Solvent free L-proline-catalysed domino Knoevenagel/6π-electrocyclization for the synthesis of highly functionalised 2H-pyrans

Abstract

An environmentally benign synthesis of 2H-pyrans has been achieved in high yield using β-oxosulfones and 3,3-dialkylsubstituted α,β-unsaturated aldehydes. The key reaction is a solvent free L-proline catalysed domino Knoevenagel/6π-electrocyclization. As 3,3-dialkylsubstituted α,β-unsaturated aldehydes are a very common feature in many natural products, the transformation into highly functionalised 2H-pyrans makes this procedure a green and excellent method for a diversity oriented synthesis of biologically active compounds.

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Introduction

Molecules with a pyran heterocycle in their structure are very interesting due to their biological activities and applications in medicine.¹ Benzopyrans, such as daurichromenic acid, an anti-HIV agent,² seselin, an antinociceptive along with other activities,³ or privileged structures, such as 2-pyrones, an essential pharmacophore in many naturally occurring and biologically active compounds,⁴ led our attention to the 2H-pyran ring. Although these compounds are very interesting, there is not a great variety of starting materials to synthesise them, being usually made by iminium activation of a carbonyl group and a 1,3-dicarbonyl compound.⁵ As an example, Profs. Chang and Marsella et al. described the reaction of the E/Z mixture of citral with 1,3-cyclohexanodione to yield perhydro-CBC (cannabichromene), which was later transformed into a Δ¹-tetrahydrocannabinol analogue⁶ (Fig. 1). Prof. Jørgensen et al. have reported other very interesting uses of β-ketoesters in organocatalytic conditions.^6b,c

Fig. 1 Synthesis of perhydro-CBC by Profs. Chang and Marsella.

In our group we have been interested in the reactivity of β-oxosulfones, which are known substrates in organocatalysis,⁷ for the synthesis of 2-alkylidene cyclohexenones by a Michael addition⁸ using organocatalyst 5 followed by a Morita–Baylis–Hillman reaction after addition of L-proline (Scheme 1). The use of β-oxosulfones over 1,3-dicarbonyl compounds will add the extra versatility of the sulfone moiety, mainly due to easy elimination and reactivity.

Scheme 1 Synthesis of 2-alkylidene cyclohexenones.

Prof. Inokuchi et al. established that 2-alkylsubstituted enals favour the formation of (E)-Knoevenagel adducts for the ensuing electrocyclization.⁴ We became interested in carrying out the reaction with our β-oxosulfones and 3,3-dialkylsubstituted enals, because of its profusion in nature,⁹ as in the case of Chang and Marsella,⁶ using organocatalysts in order to develop environmentally benign processes for the synthesis of 2H-pyrans. We were also wondering if it would be possible to obtain the corresponding pyrans by changing the mechanism of the reaction between Nazarov reagents such as 1a and 3,3-dialkylsubstituted α,β-unsaturated aldehydes.

L-Proline has been, since the leading paper of List, Lerner and Barbas,¹⁰ one of the most widely employed organocatalysts, not only for simple reactions such as the aldol,¹¹ Mannich,¹² Michael,¹³ Biginelli,¹⁴ Diels–Alder/Knoevenagel,¹⁵ Baylis–Hillman,¹⁶ aza-Morita–Baylis–Hillman,¹⁷ α-selenylation,¹⁸ α-halogenation¹⁹ and oxidation²⁰ reactions, among others, but also in tandem or multicomponent reactions.²¹ Proline is a very cheap, nontoxic amino acid available in both enantiomeric forms, from which many derivatives have been developed for its use in organocatalysis,²² and ideal for green chemistry.^21a,b This is an area of growing interest in recent years, as better procedures with less toxic solvents and no hazardous chemicals should be the aim of any chemist.²³

Herein we report, to the best of our knowledge, the first synthesis of highly substituted 2H-pyrans using an efficient, practical and environmentally friendly methodology under solvent-free conditions, using L-proline as a catalyst.

Results and discussions

The key strategy is the reaction of a β-oxosulfone with 3,3-disubstituted enals.²⁴ First of all we decided to screen different catalysts and additives (Table 1 and Fig. 2) in the reaction between β-oxosulfone 1a and the E/Z mixture of citral in isopropyl alcohol, as it was the best solvent used in our previous studies for the synthesis of 2-alkylidene cyclohexenones.⁸

Fig. 2 Catalysts and additives for use in the synthesis of 2H-pyrans.

Table 1 Screening of catalysts and additives for the reaction between β-oxosulfone 1a and E/Z-citral in isopropyl alcohol^ab

Entry	Catalyst	Additive	Time^c	Yield^d (%)
				2	3a
a All the reactions were carried out at r.t., in iPrOH at 0.18 M, with a 2 : 1 ratio of sulfone to E/Z-citral, 20 mol% catalyst and 20 mol% additive. b S.M. = starting materials; B.A. = benzoic acid; 12 = BinapPOH = (S)-(+)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate; 13 = CF3-BinapPOH = (R)-3,3′-bis[3,5-bis(trifluoromethyl)phenyl]-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate. c Time in which highest yield was observed with no decomposition (the consumption of starting materials was monitored by TLC). d Isolated yield after chromatography on silica gel. e Benzoic acid was added 6 days after catalyst 4. f Benzoic acid was added 6 days after catalyst 5. g Catalyst 5 was added 10 h after BinapPOH. h L-Proline was added 26 h after catalyst 5. i Benzoic acid was added 6 days after catalyst 10.
1	DABCO	—	21 h	S.M.
2	DBU	—	3 d	S.M.
3	Et3N	—	3 d	S.M.
4	Piperidine	—	3 d	Decomposition
5	Pyrrolidine	—	2 h	Decomposition
6	Pyridine	—	3 d	—	16
7	—	B.A.	45 d	<5	—
8	—	12	10 h	S.M.
9	—	13	12 h	S.M.
10	11	B.A.	8 d	S.M.
11	L-Proline	—	6 h	11	63
12	L-Proline	LiOAc	13 h	29	44
13	L-Proline	B.A.	17 h	9	62
14	L-Proline	12	24 h	4	96
15	L-Proline	13	17 h	1	99
16^e	4	B.A.	8 d	S.M.
17^f	5	B.A.	8 d	S.M.
18^g	5	12	60 d	—	15
19^f^h	5 + L-Proline	LiOAc	39 h	10	—
20^f^h	5 + L-Proline	B.A.	39 h	7	33
21	6	—	6 d	—	60
22	7	—	13 h	—	33
23	8	—	25 d	S.M.
24	9	—	10 d	—	11
25^i	10	B.A.	8 d	S.M.

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We first used the usual bases to see if the Knoevenagel reaction proceeded as the first step, but these led to low yields, decomposition or simply no reaction after several days (Table 1, entries 1–6). Benzoic acid or even chiral acids, i.e.12 and 13,²⁵ were tested, as they can be used as additives, and thioureas, i.e.11, were also tested, but the reaction either did not proceed at all or did not proceed in a reasonable time (entries 7–10). Only the citral dimer 2 was formed in very low yield after 45 days with benzoic acid, previously obtained by Watanabe et al. in the reaction of citral with proline²⁶ (entry 7). Then several organocatalysts (Fig. 2) were tested, with and without additives. When L-proline was used, the yield of 2H-pyran 3a increased dramatically, especially when acid 13 was used as an additive (entries 11–15). Other organocatalysts did not give any good results with or without additives (entries 16–25).

As L-proline was found to be the best organocatalyst, we then screened different solvents (Table 2). From this study, solvent free conditions with no additive turned out to be the best conditions (entry 10). Surprisingly, using additive 13 did not lead to any increase in the yield, but suppressed the production of the citral dimer in no solvent conditions (Table 2, entries 11 and 12). In all cases racemic mixtures were obtained, ascertained by HPLC and optical rotatory power, even when additives 12 or 13 were used in order to induce chirality. Although the yield was excellent when isopropyl alcohol and additive 13 were used (Table 1, entry 15) the use of no solvent and no expensive additives makes this procedure to obtain 2H-pyrans easier and more environmentally efficient than the previous ones. In the case of reagent solubility problems, the use of isopropyl alcohol is a green alternative too. These conditions are not exclusive to β-oxosulfones and can be applied to 1,3-diketones, β-ketoesters or β-ketoamides.

Table 2 Screening of solvents for the synthesis of 2H-pyrans with L-proline and additives^a

Entry	Solvent	Time^b (h)	Yield^c (%)
			2	3a
a All the reactions were carried out at r.t., at 0.18 M, with a 2 : 1 ratio of sulfone to E/Z-citral, 20 mol% L-proline and 20 mol% 12. b Time in which the highest yield was observed with no decomposition (the consumption of starting materials was monitored by TLC). c Isolated yield after chromatography on silica gel. d S.M. = starting materials. e No additives used. f 20 mol % 13 added to the reaction as additive instead of 12.
1	Hexane	54	12	72
2	Toluene	29	—	32
3	CHCl2	29	13	34
4	CHCl3	29	—	42
5	Diethyl ether	29	—	37
6	THF	29	—	20
7	MeOH	8	—	28
8	EtOH	8	—	39
9	H2O	56	S.M.^d
10 ^e	NO SOLVENT	22	13	87
11	NO SOLVENT	24	—	58
12^f	NO SOLVENT	21	—	49

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Having established the best conditions, we decided to evaluate our method with different aldehydes, using firstly the same starting material, the β-oxosulfone 1a, as shown in Table 3. In all cases where the unsaturated aldehyde was 3,3-dialkylsubstituted, the 2H-pyran was obtained in a very good yield but as a racemic mixture, ascertained by HPLC and optical rotatory power, entries 1–6, or even in the case of entry 7. In the case of compounds 18 and 20, entries 5 and 6, the corresponding diastereoisomeric mixtures were obtained due to the presence of epimers at the tetrasubstituted carbon of the pyran ring. These results can be explained by the proposed mechanism (Fig. 3): initial Knoevenagel condensation leads to intermediate A, which after 6π-electrocyclization produces the corresponding 2H-pyran.²⁷ Other aldehydes, with a different substitution pattern, only gave the corresponding Knoevenagel products (entries 8–10), whose stereochemistry was established by bidimensional NMR and NOE experiments. A similar result was obtained by Profs. Mischne and Riveira in polycyclization reactions of 1,3-dicarbonyl compounds and α,β,γ,δ-unsaturated aldehydes, where the unsubstituted one gives only condensation and no cyclization.²⁸ Of special interest are the compounds obtained in entries 5 and 6, analogues of marine natural products, such as the pyranocoumarin ferprenin.²⁹ As there are many natural products with a 3,3-dialkylsubstituted α,β-unsaturated aldehyde functionality,⁹ this procedure opens up an environmentally acceptable method for the synthesis of 2H-pyrans for diversity oriented synthesis.³⁰

Fig. 3 Proposed mechanism for the formation of 2H-pyrans.

Table 3 Screening of α,β-unsaturated aldehydes^a

Entry	α,β-Unsaturated aldehyde	Time^b	Product	Yield^c (%)
a All the reactions were carried out at r.t., in iPrOH at 0.18 M, with a 2 : 1 ratio of sulfone 1a to aldehyde and 20 mol% L-proline or under solvent free conditions. In all cases the yields were similar. b Time in which highest yield was observed with no decomposition (the consumption of starting materials was monitored by TLC). c Isolated yield after chromatography on silica gel. d 20 mol% of BinapPOH, 12, added to the reaction.
1		4.5 h		82
2		6 h		63
3		15 h		58
4^d		15 h		58
5		7 h		38
6		3 d		63
7		5 d		43
8		21 h		87
9		1 d		99
10		15 h		56

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Once the procedure for the synthesis of 2H-pyrans had been carried out consistently with different aldehydes, it was subjected to a study with other β-oxosulfones in order to define the scope and consistency of the reaction (Table 4).

Table 4 2H-pyrans using different β-oxosulfones and E/Z-citral^a

Entry	β-oxosulfone	Product	Time^b (h)	Yield^c (%)
				2	3(b,c)
a All the reactions were carried out at r.t., in iPrOH at 0.18 M, or under free solvent conditions with a 2 : 1 ratio of sulfone to E/Z-citral, and 20 mol% L-proline. In all cases the yield was similar, except for compound 1c which, being a solid, was reacted in iPrOH only. b Time in which the highest yield was observed with no decomposition (the consumption of starting materials was monitored by TLC). c Isolated yield after chromatography on silica gel.
1			7	3	97
2			5	12	88
3			15	36	64

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The synthesis of these β-oxosulfones is shown in Scheme 2. After monoprotection under standard conditions of the commercially available E-1,4-butenediol with 3,4-dihydro-2H-pyran (DHP) gave 26,³¹ which was oxidised with pyridinium dichromate (PDC) and condensed with the lithium derivative of methylphenylsulfone, leading to the corresponding alcohol 28, whose oxidation gave the corresponding mixture of β-oxosulfones 1b and 1c in a 99 : 1 ratio. Use of other oxidising conditions, including the use of catalytic tetrapropylammonium perruthenate (TPAP), led to a decrease in the yield of the oxidation steps. These sulfones were separated by flash chromatography on silica gel and deprotection of the major compound gave the β-oxosulfone 1d. As shown in Table 4, the three sulfones 1b, 1c, and 1d behave exactly as before, yielding the corresponding 2H-pyrans when reacted with E/Z-citral, making this procedure ideal for the synthesis of highly functionalised 2H-pyrans in environmentally safe conditions. The presence of the sulfone group in these compounds adds an extra functionality and so more versatility for further research.

Scheme 2 Reagents and conditions for the synthesis of β-oxosulfones 1b, 1c and 1d: (a) DHP, pTsOH (1%), DCM, r.t., 96%; (b) PDC (2 equiv.), molecular sieves, DCM, r.t., 91%; (c) methylphenylsulfone (0.9 equiv.), n-BuLi (0.9 equiv.), THF, −78 °C, 61%; (d) PDC (2 equiv.), molecular sieves, r.t., 58%, (ratio 1b : 1c = 99 : 1); and (e) pTsOH (10%), THF–H₂O (1 : 1), r.t., 88%.

Conclusions

We have established a new and simple procedure for the synthesis of 2H-pyrans. This method shows once again the versatility of L-proline as a catalyst, since it is the only one that gives the reaction. The reaction proceeds under solvent free conditions, becoming a green way to obtain compounds of high impact for the synthesis of natural compound analogues with biological activity in diversity oriented synthesis.

Experimental section

Unless otherwise stated, all chemicals were purchased as the highest purity commercially available and were used without further purification, except for 1a,⁸ 10-hydroxycitral 15,³² farnesal,³³18^9c and 20,^9d,f which were synthesised according to the literature procedures. For more details see the ESI.†

1. Synthesis of the Nazarov reagents (1b–1d)

1.1 Monoprotection of (E)-1,4-butanediol with DHP: (E)-4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-en-1-ol (26). (E)-1,4-Butanediol (4 ml, 48.66 mmol) was dissolved in 194 ml DCM under Ar at r.t. 3,4-Dihydro-2H-pyran (97%, 4.22 g, 48.66 mmol) and p-toluenesulfonic acid monohydrate (93 mg, 0.486 mmol) were added and left to stir for 3 h. The reaction was quenched with a NaHCO₃ saturated solution, and extracted with DCM. The combined organics were washed with H₂O and brine, dried (Na₂SO₄), filtered and concentrated in vacuo to afford 26 (8.01 g, 96%). υ_max (liquid film) 3417, 2943, 2870, 1454, 1352, 1261, 1134; δ_H (200 MHz; CDCl₃) 5.88–5.33 (2H, m, H2 and H3), 4.67–4.60 (1H, m, H6), 4.32–3.99 (4H, m, H1 and H4), 3.92–3.71 (1H, m, H8_a), 3.57–3.40 (1H, m, H8_b), 1.91–1.36 (6H, m, H9, H10, and H11); δ_C (50 MHz; CDCl₃) 132.6, 127.3, 97.6, 62.6, 62.0, 57.9, 30.5, 25.4, 19.3; EIHRMS: Calcd for C₉H₁₆O₃ (M + Na): 195.0592; found: 195.0991 (M + Na).

1.2 Oxidation of 26 with PDC: (E)-4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-enal (27). A mixture of monoprotected diol 26 (8.01 g, 46.5 mmol) and molecular sieves was dissolved in 232 ml DCM under Ar and stirred at room temperature for 5 min. PDC (34.9 g, 93.02 mmol) was added and left to stir for 5 h. The mixture was filtered through a pad of Celite®/Silica/Celite®, and then extracted with EtOAc to afford 27 (7.19 g, 91%). υ_max (liquid film) 2945, 2870, 2853, 2727, 1693, 1454, 1352, 1261, 1201, 1120; δ_H (200 MHz; CDCl₃) 9.54 (1H, d, J = 8.0 Hz, CHO), 6.85 (1H, dt, J = 15.7, 4.0 Hz, H3), 6.34 (1H, ddt, J = 15.7, 8.0, 2.0, Hz, H2), 4.68–4.61 (1H, m, H6), 4.49 (1H, ddd, J = 17.3, 4.0, 2.0 Hz, H4_a), 4.21 (1H, ddd, J = 17.3, 4.0, 2.0 Hz, H4_b), 3.86–3.72 (1H, m, H8_a), 3.56–3.42 (1H, m, H8_b), 1.86–1.43 (6H, m, H9, H10, and H11); δ_C (50 MHz; CDCl₃) 193.5, 153.7, 131.5, 98.4, 65.6, 62.2, 30.4, 25.4, 19.2; EIHRMS: Calcd for C₉H₁₄O₃ (M + Na): 193.0835; found: 193.0835 (M + Na).

1.3 Addition of methylphenylsulfone to 27: (E)-1-(phenylsulfonyl)-5-((tetrahydro2H-pyran-2-yl)oxy)pent-3-em-2-ol (28). Methylphenylsulfone (3.64 g, 23.29 mmol) was dissolved in 100 ml THF under Ar at −78 °C. n-BuLi (1.6 M in hexanes, 14.9 ml, 23.29 mmol) was added and the mixture was stirred for 15 min. Separately, 27 (4.40 g, 25.88 mmol) was dissolved in 30 ml THF under Ar at r.t. This solution was added via cannula to the former, and the mixture was stirred at −78 °C under Ar for 2 h. Then the reaction was quenched with a NH₄Cl saturated solution and left to warm at room temperature. Then it was extracted with EtOAc and the combined organics were washed with H₂O and brine, dried (Na₂SO₄), filtered and concentrated in vacuo to leave a crude yellow oil. Flash chromatography (hexane–EtOAc, 6 : 4) afforded 28 (4.63 g, 61%). υ_max (liquid film) 3444, 2953, 2872, 2250, 1732, 1446, 1288, 1138 δ_H (200 MHz; CDCl₃) 7.97–7.83 (2H, m, ArH_ortho), 7.71–7.46 (3H, m, ArH_meta, ArH_para), 5.83 (1H, dt, J = 15.5, 5.2 Hz, H4), 5.62 (1H, dd, J = 15.5, 5.2 Hz, H3), 4.76–4.59 (1H, m, H7), 4.59–4.49 (1H, m, H2), 4.15 (1H, dd, J = 13.3, 4.6 Hz, H5_a), 3.95–3.69 (2H, m, H1_a and H5_a), 3.55–3.41 (2H, m, H9), 3.30–3.19 (2H, m, H1_b and 5_b), 1.84–1.37 (6H, m, H10, H11, and H12); δ_C (50 MHz; CDCl₃) 139.7, 134.1, 131.4, 129.5 (2C), 128.8, 128.1 (2C), 98.1, 66.6, 66.5, 62.2, 62.1, 30.6, 25.5, 19.5; EIHRMS: Calcd for C₁₆H₂₂O₅S (M + Na): 349.1080; found: 349.1080 (M + Na).

1.4 Oxidation of 28 with PDC: (E)-1-(phenylsulfonyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-2-one(1b and 1c). A mixture of 28 (537 g, 1.65 mmol) and molecular sieves was dissolved in 8 ml DCM under Ar and stirred at r.t. for 5 min. PDC (1.24 g, 3.30 mmol) was added and left to stir for 4 h. The mixture was filtered through a pad of Celite®/Silica/Celite®, and then extracted with EtOAc to afford a crude brown oil. Flash chromatography (hexane–EtOAc, 6 : 4) afforded 1b (304 mg, 57%) and 1c (5 mg, 1%). 1b: υ_max (liquid film) 2943, 2870, 2852, 1693, 1666, 1633, 1446, 1384, 1325, 1153; δ_H (200 MHz; CDCl₃) 7.89 (2H, d, J = 7.0 Hz, ArH_ortho), 7.74–7.50 (3H, m, ArH_meta and ArH_para), 6.98 (1H, dt, J = 15.8, 3.9 Hz, H4), 6.54 (1H, dt, J = 15.8, 1.9 Hz, H3), 4.65 (1H, t, J = 3.1 Hz, H7), 4.46 (1H, ddd, J = 17.6, 3.9, 1.9 Hz, H5_a), 4.32 (2H, s, H1), 4.18 (1H, ddd, J = 17.6, 3.9, 2.0 Hz, H5_b), 3.89–3.74 (1H, m, H9_a), 3.59–3.42 (1H, m, H9_b), 1.90–1.40 (6H, m, H10, H11, and H12); δ_C (50 MHz; CDCl₃) 187.3, 147.7, 138.9, 134.4, 129.4 (2C), 128.6 (2C), 128.0, 98.4, 65.6, 65.3, 62.2, 30.5, 25.5, 19.3; EIHRMS: Calcd for C₁₆H₂₀O₅S (M + Na): 347.0924; found: 347.0924 (M + Na). 1c: υ_max (liquid film) 2943, 2872, 2852, 1693, 1666, 1614, 1448, 1377, 1323, 1155; δ_H (200 MHz; CDCl₃) 8.01–7.80 (2H, m, ArH_ortho), 7.79–7.50 (3H, m, ArH_meta and ArH_para), 6.65–6.37 (2H, m, H3 and H4), 4.75–4.39 (3H, m, H5 and H7), 4.21 (2H, s, H1), 3.92–3.71 (1H, m, H9_a), 3.58–3.38 (1H, m, H9_b), 1.95–1.36 (6H, m, H10, H11, and H12); δ_C (50 MHz; CDCl₃) 187.4, 152.4, 138.8, 134.5, 129.6 (2C), 128.5 (2C), 124.7, 99.2, 68.1, 67.2, 62.8, 30.8, 25.6, 19.8; EIHRMS: Calcd for C₁₆H₂₀O₅S (M + Na): 347.0924; found: 347.0924 (M + Na).

1.5 Deprotection of 1b with pTsOH: (E)-5-hydroxy-1-(phenylsulfonyl)pent-3-en-2-one (1d). 1b (203 mg, 0.62 mmol) and p-toluenesulfonic acid monohydrate (12 mg, 0.06 mmol) were dissolved in 6 ml of a 1 : 1 mixture of THF–H₂O, and the whole mixture was stirred for 5 days. The reaction was quenched with H₂O, extracted with EtOAc and the combined organics were washed with NaHCO₃ (5%), H₂O and brine, dried (Na₂SO₄), filtered and concentrated in vacuo to afford 1d (130.2 mg, 88%). υ_max (liquid film) 3504, 2931, 1691, 1664, 1627, 1448, 1309, 1151; δ_H (200 MHz; CDCl₃) 7.93–7.82 (2H, m, ArH_ortho), 7.72–7.50 (3H, m, ArH_meta and ArH_para), 7.04 (1H, dt, J = 15.8, 3.6 Hz, H4), 6.58 (1H, dt, J = 15.8, 2.0 Hz, H3), 4.38 (2H, m, H5), 4.33 (2H, s, H1); δ_C (50 MHz; CDCl₃) 187.2, 150.4, 138.8, 134.6, 129.6 (2C), 128.6 (2C), 127.1, 65.8, 62.0; EIHRMS: Calcd for C₁₁H₁₂O₄S (M + Na): 263.0349; found: 263.0349 (M + Na).

2. General procedure for the synthesis of 2H-pyrans (3a–3c)

β-Oxosulfone (1a–1d) (17.6 mmol) and E/Z-citral (8.7 mmol) were dissolved in 1 ml isopropyl alcohol. Next, L-proline (20 mol%), and an additive (20 mol%) if needed, were added and left stirring for the appropriate time. All products were purified by flash chromatography on silica gel using different mixtures of hexane–EtOAc.

2.1 (E)-6-(3-(Methoxymethoxy)prop-1-en-1-yl)-2-methyl-2-(4-methylpent-3-en-1-yl)-5-(phenylsulfonyl)-2H-pyran, 3a. υ _max (liquid film) 2926, 1674, 1539, 1446, 1377, 1321, 1151; δ_H (400 MHz; CDCl₃) 7.84 (2H, d, J = 8.3 Hz, ArH_ortho), 7.59–7.41 (3H, m, ArH_meta, ArH_para), 7.42 (1H, dt, J = 15.4, 1.8 Hz, H1′), 6.56 (1H, dt, J = 15.4, 5.2 Hz, H2′), 6.36 (1H, d, J = 10.0 Hz, H4), 5.34 (1H, d, J = 10.0 Hz, H3), 5.05–4.93 (1H, m, H3′′), 4.67 (2H, s, O–CH₂–O), 4.25 (2H, dd, J = 5.2, 1.8 Hz, H3′), 3.39 (3H, s, O–CH₃), 2.06–1.86 (2H, m, H2′′), 1.63 (6H, s, (CH₃)₂–C4′′), 1,40 (2H, m, H1′′), 1.27 (3H, s, CH₃–C2); δ_C (101 MHz; CDCl₃) 156.0, 143.0, 136.1, 132.6, 132.0, 129.0 (2C), 126.4 (2C), 124.2, 123.4, 121.5, 119.1, 114.3, 96.0, 80.6, 66.9, 55.4, 40.8, 25.7, 22.2, 17.7 (2C); EIHRMS: Calcd for C₂₃H₃₀O₅S (M + Na): 441.1712; found: 441.1706 (M + Na).

2.2 (E)-2-Methyl-2-(4-methylpent-3-en-1-yl)-5-(phenylsulfonyl)-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-en-1-yl)-2H-pyran (3b). υ _max (liquid film) 2926, 1647, 1537, 1446, 1377, 1321, 1153; δ_H (200 MHz; CDCl₃) 7.94–7.77 (2H, m, ArH_ortho), 7.60–7.45 (3H, m, ArH_meta, ArH_para), 7.45–7.32 (1H, m, H1′), 6.58 (1H, dt, J = 15.3, 5.0 Hz, H2′), 6.38 (1H, d, J = 10.0 Hz, H4), 5.33 (1H, d, J = 10.0 Hz, H3), 5.05–4.92 (1H, m, H3′′), 4.67 (1H, t, J = 3.2 Hz, O–CH–O), 4.50–4.33 (1H, m, H3′_a), 4.27–4.07 (1H, m, H3′_b), 3.94–3.76 (1H, m, H7′_a), 3.60–3.45 (1H, m, H7′_b), 2.06–1.86 (2H, m, H2′′), 1.64 (6H, s, (CH₃)₂–C4′′), 1.60–1.53 (4H, m, H10′ and H1′′), 1.53–1.44 (4H, m, H8′ and H9′), 1.27 (3H, s, CH₃–C2); δ_C (50 MHz; CDCl₃) 156.5, 143.4, 136.8, 132.8, 132.3, 129.2 (2C), 126.7 (2C), 124.3, 123.7, 121.3, 119.5, 114.3, 98.4, 80.8, 66.8, 62.3, 40.8, 30.7, 25.9, 25.8, 25.7, 22.5, 19.5, 17.8; EIHRMS: Calcd for C₂₆H₃₄O₅S (M + Na): 481.2025; found: 481.2019 (M + Na).

2.3 (E)-3-(2-Methyl-2-(4-methylpent-3-en-1-yl)-5-(phenylsulfonyl)-2H-pyran-6-yl)prop-2-en-1-ol (3c). υ _max(liquid film) 3493, 2968, 2916, 2850, 1645, 1621, 1537, 1446, 1317, 1155; δ_H (200 MHz; CDCl₃) 7.91–7.78 (2H, m, ArH_ortho), 7.60–7.47 (3H, m, ArH_meta, ArH_para), 7.41 (1H, dt, J = 15.3, 1.8 Hz, H1′), 6.64 (1H, dt, J = 15.3, 4.9 Hz, H2′), 6.36 (1H, d, J = 10.0 Hz, H4), 5.34 (1H, d, J = 10.0 Hz, H3), 5.07–4.94 (1H, m, H3′′), 4.43–4.30 (2H, m, H3′), 2.02–1.88 (2H, m, H2′′), 1.76–1.51 (8H, m, H1′′ and (CH₃)₂–C4′′), 1.27 (3H, s, CH₃–C2); δ_C (50 MHz; CDCl₃) 156.3, 143.2, 139.2, 132.9, 132.3, 129.3 (2C), 126.7 (2C), 124.4, 123.6, 120.6, 119.4, 114.5, 80.9, 63.2, 40.8, 25.9, 25.8, 22.5, 17.8; EIHRMS: Calcd for C₂₁H₂₆O₄S (M + Na): 397.1444; found: 397.1444 (M + Na).

3. General procedure for the synthesis of 2H-pyrans and Knoevenagel adducts

β-Oxosulfone 1a (50 mg, 17.6 mmol) and the corresponding aldehyde (8.7 mmol) were dissolved in 1 ml isopropyl alcohol. Next, L-proline (20 mol%), and an additive (20 mol%) if needed were added and left stirring for the appropriate time. All products were purified by flash chromatography on silica gel using different mixtures of hexane–EtOAc.

3.1 (E)-6-(3-(Methoxymethoxy)prop-1-en-1-yl)-2,2-dimethyl-5-(phenylsulfonyl)-2H-pyran (14). υ _max (liquid film) 2935, 1647, 1537, 1446, 1379, 1319, 1153; δ_H (200 MHz; CDCl₃) 7.85 (2H, dd, J = 7.9, 1.7 Hz, ArH_ortho), 7.59–7.41 (3H, m, ArH_meta, ArH_para), 7.39 (1H, dt, J = 15.4, 1.7 Hz, H1′), 6.57 (1H, dt, J = 15.4, 5.2 Hz, H2′), 6.33 (1H, d, J = 9.9 Hz, H4), 5.38 (1H, d, J = 9.9 Hz, H3), 4.68 (2H, s, O–CH₂–O), 4.25 (2H, dd, J = 5.2, 1.7 Hz, H3′), 3.39 (3H, s, O–CH₃), 1.31 (6H, s, (CH₃)₂–C2); δ_C (50 MHz; CDCl₃) 156.2, 143.3, 137.1, 132.9, 129.3 (2C), 126.7 (2C), 125.5, 121.9, 119.1, 114.9, 96.3, 78.3, 67.2, 55.6, 27.4 (2C); EIHRMS: Calcd for C₁₈H₂₂O₅S (M + Na): 373.1086; found: 373.1080 (M + Na).

3.2 (E)-5-(6-((E)-3-(Methoxymethoxy)prop-1-en-1-yl)-2-methyl-5-(phenylsulfonyl)-2H-pyran-2-yl)-2-methylpent-2-en-1-ol (16). υ _max (liquid film) 3469, 2934, 2889, 1649, 1537, 1446, 1307, 1213, 1151; δ_H (200 MHz; CDCl₃) 7.84 (2H, d, J = 7.9 Hz, ArH_ortho), 7.62–7.35 (4H, m, ArH_meta, ArH_para and H1′), 6.56 (1H, dt, J = 15.3, 5.4 Hz, H2′), 6.37 (1H, d, J = 10.1 Hz, H4), 5.39–5.22 (2H, m, H3 and H3′′), 4.67 (2H, s, O–CH₂–O), 4.25 (2H, d, J = 4.7 Hz, H3′), 3.94 (2H, s, CH₂–OH), 3.39 (3H, s, O–CH₃), 2.12–1.95 (2H, m, H2′′), 1.80–1.58 (2H, m, H1′′), 1.55 (3H, s, CH₃–C4′′), 1.25 (3H, s, CH₃C2); δ_C (50 MHz; CDCl₃) 156.2, 143.2, 136.4, 135.5, 132.9, 129.3 (2C), 126.7 (2C), 125.0, 124.3, 121.8, 119.6, 114.5, 96.3, 80.9, 68.8, 67.2, 55.6, 40.5, 26.1, 22.2, 13.8; EIHRMS: Calcd for C₂₃H₃₀O₆S (M + Na): 457.1655; found: 457.1655 (M + Na).

3.3 2-((E)-4,8-Dimethylnona-3,7-dien-1-yl)-6-((E)-3-(methoxymethoxy)prop-1-en-1-yl)-2-methyl-5-(phenylsulfonyl)-2H-pyran (17). υ _max (liquid film) 2926, 1649, 1539, 1446, 1379, 1321, 1151; δ_H (200 MHz; CDCl₃) 7.85 (2H, dd, J = 7.9, 1.7 Hz, ArH_ortho), 7.59–7.44 (3H, m, ArH_meta, ArH_para), 7.40 (1H, dt, J = 15.3, 1.7 Hz, H1′), 6.57 (1H, dt, J = 15.3, 5.2 Hz, H2′), 6.36 (1H, d, J = 10.0 Hz, H4), 5.35 (1H, d, J = 10.0 Hz, H3), 5.13–4.91 (2H, m, H3′′ and H7′′), 4.68 (2H, s, O–CH₂–O), 4.25 (2H, dd, J = 5.2, 1.7 Hz, H3′), 3.40 (3H, s, O–CH₃), 2.11–1.85 (8H, m, H1′′, H2′′, H5′′ and H6′′), 1.67 (3H, s, CH₃–C4′′), 1.59 (3H, s, CH_3a–C8′′), 1.50 (3H, s, CH_3b–C8′′), 1.28 (3H, s, CH₃–C2); δ_C (50 MHz; CDCl₃) 156.3, 143.3, 136.4, 136.0, 132.8, 131.6, 129.5 (2C), 126.7 (2C), 124.5, 124.4, 123.5, 121.9, 119.4, 114.6, 96.3, 80.9, 67.2, 55.6, 40.8, 39.8,26.8, 26.0 (2C), 22.4, 17.9, 16.1; EIHRMS: Calcd for C₂₈H₃₈O₅S (M + Na): 509.2338; found: 509.2332 (M + Na).

3.4 (1S,5S,6R,8aS)-Methyl 5-(3-(6-((E)-3-(methoxymethoxy)prop-1-en-1-yl)-2-methyl-5-phenylsulfonyl)-2H-pyran-2-yl)propyl)-1,5,6-trimethyl-1,2,3,5,6,7,8,8a-octahydronaphthalene-1-carboxylate (19). Caution: the name does not correspond to the numeration used.

[α]^D = +35.4 (c 1.07, CHCl₃); υ_max (liquid film) 2932, 2874, 1726, 1539, 1446, 1321, 1157; δ_H (400 MHz; CDCl₃) 7.86 (2H, d, J = 7.3 Hz, ArH_ortho), 7.59–7.41 (3H, m, ArH_meta, ArH_para), 7.41 (1H, m, H1′), 6.59 (1H, m, H2′), 6.37 (1H, dd, J = 9.8, 3.0 Hz, H4), 5.33 (1H, d, J = 9.8 Hz, H3), 5.29–5.17 (1H, m, H9′′), 4.68 (2H, s, O–CH₂–O), 4.26 (2H, d, J = 5.2, Hz, H3′), 3.61 (3H, s, COO–CH₃), 3.40 (3H, s, O–CH₃), 2.65–2.50 (1H, m, H5′′), 1.97–0.65 (25H, m, H1′′, H2′′, H6′′, H7′′, H8′′, H10′′, H11′′, H13′′, H14′′, H16′′, H1′′′); δ_C (101 MHz; CDCl₃) 178.3, 156.3, 143.1, 141.1, 135.9, 132.5, 129.0 (2C), 126.4 (2C), 124.8, 121.5, 119.8, 119.1, 114.3, 96.0, 80.9, 67.1, 55.3, 51.6, 44.8, 42.7, 38.3(2C), 34.6, 31.4, 30.6, 28.6, 26.2, 22.9, 22.8, 22.3, 19.9, 15.4; EIHRMS: Calcd for C₃₄H₄₆O₇S (M + Na): 621.2856; found: 621.2856 (M + Na).

3.5 6-((E)-3-(Methoxymethoxy)prop-1-en-1-yl)-2-methyl-5-(phenylsulfonyl)-2-(2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl)-2H-pyran (21). Caution: the name does not correspond to the numeration used.

[α]^D = +4.58 (c 0.3, CHCl₃); υ_max (liquid film) 2918, 2848, 1539, 1446, 1321, 1153; δ_H (200 MHz; CDCl₃) 7.85 (2H, dd, J = 7.6, 1.6 Hz, ArH_ortho), 7.60–7.47 (3H, m, ArH_meta, ArH_para), 7.40 (1H, m, H1′), 6.56 (1H, dt, J = 10.1, 5.4 Hz, H2′), 6.36 (1H, dd, J = 10.1, 1.3 Hz, H4), 5.34 (1H, d, J = 10.1, H3), 4.74 (1H, s, H29′′_a), 4.68 (2H, s, O–CH₂–O), 4.38 (1H, s, H29′′_b), 4.25 (2H, d, J = 5.4, Hz, H3′), 3.40 (3H, s, O–CH₃), 2.44–0.87 (28H, m, H1′′, H2′′, H3′′, H5′′, H6′′, H7′′, H9′′, H10′′, H11′′, H13′′, H15′′, H16′′, H1′′′); δ_C (50 MHz; CDCl₃) 156.3, 148.5, 143.4, 136.4, 132.8, 129.3 (2C), 126.7 (2C), 124.6, 121.8, 119.5, 114.5, 106.6, 96.2, 81.3, 67.2, 57.3, 55.7, 55.6, 42.4, 40.1, 40.0, 39.1, 38.5, 33.8, 33.5, 26.2, 24.6, 21.9, 19.6, 19.2, 14.6; EIHRMS: Calcd for C₃₃H₄₆O₅S (M + Na): 577.2958; found: 577.2958 (M + Na).

3.6 (E)-2-(3-(Methoxymethoxy)prop-1-en-1-yl)-3-(phenylsulfonyl)-6,7,8,8a-tetrahydro-5H-chromene (22). υ _max (liquid film) 2933, 1722, 1446, 1321, 1151; δ_H (200 MHz; CDCl₃) 7.86 (2H, dd, J = 7.8, 1.7 Hz, ArH_ortho), 7.64–7.44 (3H, m, ArH_meta and ArH_para), 7.36 (1H, dd, J = 14.9, 1.7 Hz, H1′), 6.48 (1H, dt, J = 14.9, 5.4 Hz, H2′), 5.98 (1H, s, H4), 4.91–4.73 (1H, m, H2), 4.66 (2H, s, O–CH₂–O), 4.23 (2H, d, J = 5.4 Hz, H3′), 3.39 (3H, s, O–CH₃), 2.45–1.18 (8H, m, H7, H8, H9, and H10); δ_C (50 MHz; CDCl₃) 155.0, 145.3, 134.7, 133.5, 132.8, 129.3 (2C), 126.8 (2C), 121.5, 116.9, 112.2, 96.2, 77.4, 67.2, 55.6, 34.5, 32.5, 26.3, 24.1; EIHRMS: Calcd for C₂₀H₂₄O₅S (M + Na): 399.1237; found: 399.1237 (M + Na).

3.7 (1Z,4E)-1-(Furan-2-yl)-6-(methoxymethoxy)-2-(phenylsulfonyl)hexa-1,4-dien-3-one (23). υ _max (liquid film) 2947, 2889, 1659, 1622, 1446, 1319, 1197, 1149; δ_H (400 MHz; CDCl₃) 7.86 (2H, dd, J = 8.4, 1.3 Hz, ArH_ortho), 7.64–7.57 (2H, m, H1 and ArH_para), 7.57–7.49 (2H, m, ArH_meta), 7.49–7,43 (1H, m, H5′), 6.84 (1H, dt, J = 16.0, 4.1 Hz, H5), 6.78 (1H, d, J = 3.5 Hz, H3′), 6.54 (1H, dt, J = 16.0, 2.0 Hz, H4), 6.46 (1H, dd, J = 3.5, 1.8 Hz, H4′), 4.60 (2H, s, O–CH₂–O), 4.21 (2H, dd, J = 4.1, 2.0 Hz, H6), 3.33 (3H, s, O–CH₃); δ_C (101 MHz; CDCl₃) 190.1, 147.9, 147.5, 146.9, 139.8, 135.7, 133.6), 129.8, 129.1 (2C), 128.3 (2C), 126.9, 119.3, 112.8, 96.0, 65.7, 55.4; EIHRMS: Calcd for C₁₈H₁₈O₆S (M + Na): 385.0716; found: 385.0716 (M + Na).

3.8 (1Z,4E)-1-(Furan-3-yl)-6-(methoxymethoxy)-2-(phenylsulfonyl)hexa-1,4-dien-3-one (24). υ _max (liquid film) 2949, 2889, 1654, 1622, 1446, 1309, 1205, 1149; δ_H (400 MHz; CDCl₃) 7.85 (2H, dd, J = 8.5, 1.3 Hz, ArH_ortho), 7.74 (1H, dd, J = 1.1, 0.5 Hz, H1), 7.72–7.71 (1H, m, H2′), 7.63–7.58 (1H, m, ArH_para), 7.55–7.49 (2H, m, ArH_meta), 7.40–7.35 (1H, m, H5′), 6.92 (1H, dt, J = 15.9, 4.0 Hz, H5), 6.55 (1H, dt, J = 15.9, 2.1 Hz, H4), 6.29 (1H, dtd, J = 1.4, 0.9, 0.4 Hz, H4′), 4.60 (2H, s, O–CH₂–O), 4.22 (2H, dd, J = 4.0, 2.1 Hz, H6), 3.33 (3H, s, O–CH₃); δ_C (101 MHz; CDCl₃) 191.2, 149.5, 147.3, 144.7, 139.7, 138.1, 136.6, 131.6, 129.1 (2C), 129.0, 128.3 (2C), 119.0, 109.3, 96.0, 65.7, 55.4; EIHRMS: Calcd for C₁₈H₁₈O₆S (M + Na): 385.0716; found: 385.0716 (M + Na).

3.9 (2E,5Z,7E)-8-(Furan-2-yl)-1-(methoxymethoxy)-5-(phenylsulfonyl)octa-2,5,7-trien-4-one (25). υ _max (liquid film) 2933, 2889, 1647, 1616, 1583, 1463, 1446, 1307, 1147; δ_H (400 MHz; CDCl₃) 7.88 (2H, d, J = 7.9 Hz, ArH_ortho), 7.72–7.43 (5H, m, H6, ArH_meta, ArH_para and H5′), 7.00–6.80 (3H, m, H2, H7 and H8), 6.71 (1H, d, J = 15.7 Hz, H3), 6.60 (1H, m, H3′), 6.48 (1H, m, H4′), 4.65 (2H, s, O–CH₂–O), 4.33–4.22 (2H, m, H1), 3.37 (3H, s, O–CH₃); δ_C (101 MHz; CDCl₃) 188.5, 151.5, 148.0, 145.1, 143.5, 140.5, 138.6, 133.4, 132.2, 129.0 (3C), 128.1 (2C), 119.9, 114.9, 112.6, 96.1, 65.9, 55.4; EIHRMS: Calcd for C₂₀H₂₀O₆S (M + Na): 411.0873; found: 411.0873 (M + Na).

Acknowledgements

The authors gratefully acknowledge the help of A. Lithgow (NMR) and C. Raposo (MS) of Universidad de Salamanca and FSE, MICINN CTQ2009-11172BQU, Junta de Castilla and León for financial support. J.P. is grateful to the MICINN for its fellowship.

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Footnote

† Electronic Supplementary Information (ESI) available: General information, experimental details and copies of representative spectra. See DOI: 10.1039/c2ra21306k/

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