A one-pot diastereoselective synthesis of 1,3-diols and 1,3,5-triols via cascade reactions of arylalkynyl Grignard reagents with enol esters

Abstract

An efficient cascade reaction has been developed to synthesize a series of 1,3-diols and 1,3,5-triols via reactions of arylalkynyl Grignard reagents with enol esters. The stereoselectivity of reactions and the molecular configurations of the products were confirmed by nuclear magnetic resonance, X-ray diffraction, and high-performance liquid chromatography analysis. A possible reaction mechanism was analyzed with the results indicating that it proceeded through a 1,2-addition/rearrangement and reverse O-acylation to produce the 1,3-diol and via C-acylation to form the 1,3,5-triol.

Keywords

1,3-polyols arylalkynyl Grignard reagents cascade reactions enol esters reaction mechanism

Introduction

The 1,3-skipped polyol motif with anti/syn-configuration is often present in polyketides^1–3 exhibiting antibacterial, antitumor, and antiviral activities. Examples include nystatin,⁴ mycoticins A and B,^5,6 bastimolide A,⁷ and caylobolide A.⁸ Several iterative systematic approaches to construct the stereoisomers of 1,3-polyols have been developed using the catalytic asymmetric Overman esterification with allylic alcohols^9,10 or through iterative chain elongation with chiral building blocks.¹¹ Asymmetric addition of allyl compounds using stoichiometric chiral boron or titanium,¹² stereoselective reduction of β-diketones or β-hydroxyketones using a chiral catalyst,¹³ and formation of a new C–C bond¹⁴ to construct 1,3-diol fragments have also been developed. The construction of 1,3,5-triol fragments has attracted the interest of synthetic chemists and much progress has been made in recent years.^1,15–18 Shepherd reported the diastereoselective acetalization of pseudo-C₂-symmetric 1,3,5-triol systems, which can be applied in the synthesis of all stereochemical variants of the 1,3,5-triol unit.¹⁹ Kondekar and Kumar²⁰ developed a practical and efficient iterative approach for the synthesis of 1,3-polyols using proline as the catalyst and further extended this method to all possible 1,3,5-triols. Furthermore, methods for 1,5-syn/anti induction in aldol reactions were reported by Yamaoka,²¹ which can be used to easily obtain 1,3,5-triol stereoisomers. Therefore, it is of certain significance for us to continue studies on 1,3,5-triols.

In recent years, significant advances in cascade reactions involving Grignard reagent–mediated rearrangements have been reported.^22–26 In addition, nucleophilic addition of Grignard reagents to esters is one of the methods for the synthesis of tertiary alcohols. Initially, Zwahlen et al.²⁷ reported a nucleophilic/rearrangement/nucleophilic addition cascade between a Grignard reagent and an enol lactone to afford a 1,3-diol compound. Later, the use of a cascade reaction of Grignard reagents and carbonyl compounds to produce 1,3-diol compounds was demonstrated by Cannone and colleagues.^28,29 We have previously reported on the reactions of substituted aryl Grignard reagents with isopropenyl acetate in one step to form a series of symmetrical aromatic anti/syn-1,3-diols with the anti-products as the major species.^30–32 The stereoselectivity of the reaction was confirmed, and the reaction mechanism of the reaction was speculated upon. In subsequent studies, we found that a 1,3,5-triol was the trace by-product of the reaction and this aroused our interest in further research on this process. When we use an arylalkynyl Grignard reagent, the amount of triol increased. Herein, we report the reactions of substituted arylalkynyl Grignard reagents with different enol esters and our investigations on whether a similar reaction occurred to give the products when using aryl Grignard reagents (Scheme 1).

Scheme 1.

The rearrangement reaction of Grignard reagents with enol esters.

Results and discussion

The reaction between PhC≡CMgBr and 1a was first carried out under the same conditions as those used in the reaction of PhMgBr with 1a.³⁰ At 0 °C to room temperature (rt), the expected products 4aa and unexpected by-product 5aa were obtained in 65% yield under N₂ overnight (Table 1, entry 1). Further measurements revealed that the ratio of anti/syn-1,3-diols 4aa is 2.2:1 and that of anti,syn/anti,anti-1,3,5-triols 5aa is 7.7:1. For compounds 5a, there are three diastereomers (anti,syn/anti,anti/syn,syn) possible, but we only obtain products with the first two configurations. For the anti-1,3-diol, the two hydrogens on the central carbon are not diastereotopic. They are identical as far as nuclear magnetic resonance (NMR) is concerned hence the observation of a 2H singlet. For the 1,3-syn-isomer, they are diastereotopic and give rise to two doublets as observed. In the ¹H NMR spectra of the 1,3,5-triols, there are three distinct OH peaks for the syn,anti-triol and two peaks for the anti,anti-triol, in which one is for the central OH and the other is due to the two other OHs.

Table 1.

Profile of the reaction of 3 with 1a.^a


Entry	Ar(X)	Diolanti:syn	Yield (%)4a	Triolsyn,anti:anti,anti	Yield (%)5a	Yield (%)4a + 5a
1	Ph–	2.2:1	57 (4aa)	7.7:1	8 (5aa)	65
2	p–H₃CC₆H4–	4.1:1	65 (4ab)	0.05:1	9 (5ab)	74
3	p–H₃COC₆H4–	6.4:1	51 (4ac)	0.07:1	7 (5ac)	58
4	p–ClC₆H4–	1.7:1	33 (4ad)	5.3:1	11 (5ad)	44
5	p–FC₆H4–	2.1:1	60 (4ae)	7.9:1	6 (5ae)	66

Reaction conditions unless specified otherwise: 1a:3 = 2:1; 0 °C to rt.

The scope of the reaction was explored using various arylalkynyl Grignard reagents, indicating that Grignard reagents 3 are applicable regardless of the substituents. The corresponding products 4 and 5 were obtained in good yields (Table 1, entries 1–5). Some of the isomers were separated. As shown in Table 1, the anti-diol is the major isomer, the yield of p–CH₃C₆H₄C≡CMgBr was the highest, and the ratio of anti/syn-1,3-diols was 4.1:1 (entry 2). The 1,3,5-triol products of XC₆H₄C≡CMgBr (X = p–Me, p–OMe) were dominated by the anti,anti-form. The ratio of syn,anti/anti,anti-1,3,5-triols was 0.05:1 and 0.07:1 (entries 2 and 3). The ratio of isomers reflects the stereoselectivity of the reaction. For the diol products, when the Grignard reagents had an electron-donating substituent such as p–Me or p–MeO, higher stereoselectivity was obtained, and the ratios of the anti/syn-diols were 4.1:1 and 6.4:1. XC₆H₄C≡CMgBr, with electron-withdrawing groups such as X = p–F and p–Cl, afforded lower stereoselectivities (entries 4 and 5). The preferred formation of the 1,3-anti-diols 4 may involve chelation control.³⁰ 1,3,5-Triols 5 are expected via similar mechanisms.

A total of 14 products were obtained, in which (syn,anti)-1,9-bis(4-chlorophenyl)-3,5,7-trimethylnona-1,8-diyne-3,5,7-triol (syn,anti-5ad) was unambiguously assigned by X-ray analysis (see the Supporting Information). To improve the stereoselectivity, organometallic catalysts^33–35 such as dppe·NiCl₂,³⁶ NiCl₂(PPh₃)₂,³⁷ PdCl₂(PPh₃)₂,³⁸ Pd(PPh₃)₄,³⁹ dppp·PdCl₂⁴⁰ and Pd(OAc)₂⁴¹ were investigated at −15 °C. In addition, different Lewis acids and Lewis bases were also examined, for instance, Yb(OTf)₃, La(OTf)₃, AlCl₃, t-BuOK, lithium diisopropylamide (LDA), NaH, Py, and 4-(dimethylamino)pyridine (DMAP), but the efforts were unsuccessful (Table 2).

Table 2.

The influence of different catalysts on the reaction of the p-chlorophenylacetylene Grignard reagent with 1a.^a


Entry	Catalyst	Diol, 4ad anti:syn	Yield (%)4ad	Triol, 5ad syn,anti:anti,anti	Yield (%)5ad	Yield (%)4ad + 5ad
1	–	1.5:1	23	6.0:1	6	29
2	dppe. NiCl₂	1:1	16	7.8:1	6	22
3	NiCl₂(PPh₃)₂	1.9:1	8	–	3	11
4	Pd(OAc)₂	–	NR	–	NR	NR
5	Yb(OTf)₃	–	NR	–	NR	NR
6	La(OTf)₃	3.6:1	16	–	1	17
7	Py	1.8:1	9	4.5:1	2	11
8	DMAP	1.6:1	13	5.2:1	4	17
9	AlCl₃	–	NR	–	NR	NR

Reaction conditions 1a:3 = 2:1, time: 8 h, −15 °C.

Different temperatures were examined for the reaction of 1a and p-MeC₆H₄C≡CMgBr, with temperatures of 0 and −40 °C giving less favorable yields (Table 3, entries 2 and 5). As shown in Table 3, the yield and stereoselectivity of the reaction decreased at lower temperature, mainly because the yield of the 1,3-diol decreased. It is worth mentioning that the quantity of the 1,3,5-triol increased significantly at −15 and −20 °C (entries 3 and 4). In addition, the effect of the reactant ratio (3:1a = 2:1, 4:1, 6:1, 8:1, 10:1) on the yield and stereoselectivity was also investigated. It appears that increasing the Grignard reagent concentration is beneficial to the coupling reaction.

Table 3.

The influence of temperature on the reaction of the p-methylphenylacetylene Grignard reagent with 1a.^a


Entry	Temperature (°C)	Diol, 4ab anti:syn^b	Yield (%)4ab	Triol, 5ab anti:syn	Yield (%)5ab	Yield (%)4ab + 5ab
1	0 to rt	4.1:1	65	0.05:1	9	74
2	0	2.0:1	13	0.3:1	3	16
3	−15	2.8:1	38	0.1:1	11	49
4	−20	2.1:1	44	0.1:1	10	54
5	−40	1.1:1	11	0.2:1	1	12

Reaction conditions: 1a:3 = 2:1, time: 8 h.

Determined by HPLC.

In order to study the reaction activity and stereoselectivity, vinyl acetate 1b and vinyl benzoate 1c were used with alkynyl Grignard reagents to afford a series of unsymmetric 1,3-diols and 1,3,5-triols. Unsymmetric 1,3,5-triols have three stereogenic centers and four racemic diastereoisomers, although only three were isolated. Further investigations revealed that triols 5b and 5c possess three main configurations (anti,anti/syn,anti/syn,syn), although there should be four configurations. The stereoselectivity was determined from the ratio of anti/syn-diols and triols. The structures of the triols were unambiguously confirmed by X-ray structure analysis (Figure 1). As for 1b, various substituents in X–C₆H₄C≡CMgBr were tolerated. Regardless of their electronic properties, the reactions proceed smoothly with yields of 61%–86% (Table 4, entries 1–5).

Figure 1.

X-ray crystal structures of 5cb(I), 5ca(II), and 5ca(III).

Table 4.

Substrate scope of arylalkynyl Grignard reagents 3 with 1b.^a


Entry	Ar	Diol, 4b anti:syn^b	Yield (%)^c 4b	Ratio^d 5b	Yield (%)5b	Yield (%)4b + 5b
1	Ph–	1.5:1	56 (4ba)	1.7:1.3:1	12 (5ba)	68
2	p–H₃C–C₆H4–	1.8:1	67 (4bb)	1.9:1.6:1	12 (5bb)	79
3	p–CH₃O–C₆H4–	2.1:1	52 (4bc)	2.3:1.7:1	14 (5bc)	66
4	p–Cl–C₆H4–	1.4:1	65 (4bd)	2.8:2.0:1	21 (5bd)	86
5	p–F–C₆H4–	1.5:1	50 (4be)	1.7:1.4:1	11 (5be)	61

HPLC: high-performance liquid chromatography.

1b:3 = 2:1; 0 °C to rt.

Determined by HPLC.

Yield of diol.

anti,anti/syn,anti/syn,syn.

As shown in Tables 4 and 5, lower stereoselectivity was observed for 1b and 1c than for 1a. The ratio of anti/syn-diols produced by 1b and 1c is close to 1.5:1, being much less than that of 1a. It is worth mentioning that for the three reactions, the 1,3-diol is predominantly in the anti-configuration. In addition, 1c provided a higher yield of 1,3,5-triols and a lower yield of 1,3-diols compared to 1a and 1b. For example, when p–CH₃OC₆H₄C≡C– was reacted with 1c, the yield of the corresponding 1,3,5-triols increased to 42% (Table 5, entry 3), being much higher than the 7% and 14% yields obtained with 1a and 1b.

Table 5.

Substrate scope of arylalkynyl Grignard reagents with 1c.^a


Entry	Ar	Diol, 4c anti:syn^b	Yield (%)^c 4c	Ratio^d 5c	Yield (%)5c	Yield (%)4c + 5c
1	Ph–	1.4:1	36 (4ca)	0.8:5.3:1	28 (5ca)	64
2	p–H₃C–C₆H4–	1.5:1	19 (4cb)	1.0:1.1:1	27 (5cb)	46
3	p–CH₃O–C₆H4–	1.5:1	21 (4cc)	0.3:0.4:1	42 (5cc)	63
4	p–Cl–C₆H4–	1.4:1	37 (4cd)	0.8:1.4:1	36 (5cd)	73
5	p–F–C₆H4–	1.4:1	29 (4ce)	0.2:0.4:1	34 (5ce)	63
6	m–F–C₆H4–	1.2:1	35 (4cf)	0.6:2.2:1	20 (5cf)	55

HPLC: high-performance liquid chromatography.

1c:3 = 2:1; 0 °C to rt.

Determined by HPLC.

Yield of diol.

anti,anti/syn,anti/syn,syn.

For triols of 1c (Figure 1), in I, the three OH groups are all facing in the same direction forming intramolecular hydrogen bonds. In II and III, two OH groups are oriented in the same direction. In I and II, the two PhC≡C groups are located on the same side of the carbon chain, but are opposite in III. We defined from the crystal structures that I is anti,anti-5cb, II is syn,anti-5ca, and III is syn,syn-5ca.

A cascade mechanism is applicable to the reaction of the phenylacetylene Grignard reagents with 1 (Scheme 2). Initially, intermediate A was formed through the 1,2-addition between ArC=CMgBr and 1, which would then produce B and enolate magnesium bromide C. Then D was formed through the rearrangement of B and C through an intermolecular aldol reaction as a reverse O-acylation.^42–44 Finally, the arylalkynyl Grignard reagent reacts with D to form the anti/syn-1,3-diol 4.³⁰ Simultaneously, the enolate magnesium bromide can react with D to form intermediate F through C-acylation which then further reacts with the arylalkynyl Grignard reagent to form G and finally produces 1,3,5-riols 5 with different configurations. In short, the process involves a 1,2-addition/rearrangement/reverse O-acylation/C-acylation cascade mechanism.³⁰

Scheme 2.

The mechanism of the reaction of arylalkynyl Grignard reagents with 1.

Conclusion

In summary, we have developed a cascade reaction of arylalkynyl Grignard reagents with isopropenyl acetate, vinyl acetate, and vinyl benzoate to synthesize a series of anti/syn-1,3-diols and 1,3,5-triols with three different configurations. The reaction proceed via a 1,2-addition/rearrangement/reverse O-acylation/C-acylation cascade mechanism. The method is a simple and convenient process for the synthesis of 1,3-diols and 1,3,5-triols simultaneously in one step. Further studies on the scope of these reactions are in progress.

Experimental

General methods

Unless otherwise stated, all the reactions were performed using dried reaction glassware under an atmosphere of nitrogen. Anhydrous tetrahydrofuran (THF) was distilled from sodium. Reactions were monitored by thin-layer chromatography (TLC) with samples exposed to ultraviolet light (254 nm). Column chromatography was performed using silica gel (particle size: 200–300 mesh). NMR spectra were recorded at 25 °C using a Bruker AC 500 MHz spectrometer. Chemical shifts are reported relative to the residual solvent signal (¹H NMR: δ = 7.26 (CDCl₃); ¹³C NMR: δ = 77.00 (CDCl₃)). Melting points were measured with a WRS-1B melting point apparatus. High-performance liquid chromatography (HPLC) analysis: yields were determined for the crude product by HPLC analysis on a Waters-2695 instrument. A Sun Fire C18 column, 4.6 × 250 mm, 5 μm, was used for separation. The mobile phase consisted of water and acetonitrile. The crystallographic analysis was performed on a Smart CCD Apex II diffractometer.

Preparation of substituted alkynyl Grignard reagents

Anhydrous THF was dried and distilled from sodium metal immediately before use. Bromoethane (5.45 g, 0.05 mol, 1.0 equiv.) dissolved in THF (50 mL) was added dropwise from a constant pressure dropping funnel into a round-bottomed flask containing one of grain iodine and magnesium turnings (1.44 g, 0.06 mol, 1.2 equiv.) under N₂. After addition was complete, the mixture was heated to reflux at 35 °C for 1 h. Following cooling to room temperature, the preparation of ethylmagnesium bromide was complete. Next, phenylacetylene (5.11 g, 0.05 mol, 1.0 equiv.) in THF (50 mL) was added dropwise to the ethylmagnesium bromide solution under a nitrogen atmosphere. After the addition was complete, the mixture was cooled and stirred at 0 °C to rt for 30 min. Unless otherwise indicated, all substituted arylalkynyl Grignard reagents were prepared as above.

General procedure for the reaction of substituted arylalkynyl Grignard reagents with enol esters

The enol ester (0.1 mol, 2.0 equiv.) was dissolved in THF (40 mL) and added dropwise to a solution of the above prepared arylalkynyl Grignard reagent. After the mixture had been stirred under a nitrogen atmosphere overnight, the reaction was quenched with saturated NH₄Cl solution. The organic products were extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na₂SO₄. The organic phase was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 15:1 to 6:1) to give the title compounds.

anti-3,5-Dimethyl-1,7-diphenylhepta-1,6-diyne-3,5-diol ( anti-4aa ). Light yellow oil, yield 39%; ¹H NMR (500 MHz, CDCl₃): δ = 7.32 (dd, J = 7.4, 1.6 Hz, 4H), 7.16–7.15 (m, 6H), 4.40 (s, 2H), 2.25 (s, 2H), 1.64 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 131.48, 128.55, 128.27, 122.01, 92.60, 85.08, 67.18, 53.62, 31.23; high resolution mass spectrometry (HRMS) (electrospray ionization (ESI)): m/z calcd for C₂₁H₂₀O₂ ([M + Na]⁺): 327.1356; found: 327.1353.

syn-3,5-Dimethyl-1,7-diphenylhepta-1,6-diyne-3,5-diol ( syn-4aa ). Light yellow oil, yield 18%; ¹H NMR (500 MHz, CDCl₃): δ = 7.19–7.02 (m, 10H), 4.01 (s, 2H), 2.24 (d,J = 14.6 Hz, 1H), 2.13 (d,J = 14.6 Hz, 1H), 1.60 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 131.24, 127.60, 127.55, 122.27, 91.91, 84.60, 67.39, 52.37, 32.48; HRMS (ESI): m/z calcd for C₂₁H₂₀O₂ ([M + Na]⁺): 327.1356; found: 327.1352.

anti-3,5-Dimethyl-1,7-Di-p-tolylhepta-1,6-diyne-3,5-diol ( anti-4ab ). White solid, yield 49%, m.p. 90.1–90.4 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.33 (d, J = 7.9 Hz, 4H), 7.10 (d, J = 7.8 Hz, 4H), 4.49 (s, 2H), 2.34 (s, 8H), 1.74 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 138.60, 131.33, 128.97, 118.88, 91.90, 85.19, 67.10, 53.69, 31.18, 21.33; HRMS (ESI): m/z calcd for C₂₃H₂₄O₂ ([M + K]⁺): 371.1408; found: 371.1410.

syn-3,5-Dimethyl-1,7-di-p-tolylhepta-1,6-diyne-3,5-diol ( syn-4ab ). White solid, yield 12%, m.p. 116.2–116.8 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.17 (d, J = 7.8 Hz, 4H), 6.96 (d, J = 7.7 Hz, 4H), 3.80 (s, 2H), 2.34 (d, J = 14.5 Hz, 1H), 2.30 (s, 6H), 2.21 (d, J = 14.5 Hz, 1H), 1.68 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 138.10, 131.53, 128.70, 119.52, 91.57, 85.15, 67.70, 53.10, 32.77, 21.40; HRMS (ESI): m/z calcd for C₂₃H₂₄O₂ ([M + Na]⁺): 355.1669; found: 355.1667.

(anti,anti)-3,5,7-Trimethyl-1,9-di-p-tolylnona-1,8-diyne-3,5,7-triol ( anti,anti-5ab ). White solid, yield 9% m.p. 102.1–102.5 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.28 (d, J = 7.7 Hz, 4H), 7.04 (d, J = 5 Hz, 4H), 4.56 (s, 1H), 4.24 (s, 2H), 2.70 (d, J = 14.9 Hz, 2H), 2.31 (s, 6H), 2.07 (d, J = 14.9 Hz, 2H), 1.65 (s, 6H), 1.55 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 138.36, 131.32, 128.97, 119.35, 92.96, 84.80, 75.28, 67.38, 51.87, 32.99, 31.31, 21.38; HRMS (ESI): m/z calcd for C₂₆H₃₀O₃ ([M + Na]⁺): 413.2087; found: 413.2088.

anti-1,7-Bis(4-methoxyphenyl)-3,5-dimethylhepta-1,6-diyne-3,5-diol ( anti-4ac ). White solid, yield 44%, m.p. 114.6–115.6 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.36 (d, J = 8.7 Hz, 4H), 6.82 (d, J = 8.7 Hz, 4H), 4.27 (s, 2H), 3.79 (s, 6H), 2.30 (s, 2H), 1.69 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.83, 133.01, 113.95, 91.18, 85.37, 67.01, 55.24, 54.15, 31.34; HRMS (ESI): m/z calcd for C₂₆H₃₀O₅ ([M + Na]⁺): 387.1567; found: 387.1569.

(anti,anti)-1,9-Bis(4-methoxyphenyl)-3,5,7-trimethylnona-1,8-diyne-3,5,7-triol ( anti,anti-5ac ). White solid, yield 6%, m.p. 106.8–109.6 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.33 (d, J = 8.7 Hz, 4H), 6.76 (d, J = 8.7 Hz, 4H), 4.56 (s, 1H), 4.07 (s, 2H), 3.77 (s, 6H), 2.71 (d, J = 14.9 Hz, 2H), 2.06 (d, J = 15.0 Hz, 2H), 1.65 (s, 6H), 1.54 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.55, 132.91, 114.48, 113.85, 92.26, 84.58, 75.35, 67.45, 55.19, 51.82, 33.01, 31.36; HRMS (ESI): m/z calcd for C₂₆H₃₀O₅ ([M + Na]⁺): 445.1985; found: 445.1990.

anti-1,7-Bis(4-chlorophenyl)-3,5-dimethylhepta-1,6-diyne-3,5-diol ( anti-4ad ). White solid, yield 21%, m.p. 90.7–90.9 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.34 (d, J = 8.5 Hz, 4H), 7.28 (d, J = 8.5 Hz, 4H), 4.05 (s, 2H), 2.33 (s, 2H), 1.73 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 134.69, 132.71, 128.67, 120.51, 93.55, 83.88, 67.34, 53.21, 31.20; HRMS (ESI): m/z calcd for C₂₁H₁₈O₂Cl₂ ([M + Na]⁺): 395.0576; found: 395.0582.

syn-1,7-Bis(4-chlorophenyl)-3,5-dimethylhepta-1,6-diyne-3,5-diol ( syn-4ad ). White solid, yield 13%, m.p. 125.4–128.3 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.13 (d, J = 8.5 Hz, 4H), 7.09 (d, J = 8.5 Hz, 4H), 4.00 (s, 2H), 2.29 (d, J = 14.6 Hz, 1H), 2.19 (d, J = 14.6 Hz, 1H), 1.66 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 134.15, 132.70, 128.27, 121.16, 93.27, 84.00, 67.87, 52.55, 32.86; HRMS (ESI): m/z calcd for C₂₁H₁₈O₂Cl₂ ([M + K]⁺): 411.0315; found: 411.0316.

(syn,anti)-1,9-Bis(4-chlorophenyl)-3,5,7-trimethylnona-1,8-diyne-3,5,7-triol ( syn,anti-5ad ). White solid, yield 9%, m.p. 161.9–163.6 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.36–7.27 (m, 8H), 4.93 (d, J = 7.2 Hz, 2H), 4.52 (s, 1H), 2.04 (d, J = 14.9 Hz, 3H), 1.78 (s, 1H), 1.70 (s, 3H), 1.63 (d, J = 3.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 134.32, 132.53, 128.63, 121.21, 94.62, 94.51, 83.68, 83.43, 75.91, 67.82, 67.32, 53.44, 49.59, 33.96, 33.45, 29.86; HRMS (ESI): m/z calcd for C₂₄H₂₄O₃ ([M + Na]⁺): 453.0995; found: 453.1030.

anti-1,7-Bis(4-fluorophenyl)-3,5-dimethylhepta-1,6-diyne-3,5-diol ( anti-4ae ). Light yellow oil, yield 40%, ¹H NMR (500 MHz, CDCl₃): δ = 7.43 (dd, J = 8.7, 5.4 Hz, 4H), 7.03 (t, J = 8.7 Hz, 4H), 4.57 (s, 2H), 2.40 (s, 2H), 1.81 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.52 (d, J_C-F = 247.9 Hz), 133.35 (d, J_C-F = 8.5 Hz), 118.21 (d, J_C-F = 3.5 Hz), 115.16 (d, J_C-F = 21.8 Hz), 92.49, 83.68, 67.37, 53.10, 31.16; HRMS (ESI): m/z calcd for C₂₁H₁₈O₂F₂ ([M + Na]⁺): 363.1167; found: 363.1169.

syn-1,7-Bis(4-fluorophenyl)-3,5-dimethylhepta-1,6-diyne-3,5-diol ( syn-4ae ). White solid, yield 20%, m.p. 95.9–97.8 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.21 (dd, J = 8.7, 5.4 Hz, 4H), 6.82 (t, J = 8.7 Hz, 4H), 4.01 (s, 2H), 2.30 (d, J = 14.6 Hz, 1H), 2.19 (d, J = 14.6 Hz, 1H), 1.66 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.25 (d, J_C-F = 249.48 Hz), 133.40 (d, J_C-F = 8.82 Hz), 118.76 (d, J_C-F = 3.78 Hz), 115.16 (d, J_C-F = 22.68 Hz), 91.97, 83.92, 77.25, 52.53, 32.88; HRMS (ESI): m/z calcd for C₂₁H₁₈O₂F₂ ([M − H]⁻): 339.1202; found: 339.1213.

(syn,anti)-1,9-Bis(4-fluorophenyl)-3,5,7-trimethylnona-1,8-diyne-3,5,7-triol ( syn,anti-5ae ). White solid, yield 5%, m.p. 157.2–159.1 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.38 (dt, J = 19.5, 6.7 Hz, 4H), 6.98 (t, J = 7.0 Hz, 4H), 4.98 (s, 2H), 4.60 (s, 1H), 3.11 (d, J = 14.8 Hz, 1H), 2.05–1.83 (m, 4H), 1.71 (s, 3H), 1.62 (d, J = 5.3 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.48 (d, J_C-F = 248.4 Hz), 133.24 (d, J_C-F = 3.6 Hz), 133.17 (d, J_C-F = 3.6 Hz), 118.82 (t, J_C-F = 3.9 Hz), 115.65 (d, J_C-F = 4.7 Hz), 115.48 (d, J_C-F = 4.6 Hz), 93.38, 93.26, 83.75, 83.50, 75.89, 67.85, 67.32, 53.54, 49.71, 34.04, 33.55, 29.89; HRMS (ESI): m/z calcd for C₂₄H₂₄F₂O₃ ([M + Na]⁺): 421.1586; found: 421.1583.

anti-3-Methyl-1,7-diphenylhepta-1,6-diyne-3,5-diol ( anti-4ba ). White solid, yield 34%, m.p. 95.5–95.8 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.45 (t, J = 6.7 Hz, 4H), 7.31 (s, 6H), 5.38 (d, J = 10.7 Hz, 1H), 4.44 (d, J = 10.7 Hz, 1H), 3.55 (d, J = 19.7 Hz, 1H), 2.36–2.29 (m, 1H), 2.18 (d, J = 14.4 Hz, 1H), 1.65 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 131.68, 131.64, 128.47, 128.36, 128.24, 128.22, 122.41, 122.30, 91.18, 89.16, 85.07, 84.52, 68.58, 61.88, 48.74, 30.77; HRMS (ESI): m/z calcd for C₂₀H₁₅O₂ ([M + K]⁺): 329.0938; found: 329.0942.

syn-3-Methyl-1,7-diphenylhepta-1,6-diyne-3,5-diol ( syn-4ba ). White solid, yield 22%, m.p. 91.8–92.3 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.43 (d, J = 7.0 Hz, 4H), 7.24–7.20 (m, 6H), 5.08–5.04 (m, 1H), 3.46 (s, 1H), 3.33 (s, 1H), 2.49 (q, J = 8.3 Hz, 1H), 2.31 (dd, J = 14.4, 4.6 Hz, 1H), 1.71 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 131.64, 131.63, 128.45, 128.40, 128.19, 122.24, 122.22, 92.03, 89.40, 85.64, 84.14, 67.26, 60.24, 49.24, 29.82; HRMS (ESI): m/z calcd for C₂₀H₁₅O₂ ([M + K]⁺): 329.0938; found: 329.0932.

anti-3-Methyl-1,7-di-p-tolylhepta-1,6-diyne-3,5-diol ( anti-4bb ). White solid, yield 42%, m.p. 93.3–93.8 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.34 (t, J = 7.6 Hz, 4H), 7.11 (d, J = 7.6 Hz, 4H), 5.37 (d, J = 10.6 Hz, 1H), 4.39 (s, 1H), 3.47 (s, 1H), 2.34 (s, 6H), 2.29 (d, J = 10.9 Hz, 1H), 2.17 (d, J = 14.2 Hz, 1H), 1.64 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 138.56, 138.41, 131.57, 131.53, 128.94, 128.98, 119.36, 119.24, 90.52, 88.53, 85.16, 84.60, 68.58, 61.92, 48.84, 30.79, 21.38; HRMS (ESI): m/z calcd for C₂₂H₂₁O₂ ([M + Na]⁺): 341.1512; found: 341.1513.

syn-3-Methyl-1,7-di-p-tolylhepta-1,6-diyne-3,5-diol ( syn-4bb ). White solid, yield 24%, m.p. 116.2–116.7 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.32 (d, J = 7.0 Hz, 4H), 7.08 (d, J = 7.6 Hz, 4H), 5.10 (s, 1H), 3.43 (s, 1H), 3.29 (s, 1H), 2.46 (dd, J = 14.2, 8.4 Hz, 1H), 2.33 (s, 6H), 2.28 (dd, J = 14.3, 4.1 Hz, 1H), 1.69 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 138.58, 138.51, 131.57, 131.54, 128.95, 119.16, 119.15, 91.35, 88.74, 85.80, 84.27, 67.23, 60.29, 49.42, 29.80, 21.39; HRMS (ESI): m/z calcd for C₂₂H₂₁O₂ ([M + Na]⁺): 341.1512; found: 341.1514.

(anti,anti)-3-Methyl-1,9-di-p-tolylnona-1,8-diyne-3,5,7-triol ( anti,anti-5bb ). White solid, yield 5%, m.p. 123.7–124.5 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.28–7.22 (m, 4H), 6.98 (t, J = 8.6 Hz, 4H), 5.03 (t, J = 9.6 Hz, 1H), 4.92 (d, J = 4.2 Hz, 1H), 4.49 (s, 1H), 4.24 (s, 1H), 3.83 (s, 1H), 2.31 (d, J = 5.4 Hz, 6H), 2.08–2.03 (m, 1H), 1.96 (t, J = 14.0 Hz 1H), 1.89–1.85 (m, 1H), 1.78 (d, J = 14.1 Hz, 1H), 1.60 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 138.33, 138.17, 131.59, 128.92, 119.39, 119.29, 91.09, 88.47, 85.58, 84.26, 69.21, 68.99, 61.54, 47.95, 42.77, 31.36, 21.41; HRMS (ESI): m/z calcd for C₂₄H₂₆O₃ ([M + Na]⁺): 385.1774; found: 385.1773.

(syn,syn)-3-Methyl-1,9-di-p-tolylnona-1,8-diyne-3,5,7-triol ( syn,syn-5bb ). White solid, yield 3%, m.p. 106.1–112.4 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.28 (m, 4H), 7.08–7.02 (m, 4H), 4.95–4.90 (m, 1H), 4.70 (d, J = 13.2 Hz, 1H), 4.25–4.08 (m, 2H), 3.84 (s, 1H), 2.32 (d, J = 3.6 Hz, 6H), 2.20–1.88 (m, 4H), 1.67–1.59 (m, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 138.45, 130.30, 131.53, 128.91, 119.47, 119.11, 92.15, 88.89, 85.10, 83.80, 67.71, 66.77, 60.88, 48.36, 43.24, 29.66, 21.35; HRMS (ESI): m/z calcd for C₂₄H₂₆O₃ ([M + Na]⁺): 385.1774; found: 385.1773.

anti-1,7-Bis(4-methoxyphenyl)-3-methylhepta-1,6-diyne-3,5-diol ( anti-4bc ). White solid, yield 35%, m.p. 82.7–83.0 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.36 (t, J = 7.5 Hz, 4H), 6.81 (d, J = 8.1 Hz, 4H), 5.35 (d, J = 10.6 Hz, 1H), 4.40 (s, 1H), 3.78 (s, 6H), 3.55 (s, 1H), 2.31–1.98 (m, 2H), 1.62 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.63, 159.54, 133.11, 133.70, 114.54, 114.40, 113.86, 113.82, 89.85, 87.90, 84.92, 84.35, 68.58, 61.93, 55.19, 48.89, 30.84; HRMS (ESI): m/z calcd for C₂₀H₁₅O₂ ([M + Na]⁺): 373.1410; found: 373.1407.

syn-1,7-Bis(4-methoxyphenyl)-3-methylhepta-1,6-diyne-3,5-diol ( syn-4bc ). White solid, yield 17%, m.p. 105.5–109.0 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.33 (d, J = 6.7 Hz, 4H), 6.78 (d, J = 8.1 Hz, 4H), 5.09 (s, 1H), 3.77 (s, 6H), 3.59 (s, 1H), 3.47 (s, 1H), 2.44 (dd, J = 14.3, 8.3 Hz, 1H), 2.26 (dd, J = 14.3, 4.6 Hz, 1H), 1.66 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.60, 159.55, 133.11, 133.07, 114.34, 114.31, 113.79, 90.73, 88.13, 85.52, 83.96, 67.21, 60.25, 55.16, 49.43, 29.83; HRMS (ESI): m/z calcd for C₂₄H₂₇O₄ ([M + Na]⁺): 373.1410; found: 373.1415.

anti-1,7-Bis(4-chlorophenyl)-3-methylhepta-1,6-diyne-3,5-diol ( anti-4bd ). White solid, yield 38%, m.p. 120.2–121.6 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.33 (t, J = 8.5 Hz, 4H), 7.25 (d, J = 6.8 Hz, 4H), 5.30 (d, J = 11.0 Hz, 1H), 4.17 (s, 1H), 3.27 (s, 1H), 2.27 (q, J = 3.2 Hz, 1H), 2.14 (d, J = 14.35 Hz, 1H), 1.61 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 134.68, 134.53, 132.88, 128.62, 120.84, 120.70, 92.05, 89.91, 84.13, 83.54, 68.59, 61.90, 48.60, 30.80; HRMS (ESI): m/z calcd for C₂₀H₁₆O₂Cl₂ ([M + Na]⁺): 381.0420; found: 381.0423.

syn-1,7-Bis(4-chlorophenyl)-3-methylhepta-1,6-diyne-3,5-diol ( syn-4bd ). White solid, yield 27%, m.p. 136.4–136.9 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.27 (d, J = 8.2 Hz, 4H), 7.20 (d, J = 7.8 Hz, 4H), 5.02 (t, J = 4.3 Hz, 1H), 3.07 (s, 1H), 2.97 (s, 1H), 2.39 (q, J = 8.3 Hz, 1H), 2.22 (dd, J = 14.50, 4.4 Hz, 1H), 1.20 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 134.63, 132.89, 128.63, 120.71, 92.91, 90.21, 84.64, 83.21, 67.34, 60.32, 49.04, 29.95; HRMS (ESI): m/z calcd for C₂₀H₁₆O₂Cl₂ ([M + Na]⁺) 381.0420; found: 381.0426.

(anti,anti)-1,9-Bis(4-chlorophenyl)-3-methylnona-1,8-diyne-3,5,7-triol ( anti,anti-5bd ). White solid, yield 10%, m.p. 143.3–143.7 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.27–7.22 (m, 4H), 7.16 (t, J = 8.6 Hz, 4H), 5.01 (t, J = 9.5 Hz, 1H), 4.93 (q, J = 5.1 Hz, 1H), 4.17 (s, 1H), 4.05 (s, 1H), 3.55 (d, J = 5.6 Hz, 1H), 2.10–2.05 (m, 1H), 1.98 (dd, J = 14.3, 10.6 Hz, 1H), 1.87 (ddd, J = 14.3, 5.6, 2.4 Hz, 1H), 1.79 (d, J = 14.1 Hz, 1H), 1.61 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 134.56, 134.41, 132.83, 128.59, 128.54, 120.91, 120.77, 92.78, 90.09, 84.46, 83.15, 69.31, 69.06, 61.65, 47.92, 42.56, 31.26; HRMS (ESI): m/z calcd for C₂₂H₂₀O₃Cl₂ ([M + Na]⁺): 425.0682; found: 425.0686.

(syn,anti)-1,9-Bis(4-chlorophenyl)-3-methylnona-1,8-diyne-3,5,7-triol ( syn,anti-5bd ). White solid, yield 7%, m.p. 114.4–115.7 °C: ¹H NMR (500 MHz, CDCl₃): δ = 7.34–7.27 (m, 4H), 7.26–7.21 (m, 4H), 4.94–4.90 (m, 1H), 4.68 (q, J = 7.0 Hz, 1H), 4.33 (d, J = 165.5 Hz, 1H), 3.99–3.89 (m, 1H), 3.51–3.44 (m, 1H), 2.21–1.79 (m, 5H), 1.64 (d, J = 42.7 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 134.59, 132.85, 128.62, 120.95, 120.66, 120.59, 93.60, 92.78, 90.37, 90.05, 84.09, 82.98, 82.73, 70.53, 69.09, 67.83, 66.91, 62.36, 61.10, 48.12, 44.12, 42.85, 31.21, 29.63; HRMS (ESI): m/z calcd for C₂₂H₂₀O₃Cl₂ ([M + Na]⁺): 425.0682; found: 425.0685.

(syn,syn)-1,9-Bis(4-chlorophenyl)-3-methylnona-1,8-diyne-3,5,7-triol ( syn,syn-5bd ). White solid, yield 4%, m.p. 147.1–147.4 °C: ¹H NMR (500 MHz, CDCl₃): δ = 7.34 (d, J = 8.3 Hz, 4H), 7.30–7.23 (m, 4H), 4.91 (dt, J = 9.0, 3.6 Hz, 1H), 4.44 (t, J = 9.6 Hz, 1H), 3.95 (s, 1H), 3.53 (d, J = 3.3 Hz, 1H), 3.42 (s, 1H), 2.18 (ddt, J = 14.0, 9.5, 4.6 Hz, 2H), 2.01–1.89 (m, 2H), 1.68 (s, 3H); ¹³C NMR (125 MHz, dimethyl sulfoxide (DMSO)): δ = 132.80, 132.77, 128.63, 128.57, 121.38, 96.00, 93.67, 82.14, 80.91, 66.37, 65.53, 59.18, 50.87, 46.59, 30.56; HRMS (ESI): m/z calcd for C₂₂H₂₀O₃Cl₂ ([M + Na]⁺): 425.0682; found: 425.0654.

anti-1,7-Bis(4-fluorophenyl)-3-methylhepta-1,6-diyne-3,5-diol ( anti-4be ). White solid, yield 29%, m.p. 99.6–100.3 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.40 (q, J = 7.1 Hz, 4H), 6.98 (t, J = 8.1 Hz, 4H), 5.33 (d, J = 10.7 Hz, 1H), 4.44 (s, 1H), 3.66 (d, J = 3.2 Hz, 1H), 2.34–2.11 (m, 2H), 1.63 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.57 (d, J_C-F = 248.4 Hz), 162.50 (d, J_C-F = 248.3 Hz), 133.60 (d, J_C-F = 2.7 Hz), 133.53 (d, J_C-F = 2.7 Hz), 118.42 (d, J_C-F = 3.5 Hz), 118.32 (d, J_C-F = 3.5 Hz), 115.63 (d, J_C-F = 6.2 Hz), 115.46 (d, J_C-F = 6.1 Hz), 90.77, 88.76, 84.06, 83.53, 68.59, 61.80, 48.62, 30.76; HRMS (ESI): m/z calcd for C₂₀H₁₅O₂ ([M − H]⁻): 325.1046; found: 325.1050.

syn-1,7-Bis(4-fluorophenyl)-3-methylhepta-1,6-diyne-3,5-diol ( syn-4be ). White solid, yield 20%, m.p. 104.4–104.7 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.37 (t, J = 7.7 Hz, 4H), 6.95 (t, J = 8.4 Hz, 4H), 5.08 (t, J = 4.0 Hz, 1H), 3.41 (d, J = 42.4 Hz, 2H), 2.47–2.43 (m, 1H), 2.27 (dd, J = 14.4, 4.3 Hz, 1H), 1.68 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.57 (d, J_C-F = 248.6 Hz), 162.54 (d, J_C-F = 248.3 Hz), 133.59 (d, J_C-F = 2.7 Hz), 133.52 (d, J_C-F = 2.8 Hz), 118.31 (d, J_C-F = 1.6 Hz), 118.29 (d, J_C-F = 1.4 Hz), 115.60 (d, J_C-F = 2.2 Hz), 115.43 (d, J_C-F = 1.8 Hz), 91.72, 89.03, 84.62, 83.15, 67.30, 60.23, 49.08, 29.83; HRMS (ESI): m/z calcd for C₂₀H₁₆O₂F₂ ([M + Na]⁺): 349.1011; found: 349.1016.

(anti,anti)-1,9-Bis(4-fluorophenyl)-3-methylnona-1,8-diyne-3,5,7-triol ( anti,anti-5be ). White solid, yield 5%, m.p. 114.6–115.1 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.31 (m, 4H), 6.87 (t, J = 8.6 Hz, 4H), 5.00 (t, J = 9.5 Hz, 1H), 4.92 (d, J = 4.0 Hz, 1H), 4.46 (s, 1H), 4.23 (s, 1H), 3.83 (d, J = 5.3 Hz, 1H), 2.09–2.03 (m, 1H), 1.98–1.94 (m, 2H), 1.87 (dd, J = 14.1Hz, 3.4 Hz, 1H), 1.60 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.46 (d, J_C-F = 248.4 Hz), 162.42 (d, J_C-F = 248.2 Hz), 133.54 (d, J_C-F = 8.3 Hz), 118.54 (d, J_C-F = 3.5 Hz), 118.42 (d, J_C-F = 3.5 Hz), 115.55 (d, J_C-F = 6.7 Hz), 115.37 (d, J_C-F = 7.0 Hz), 91.52, 88.89, 84.43, 69.25, 68.99, 61.48, 47.92, 42.70, 31.26; HRMS (ESI): m/z calcd for C₂₂H₂₀O₃F₂ ([M − H]⁻): 369.1308; found: 393.11306.

anti-1,3,7-Triphenylhepta-1,6-diyne-3,5-diol ( anti-4ca ). White solid, yield 21%, m.p. 82.1–87.9 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.66 (d, J = 7.3 Hz, 2H), 7.44–7.43 (m, 2H), 7.33–7.16 (m, 11H), 5.43 (d, J = 10.8 Hz, 1H), 4.33 (s, 1H), 3.27 (d, J = 3.3 Hz, 1H), 2.46–2.41 (m, 1H), 2.23 (dd, J = 14.5, 1.9 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 144.29, 131.80, 131.64, 128.69, 128.50, 128.36, 128.32, 128.24, 127.92, 125.24, 122.21, 122.18, 89.79, 88.82, 87.24, 85.24, 73.73, 62.09, 51.28; HRMS (ESI): m/z calcd for C₂₅H₂₀O₂ ([M + Na]⁺): 375.1356; found: 375.1355.

syn-1,3,7-Triphenylhepta-1,6-diyne-3,5-diol ( syn-4ca ). White solid, yield 15%, m.p. 89.3–91.4 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.56 (d, J = 7.6 Hz, 2H), 7.32–7.11 (m, 13H), 4.62–4.58 (m, 1H), 3.81 (s, 1H), 3.03 (s, 1H), 2.66–2.61 (m, 1H), 2.40 (dd, J = 14.6, 3.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.34, 131.73, 131.65, 128.62, 128.45, 128.43, 128.23, 128.18, 127.85, 125.33, 122.20, 122.10, 91.29, 88.92, 85.82, 85.38, 72.42, 60.30, 50.97; HRMS (ESI): m/z calcd for C₂₀H₁₅O₂ ([M + Na]⁺): 375.1356; found: 375.1357.

(syn,syn)-1,3,9-Triphenylnona-1,8-diyne-3,5,7-triol ( syn,syn-5ca ). White solid, yield 4%, m.p. 134.4–135.6 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.63 (d, J = 7.6 Hz, 2H), 7.43–7.19 (m, 13H), 4.75–4.72 (m, 1H), 4.05–4.01 (m, 2H), 3.76 (s, 1H), 3.24 (d, J = 3.2 Hz, 1H), 2.45–2.41 (m, 1H), 2.18–2.03 (m, 2H), 1.82 (d, J = 14.3 Hz, 1H), 1.65 (s, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 144.00, 131.72, 131.67, 128.67, 128.41, 128.31, 128.21, 127.74, 125.32, 122.40, 122.15, 91.96, 89.23, 85.61, 84.97, 72.87, 68.98, 62.57, 50.83, 44.13; HRMS (ESI): m/z calcd for C₂₇H₂₄O₃ ([M + Na]⁺): 419.1618; found: 419.1617.

anti-3-Phenyl-1,7-di-p-tolylhepta-1,6-diyne-3,5-diol ( anti-4cb ). White solid, yield 11%, m.p. 84.0–87.0 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.74 (d, J = 7.4 Hz, 2H), 7.43–7.28 (m, 7H), 7.15 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 5.51 (dt, J = 10.9, 2.6 Hz, 1H), 4.38–4.35 (m, 1H), 3.26 (s, 1H), 2.51 (dd, J = 14.7, 10.7 Hz, 1H), 2.35 (d, J = 18.5 Hz, 6H), 2.33–2.28 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 144.49, 138.85, 138.64, 131.71, 131.56, 129.08, 129.01, 128.33, 127.87, 125.28, 119.15, 89.18, 88.22, 87.42, 85.40, 73.75, 62.18, 51.45, 21.43; HRMS (ESI): m/z calcd for C₂₇H₂₄O₂ ([M + Na]⁺): 403.1669; found: 403.1672.

syn-3-Phenyl-1,7-di-p-tolylhepta-1,6-diyne-3,5-diol ( syn-4cb ). White solid, yield 8%, m.p. 127.1–128.4 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.63 (d, J = 8.1 Hz, 2H), 7.36–7.19 (m, 7H), 7.02 (dd, J = 15.2, 7.9 Hz, 4H), 4.68 (dt, J = 8.8, 3.4 Hz, 1H), 3.77 (s, 1H), 2.98 (s, 1H), 2.68 (dd, J = 14.6, 9.2 Hz, 1H), 2.46 (dd, J = 14.6, 3.3 Hz, 1H), 2.27 (d, J = 9.0 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.56, 138.79, 138.58, 131.65, 131.58, 129.00, 128.95, 128.40, 127.80, 125.36, 119.17, 119.09, 90.67, 88.33, 86.06, 85.56, 72.43, 60.39, 51.25, 21.45; HRMS (ESI): m/z calcd for C₂₇H₂₄O₂ ([M + Na]⁺): 403.1669; found: 403.1669.

(syn,syn)-3-Phenyl-1,9-di-p-tolylnona-1,8-diyne-3,5,7-triol ( syn,syn-5cb ). White solid, yield 9%, m.p. 116.0–121.1 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.69 (d, J = 7.8 Hz, 2H), 7.36 (dt, J = 29.8, 7.4 Hz, 5H), 7.19–7.07 (m, 6H), 4.84 (s, 1H), 4.42 (t, J = 12.2 Hz, 1H), 3.66 (d, J = 11.4 Hz, 2H), 3.44 (d, J = 6.3 Hz, 1H), 2.48 (dd, J = 14.4, 9.6 Hz, 1H), 2.35 (s, 6H), 2.17 (d, J = 14.1 Hz, 1H), 2.05 (td, J = 13.8, 3.4 Hz, 1H), 1.81 (dd, J = 14.3, 4.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 144.08, 138.91, 138.46, 131.66, 131.62, 129.08, 128.90, 128.43, 127.73, 125.34, 118.95, 91.15, 88.50, 85.95, 85.37, 72.94, 67.21, 61.52, 50.75, 42.71, 21.48; HRMS (ESI): m/z calcd for C₂₉H₂₈O₃ ([M + Na]⁺): 447.1931; found: 447.1928.

(syn,anti)-3-Phenyl-1,9-di-p-tolylnona-1,8-diyne-3,5,7-triol ( syn,anti-5cb ). White solid, yield 9%, m.p. 121.9–122.7 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.63 (d, J = 7.5 Hz, 2H), 7.37–7.31 (m, 5H), 7.21 (d, J = 7.8 Hz, 2H), 7.05 (t, J = 10.3Hz, 4H), 4.73 (t, J = 4.0 Hz, 1H), 4.15 (s, 1H), 4.02 (t, J = 8.9 Hz, 1H), 3.84 (s, 1H), 3.38 (s, 1H), 2.42 (dd, J = 14.3, 9.5 Hz, 1H), 2.30 (s, 6H), 2.14 (d, J = 14.4 Hz, 1H), 2.09–2.02 (m, 1H), 1.82 (s, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 144.09, 138.76, 138.44, 131.59, 131.54, 129.02, 128.92, 128.33, 127.61, 125.32, 119.30, 119.04, 91.30, 88.55, 85.65, 85.02, 72.79, 68.94, 62.48, 50.77, 44.08, 21.41; HRMS (ESI): m/z calcd for C₂₉H₂₈O₃ ([M + Na]⁺): 447.1931; found: 447.1932.

(anti,anti)-3-Phenyl-1,9-di-p-tolylnona-1,8-diyne-3,5,7-triol ( anti,anti-5cb ). White solid, yield 9%, m.p. 121.7–122.7 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.73 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.33–7.30 (m, 3H), 7.26 (d, J = 8.0 Hz, 2H), 7.00 (t, J = 7.3 Hz, 4H), 5.20 (t, J = 9.7 Hz, 1H), 4.92 (q, J = 5.1 Hz, 1H), 4.25–4.11 (m. 2H), 3.51–3.43 (m, 1H), 2.34 (s, 6H), 2.20 (dd, J = 14.3, 10.5 Hz, 1H), 2.07 (dt, J = 14.2, 3.5 Hz, 1H), 1.95–1.86 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ = 145.09, 138.55, 138.33, 131.71, 131.64, 128.99, 128.94, 128.32, 127.80, 125.20, 119.39, 119.21, 89.72, 88.51, 87.19, 85.64, 74.45, 69.16, 61.80, 50.90, 42.56, 21.45, 21.43; HRMS (ESI): m/z calcd for C₂₉H₂₈O₃ ([M + Na]⁺): 447.1931; found: 447.1922.

anti-1,7-Bis(4-methoxyphenyl)-3-phenylhepta-1,6-diyne-3,5-diol ( anti-4cc ). White solid, yield 13%, m.p. 150.7–151.2 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.70 (d, J = 7.8 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.30–7.22 (m, 3H), 6.82 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 5.45 (d, J = 10.6 Hz, 1H), 4.35 (s, 1H), 3.76 (d, J = 15.1 Hz, 6H), 3.30 (d, J = 3.4 Hz, 1H), 2.46 (dd, J = 14.7, 10.6 Hz, 1H), 2.26 (dd, J = 14.7, 2.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.85, 159.71, 144.60, 133.28, 133.14, 128.31, 127.83, 125.29, 114.37, 114.34, 113.95, 113.88, 88.55, 87.62, 87.19, 85.18, 73.76, 62.18, 55.22, 51.52; HRMS (ESI): m/z calcd for C₂₇H₂₄O₄ ([M + Na]⁺): 435.1567; found: 435.1567.

syn-1,7-Bis(4-methoxyphenyl)-3-phenylhepta-1,6-diyne-3,5-diol ( syn-4cc ). White solid, yield 8%, m.p. 100.8–102.7 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.70 (d, J = 7.7 Hz, 2H), 7.44–7.36 (m, 4H), 7.32 (t, J = 7.3 Hz, 3H), 6.81 (dd, J = 13.5, 8.6 Hz, 4H), 4.74 (dt, J = 9.1, 3.5 Hz, 1H), 3.92–3.87 (m, 1H), 3.79 (d, J = 7.2 Hz, 6H), 3.11 (s, 1H), 2.74 (dd, J = 14.6, 9.2 Hz, 1H), 2.52 (dd, J = 14.6, 3.5 Hz, 1H);¹³C NMR (125 MHz, CDCl₃): δ = 159.81, 159.67, 143.67, 133.23, 133.16, 128.38, 127.76, 125.37, 114.35, 114.23, 113.88, 113.83, 90.06, 87.71, 85.84, 85.35, 72.42, 60.40, 55.25, 55.21, 51.30; HRMS (ESI): m/z calcd for C₂₇H₂₄O₄ ([M + Na]⁺): 435.1567; found: 435.1569.

(syn,syn)-1,9-Bis(4-methoxyphenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( syn,syn-5cc ). White solid, yield 24%, m.p. 103.1–105.3 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.66 (d, J = 7.3 Hz, 2H), 7.39 (t, J = 7.3 Hz, 4H), 7.35–7.26 (m, 3H), 6.80 (t, J = 9.2 Hz, 4H), 4.76 (dt, J = 8.8, 3.7 Hz, 1H), 4.13–4.03 (m, 2H), 3.85 (d, J = 1.6 Hz, 1H), 3.79 (d, J = 1.9 Hz, 6H), 3.29 (d, J = 3.4 Hz, 1H), 2.45 (dd, J = 14.5, 9.5 Hz, 1H), 2.19–2.07 (m, 2H), 1.85 (dt, J = 14.3, 3.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.74, 159.54, 144.14, 133.16, 133.09, 128.32, 127.59, 125.31, 114.43, 114.15, 113.86, 113.77, 90.62, 87.86, 85.42, 84.78, 72.79, 68.99, 62.53, 55.20, 50.74, 44.05; HRMS (ESI): m/z calcd for C₂₉H₂₈O₅ ([M + Na]⁺): 479.1829; found: 479.1823.

(syn,anti)-1,9-Bis(4-methoxyphenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( syn,anti-5cc ). White solid, yield 11%, m.p. 143.6–144.0 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.72 (d, J = 7.2 Hz, 2H), 7.41–7.37 (m, 4H), 7.32 (t, J = 8.6 Hz, 3H), 6.79 (dd, J = 8.8, 3.0 Hz, 4H), 4.95–4.92 (m, 1H), 4.86 (t, J = 10.9 Hz, 1H), 4.42 (s, 1H), 4.12 (s, 1H), 3.80 (d, J = 3.7 Hz, 6H), 3.05 (d, J = 3.6 Hz, 1H), 2.17 (dd, J = 14.4, 10.3 Hz, 1H), 2.11–2.04 (m, 1H), 1.98–1.87 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.68, 159.60, 145.10, 133.23, 133.16, 128.29, 127.73, 125.20, 114.37, 113.87, 113.82, 89.12, 87.87, 86.76, 85.11, 74.27, 70.48, 62.39, 55.23, 55.20, 51.09, 44.21; HRMS (ESI): m/z calcd for C₂₉H₂₈O₅ ([M + Na]⁺): 479.1829; found: 479.1826.

(anti,anti)-1,9-Bis(4-methoxyphenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( anti,anti-5cc ). White solid, yield 7%, m.p. 106.5–107.4 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.72 (d, J = 7.4 Hz, 2H), 7.41–7.25 (m, 7H), 6.71 (dd, J = 11.0, 8.5 Hz, 4H), 5.22 (t, J = 9.4 Hz, 1H), 4.91 (q, J = 5.0 Hz, 1H), 4.36 (s, 1H), 4.24 (s, 1H), 3.78 (d, J = 4.9 Hz, 6H), 3.67 (d, J = 6.0 Hz, 1H), 2.18 (dd, J = 14.4, 10.4 Hz, 1H), 2.09–2.04 (m, 1H), 1.93–1.81 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.64, 159.51, 145.12, 133.26, 133.18, 128.30, 127.76, 125.19, 114.54, 114.34, 113.82, 113.78, 89.04, 87.82, 86.94, 85.39, 74.46, 69.23, 61.88, 55.17, 50.86, 42.43; HRMS (ESI): m/z calcd for C₂₉H₂₈O₅ ([M + Na]⁺): 479.1829; found: 479.1800.

anti-1,7-Bis(4-chlorophenyl)-3-phenylhepta-1,6-diyne-3,5-diol ( anti-4cd ). White solid, yield 21%, m.p. 146.1–147.0 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.71 (d, J = 7.4 Hz, 2H), 7.46–7.22 (m, 11H), 5.46 (dt, J = 10.9, 2.4 Hz, 1H), 4.44 (s, 1H), 3.49 (d, J = 3.1 Hz, 1H), 2.53–2.48 (m, 1H), 2.30 (dd, J = 14.7, 1.9 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 144.02, 134.82, 134.63, 133.02, 132.86, 128.70, 128.63, 128.43, 128.07, 125.15, 120.63, 120.57, 90.69, 89.64, 86.16, 84.22, 73.72, 62.01, 51.08; HRMS (ESI): m/z calcd for C₂₅H₁₈O₂Cl₂ ([M − H]⁻): 419.0611; found: 419.0614.

syn-1,7-Bis(4-chlorophenyl)-3-phenylhepta-1,6-diyne-3,5-diol ( syn-4cd ). White solid, yield 15%, m.p. 130.5–131.9 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.67 (d, J = 7.5 Hz, 2H), 7.42 (t J = 7.5 Hz, 2H), 7.37–7.33 (m, 3H), 7.29–7.23 (m, 6H), 4.69 (d, J = 9.2 Hz, 1H), 3.96 (s, 1H), 3.18 (d, J = 3.6 Hz, 1H), 2.78–2.73 (m, 1H), 2.52 (dd, J = 14.6, 3.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.06, 134.75, 134.57, 132.94, 132.85, 128.61, 128.56, 128.51, 127.99, 125.25, 120.66, 120.55, 92.22, 89.79, 84.71, 84.32, 72.45, 60.24, 50.67; HRMS (ESI): m/z calcd for C₂₅H₁₈O₂Cl₂ ([M − H]⁻): 419.0611; found: 419.0611.

(syn,syn)-1,9-Bis(4-chlorophenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( syn,syn-5cd ). White solid, yield 3%, m.p. 153.1–154.0 °C; ¹H NMR (500 MHz, CDCl₃): 7.67 (d, J = 7.4 Hz, 2H), 7.44–7.26 (m, 11H), 4.81–4.78 (m, 1H), 4.16–4.05 (m, 2H), 3.76 (s, 1H), 3.22 (d, J = 3.4 Hz, 1H), 2.50 (dd, J = 14.5, 9.5 Hz, 1H), 2.21 (dd, J = 14.4, 1.9 Hz, 1H), 2.14–2.09 (m, 1H), 1.87 (dt, J = 14.2, 3.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.68, 134.78, 134.52, 132.93, 132.86, 128.67, 128.58, 128.47, 127.83, 125.25, 120.81, 120.60, 92.90, 90.09, 84.33, 83.88, 72.89, 68.94, 62.50, 50.56, 43.93; HRMS (ESI): m/z calcd for C₂₇H₂₂O₃Cl₂ ([M + Na]⁺): 487.0838; found: 487.0840.

(syn,anti)-1,9-Bis(4-chlorophenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( syn,anti-5cd ). White solid, yield 5%, m.p. 155.5–156.9 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.67 (d, J = 7.2 Hz, 2H), 7.41–7.17 (m, 11H), 4.82 (td, J = 6.1, 3.6 Hz, 1H), 4.38 (dt, J = 9.6, 2.1 Hz, 1H), 3.76 (s, 1H), 3.60 (d, J = 1.7 Hz, 1H), 3.43 (d, J = 6.4 Hz, 1H), 2.49 (dd, J = 14.5, 9.6 Hz, 1H), 2.17 (dd, J = 14.5, 2.1 Hz, 1H), 2.08–2.02 (m, 1H), 1.79 (ddd, J = 14.4, 6.0, 2.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.67, 134.83, 134.46, 132.94, 128.69, 128.51, 127.84, 125.28, 120.87, 120.53, 92.78, 90.09, 84.49, 84.18, 72.97, 67.16, 61.43, 50.41, 42.51; HRMS (ESI): m/z calcd for C₂₇H₂₂O₃Cl₂ ([M + Na]⁺): 487.0838; found: 487.0842.

(anti,anti)-1,9-Bis(4-chlorophenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( anti,anti-5cd ). White solid, yield 3%, m.p. 125.5–126.2 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.67 (d, J = 7.2 Hz, 2H), 5.16 (t, J = 7.5 Hz, 2H), 7.34–7.31 (m, 3H), 7.25 (d, J = 8.2 Hz, 2H), 7.18 (t, J = 7.9 Hz, 4H), 5.16 (t, J = 10.0 Hz, 1H), 4.91 (q, J = 5.0 Hz, 1H), 4.33 (s, 1H), 4.15 (s, 1H), 3.59 (s, 1H), 2.20 (dd, J = 14.4, 10.4 Hz, 1H), 2.10–2.04 (m, 1H), 1.92 (d, J = 14.4 Hz, 1H), 1.86 (ddd, J = 14.4, 5.4, 2.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 144.65, 134.74, 134.55, 132.92, 132.84, 128.62, 128.59, 128.43, 127.99, 125.09, 120.84, 120.66, 91.42, 90.15, 85.90, 84.42, 74.49, 69.16, 61.76, 50.75, 42.35, 26.89; HRMS (ESI): m/z calcd for C₂₇H₂₂O₃Cl₂ ([M + Na]⁺): 487.0838; found: 487.0807.

anti-1,7-Bis(4-fluorophenyl)-3-phenylhepta-1,6-diyne-3,5-diol ( anti-4ce ). White solid, yield 17%, m.p. 108.9–109.3 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.62 (d, J = 7.6 Hz, 2H), 7.42–7.14 (m, 7H), 6.90 (dt, J = 27.9, 8.3 Hz, 4H), 5.37 (d, J = 10.7 Hz, 1H), 4.39 (s, 1H), 3.47 (s, 1H), 2.41 (dd, J = 14.7, 10.7 Hz, 1H), 2.19 (d, J = 14.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.69 (d, J_C-F = 249.1 Hz), 162.56 (d, J_C-F = 248.3 Hz), 144.16, 133.73 (d, J_C-F = 8.2 Hz), 133.56 (d, J_C-F = 8.8 Hz), 128.40, 128.00, 125.17, 118.25 (d, J_C-F = 3.5 Hz), 118.21 (d, J_C-F = 3.6 Hz), 115.73 (d, J_C-F = 10.0 Hz), 115.51 (d, J_C-F = 10.6 Hz), 89.47, 88.48, 86.20, 84.24,73.70, 61.99, 51.18; HRMS (ESI): m/z calcd for C₂₅H₁₈O₂F₂ ([M − H]⁻): 387.1202; found: 387.1203.

syn-1,7-Bis(4-fluorophenyl)-3-phenylhepta-1,6-diyne-3,5-diol ( syn-4ce ). White solid, yield 12%, m.p. 101.7–102.6 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.68 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 8.0 Hz, 4H), 7.38–7.31 (m, 3H), 6.98 (dt, J = 13.9, 8.6 Hz, 4H), 4.70 (dt, J = 9.2, 3.4 Hz, 1H), 3.97–3.93 (m, 1H), 3.18–3.14 (m, 1H), 2.76 (dd, J = 14.6, 9.2 Hz, 1H), 2.52 (dd, J = 14.6, 3.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.66 (d, J_C-F = 248.4 Hz), 162.55 (d, J_C-F = 248.3 Hz), 143.21, 133.67 (d, J_C-F = 8.2 Hz), 133.57 (d, J_C-F = 8.4 Hz), 127.94, 125.28, 118.26 (d, J_C-F = 3.6 Hz), 118.16 (d, J_C-F = 3.6 Hz), 115.62 (d, J_C-F = 7.2 Hz), 115.45 (d, J_C-F = 6.9 Hz), 91.01, 88.57, 84.77, 84.36, 72.43, 60.25, 50.82; HRMS (ESI): m/z calcd for C₂₅H₁₈O₂F₂ ([M − H]⁻): 387.1202; found: 387.1203.

(syn,syn)-1,9-Bis(4-fluorophenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( syn,syn-5ce ). White solid, yield 22%, m.p. 147.3–147.9 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.66 (d, J = 7.7 Hz, 2H), 7.45–7.37 (m, 4H), 7.32 (t, J = 7.1 Hz, 3H), 6.98 (dt, J = 11.4, 8.5 Hz, 4H), 4.77 (m, 1H), 4.05 (t, J = 5.4 Hz, 2H), 3.80 (s, 1H), 3.24 (d, J = 3.3 Hz, 1H), 2.47 (dd, J = 14.5, 9.5 Hz, 1H), 2.18 (d, J = 14.4 Hz, 1H), 2.13–2.04 (m, 1H), 1.84 (d, J = 14.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.70 (d, J_C-F = 248.3 Hz), 162.55 (d, J_C-F = 248.3 Hz), 143.81, 133.66 (d, J_C-F = 8.2 Hz), 133.58 (d, J_C-F = 8.2 Hz), 128.45, 127.80, 125.27, 118.39 (d, J_C-F = 3.6 Hz), 118.18 (d, J_C-F = 3.6 Hz), 115.67 (d, J_C-F= 13.4 Hz), 115.49 (d, J_C-F= 13.5 Hz), 91.65, 88.82, 84.42, 83.92, 72.89, 69.01, 62.59, 50.63, 43.97; HRMS (ESI): m/z calcd for C₂₇H₂₂O₃F₂ ([M − H]⁻): 431.1464; found: 431.1466.

(syn,anti)-1,9-Bis(4-fluorophenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( syn,anti-5ce ). White solid, yield 9%, m.p. 114.2–16.8 °C;¹H NMR (500 MHz, CDCl₃): δ = 7.67 (d, J = 7.7 Hz, 2H), 7.44–7.38 (m, 4H), 7.33 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.4, 5.6 Hz, 2H), 6.99–6.94 (m, 4H), 4.82 (d, J = 3.9 Hz, 1H), 4.37 (t, J = 9.4 Hz, 1H), 3.92 (s, 1H), 3.73 (s, 1H), 3.56 (d, J = 6.2 Hz, 1H), 2.51–2.45 (m, 1H), 2.16 (d, J = 14.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.66 (d, J_C-F = 248.7 Hz), 162.49 (d, J_C-F = 248.2 Hz), 143.76, 133.66 (d, J_C-F = 2.5 Hz), 133.59 (d, J_C-F = 2.2 Hz), 128.42, 127.72, 125.27, 118.42 (d, J_C-F = 3.5 Hz), 118.12 (d, J_C-F = 3.6 Hz), 115.61 (d, J_C-F = 21.7 Hz), 115.41 (d, J_C-F = 21.8 Hz), 91.58, 88.78, 84.45, 84.19, 72.88, 67.13, 61.31, 50.32, 42.50; HRMS (ESI): m/z calcd for C₂₇H₂₂O₃F₂ ([M − H]⁻): 431.1464; found: 431.1466.

(anti,anti)-1,9-Bis(4-fluorophenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( anti,anti-5ce ). White solid, yield 3%, m.p. 120.1–120.6 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.70 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.0 Hz, 4H), 7.32 (dd, J = 8.3, 5.7 Hz, 3H), 6.90 (q, J = 6.7 Hz, 4H), 5.17 (t, J = 9.6 Hz, 1H), 4.91 (q, J = 5.6 Hz, 1H), 4.41 (s, 1H), 4.23 (s, 1H), 3.68 (d, J = 5.9 Hz, 1H), 2.19 (dd, J = 14.4, 10.4 Hz, 1H), 2.09–2.04 (m, 1H), 1.92 (d, J = 14.4 Hz, 1H), 1.86 (ddd, J = 14.4, 5.5, 2.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.58 (d, J_C-F = 248.5 Hz), 162.53 (d, J_C-F = 248.3 Hz), 144.75, 133.65 (d, J_C-F = 8.4 Hz), 133.54 (d, J_C-F = 8.2 Hz), 128.39, 127.93, 125.09, 118.45 (d, J_C-F = 3.5 Hz), 118.28 (d, J_C-F = 3.5 Hz), 115.60 (d, J_C-F = 5.4 Hz), 115.42 (d, J_C-F = 5.4 Hz), 90.13, 88.88, 85.90, 84.40, 74.42, 69.14, 61.67, 50.71, 42.33; HRMS (ESI): m/z calcd for C₂₇H₂₂O₃F₂ ([M + Na]⁺): 455.1429; found: 455.1432.

anti-1,7-Bis(3-fluorophenyl)-3-phenylhepta-1,6-diyne-3,5-diol ( anti-4cf ). White solid, yield 19%, m.p. 87.7–89.6 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.68 (d, J = 1.9 Hz, 2H), 7.36 (t, J = 1.9 Hz, 2H), 7.30–7.12 (m, 6H), 7.05–6.95 (m, 3H), 5.43 (dt, J = 10.5, 2.5 Hz, 1H), 4.38 (s, 1H), 3.35 (s, 1H), 2.48 (dd, J = 14.7, 10.6 Hz, 1H), 2.27 (dd, J = 14.7, 1.9 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.29 (d, J_C-F = 245.4 Hz), 162.22 (d, J_C-F = 245.2 Hz), 143.97, 129.97 (d, J_C-F = 8.6 Hz), 129.86 (d, J_C-F = 8.6 Hz), 128.45, 128.08, 127.70 (d, J_C-F = 2.5 Hz), 127.54 (d, J_C-F = 2.5 Hz), 125.16, 124.00 (t, J_C-F = 9.4 Hz), 118.63 (d, J_C-F = 20.1 Hz), 118.46 (d, J_C-F = 20.2 Hz), 116.12 (d, J_C-F = 21.4 Hz), 115.93 (d, J_C-F = 21.6 Hz), 90.72, 89.66, 86.00, 83.99, 73.66, 61.93, 51.07; HRMS (ESI): m/z calcd for C₂₅H₁₈O₂F₂ ([M − H]⁻): 387.1202; found: 387.1208.

syn-1,7-Bis(3-fluorophenyl)-3-phenylhepta-1,6-diyne-3,5-diol ( syn-4cf ). White solid, yield 16%, m.p. 141.7–142.0 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.71 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H), 7.31–7.22 (m, 3H), 7.20–7.13 (m, 2H), 7.11–6.98 (m, 3H), 4.73 (dt, J = 9.0, 3.5 Hz, 1H), 3.92 (s, 1H), 3.14 (d, J = 3.7 Hz, 1H), 2.78 (dd, J = 14.6, 9.1 Hz, 1H), 2.56 (dd, J = 14.6, 3.4 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.22 (d, J_C-F = 245.1 Hz), 162.19 (d, J_C-F = 245.1 Hz), 143.03, 129.84 (t, J_C-F = 8.5 Hz), 128.54, 128.04, 127.62 (d, J_C-F = 2.4 Hz), 127.53 (d, J_C-F = 2.0 Hz), 125.27, 124.04 (d, J_C-F = 9.3 Hz), 123.92 (d, J_C-F = 9.2 Hz), 118.59 (d, J_C-F = 11.3 Hz), 118.41 (d, J_C-F = 11.3 Hz), 115.96 (t, J_C-F = 21.2 Hz), 92.15, 89.76, 84.64, 84.21, 72.43, 60.22, 50.64; HRMS (ESI): m/z calcd for C₂₅H₁₈O₂F₂ ([M − H]⁻): 387.1202; found: 387.1201.

(syn,syn)-1,9-Bis(3-fluorophenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( syn,syn-5cf ). White solid, yield 5%, m.p. 125.5–126.7 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.69 (d, J = 7.7 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H), 7.33–7.24 (m, 3H), 7.17 (t, J = 7.7 Hz, 2H), 7.11–7.01 (m, 3H), 4.82–4.79 (m, 1H), 4.17 (s, 1H), 4.07 (t, J = 9.0 Hz, 1H), 3.82 (s, 1H), 3.30 (d, J = 3.4 Hz, 1H), 2.52 (dd, J = 14.5, 9.5 Hz, 1H), 2.25–2.11 (m, 2H), 1.88 (dt, J = 14.3, 3.4 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.31 (d, J_C-F = 245.4 Hz), 162.27 (d, J_C-F = 245.0 Hz), 143.64, 129.95 (d, J_C-F = 8.6 Hz), 129.85 (d, J_C-F = 8.6 Hz), 128.52, 127.91, 127.64 (d, J_C-F = 2.6 Hz), 127.55 (d, J_C-F = 2.6 Hz), 125.29, 124.21 (d, J_C-F = 9.4 Hz), 124.02 (d, J_C-F = 9.4 Hz), 118.61 (d, J_C-F = 8.0 Hz), 118.43 (d, J_C-F = 8.0 Hz), 116.09 (d, J_C-F = 21.0 Hz), 115.85 (d, J_C-F = 21.0 Hz), 92.90, 90.09, 84.22, 83.79, 72.91, 68.92, 62.45, 50.57, 43.96; HRMS (ESI): m/z calcd for C₂₇H₂₂O₃F₂ ([M − H]⁻): 431.1464; found: 431.1460.

(anti,anti)-1,9-Bis(3-fluorophenyl)-3-phenylnona-1,8-diyne-3,5,7-triol ( anti,anti-5cf ). White solid, yield 3%, m.p. 87.3–89.5 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.77 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.28–7.16 (m, 5H), 7.15–7.04 (m, 3H), 5.22 (t, J = 9.6 Hz, 1H), 4.99 (q, J = 5.3 Hz, 1H), 4.42 (d, J = 4.0 Hz, 1H), 4.24 (s, 1H), 3.69 (d, J = 3.6 Hz, 1H), 2.27 (dd, J = 14.5, 10.4 Hz, 1H), 2.17–2.11 (m, 1H), 2.00 (d, J = 14.4 Hz, 1H), 1.94 (ddd, J = 14.5, 5.6, 2.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ = 162.20 (d, J_C-F = 245.2 Hz), 144.59, 129.85 (t, J_C-F = 7.9 Hz), 128.43, 127.99, 127.64 (d, J_C-F = 1.9 Hz), 127.54 (d, J_C-F = 1.9 Hz), 125.06, 124.15 (d, J_C-F = 9.2 Hz), 123.96 (d, J_C-F = 9.2 Hz), 118.48 (d, J_C-F = 10.9 Hz), 118.30 (d, J_C-F = 10.92 Hz), 115.99 (d, J_C-F = 21.3 Hz), 115.79 (d, J_C-F = 21.3 Hz), 91.27, 90.01, 85.70, 84.25, 74.38, 69.12, 61.63, 50.67, 42.24; HRMS (ESI): m/z calcd for C₂₇H₂₂O₃F₂ ([M + Na]⁺): 455.1429; found: 455.1431.

Supplemental Material

2-SI_1 – Supplemental material for A one-pot diastereoselective synthesis of 1,3-diols and 1,3,5-triols via cascade reactions of arylalkynyl Grignard reagents with enol esters

Supplemental material, 2-SI_1 for A one-pot diastereoselective synthesis of 1,3-diols and 1,3,5-triols via cascade reactions of arylalkynyl Grignard reagents with enol esters by Yinchun Jiao, Wenjing Zhao, Shuang Deng, Zilong Tang, Wanqiang Liu, Yichao Wan and Fuqi Zhong in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (nos 21402048, 2147204, 21877034) and the Natural Science Foundation of Hunan Province (2019JJ50161).

ORCID iD

Wanqiang Liu

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