91, 127.52, 125.98, 125.72, 125.40, 124.94, 124.64, 124.55, 123.79, 74.99, 71.91, 43.15, 34.21, 31.01, 29.55, 28.84, 25.79, 22.99. HR-MS (ESI) m/z: Calcd. for C30H37NO3 [M+H]+, 460.2846; Found, 460.2840.

(6R,2E)-3-(Naphthalen-2-yl)-6,7-dihydroxy-7-methyl-1-morpholinooct-2-en-1-one ()-11g. A colorless liquid, 102 mg, yield 93%. [α = −54.7 (c 2.5, CHCl3), ee 95.4%. 1H NMR (300 MHz, CDCl3) δ: 7.87–7.82 (m, 4H), 7.52–7.48 (m, 3H), 6.32 (s, 1H), 5.94 (d, J = 3.4 Hz, 1H), 3.85–3.50 (m, 8H), 3.44–3.26 (m, 2H), 2.97 (s, 1H), 2.86 (dt, J = 13.8, 4.3 Hz, 1H), 1.59–1.43 (m, 2H), 0.99 (s, 3H), 0.87 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.72, 152.81, 137.08, 133.00, 132.89, 128.16, 127.88, 127.33, 126.27, 126.25, 125.61, 124.10, 120.64, 74.79, 71.67, 66.51, 66.39, 46.48, 41.76, 28.51, 27.17, 25.60, 22.98. HR-MS (ESI) m/z: Calcd. for C23H29NO4 [M+H]+, 384.2169; Found, 384.2163.

(6S,2E)-3-(Naphthalen-2-yl)-6,7-dihydroxy-7-methyl-1-morpholinooct-2-en-1-one ()-11g. A colorless liquid, 101 mg, yield 92%. [α = +54.1 (c 2.5, CHCl3), ee 92.6%. 1H NMR (300 MHz, CDCl3) δ: 7.88–7.82 (m, 4H), 7.52–7.48 (m, 3H), 6.32 (s, 1H), 5.94 (d, J = 3.4 Hz, 1H), 3.86–3.49 (m, 8H), 3.44–3.26 (m, 2H), 2.97 (s, 1H), 2.86 (dt, J = 13.6, 4.2 Hz, 1H), 1.58–1.44 (m, 2H), 0.99 (s, 3H), 0.87 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.71, 152.79, 137.10, 133.00, 132.89, 128.15, 127.88, 127.33, 126.27, 126.25, 125.61, 124.10, 120.63, 74.81, 71.66, 66.51, 66.38, 46.48, 41.76, 28.53, 27.18, 25.60, 23.01. HR-MS (ESI) m/z: Calcd. for C23H29NO4 [M+H]+, 384.2169; Found, 384.2163.

(6R,2E)-N-(4-tert-Butylbenzyl)-3-(naphthalen-2-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11h. A colorless liquid, 97 mg, yield 87%. [α= −76.1 (c 2.1, CHCl3), ee 96.4%. 1H NMR (300 MHz, CDCl3) δ: 7.86–7.80 (m, 4H), 7.56–7.43 (m, 3H), 7.39 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 6.33 (brs, 1H), 6.13 (s, 1H), 5.69 (s, 1H), 4.50 (d, J = 5.7 Hz, 2H), 3.80–3.71 (m, 1H), 3.40 (d, J = 10.5 Hz, 1H), 2.97–2.87 (m, 2H), 1.61–1.42 (m, 2H), 1.33 (s, 9H), 1.03 (s, 3H), 0.94 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.62, 155.56, 150.48, 137.79, 134.44, 134.44, 133.08, 132.89, 128.10, 127.95, 127.50, 127.30, 126.28, 126.23, 125.72, 125.40, 124.07, 121.41, 74.98, 71.78, 43.2, 34.21, 30.99, 29.06, 26.58, 25.68, 22.97. HR-MS (ESI) m/z: Calcd. for C30H37NO3 [M+H]+, 460.2846; Found, 460.2845.

(6S,2E)-N-(4-tert-Butylbenzyl)-3-(naphthalen-2-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11h. A colorless liquid, 102 mg, yield 92%. [α = +77.5 (c 2.5, CHCl3), ee 90.6%. 1H NMR (300 MHz, CDCl3) δ: 7.86–7.80 (m, 4H), 7.55–7.43 (m, 3H), 7.39 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 6.33 (brs, 1H), 6.13 (s, 1H), 5.69 (s, 1H), 4.50 (d, J = 5.7 Hz, 2H), 3.80–3.70 (m, 1H), 3.40 (d, J = 10.5 Hz, 1H), 2.97–2.87 (m, 2H), 1.60–1.42 (m, 2H), 1.33 (s, 9H), 1.03 (s, 3H), 0.94 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 166.67, 155.35, 150.41, 137.81, 134.50, 133.07, 132.89, 128.10, 127.97, 127.50, 127.31, 126.28, 126.24, 125.72, 125.38, 124.10, 124.10, 121.50, 75.01, 71.82, 43.17, 34.21, 31.01, 29.07, 26.56, 25.69, 22.99. HR-MS (ESI) m/z: Calcd. for C30H37NO3 [M+H]+, 460.2846; Found, 460.2845.

(6R,2E)-N-(2-Chloro-4-trifluoromethylphenyl)-3-(4-tert-butylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11i. A colorless liquid, 100 mg, yield 78%. [α = −111.7 (c 1.5, CHCl3), ee 97.6%. 1H NMR (300 MHz, CDCl3) δ: 8.66 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.65 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 6.20 (s, 1H), 4.81 (d, J = 3.2 Hz, 1H), 3.64–3.56 (m, 1H), 3.41–3.35 (m, 1H), 2.99–2.90 (m, 1H), 2.74 (s, 1H), 1.63–1.52 (m, 2H), 1.34 (s, 9H), 1.08 (s, 3H), 1.03 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 165.07, 160.06, 152.65, 137.25, 136.97, 126.10, 125.87 (q, J =3.9 Hz), 125.47, 124.62 (q, J = 3.7 Hz), 122.26, 120.92, 119.53, 75.59, 71.90, 34.40, 30.87, 29.57, 26.83, 25.65, 23.13. HR-MS (ESI) m/z: Calcd. for C26H31ClF3NO3 [M+H]+, 498.2017; Found, 498.2014.

(6S,2E)-N-(2-Chloro-4-trifluoromethylphenyl)-3-(4-tert-butylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11i. A colorless liquid, 99 mg, yield 77%. [α = +111.5 (c 1.1, CHCl3), ee 97.2%. 1H NMR (300 MHz, CDCl3) δ: 8.67 (d, J = 8.7 Hz, 1H), 7.92 (s, 1H), 7.66 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 6.20 (s, 1H), 4.81 (d, J = 3.5 Hz, 1H), 3.64–3.55 (m, 1H), 3.41–3.35 (m, 1H), 2.99–2.90 (m, 1H), 2.73 (s, 1H), 1.63–1.52 (m, 2H), 1.34 (s, 9H), 1.08 (s, 3H), 1.03 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 165.07, 160.07, 152.66, 137.24, 136.97, 126.10, 125.87 (q, J = 3.9 Hz), 125.47, 124.62 (q, J = 3.8 Hz), 122.24, 120.90, 119.54, 75.58, 71.89, 34.40, 30.87, 29.56, 26.83, 25.64, 23.12. HR-MS (ESI) m/z: Calcd. for C26H31ClF3NO3 [M+H]+, 498.2017; Found, 498.2014.

(6R,2E)-N-(2-(4-Chlorophenyl)phenyl)-3-(4-tert-butylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11j. A colorless liquid, 102 mg, yield 79%. [α = −108.3 (c 0.9, CHCl3), ee 93.8%. 1H NMR (300 MHz, CDCl3) δ: 8.39 (d, J = 8.1 Hz, 1H), 7.46–7.21 (m, 12H), 5.85 (s, 1H), 5.26 (s, 1H), 3.65–3.58 (m, 1H), 3.34 (d, J = 9.0 Hz, 1H), 2.85–2.75 (m, 2H), 1.56–1.48 (m, 2H), 1.32 (s, 9H), 1.06 (s, 3H), 0.99 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 165.01, 157.78, 152.19, 137.20, 136.12, 134.12, 133.91, 130.97, 130.28, 129.73, 129.07, 128.46, 126.07, 125.34, 124.47, 121.62, 120.32, 75.17, 71.78, 34.34, 30.88, 29.24, 26.56, 25.63, 23.04. HR-MS (ESI) m/z: Calcd. for C31H36ClNO3 [M+H]+, 506.2456; Found, 506.2455.

(6S,2E)-N-(2-(4-Chlorophenyl)phenyl)-3-(4-tert-butylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11j. A colorless liquid, 105 mg, yield 82%. [α = +106.1 (c 2.1, CHCl3), ee 90.5%. 1H NMR (300 MHz, CDCl3) δ: 8.38 (d, J = 8.1 Hz, 1H), 7.44–7.21 (m, 12H), 5.86 (s, 1H), 5.24 (s, 1H), 3.65–3.58 (m, 1H), 3.34 (d, J = 9.0 Hz, 1H), 2.85–2.75 (m, 2H), 1.55–1.48 (m, 2H), 1.32 (s, 9H), 1.06 (s, 3H), 0.99 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 165.05, 157.72, 152.17, 137.21, 136.16, 134.13, 133.89, 131.07, 130.28, 129.75, 129.06, 128.44, 126.09, 125.34, 124.51, 121.75, 120.32, 75.20, 71.80, 34.34, 30.89, 29.25, 26.57, 25.64, 23.07. HR-MS (ESI) m/z: Calcd. for C31H36ClNO3 [M+H]+, 506.2456; Found, 506.2455.

(6R,2E)-N-(2-Chloro-4-trifluoromethylphenyl)-3-(4-phenylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11k. A colorless liquid, 120 mg, yield 93%. [α = −107.5 (c 1.5, CHCl3), ee 96.2%. 1H NMR (300 MHz, CDCl3) δ: 8.67 (d, J = 8.7 Hz, 1H), 7.98 (s, 1H), 7.68–7.35 (m, 11H), 6.27 (s, 1H), 4.81 (s, 1H), 3.75–3.58 (m, 1H), 3.45–3.33 (m, 1H), 3.05–2.94 (m, 1H), 2.74 (brs, 1H), 1.66–1.55 (m, 2H), 1.09 (s, 3H), 1.04 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.98, 159.54, 142.07, 139.67, 138.76, 137.19, 128.60, 127.52, 127.17, 126.87, 126.69, 125.91 (q, J = 3.6 Hz), 124.64 (q, 4.1 Hz), 122.36, 121.02, 120.05, 75.60, 71.92, 29.51, 26.86, 25.70, 23.12. HR-MS (ESI) m/z: Calcd. for C28H27ClF3NO3 [M+H]+, 518.1704; Found, 518.1702.

(6S,2E)-N-(2-Chloro-4-trifluoromethylphenyl)-3-(4-phenylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11k. A colorless liquid, 122 mg, yield 95%. [α = +106.8 (c 1.1, CHCl3), ee 93.5%. 1H NMR (300 MHz, CDCl3) δ: 8.68 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.68–7.36 (m, 11H), 6.27 (s, 1H), 4.81 (s, 1H), 3.74–3.59 (m, 1H), 3.41 (brs, 1H), 3.05–2.94 (m, 1H), 2.73 (s, 1H), 1.64–1.58 (m, 2H), 1.09 (s, 3H), 1.04 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.98, 159.55, 142.07, 139.67, 138.76, 137.19, 128.60, 127.52, 127.17, 126.87, 126.69, 125.91 (q, J = 3.8 Hz), 124.64 (q, 3.9 Hz), 122.35, 121.01, 120.05, 75.59, 71.92, 29.51, 26.86, 25.70, 23.11. HR-MS (ESI) m/z: Calcd. for C28H27ClF3NO3 [M+H]+, 518.1704; Found, 518.1702.

(6R,2E)-N-(2-(4-Chlorophenyl)phenyl)-3-(4-phenylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11l. A colorless liquid, 107 mg, yield 83%. [α = −99.9 (c 1.3, CHCl3), ee 96.5%. 1H NMR (300 MHz, CDCl3) δ: 8.37 (d, J = 8.1 Hz, 1H), 7.64–7.23 (m, 17H), 5.94 (s, 1H), 5.22 (s, 1H), 3.75–3.64 (m, 1H), 3.36 (d, J = 9.6 Hz, 1H), 2.89–2.80 (m, 2H), 1.62–1.50 (m, 2H), 1.07 (s, 3H), 1.00 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.94, 157.22, 141.69, 139.76, 139.02, 136.17, 134.04, 133.92, 131.17, 130.29, 129.79, 129.07, 128.56, 128.47, 127.41, 127.06, 126.85, 126.67, 124.64, 121.86, 120.85, 75.19, 71.82, 29.17, 26.59, 25.69, 23.03. HR-MS (ESI) m/z: Calcd. for C33H32ClNO3 [M+H]+, 526.2143; Found, 526.2138.

(6S,2E)-N-(2-(4-Chlorophenyl)phenyl)-3-(4-phenylphenyl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11l. A colorless liquid, 275 mg, yield 80%. [α = +101.9 (c 1.7, CHCl3), ee 94.6%. 1H NMR (300 MHz, CDCl3) δ: 8.37 (d, J = 8.1 Hz, 1H), 7.65–7.23 (m, 17H), 5.95 (s, 1H), 5.22 (s, 1H), 3.75–3.65 (m, 1H), 3.37 (d, J = 9.2 Hz, 1H), 2.89–2.80 (m, 2H), 1.62–1.49 (m, 2H), 1.07 (s, 3H), 1.00 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.95, 157.20, 141.68, 139.76, 139.03, 136.18, 134.04, 133.92, 131.21, 130.29, 129.80, 129.07, 128.56, 128.46, 127.41, 127.06, 126.86, 126.67, 124.66, 121.91, 120.85, 75.20, 71.82, 29.18, 26.59, 25.69, 23.04. HR-MS (ESI) m/z: Calcd. for C33H32ClNO3 [M+H]+, 526.2143; Found, 526.2138.

(6R,2E)-N-(2-chloro-4-trifluoromethylphenyl)-6,7-dihydroxy-7-methyl-3-(naphthalen-1-yl)oct-2-enamide ()-11m. A colorless liquid, 97 mg, yield 75%. [α = −99.8 (c 1.5, CHCl3), ee 93.2%. 1H NMR (300 MHz, CDCl3) δ: 8.71 (d, J = 8.7 Hz, 1H), 7.99–7.85 (m, 4H), 7.66 (s, 1H), 7.56–7.45 (m, 4H), 7.30 (d, J = 6.8 Hz, 1H), 6.19 (s, 1H), 4.88 (d, J = 3.4 Hz, 1H), 3.80–3.72 (m, 1H), 3.65–3.54 (m, 1H), 2.98–2.90 (m, 1H), 2.85 (s, 1H), 1.56–1.49 (m, 2H), 1.08 (s, 3H), 1.07 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.70, 160.49, 139.09, 137.11, 133.53, 130.16, 128.43, 128.34, 126.27, 125.92, 124.71, 124.68, 124.48, 123.24, 122.39, 121.01, 76.27, 75.61, 72.00, 30.03, 29.28, 25.76, 23.05. HR-MS (ESI) m/z: Calcd. for C26H25ClF3NO3 [M+H]+, 492.1548; Found, 492.1547.

(6S,2E)-N-(2-Chloro-4-trifluoromethylphenyl)-3-(naphthalen-1-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11m. A colorless liquid, 110 mg, yield 85%. [α = +99.8 (c 1.7, CHCl3), ee 99.4%. 1H NMR (300 MHz, CDCl3) δ: 8.71 (d, J = 8.7 Hz, 1H), 7.99–7.87 (m, 4H), 7.66 (s, 1H), 7.55–7.45 (m, 4H), 7.30 (d, J = 6.8 Hz, 1H), 6.19 (s, 1H), 4.88 (d, J = 3.4 Hz, 1H), 3.80–3.72 (m, 1H), 3.65–3.54 (m, 1H), 2.98–2.90 (m, 1H), 2.84 (s, 1H), 1.56–1.50 (m, 2H), 1.07 (s, 3H), 1.06 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.70, 160.49, 139.10, 137.12, 133.53, 130.16, 128.42, 128.34, 126.27, 125.91, 124.71, 124.68, 124.48, 123.24, 122.40, 121.03, 75.63, 72.00, 30.04, 29.21, 25.76, 23.06. HR-MS (ESI) m/z: Calcd. for C26H25ClF3NO3 [M+H]+, 492.1548; Found, 492.1547.

(6R,2E)-N-(2-(4-Chlorophenyl)phenyl)-3-(naphthalen-1-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11n. A colorless liquid, 116 mg, yield 94%. [α = −107.9 (c 1.6, CHCl3), ee 96.2%. 1H NMR (300 MHz, CDCl3) δ: 8.40 (d, J = 8.2 Hz, 1H), 7.94–7.80 (m, 3H), 7.54–7.38 (m, 6H), 7.34–7.19 (m, 6H), 5.85 (s, 1H), 5.30 (d, J = 2.9 Hz, 1H), 3.85–3.75 (m, 1H), 3.59 (d, J = 9.8 Hz, 1H), 2.94 (s, 1H), 2.88–2.77 (m, 1H), 1.53–1.40 (m, 2H), 1.06 (s, 3H), 1.05 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.69, 157.91, 139.26, 136.06, 133.98, 133.93, 133.48, 131.34, 130.22, 129.77, 129.05, 128.49, 128.28, 128.16, 126.11, 125.82, 124.77, 124.65, 124.51, 123.82, 121.92, 75.24, 71.91, 29.68, 29.00, 25.76, 23.00. HR-MS (ESI) m/z: Calcd. for C31H30ClNO3 [M+H]+, 500.1987; Found, 500.1985.

(6S,2E)-N-(2-(4-Chlorophenyl)phenyl)-3-(naphthalen-1-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11n. A colorless liquid, 114 mg, yield 92%. [α = +109.1 (c 2.0, CHCl3), ee 93.2%. 1H NMR (300 MHz, CDCl3) δ: 8.40 (d, J = 8.2 Hz, 1H), 7.94–7.80 (m, 3H), 7.54–7.38 (m, 6H), 7.34–7.19 (m, 6H), 5.85 (s, 1H), 5.30 (d, J = 2.9 Hz, 1H), 3.85–3.75 (m, 1H), 3.59 (d, J = 9.8 Hz, 1H), 2.94 (s, 1H), 2.88–2.78 (m, 1H), 1.53–1.40 (m, 2H), 1.06 (s, 3H), 1.05 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.70, 157.90, 139.26, 136.07, 133.98, 133.92, 133.48, 131.36, 130.23, 129.78, 129.05, 128.49, 128.28, 128.16, 126.11, 125.83, 124.77, 124.65, 124.52, 123.83, 121.94, 75.24, 71.92, 29.68, 29.00, 25.76, 23.00. HR-MS (ESI) m/z: Calcd. for C31H30ClNO3 [M+H]+, 500.1987; Found, 500.1985.

(6R,2E)-N-(2-Chloro-4-trifluoromethylphenyl)-3-(naphthalen-2-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11o. A colorless liquid, 62 mg, yield 78%. [α = −102.1 (c 0.5, CHCl3), ee 95.2%. 1H NMR (300 MHz, CDCl3) δ: 8.69 (d, J = 8.7 Hz, 1H), 7.99 (s, 1H), 7.95–7.84 (m, 4H), 7.67 (s, 1H), 7.60–7.50 (m, 4H), 6.34 (s, 1H), 4.83 (d, J = 3.6 Hz, 1H), 3.74 (ddd, J = 13.6, 10.4, 6.4 Hz, 1H), 3.47–3.40 (m, 1H), 3.09–3.04 (m, 1H), 2.71 (s, 1H), 1.63–1.55 (m, 2H), 1.05 (s, 3H), 0.98 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.98, 159.97, 137.28, 137.18, 133.37, 132.86, 128.39, 128.08, 127.37, 126.67, 126.46, 126.04, 125.92 (q, J =3.9 Hz), 124.65 (q, J =3.3 Hz), 123.81, 122.35, 121.01, 120.67, 76.24, 75.58, 71.88, 29.50, 26.96, 25.67, 23.05. HR-MS (ESI) m/z: Calcd. for C26H25ClF3NO3 [M+H]+, 492.1548; Found, 492.1546.

(6S,2E)-N-(2-Chloro-4-trifluoromethylphenyl)-3-(naphthalen-2-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11o. A colorless liquid, 89 mg, yield 83%. [α = +102.5 (c 1.3, CHCl3), ee 93.4%. 1H NMR (300 MHz, CDCl3) δ: 8.68 (d, J = 8.7 Hz, 1H), 8.00 (s, 1H), 7.95–7.84 (m, 4H), 7.67 (s, 1H), 7.60–7.50 (m, 4H), 6.35 (s, 1H), 4.84 (d, J = 3.6 Hz, 1H), 3.74 (ddd, J = 13.6, 10.4, 6.4 Hz, 1H), 3.47–3.40 (m, 1H), 3.09–3.04 (m, 1H), 2.74 (s, 1H), 1.63–1.55 (m, 2H), 1.05 (s, 3H), 0.98 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 164.99, 159.93, 137.29, 137.20, 133.37, 132.86, 128.38, 128.09, 127.37, 126.67, 126.46, 126.04, 125.92 (q, J = 3.8 Hz), 124.64 (q, 4.4 Hz), 123.82, 122.40, 121.06, 120.66, 76.26, 75.62, 71.90, 29.52, 26.97, 25.67, 23.07. HR-MS (ESI) m/z: Calcd. for C26H25ClF3NO3 [M+H]+, 492.1548; Found, 492.1546.

(6R,2E)-N-(2-(4-Chlorophenyl)phenyl)-3-(naphthalen-2-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11p. A colorless liquid, 110 mg, yield 85%. [α = −97.4 (c 1.9, CHCl3), ee 97.8%. 1H NMR (300 MHz, CDCl3) δ: 8.37 (d, J = 8.1 Hz, 1H), 7.86–7.83 (m, 4H), 7.55–7.23 (m, 11H), 6.02 (s, 1H), 5.26 (d, J = 3.0 Hz, 1H), 3.80–3.64 (m, 1H), 3.43–3.38 (m, 1H), 3.00–2.90 (m, 1H), 2.85 (s, 1H), 1.62–1.44 (m, 2H), 1.03 (s, 3H), 0.94 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 165.00, 157.52, 137.56, 136.21, 134.03, 133.89, 133.19, 132.84, 131.36, 130.28, 129.83, 129.05, 128.46, 128.22, 128.00, 127.33, 126.46, 126.35, 125.86, 124.72, 124.00, 122.06, 121.52, 75.22, 71.82, 29.17, 26.70, 25.67, 22.98. HR-MS (ESI) m/z: Calcd. for C31H30ClNO3 [M+H]+, 500.1987; Found, 500.1987.

(6S,2E)-N-(2-(4-Chlorophenyl)phenyl)-3-(naphthalen-2-yl)-6,7-dihydroxy-7-methyloct-2-enamide ()-11p. A colorless liquid, 100 mg, yield 78%. [α = +98.6 (c 1.8, CHCl3), ee 94.2%. 1H NMR (300 MHz, CDCl3) δ: 8.37 (d, J = 8.1 Hz, 1H), 7.86–7.83 (m, 4H), 7.55–7.23 (m, 11H), 6.02 (s, 1H), 5.26 (d, J = 3.0 Hz, 1H), 3.80–3.67 (m, 1H), 3.43–3.38 (m, 1H), 3.00–2.90 (m, 1H), 2.85 (s, 1H), 1.62–1.45 (m, 2H), 1.03 (s, 3H), 0.94 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 165.02, 157.50, 137.56, 136.23, 134.04, 133.88, 133.19, 132.84, 131.38, 130.28, 129.84, 129.04, 128.45, 128.22, 128.00, 127.33, 126.46, 126.35, 125.86, 124.73, 124.01, 122.10, 121.51, 75.23, 71.82, 29.17, 26.71, 25.67, 22.99. HR-MS (ESI) m/z: Calcd. for C31H30ClNO3 [M+H]+, 500.1987; Found, 500.1987.

3.6. Fungicidal Activity of the Amides –

The in vitro fungicidal activities of compounds 11a–11p against R. Solani, A. Solani, F. graminearum, S. Sclerotiorum, B. cinerea and P. capsici were evaluated using methods in the references [27,28] by the mycelium growth rate. Procedure for inhibition rate: The stock 2000 µg/mL DMSO solutions of tested compounds were prepared in advance. Then hot potato dextrose agar (PDA) culture medium (9.75 mL) was added into a plate, and we added sample solution (0.25 mL) or blank DMSO (0.25 mL) to the plate and mixed with PDA culture medium, to make the final concentration 50 µg/mL. When the plate was made, we put a 5 mm diameter fungus cake into the center of plate, incubated them at 25 ± 0.5 °C for 24–48 h, checked the growth status and calculated the inhibition rate according to the reference. Three replicates were performed and the mean measurements were calculated from the three replicates for each concentration. The EC50 values were determined from the inhibition rates of six different concentrations (100, 25.0, 6.25, 1.56, 0.39, 0.10 µg/mL) based on the statistics method for the compounds which had more than 70% inhibition rates in the preliminary evaluation. Dimethomorph and pyrimorph were used as the positive control in the mycelium growth rate test.

The in vivo fungicidal activities of compounds 11a–11p against Pseudoperonospora cubensis, Erysiphe graminis, Puccinia sorghi and Colletotrichum gloeosporioides were evaluated using the potted plant method in a greenhouse [29,30]. Flumorph and pyrimorph were used as the positive control. The evaluation experiments were performed by State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Co. Ltd., Shenyang, China.

4. Conclusions

In conclusion, novel cinnamide fungicidal leads with optical hydroxyl side chain (R)-11a–11p and (S)-11a–11p were designed and synthesized through amidation of the olefin acids 7 and 8a–8d or Mizoroki–Heck arylation of the amides 9a and 9b, and stereoselective synthesis of optical isomers of 3-aryl-7-methyl-6,7-dihydroxyoct-2-enamide with Sharpless asymmetric dihydroxylation as the key steps. Their structures were characterized by the 1H, 13C NMR and HR-ESI-MS spectra data, and the e.e values were analyzed by chiral HPLC. The EC50 values of (R)-11f, (R)-11m, (S)-11m and (R)-11n were 0.16, 0.28, 0.41 and 0.47 µg/mL against S. sclerotiorum in the in vitro evaluation, respectively. The efficacies of (R)- and (S)-11i and 11j against P. cubensis in the in vivo evaluation were 100% at 400 µg/mL, which showed they were the most active compounds and could be used as the potential lead structures for the further modification.